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Recent advances in Pd-catalyzed asymmetric

cyclization reactions
Cite this: Chem. Soc. Rev., 2024,
53, 883
Bing Xu,ab Quanpu Wang,a Chao Fang,a Zhan-Ming Zhang*ac and
Junliang Zhang *acd

Over the past few decades, there have been major developments in transition metal-catalyzed
asymmetric cyclization reactions, enabling the convenient access to a wide spectrum of structurally
diverse chiral carbo- and hetero-cycles, common skeletons found in fine chemicals, natural products,
pharmaceuticals, agrochemicals, and materials. In particular, a plethora of enantioselective cyclization
Received 29th July 2023 reactions have been promoted by chiral palladium catalysts owing to their outstanding features. This
DOI: 10.1039/d3cs00489a review aims to collect the latest advancements in enantioselective palladium-catalyzed cyclization
reactions over the past eleven years, and it is organized into thirteen sections depending on the different
rsc.li/chem-soc-rev types of transformations involved.

1. Introduction synthesizing structurally complex and diversely functionalized cyc-

lic skeletons, in which cyclization reactions occupy a preeminent
Chiral carbo- and hetero-cycles are ubiquitous structural cores position among a myriad of organic transformations.7–14 In this
in natural products, biologically relevant compounds and regard, despite the explosive growth of asymmetric organo-
pharmaceuticals, and they also serve as important building catalysis,13 asymmetric transition metal catalysis continues to be
blocks for the construction of value-added molecules in fine a major focus of research efforts and has emerged as one of the
chemicals.1–6 Over the past few decades, enormous endeavors most useful and powerful tools for performing reactions with
have been devoted to establishing substantial methods for excellent stereocontrol and catalytic efficiency. In particular,
palladium-catalyzed asymmetric cyclization reactions, character-
a
Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai, ized by their excellent functional group tolerance, mild conditions
200438, P. R. China. E-mail: [email protected], as well as high stereo- and regio-selectivity, have been among the
[email protected] most powerful and economically feasible tools for the preparation
b
Zhuhai Fudan Innovation Institute, Zhuhai 519000, China
c of enantioenriched cyclic compounds.
Fudan Zhangjiang Institute, Shanghai 201203, China
d
School of Chemisty and Chemical Engineering, Henan Normal University, Although several palladium-catalyzed reviews have been
Xinxiang, Henan, 453007, China dedicated to specific aspects, such as reagent types, processes

Bing Xu obtained her BS in Quanpu Wang obtained his BS in

chemistry in 2014 and PhD in chemistry in 2021 from the
2019 from East China Normal University of Shanghai for
University under the supervision of Science and Technology. He is
Professor Junliang Zhang. In 2019– now doing his PhD research at
2021, she worked as a postdoctoral Fudan University, under the
fellow at East China Normal Uni- guidance of Professor Junliang
versity. Currently, she is working as Zhang and Young Scholar Zhan-
a postdoctoral fellow at the Zhuhai Ming Zhang.
Fudan Innovation Institute. Her
research interests focus on the
design and synthesis of novel chiral
Bing Xu phosphine ligands, as well as their Quanpu Wang
applications in asymmetric transi-
tion metal catalysis.

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and catalyst, have been published, none of them is devoted to substitution, double allylic substitution, and other types of
Pd-catalyzed asymmetric cyclization reactions.15 Thus, the aim allylic substitution. Cyclization involving p-allyl palladium zwit-
of this review is to collect the advances in enantioselective terions discussed in Section 4 is subdivided into three parts,
palladium-catalyzed cyclization reactions from the beginning of dealing successively with p-allyl palladium zwitterions bearing
2012 to November of 2022, making a comprehensive summary a carbanion, p-allyl palladium zwitterions bearing a N-centered
of synthetically useful protocols, although selected more recent anion and p-allyl palladium zwitterions bearing a O-centered
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references have also been included. Noteworthily, cyclization anion, which are further subdivided according to different
reactions catalyzed by not only chiral palladium catalysts but classes of substrates in each part. Section 5 describes cycliza-
also dual catalysis involving palladium catalysts and organoca- tion based on the Heck reaction, following the classifications of
talysts are both considered in this review, whereas diastereose- cyclization via single Heck reactions, cyclization via double
lective reactions using chiral auxiliaries catalyzed by achiral Heck reactions, cyclization via Heck cascade reactions and
palladium catalysts are not included. cyclization via aza-Heck reactions. Sections 6–8 focus on cycli-
This review is categorized into thirteen sections according to zation initiated by heteropalladation of alkenes, alkynes and
the different types of transformations involved. Section 2 dis- allenes, respectively, while cyclization via allenylpalladium
cusses cyclization initiated by addition reactions, which is intermediates, subdivided into intermolecular Heck-type reac-
subdivided into two categories: 1,4-addition reactions and tion, [3+2] annulation and [4+2] annulation, is showed in
nucleophilic addition reactions. Section 3 dedicated to cycliza- Section 9. Section 10 devoted to cyclization initiated by hydro-
tion initiated by allylic substitution reaction is subdivided into palladation of unsaturated C–C bonds is subdivided into two
three categories, dealing successively with single allylic categories: via hydropalladation of alkynes and via hydropalla-
dation of allenes, considering the different types of unsaturated
C–C bonds. Cyclization based on C–H bond activation is
described in Section 11, which is roughly subdivided into
Chao Fang obtained his BS in C(sp2)–H and C(sp3)–H functionalization depending on the
chemistry in 2021 from Yunnan hybridization of the reacting carbon, further minutely subdi-
University. He is now doing his vided according to different catalytic cycles. Section 12 dedi-
PhD research at Fudan cated to cyclization via a-, b- or g-functionalization of carbonyl
University, under the guidance containing compounds is classified into five categories depend-
of Professor Junliang Zhang and ing on different classes of substrates. Section 13 focused on
Young Scholar Zhan-Ming Zhang. cyclization via catalytic asymmetric dearomatization is classi-
fied into two categories: dearomatization reaction of naphthol
or phenol derivatives and dearomatization reaction of indoles.
However, several cyclization reactions still cannot be categor-
ized in above sections and are better discussed as miscella-
neous cyclization reactions in Section 14.
Chao Fang

Zhan-Ming Zhang obtained his Prof. Junliang Zhang obtained his

PhD in 2016 from East China BS in chemistry in 1997 from
Normal University under the Tianjin University and PhD from
supervision of Professor Junliang the Shanghai Institute of Organic
Zhang. Then, he worked as a Chemistry, Chinese Academy of
postdoctoral fellow successively Sciences, in 2002 under the
at East China Normal University supervision of Prof. Shengming
and Fudan University. He is Ma. Then, he worked as a
currently a Young Scholar at postdoctoral fellow successively
Fudan University and cooperates at the University of Cologne
with Professor Junliang Zhang, (Humboldt Fellowship) and then
where his research focuses on the University of Chicago. In
Zhan-Ming Zhang the design and synthesis of novel Junliang Zhang 2006, he joined East China
chiral phosphine ligands, as well Normal University as a full
as their applications in professor. Then, he moved to Fudan University in 2017 as a
asymmetric transition metal professor of chemistry. His research interests include enyne
catalysis. chemistry, small ring chemistry, and developing novel chiral
sulfinamide-based phosphine (Sadphos) ligands and catalysts,
which are commercially available in many companies.

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2. Cyclization initiated by addition relatively higher temperature, finally yielding the cyclic
reactions phosphines.
In 2013, an enantioselective 1,4-addition/Nef-type cascade
2.1. 1,4-Addition reaction reaction to prepare biologically interesting quaternary amino
In 2012, the Leung research group reported the synthesis of succinimides 7 from N-benzoyl a-amino acids 5 and nitroole-
chiral tertiary bulky P-heterocycles 3 through a palladacycle- fins 6 was developed by Peters and co-workers (Scheme 1).17 To
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catalyzed double 1,4-addition reaction between bis(enones) 1 enhance catalytic activity, the planar–chiral ferrocene bisimi-
and PhPH2 2 (Scheme 1).16 Compared to C,N-palladacycles, C,P- dazoline bispalladacycle [FBIP-Cl]2 was subjected to a reaction
palladacycles were found to be efficient catalysts for catalyzing with AgOTf in acetonitrile to form the monomeric complexes in
cyclization reactions with high yields. It was found that the order to remove the otherwise inert chloro bridges. Regarding
electronic nature or steric hindrance of the substituents on the substrate scope of the reaction, electron-donating and
bis(enones) appeared to have significant effects on the results. -withdrawing substituents at meta or para positions on the
Bis(enones) with electron-withdrawing groups showed good aromatic residues in the nitroolefin component were well-
reactivity and excellent enantioselectivity, while those with tolerated, but ortho substituents impeded the product for-
electron-donating groups or more steric substituents showed mation. Aliphatic nitroolefins were also suitable substrates to
poor reactivity and failed to produce desired products. A obtain ideal products with high ee. A mechanism was sug-
mechanism was proposed for this asymmetric stepwise double gested by the authors. First, the N-coordination of the in situ-
1,4-addition reaction. Free PhPH2 and bis(enones) coordinated generated azlactone Int-I to a Pd center triggered the enoliza-
to palladium, resulting in the release of the relatively weakly tion, enabling conjugate addition to the nitroolefin 6, leading
coordinated MeCN of the palladacycle. The subsequent depro- to the formation of the 1,4-adduct Int-II. Then, O-acylation of
tonation of PhPH2 with the assistance of Et3N generated the 1,4-adduct Int-II produced the dipolar species Int-III, and
reactive phosphido species, which then underwent the first the subsequent 1,2-addition of acetate to the CQN bond led to
1,4-addition with the coordinated bis(enone) to form the sec- the generation of the nucleophilic nitrogen center Int-IV, which
ondary phosphine intermediate. Subsequent addition of was suitable for the following intramolecular azlactone ring-
another P–H bond was more challenging and needed a opening, resulting in the formation of ammonium oxide Int-V.
The subsequent elimination of acetic acid and the acyl transfer
process furnished the final product 7. Moreover, the authors
also demonstrated the synthetic value of the products by
describing a rapid method to access a suicide inhibitor
analogue.
In 2022, a Pd(II)/chiral N,N 0 -disulfonyl bisimidazoline (Bim)
ligand-catalyzed asymmetric reaction of yne-allenones 8 and
arylboronic acids 9 was developed by Jiang, Yu, Wang and co-
workers, in which a 6-6-4 skeleton with a ring-junction all-
carbon stereocenter was formed through a one-step process
(Scheme 2).18 This transformation began with an intra-
molecular [2+2] reaction of allenes with alkynes resulting in
the generation of cyclic enones Int-I in situ, followed by Pd-
catalyzed asymmetric 1,4-addition of arylboronic acids to cyclic
enones. The use of tert-butylyne-allenone resulted in severe
decomposition and the formation of trace products, demon-
strating the importance of the conjugated group in stabilizing

Scheme 2 Pd(II)/chiral N,N 0 -disulfonyl bisimidazoline ligand-catalyzed

Scheme 1 Cyclization initiated by 1,4-addition reactions. asymmetric reaction of yne-allenones and arylboronic acids.

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yne-allenones. The authors also performed density functional

theory (DFT) calculations to reveal the mechanisms underlying
the present reactions and explained why the reaction with aryl-
tethered yne-allenones was a one-step process while the reac-
tion with alkyl-tethered yne-allenones must be a two-step
process.
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Soon after, Reyes and Hornillos reported a palladium-

catalyzed asymmetric 1,4-addition/aldol cascade reaction invol-
ving aryl boronic acids and medium-sized cycloalkenones 11
for the direct synthesis of complex (hetero)aryl bicyclic struc-
tures containing three contiguous stereocenters (Scheme 3).19
It should be noted that substrates bearing fused aromatic
systems offered products with opposite configurations at the
bridgehead carbons. Then, the authors proposed a tentative
model to account for the stereochemical outcome of the reac-
tion. The transmetallation of (QuinoxP*)Pd(X)OH with aryl-
boronic acid resulted in the formation of (QuinoxP*)PdArX Scheme 4 Pd-Catalyzed asymmetric 1,4-addition/carbo-cyclization or
Int-I, which underwent enantioselectivity-determining syn allylic alkylation cascade reaction.
insertion of the enone, yielding the palladium enolate inter-
mediate Int-II. Thus, the isomerization of the Pd–enolate
intermediate via oxa-p-allylpalladium species Int-III could developed an asymmetric cascade 1,4-addition/carbocyclization
explain the formation of the two observed diastereomers. The transformation involving propargyl nucleophiles 15, 18 and
subsequent attack of the enolate on the ketone carbonyl and enals 14 catalyzed by a heterogeneous Pd-catalyst in combi-
the protonolysis process finally yielded two corresponding nation with a simple chiral amine co-catalyst (Scheme 4).20
bicyclic products. Synergistic co-catalysis enabled the enantioselective synthesis
Combining transition metal catalysis and organocatalysis in of highly substituted cyclopentenes, functionalized dihydrofur-
one process has attracted considerable attention and has ans and dihydropyrrolidines. Moreover, it was established that
emerged as a promising strategy for developing new and the chiral amine and the heterogeneous Pd catalysts must
unprecedented transformations. In 2012, Córdova et al. operate in concert to form the desire product. The authors also
investigated the recycling and life-time of heterogeneous cata-
lysts and revealed that the recovered catalyst was successfully
reused 8 times in CH2Cl2 under the same reaction conditions
without any decrease in activity. One year later, using a combi-
nation of homogeneous Pd and chiral amine catalysts, a novel
dynamic catalytic asymmetric 1,4-addition/allylic alkylation
cascade reaction between compounds 20 and enals, which
provided access to polysubstituted cyclopentane and cyclohex-
ane products bearing four stereocenters with excellent enan-
tioselectivities, was presented by the same group (Scheme 4).21
They further investigated the reaction mechanism for the
homogeneous palladium and amine co-catalyzed carbocycliza-
tion of aldehydes with alkynes by means of DFT calculations
and experiments in 2014 (Scheme 5).22 The results revealed that
the C–C bond-forming step achieved through the carbocycliza-
tion of the in situ-generated enaminynes was a two-step process
promoted by a Pd(II) species, which included the nucleophilic
enamine attack on the electrophilic Pd(II) and a Heck-like
insertion into the alkyne. Notably, this transformation was
efficiently linked to a highly enantioselective aerobic allylic
alcohol oxidation/1,4-addition/carbocyclization catalytic relay.
Simultaneously activating two substrates in different cataly-
tic cycles, known as cooperative catalysis, has been shown to be
a powerful strategic approach for creating molecular frame-
works from readily available starting materials. In this context,
Scheme 3 Pd-Catalyzed asymmetric 1,4-addition/aldol cascade chiral Pd–aqua complexes, which act as cooperative Brønsted
reaction. acid/base catalysts, have been shown to be powerful chiral

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Scheme 5 Homogeneous palladium and amine co-catalyzed carbocyclization.

catalysts in numerous asymmetric reactions. In 2018, Schnei- excellent enantioselectivities. The same group further extended
der and co-workers described a cooperative Brønsted acid/base- this nice approach to the 1,4-addition of chiral palladium
catalyzed process for the 1,4-addition of chiral palladium enolates to in situ generated a,b-unsaturated N-acyliminium
enolates to ortho-quinone methides, which were both generated ions Int-II, offering polycyclic oxoisoindoles 29 and 30 with
in situ (Scheme 6).23 Notably, Pd–aqua complexes not only acted three adjacent stereocenters with good results through subse-
as a Brønsted basic catalyst to form the reactive enolate, but quent cyclization (Scheme 6).24 It should be mentioned here
also functioned as a catalytic source of triflic acid, resulting in that a reactive vinylogous iminium ion Int-II generated in situ
the generation of ortho-quinone methide Int-I. Upon hemiace- from indolyl-2-carbinols 32, could also react with chiral metal
talization, a variety of densely functionalized chiral chromans enolates, resulting in the formation of densely functionalized
27 with two adjacent and one additional tertiary stereogenic N-fused polycyclic indoles 33 with three contiguous stereocen-
centers were obtained with good diastereoselectivities and ters, which was showed in 2020 by the group of Schneider
(Scheme 7).25

2.2. Nucleophilic addition reaction

A preliminary exploration of making chiral 3,3-dimethyl-
chroman-4-ols was described by Burke et al. in 2018, which
involved an intramolecular nucleophilic addition reaction of
aryl bromides to carbonyls by using PdCl2(CH3CN)2
as a precatalyst and (S)-iPrMeOBIPHEP as a chiral ligand

Scheme 6 Cooperative Brønsted acid/base catalyzed 1,4-addition of Scheme 7 Pd-Catalyzed enantioselective [3+2]-cycloannulation of b-
chiral palladium enolates. keto esters with indolyl-2-carbinols.

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(NHC) catalyst to the nitrovinyl group to form anion intermedi-

ate Int-II, which underwent nucleophilic addition to the azo
bond of azodicarboxylates, forming a hydrazine anion Int-III.
The subsequent proton transfer and removal of the NHC
catalyst would yield intermediate Int-V, which transformed into
a p-allyl palladium complex Int-VI in the presence of a palla-
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dium catalyst. After deprotonation of the hydrazine group of

Int-V with DMAP, N-allylation reaction occurred, generating the
final products.

Scheme 8 Intramolecular nucleophilic addition reactions of aryl bro-

mides to carbonyls.
3. Cyclization initiated by allylic
substitution reaction
(Scheme 8).26 It is noteworthy that tetrabutylammonium acet-
ate (TBAAc) was chosen as the base due to its enhanced Palladium-catalyzed asymmetric allylic substitution, as an
hydrophobicity. extremely useful class of organic transformation, has become
In 2020, Cheng and co-workers reported the construction of a popular and reliable method for creating carbon–carbon and
chiral 2,3-benzodiazepine compounds catalyzed by a carbon–heteroatom bonds, providing a range of structurally
thiazolium-derived carbene and a palladium-chiral bidentate diverse allyl-substituted compounds which serve as prevalent
phosphine complex in a cascade nucleophilic addition and functional molecules and building blocks for the construction
intramolecular N-allylation reaction involving the use of 1-(2- of biologically active natural products. This part of the review is
(2-nitrovinyl)aryl)allyl esters 36 and azodicarboxylates 37 as subdivided into three sections according to the type of allylic
reaction partners (Scheme 9).27 The substrate scope was wide electrophile involved, including single allylic substitution, dou-
since various aryl- and heterocyclic aryl-substituted allyl acetate ble allylic substitution and other type of allylic substitution.
analogues were well-tolerated. It should be pointed out that the
reaction of 1-(3-(2-nitrovinyl)thiophen-2-yl)allyl acetate with 3.1. Single allylic substitution
azodicarboxylates did not yield the expected product because In 2015, an asymmetric umpolung cyclization of allylic acetate–
of the poisoning effect of thiophene imposed on the palladium aldehyde 39 catalyzed by a palladium/chiral diphosphine
catalyst. The proposed mechanism of the process involves the complex for versatile access to cis-disubstituted pyrrolidine,
initial nucleophilic addition of the N-heterocyclic carbene tetrahydrofuran, and spiro-carbocycle with high performance,
was described by the group of Tsukamoto (Scheme 10).28
Notably, formate was used as the terminal reductant and did
not reduce allylpalladium under the catalytic conditions. Based
on their studies, the proposed mechanism for the process
involves the initial oxidative addition of allylic acetate to
Pd(0) resulting in the production of Z3-allylpalladium, which
is in equilibrium with Z1-allylpalladium. Then, the intra-
molecular allylation of the carbonyl group occurred via a six-
membered cyclic transition state leading to the formation of
the final product in the presence of formate.
Soon afterwards, the group of Gennari and Pignataro
reported the first enantioselective synthesis of 4-vinyltetrahy-
drocarbazole 42 through Pd-catalyzed asymmetric allylic

Scheme 9 A cascade nucleophilic addition and intramolecular N-

allylation reaction catalyzed by a thiazolium-derived carbene and a Scheme 10 Palladium/chiral diphosphine complex-catalyzed asym-
palladium-chiral bidentate phosphine complex. metric umpolung cyclization of allylic acetate–aldehyde.

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alkylation of suitable indole-containing allylic carbonates 41 with this process; however, the reaction of alkylated nitro-
(Scheme 11).29 Chiral Pd catalysts were formed in situ from a containing allylic carbonate could not proceed mainly due to
stable Pd source such as Pd(OAc)2 and members of the Phtha- the necessity of a certain degree of acidity of the a-proton of the
laPhos ligand library. Remarkably, both enantiomers of the nitro-group. Moreover, the stereochemistry of the transforma-
product can be efficiently prepared using the same enantiomer tion was rationalized through DFT calculations.
of a chiral ligand via changing the configuration of the sub- In 2020, the group of Toste and Sigman investigated the
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strate’s double bond. By using the in situ generated N- origin of asymmetric induction of intramolecular allylic sub-
nucleophiles, an intramolecular asymmetric allylic amination stitution via synergistic palladium/chiral phosphoric acid cata-
of Ugi adducts 43 to provide access to a wide range of highly lysis through a combined experimental and statistical
functionalized spiro-diketopiperazines 44 was described by modeling approach (Scheme 12).32 The authors conducted
Ruijter et al. in 2019 (Scheme 11).30 It is notable that the deuterium-labelling, nonlinear effect and other control experi-
concentration plays a crucial role in the reaction. The mecha- ments, which revealed that the enantio-determining step of this
nism was proposed to proceed via a p-allylpalladium inter- transformation was the nucleophilic attack on the p-
mediate and subsequent cross-coupling with the deprotonated allylpalladium intermediate and the chiral phosphate anion
secondary amide. Later, employing nitroalkanes as O-nucleo- was involved in stereoinduction. The multivariable linear regres-
philes, Zhang, Kan and co-workers reported the enantio- sion analysis also showed that multiple noncovalent interactions
selective synthesis of isoxazoline N-oxides 46 via Pd-catalyzed with the chiral environment of the phosphate anion played sub-
asymmetric allylic cycloaddition of nitro-containing allylic car- stantial role in enantiocontrol. The synthetic protocol was not only
bonates 45 (Scheme 11).31 This reaction proceeded via the key efficient in forming chiral pyrrolidines, but also applicable to the
nitronate intermediate Int-II, which was the resonant form of asymmetric construction of C–O bonds, resulting in the formation
zwitterionic p-allylpalladium intermediate Int-I. A variety of of chiral 2,2-disubstituted benzomorpholines.
arylated nitro-containing allylic carbonates were compatible An enantioselective ring-contraction of 5,6-dihydro-2H-
benzo[b][1,4]oxazocines to produce enantiomerically enriched
3,4-dihydro-2H-1,4-benzoxazines 54 as single regioisomers was
realized by Zhang, Yuan and co-workers in 2021 (Scheme 13).33
It should be noted that the reaction was sensitive to the
substituents on the phenyl ring of the substrate. The presence
of substituents at the 3-position of the phenyl ring of the
substrate had a negative effect on the enantioselectivity of this
transformation and a substrate bearing a tetrasubstituted
alkene failed to give the desired product. Additionally, an acidic
additive was necessary to increase the yield and enantiomeric
ratios of the products.
Asymmetric allylic substitution reactions have played a
crucial role in the total synthesis of natural products. In 2012,

Scheme 11 Intramolecular asymmetric allylic substitution reactions of Scheme 12 Intramolecular allylic substitution via synergistic palladium/
various allylic carbonates. chiral phosphoric acid catalysis.

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been recognized as powerful and versatile tools for constructing

a wide range of chiral heterocyclic molecules with comprehen-
sive value. Specifically, 1,4-diacetoxybut-2-ene serving as a bis-
allylic electrophile has been a competent reactant. In 2012, a
palladium-catalyzed cyclization of 2-amidophenylmalonates 60
with allylic bisacetates 61 to produce optically active tetrahy-
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droquinoline bearing a vinyl group at the 3- or 2-position was

described by Yoshida et al. (Scheme 15).36 It is worth noting
Scheme 13 Pd-Catalyzed enantioselective ring-contraction for the con- that the regioselectivity of this transformation was dependent
struction of 1,4-benzoxazines. on the choice of base. When K2CO3 and KOH were employed in
the reactions, 3-vinyltetrahydroquinoline 62 and 2-vinyltetrahy-
droquinoline 63 were formed as the sole product, respectively.
Takemoto and colleagues accomplished the total synthesis of
By employing their own developed Fei-Phos as a chiral ligand,
()-aurantioclavine based on an intramolecular asymmetric
Xu and co-workers reported the synthesis of 2-vinyl-2,3-dihydro-
amination of allyl carbonate (Scheme 14).34 This asymmetric
benzo[1,4]dioxin products 65 with low ee by the reaction of
allylic amination was a powerful tool for the construction of the
catechol 64 with allylic diacetate in 2018 (Scheme 15).37 Addi-
enantiomeric azepinoindole skeleton. Additionally, the key
tionally, a tandem allylic substitution/cyclization and cascade
intermediate azepane could also be used for the synthesis of
hydrosilylated reduction with the aid of methylphenylsilane
the substructure of communesin F. A distinctive intramolecular
was also developed in this work. Afterwards, a remarkable
asymmetric allylic alkylation of indole via parallel kinetic
example of this type of annulation was the formation of a series
resolution for the synthesis of cage-like indole alkaloid arbor-
of chiral vinyl-substituted heterocycles, including tetrahydro-
isidine was disclosed by Jiao’s group in 2021 (Scheme 14).35
quinoxalines, piperazines, dihydro-2H-benzo[b][1,4]-oxazines,
This scenario took the advantage of the C3/N ambident nucleo-
and morpholines powered by a chiral bisphosphorus ligand
philicity of indole, where one enantiomer of the substrate could
WingPhos with palladium loading as low as 0.1 mol%, a
undergo C3-allylation while the other could undergo N-
transformation pioneered by the group of Tang in 2020
allylation. The successful preparation of the C3-attack product
(Scheme 15).38 Mechanistic investigations supported a tandem
paved the way towards ()-arborisidine, while the N-attack
allylic substitution process and the high turnover number (up
product was useful in target-oriented synthesis of the bioactive
to 1000) proved its practicality for industrial applications. In
tetrahydro-b-carboline (THBC) scaffold.
2022, Jiang, Hao, Tu and co-workers further extended the scope
of dual nucleophiles to 2-[(1H-indol-2-yl)methyl]malonates 70,
3.2. Double allylic substitution leading to the regio- and enantio-selective synthesis of
Enantioselective Pd-catalyzed tandem allylic substitution reac- dihydropyrido[1,2-a]indoles with a chiral cyclic allyl stereocen-
tions involving dual electrophiles and dual nucleophiles have ter adjacent to the ring-junction nitrogen atom (Scheme 15).39

Scheme 14 Application of the asymmetric allylic substitution reaction in the total synthesis of natural products.

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Scheme 15 Pd-Catalyzed tandem allylic substitution reactions employing 1,4-diacetoxybut-2-ene as bis-allylic electrophiles.

In addition to 1,4-diacetoxybut-2-ene, it has been shown that yielding chiral hexahydrocinnoline derivatives with high
cyclic substrates, such as meso-dicarbonatecyclohexene, can performance.43 It should be noted that this reaction involved
also undergo Pd-catalyzed asymmetric allylic substitution cas- the first nitrogen nucleophilic process followed by the second
cade reactions. In this regard, Zhang, Liu and co-workers have intramolecular carbon nucleophilic substitution revealed by
devoted much attention to the enantioselective desymmetriza- mechanistic studies; this pathway differed from that of their
tion of meso-allyl substrates and established a practical previous work. In 2022, an interesting temperature-controlled
RuPHOX/Pd catalytic system, which has shown excellent cata- asymmetric allylic substitution cascade process of meso-allyl
lytic performance in asymmetric tandem allylic substitution for dicarbonates with 4-hydroxy-2H-pyrones 83 was disclosed by
the formation of various chiral heterocycles (Scheme 16). Liu and co-workers for the direct synthesis of chiral tetrahydro-
Employing cyclic N-sulfonylimines 74 as binucleophiles and 1H-pyrano[4,3-b]benzofuran-1-ones 84 which are kinetic
cis-cyclic allyl diacetates 73 as allylic substrates, they realized products.44 By means of experimental results and control
the construction of fused tetrahydroindole derivatives bearing experiments, the authors illustrated the formation of these
two chiral centers.40 Mechanistic studies confirmed that the chiral kinetic products through a temperature-controlled
cascade reaction proceeded through initial allylic alkylation, kinetic control process.
which was the chirality-control step, and subsequent allylic
amination. However, the cyclic N-sulfonylimines 74 are derived 3.3. Other types of allylic substitution
from saccharin directly or from substituted benzenesulfonyl Besides allylic alcohols and carbonates, other allylation part-
choride over four steps, resulting in very limited substituent ners also have been studied as electrophiles.45 In 2018, Trost
scope and poor overall yields. In order to address the short- et al. realized the first use of vinylcyclopropanes (VCPs) 86 as
comings, the authors further introduced enolizable ketimines electrophiles for the rapid synthesis various indolenine and
76 as nucleophiles, which can be obtained easily from various indoline products by employing 3-substituted 1H-indoles and
enolizable ketones through reactions with amines in the annu- tryptophan derivatives as nucleophiles via a Pd-catalyzed asym-
lation reaction, resulting in the production of a variety of chiral metric allylic alkylation (Scheme 17).46 Noteworthily, in the
tetrahydroindoles 77.41 Utilizing a similar strategy, Zhang et al. presence of a palladium catalyst, vinylcyclopropanes were pre-
in 2019 synthesized chiral bicyclic dihydrofurans 80 bearing viously used to generate 1,3-dipoles which initially served as
two vicinal carbon stereocenters through the reaction of allylic nucleophiles. This work represented the first example of utiliz-
meso-dicarbonates 78 with 3-oxo-nitriles 79.42 One year later, ing these 1,3-dipoles as electrophiles rather than nucleophiles.
the same group demonstrated the desymmetrization of meso- In addition, the borane reagent was responsible for both
dicarbonatecyclohexene with b-hydrazino carboxylic esters 81, reactivity and chemoselectivity of this transformation, which

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Scheme 16 Pd-Catalyzed tandem allylic substitution reactions employing meso-dicarbonatecyclohexene as a bis-allylic electrophile.

Scheme 17 Pd-Catalyzed asymmetric allylic alkylation employing vinylcyclopropanes as electrophiles.

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was explained in the proposed catalytic cycle. The method was decarboxylative cycloaddition reaction, was disclosed by Li
suitable for the rapid synthesis if mollenine A in three steps and colleagues (Scheme 19).48 This transformation, which
with an overall yield of 60%. Subsequently, the authors involved the formation of palladacyclobutane as the key
depicted the proposed catalytic cycle. The zwitterionic p- intermediate, was promoted by the (R,R)-BenzP* ligand and
allylpalladium complex Int-I was generated through the ring provided an efficient tool to synthesize various 2-methyl-3-
opening of the VCP derivative 86 with the assistance of the methyleneindoline 94. Specifically, the methyl group of vinyl
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palladium catalyst. Protonating the malonate anion of Int-I benzoxazinanones was essential to ensure the occurrence of b-
using the indole proton, whose acidity was dramatically hydride elimination of the palladacyclobutane species. When
increased through binding triethylborane to indole 85, resulted the methyl group was replaced with an ethyl group, the corres-
in the formation of p-allylpalladium complex III. The following ponding product was obtained with 20% ee, probably due to
nucleophilic attack of complex Int-III at the terminal position the relatively slow interconversion of the substrate. Based on
and dissociation of the palladium catalyst gave the final the deuterium-labelling and other control experiments, the
product. authors proposed a plausible mechanism. The oxidative addi-
Employing a synergistic catalytic system which was tion of 93 to the Pd complex led to the release of CO2, resulting
composed of a palladium complex, a Brønsted acid, and a in the formation of zwitterionic intermediate Int-I, which
chiral secondary amine, an asymmetric [3+2] cycloaddition of 2- could undergo intramolecular C2 attack on the p-allyl Pd
indolylmethanols 89 with a,b-unsaturated aldehydes 90 was complex, producing the palladacyclobutane intermediate Int-
reported by Deng, Luo and co-workers in 2019, providing II. The following b-hydride-elimination and reductive elimina-
biologically active cyclopenta[b]indole derivatives 92 with tion sequence generated the final product 94.
high efficiency (Scheme 18).47 The hypothesized mechanism Recently, Huang and Liu reported an enantioselective ami-
involves the dehydration of 2-indolylmethanols 89 promoted by nomethylative annulation reaction between dienyl alcohols 95
Pd(0)/BH to form the p-allylpalladium complex Int-II. Then, the and aminals 96 to provide a straightforward way to access
g-position of the enamine intermediate Int-I which was gener- various chiral cis-disubstituted isochromans 97 with moderate
ated through the reaction between 90 and 91, could undergo to good enantioselectivities (Scheme 20).49 Notably, the hydro-
nucleophilic attack on the intermediate Int-II, resulting in the xyl group of dienyl alcohols 95 was essential for facilitating the
formation of a transient intermediate Int-III. The subsequent Pd-catalyzed Heck insertion regioselectively to generate the p-
intramolecular cyclization and rapid isomerization resulted in allylpalladium intermediate Int-II through hydrogen-bonding
the formation of intermediate Int-IV. Finally, the hydrolysis of between the hydroxyl group and aminal moiety in intermediate
intermediate Int-IV and the subsequent NaBH4 reduction gen- Int-I. It was found that owing to the strong p-accepting ability of
erated the product. the chiral phosphinamide ligand, the palladium center could
A particular intramolecular reaction of vinyl benzoxazina- coordinate with the alcohol in intermediate Int-II, followed by
nones which have been widely applied in palladium-catalyzed

Scheme 18 Synergistic catalysis for asymmetric [3+2] cycloadditions of Scheme 19 Pd-Catalyzed enantioselective synthesis of 2-methyl-3-
2-indolylmethanols with a,b-unsaturated aldehydes. methyleneindoline.

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Scheme 20 Enantioselective aminomethylative annulation reaction

between dienyl alcohols and aminals.

inner-sphere reductive elimination to produce the cis-diastereo-

selective product.

Scheme 21 Pd-Catalyzed enantioselective [3+2] cycloaddition of 1,3-

4. Cyclization involving p-allyl dipole precursors with azadienes.

palladium zwitterions
4.1. p-Allyl palladium zwitterions bearing a carbanion 100 bearing a quaternary stereogenic center with high effi-
4.1.1. Activated vinylcyclopropanes. Owing to the posses- ciency (Scheme 21).53
sion of an olefin ligand which could direct the transition-metal An interesting method for producing a range of chiral
for the selective C–C bond cleavage, vinylcyclopropanes (VCPs) benzoxepins 103 with up to 77% ee was described by Ruijter
have been widely used in transition-metal-catalyzed cycloaddi- et al. in 2021, which involved a formal [3+4] cycloaddition of
tion reactions with a broad variety of unsaturated acceptors. phosphonate-functionalized vinylcyclopropanes 102 with sali-
VCPs could serve as three- or five-carbon synthons depending cylaldehydes 101 (Scheme 22).54 Noteworthily, the exact roles of
on whether the vinyl substituent participates in the cycloaddi- LiCl and traces of water were not completely clear, but they
tion. The development of cycloaddition and related addition were essential for the success of the reaction. Based on experi-
reactions involving VCPs was reviewed by Tang, Li and co- mental results, this reaction was thought to proceed through a
workers in 2020.50 Soon afterwards, catalytic enantioselective sequence involving the ring opening of VCPs and HWE olefina-
ring-opening reactions of cyclopropanes including VCPs were tion with aldehydes, followed by O-allylation.
summarized by the group of Waser.51 Thus, here we will Later, studies by the Miao group showed that oxidopyrylium
present the recent advances in the asymmetric Pd-catalyzed ylides, which were generated in situ from benzopyranones 104,
cycloaddition reactions of activated VCPs after 2020. could serve as reactive partners in Pd-catalyzed [5+3] cycloaddi-
In 2021, the group of Trost presented the synthesis of tions with VCPs with the use of a chiral PHOX ligand, providing
spirocyclic compounds via asymmetric Pd-catalyzed [3+2] spir- a useful method for the construction of highly functionalized
oannulation of azadiene 98 with 1,3-dipole precursors bridged oxa-[3.3.1]carbocycles 105 with three stereogenic
(Scheme 21).52 In the presence of chiral palladium catalysts
ligated by (R)-Segphos, a series of vinyl cyclopropanes 86
reacted smoothly with azadiene, yielding optically enriched
all-carbon spirocyclic compounds 99 with high enantioselec-
tivity. The Pd–p-allyl intermediate which was generated via the
oxidative addition of Pd0 species to vinyl cyclopropane pre-
ferred to undergo 1,4-addition with azadiene, followed by the C-
attack of the ketimine anion, leading to the formation of all-
carbon spirocyclic compounds. Almost simultaneously, Li and
co-workers showed that the catalytic system with Pd(0) and
Feringa’s phosphoramidite ligand bearing the chiral methyl-
protected diarylprolinol worked equally well for enantio-
selective [3+2] cycloaddition of VCPs with azadienes via a Scheme 22 Pd-Catalyzed enantioselective [3+4] cycloaddition of
similar mechanism, furnishing enantioenriched spirocycles phosphonate-functionalized vinylcyclopropanes with salicylaldehydes.

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centers (Scheme 23).55 This reaction involved the formation of various spirooxindole-3,4-benzo[b]oxepanes 108 via [4+3]
two key intermediates: one was Pd–p-allyl zwitterionic inter- cycloaddition reactions. For [2+3] cycloaddition reactions, pal-
mediate Int-B through Pd-catalyzed ring opening of VCP and ladium catalysts containing chiral Trost’s ligand were needed
the other was oxidopyrylium ylides Int-A via elimination of to directly synthesize a series of bispirooxindole heterocyclic
benzopyranone with the assistance of DBU. In their further compounds 109. Moreover, based on the calculated ADCH
studies, Miao and Xu disclosed ligand-controlled asymmetric charges and ‘‘the hard and soft acids and bases theory’’ (HSAB),
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[4+3] and [2+3] annulation reactions between o-quinone the authors explained how the steric and electronic variations
methides 106 and spirovinylcyclopropyl oxindoles 107 of ligands affect the two competing cyclization processes. Soon
(Scheme 23).56 It was found that the use of a palladium/(R)- afterwards, employing o-quinone methides generated in situ
Segphos catalyst was optimal for the efficient synthesis of from the phenol derivative 106, asymmetric [2+3] cycloaddition
reactions with VCPs catalyzed by the Pd-PyOX complex to
construct highly functionalized spiro-[5,6] bicycles 111 was
accomplished by Liu, Bai, Shao and Chu (Scheme 23).57 The
authors also performed DFT calculations to reveal that this
[2+3] annulation was more thermodynamically favorable than
[4+3] annulation. Very recently, the components of [3+2]
cycloaddition with VCPs were further extended to alkenyl N-
heteroarenes 112. Liu, He, Chen and Chu showed a catalytic
system consisting of the Pd(0) complex, (S)-Segphos and LiBr
was effective for this transformation, providing ready access to
a wide array of aza-arene-substituted cyclopentanes 113 with
moderate to high diastereoselectivity and excellent enantios-
electivity (Scheme 23).58 Notably, 1H NMR studies indicated
that LiBr served as a Lewis acid to improve the reactivity of
alkenyl N-heteroarenes.
An efficient method for making enantioenriched seven-
membered lactones 116 was described by Lu, Lan and co-
workers in 2020, and it involved an asymmetric [5+2] dipolar
cycloaddition between VCPs 115 and a-diazoketones 114
(Scheme 24).59 The reaction, which involved the formation of
the key oxo-1,5-dipole Int-A, was promoted by combining
visible-light activation and asymmetric palladium catalysis in
the presence of their developed chiral P,S-ligand. Moreover, the
authors proposed four possible cycloaddition reactions,
and computational investigations indicated that the intermo-
lecular [5+2] cycloaddition was the most kinetically favorable
process.
4.1.2. Pd-Methylene-TMM. Employing their developed
diamidophosphite ligand which features a sterically more

Scheme 23 Pd-Catalyzed [5+3], [4+3] and [2+3] cycloadditions with Scheme 24 Pd-Catalyzed [5+2] dipolar cycloadditions between VCPs
VCPs. and a-diazoketones.

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demanding trans-1,2-stilbenediamine backbone, the palladium- enabled by a chiral phosphoramidite ligand was investigated by
catalyzed asymmetric [3+2] cycloaddition reaction of a Guo and co-workers, opening a new avenue for the synthesis of
methylene-TMM donor 117 with a,b-unsaturated N-acyl pyr- functionalized chiral hexahydropyrazolo[5,1-a]isoquinoline
roles 118 that provided expedient access to substituted vinyli- derivatives 123 (Scheme 25).62 The authors envisioned that
denecyclopentanes 119, was discovered by the group of Trost in the catalytic cycle initiated with the formation of the Pd-
2013 (Scheme 25).60 This transformation was proposed to methylene–TMM complex, simultaneously releasing TMSOAc,
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proceed via the key Pd-methylene-trimethylenemethane inter- by the reaction of a palladium catalyst with the methylene-
mediate (TMM), demoted as Int-A. Later studies by the same substituted TMM donor, followed by cycloaddition with azo-
group showed that the Pd-diamidophosphite ligand system is methine imine 122 to generate intermediate Int-A, which could
also an effective catalyst for the facile synthesis of cyclopen- undergo allylation of the acetyloxy anion to produce the
tanes, pyrrolidines, and spirocycles bearing chiral allenes via product.
asymmetric [3+2] cycloaddition reactions of racemic allenyl 4.1.3. Pd-TMM. In Pd-TMM chemistry, these zwitterionic
TMM donors 117 (Scheme 25).61 A wide range of acceptors, allylpalladium intermediates generally serve as three-carbon
including b-imino nitro olefin, N-acyl pyrrole-substituted ole- synthons, reacting with a wide spectrum of acceptors to furnish
fins and imines, 3-isopropylidene oxindole as well as tropone, the [3+n] cycloadditions, yielding various carbo- and hetero-
were all amenable to this transformation. It was found that this cyclic compounds. Palladium-catalyzed asymmetric cycloaddi-
reaction involved a dynamic kinetic asymmetric transformation tions of trimethylenemethane to forge odd-membered rings
(DYKAT) and a stepwise mechanism. Besides as three-carbon were summarized by Mata and Trost in 2020.63 Therefore, we
synthons, Pd-methylene-TMM could also serve as a two-carbon will present the recent advancements in the asymmetric Pd-
synthon in the presence of a suitable dipole. With the use of Pd- TMM chemistry which were not covered in previous reviews.
methylene-TMM as a dipolarophile, an asymmetric tandem
[3+2] cycloaddition/allylation reaction with azomethine imine 4.1.3.1. Pd-TMM zwitterionic intermediates generated via desi-
lylation or decarboxylation. In 2020, Fan, Zhao and co-workers
demonstrated that CN-substituted trimethylenemethane 125
reacted with p-quinone methides 124 in the presence of a novel
type of non-C2-symmetric phosphoramidite ligand with L-
hydroxyproline-derived amine units via a palladium-catalyzed
asymmetric [2+3] annulation, providing a simple route to
highly functionalized chiral spirocyclopentyl p-dienones 126
(Scheme 26).64 A series of p-QMs bearing different aromatic
and heteroaryl group at their d position were well tolerated,
whereas the ester- and amide-substituted p-QMs led to
decreased enantioselectivity perhaps because the electron-
withdrawing carbonyl group at its d position had a detrimental
effect on this transformation. Based on experimental results,
this reaction was thought to proceed through a sequence
involving an asymmetric 1,6-addition and intramolecular dear-
omative cyclization.
Recently, a remarkable example of this type of annulation
involved the formation of highly substituted or fused pyrroli-
dine and tetrahydrofuran rings 130 through the reaction of

Scheme 25 Pd-Catalyzed asymmetric [3+2] cycloaddition reactions of Scheme 26 Pd-Catalyzed asymmetric [2+3] annulation of CN-
the methylene-substituted TMM donor. substituted trimethylenemethane with p-quinone methides.

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electrophilic palladium-heteroallyl zwitterion intermediates

(Pd-OTMM or Pd-NTMM) with cyclic or acyclic 1,3-dienes 129,
a transformation pioneered by Zhang’s group (Scheme 27).65
Notably, the use of PC-Phos bearing di-tert-butyl or/and 3,5-
difluorophenyl groups played a crucial role in facilitating the
reaction and achieving excellent enantioselectivity. The tenta-
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tive mechanism considered the oxidative addition of the het-

eroxyallyl precursor to a palladium complex to generate
intermediate Pd-heteroallyl Int-I or Int-I 0 via desilylation or
decarboxylation, followed by akene insertion to produce inter-
mediate Int-II, which underwent Z1 to Z3 isomerization to form
complex Int-III or Int-III 0 and subsequent intramolecular Scheme 28 Pd-Catalyzed asymmetric aromative [4+3] cyclization reac-
nucleophilic attack on the highly electrophilic Z3 Pd-allyl tion between amino-trimethylenemethanes and fused 1-azadienes.
moiety would lead to the formation of the final product.

4.1.3.2.2. Sulfonyl TMM donor. An interesting [4+3] annula-

tion involving the use of sulfonyl-trimethylenemethane donor
4.1.3.2. Pd-TMM zwitterionic intermediates generated via 133 with azadienes 98 as reaction partners using H8-BINOL-
deprotonation derived phosphoramidite as a chiral ligand to give various
4.1.3.2.1. Amino-TMM donor. In 2020, the group of Shao sulfonyl-fused azepines 134 with exclusive regioselectivities
and Deng reported a Pd-catalyzed asymmetric aromative [4+3] and excellent stereoselectivities was accomplished by Deng
cyclization reaction between amino-trimethylenemethanes 131 and Liu in 2021 (Scheme 29).67 This reaction involved the
and fused 1-azadienes 98 for convenient access to a series of generation of the key Pd-TMM species via oxidative addition
synthetically important and biologically active benzofuran and self-deprotonation of the Pd complex and sulfonyl TMM
fused azepines and indeno-azepines 132 with high perfor- donor. Moreover, sulfone, acting as a transient activating group
mance (Scheme 28).66 It was notable that using (R)-H8-BINOL- of the TMM species, could be easily removed to furnish
derived phosphoramidite was essential to achieve high enan- structurally simple fused azepines. Soon afterwards, using
tioselectivity, as the diastereomer of the ligand resulted in no in situ generated sulfone-TMM species, expedient synthesis of
enantiofacial discrimination. chiral cyclopentyl sulfones 137 bearing three chiral centers via
palladium-catalyzed [3+2] cycloaddition was disclosed by Trost
and co-workers (Scheme 29).68 The reaction, which required the
presence of a chiral diamidophosphite ligand to facilitate the
reactivity and control the selectivity, tolerated a wide range of
sulfone-TMM donors and acceptors.

Scheme 27 Pd-Catalyzed asymmetric [2+3] annulation to form highly Scheme 29 Pd-Catalyzed asymmetric annulation involving the use of
substituted or fused pyrrolidine and tetrahydrofuran rings. sulfone-TMM donors.

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4.1.3.2.3. 2-Acyl TMM donor. Later studies by the Trost

group showed that Pd-diamidophosphite complexes were also
effective catalysts for enantioselective intermolecular cycloaddi-
tion of 2-acyl TMM donor 138 with various p-system coupling
partners 136, including nitroolefins, trisubstituted olefins,
imines and azadiene, providing a useful method for the con-
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struction of various synthetically useful and flexible cyclic

compounds bearing carbonyl groups (Scheme 30).69 In the
presence of a suitable Pd0 complex, a 2-acyl TMM donor could
in situ generate Pd–TMM zwitterionic intermediates via the
abstraction of the acidic proton adjacent to the carbonyl group.

4.1.3.2.4. Homo-TMM donor. In the presence of chiral

palladium catalysts ligated by two kinds of phosphoramidite
ligands, palladium-catalyzed enantioselective cycloadditions of
aliphatic 1,4-dipoles generated from different malonates, 2-
coumaranone, 2-oxindole, heterocyclic arenes, 2-pyramidinyl
precursors with 2-benzylidenemalononitrile and N-contained
acceptors, were described by Trost’s group in 2020, providing
versatile access to various chiral 6-membered rings 141 and
spiro [2.4] heptanes 142 (Scheme 31).70 The reaction involved
the formation of palladium-homo-TMM species via a deproto-
nation strategy, followed by the initial nucleophilic attack on
the electron-deficient olefin leading to complex Int-A, which
could undergo two distinctive ring closure process to generate
different products. One route involved nucleophilic attack at
the C1 position through a classic Tsuji–Trost type mechanism Scheme 31 Pd-Catalyzed asymmetric annulation involving the use of the
homo-TMM donor.
to afford 6-membered products. The other involved nucleophi-
lic attack at the C2 position to produce a palladacyclobutane
intermediate, followed by reductive elimination to deliver the
spiro products. Soon afterwards, the same group realized a kinds of Segphos-type ligands to furnish distinct 2l2-
novel palladium-catalyzed enantioselective cycloaddition azepino[4,3-b]indole and 2l2-pyrrolo[3,4-b]indole frameworks
employing electron-deficient allylic carbonates 143 as carbony- was established by Chen, Du and co-workers in 2021
logous 1,4-dipole precursors, offering an unprecedented effi- (Scheme 32).72 It should be noted that the presence of chiral
cient route for the selective synthesis of chiral cyclohexanones tartrate as an additive was essential for both enantioselectivity
144 with excellent results (Scheme 31).71 Notably, the use of and reactivity, perhaps because it may act as a hydrogen donor
their developed C2-unsymmetric phosphoramidite ligand and cocatalyst. Besides, activated alkenes, including a-cyano chal-
the electronic interactions between the ester group and the cones and alkylidene indene-1,3-diones, were also suitable
cationic Pd-allyl moiety in key intermediate Int-A both play substrates for switchable asymmetric [5+2] or [3+2] annulations
crucial roles in this transformation. for creating relevant carbocycles with good results.
4.1.4. Vinyl indoloxazolidones. The asymmetric [5+2] and 4.1.5. c-Methylidene-d-valerolactones (GMDVs). In 2012,
[3+2] annulations involving the use of vinyl indoloxazolidones the group of Hayashi and Shintani reported the facile synthesis
145 as 1,5-carbodipoles or 1,3-carbodipoles and sulfamate- of 2-pyrrolidinones with a quaternary stereocenter at the 3-
derived cyclic imine 146 as reaction partners enabled by two position via a palladium-catalyzed asymmetric cycloadditions
between g-methylidene-d-valerolactones (GMDVs) 150 and alkyl
isocyanates 151 employing their newly synthesized chiral phos-
phoramidite ligand (Scheme 33).73 In addition to alkyl isocya-
nates, the use of aryl isocyanates as reaction partners also
resulted in smooth reactions, leading to the synthesis of chiral
3,3-disubstituted 2-piperidinones under the same reaction con-
ditions. Subsequent studies conducted by the group of Fan
and Zhao showed that isatin-derived para-quinone methides
(p-QMs) 154 could serve as reactive partners in palladium-
catalyzed asymmetric [4+2] annulation with GMDVs enabled
Scheme 30 Pd-Catalyzed asymmetric annulation involving the use of the by (S,S,S)-()-Xyl-SKP, providing chiral cyclohexadienone-fused
2-acyl TMM donor. cyclohexyl spirooxindoles 155 bearing three highly congested

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Scheme 32 Pd-Catalyzed asymmetric [5+2] and [3+2] annulations of

vinyl indoloxazolidones and sulfamate-derived cyclic imine.

contiguous tetrasubstituted carbon atoms (Scheme 33).74 The

proposed mechanism for this transformation involved the
formation of 1,4-zwitterionic species Int-A through decarbox-
ylative oxidative addition of palladium(0) to GMDVs, followed
by enantioselective 1,6-conjugate addition and subsequent
intramolecular dearomative Friedel–Crafts-type cyclization to
afford the final products. In subsequent studies, Li and Liu
demonstrated that anthranils 156 could react with GMDVs in
the presence of chiral palladium catalysts ligated by a H8-
BINOL-derived phosphoramidite ligand, yielding highly func-
tionalized tetrahydrobenzo[b]-azocine derivatives 157 with high
performance.75 The control experiment indicated that Et3B may
enhance the electrophilicity of anthranil via coordination,
functioning as an activator for this catalytic transformation. It
was found that complex substrates derived from natural pro-
ducts were all amenable to this transformation. The same
group further extended the scope of dipolarophiles to ortho-
quinone methides 158, leading to the enantioselective synth-
esis of functionalized benzo[b]oxocines bearing adjacent Scheme 33 Pd-Catalyzed asymmetric annulation employing GMDVs as
all-carbon quaternary and tertiary stereocenters (Scheme 33).76 the 1,4-dipolar precursor.
DFT calculations revealed that the conjugate addition step was
likely to be the enantio-determining step.
Besides their role as 1,4-dipolar precursors, GMDVs mechanism was suggested by the authors. Oxidative addition of
could serve as 1,3-dipolar precursors, reacting with nitroo- GMDVs to Pd(0) catalysts with the release of CO2 could lead to
lefins 120 for the facile synthesis of multisubstituted chiral the production of 1,4-zwitterionic species. Simultaneously, the
spiro[2.4]heptanes bearing three contiguous stereogenic cen- urea-tertiary amine coordinated with nitroolefins via strong
ters via asymmetric decarboxylative [3+2] cycloaddition through hydrogen bonds. The following intermolecular Michael addi-
the cooperative catalysis of a palladium complex of a chiral tion would form intermediate Int-A, followed by the C2 attack
phosphoramidite ligand and a chiral urea-tertiary amine, as of the anion on the central carbon of the allylpalladium species
described by the group of Liu and Wu in 2022 (Scheme 34).77 and reductive elimination, yielding the final products.
Both indolyl nitroolefins and 2-nitrobenzofurans were well-
tolerated, yielding complex polycyclic scaffolds. Notably, the 4.2. p-Allyl palladium zwitterions bearing a N-centered anion
addition of organocatalysts played a crucial role in significantly 4.2.1. Vinyl aziridines. Vinyl aziridines are widely applied
increasing the diastereoselectivity of this reaction. Moreover, a as a 1,3-dipole precursor; they can3 undergo oxidative addition

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Scheme 34 Pd-Catalyzed asymmetric annulation employing GMDVs as

the 1,3-dipolar precursor.

Scheme 35 Generating a p-allyl–Pd complex with an amide anion from

vinyl aziridines.

with Pd(0) catalysts to generate a p-allyl–Pd complex with an

amide anion (Scheme 35), serving as the N1-1,3-dipole to
participate in [3+n] cycloadditions with various dipolarophiles.
In 2015, Hou, Ding and co-workers reported a palladium-
catalyzed asymmetric [3+2] cycloaddition reaction between Scheme 36 Pd-Catalyzed asymmetric [3+2] cycloaddition reaction of
vinyl aziridines with a,b-unsaturated ketones, methyleneindolinones and
vinyl aziridines 163 and a,b-unsaturated ketones 164 for effi-
3-nitroindoles.
cient synthesis of chiral 3,4-disubstituted pyrrolidines 165 with
high performance using (Rphos,Ra)-SIOCPhox as the chiral
ligand (Scheme 36).78 It was notable that substituents on the
vinyl group of the aziridines had a considerable effect on the the catalytic system with Pd(0) and Walphos type ligand worked
diastereoselectivity of this transformation. Substituents such as equally well for asymmetric dearomative [3+2] cycloaddition of
methyl and ethyl on the vinyl group could result in high dr and 3-nitroindoles with vinyl aziridines (Scheme 36).81
ee values, whereas employing substrates bearing hydrogen, A remarkable example for expedient access to chiral benzox-
phenyl and isopropyl on the vinyl group led to lower dr values azepine derivatives 171 through a scarce catalytic enantio-
albeit with high ee values. Utilizing methyleneindolinones 166 selective [4+3] cyclization of vinyl aziridines with p-QM
as dipolarophiles, a series of 3,3 0 -pyrrolinyl spirooxindoles 167 derivatives 170 was disclosed by Shi, Mei and co-workers in
were prepared efficiently via a highly stereoselective [3+2] 2018 (Scheme 37).82 This transformation involved the for-
cycloaddition reaction, which was described by the group of mation of zwitterionic p-allyl Pd intermediate Int-I, as well as
Lu in 2016 (Scheme 36).79 This reaction was proposed to oxygen anions through p-QM and a base, followed by the
proceed through a sequence involving a Michael addition and nucleophilic attack to generate transient intermediate Int-II,
an intramolecular asymmetric allylic alkylation. Subsequent which underwent aza-1,6-addition, yielding the final product.
studies by Wang’s group showed that 3-nitroindoles 168 could 4.2.2. Vinyloxazolidinones. In addition to vinyl aziridines,
serve as reactive partners in Pd-catalyzed asymmetric dearoma- vinyloxazolidinones could also react with Pd(0) complexes to
tive [3+2] cycloaddition reactions with vinyl aziridines in the produce the N1-1,3-dipole with the release of CO2. By employing
presence of the chiral Box ligand, providing a novel method for a catalyst composed of a Pd(0) complex and a newly devised
the construction of enantiomerically enriched 3a-nitro- phosphine ligand with a chiral ammonium salt component, a
hexahydropyrrolo[2,3-b]-indole derivatives 169 (Scheme 36).80 highly enantio- and diastereo-selective [3+2] cyclization of 5-
Besides, the authors also found that Pd–Box complexes were vinyloxazolidinones 172 with activated trisubstituted alkenes
effective catalysts for [3+2] cycloaddition reactions of 3- 173 was presented by Ooi et al. in 2014, providing a simple
nitroindoles with vinyl cyclopropanes for convenient access to route for the synthesis of densely functionalized pyrrolidines
various 8b-nitrohexahydrocyclopenta[b] indole derivatives. 174 (Scheme 38).83 This transformation involved the generation
Soon afterwards, Hou, Ding and co-workers discovered that of three contiguous stereocentres in one step, including vicinal

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Scheme 39 Pd-Catalyzed asymmetric [3+2] and [4+2] cycloaddition

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reactions.

addition of vinyl benzoxazinanones to Pd complexes, releasing

CO2, gives rise to a zwitterionic p-allyl Pd species which may be
regarded as an N1-1,4-dipole and has been employed in various
[4+n] cycloaddition reactions. Asymmetric palladium-catalyzed
[4+n] cycloaddition reactions of vinyl benzoxazinanones were
Scheme 37 Pd-Catalyzed asymmetric [4+3] cyclization of vinyl aziridines
reviewed by Zhao, Hou and co-workers in 2021.85 Therefore,
with p-QM derivatives.
this type of reaction will not be covered here.
4.2.4. N-Containing allylic carbonates. Utilizing nitrogen-
containing allylic carbonates as N1-1,3-dipole and N1-1,4-dipole
precursors for the enantioselective synthesis of cyclic urea 180
via asymmetric allylic cycloaddition with isocyanates 151 was
demonstrated by the group of Zhang and Xu in 2019
(Scheme 39).86 In the presence of chiral palladium catalysts
ligated by two kinds of phosphoramidite ligands, chiral imida-
zolidinones and tetrahydropyrimidinones were efficiently
synthesized through [3+2] and [4+2] cycloaddition reactions,
respectively.

4.3. p-Allyl palladium zwitterions bearing a O-centered anion

4.3.1. Vinyl carbamates. By combining visible-light activa-
tion and asymmetric palladium catalysis, a [8+2] cycloaddition
between vinyl carbamates 181 and a-diazoketones 114 to con-
struct 10-membered monocyclic architectures 182 bearing
Scheme 38 Pd-Catalyzed asymmetric [3+2] cyclization of vinyloxazoli- chiral quaternary stereocenters was accomplished by Lu, Lan
dinones with activated trisubstituted alkenes and N-sulfonyl imines. and their co-workers in 2020 (Scheme 40).87 The hypothesized
mechanism for this transformation involved the generation of
Pd-containing 1,8-dipoles Int-I through the oxidative addition
all-carbon quaternary stereocentres. Notably, the chiral onium– of vinyl carbamates to Pd(0) catalysts without the release of
phosphine hybrid ligand played an essential role in facilitating CO2. Simultaneously, reactive ketene dipolarophiles Int-II were
the intermolecular cycloaddition while allowing precise control
of the individual absolute stereochemistry. The significance of
this method was demonstrated by the efficient asymmetric
synthesis of the core structure of the analogue of thrombin
inhibitors. Soon afterwards, the same group showed that
the catalytic system with a Pd(0) complex and a chiral
ammonium-phosphine hybrid ligand was also effective for an
asymmetric [3+2] cycloaddition reaction between racemic 5-
vinyloxazolidinones and N-sulfonyl imines 176 that provided
expedient access to various chiral imidazolidines 177 bearing a-
amino quaternary stereocenters (Scheme 38).84 It was found
that an array of aromatic imines and aliphatic imines posses-
sing primary or secondary alkyl substituents were well-tolerated
except for 4-methoxyphenyl-substituted imines, leading to a
decrease in the reaction efficiency and diastereoselectivity.
4.2.3. Vinyl benzoxazinanones. Besides many transforma- Scheme 40 Pd-Catalyzed asymmetric [8+2] dipolar cycloadditions of
tions utilizing the widely known N1-1,3-dipole, the oxidative vinyl carbamates and photogenerated ketenes.

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Scheme 41 Pd-Catalyzed asymmetric [3+2] cycloaddition of para-

quinone methides with vinyl epoxide.

generated from a-diazoketone upon irradiating with 6 W blue

LEDs. Then, the nucleophilic addition of carbonate anions to
the ketenes and the following intramolecular allylation resulted
in the formation of the target 10-membered monocyclic pro- Scheme 42 Pd-Catalyzed asymmetric dearomative [3+2] cycloaddition.
ducts. Moreover, DFT calculations suggested that the oxidative
addition process was the rate-determining step, and breaking
the C–N bond to release CO2 was more difficult. 190 with excellent diastereo- and enantio-selectivity
4.3.2. Vinyl epoxides. In 2016, Zhao’s group disclosed an (Scheme 43).91 Recently, the group of Zhang reported their
unprecedented formal [3+2] cycloaddition of p-QM 124 with studies on the Pd-catalyzed asymmetric allylic cycloaddition of
vinyl epoxides 183 to provide straightforward access to various vinyl epoxides with b-keto enol ethers 191 utilizing BINAP or
chiral spiro[4.5]decanes 184 with high performance using OMe,Cl-Biphep as a chiral ligand, giving readily access to
palladium catalysts containing chiral ferrocene-based N,P- functionalized chiral tetrahydrofuran acetals 192 bearing three
ligands (Scheme 41).88 Notably, the bulky t-butyl substituents stereocenters.92 Notably, the process provided a novel and
on the p-QM structure were essential for achieving high dia- useful method for late-state functionalization of natural pro-
stereoselectivity and enantioselectivity, as changing the t-butyl ducts employing b-keto enol ethers bearing chiral alkoxides or
to smaller isopropyl or methyl groups led to reduced dr and ee natural fragments.
values. The authors further extended the scope of dipole Interestingly, Guo’s group found that the [3+2] annulations
precursors to vinyl cyclopropane employing SDP as a chiral could also be achieved using a-N-heterocyclic acrylates as
ligand. dipolarophiles, providing a direct entry to chiral functionalized
A remarkable example of this type of annulation is the tetrahydrofuran skeletons (Scheme 44).93 With the use of
formation of tetrahydrofurobenzofurans and tetrahydrofuro- a catalyst composed of Pd(PPh3)4 and (S,S)-tBu-FOXAP,
benzothiophenes through the reaction of nitrobenzofurans or a-benzimidazole, benzotriazole and purine-derived acrylates
nitrobenzothiophenesanilides 185 with vinyl epoxides 183 via a could react to afford purine isonucleoside analogs 194 with
dearomative [3+2] cycloaddition, a transformation pioneered by
You et al. in 2017 (Scheme 42).89 The key to the success of the
reaction was fine-tuning of the electronic and steric character-
istics of PHOX ligands. Another example of a dearomatizing
[3+2] cycloaddition of nitroindoles 168 with vinyl epoxides
for stereodivergent synthesis of tetrahydrofuroindoles in
the presence of chiral palladium catalysts ligated by a PHOX
ligand decorated with fluorine and trifluoromethyl groups, was
described by the group of You and Guo in 2018 (Scheme 42).90
It was notable that the polarity of the solvent played a crucial
role in the diastereoselectivity. Mechanistic studies indicated
that reactions in different solvents proceeded through the same
pathway but with different rate-limiting steps, that is, the rate-
limiting step was thought to be the Michael addition process in
toluene or the allylic cyclization step in acetonitrile.
Subsequent studies by Hou, Peng, Ding and co-workers
showed that a,b-unsaturated ketones 189 could be reactive
partners in palladium-catalyzed [3+2] cycloaddition with vinyl Scheme 43 Pd-Catalyzed [3+2] cycloaddition of vinyl epoxides with a,b-
epoxides, providing various highly substituted tetrahydrofurans unsaturated ketones and b-keto enol ethers.

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heterocycles 200 with high performance (Scheme 44).95 In

addition to [5+4] cycloaddition, various chiral spirooxazolidine
derivates 201 could be efficiently synthesized through [3+2]
cycloaddition between 98 and 183 employing (R)-BINAP as a
chiral ligand, which was disclosed by the group of Trost in
2021 (Scheme 44).52 In this catalyst system, O-substituted
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zwitterionic palladium intermediates were likely to attack the

ketimino group of azadiene, followed by the attack of the
resulting nitrogen anion to furnish spirooxazolidines. Recently,
with the use of a chiral benzylic substituted P,N-ligand, an
interesting Pd-catalyzed formal [3+2] annulation involving
the use of substituted propiolates 202 and vinyl epoxides as
reaction partners, providing convenient access to a wide array
of chiral dihydrofurans 201 was developed by Hou’s group
(Scheme 44).96
4.3.3. Vinyl oxetanes. In 2018, an unprecedented [6+4]
cycloaddition involving the use of vinyl oxetanes 204 with
azadienes 98 to construct ten-membered heterocycles 205 was
accomplished by Zhao and co-workers (Scheme 45).95 In the
presence of a Pd catalytic system derived from the SIPHOX
ligand, a wide array of benzofuran- and indole-fused hetero-
cycles were efficiently synthesized. The authors further discov-
ered unique fragmentation of these compounds via Lewis acid
catalysis. Using vinyl oxetanes as 1,4-dipole precursors, asym-
metric allylic cycloaddition with formaldehyde, an abundant
feedstock, catalyzed by palladium catalysts containing chiral
phosphoramidite ligands was demonstrated by Zhang’s group
in 2019, providing a simple route to various chiral 1,3-dioxanes
206 (Scheme 45).97 A wide range of aryl-substituted vinyl
oxetanes proved to be amenable to this transformation except
for 1- or 2-naphthyl substituted substrates which resulted in
low yield or enantioselectivity. It was also found that aliphatic-
substituted vinyloxetanes were not suitable substrates, leading
to poor yields and ee values. Moreover, the significance of this
method was demonstrated by the transformation of 1,3-dioxane
into a triol bearing a tetrasubstituted stereocenter.
4.3.4. Vinylethylene carbonates (VECs). Vinylethylene car-
bonates (VECs) have been employed as alternatives to vinyl
epoxides for the generation of a zwitterionic p-allyl Pd species
Scheme 44 Pd-Catalyzed [3+2] cycloaddition of vinyl epoxides with a- through decarboxylation which may be regarded as 1,3-dipoles
N-heterocyclic acrylates, gem-difluoroalkenes, azadienes and substituted or 1,5-dipoles. Palladium-catalyzed decarboxylative annulations
propiolates.
of VCEs to construct diverse functionalised heterocycles have

high performance. For the annulations of a-pyrimidine-

substituted acrylates to synthesize pyrimidine isonucleoside
analogs 196, palladium catalysts containing (R)-Segphos were
needed. In 2021, Zhao, Zheng and their co-workers showed that
[3+2] cycloaddition was also viable with gem-difluoroalkenes
197 employing (R)-BINAP as the chiral ligand, providing enan-
tioenriched 2,2-difluorotetrahydrofurans 198 with good to
excellent enantioselectivity but with low diastereoselectivity
(Scheme 44).94 In 2018, Zhao and co-workers demonstrated
that Pd–SIPHOX complexes were effective catalysts for enantio-
selective [5+4] cycloaddition between vinyl epoxides 183 and Scheme 45 Pd-Catalyzed asymmetric cycloaddition of vinyl oxetanes
azadienes 98 for the direct synthesis of nine-membered with azadienes and formaldehyde.

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allowed convenient access to a series of chiral 3,3 0 -

tetrahydrofuryl spirooxindoles 210 with high performance
(Scheme 47).100 Further studies by Zhang’s group showed that
3-nitrochromone 211 could serve as reactive partners in
palladium-catalyzed allylic cycloaddition in the presence of
Scheme 46 Pd-Catalyzed asymmetric [5+4] annulation of VECs with
the chiral phosphoramidite ligand, offering an efficient
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ortho-quinone methides.
route for the selective synthesis of furanochromanones
bearing versatile nitro-groups and multi-stereocenters with
been summarized independently by the groups of Zhang, Li excellent enantioselectivities and moderate diastereoselectiv-
and Ullah.98 Thus, we will present the recent advances in the ities (Scheme 47).101 Using (R)-BINAP in combination with
asymmetric decarboxylative annulation of VECs which were not Al(OiPr)3 as a cocatalyst, an asymmetric palladium-catalyzed
covered in previous reviews. [3+2] cycloaddition reaction of VECs with pyrrolidone-derived
Employing VECs as 1,5-dipole precursors, a highly enantio- enones 214 for the direct synthesis of enantioenriched tetra-
selective [5+4] annulation with ortho-quinone methides 106 hydrofuranyl spiroketolactams 215, was established by the
using a Pd catalytic system derived from (R)-BINAP was dis- group of Li in 2021 (Scheme 47).102 DFT calculations revealed
covered by Guo et al. in 2020, providing a novel and useful that the electronic interactions between substrates and cocata-
method for the construction of various nine-membered benzo- lysts played a crucial role in affecting the difference in relative
dioxonines 208 (Scheme 46).99 It was found that increasing the Gibbs free energies. Zhao, Zheng and co-workers found that
electron-withdrawing groups in the phenyl moiety of VECs had gem-difluoroalkenes 197 could also undergo mechanistically
an adverse effect on enantioselectivity. Moreover, silica gel was related annulation to give easy access to enantioenriched 2,2-
found to efficiently promote the rearrangement of the nine- difluorotetrahydrofurans 198 and 199 with excellent enantios-
membered ring product to a seven-membered ring isomer. electivity, albeit with low diastereoselectivity (Scheme 47).95
Soon afterwards, Hu, Wang and co-workers disclosed Another example of this type of annulation was the formation
a palladium-catalyzed asymmetric [3+2] cycloaddition of indoloquinazolinone derivatives from the reaction of
reaction between methyleneindolinones 209 and VECs that VECs with tryptanthrin-based ketones 216 using a chiral

Scheme 47 Pd-Catalyzed asymmetric [5+4] annulation of VECs with methyleneindolinones, 3-nitrochromone, gem-difluoroalkenes, pyrrolidone-
derived enones, tryptanthrin-based ketones and N-sulfonyl imines.

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spiroketal-based diphosphine ligand, a transformation pio- Cope rearrangement is an exothermic process, and the
neered by Zhang, Zou and co-workers (Scheme 47).103 Notably, presence of a cis-configuration of the enyne unit is indispen-
preliminary biological studies revealed that some of the indo- sable for the rearrangement.
loquinazolinone derivatives exhibited promising antibacterial 4.3.5. 2-Alkylidenetrimethylene carbonates. By using palla-
activity. Recently, the group of Chen and Lan found that the dium complexes generated in situ from [Pd2(dba)3]CHCl3 and
[3+2] annulations could also be achieved using cyclic N-sulfonyl (R)-Segphos as a catalyst, an asymmetric [4+2] cycloaddition
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imines 218 as dipolarophiles, which provided a direct entry to between 2-methylidenetrimethylene carbonate 222 and
chiral tetrahydrofuran scaffolds bearing three vicinal and qua- alkenes derived from pyrazolones, indandione, or barbiturate
ternary stereocenters (Scheme 47).104 DFT calculations revealed for versatile access to pharmacologically interesting chiral
that the enantio-determining step of this transformation tetrahydropyran-fused spirocyclic scaffolds, was realized by
was the annulation process, and methanol was involved in the group of Guo in 2020 (Scheme 49).106 The application of
stabilizing the reactive zwitterionic p-allylpalladium via H-bond this methodology was underscored by further constructing
interactions. other useful chiral spiropyrazolone and spiroindandione deri-
By combining Pd-catalyzed asymmetric [3+2] annulation vatives. Subsequent studies by Chen’s group showed that
with enyne-Cope rearrangement, a novel and useful method cooperative catalytic systems combining tertiary amine and
for the construction of chiral 9-membered endocyclic allenes palladium complexes were effective for asymmetric [4+3]
221 with high efficiency and enantioselectivity using a chiral P,S
ligand through the reaction of enynes 220 with VECs, was
established by Lu et al. in 2022 (Scheme 48).105 Control experi-
ments revealed that both chiral BINOL and diphenyl ethyl
scaffolds were indispensable for achieving high reactivity and
enantioselectivity. The reaction tolerated a wide range of sub-
stituents such as aryl and heteroaryl groups, both in enynes and
in vinyl carbonates, although it failed with non-aryl substituted
cyclic and noncyclic enynes. The mechanism of the process
involves the initial generation of a Pd–p-allyl zwitterionic inter-
mediate Int-I through Pd-catalyzed ring opening of VECs,
followed by an oxa-Michael addition to enynes to form inter-
mediate Int-II, which underwent intramolecular branch-
selective allylic alkylation to provide the key cis-intermediate
Int-III. Then, heat-accelerated enyne-Cope rearrangement of
complex Int-III would lead to the production of the desired
product via Int-IV, thus completing central-to-axial chirality
transfer. Moreover, DFT calculations indicated that the enyne-

Scheme 49 Pd-Catalyzed asymmetric annulation of 2-

Scheme 48 Palladium-catalyzed asymmetric annulation followed by methylidenetrimethylene carbonate with alkenes, MBH carbonates and
Cope rearrangement. gem-difluoroalkyl ketones.

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annulations between isatin-derived Morita–Baylis–Hillman

(MBH) carbonates 229 and vinyl carbonate 222, allowing con-
venient access to a series of spirooxindoles incorporating an
oxepane motif (Scheme 49).107 This transformation involved
the formation of N-allylic ylides Int-B and p-allylpalladium oxa-
1,4-dipole species Int-A. Recently, a remarkable example of this
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type of annulation was the formation of chiral 1,3-dioxanes 232

bearing tetrasubstituted gem-difluoroalkyl stereogenic centers,
which was achieved by the reaction of substituted-2-alkylide-
netrimethylene carbonates 222 with gem-difluoroalkyl ketones
231 using a novel phosphoramidite ligand containing a bulky
1,1-dinaphthylmethanamino moiety, a transformation described
by Shibata (Scheme 49).108 Besides cyclic and linear difluoroalkyl
ketones, pentafluoroethylketone, an a,a-difluorinated b-ketoester,
and a b-ketosulfone were also amenable to this transformation.
4.3.6. 4-Vinyl-1,3-dioxan-2-ones. In 2020, Hou, Ding and
co-workers reported the synthesis of tetrahydropyrans bearing three
continuous chiral centers through asymmetric decarboxylative
[4+2] dipolar cycloaddition between 4-vinyl-1,3-dioxan-2-ones 233
and a,b-disubstituted nitroalkenes 120 enabled by a newly devel-
oped benzylic substituted P,N-ligand (Scheme 50).109 This reaction
was proposed to proceed via a stepwise mechanism involving
Michael addition and subsequent intramolecular allylic alkylation.
Subsequent studies by Chen’s group showed that MBH carbonates
were also reactive partners in this decarboxylative [4+2] cycloaddi-
tion with vinyl carbonate 233, providing a simple route to enantio- Scheme 51 Pd-Catalyzed enantioselective [3+2] cycloaddition reactions
merically enriched spirooxindoles containing an oxepane motif, employing VMCCs as C,C- and C,O dipolar precursors.
although with moderate yields. Key to the success of the reaction
was the use of cooperative catalytic systems. (Scheme 50).107
4.3.7. Vinyl methylene cyclic carbonates (VMCCs). Employ- this transformation, oxidative addition of VMCCs to Pd(0)
ing vinyl methylene cyclic carbonates (VMCCs) 237 as C,C- could generate a vinyl-substituted Pd-oxyallyl species Int-A after
dipolar precursors for vinyl-oxyallyl-Pd species, enantioselective the release of CO2, which was in equilibrium with Pd-
inverse electron demand [3+2] cycloaddition reactions with oxypentadienyl species Int-B through charge delocalization,
nitroalkenes 120 providing easy access to chiral cyclopenta- enhancing the electron density at C1 position to achieve inverse
nones 238 with up to three contiguous stereocenters was electron demand cycloaddition. Notably, the rationally
demonstrated by Zi and co-workers in 2021 (Scheme 51).110 In designed hydrogen-bond-donating ligand (FeUrPhos) played a
vital role in controlling the stereochemistry of this transforma-
tion. Later, a catalytic system consisting of Pd2(dba)3 and the
(R)-H8-BINOL-derived bis-phosphite ligand was shown to be
effective for enantioselective [3+2] cycloaddition reactions of
VMCCs as C,O-dipolar precursors with isocyanates 151 and
trifluoromethyl aryl ketones 240, giving a variety of multi-
substituted and enantioenriched oxazolidinones and 1,3-
dioxolanes, which was established by the group of Cao and
Xu in 2022 (Scheme 51).111 The significance of this method was
further demonstrated by the efficient synthesis of a-chiral
tetrasubstituted aminoketone.
4.3.8. Allyl carbonates. In 2016, You’s group reported their
studies on palladium-catalyzed asymmetric intermolecular
allylic dearomatization of indoles 243 via a formal [4+2]
cycloaddition reaction with allyl carbonates 242 bearing a
nucleophilic alcohol side-chain (Scheme 52).112 With appropri-
ate choice of three kinds of chiral phosphoramidite ligands, a
Scheme 50 Pd-Catalyzed asymmetric decarboxylative [4+2] cycloaddi-
wide array of structurally diverse bridged indolines 244 were
tion of 4-vinyl-1,3-dioxan-2-ones with a,b-disubstituted nitroalkenes and efficiently synthesized with high levels of enantiocontrol. Later,
MBH carbonates. a preliminary exploration of asymmetric [4+2] cycloaddition

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cycloaddition reactions, palladium catalysts containing chiral

P,P-ligand (S)-Cl-MeO-BIPHEP were needed.

5. Cyclization based on Heck reaction

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5.1. Cyclization via single Heck reaction

In 2016, the group of Kitamura and Fukuyama accomplished
the enantioselective total synthesis of (+)-hinckdentine A, in
which palladium-catalyzed asymmetric dearomative Heck reac-
tion of N-acyl indole 248 was used as a key step, allowing for the
efficient construction of a polycyclic indoline intermediate 249
bearing a crucial tetrasubstituted stereogenic carbon center
(Scheme 53).115 Notably, the reactions with Feringa’s phosphor-
amidite ligands provided the key indoline intermediate 249 in
98% yield with 86% ee. Two years later, an asymmetric dear-
omative Heck reaction of pyrrole derivatives 250 for rapid and
enantioselective assembly of highly functionalized pyrroline
derivatives 251 with a quaternary stereogenic center was pre-
sented by You and co-workers (Scheme 53).116 It should be
noted that substituents on the pyrrole ring imparted significant
effects on the enantioselectivity. For instance, the pyrrole rings
bearing two methyl, ethyl or isopropyl groups all performed
well, while low ee was achieved with the dibenzyl-substituted or
trisubstituted substrates. An interesting method for the effi-
cient synthesis of sila-bicyclo[3.2.1]octanes 253 bearing both C-
and Si-stereocenters via an asymmetric Heck desymmetrization
of silacyclopentenes with aryl halides was demonstrated by

Scheme 52 Pd-Catalyzed enantioselective cycloaddition reaction of allyl

carbonates with indoles, para-quinone methides and benzofuran-derived
azadienes.

reaction of allyl carbonates bearing a nucleophilic alcohol side-

chain with p-QM 124 was presented by Yao, Lin and co-workers
in 2017, in which optically active 2-oxaspiro[5.5]undeca-7,10-
dien-9-ones 245 were produced with 74% ee employing (S)-
BINAP as a chiral ligand (Scheme 52).113 This reaction involved
the formation of the key zwitterionic p-allylpalladium inter-
mediate Int-B through the oxidative addition of allylic carbo-
nate to Pd(0) species leading to the formation of the p-
allylpalladium intermediate Int-A with tert-butoxy anions as
well as CO2, followed by deprotonation of the hydroxyl group
with the assistance of the liberated tert-butoxy anion. In sub-
sequent studies, the same group showed that benzofuran-
derived azadienes 98 could act as reactive partners in
palladium-catalyzed asymmetric [4+4] and [2+4] cycloadditions
enabled by different chiral ligands (Scheme 52).114 In the
presence of chiral palladium catalysts ligated by chiral P,N-
ligand (S,Rp)-PPFA, various benzofuro[2,3-c][1,5]oxazocines 246
could be prepared efficiently with excellent enantioselectivities
via [4+4] cycloaddition reactions. For the facile synthesis of Scheme 53 Palladium-catalyzed asymmetric intramolecular Heck reac-
tetrahydropyran-fused spirocyclic compounds 247 via [2+4] tion of aryl halides.

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Zhao, Li and co-workers in 2022 (Scheme 53).117 Key to the palladium catalysts ligated by the (Rp,Rp)-(S)-Mandyphos
success of the reaction is matching the absolute configuration ligand, the enantioenriched (S)-259 was obtained in 42% yield
of the chiral oxazoline skeleton on FOXAP ligands. Moreover, with 86% ee and the unreactive starting substrate (S)-258 was
replacing the substituent on silicon with hydrogen prevents the recovered with 88% ee. The author also illustrated additional
intramolecular Heck reaction. The authors performed DFT examples with the (Sp,Sp)-(R)-Mandyphos ligand. Notably, sev-
calculations and revealed that a ligand-controlled kinetic eral control experiments indicated there were obvious match/
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stereo-differentiation during the migratory insertion was mismatch phenomena in this kinetic resolution process.
responsible for the high enantioselectivity.
Besides aryl halides, aryl triflates are also used as
5.2. Cyclization via double Heck reaction
electrophiles. In 2012, Oestreich et al. found that hemilabile
BINAP(O) as a chiral ligand was more efficient than BINAP in The palladium-catalyzed double Heck reaction, a particularly
enantioselective desymmetrizing Mizoroki–Heck cyclizations appealing transformation applied to the stereo- and regio-
(Scheme 54).118 Using a Pd-(S)-BINAP(O) system, an aryl triflate selective synthesis of diverse cyclic scaffolds, also provides an
with an E configuration of both alkenes, and an oxygen donor- ideal platform to introduce alkenyl group for further functio-
free substrate 254, performed well, and produced the target nalization. In 2013, the Zhou group presented an asymmetric
product 255 in 94% yield with 36% ee. It was found that using inter–intramolecular domino cyclization of o-vinylaryl triflates
an oxygen donor substrate 256 in this catalytic system pro- 260 with cyclic alkenes 261 for rapid access to fused carbo- and
ceeded without any issue, providing the desired product 257 in heterocycles with excellent enantioselectivity (Scheme 55).120
69% yield with 44% ee. The authors thought that BINAP(O) Cyclic alkenes, including 2,3-dihydrofuran, cyclopentene, cyclo-
could act as either a bi- or mono-dentate ligand owing to its heptene, cyclooctene and N-Boc-2-pyrroline, were all coupled
hemilabile nature. efficiently with o-vinylaryl triflates to offer the desired tricyclic
The use of unique diarylmethyl tert-butyl carbonates as products, whereas the reaction with cyclohexene failed because
secondary benzyl electrophiles was first reported by the group
of Miura and Hirano (Scheme 54).119 It was proposed that this
transformation proceeded through a Pd/chiral Mandyphos
ligand-mediated kinetic resolution. In the presence of chiral

Scheme 54 Pd-Catalyzed asymmetric intramolecular Heck reaction

employing aryl triflates or diarylmethyl tert-butyl carbonates as
electrophiles. Scheme 55 Pd-Catalyzed asymmetric double Heck reaction.

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of its half-chair conformation interfering with its binding and

insertion. Noteworthily, the authors applied this transforma-
tion to an asymmetric synthesis of ()-martinellic acid, which
is a primary ingredient in folk eye medicine in South America.
Additionally, this strategy was also suitable for norbornene and
related bicyclic alkenes 264, and the corresponding tricyclic
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products 265 were obtained as single stereoisomers. DFT

calculations revealed that the first alkene-insertion step favored
the cis pathway. Later, an asymmetric intra-intramolecular
domino cyclization to construct the key tetracyclic core of
lycorane alkaloids was accomplished by Lete and co-workers
(Scheme 55).121 The use of PMP as a base and CH3CN as a
solvent was essential to ensure the completion of this reaction.
Although, low to moderate enantioselectivities were achieved in
most cases, a single crystallization could significantly improve
the optical purity of products. In addition to inter–intra-
molecular or intra–intramolecular double Heck cyclization,
the intra–intermolecular double Heck reaction of arenediazo-
nium salts 268 with simple alkenes 164 was also established by
Kong, Chen and colleagues in 2019, providing an immediate
access to functionalized dihydrobenzofurans 269 bearing all-
carbon quaternary centers (Scheme 55).122 The exact role of
Ag2CO3 is unclear, but it is essential for both reactivity and
enantioselectivity. It may play a dual role, acting as a Lewis acid
to promote the oxidative addition and as a chloride scavenger.
The authors also applied this reaction to the efficient synthesis
of an enantiopure tricyclic dihydrobenzofuran framework,
Scheme 56 Pd-Catalyzed asymmetric reductive Heck reaction employ-
which is commonly found in a large number of natural ing tertiary amine as a hydride donor.
products.

5.3. Cyclization via Heck cascade reaction hydride donors, an impressive synthesis of 1H-pyrazolo[5,1-
Palladium-catalyzed Heck cascade reactions, involving intra- a]isoindol-2(8H)-ones 275 containing a quaternary stereocenter
molecular carbopalladation of alkene to generate alkylpalla- via Pd-catalyzed intramolecular asymmetric hydroarylation
dium intermediates, terminated by a variety of trapping agents, enabled by their developed axially chiral cyclic diphosphine
have been widely employed to generate rings of various sizes ligand was established by Fu et al. in 2018 (Scheme 56).125
and are a key step in achieving molecular complexity in the In addition, formates and formic acid have been routinely
total synthesis of complex molecules. used as hydride donors. In 2015, Jia and co-workers described
5.3.1. Reductive Heck reaction. In 2015, Zhou’s group an asymmetric dearomative arylation of indoles 276 via Pd-
realized an asymmetric reductive Heck reaction of aryl halides catalyzed intramolecular reductive Heck reactions in the
270, especially bromides and chlorides, directly to produce 3- presence of HCO2Na that yielded optically active tetracyclic
arylindanones 271 with high performance (Scheme 56).123 A indolines 277 bearing C2-quaternary stereogenic centers
1 : 3 molar combination of benzoic acid and iPr2NEt was used to (Scheme 57).126 Various substituents on the indole and 2-
in situ generate an alkylammonium salt, which could ionize the bromobenzoyl moiety were compatible with this transforma-
arylpalladium halide in ethylene glycol through hydrogen tion, except for substitution at C3 of the bromobenzoyl moiety
bonding. Meanwhile, the excess iPr2NEt was used as a hydride that disfavored the reaction because of significant steric hin-
donor to form a palladium hydride intermediate. The reaction drance. Using a combination of an amine with formic acid
tolerated a wide range of various b-aryl rings of chalcones, as a hydride source, the same group further achieved success
although the presence of a b-cyclopropyl group and other alkyl in the asymmetric dearomative alkenylation of indoles,
groups led to moderate to even low enantioselectivity. Later, providing access to tetracyclic indolines 279 bearing C2-
Minnaard, de Vries and co-workers further extended the scope alkenylated quaternary stereocenters with high enantioselectiv-
to 2-iodo chalcones 272, using TADDOL-based phosphorami- ities (Scheme 57).127 Similarly, employing HCO2H/DIPEA as the
dites as a chiral ligand and N-methyl dicyclohexylamine as a hydride source, the asymmetric reductive Heck reaction of (Z)-
hydride donor (Scheme 56).124 It was notable that this reaction 1-iodo-1,6-dienes 280 enabled by a Pd(0)/(S)-p-MeO-BnPHOX
does not require the addition of stoichiometric benzoic acid, catalytic system was established by Tong et al., providing access
and diethyl carbonate was vital for the chemo- and enantio- to a series of chiral quaternary tetrahydropyridines 281
selectivity. Employing N,N-dimethylbenzylamine/TFA as the (Scheme 57).128 Notably, a wide range of substituted alkene

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Scheme 57 Pd-Catalyzed asymmetric reductive Heck reaction employ-

ing formates or formic acid as hydride donors. Scheme 58 Pd-Catalyzed asymmetric reductive Heck reaction employ-
ing HCOONa as a hydride donor.

moieties, including 1,1-disubstituted, 1,1,2-trisubstituted as elimination. Additionally, deuterium-labelling experiments

well as 1,2-disubstituted alkenes, were all tolerated in this suggested that sodium formate served as the hydride donor
process. Changing the N-linkage to O-linkage exhibited similar in the reaction. Two years later, Dai et al. reported an effective
reactivity, whereas a substrate with a C(CO2Me)2-linkage failed catalytic system consisting of Pd(OAc)2, (R)-BINAP and
to produce the chiral product because of the lack of the CuTC for the asymmetric dearomatization of indoles 286
corresponding assistant coordination. via a decarbonylative Heck-type reaction of thioesters to con-
In 2018, Zhang’s group utilized their newly developed chiral struct chiral indolines 287 with an aza-quaternary stereocenter
sulfinamide phosphine ligand (N-Me-XuPhos) which could be (Scheme 58).131 The reaction outcome was significantly influ-
obtained from readily available starting materials through a enced by the hydride source, palladium catalyst and CuTC
one-pot synthesis approach, to accomplish the first example of which were indispensable, and phosphine ligands were essen-
highly enantioselective intramolecular hydroarylation of allyl tial for the decarbonylation of thioesters.
aryl ethers 282 with HCOONa, allowing efficient stereoselective Impressively, using diboron–water as a hydride source, Zhu
syntheses of optically active 2,3-dihydrobenzofurans 283 bear- and co-workers realized the synthesis of enantioenriched 3,3-
ing a quaternary stereocenter (Scheme 58).129 Strikingly, this disubstituted oxindoles 289 via Pd-catalyzed intramolecular
method was applied to straightforwardly prepare a series asymmetric reductive Heck reaction of N-aryl acrylamides 288
of enantioenriched CB2 receptor agonists with high perfor- in 2017 (Scheme 59).132 It was found that (S)-tBuPHOX not only
mance. Using DCO2Na as a D atom source under standard determined the enantioselectivity of the reaction, but also
reaction conditions, high-level D-labelled compounds were switched the reaction pathway to afford reductive Heck pro-
easily obtained, which indicated that the source of hydride ducts rather than carboborylation products. The structure of
was sodium formate. In subsequent studies, palladium- the base played an important role in the selective conversion
catalyzed asymmetric intramolecular reductive Heck employing with DABCO being optimal. Control experiments suggested
HCOONa as a hydride source was successfully applied to the that both H2O and the diboron reagent were crucial for the
desymmetrization of cyclopentenes 284, obtaining a series of reaction and H2O served as the hydride source for this trans-
chiral bicyclo[3.2.1]octanes 285 bearing quaternary and tertiary formation. Moreover, the reaction process could also be
carbon stereocenters, which was disclosed by Yao, Lin and co- extended to oxindoles bearing a CH2D substituents using D2O
workers in 2019 (Scheme 58).130 (S)-Difluorphos was found and Cat2B2. A possible catalytic cycle is outlined Scheme 29.
to be vital for controlling the enantioselectivity and stabilizing The oxidative addition of aryl triflate 288 to a Pd complex and
the alkyl-palladium intermediate Int-I to prevent b-hydride subsequent intramolecular carbopalladation generated the

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Scheme 60 Pd-Catalyzed asymmetric Heck/Suzuki coupling reaction.

carbon quaternary centers was accomplished by Kong, Chen

and co-workers in 2019 (Scheme 60).135 Notably, this transfor-
mation occurred under open-flask conditions, and Ag2CO3 was
Scheme 59 Pd-Catalyzed asymmetric reductive Heck reaction employ-
indispensable perhaps because it may act as a base to promote
ing diboron–water as a hydride donor.
the transformation and as a chloride scavenger to establish a
cationic pathway. Besides dihydrobenzofuran, the reaction
process could also be extended to bis-dihydrobenzofuran when
cationic C(sp3)–PdII intermediate Int-I, which was converted to (4-vinylphenyl)boronic acid was used as the coupling partner
a PdII hydroxo complex Int-II in the presence of H2O. Alkyl-PdII- through successive cyclization/Heck and cyclization/Suzuki
boron complex Int-III, which was provided via transmetallation coupling processes.
of intermediate Int-II with the diboron reagent, reacted with a In 2021, Chen et al. presented the synthesis of 3-benzylic or
molecule of H2O to produce complex Int-IV. The subsequent s- allylic substituted isoindolinones 296 via tandem Heck/Suzuki
bond metathesis and reductive elimination delivered the coupling of aryl bromides 295 with aryl/alkenyl boronic acids
desired product. (Scheme 61).136 The addition of Pd(cod)(CH2TMS)2 significantly
5.3.2. Heck/Suzuki coupling. In 2019, Zhang and co-
workers showed that Pd-N-Me-XuPhos complexes were effective
catalysts for the enantioselective dicarbofunctionalization of
unactivated alkenes 282 through the tandem Heck/Suzuki
coupling reaction.133 Various chiral benzene-fused cyclic com-
pounds 290, including dihydrobenzofurans, indolines, chro-
manes, and indanes bearing a quaternary stereocenter were
obtained with excellent enantioselectivities, employing alkyl-,
alkenyl- or arylboronic acids 9 as coupling partners
(Scheme 60). Moreover, this reaction was also applicable to
the late-stage modification of biologically complex molecules,
such as peptides, piperitol, CB2 receptor agonists, etc. A pair of
enantiomers could be easily furnished by simply changing the
order of the steps for the coupling sequence. In their further
studies, the catalytic system with Pd(0) and N-Me-XuPhos
worked equally well for the asymmetric Heck/Suzuki domino
reaction of various 2-iodobenzamides 291 with aryl/alkenyl
borates 292, resulting in the synthesis of a series of chiral
disubstituted dihydroisoquinolinones 293 with an all-carbon
chiral quaternary center (Scheme 60).134
An asymmetric Heck/Suzuki coupling reaction of arylboro-
nic acids with arenediazonium salts 294 instead of aryl iodides
to provide an efficient route to dihydrobenzofurans with all- Scheme 61 Pd-Catalyzed asymmetric Heck/Suzuki coupling reaction.

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promoted this transformation probably due to the rapid for- the addition of CuI could completely inhibit this transforma-
mation of the reactive Pd(0) species. The practicality of this tion. Various terminal alkynes reacted efficiently, whereas
reaction was also validated in the convenient synthesis of the reacting with internal alkynes such as 3-phenylpropiolic
precursor of the biologically active phosphoinositide 3- acid and 2-methyl-4-phenylbut-3-yn-2-ol, resulted in either
kinasedelta (PI3K-delta) inhibitor. Soon afterwards, Zhao, lower yield or lower ee, perhaps due to the poor solubility
Han and co-workers reported their studies on the asymmetric of the acid and the background reactions. Using CuI as a
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intramolecular cascade cyclization of aryl halides with arylboro- co-catalyst, the Heck/Sonogashira reaction between CF3-
nic acids with BINOL-based phosphoramidite as the chiral substituted o-iodoacrylanilides 300 and terminal alkynes to
ligand to provide access to optically active indoline derivatives furnish a wide range of chiral oxindoles 301 containing tri-
297 (Scheme 61).137 Copper salt was found to be crucial for this fluoromethylated quaternary stereogenic centers was estab-
transformation with Cu2O being optimal, as it acted as a co- lished by Lu, Ge and co-workers in 2020 (Scheme 62).139 In
catalyst in the reaction. It is worth noting that both the steric addition to CF3-substituted o-iodoacrylanilides, this asym-
hindrance effect of arylboronic acids and the electronic effect metric reaction was also applied to other alkyl- or aryl-
on the indole ring could significantly affect the enantioselec- substituted o-iodocrylanilides. The authors also showcased an
tivity of the reaction. enantioselective synthesis of EGIS-12 which was a potent and
5.3.3. Heck/Sonogashira coupling. In 2017, Jia et al. rea- selective antagonist for 5-HT6/7 receptors, utilizing this Pd/Cu-
lized an asymmetric dearomative arylalkynylation of N- catalyzed Heck/Sonogashira coupling sequence. Almost
substituted indoles 276 with alkynes 298 through a Heck/ simultaneously, Zhang’s group showed the high efficiency of
Sonogashira coupling sequence employing BINOL-based phos- their developed catalytic system consisting of a Pd complex and
phoramidite as the chiral ligand, giving a wide range of chiral Sadphos for the intramolecular Heck/Sonogashira reactions of
2,3-disubstituted indolines 299 bearing vicinal quaternary and alkenes with terminal alkynes, which provided a variety of
tertiary stereocenters (Scheme 62).138 It was notable that benzene-fused heterocycles bearing a propargyl-substituted
all-carbon quaternary stereocenter (Scheme 62).140 Various N-
allyl carboxamide were successfully employed, furnishing
3,4-dihydroisoquinolin-1(2H)-one derivatives 302 with high
enantioselectivities using Ming-Phos as a chiral ligand. Besides,
the use of Xu-Phos instead of Ming-Phos successfully facilitated
the construction of 3,3-disubstituted dihydrobenzofuran, indo-
line, and chromane derivatives 303. Notably, this reaction
required no external copper as a co-catalyst.
Attractive examples involving the Heck/decarboxylative cou-
pling process of aryl iodides 276 with internal alkynes 304 like
alkynyl carboxylic acids as coupling partners was demonstrated
by Zhao, Han and co-workers in 2021, thus rendering the
construction of diverse 2,3-disubstituted indolines 305 bearing
vicinal tertiary and quaternary stereocenters (Scheme 63).141
Notably, the phosphoramidite ligand bearing an electron-
donating group was more efficient than the one with an
electron-withdrawing group. Aryl and hetero-aromatic alkynyl
carboxylic acids participated well in the reaction, while alkyl-
substituted alkynyl carboxylic acid failed to give the anticipated
product. Later, a preliminary exploration of enantioselective
domino Heck/decarboxylative alkynylation reactions to make
chiral 3,3-disubstituted oxindole and spirooxindole was pre-
sented by Guo, Wang and co-workers in 2022.142

Scheme 62 Pd-Catalyzed asymmetric Heck/Sonogashira coupling Scheme 63 Pd-Catalyzed asymmetric Heck/decarboxylative coupling
reaction. process of aryl iodides with internal alkynes.

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5.3.4. Heck/iodination reaction. A perfect atom economy to forge numerous bis-heterocycles with high performance
method for synthesizing a series of optically active 2,3- using the Pd(0)–Xu-Phos catalyst system developed by
dihydrobenzofuran, indolines and chromane derivatives bear- Zhang’s group (Scheme 65). In Lautens’ work, in addition to
ing an alkyl iodide and one all-carbon quaternary stereocenter o-alkynylanilines, the enantioselective consecutive cyclization/
via palladium-catalyzed carboiodination of olefin-tethered aryl coupling process was also applied to other nucleophile-
iodides 282 employing their developed Xu-Phos as the chiral appended alkynes, including sulfonamides, amides, carboxylic
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ligand was established by Zhang, Li and colleagues in 2019 acids, imines, ureas, and phenols, producing various dihydro-
(Scheme 64).143 It was found that substituting the methyl group benzofuran-, indoline-, indane-, and chroman-substituted
on the alkene with other groups failed to yield the target heterocycles.145 Using nucleophile-appended alkenes as cou-
racemic products with a series of known phosphine ligands, pling partners exhibited similar reactivity but with poor dia-
so the authors employed a pair of enantiomers of Xu-Phos to stereocontrol. In their studies, Zhang and co-workers found
carry out this reaction. Of note, the addition of K2CO3 as an that 2-substituted indole rather than 3-substituted indole was
additive could ensure the completion of the reaction, perhaps obtained when a terminal alkyne substrate was used, which
by accelerating the reductive elimination. The authors also demonstrated that C–H activation or dearomatization of indole
carried out DFT calculations to investigate the mechanism of was less likely to participate in this reaction.146 It was proposed
this transformation, which revealed that the alkene insertion that the terminal alkyne substrate may undergo the Heck/
process was the rate-determining step and responsible for Sonogashira reaction and subsequent cyclization to furnish
enantioselectivity and high reactivity. Two years later, Pd(0)- the 2-substituted indole.
catalyzed asymmetric carboiodination of (Z)-1-iodo-1,6-dienes 5.3.6. Heck/borylation reaction. A practical Pd(0)/phosphi-
307 enabled by a chiral FerroPhos ligand was disclosed by nooxazoline (PHOX) catalyst system was employed to construct
Tong, Liu and co-workers, which required [Et3NH]+[BF4] as an chiral tetrahydropyridines bearing an all carbon quaternary
H-bond donor under a toluene/water/(CH2OH)2 biphasic sys- center via asymmetric vinylborylation of (Z)-1-iodo-dienes 280
tem (Scheme 64).144 Besides carboiodination, more challenging and B2pin2, as described by Tong’s group in 2017
asymmetric carbobromination of (Z)-1-bromo-1,6-dienes 309 (Scheme 66).147 It was found that electronically modified PHOX
was also accomplished with the use of an electron-richer ligands played a crucial role in enhancing reaction efficiency
FerroPhos ligand. Notably, mechanistic studies indicated that and stereoselectivity, among which electron-poor (S)-p-CF3-
H-bonding interaction between [Et3NH]+[BF4] and halogen– BnPHOX was proven to be superior. The authors also showed
PdII–C(sp3) bonds in the key intermediate Int-I was of utmost that owing to the coordination with the metal center, the
importance to reduce the energy barrier of C(sp3)–halogen linkage between vinyl iodide and the alkene was essential for
reductive elimination. the reaction performances with the NN-linkage being optimal.
5.3.5. Heck/Cacchi reaction. In 2021, Lautens and Zhang Besides 1,1-disubstituted alkenes, 1,2-disubstituted alkenes
independently reported a tandem Heck/Cacchi reaction containing hydrogen susceptible to b-elimination were also
between inactivated alkenes and alkyne-tethered nucleophiles well-tolerated. Control experiments revealed that the transme-
tallation step occurred prior to alkene insertion. Using a pre-

Scheme 64 Pd-Catalyzed asymmetric Heck/iodination reaction. Scheme 65 Pd-Catalyzed asymmetric Heck/Cacchi reaction.

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Scheme 66 Pd-Catalyzed asymmetric Heck/borylation reaction.

Scheme 67 Pd-Catalyzed asymmetric Heck/borylation reaction.

activated sp2–sp3 mixed-boron reagent 317, Lautens, Jia and 323 (Scheme 68).151 The authors found that aryl triflate was a
co-workers presented an enantioselective dearomative arylbor- suitable substrate whereas much diminished ee was achieved
ylation of indoles to produce chiral boron-containing using aryl iodide, suggesting that this enantioselective
tetracyclic indolines 177 in the presence of a new BINOL- transformation may take place via a cationic pathway. Kinetic
based chiral phosphoramidite ligand in 2019 (Scheme 66).148 isotope studies revealed that the C–H activation step might not
Notably, both the steric influence at the halide and function- be a turnover-limiting step in this domino process. The
alities para to the amide tether could affect enantioselectivities synthetic potential of this reaction was illustrated with a
of this transformation. concise enantioselective synthesis of (+)-esermethole. In the
Recently, Zhang et al. disclosed a palladium-catalyzed presence of chiral palladium catalysts ligated by (S)-
enantioselective Heck/borylation reaction of alkene-tethered difluorphos, the same group further reported their studies on
aryl iodides with the use of Xu-Phos to deliver various 2,3- the synthesis of the bisoxindoles 324 via enantioselective
dihydrobenzofuranyl boronic esters 319 with high performance double Heck/C–H functionalization of acetanilide with
(Scheme 67).149 Additionally, this asymmetric transformation oxadiazole.152 Several control experiments were performed,
could also be applied to the synthesis of chromane, indane and which suggested that the second stereocenter-generating step
indoline containing boronic ester. A series of enantiospecific was likely catalyst-controlled.
transformations of carbon–boron bonds were presented, By means of high-throughput screening of TADDOL-derived
including oxidation, coupling, etc. Soon afterwards, Lu, Ge phosphoramidites, an asymmetric Heck/C–H activation
and co-workers extended the Heck/borylation reaction to sequence between aryl iodide 282 and hexamethyldisilane 325
both nonactivated and activated alkenes (Scheme 67).150 A
catalytic system consisting of a Pd complex, (R)-Segphos or
(R)-Difluorphos was shown to be effective for the carboboryla-
tion of N-allyl-o-iodobenzamides 291, yielding a series of
chiral 3,4-dihydroisoquinolinones 320. As for activated alkenes,
o-iodoacrylanilides 300 could smoothly react with B2pin2 to
afford various borylated oxindoles 321 using chiral palladium
catalysts ligated by two different Josiphos-type ligands. The
synthetic utility of the reaction process was illustrated with the
synthesis of enantioenriched Roche anticancer agent (S)-
RO4999200.
5.3.7. Heck/C–H functionalization reaction. In 2015, Zhu
and co-workers established the first enantioselective domino
Heck/intermolecular C–H bond functionalization between N-
aryl acrylamides 282 and azoles 322 using tBuPHOX as a chiral Scheme 68 Pd-Catalyzed asymmetric Heck/C–H functionalization
ligand, efficiently creating various 3,3-disubstituted oxindoles reaction.

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to synthesize disilylated 2.3-dihydrobenzofunan derivatives 326

was disclosed by Xu et al. in 2021, albeit with low to moderate
enantioselectivity (Scheme 69).153 Key to the success of this
reaction was the disilylation of spirocyclic palladapentanecycles
with a suitable chiral ligand. Recently, Zhang’s group estab- Scheme 70 Mode for the Heck/CO insertion reaction.
lished a robust palladium/Xu-Phos catalytic system for a tan-
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dem Heck/remote C–H bond alkylation, providing facile access

to highly enantioenriched 5,4- and 5,5-spirocycles 327 bearing substituted quaternary carbon centers (Scheme 71).155 In addi-
an all-carbon quaternary stereocenter, which were generated tion to dihydrobenzofurans, dihydrobenzopyran was also effi-
through the reductive elimination of spiropalladacycles ciently obtained in 85% yield albeit with lower ee. Notably, the
(Scheme 69).154 Using the same enantiomer of a chiral catalyst, use of heteroaromatic boronic acids was essential to prevent
a novel position of the phenyl ring-dependent enantiodivergent the competitive formation of the methoxylated product.
synthesis could efficiently yield both enantiomers of the pro- Subsequent studies by the group of Zhu and Luo showed
duct. Notably, through experiments, the authors demonstrated that diverse chiral spirooxindole g- and d-lactones/lactams 331
for the first time that the steps of C(sp2)–H activation, alkene and 332 were efficiently created through an asymmetric Heck/
insertion, and C–I reductive elimination were reversible. carbonylative lactonization and lactamization sequence using
5.3.8. Heck/CO insertion reaction. The Heck/CO insertion an alkenyl substrate containing an embedded oxygen- or
reaction, known as carbonylative Heck reactions, proceeds nitrogen-based nucleophile under balloon pressure of CO
through oxidative addition and migratory insertion to generate (Scheme 72).156 As for the reaction of substrates containing
a s-alkylpalladium intermediate, which undergoes the inser- an intramolecular nitrogen nucleophile, nitrogen protecting
tion of CO which is prone to further nucleophilic attack, thus groups played an important role in facilitating the reaction.
resulting in the formation of various carbonylated compounds For instance, nitrogen protecting groups such as Bn, Boc, Ts,
(Scheme 70). Gaseous carbon monoxide and formate esters are and Bz were unable to deliver the desired lactams, whereas aryl-
usually used as the desirable source of CO. protected substrates could react smoothly. Moreover, the syn-
In 2018, Correia and colleagues reported an unprecedented thetic application of this method was demonstrated by the
enantioselective Heck/carbonylative cyclization of arenediazo- efficient synthesis of the natural product coixspirolactam A
nium salts 294 in the presence of MeOH or boronic acids as as well as an effective CRTH2 receptor antagonist. In their
nucleophilic regents and a chiral N,N ligand under atmo- further studies, under atmospheric pressure of CO, they
spheric pressure of CO, providing various enantioenriched described an enantioselective 7-exo-trig cyclocarbopalladation-
functionalized dihydrobenzofurans bearing ketone- or ester- initiated carbonylation cascade reaction to synthesize a series
of chiral seven-membered dibenzolactams 336 and 337 in
2021 (Scheme 72).157 Employing alcohols/phenols or anilines
as nucleophiles, various 7-acetate- or 7-acetamide-substituted
dibenzo[b,d]azepin-6-ones bearing a thermodynamically
controlled stereogenic axis were efficiently created with high
performance. Recently, an unprecedented tandem Heck/carbo-
nylation/aminocarbonylation in the presence of CO using alky-
lamine as the nucleophile to deliver enantiomerenriched
heterocyclic a-ketoamides 339 was further accomplished by
the same group (Scheme 72).158 Various alkylamines, including
primary amines and cyclic amines, were compatible for this
transformation, whereas sterically hindered tBuNH2 was an
unsuitable substrate and the use of secondary amines resulted

Scheme 69 Pd-Catalyzed asymmetric Heck/C–H functionalization Scheme 71 Pd-Catalyzed enantioselective Heck/carbonylative cycliza-
reaction. tion of arenediazonium salts.

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Scheme 73 Pd-Catalyzed enantioselective Heck/CO insertion reaction

of N-aryl acrylamides and various nucleophiles.

b-carbonyl-substituted all-carbon quaternary stereocenters

via an enantioselective Heck/CO insertion reaction of N-aryl
acrylamides 300 and various nucleophiles, including arylboro-
nic acids, anilines, and alcohols (Scheme 73).159 Notably, the
domino Heck esterification reaction of N-aryl acrylamides and
alcohols served as the key step in the straightforward synthesis
of HPI alkaloids, such as (+)-physostigmine, (+)-physovenine,
and (+)-phenserine, and dimeric HPI alkaloids (+)-folicanthine.
Soon afterwards, Yao and Lin extended the asymmetric
tandem Heck/carbonylation to construct chiral bicyclo[3.2.1]-
octanes via the desymmetrization of cyclopentenes under atmo-
spheric pressure of CO (Scheme 74).160 Various alcohols,
including primary alcohols, cyclic and acyclic secondary alco-
hols, all performed well as nucleophilic reagents. Besides,

Scheme 72 Pd-Catalyzed enantioselective Heck/carbonylative cycliza-

tion of aryl iodides.

in the formation of a significant amount of monocarbonylated

by-products. Besides five-membered heterocycle substituted a-
ketoamides, this method could also be extended to construct a
seven-membered heterocycle containing a-ketoamides 340,
such as 5,7-dihydro-6H-dibenzo[b,d]azepin-6-ones containing
a thermodynamically stabilized stereogenic biaryl axis. The
potential application of this transformation was illustrated with
the synthesis of (+)-physovenine derivatives.
In the presence of chiral palladium catalysts ligated by Xida-
Phos, a novel monodentate phosphoramidite ligand developed
by their group, Guan et al. established a straightforward route Scheme 74 Pd-Catalyzed asymmetric tandem Heck/carbonylation
to produce a diverse array of enantioenriched oxindoles with desymmetrization of cyclopentenes.

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phenyl formate could react with Na2CO3 to generate CO

in situ, along with phenol as a nucleophile.
5.3.9. Heck/isocyanide insertion. Isocyanides, being iso-
electronic with CO, easily undergo migratory insertion with s-
alkylpalladium to generate alkylimidoyl-PdII complexes, which
can be intercepted by several nucleophiles. In 2016, Zhu et al.
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realized an unprecedented palladium-catalyzed Heck/isocya-

nide insertion/methoxylation process using Duanphos as a
chiral ligand, yielding chiral imidates 356 with up to 75% ee
(Scheme 77).163 This asymmetric domino imidoylative Heck
Scheme 75 Pd-Catalyzed enantioselective domino Heck carbonylation
reaction was further applied to synthesize a known precursor
reaction of o-iodoacrylanilides with terminal alkynes and water.
of ()-physovenine, ()-esermethole, and ()-physostigmine.
Later, a preliminary exploration of an enantioselective Heck/
phenols and alkylamines were also employed as efficient versa- isocyanide insertion reaction combined with triple bond activa-
tile coupling reagents. tion and a final nucleophilic attack of N-(2-iodophenyl)-N-
Recently, in the presence of o-iodoacrylanilides 300 and methylacrylamide 300 with 2-(2-phenylethynyl)phenyl isocya-
under balloon pressure of CO, the group of Ding and Wang nides 353 was presented by Sharma’s group in 2021, affording
further extended the scope of nucleophilic coupling reagents to 2,3-difunctionalized indoles with 73% ee (Scheme 77).164
terminal alkynes or water, producing a broad variety of 2- 5.3.10. Heck/carbene insertion. A catalytic system consist-
oxindole-bearing chiral ynones 349 and carboxylic acids 350 ing of a Pd complex and a chiral BINOL-based phosphoramidite
having a quaternary stereocenter (Scheme 75).161 Using term- ligand was shown to be effective for the dearomative arylvinyla-
inal alkynes as a coupling partner, it was found that the N- tion reaction of indoles 276 with N-arylsulfonylhydrazones 357
protecting group of o-iodoacrylanilide was indispensable with as carbene precursors via a tandem Heck/carbene insertion
NTs being the optimal choice. A Pd/Cu catalytic system was process, yielding 3-vinylindolines 358 bearing vicinal quatern-
effective for the reaction between N-(2-iodophenyl)acrylamides ary and tertiary carbon stereocenters with moderate ee values,
and phenylacetylenes, whereas Cu salt as a co-catalyst was not as discovered by the group of Jia in 2019 (Scheme 78).165 It
necessary for the transformation when water was used as a was found that employing (2,4,6-triisopropylphenyl)sulfonyl-
nucleophile. hydrazone as a coupling partner resulted in the best result
In addition to gaseous carbon monoxide, formate esters with 79% ee. A single crystallization in a mixture of pentane/
with low cost and low toxicity were also considered a desirable CH2Cl2 could significantly improve the optical purity of
source of CO. In 2019, Zhang’s group reported that the products.
Pd-(R)-Segphos complex was an effective catalyst for the 5.3.11. Heck/ring-opening reaction. In 2021, Murakami
enantioselective synthesis of quaternary 3,4-dihydroisoquin- and Liu realized an enantioselective diarylation of inactivated
olines 352 via Heck carbonylation reactions employing formate olefins through a tandem Heck/ring-opening reaction between
esters as the source of CO (Scheme 76).162 Of note, the exact diverse aryl halide-tethered alkenes 282 and benzocyclobute-
role of H2O is not clear; perhaps it could accelerate the nols 359 in the presence of the Xu-Phos ligand developed
reduction of PdII to Pd0. Various amides, heteroarene-derived by Zhang’s group, allowing expedient access to chiral
amides and benzamides bearing different substituents on the
allyl groups were all compatible with this transformation.
However, the unprotected benzamide and phenyl-protected
benzamide failed to yield the desired product. The significance
of this method was demonstrated by the synthesis of the
Minalrestat analogue. Moreover, the authors thought that

Scheme 76 Pd-Catalyzed enantioselective Heck carbonylation reactions

employing formate esters as the source of CO. Scheme 77 Pd-Catalyzed enantioselective Heck/isocyanide insertion.

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Scheme 78 Pd-Catalyzed enantioselective tandem Heck/carbene

insertion. Scheme 80 Pd-Catalyzed enantioselective tandem Heck/ring expansion
reaction.

2,3-dihydrobenzofurans bearing a quaternary stereocenter in a

highly enantioselective manner (Scheme 79).166 The authors the key spiro p-allyl palladium intermediate formed by a Heck-
suggested that this process involved a PdII complex Int-II as the type insertion into the furan diene, could coordinate with the
key intermediate, which was generated through a ring opening hydroxyl group and undergo a 1,2-alkyl shift via back-side of the
reaction via regioselective b-carbon elimination of intermediate palladium atom, thus leading to the formation of the desired
Int-I. Soon afterwards, the scope of this asymmetric cascade products.
reaction was extended to a broad range of cyclobutanol deriva- 5.3.13. Heck/Tsuji–Trost reaction. In 2016, Han and co-
tives 361 to construct more challenging C(sp3)–C(sp3) bonds, workers described the first enantioselective heteroannulation
established by Chen, Zhang, and co-workers (Scheme 79).167 of 1,3-dienes 129 with functionally substituted aryl iodides 365
Notably, both C- or O-tethered alkenes and oxetanol or cyclo- and 366 that yielded chiral indolines 367 and isochromans 368
butanols were suitable substrates, yielding the corresponding with up to 87% ee (Scheme 81).169 Key to the success of the
products containing a chiral 2,3-dihydrobenzofuran or indane reaction was the use of a BINOL-derived phosphoramidite
skeleton with excellent enantioselectivities. ligand bearing electron-withdrawing substituents. It was
5.3.12. Heck/ring expansion reaction. In the presence of found that employing 2-iodoanilines as nucleophiles, the
palladium catalysts containing chiral phosphoramidite ligands, position of the substituent on the benzene had a significant
a novel Heck/ring expansion reaction of furylcyclobutanols 363 effect on both yield and enantioselectivity, with 5-substituted
involving a spiro p-allyl palladium intermediate to produce five 2-iodoanilines performing better than substituents at the
examples of dispirooxindoles 364 bearing two quaternary car- 4-position. Notably, AcCl/Et3N was used to obtain more stable
bon centers with good enantioselectivities, was accomplished
by the group of Yin in 2016 (Scheme 80).168 It was proposed that

Scheme 79 Pd-Catalyzed enantioselective tandem Heck/ring-opening

reaction. Scheme 81 Pd-Catalyzed enantioselective Heck/Tsuji–Trost reactions.

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Ac-protected indolines. Besides o-iodolanilines, o-iodobenzyl

alcohols were also well-tolerated in this transformation.
A catalytic system consisting of a Pd complex and PC-Phos
was shown to be effective in asymmetric Heck/Tsuji–Trost
reactions of amino tethered 1,3-cyclohexadienes 369 with aryl
and alkenyl halides 370, allowing convenient access to various
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functionalized chiral hexahydroindoles 371 with excellent ee

values, which was discovered by Zhang, Xiao and Li for the first
time in 2022 (Scheme 81).170 A variety of substituted aryl
iodides or alkenyl bromides and N-Ts-protected amino 1,3-
Scheme 83 Pd-Catalyzed enantioselective domino allylstannylation/
cyclohexadienes were compatible for this transformation,
Heck reaction.
except for 1,3-cyclohexadienes bearing a methyl group on the
ring and larger cyclic dienes, mainly due to steric effects or
molecular conformation factors. Additionally, this transforma- donating groups performed well, whereas those with electron-
tion served as a key step in the concise synthesis of ()-a- withdrawing groups, such as nitro and carbomethoxy groups,
lycorane. DFT calculations suggested that the enantioselectivity only yielded the corresponding products with 0–33% yields.
of the reaction was determined by the difference in distortion The use of 5- and 6-substituted substrates resulted in the
energies of two migration insertion transition states. formation of a significant amount of Stille coupling product.
Very recently, employing their newly developed electron-rich In this process, the key intermediate Int-I formed through
ligand TY-Phos, Zhang’s group accomplished a highly enantio- oxidative addition, could activate the aldehyde, making it
selective Pd-catalyzed Heck/Tsuji–Trost reaction between o- susceptible to further allylstannylation.
bromophenols 372 and 1,3-dienes 129, opening a new avenue 5.3.15. Allylboration/Heck reaction. In 2015, Sutherland
for the synthesis of chiral substituted 2,3-dihydrobenzofurans et al. reported an enantioselective synthesis of 3-methyl-
373 with high performance (Scheme 82).171 It was found that eneindan-1-ols 380 with up to 96% ee through a one-pot
various aryl and alkyl-chain-substituted 1,3-dienes were amen- allylboration/Heck reaction of 2-bromobenzaldehydes 377
able to this transformation while 1,3-cyclohexadiene led to (Scheme 84).173 Using chiral binaphthyl-derived phosphoric
lower yield and ee values. Notably, the electronic nature of acid, benzaldehydes bearing electron-rich or electron-
the substituent on the aromatic ring of o-bromophenol had a deficient substituents all reacted smoothly with allylboronic
significant influence on the efficiency of the reaction, where acid pinacol ester, resulting in higher ee values when electron-
electron-withdrawing groups resulted in lower reactivity. More- deficient groups were present. The reaction was proposed to
over, application of this methodology was underscored by the
efficient asymmetric synthesis of optically pure natural pro-
ducts (R)-tremetone and fomannoxin.
5.3.14. Allylstannylation/Heck reaction. In the presence of
chiral palladium catalysts ligated by ClickFerrophos ligands
developed by their group, Fukuzawa and co-workers presented
an asymmetric domino allylstannylation/Heck reaction of o-
formylaryl triflate 374 with allyltributyltin 375, resulting in
chiral 3-methylene-indan-1-ols 376 with good to excellent enan-
tioselectivities (Scheme 83).172 Notably, both the electronic
nature and positions of the substituent on the aromatic ring
of o-formylphenyl triflates appeared to have significant effects
on the results. 4-Substituted substrates bearing electron-

Scheme 82 Pd-Catalyzed Heck/Tsuji–Trost reactions between o- Scheme 84 Pd-Catalyzed enantioselective domino allylboration/Heck
bromophenols and 1,3-dienes. reaction.

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proceed via allylboration of 2-bromobenzaldehydes, generating

homoallylic alcohols, followed by an intramolecular Heck reac-
tion. The authors further extended this cascade reaction to the
asymmetric synthesis of 3-methyleneindanes 383 bearing a
tertiary alcohol center, employing (S)-3,3 0 -Br2-BINOL as a chiral
Brønsted acid and 2-bromoaryl ketones 381 as substrates
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(Scheme 84).174 Of note, both chiral indanols 383 and their

endo-alkene isomers 384 were obtained in this transformation.

5.4. Cyclization via aza-Heck reaction

Employing a SPINOL-derived P,N-ligand system, the first highly
enantioselective Narasaka–Heck cyclization of oxime esters
with trisubstituted alkenes 386, providing expedient access to Scheme 86 Pd-Catalyzed enantioselective aza-Heck cyclizations of N-
dihydropyrroles 387 containing tetrasubstituted nitrogen- (tosyloxy)carbamates.
bearing stereocenters with up to 90% ee, was accomplished
by the group of Bower in 2016 (Scheme 85).175 Three key steps
including N–O oxidative addition, imino-palladation and b- phosphoramidates as effective ligands (Scheme 86).177 In the
hydride elimination were incorporated in this transformation. presence of chiral palladium catalysts ligated by (S)-SIPHOS-PE
Of note, the geometry of alkene was of utmost importance for (L94), chiral pyrrolidines were efficiently synthesized via highly
enantioinduction of this reaction, as the (Z)-isomer afforded enantioselective 5-exo aza-Heck cyclizations. Besides, 6-exo aza-
the corresponding product with a low ee value. Soon after- Heck cyclizations of alkenyl N-(tosyloxy)carbamates to form
wards, in the presence of a chiral bidentate phosphine ligand enantioenriched piperidines also proceeded smoothly with
(Synphos), Zhu’s group presented the iminoarylation of alkenes palladium catalysts containing the less sterically demanding
via palladium-catalyzed enantioselective Narasaka–Heck/C–H ligand (S)-SIPHOS-IP (L95). The significance of this method was
alkylation (Scheme 85).176 Oxime esters with different aryl illustrated with the synthesis of the precursor of the natural
and alkyl substituents reacted smoothly with oxadiazoles product caulophyllumine B.
bearing diverse substituents, affording a variety of chiral
2,5,5-trisubstituted dihydropyrroles 389. Based on control
experiments, the authors thought that a cationic Heck-like 6. Cyclization initiated by
manifold and a radical pathway occurred concurrently, which heteropalladation of double bonds
made it more difficult to control the enantioselectivity in this
transformation. 6.1. Via aminopalladation of double bonds
In addition to oxime esters, alkenyl carbamates have also 6.1.1. Cyclization via cross-coupling with aryl halides. In
been identified as suitable N–O donors in aza-Heck reactions. 2012, Wolfe and co-workers presented the first catalytic asym-
In 2019, Brown’s group reported enantioselective aza-Heck metric alkene carboamination reaction of N-allyl urea deriva-
cyclizations of N-(tosyloxy)carbamates 390 for the direct synth- tives 392 with aryl or alkenyl halides 370 using a Pd-(S)-Siphos-
esis of challenging N-heterocycles using SPINOL-derived PE catalyst system that offered an efficient route for the
selective synthesis of enantiomerically enriched imidazolidin-
2-ones 393 (Scheme 87).178 It should be noted that addition of
2.0 equiv. of water played a crucial role in improving and
reproducing enantioselectivities. As for N-allyl urea derivatives,
the p-substituent on the N-aryl moiety bearing strong electron-
withdrawing groups could efficiently improve the level of
asymmetric induction, and monosubstituted alkenes proved
to be amenable to this transformation, whereas substrates
bearing disubstituted alkenes led to worse results or were
unreactive. Additionally, deuterium-labelling experiments sug-
gested that this transformation proceeded with syn-
aminopalladation of the alkene. The authors further demon-
strated that the Pd-(S)-Siphos-PE catalyst system was also
effective in the enantioselective synthesis of tetrahydroquino-
lines 397, tetrahydroquinoxalines 398, and tetrahydroisoquino-
lines 399 through alkene carboamination reactions of aniline
derivatives bearing pendant alkenes or 2-allylbenzylamines
with aryl or alkenyl halides (Scheme 87).179 Subsequent studies
Scheme 85 Pd-Catalyzed enantioselective Narasaka–Heck cyclizations. by the same group in 2016 showed that N-allylsulfamides 400

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involving an amine nucleophile coupled with an alkene bearing

a pendant electrophile were also investigated by the group of
Wolfe in 2015 (Scheme 88).182 In the presence of chiral palla-
dium catalysts ligated by (S)-tert-butylPHOX, a series of 2-
allylphenyltriflate derivatives 263 reacted with aliphatic amines
347, yielding enantioenriched 2-aminoindanes 404 with up to
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98% ee. Cyclic, linear and a-branched 11 amines were well-

tolerated, while acyclic secondary amines resulted in lower
yield and selectivity. Aryl triflates bearing electron-rich groups
proceeded in modest yields, possibly due to the reduced
electrophilicity of the cationic Pd-intermediate. Moreover,
deuterium-labelling experiments indicated that this reaction
proceeded with anti-addition to the alkene.

Scheme 87 Alkene carboamination reactions involving the coupling of

an alkene bearing a tethered nucleophile with an exogenous electrophile.

could react as nitrogen nucleophiles in alkene carboamination

reactions with aryl or alkenyl bromides, providing chiral cyclic
sulfamides with up to 90% ee (Scheme 87).180 In 2021, an
efficient synthesis of various substituted isoxazolidines and
pyrrolidines with up to 97% ee via an enantioselective carboa-
mination reaction between N-Boc-O-homoallyl-hydroxylamines
and N-Boc-pent-4-enylamines with aryl or alkenyl bromides was
accomplished by Zhang, Liu and co-workers (Scheme 87).181 A
variety of aryl, heteroaryl, cyclic and linear alkenyl bromides
were smoothly reacted with N-Boc-O-homoallyl-hydroxylamine
bromides. This transformation also offered isoxazolidine bear-
ing an aza-quaternary carbon stereocenter with moderate ee.
Besides, C-linked alkenyl carbamates were further shown to be
suitable substrates for this reaction. Noteworthily, the ortho-
effect of the newly designed Xu-Phos ligand bearing an ortho-
OiPr group played a crucial role in facilitating the reaction and
controlling the enantioselectivity.
In addition to alkene carboamination reactions involving
the coupling of an alkene bearing a tethered nucleophile with
an exogenous electrophile such as an aryl halide, reactions Scheme 88 Pd-Catalyzed intermolecular carboamination.

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In 2016, Mazet’s group reported their preliminary studies on

a Pd-catalyzed intermolecular syn-carboamination of dihydro-
furans 405, providing a simple route to chiral furoindolines 407
with moderate ee values using Buchwald-type biarylphosphines
(Scheme 88).183 Later, mechanistic studies by the same group
proposed a catalytic cycle for this transformation.184 The reac-
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tion commenced with a classical oxidative addition of aryl

bromide, followed by ligand exchange using alkoxide bases to
form the palladium alkoxo intermediate Int-II. Subsequent
deprotonation of the neighboring nucleophile generated zwit-
terionic intermediate Int-III, which coordinated with dihydro-
furan. The following syn-heteropalladation and reductive
elimination steps generated the final product. In 2020, employ-
ing their two newly modified N-Me-Xiang-Phos as chiral
ligands, a highly enantioselective intermolecular carbohetero-
functionalization of 2,3-dihydrofurans was accomplished by
Scheme 90 Pd-Catalyzed enantio- and diastereo-selective synthesis of
Zhang’s group (Scheme 88).185 Various substituted N-(2- pyrrolidine derivatives.
bromophenyl)-p-tolylsulfonamide derivatives reacted smoothly,
yielding chiral fused furoindolines with high performance. It
was found that nitrogen protecting groups on aniline were extended the scope to a tethered amine as the intramolecular
crucial for the reaction, because the protective groups on the nucleophile for enantio- and diastereo-selective synthesis
nitrogen atom with Ms, Ns, Boc, Cbz and Bz were not tolerated. of pyrrolidine derivatives 418 in 2012 (Scheme 90).187c This
Besides, a series of substituted 2-bromophenol derivatives were transformation proceeded via an initial intramolecular nucleo-
also suitable substrates, yielding optically active tetrahydrofur- palladation of the tethered protected amine, generating a
obenzofurans 410 with up to 99% ee. quinone methide intermediate Int-II, trapped by various
In the presence of chiral palladium catalysts ligated by exogenous nucleophiles. Notably, the geometry of alkene
Josiphos, the reaction was also viable with norbornadiene or was crucial to facilitate the reaction, and the use of predomi-
norbornene. A two step synthesis of the pseudo-C2-symmetrical nantly Z-alkene could afford the desired product with satisfac-
and pseudo-meso bis-indoline scaffolds from norbornadiene tory results. Various exogenous nucleophiles, including
411 and 412 and substituted o-iodo-anilines 413 was presented N-protected indoles, substituted furans and indolizines were
by Gansäuer et al. in 2019 (Scheme 89).186 This process involved suitable for this transformation, whereas the scope of intra-
the initial desymmetrizing carboamination with high enantios- molecular nucleophiles was limited to substrates with a pen-
electivity and catalyst-controlled regiodivergent catalysis of the dant tosylamide.
substituted norbornene. In 2012, Zhang and co-workers demonstrated an asymmetric
6.1.2. Aza-Wacker process. Based on their previous studies aerobic aza-Wacker cyclization catalyzed by the Pd/tBu-Pyrox
using a pendant alcohol nucleophile,187a,b the group of Sigman complex, under atmospheric pressure of O2, providing expedi-
ent access to various chiral isoindolinones 420 bearing tetra-
substituted carbon stereocenters (Scheme 91).188 Substrates

Scheme 89 Pd-Catalyzed carboamination in enantioselective desymme-

trization and regiodivergent catalysis. Scheme 91 Pd-Catalyzed asymmetric aerobic aza-Wacker cyclization.

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containing different terminal substituents on the olefin moiety

were well-tolerated, except for ethyl or a 2-phenylethyl group
which resulted in the formation of a mixture of olefin isomers.
The potential application of the reaction process was illustrated
with the synthesis of an analogue of the renin inhibitor. In
subsequent studies, the same group demonstrated that the
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Pd-tBu-Pyrox system was also an effective catalyst for the aza-

Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubsti-
tuted olefins 421, providing an expedient route to optically
active pyrazolines bearing chiral tetrasubstituted carbon stereo-
centers (Scheme 91).189 The reaction could also be applied to
generate two vicinal stereocenters on the double bonds with
high selectivity. Notably, when two alkyl substituents on the
outer carbon atom of the olefin were both larger than a methyl
group, b-hydride elimination proceeded more readily at the
substituent which was cis to the intranucleophilic group. Sub-
strates bearing two linear alkyl substituents on the outer carbon
atom of the olefin, one of which was a methyl group, showed a
higher propensity for methylene side participation in b-hydride
elimination. Moreover, switching the configuration of the
olefin allowed for the efficiently preparation of both diaster-
eomers. Mechanistic studies confirmed that the reaction pro-
ceeded via a syn-aminopalladation process.
Utilizing the commercially available chiral X-type ligand
(1S)-(+)-camphorsulfonic acid, Rainey et al. in 2017 applied
the Pd(II)-catalyzed intramolecular oxidative amination reaction
to produce chiral indoline products 425 with up to 45% ee
(Scheme 92).190 The authors thought that Pd[(+)-CSA]2 gener- Scheme 92 Pd(II)-Catalyzed intramolecular oxidative amination reaction.
ated from acid-promoted ligand exchange was the active
catalyst in this transformation, and the addition of the sodium
salt of (+)-camphorsulfonic acid [(+)-NaCSA] was proved to method was further demonstrated by the concise and divergent
improve the yield. DFT calculations revealed that this transfor- asymmetric total synthesis of (+)-mesembrane and (+)-crinane.
mation proceeded via a trans-aminopalladation mechanism. The palladium(II)-catalyzed enantioselective aza-Wacker-type
Subsequent studies by Sasai and Takenaka showed that using oxidation/cyclization cascade reaction has emerged as a pro-
oxone as an oxidant, alkenyl sulfonamides could serve as mising strategy for directly generating complex polycyclic pro-
suitable substrates in an enantioselective aza-Wacker-type reac- ducts, which serve as core structural elements in the
tion catalyzed by the Pd-SPRIX complex, yielding various het- construction of natural alkaloids. In the presence of chiral
erocycles, including morpholines, piperazines, piperidines, palladium catalysts ligated by a chiral tBu-QUOX ligand and a
and their benzo-fused derivatives, with up to 80% ee chiral phosphoric acid, a series of chiral 6,5-bicyclic azahetero-
(Scheme 92).191 Control experiments revealed that this trans- cycles 431 were efficiently synthesized through an asymmetric
formation proceeded through the Wacker-type mechanism oxidative tandem cyclization of N-(2,2-disubstituted hex-5-en-1-
rather than oxidative allylic amination via activation of an yl)acrylamides 430, as disclosed by Gong et al. in 2014
allylic C–H bond. (Scheme 93).193 It was found that the electronic features of
An unprecedented catalytic enantioselective desymmetrizing substituents on the phenyl group of cinnamamide had a
aza-Wacker reaction of prochiral 3,3-disubstituted cyclohexa- significant effect, while the substitution pattern exerted a
1,4-dienes 428 with a newly developed Pd(CPA)2(MeCN)2 marginal effect on the stereoselectivity. Kinetic studies sug-
catalyst, a pyrox ligand, and molecular oxygen, was realized gested that the synergistic effect between the chiral ligand and
by the group of Zhu in 2018, offering versatile access to various Brønsted acid was vital in this enantioselective catalysis. The
enantioenriched cis-3a-substituted tetrahydroindoles 429 facile synthesis of chiral 5,5-bicyclic azaheterocycles 433 via
(Scheme 92).192 Different C3a-aromatic and C3a-unsubstituted enantioselective oxidative cascade cyclization of alkene-
substrates participated smoothly with excellent ee values, while tethered aliphatic acrylamides 432 was presented by Yang’s
slightly reduced enantiomeric excess values were obtained group in 2017 (Scheme 93), employing a catalytic system of
using substrates with an alkyl group at the C3a position. It Pd(TFA)2/(S,S)-diPh-pyrox.194 It was notable that substrates with
was notable that a strong cooperative effect between the CPA gem disubstituents could lead to better results than those
and the pyrox ligand played a crucial role in improving both without backbone substitution or monosubstitution. Both
yield and ee values. Additionally, the significance of this experimental and theoretical mechanistic studies suggested

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Scheme 94 Pd(II)-Catalyzed enantioselective oxidative cyclization of

aromatic nitrogen-containing dienes.

Scheme 95 Pd(II)-Catalyzed asymmetric aminohydroxylation between

1,3-dienes and N-tosyl-2-aminophenols.

pyridine bis(oxazoline) ligand and thymoquinone as the oxi-

dant. Notably, N-tosyl-2-aminophenol derivatives bearing a
Scheme 93 Pd(II)-Catalyzed enantioselective aza-Wacker-type oxida-
tion/cyclization cascade reaction.
strong electron-withdrawing group at the 4-position required
molecular oxygen as the oxidant. This cascade process was a
highly reliable transformation as it was used to generate a key
intermediate for the synthesis of a prostaglandin D2 receptor
that the reaction proceeded through an anti-aminopalladation
antagonist.
pathway. Soon afterwards, the same group showed that the
A catalytic system consisting of a Pd complex and quinoline–
palladium/(+)-sparteine complex was an effective catalyst for
oxazoline chiral ligands was shown to be effective for the
the enantioselective oxidative cyclization of 2-allyl-acrylanilide
intramolecular oxidative aminoarylation of alkenes, providing
434 to forge the basic 6/5/5-fused ring skeleton 435, which was a
expedient access to chiral indolines 277 containing a quatern-
key building block for the synthesis of (+)-mitomycin K, a
ary stereogenic center, as discovered by the group of Liu
representative of G series mitomycins (Scheme 65).195 With
(Scheme 96).198 Using Ag2CO3 as the oxidant, various
10 mol% Pd(TFA)2, 40 mol% (+)-sparteine, 3 Å MS (100 mg), and
O2 (1 atm) in toluene, the desired 6/5/5-fused ring skeleton was
obtained in 78% yield with 83% ee. Later, in the presence of
novel chiral cinchona alkaloid oxazoline ligands, the synthesis
of chiral dihydroindole nitrogen-containing polycyclic com-
pounds 437 via PdII-catalyzed aza-Wacker oxidation tandem
cyclization of aromatic nitrogen-containing dienes was also
established by He’s group (Scheme 94).196
A straightforward and efficient route for synthesizing chiral
3,4-dihydro-2H-1,4-benzoxazines 438 was described by Gong,
Han and co-workers in 2018, which involved asymmetric
aminohydroxylation between 1,3-dienes 129 and N-tosyl-2-
aminophenols 64 (Scheme 95).197 This reaction proceeded
via an aminopalladation followed by an asymmetric intra- Scheme 96 Pd(II)-Catalyzed asymmetric intramolecular oxidative ami-
molecular allylation cascade process, employing a chiral noarylation of alkenes.

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substituents on anilines or double bonds and substrates bear-

ing a 3-aminodibenzofuran moiety were well-tolerated in this
transformation, whereas a substrate with a pyridyl moiety failed
to produce the product perhaps duo to its strong coordination
to the palladium catalyst. Deuterium-labelling and kinetic
isotope studies suggested that the reaction proceeded through
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cis-aminopalladation and phenylglyoxylic acid was essential to

facilitate the reaction and improve the enantioselectivity. The
authors proposed that this reaction involved the cis-
aminopalladation of alkene to generate Int-I, followed by C–H
activation to produce Int-II, which underwent reductive elim-
ination, furnishing the final product.
Utilizing N-fluorobenzenesulfonimide 440 as both an oxi-
dant and a source of nitrogen, an enantioselective palladium-
catalyzed diamination of alkenes was described by Michael and
co-workers in 2013 (Scheme 97).199 It was found that substrates
bearing carbamate protecting groups performed well, affording
high enantioselectivities albeit with lower yields compared to
amides. Geminal disubstitution on the backbone was essential
to obtain the desired products in good yields with high enan-
tioselectivity. Additionally, a single stereoisomer of the inter-
mediate alkylpalladium complex was isolated, which
demonstrated that aminopalladation served as the enantio-
determining step in this transformation.
In 2018, Liu’s group disclosed a novel asymmetric 6-endo
aminoacetoxylation in the presence of chiral palladium cata-
lysts ligated by a new designed pyridine–oxazoline (Pyox) ligand
and PhI(OAc)2 as the oxidant, providing straightforward access
to enantioenriched 3-acetoxy piperidines 443 (Scheme 98).200
Notably, a remarkable Thorpe–Ingold effect was observed in
this cyclization, as substrates without gem disubstituents
resulted in poor regioselectivity. The authors also found that
the Pyox ligand bearing a sterically bulky group at the C-6
position was vital to enhance the reactivity of this transforma-
tion. Deuterium-labelling experiments suggested that inter-
Scheme 98 Pd(II)-Catalyzed asymmetric palladium-catalyzed intra-
mediate Int-I was generated via the stereoselective trans- molecular oxidative amination of alkenes.
aminopalladation, followed by sequential oxidation and direct
reductive elimination of PdIV complex Int-II gave rise to the C–
OAc bond with stereoretention. Employing readily accessible
and stable CsOCF3 as a trifluoromethoxide source, asymmetric in terms of reactivity and enantioselectivity for the reaction.
PdII-catalyzed intramolecular aminotrifluoromethoxylation of Subsequent studies by their group showed that Et4NF3HF
unactivated alkenes that offered a series of b-substituted OCF3- could serve as a fluoride source in PdII-catalyzed aminofluor-
containing piperidines 444 was further realized by the same ination of unactivated alkenes using chiral quinoline-
group (Scheme 98).201 The authors also underlined the impor- oxazolines (Quox) as ligands, offering a simple route to enan-
tance of incorporating a sterically bulky group into Pyox ligands tiomerically enriched b-fluoropiperidines 445 (Scheme 98).202
Notably, it was found that Et4NF3HF was vital for the enantio-
selective control, and the addition of CsOCF3 also helped in
improving the ee value of products. They further applied
the Pd-Pyox ligand catalytic system to the azidation of unac-
tivated alkenes using 1-azido-1,2-benziodoxol-3(1H)-one 446
as an electrophilic azidating reagent, providing a wide
array of 3-N3-substituted piperidines 447 with high efficiency
(Scheme 98).203 It should be noted that employing the Quox
ligand, substrates bearing gem-diaryl groups or no substituent
also proceeded smoothly. Mechanistic studies indicated that
Scheme 97 Pd(II)-Catalyzed asymmetric diamination of alkenes. this transformation proceeded through a sequential process,

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Scheme 99 Pd(II)-Catalyzed diastereoselective and enantioselective

domino cyclization/cycloaddition reactions of alkenyl oximes.

Scheme 100 Pd(0)-Catalyzed carboalkoxylation, aryloxy-arylation and

carboetherification reactions of alkenes.
including an asymmetric trans-aminopalladation, oxidation
and direct reductive elimination of PdIV species.
In 2015, in the presence of a Pd(II)–(R)-Tol-SDP complex and
the substrate was essential to control the enantioselectivity.
triflic acid, diastereoselective and enantioselective domino
Later, employing their developed chiral monophosphorus
cyclization/cycloaddition reactions of alkenyl oximes 448 were
ligand, enantioselective palladium-catalyzed alkene aryloxyar-
achieved by the group of Takizawa, providing convenient access
ylation reactions were established by the group of Tang, allow-
to a series of polycyclic heterocycles 450 with four chiral
ing convenient access to a series of chiral heterocycles bearing
stereogenic centers with up to 70% ee (Scheme 99).204 HOTf
quaternary stereocenters, including 1,4-benzodioxanes, 1,4-
was found to be a crucial additive that promoted the domino
benzooxazines, and chromans (Scheme 100).206 It was notable
process effectively. The authors proposed a plausible reaction
that the chiral monophosphorus ligand with substituents at the
mechanism. The Pd complex coordinated with the alkenyl
2-position is vital for both the yield and enantioselectivity in
oxime to generate intermediate Int-I, which could undergo
this reaction. The authors also found that the chiral palladium
intramolecular nucleopalladation, giving rise to the cyclic inter-
catalyst was more effective for constructing benzo-fused six-
mediates Int-II and Int-III. The protonation of complex Int-II or
membered oxygen heterocycles, because the chiral benzofuran
Int-III with the assistance of HOTf resulted in the formation of
compound was afforded with low ee. The hypothesized mecha-
nitrone Int-IV, which underwent 1,3-dipolar cycloaddition with
nism for this transformation involved the oxidative addition of
449, yielding the domino product 450.
aryl bromine to the Pd complex and subsequent ligand
exchange using NaOtBu as a base to generate the key inter-
6.2. Via oxypalladation of double bonds mediate. The following syn-oxopalladation and reductive elim-
6.2.1. Cyclization via cross-coupling with aryl halides. In ination delivered the desired product. In subsequent studies,
2015, Wolfe and co-workers described the synthesis of enantio- Zhang, Zhao and co-workers presented an asymmetric car-
merically enriched 2-(arylmethyl)tetrahydrofuran derivatives boetherification of g,d-alkenyl oximes silyl ethers 455 with
452 through palladium-catalyzed alkene carboalkoxylation (hetero)aryl and alkenyl halides, providing a simple route to
reactions between g-hydroxyalkenes 451 and aryl bromides chiral 5,6-dihydro-4H-1,2-oxazines 456 (Scheme 100).207 Nota-
370 (Scheme 100).205 Key to the success of the reaction was bly, sluggish reactivity was observed when using g,d-
the use of a new TADDOL/2-arylcyclohexanol-derived chiral alkenyloxime as a substrate. In addition to g,d-alkenyl oximes
phosphite ligand, in which the structure of the phosphite silyl ethers, b,g-alkenyl oxime silyl ether were investigated next
alkoxy group played a vital role in asymmetric induction of this to obtain isooxazoline with moderate yield and ee. Almost
transformation. It was found that various aryl bromides served simultaneously, a highly enantioselective carboetherification
as suitable electrophiles whereas low yield and poor enantios- of alkenyl oximes 457 with either aryl or alkenyl halides utiliz-
electivity were achieved with the use of alkenyl bromide, and ing their developed Xiang-Phos as a chiral ligand to provide
substrates bearing internal alkenes were unreactive under these expedient access to chiral isoxazolines 458 with up to 97% ee,
conditions. Notably, gem-disubstitution at the C1 position of was established by Zhang’s group (Scheme 101).208 The

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Scheme 101 Pd(0)-Catalyzed enantioselective carboetherification of

alkenyl oximes with either aryl or alkenyl halides.

catalytic system with Pd2(dba)3 and the sterically bulky and

electron-rich (S,Rs)-N-Me-Xiang-Phos ligand was shown to be
effective for the synthesis of both 3,5-disubstituted and 3,5,5-
trisubstituted isoxazolines. In addition to aryl or alkenyl bro-
mides, various aryl chlorides were also compatible with this Scheme 103 Pd(II)-Catalyzed asymmetric Wacker-type cyclization of o-
transformation. The potential application of this method was trisubstituted 3-butenylphenols.
demonstrated by the enantioselective synthesis of the potent
firefly luciferase inhibitor.
Besides intramolecular oxypalladation of double bonds, a
novel intermolecular carboetherification of dihydrofurans 459 order to prevent the decomposition of p-benzoquinone. Both
with 2-bromophenols 372 to allow convenient access to a series (Z)-and (E)-olefins were well-tolerated, with (E)-isomers proving
of chiral fused tetrahydrofurobenzofurans 460 was disclosed by to be more effective in affording the target products with up to
Mazet and co-workers in 2016 (Scheme 102).209 The chiral bis- 92% ee. Later, the group of Tietze found that in the presence of
phosphine mono-oxide, which was generated in situ using a chiral palladium catalyst ligated by (S,S)-iPr-BOXAX, a chiral
Pd(OAc)2 in the presence of 40 mol% H2O, was essential to chroman 464 with a quaternary carbon stereogenic center could
promote the reaction and control the enantioselectivity. Var- be afforded with 499% ee via a Wacker-type cyclization of a
ious 2-bromophenols participated efficiently except for 2- methoxyphenolic compound (Scheme 103).211 The authors
bromo-3-methoxyphenol which had negative effects on both further used this highly reliable transformation as one of the
reactivity and enantioselectivity. Of note, substituted dihydro- key steps in total syntheses of various natural products, such as
furans, which are notoriously more difficult to engage in cross- secalonic acid E, dicerandrol C,212 blennolide H and
coupling reactions, also worked equally well. phomopsis-H76 A.213
6.2.2. Via Wacker process. In 2012, Zhang and co-workers An asymmetric dihydroxylation of 1,3-dienes 129 with cate-
reported Pd(II)-catalyzed asymmetric Wacker-type cycliza- chols 465 to provide a simple route to chiral 2-substituted 1,4-
tion of o-trisubstituted 3-butenylphenols 461 using a benzodioxanes 466 was realized by Gong, Han and co-workers
chelation-induced axially chiral biphenyl tetraoxazoline ligand, in 2019 (Scheme 104).214 This reaction was thought to proceed
giving readily access to chiral chroman derivatives 462 through a cascade Wacker-type hydroxypalladation/asymmetric
(Scheme 103).210 Notably, employing p-benzoquinone as an allylation process. It was found that the diphenyl substituents
oxidant, the reaction temperature should not exceed 60 1C in on the chiral pyridinebis(oxazoline) ligand were essential to
achieve high reactivity and enantioselectivity. Various (E)-1-aryl-
1,3-butadienes bearing electron-donating or -withdrawing sub-
stituents were amenable to this transformation, in which
substrates containing electron-donating groups led to higher
yield and enantioselectivity. Electron-withdrawing group-
substituted pyrocatechol resulted in low yield and moderate
ee values, whereas 2,3-dihydro-1H-indene-5,6-diol could react
smoothly with a number of dienes to give desired products with
high ee values. Additionally, the synthetic application of the
reaction process was illustrated by generating a key intermedi-
ate chiral alcohol for the synthesis of MKC-242 and WB4101.
Soon afterwards, employing their newly developed chiral
ligand, which was synthesized in two steps from (1S,2S)-1,2-
diphenylethane-1,2-diamine, an asymmetric iodoetherification
Scheme 102 Pd(0)-Catalyzed intermolecular carboetherification of di- of alkenes for the synthesis of nucleoside analogs 468 was
hydrofurans with 2-bromophenols. established by the group of Trost (Scheme 105).215 The reaction,

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Scheme 104 Pd(II)-Catalyzed asymmetric dihydroxylation of 1,3-dienes

with catechols. Scheme 106 Pd(II)-Catalyzed asymmetric dioxygenation of (aza-)alkenols.

Scheme 105 Pd(II)-Catalyzed asymmetric iodoetherification of alkenes.

Scheme 107 Enantioselective [COP-OAc]2-catalyzed cyclization of phe-
nolic (E)-allylic trichloroacetimidate precursors.
which required NIS as both an oxidant and a source of iodine,
was quite general and efficient, and tolerated a wide range of
5-substituted pyrimidine nucleobases and differently substi-
tuted rings. Besides the common 5-, 6-, and 7-membered rings, (E)-allylic trichloroacetimidate precursors 471 was applied to
more challenging 8- to 12-membered rings were also efficiently the synthesis of 2-vinylchromanes, 2-vinyl-1,4-benzodioxanes,
synthesized with the same catalyst system. Moreover, the and 2,3-dihydro-2-vinyl-2H-1,4-benzoxazines with high perfor-
pyrimidine nucleoside analogs bearing an iodide functional mance under neutral conditions, which was accomplished by
group were easily transformed into various new pyrimidine Solomon, Overman and co-workers in 2012 (Scheme 107).217
nucleoside analogs. The authors also proposed a Pd(II)/(IV) Notably, (E)-allylic acetate precursors were also suitable sub-
catalytic cycle for this transformation. strates to afford 2-vinylchromanes in good yields with high ee
In 2021, Beccalli and co-workers reported their studies on values, which indicated that acetate was a competent leaving
asymmetric dioxygenation of (aza-)alkenols 469 by using a C-6 group in COP-catalyzed SN2 0 substitution reactions. The
modified pyridinyl-oxazoline (Pyox) ligand and hypervalent authors conducted deuterium-labelling experiments and DFT cal-
iodine bearing an aromatic ring as an oxidant and a nucleo- culations, which revealed that this transformation took place via an
philic source, allowing convenient access to a series of enan- anti-oxypalladation/syn-deoxypalladation mechanism.
tioenriched acyloxy-substituted morpholines and pyrans 470
(Scheme 106).216 Through 1H NMR studies, the authors
hypothesized that p–p interactions between the benzoate of 7. Cyclization initiated by
the uncommon hypervalent iodine and the aromatic ring of the heteropalladation of triple bonds
ligand, which stabilized the new species formed with
PhI(mcba)2, may account for achieving high reactivity and 7.1. Via aminopalladation of triple bonds
enantioselectivity. It was notable that the Thorpe–Ingold effect In 2016, Kitagawa and colleagues described a Pd(II)-catalyzed
was observed in this transformation, as having di-substitution 5-endo-hydroaminocyclization of 2-(tert-butyl)-N-(2-ethynylphenyl)
at the a-position to the amino group favored both cyclization anilines 472 using (R)-Segphos as a chiral ligand, providing
and enantioselectivity. The significance of this method was various chiral N–C axially chiral N-(2-tert-butylphenyl)indole
demonstrated by the efficient synthesis of an important inter- derivatives 473 with up to 83% ee (Scheme 108).218 It was found
mediate for the natural product (+)-centrolobine. that the bulkiness of ortho-substituents and the electron den-
In addition to reactions under oxidative conditions, an sity on the arylethynyl group were crucial for controlling the
enantioselective [COP-OAc]2-catalyzed cyclization of phenolic enantioselectivity. Later, a novel method for synthesizing

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various optically active cyclohexenone-fused tetrahydropyrano[3,4-b]

indoles 475 was disclosed by the group of Lu and Han, invol-
ving an asymmetric intramolecular aminopalladation/1,4-
addition sequence of aniline-tethered alkynyl cyclohexadie-
nones 474 (Scheme 108).219 The reaction was promoted by a
practical chiral bipyridine/Pd catalytic system, and required a
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redox-neutral condition. Notably, even substrates containing Br

and CF3 groups were amenable to this transformation, perhaps
because the tethered oxygen atom in the chiral ligand changed
its ability to coordinate with the palladium(II) catalyst. The
same group further showed that the Pd-PyrOx system was an
effective catalyst for the cyclization of 2-aminoaryl alkynones
476 through an aminopalladation/1,2-addition sequence, allow-
ing expedient access to chiral 1,2,3,4-tetrahydro-b-carbolines Scheme 109 Enantioselective aminopalladation–Heck cascade
477 (Scheme 108).220 The authors also found that the addition reactions.
of BQ was beneficial for the efficiency of cyclization.
A catalytic system consisting of Pd(OAc)2, a chiral bidentate
pyrox ligand and O2 as the terminal oxidant was shown to be cascade reactions for the facile construction of indole-fused
effective for enantioselective aminopalladation–Heck cascade bicyclo[3.2.1]octanes 482 bearing an all-carbon quaternary
reactions between 2-alkynylanilines 478 and prochiral cyclo- bridgehead stereocenter was developed by Ye and co-workers
pentenes 479, yielding a variety of optically enriched indole- (Scheme 109).222 It was found that the electronic properties of
cyclopentene conjugates 480 bearing two stereocenters, which ortho-alkynylanilines had a considerable effect on both the
was demonstrated by Zhu’s group in 2021 (Scheme 109).221 The reactivity and enantioselectivity of this reaction, as ortho-
significance of this method was illustrated through the synth- alkynylanilines bearing electron-withdrawing substituents only
esis of a heavily functionalized tetracyclic indolinone derivative, led to moderate yields and ee values. Control experiments
which is reminiscent of the rearranged eburnane alkaloids. suggested that the intermediate indol-3-yl palladium species
Soon afterwards, another example of aminopalladation–Heck formed via C–H activation was excluded.
Subsequent studies by Liu’s group showed that in the
presence of chiral palladium catalysts ligated by (S)-tBu-Phox,
a series of chiral a-quaternary carbazolones 484 were efficiently
synthesized through the aminopalladation/desymmetrizing
nitrile addition cascade reaction of alkyne-tethered malononi-
triles 483 (Scheme 110).223 The hypothesized mechanism for
this transformation involved trans-aminopalladation of the
substrate to generate arylpalladium(II) intermediates, followed
by insertion into the nitrile group to produce carbazolones,
which underwent hydrolysis, generating the final product. The
potential application of this methodology was demonstrated by
the efficient asymmetric synthesis of core structures of alka-
loids and a leucomidine A analog.

Scheme 110 Enantioselective aminopalladation/de-symmetrizing nitrile

Scheme 108 Cyclization initiated by intramolecular aminopalladation. addition cascade reaction.

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the reaction, and the manipulation procedure by premixing

the palladium complex and naphthyl halide was indispensable.

7.2. Via oxypalladation of triple bonds

Employing a cooperative binary catalysis of Pd(OAc)2 and (S)-
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Trip, Yao and co-workers in 2013 accomplished an enantio-

selective oxa-Diels–Alder cycloaddition of in situ generated
isochromenyliums Int-I via an intramolecular oxypalladation
of triple bonds, offering an efficient route for the synthesis of
various bridged ring systems bearing dense multiple chiral
centers with quaternary carbons (Scheme 112).227 It should be
noted that substitutions on 2-alkynylbenaldehyes had a con-
siderable effect on the enantioselectivity. When the electron
density of the phenyl ring of 2-alkynylbenaldehyes decreased,
products were obtained with lower ees, which indicated that
the electron-donating substituents could stabilize the in situ-
generated isochromenylium intermediate. It was also found
that aliphatic or alicyclic substituents at the alkyne-tethered
position resulted in low ee values. Key to the success of
the reaction is the use of 2-hydroxystyrenes, as shifting
the ortho-phenolic hydroxyl group to the meta- or para-
position led to no reaction or much lower yield. In addition
to 2-alkynylbenaldehyes, 1-(2-alkynylphenyl)ketones were also
Scheme 111 Pd(II)-Catalyzed enantioselective Cacchi reaction.
found to be suitable substrates for producing desired products
containing a newly formed quaternary carbon with satisfactory
results. Moreover, mechanism studies indicated that (S)-Trip
In 2020, Zhu et al. established an efficient catalytic system played multiple roles in assembling the reactants and control-
employing the (R,R)-QuinoxP* ligand to readily access enan- ling the stereoselectivity.
tioenriched 2,3-disubstituted indoles 486 bearing a chiral In addition to the asymmetric amino-palladation/desymme-
C2-aryl axis via an enantioselective Cacchi reaction of trizing nitrile addition cascade reaction, Liu’s group showed
N-aryl(alkyl)sulfonyl-2-alkynylanilides 485 with arylboronic that Pd-(S)-tBu-Phox complexes described in Scheme 82 also
acids under atmospheric pressure of O2 (Scheme 111).224 served as effective catalysts for the oxy-palladation/desymme-
This reaction exhibits good substrate tolerance except for 2- trizing nitrile addition cascade reaction, allowing for the effi-
methylphenylboronic acid which furnished the desired com- cient synthesis of chiral 3,4-ring-fused isocoumarins 494
pound bearing two axial chirality as a mixture of two diaster- (Scheme 113).228 Various substituents on the benzoate moiety
eomers with low ee values. The authors also conducted control were amenable to this transformation, except for sterically
experiments which indicated that complexation-induced chir- bulky ortho-methyl-substituted benzoates which failed to yield
ality transfer was responsible for the transmission of chirality the expected product. The ester groups substituted with methyl
from the ligand to the product. Later, Li and Qi reported their and ethyl proceeded smoothly whereas the tert-butyl ester
studies on the enantioselective Cacchi reaction between aryl substrate resulted in a dramatically reduced yield.
bromides and o-alkynylanilines with the use of ferrocene-based
N,P-ligand, offering a simple route to C(3)–C(aryl) axially chiral
indoles 488 (Scheme 111).225 In this transformation, B(OH)3 as
the additive could effectively suppress the formation of 3-
unfunctionalized indole. The use of phenol instead of aniline
as an ortho nucleophile allowed the generation of axially chiral
naphthylbenzofuran with lower yield and enantioselectivity.
Moreover, control experiments revealed that the active organo-
palladium species in the catalytic cycle was the cyclization-
derived Pd–C bond. Another example of an asymmetric Cacchi
reaction of 2-alkynylanilines with sterically congested naphthyl
halides 487 catalyzed by Pd(0)/(S)-Segphos was developed by the
group of Wang, yielding an array of axially chiral naphthyl-C3-
indoles 489 containing a free NH moiety (Scheme 111).226 Scheme 112 Pd(II)-Catalyzed enantioselective oxa-Diels–Alder cycload-
Notably, the addition of water was essential for facilitating dition reaction.

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Scheme 113 Enantioselective oxypalladation/desymmetrizing nitrile

addition cascade reaction. Scheme 115 Pd(II)-Catalyzed asymmetric cycloisomerization of enynes.

7.3. Via carbopalladation of triple bonds more favorable. The rapid assembly of the kopsifoline core also
demonstrated the efficiency of this approach.
In the presence of chiral palladium catalysts ligated by
A cationic palladium(II)/(R)-BINAP complex catalyzed asym-
(R)-DTBM-Segphos, enantioselective cyclization of 1,6-silyl-
metric cycloisomerization of enynes 499 to produce axially
oxyenynes bearing a terminal alkyne to provide a simple route
chiral biaryls 500 was accomplished by Uemura and co-
to chiral five-membered rings 496 was realized by Toste’s group
workers in 2012 (Scheme 115).231 Notably, owing to its strong
in 2012 (Scheme 114).229 It was found that the alkene geometry
Lewis acidic character, this cationic Pd(II) catalyst could
had a limited effect on the enantioselectivity. The application of
enhance the coordinating ability with the triple bond. The
this methodology was underscored by the further synthesis of
nature and position of the substituent on the arene ring played
naturally occurring dimeric sesquiterpene ()-laurebiphenyl.
important roles in the reactivity and enantioselectivity of this
Soon afterwards, the same group reported their further studies
transformation; enynes bearing an ortho methoxy groups on the
on the asymmetric cyclization of 1,6-enamidynes to form
arene at the alkyne terminus led to chiral biaryls with good
spirocyclic ring systems (Scheme 114).230 This reaction
enantioselectivity.
occurred through the trapping of the iminium intermediate
The group of Lu and Han demonstrated an enantioselective
by an external alcohol nucleophile, resulting in an aminal
arylative cyclization of alkyne-tethered enals or enones 501 with
product and a mixture of diastereomers could be reduced to
arylboronic acids catalyzed by the Pd(II)-(S)-Segphos complex
the corresponding piperidines using triethylsilane. Besides six-
(Scheme 116).232 This cyclization was initiated by carbopallada-
membered rings, five- and seven-membered rings were well-
tion of alkynes and did not require a redox system. It was
tolerated, and the seven-membered ring system was found be
notable that the addition of H2O was beneficial for the effi-
ciency of cyclization. Employing a chiral phosphinooxazoline/
palladium(II) catalyst, the synthesis of 2,3-disubstituted chiral
indenols 504 was realized by Xu and Chen in 2020; this process
involved the asymmetric annulation of 2-formylboronic acids
503 with internal alkynes 202 (Scheme 116).233 Notably, the
substituents on the 2-formylboronic acids had a considerable
effect on both the yield and enantioselectivity of this annula-
tion; when electron-withdrawing groups were present on the
benzene ring, much higher enantioselectivities could be
achieved. It was found that less reactive diaryl substituted
alkynes were also amenable to this transformation.
In 2020, utilizing achiral Xantphos and PC-Phos as co-
ligands, Zhang and Guo developed an intermolecular dynamic

Scheme 114 Pd(II)-Catalyzed enantioselective cyclization of 1,6-

silyloxyenynes and 1,6-enamidynes. Scheme 116 Cyclization initiated by the carbopalladation of alkynes.

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kinetic asymmetric dearomatization between 3-arylindoles 486

and internal alkynes 202, producing various spiro[indene-1,3 0 -
indole] compounds 506 with up to 98% ee (Scheme 117).234 A
series of substituted indoles could react smoothly with various
symmetrical internal alkynes. Besides, nonsymmetrical inter-
nal alkynes were also well-tolerated and the products with the
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alkyl groups located closer to the spirocyclic carbon centers

were obtained with high ee values. By means of solvent-assisted
electrospray ionization mass spectrometry (SAESI-MS), the key
reaction intermediate, a ligand-hybridized Pd0 complex, was
detected. The mechanism of this transformation was proposed
to proceed via oxidative addition of aryl bromine to the Pd Scheme 118 Pd-Catalyzed asymmetric cyclization–dimerization of
complex, followed by the intermolecular carbopalladation of (ortho-alkynyl phenyl)(methoxymethyl)sulfides.
triple bonds to generate alkenyl-PdII species, which underwent
migratory insertion and b-H elimination, furnishing the final
product. Recently, Jiao and co-workers discovered a Pd- 7.4. Via sulforpalladation of triple bonds
catalyzed intermolecular asymmetric spiroannulation of 2,3- In 2019, Kato and co-workers presented the first example of an
disubstituted indoles 507 with internal alkynes 202 for the asymmetric cyclization–dimerization of (ortho-alkynyl phenyl)-
facile synthesis of chiral indoline structures 508 with a C2- (methoxymethyl)sulfides 511 that led to the formation of
quaternary stereocenter (Scheme 117).235 With respect to the various enantiomerically enriched axially chiral bibenzothio-
scope of the indole coupling partners, it was found that the phenes 512 (Scheme 118).236 The proposed mechanism for this
introduction of a methyl group at the 6-position of the phenyl transformation involved the generation of a key intermediate
moiety or replacing the phenyl group with a naphthyl group bisoxazoline initiated by the sulfur atom attacking the alkyne
could result in lower ee or yield. As for internal alkyne, the from underneath the palladium complex, followed by coordi-
ortho-substituent on the aryl groups of diarylacetylene had a nation with the second alkyne substrate leading to the second
detrimental effect on the reaction. Additionally, enantioen- cyclization, and subsequent reductive elimination, releasing
riched indolenine derivatives 509 and 510 bearing a C3- the expected product. DFT calculations revealed that the box
quaternary stereocenter could be efficiently synthesized ligand could promote the coordination of the benzothienyl
through the stereospecific aza-semipinacol rearrangement palladium(II) intermediate with the second alkyne substrate
under acidic conditions. by enhancing its alkynophilicity, which easily underwent
dimerization.

7.5. Via chloropalladation of triple bonds

A novel chlorine transfer strategy for the facile synthesis chiral
a-chloromethylene-g-butyrolactones 514 via the enantio-
selective chloropalladation cyclization of 1,6-enynes 513 was
accomplished by the group of Jiang in 2022 (Scheme 119).237
The authors found that the substrate bearing the quinoline
group may poison the palladium catalyst, thus completely
inhibiting this transformation. The steric bulk of the

Scheme 119 Pd-Catalyzed enantioselective chloropalladation cyclization

Scheme 117 Pd-Catalyzed intermolecular asymmetric spiroannulation. of 1,6-enynes.

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substituents had a considerable effect on both the yield

and the enantioselectivity, as ortho substituents resulted in
lower yields and ee values. Based on several control experi-
ments, this reaction was thought to proceed through a
cis-chloropalladation/migration insertion/b-chloro elimination
sequence. The synthetic application of this method was illu-
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strated with the synthesis of key intermediates of ()-hinokinin

and (+)-ovafolinin B.

8. Cyclization initiated by
heteropalladation of allenes
8.1. Via carbopalladation of allenes
In 2015, Lu and Han realized the synthesis of enantiomerically
enriched 3,4-cis-1,2,3,4-tetrahydroquinoline derivatives 516
through a cationic Pd(II)-catalyzed cyclization of N-tosyl-
aniline tethered allenyl aldehydes 515 with arylboronic acids
(Scheme 120).238 Key to the success of this transformation was
the use of cationic palladium species. Int-A generated via the
transmetallation of the Pd hydroxo complex with arylboronic
acid and intermolecular carbopalladation of allenes, exhibits
high Lewis acidity, and may undergo intramolecular 1,2-
addition before being transferred to an Z3-allylpalladium
complex.
An interesting method for synthesizing chiral oxazoline
derivatives 518 was described by Ma et al., involving a highly
enantioselective coupling–cyclization between N-(buta-2,3-
dienyl) amides 517 and aryl or 1-alkenyl iodides 370
(Scheme 121).239 This cyclization was initiated by the oxidative
addition of aryl or 1-alkenyl iodides, followed by intermolecular
carbopalladation of allenes. N-(Buta-2,3-dienyl)amides bearing Scheme 121 Cyclization via carbopalladation of allenes.
various aryl groups were well-tolerated, whereas only the steric
bulk of the alkyl substituents, such as iPr and tBu could achieve
excellent ee values. It was found that non-terminal allenes led o-iodoaniline into the reaction was essential for reducing the
to no reaction, and phenyl chloride, bromide, or triflate in side reactions and improve the chemoselectivity. Recently, the
place of phenyl iodide resulted in poor results. In the presence first asymmetric three-component reaction of 2,3-allenol 521,
of catalytic amounts of Pd2(dab)3 and (R)-BTFM-Garphos, aryl iodides 370, and 2-arylmethylenemolononitriles 522 cata-
an asymmetric carbonylative Heck reaction between o- lyzed by the Pd(0)/Phox complex was accomplished by the
iodoanilines 413 and allenes 519 under atmospheric pressure group of Zhang and Li, allowing direct access to a series of
of CO was established by Dong and co-workers in 2021, yielding chiral substituted tetrahydrofurans 523 (Scheme 121).241 This
chiral dihydroquinolinone derivatives 520 with up to reaction proceeded via a cascade involving allenol carbopalla-
90% ee (Scheme 121).240 Notably, the dropwise addition of dation and allylic cycloaddition. The significance of this
method was underscored by the efficient asymmetric total
synthesis of naturally occurring lignan, ()-2-episesaminone.
In 2019, Shao and co-workers disclosed the first Pd-catalyzed
asymmetric allenylic [4+1] cycloaddition of allenyl acetates 525
with pyrazolones 524 using a planar-chiral ligand, offering an
unprecedented efficient route for the synthesis of chiral cyclo-
pentenes 526 (Scheme 122).242 Besides pyrazolones, isoxazoli-
none could also react smoothly with allenyl acetate leading to
the desired product with good ee values. Additionally, the
authors proposed a plausible reaction mechanism. The oxida-
tive addition of 525 to the chiral Pd0 complex generated the PdII
Scheme 120 Pd(II)-Catalyzed cyclization of N-tosyl-aniline tethered alle- butadienyl species, which then underwent an allenylic substi-
nyl aldehydes with arylboronic acids. tution with 524 to form Int-A. The subsequent PdII-cayalyzed

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Scheme 124 Pd-Catalyzed asymmetric intermolecular Heck reaction

Scheme 122 Pd-Catalyzed asymmetric allenylic [4+1] cycloaddition of
between propargylic acetates and several types of cyclic olefins.
allenyl acetates with pyrazolones.

the presence of gem-dimethyl groups in the propargyl fragment

intramolecular carbopalladation of Int-A produced Int-B, fol-
were both key factors for the success of the reaction. The
lowed by the protonolysis process, resulted in the spirocyclic
mechanism of this transformation was proposed to proceed
product.
via oxidative addition of the Pd complex to propargylic acetate
8.2. Via oxypalladation of allenes to generate Z1-allenyl complex Int-I, followed by insertion into a
bound cycloolefin to form alkylpalladium intermediate Int-II,
Employing cooperative Pd(OAc)2/chiral phosphoric acid cata-
which induced 4-exo-dig cyclization of the allene fragment and
lysts, an enantioselective desymmetrization of prochiral allenic
subsequent b-hydride elimination, yielding the final product.
diols 527 was investigated by Zheng’s group in 2015, offering
straightforward access to optically active disubstituted dihydro-
9.2. [3+2] annulation
furans 528 (Scheme 123).243 Besides aryl-substituted substrates,
substrates bearing alkyl substitution were also amenable Utilizing their newly developed chiral ferrocene/benzimidazole-
although lower ee was obtained. In this cooperative binary based P,N-ligand, an asymmetric formal [3+2] annulation of
catalysis system, palladium activated the allene and the PQO propargylic esters 534 with b-ketoesters 533 was realized by Hu
of the phosphate used as a base deprotonated one alcohol and Zhou in 2016, offering facile access to various highly
concurrently, generating the key intermediate Int-A. functionalized chiral 2,3-dihydrofurans 535 bearing an exocyc-
lic double bond (Scheme 125).245 This reaction was thought
to proceed via p-propargylpalladium or allenylpalladium
9. Cyclization via allenylpalladium intermediates, which were attacked consecutively by C- and
intermediates O-nucleophilic atoms of b-ketoesters, producing the cyclization
product. The authors further showed that the catalytic system
9.1. Intermolecular Heck-type reaction
with a Pd(0) complex and chiral ferrocene/benzimidazole-based
In 2017, Zhou and co-workers demonstrated an asymmetric P,N-ligand worked equally well for the asymmetric [3+2] annu-
intermolecular Heck reaction between propargylic acetates 530 lation of tertiary propargylic carbonates 536 with b-ketoesters
and several types of cyclic olefins 531, including 2,3- via a similar mechanism, thus leading to the formation of
dihydrofuran, N-Boc-2,3-dihydropyrrole, cyclopentene and chiral highly functionalized chiral 2,3-dihydrofurans 408
bicyclic alkenes, yielding highly strained cyclobutenes 532 with bearing a quaternary stereocenter at the 2-position.246 Key
high enantioselectivity (Scheme 124).244 It was found that the to the success of this transformation was the loss of CO2 to
use of chiral bisoxazoline bearing rigid indanyl side groups and irreversibly form p-propargylpalladium or allenylpalladium
intermediates.

9.3. [4+2] annulation

In 2019, You’s group described an intermolecular asymmetric
cascade dearomatization reaction between indoles 538 and
propargyl carbonate 539 to construct enantioenriched multiply
substituted fused indolenines 540, which can be formally
considered as a [4+2] annulation (Scheme 126).247 Notably,
the indole ring of substrates bearing stronger electron-
withdrawing groups was found be more favorable, probably
because the electron-withdrawing substituents could
Scheme 123 Pd-Catalyzed enantioselective desymmetrization of pro- increase the acidity of the indole N–H, make it more prone to
chiral allenic diols. forming N nucleophiles. A proposed catalytic cycle involves the

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Scheme 127 Pd(II)-Catalyzed reductive asymmetric cyclization of N-

tosyl-tethered 1,7-enynes.

Scheme 125 Pd-Catalyzed asymmetric [3+2] annulation. In 2021, Jia and co-workers synthesized various structurally
diverse chiral spiro and fused indoline derivatives possessing
quaternary stereocenters and exocyclic CQC bonds through a
PdH-catalyzed heteroarenyne cycloisomerization reaction of
alkyne-tethered indole substrates (Scheme 128).249 In the
presence of chiral palladium catalysts ligated by monodentate
phosphoramidite L144, a series of C2-alkyne-tethered indoles
545 could react to afford chiral spiro indoline derivatives 417
with high enantioselectivity. For the heteroarenyne cycloisome-
rization of N-alkyne-tethered indoles 418 to form chiral fused
indolines 419, palladium catalysts containing chiral bidentate
(S)-tBuPHOX L9 were needed. The authors also showed that Pd–
Scheme 126 Pd-Catalyzed asymmetric [4+2] annulation. chiral monodentate phosphoramidite L10 complexes were
effective catalysts for the classical enantioselective cycloisome-
rization of 1,5-enynes 549. Deuterium-labelling experiments
nucleophilic side chain attacking the allenylpalladium inter- suggested that the hydride source for Pd–H species might be
mediate which is generated by the oxidative addition of pro- from the acid additive.
pargyl carbonate to the Pd complex, with the release of CO2,
resulting in the formation of p-allyl palladium species. The
subsequent deprotonation of indole N–H and C3 attack on p-
allyl palladium species finally resulted in the desired product.

10. Cyclization initiated by

hydropalladation of unsaturated C–C
bonds
10.1. Via hydropalladation of triple bonds
Utilizing ethanol as a hydrogen source, the group of Lu and
Han in 2019 disclosed a novel Pd(II)-catalyzed reductive asym-
metric cyclization of N-tosyl-tethered 1,7-enynes 542, providing
easy access to two types of chiral 1,2,3,4-tetrahydroquinolines
543 and 544 bearing a quaternary carbon center with high
efficiency (Scheme 127).248 The reaction was proposed to pro-
ceed via a Pd–H species derived from the palladium catalyst
and ethanol, and the key intermediate Int-A was formed via
hydropalladation of the carbon–carbon triple bond. If the
functional group is an electron-withdrawing group, Int-A would
undergo 1,4-addition, followed by protonolysis to generate the
product 543. Alternatively, if the functional group is a carbo-
nate, b-heteroatom elimination of Int-A could produce other Scheme 128 Pd-Catalyzed heteroarenyne cycloisomerization reaction
type of product 544. of alkyne-tethered indole substrates.

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intramolecular hydroamination under the Curtin–Hammett

principle to furnish final imidazolidinone.

10.2. Via hydropalladation of allenes

Employing a cooperative binary catalysis of Pd(OAc)2 and a
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chiral diarylprolinol-based organocatalyst, the group of Dixon

in 2012 accomplished an asymmetric carbocyclization of
aldehyde-linked allenes 557, producing chiral substituted cyclo-
pentane and pyrrolidine products 558 with up to 82% ee
(Scheme 131).252 The proposed mechanism of the process
Scheme 129 Pd-Catalyzed hydroesterificative cyclization of 1,6-enynes
involves the initial condensation of a chiral secondary amine
with alcohol.
with an aldehyde to yield an iminium ion intermediate Int-I,
in which the Pd(0) species could remove the acidic a-proton
A catalytic system consisting of Pd(OAc)2, (S)-MeO-BIPHEP, of the iminium ion to form an enamine Int-II. The sub-
and TsOHH2O was shown to be effective for the hydroester- sequent hydropalladation of the allene moiety generated a
ificative cyclization of 1,6-enynes 551 with alcohol 552 under p-allylpalladium complex Int-III, which is followed by intra-
CO (20 bar), this process yielded enantioenriched g-lactams 553 molecular nucleophilic attack and hydrolysis to yield the
with a chiral quaternary carbon center and a carboxylic ester desired product.
group, as established by Dong et al. in 2021 (Scheme 129).250 Recently, a palladium-catalyzed cascade C–H functionaliza-
Various substituted alkynes were well-tolerated, except for the tion/asymmetric allylation reaction of aryl a-diazoamides 561
tertiary butyl group which completely inhibited this transfor- and allenes 560 enabled by a standard Trost ligand to construct
mation. It was found that the substituted alkene moiety of the chiral 3,3-disubstituted oxindole derivatives 562 with high
enyne was essential for obtaining high ee, as the substrate performance was demonstrated by Gong, Han and co-workers
without a substituent on the alkene resulted in moderate ee (Scheme 132).253 The putative mechanism involved the hydro-
values. Additionally, control experiments revealed that the palladation of allene with a Pd–H species generated from Pd(0)
alkene group of the enyne substrate played a vital role in and acid, leading to the formation of a p-allyl Pd(II) complex,
affecting the site selectivity in the initial hydropalladation step, which could lead to the decomposition of the diazo compound
and the Ts group was crucial for the enantioselectivity of this to yield the palladium carbene intermediate Int-I. The following
reaction. intramolecular C(sp2)–H insertion led to the production of
Recently, Lin, Yao and co-workers presented that the cataly- intermediate Int-II and subsequent asymmetric allylation reac-
tic system consisting of Pd(OAc)2 and (S)-Segphos worked well tion led to the formation of allylic 3,3-disubstituted oxindole
for the asymmetric sequential hydroamination of 1,3-enynes
554 with various urea substrates 555 in the presence of a
sterically bulky acid (3,5-di-tert-butyl benzoic acid), delivering
a series of synthetically valuable imidazolidinones 556
(Scheme 130).251 Chiral imidazolidinones bearing a tertiary
stereocenter were efficiently synthesized, whereas this reaction
led to the construction of a tetra-substituted stereocenter with a
lower ee value. Mechanistic studies suggested that this trans-
formation proceeded via an intermolecular enyne hydroamina-
tion, producing an allene intermediate Int-A, followed by an

Scheme 130 Pd-Catalyzed asymmetric sequential hydroamination of Scheme 131 Pd-Catalyzed asymmetric carbocyclization of aldehyde-
1,3-enynes with various urea substrates. linked allenes.

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Scheme 132 Pd-Catalyzed cascade C–H functionalization/asymmetric

allylation reaction of aryl a-diazoamides and allenes.

products. Notably, control experiments indicated that the chro-

mium complex serving as a Lewis acid played a crucial role in
facilitating the generation of palladium carbene and achieving
high stereochemical control and efficiency.

11. Cyclization based on C–H bond

activation
Scheme 133 Cramer’s studies on enantioselective intramolecular Pd(0)-
11.1. C(sp2)–H functionalization
catalyzed C–H functionalization.
11.1.1. Pd(0)/Pd(II) catalytic cycle
11.1.1.1. Generating point chirality. In 2013, Cramer’s group
realized the syntheses of highly functionalized chiral dibenza- palladium catalysts ligated by the Taddol-phosphoramidite
zepinones 564 with chiral quaternary stereogenic centers ligand and the cesium salt of ortho-anisic acid as a base, the
through an enantioselective intramolecular palladium(0)- enantioselective cyclization for 1H-isoindoles with small sub-
catalyzed C–H arylation using cheap and widely available stituents also proceeded smoothly.
TADDOL-derived phosphoramidite as a chiral ligand An efficient method for synthesizing 3,4-dihydroisoqui-
(Scheme 133).254 Various aromatics as well as heteroaromatics nolines 570 with C3 quaternary stereogenic centers was
and different substitutions on the amide nitrogen atom proved described by Zhu and You in 2017, involving an enantio-
to be amenable to this transformation, whereas substrates selective isocyanide insertion/desymmetrizing C(sp2)–H bond
bearing a secondary amide failed to produce the desired activation reaction enabled by a SPINOL-derived phosphorami-
product. Notably, this reaction proceeded through an unprece- dite ligand (Scheme 134).257 It was notable that the addition of
dented enantioselective process, in which the enantiotopical a small amount of water could facilitate the reaction without
concerted metalation deprotonation (CMD) step occurred via a affecting the enantioselectivity, and the rate of addition of aryl
rare eight-membered palladacycle. Subsequent studies by the iodide to the reaction mixture was vital for the formation of the
same group showed that ketene aminal phosphates 565 could desired products. Recently, another example of isocyanide
also serve as competent electrophiles for enantioselective Pd(0)- insertion/desymmetrizing C(sp2)–H bond activation reaction
catalyzed C–H functionalizations, providing isoindoline scaf- using a SPINOL-derived phosphoramidite ligand to construct
folds 566 with high enantioselectivity (Scheme 133).255 The key 1H-isoindoles 573 containing tri- and difluoromethylated qua-
to the success of the reaction with a high degree of enantiocon- ternary stereogenic centers was accomplished by Zhu, Shang,
trol was the use of a tailored monodentate electron-rich phos- Wang and co-workers (Scheme 134).258 Besides, diverse C1-
phine ligand bearing a chiral phospholane module and a bulky tethered bis-heterocyclic scaffolds 574 were efficiently obtained
atropchiral binaphthyl backbone. Moreover, this catalytic sys- via an allene insertion cascade reaction. Notably, the fluor-
tem was shown to be effective for parallel kinetic resolution of oalkyl group of substrates played a vital role in facilitating the
racemic unsymmetrical diaryl ketene aminal phosphates. In reaction and controlling the enantioselectivity.
their further studies, employing trifluoroacetimidoyl chlorides Utilizing their newly developed chiral bifunctional ligand
567 as electrophilic components, chiral 1H-isoindoles 568 which incorporates both a phosphine and a carboxylic acid
bearing quaternary stereogenic centers could be efficiently moiety on a binaphthyl scaffold, a desymmetrizing C–H aryla-
synthesized through palladium(0)-catalyzed C–H functionaliza- tion leading to 5,6-dihydrophenanthridines 576 was accom-
tion powered by readily accessible phosphordiamidite ligands plished by Baudoin et al. in 2018 (Scheme 135).259 The
(Scheme 133).256 It was found that in the presence of chiral authors found that nitrogen protecting groups such as

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that the asymmetric cyclization was catalyzed by a palladium

catalyst with a single chiral monophosphorus ligand. It should
be noted that the a-elimination of Pd(II) species generated by
the oxidative addition of carbamoyl chloride to the Pd(0)
complex, could be effectively inhibited under a CO atmosphere.
In addition to generating carbon chirality, phosphorus
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chirality could also be efficiently constructed through C(sp2)–

H functionalization. Employing TADDOL-derived phosphora-
midite ligands, a palladium-catalyzed enantioselective C–H
arylation of N-(o-bromoaryl)diarylphosphinic amides 579 was
independently reported by the group of Duan261 and Ma262 in
2015, allowing convenient access to phosphorus compounds
580 bearing a P-stereogenic center (Scheme 136). The signifi-
cance of this method was further demonstrated by efficiently
transforming products into P-chiral biphenyl monophosphine
ligands. The transformation was proposed to involve an initial
oxidative addition of aryl bromine to the Pd complex, generat-
ing arylpalladium bromide, followed by ligand exchange with
the pivalate anion to produce palladium pivalate, which under-
went C–H bond cleavage to form the seven-membered
di(aryl)palladium species and subsequent reductive elimina-
tion, furnishing the final product.
Scheme 134 Pd-Catalyzed enantioselective isocyanide insertion/desym-
metrizing C(sp2)–H bond activation reaction. Later, Tang’s group demonstrated a Pd-catalyzed desym-
metric intramolecular cyclization of diaryl ortho-bromo
arylphosphonates 581 enabled by a novel P-chiral biaryl mono-
phosphorus ligand, providing direct access to various P-chiral
biaryl phosphonates 582 with up to 88% ee (Scheme 137).263
Application of this methodology was underscored by further
transformation of the P-chiral biaryl phosphonates into versa-
tile P-chiral biaryl monophosphine ligands.
Using a Pd-(S,S)-Me-Duphos system, an enantioselective
desymmetric C–H arylation of o-bromoaryl phosphine oxides
583 for the synthesis of various P-stereogenic phosphole oxides
584 was presented by the group of Xu and Cui in 2017
(Scheme 138).264 Noteworthily, the enantioselectivities were
closely related to the structure of substrates, and a simple
crystallization could significantly improve the optical purity of
products. Later, Duan and co-workers reported their studies on
the synthesis of P-stereogenic dibenzophospholes via asym-
metric C–H bond activation enabled by two types of catalytic
systems (Scheme 138).265 With the use of a catalyst composed

Scheme 135 Pd-Catalyzed enantioselective desymmetrizing C–H

arylation.

alkoxycarbonyl and tosyl could react smoothly, whereas methyl

or trifluoroacetyl-protected substrates made the reaction slug-
gish or inactive. Additionally, the bifunctional system was also
found to be applicable to the parallel kinetic resolution of
racemic substrates.
In 2019, Tang and co-workers reported an enantioselective
palladium-catalyzed C(sp2)–H carbamoylation of diarylmethyl
carbamoyl chlorides 577 with the use of (R)-AntPhos as the
ligand under CO (9 atm), giving easy access to various chiral Scheme 136 Pd-Catalyzed enantioselective C–H arylation of N-(o-
isoindolines 578 (Scheme 135).260 Mechanistic studies revealed bromoaryl)diarylphosphinic amides.

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triarylsilyl group. Mechanistic investigations indicated that the 1,5-

palladium migration step was likely to be the enantio-determining
step. Additionally, the authors proposed a plausible catalytic cycle
for this transformation. Oxidative addition of aryl triflate to
palladium(0) to give arylpalladium(II) species Int-I, followed by
1,5-palladium migration to one of the two aryl groups on the
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silicon to generate another arylpalladium(II) species Int-II, which

could undergo intramolecular coordination of the amino group to
the palladium center via deprotonation with the assistance of Et3N
to produce the palladacycle and subsequent reductive elimination
Scheme 137 Pd-Catalyzed desymmetric intramolecular cyclization of
diaryl ortho-bromo arylphosphonates.
resulted in the formation of desire product.

11.1.1.2. Generating axial chirality. The Gu group in 2017

showed the superior efficiency of the TADDOL-derived phos-
phoramidite ligand in palladium-catalyzed dynamic kinetic
intramolecular C–H cyclization for the construction of indole-
based atropisomers 592 (Scheme 140).268 The authors also
found that compared with the corresponding benzene deriva-
tives, the indole-based atropisomers had less steric congestion
and relatively lower rotation barriers. Subsequent studies by
Cramer’s group discovered a palladium(0)-catalyzed atropo-
enantioselective C–H arylation that provided a simple
route for the synthesis of axially chiral dibenzazepinones 594
employing a simple TADDOL-derived phosphoramidite ligand
(Scheme 140).269 It was found that steric bulk adjacent to the
biaryl linker was essential for the enantioselectivity of
this transformation. Moreover, DFT calculations indicated
that C–H functionalization proceeded via a configurationally
stable eight-membered palladacycle formed by an enantio-
determining CMD.

Scheme 138 Pd-Catalyzed enantioselective desymmetric C–H arylation

of o-bromoaryl phosphine oxides.

of Pd(PCy3)2 and chiral phosphoric acids/amides, (S)-

dibenzophospholes ent-584 could be efficiently synthesized.
For (R)-dibenzophospholes 584, palladium catalysts containing
(R)-Segphos were needed.
Besides carbon and phosphorus chirality, Hayashi and
Shintani in 2012 disclosed an enantioselective C–H bond
functionalization of prochiral 2-(arylsilyl)aryl triflates 587 cata-
lyzed by a palladium catalyst with a Josiphos-type ligand,
resulting in the formation of Si-stereogenic dibenzosiloles 588
with high chemo- and enantioselectivities (Scheme 139).266
Mechanistic studies suggested that the oxidative addition of
aryl triflate to Pd(0) was most likely the turnover-limiting step
of the catalytic cycle. In their subsequent studies, an asym-
metric synthesis of silicon-stereogenic 5,10-dihydrophenaza-
silines 590 via an unprecedented enantioselective 1,5-palladium
migration in the presence of a chiral complex derived from
Pd(OAc)2 with 4,40 -bis(trimethylsilyl) (R)-BINAP was discovered by
Nozaki and Shintani in 2017 (Scheme 139).267 It was found that a
less bulky cyclohexyl group in place of the tert-butyl group on the
silicon atom could result in lower enantioselectivity, and quite low Scheme 139 Pd-Catalyzed enantioselective C–H bond functionalization
enantioselectivity was achieved with the use of a substrate bearing a to generate silicon chirality.

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Scheme 140 Pd-Catalyzed enantioselective C–H bond functionalization

to generate axial chirality.

11.1.1.3. Generating planar chirality. In 2014, the group of

Gu and Kang described an efficient approach for the
synthesis of planar chiral metallocene compounds 596 with
high enantioselectivities via an intramolecular asymmetric C–H
functionalization/cyclization reaction of metallocenes 595 cat-
alyzed by palladium catalysts containing (R)- or (S)-BINAP
(Scheme 141).270 It was found that preinstalled chiralities on Scheme 141 Pd-Catalyzed intramolecular asymmetric C–H functionali-
the other Cp-ring did not affect the cyclization reaction. The zation/cyclization reaction.
same group further extended this C–H functionalization/cycli-
zation reaction to construct planar chiral quinilinoferrocenes
598 with low to moderate enantioselectivities using Carriera’s enantioselective C–H arylation of ferrocenyl aryl sulfides 603
O-PINAP ligands (Scheme 141).271 Besides aryl iodides, aryl (Scheme 142).274 The reaction was promoted by Pd(OAc)2 and
bromides were also amenable to this transformation, albeit (R)-Segphos, leading to the expedient formation of planar chiral
with slightly decreased ee values. Subsequent studies by Mao sulfides or bis-sulfides with high performance. It was found
and Liu showed that the Pd-(S,S)-Me-BI-DIME system was an that the obtained chiral sulfides could serve as suitable ligands
effective catalyst for the asymmetric C–H functionalization of in the asymmetric Suzuki reaction.
N-ferrocenyl o-bromobenzanilides 599, providing a simple
route to planar chiral isoquinolinone-fused ferrocenes 600 11.1.1.4. Generating helical chirality. Recently, in the
with up to 97% ee (Scheme 141).272 The preliminary appli- presence of chiral palladium catalysts ligated by SPINOL-
cation of this method was demonstrated by transforming derived phosphoramidite ligand, a modular synthesis of
isoquinolinone-fused ferrocenes into planar chiral ferrocenyl
monophosphines.
An enantioselective isocyanide insertion/desymmetric
C(sp2)–H bond activation reaction enabled by a Pd catalytic
system derived from the SPINOL-derived phosphoramidite
ligand for the facile synthesis of planar chiral pyrido[3,4-b]
ferrocenes 603 was established by Zhu, Luo and co-workers in
2018 (Scheme 142).273 Notably, both the base Cs2CO3 and the
additive PivOH were nontrivial for this transformation, and the
R group in ferrocenyl isocyanides played a vital role in facil-
itating the reaction, as replacing the substituent with hydrogen
could inhibit this transformation.
Later, an efficient method for synthesizing planar chiral
benzothiophene-fused ferrocenes cyclopropanes 604 was Scheme 142 Pd-Catalyzed enantioselective C–H bond functionalization
described by Duan et al., which involved an intramolecular to generate planar chirality.

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Scheme 143 Pd-Catalyzed double imidoylative cyclization of axially

achiral multiaryl bisisocyanides with aryl iodides.

enantioenriched pyrido[6]helicenes and furan-containing

pyrido[7]helicenes 606 through double imidoylative cyclization
of axially achiral multiaryl bisisocyanides 605 with aryl iodides
was accomplished by Zhu, Luo and Zhong (Scheme 143).275 The
reaction involved the sequential formation of four C–C bonds in
one pot to construct two pyridyl rings. Employing precyclized biaryl
monoisocyanides as substrates, the authors found that the second
pyridine-forming step was likely an enantiomer-generating step
and different groups including CF3 could be easily installed on the
helical skeleton via this separate cyclization.
11.1.2. Pd(II)/Pd(0) catalytic cycle. In 2017, Han and co-
workers reported a cascade C–H functionalization/ Scheme 144 Pd-Catalyzed cascade C–H functionalization/intra-
intramolecular asymmetric allylation reaction between aryl molecular asymmetric allylation reaction.
urea 607 and 1,3-dienes 519 employing a new chiral sulfox-
ide–oxazoline (SOX) ligand and 2,5-dimethylquinone as the
oxidant, providing expedient access to various chiral indoline reaction of N-sulfonyl benzamides 613 with 1,3-dienes, effi-
derivatives 608 (Scheme 144).276 Notably, the SOX ligand bear- ciently synthesizing various chiral 3,4-dihydroisoquinolones
ing a single chiral center on the sulfur was essential for both 614 (Scheme 144).279
the C–H cleavage step and stereocontrol of the allylation step. A highly enantioselective cyclization of 3-alkenylindole 615
Deuterium-labelling experiments indicated that the C–H activa- via Pd(II)–SPRIX-catalyzed C–H activation for the facile synth-
tion step was irreversible and proceeded via an electrophilic esis of tricyclic indole products 616 with a chiral quaternary
palladation pathway. Later, an asymmetric C–H activation/ carbon center was presented by Sasai, Takizawa and co-workers
annulation of diarylmethyltriflamide 609 with allenes 519 in in 2017 (Scheme 145).280 An N-allyl substituent on the substrate
the presence of Cu(OAc)2 as reoxidant, providing an efficient was found to be essential for both reactivity and selectivity of
route for the synthesis of highly valuable tetrahydroisoquino- this reaction. This catalytic system efficiently provided tetrahy-
line 610 was disclosed by the group of Gulı́as and Mascareñas drocyclopenta-[b]indole with high ee values, whereas tetrahy-
in 2019 (Scheme 144).277 It was notable that the designed N- drocarbazole was obtained in low yield and only 8% ee.
protected amino acid ligand played a crucial role in facilitating Additionally, kinetic isotope studies revealed that the C–H
the C–H activation to form the palladacycle. Another example of activation step might be the rate-determining step in this
the C–H functionalization/intramolecular asymmetric allyla- transformation.
tion reaction to construct various chiral heterocycles 612 was In the presence of chiral palladium catalysts ligated by (R)-
studied by Gong, Han and co-workers, and it involved an DM-Segphos, a sequential asymmetric double-Friedel–Crafts
asymmetric oxidative annulation between N-alkoxyheteroaryl
amides 611 and 1,3-dienes 129 under the atmospheric pressure
of O2 (Scheme 144).278 It was found that the novel chiral
pyridine–oxazoline possessing a methoxyl group at the C-5
position and a gem-dimethyl group on the oxazoline moiety
played a vital role in facilitating the reaction. Moreover, the
isotope labelling experiment indicated that the C–H bond
cleavage process might be the rate-limiting step. Soon after-
wards, Yang et al. showed that Pd–PyrOx complexes were also Scheme 145 Pd-Catalyzed enantioselective cyclization of 3-
effective catalysts for the C–H functionalization cascade alkenylindole.

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Scheme 148 Pd-Catalyzed enantioselective amination reaction.

lower ee values, revealing that the larger cyclic transient state

Scheme 146 Pd-Catalyzed sequential asymmetric double-Friedel–Crafts
alkylation and N-hemiketalization reaction.
generated in the C–H activation step had a detrimental effect on
enantioselectivity. Moreover, the authors also carried out DFT
calculations and the results suggested that this transformation
alkylation and N-hemiketalization reaction between 3- was involved a carbamoyl-directed C–H activation process. Soon
alkylindoles 85 and oxindolyl b,g-unsaturated a-ketoesters 617 afterwards, employing commercially available L-pyroglutamic acid
for straightforward access to a series of enantiomerically as a chiral ligand, a Pd-catalyzed enantioselective C–H carbonyla-
enriched spiro-polycyclic indole derivatives 618 was disclosed tion using silver carbonate as an oxidant under the balloon
by the group of Wang in 2017 (Scheme 146).281 It was found pressure of CO, allowing convenient access to chiral isoquinoli-
that various 3-methylindoles were well-tolerated, whereas steri- nones, was established by Xia, Lan and co-workers (Scheme 147).283
cally hindered 3-isopropylindole led to unsatisfactory results. The additive (S)-BINOL as a catalytic coordination ligand was found
This reaction was proposed to proceed first via Friedel–Crafts to be vital for improving the yield by preventing the formation of Pd
alkylation to generate intermediate Int-I, followed by N- black. Mechanistic studies and DFT calculations indicated that the
hemiketalization to produce complex Int-II, which underwent C–H activation was involved in the rate-determining step.
dehydration with the assistance of Lewis acid and the subse- A highly efficient synthesis of various indolin-2-ones 622
quent second Friedel–Crafts alkylation would lead to the for- bearing a chiral all-carbon quaternary center through a
mation of the desired product. Pd(II)-catalyzed enantioselective amination of aryl C–H bonds
In 2019, Xu’s group realized an enantioselective oxidative was discovered by the group of Wang and Li in 2020
C–H/N–H carbonylation process using a bimetallic Pd/Cu- (Scheme 148).284 Key to the success of the reaction is the use
based catalyst system in combination with a mono-N- of mono-N-protected a-amino-O-methylhydroxamic acid
protected amino acid ligand under balloon pressure with a (MPAHA) ligands, which played a crucial role in facilitating
mixture of CO/O2 for the expedient synthesis of various lactam- the reaction and controlling the enantioselectivity. It was found
type products including isoindoline-1-ones and isoquinoline-1- that hexafluoroacetylacetate and acetate counteranions were
ones (Scheme 147).282 Notably, Pd(OAc)2, CuCl2 and Cs2CO3 essential for stereocontrol and reactivity enhancement.
were all vital for facilitating the reaction. It was found Very recently, an unprecedent method for synthesizing both
that Ts-protected dibenzylmethylsulfonamides reacted smoothly spiro and nonspiro indenes 624 bearing all-carbon quaternary
whereas Ts-protected 2,2-diphenylethan-1-sulfonamide resulted in stereocenters was described by Xu, Cui and co-workers,

Scheme 147 Pd-Catalyzed enantioselective oxidative C–H/N–H

carbonylation. Scheme 149 Pd-Catalyzed [3+2] annulation of oxime ethers and alkynes.

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involving a [3+2] annulation of oxime ethers 623 and alkynes 11.2. C(sp3)–H functionalization
202 (Scheme 149).285 The reaction, which proceeded via PdII- 11.2.1. Pd(0)/Pd(II) catalytic cycle
catalyzed atroposelective C–H activation/double carbopallada- 11.2.1.1. C(sp3)–H arylation. Employing a new sterically
tion, was promoted by Pd(OAc)2 and Ac-L-Ala-OH and required hindered chiral NHC ligand, a highly enantioselective Pd-
AgOAc as an oxidant. The substituent at the nitrogen atom of catalyzed C(sp3)–H activation of prochiral N-aryl-N-cycloalkyl
the oxime directing group was found to be essential for the
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methyl carbamate 629 to provide enantioenriched trans-2,3-

reaction, and O-methyl oxime was found be more favorable fused indolines 630 was accomplished by Kündig et al. in 2012
than O-benzyl oxime since the latter decreased the yield and (Scheme 151).288 This C(sp3)–H activation occurred at the
enantioselectivity significantly. The hypothesized mechanism methylene site of a cycloalkane moiety. It was found that
considered the oxime-directed and MPAA-assisted atroposelec- the ring size of the cycloalkane moiety was essential for
tive C–H activation of oxime ether to produce axially chiral this transformation, and N-cyclopentyl carbamates failed to
palladium intermediate, followed by alkyne coordination and produce the target products whereas the N-cycloheptyl group
migratory insertion to generate an eight-membered pallada- led to higher asymmetric induction than the N-cyclohexyl
cycle Int-I, which could undergo intramolecular migratory one. Almost simultaneously, Cramer’s group demonstrated
insertion to produce alkylpalladium species Int-II accompanied the utility of their newly developed modular monodentate
by transient axial-to-central chirality transfer and subsequent b- phosphines in palladium-catalyzed C(sp3)–H activation of aryl
H elimination, resulting in the desired product. triflates 631, providing the important indoline scaffold 632 in a
11.1.3. Pd(II)/Pd(IV) catalytic cycle. In 2013, Wang’s group highly enantioselective fashion (Scheme 151).289 Notably, the
presented the first example of enantioselective C–H functiona- reactivity could be further extended to CH3 and non-cyclic
lization of phenylacetic acids 625 through Pd(II)/Pd(IV) redox methylene groups in addition to cyclic methylene groups. In
catalysis with the use of PhI(OAc)2 as an effective oxidant and this reaction, bulky carboxylic acid as a second ligand was
Boc-Ile-OH as a chiral ligand, offering a direct route for the found to be vital in the proton abstraction step and participated
synthesis of chiral benzofuranones 626 with up to 96%
ee (Scheme 150).286 Another example utilizing a Pd(II)/Pd(IV)
catalytic cycle was developed by the group of Zhang and
Huang in 2022, which involved palladium-catalyzed intra-
molecular dehydrogenative arylboration of alkenes 627 with
bis(pinacolato)diboron (B2pin2), providing easy readily access
to chiral indole-fused dihydro-pyrrole compounds 628.287 It was
found that employing a PyrOx type ligand with an electron-
withdrawing group could significantly improve the yield and
enantioselectivity of the target product. Moreover, DFT calcula-
tions revealed a detailed reaction pathway and the origin of the
enantioselectivity.

Scheme 150 Enantioselective C–H functionalizations through a Pd(II)/

Pd(IV) catalytic cycle. Scheme 151 Pd-Catalyzed enantioselective C(sp3)–H activation reaction.

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in the enantio-determining event in a highly cooperative

manner. Soon afterwards, Kündig et al. showed that Pd–NHC
complexes were effective catalysts for both methyl C–H
activation and methylene C–H activation (Scheme 151).290
Prochiral precursors could yield single 2,3-disubstituted
indolines with high enantioselectivity, whereas chiral racemic
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precursors undergo a regiodivergent reaction, resulting

in an enantioenriched mixture including 2-substituted and
2,3-disubstituted indolines. Utilizing a catalytic chiral base
and an achiral phosphine ligand, a highly enantioselective
synthesis of a variety of indoline products 637 containing
both tri- and tetra-substituted stereocenters via palladium(0)-
catalyzed asymmetric C(sp3)–H arylation was realized by Bau-
doin and co-workers in 2017 (Scheme 151).291 Notably, high
levels of enantioselectivity were achieved by fine tuning of both
BINOL-derived phosphoric acid and the reaction solvent.
Kündig et al. further extended the application of the devel-
Scheme 153 Pd-Catalyzed C(sp3)–H arylation to form chiral dihydroiso-
oped NHC ligands to the synthesis of 3,3-disubstituted oxi-
quinolones and dihydroquinolones.
ndoles 640 via palladium-catalyzed asymmetric intramolecular
a-arylation of amides (Scheme 152).292 DFT calculations
revealed that the oxidative addition was the rate-determining step
while reductive elimination was likely the enantioselectivity-
determining step.
Another example of this type of palladium(0)-catalyzed
C(sp3)–H arylation was the formation of chiral dihydroisoqui-
nolones and dihydroquinolones through the reaction of cyclo-
propanes 641. In Cramer’s work, this reaction was enabled by a
Taddol-based phosphoramidite ligand, offering an unprece-
dented efficient route to construct the 7-membered ring of
the cyclopropyl indolobenzazepine core of BMS-791325.
(Scheme 153).293 Later, Charette and co-workers showed that
the hemilabile bisphosphine monoxide (R,R)-BozPhos was also
Scheme 154 Pd-Catalyzed enantioselective C(sp3)–H arylation of N-(o-
effective for this reaction (Scheme 153).294 It was found that the Br-aryl)anilides.
pyridine substrate could react smoothly but led to a quite low
ee value probably due to the binding of the nitrogen to the
palladium complex. Notably, BozPhos most likely acted as a only facilitated the expected transformation but also allowed
monodentate ligand in the enantioselective CMD transition for the transformation into optically active quaternary amino
state and an additional ligand could minimize dissociation. acid derivatives.
In the presence of the Pd/TADDOL-derived phosphoramidite Recently, the Baudoin research group reported the synthesis
catalytic system, enantioselective C(sp3)–H arylation of N-(o-Br- of valuable indane products 646 containing a tertiary stereo-
aryl)anilides 643 for the expedient synthesis of quaternary a- center through an enantioselective intramolecular arylation of
nitro amides 644 was disclosed by Duan and co-workers in 2020 non-activated secondary C–H bonds using chiral C2-symmetric
(Scheme 154).295 Investigations on the a-substituent effect of IBiox ligands (Scheme 155).296 Indanes bearing a sensitive
substrates suggested that the presence of an electron-deficient tertiary stereocenter could also lead to an efficient synthesis
group played a vital role in facilitating the progress of the depending on the amide substituents and upon careful control
reaction. The presence of the nitro group on the substrate not of the reaction time. Moreover, an analysis of the steric maps of
the IBiox ligands suggested that these ligands possessing the
greatest difference between the two most occupied and the two
less occupied space quadrants were responsible for the high
enantiocontrol.

11.2.1.2. C(sp3)–H alkylation. Using a bulky TADDOL-derived

phosphoramidite ligand in combination with adamantyl
carboxylic acid as a cocatalyst, an asymmetric palladium(0)-
Scheme 152 Pd-Catalyzed asymmetric intramolecular a-arylation of catalyzed C(sp3)–H alkylation of readily accessible chloroaceta-
amides. mide substrates 647 for the direct synthesis of b-lactams 648

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Scheme 155 Pd-Catalyzed enantioselective intramolecular arylation of

non-activated secondary C–H bonds.
Scheme 157 Pd-Catalyzed direct alkenylation of cyclopropyl C–H
bonds.
with high efficiency, was established by Cramer’s group in 2014
(Scheme 156).297 This transformation involved the construction
of challenging C(sp3)–C(sp3) bonds and a strain-building yielding cyclopropyl-fused azacycles with 88% ee and 90% ee,
reductive elimination step to form the four-membered ring. respectively.
Several control experiments indicated that C(sp3)–H activation
occurred via a CMD mechanism. The same group later 11.2.1.4. C(sp3)–H carbamoylation. Employing a new
showed that the catalytic system with a Pd complex and a TADDOL-derived phosphonite, the enantioselective synthesis
TADDOL-derived phosphoramidite ligand in combination with of b-lactams 654 through palladium(0)-catalyzed C(sp3)–H
adamantyl carboxylic acid worked equally well for the facile carbamoylation was studied by Baudoin and co-workers
synthesis of cyclopropane-fused g-lactams 650 via C–H functio- in 2017 (Scheme 158).300 Notably, this reaction involved an
nalization of an achiral cyclopropane 649 via a similar mecha- unprecedented desymmetrization of unactivated methyl
nism (Scheme 156).298 Besides cyclopropanes as a source of groups. Chiral b-lactam could be efficiently synthesized in
activatable C–H bonds, substrates with methyl groups could 76% yield with 84% ee under the balloon pressure of CO. On
react efficiently but with lower ee values. the other hand, using 9-methylfluorene-9-carbonyl chloride
(COgen) as a nongaseous source of stoichiometric CO
11.2.1.3. C(sp3)–H olefination. In 2016, the group of enabled the formation of b-lactam in higher yield (86%) with
Charette reported their preliminary studies on palladium- slightly decreased ee (72%).
catalyzed direct alkenylation of cyclopropyl C–H bonds, provid-
ing direct access to chiral cyclopropyl-fused azacycles 652
(Scheme 157).299 Both BozPhos and IPrMonophos ligands 11.2.1.5. C(sp3)–H functionalization–addition cascade. In
exhibited high enantioinduction for this transformation, 2017, Cramer’s group demonstrated an enantioselective C–H
functionalization–addition sequence enabled by a modular and
bench-stable diazaphospholane ligand using trifluoroaceti-
midoyl chlorides 655 as electrophilic partners, providing a
novel and useful method for the construction of densely
substituted 3-azabicyclo[3.1.0]hexanes 657 (Scheme 159).301
The reaction involved an enantioselective C–H functionaliza-
tion route to perfluoroalkyl-containing cyclic ketimine products
656, which could react smoothly with a broad variety of
nucleophiles in one-pot processes. It was notable that a
remarkable Thorpe–Ingold effect was observed in this

Scheme 158 Pd-Catalyzed enantioselective C(sp3)–H carbamoylation

Scheme 156 Pd-Catalyzed asymmetric C(sp3)–H alkylation reaction. reaction.

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key p-allylpalladium intermediate Int-A, followed by an enantio-

selective semipinacol rearrangement, in which the chiral phos-
phoric acid may possibly serve as a counteranion/anionic
ligand. It was found that employing a substrate with two
possibilities of bond migration (methylene vs. phenyl), only
Scheme 159 Pd-Catalyzed enantioselective C–H functionalization–
the product resulting from methylene migration was produced.
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addition sequence.
Moreover, kinetic isotope studies revealed that allylic C–H
bonds were broken prior to or during the rate-limiting step.
cyclization, as substrates without gem disubstituents resulted Later, with the cooperative catalysis of a palladium complex of a
in poor yield. chiral phosphoramidite ligand and 2-fluorobenzoic acid, Gong
11.2.2. Pd(II)/Pd(0) catalytic cycle. An interesting method and co-workers in 2015 accomplished an enantioselective intra-
for synthesizing chiral spirocyclic indenes 659 via a Pd(II)/ molecular allylic C–H oxidation for the expedient synthesis of
Brønsted acid catalyzed enantioselective allylic C–H activation various optically active chromans 661 (Scheme 160).303 Mecha-
using BQ as an oxidant was disclosed by Rainey et al. in 2012 nistic investigations suggested that this reaction proceeded
(Scheme 160).302 This transformation was believed to initiate through a Pd-catalyzed allylic C–H activation and subsequent
with Pd(II)-catalyzed direct allylic C–H activation to generate the asymmetric allylic alkoxylation, rather than a Wacker-type

Scheme 160 Pd-Catalyzed allylic C–H functionalization reaction.

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pathway. The potential application of this method was further

demonstrated by the efficient asymmetric synthesis of a key
intermediate to access (+)-diversonol. Another example of
asymmetric allylic C–H oxidation allowing convenient access
to chiral isochroman motifs 663 was developed by White et al.
in 2016 (Scheme 160).304 Key to the success of this reaction was
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the use of a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand.

Additionally, mechanistic investigation indicated that C–H
cleavage cannot be the enantio-determining step. The signifi-
cance of the reaction process was illustrated by the synthesis of Scheme 162 Pd-Catalyzed enantioselective C(sp3)–H functionalization
PNU-109291, a pharmaceutical compound as a selective 5HT1D of cyclopropylmethylamines.

agonist. Subsequent studies by the Gong group showed that a

palladium catalyst containing a chiral phosphoramidite ligand
was effective for asymmetric intramolecular allylic C–H amina- One route involved a hydrogen bond between the NH and the
tion, offering an unprecedented efficient route for the selective phosphate ligand, and C–H cleavage via a CMD pathway with
synthesis of various substituted chiral hydropyrimidinones 665 the use of the acetate group. The other involved a hydrogen
with high enantioselectivities (Scheme 160).305 Besides, dienyl bond between the NH and an acetate group, and C–H cleavage
sodium N-sulfonyl amides 666 bearing an arylethene-1-sulfonyl mediated by the phosphate ligand.
group also reacted smoothly, yielding chiral fused An attractive example involving a Pd-catalyzed enantio-
tricyclic tetrahydropyrimidinone frameworks 667 with high selective C(sp3)–H functionalization of cyclopropylmethyla-
levels of stereoselectivity through a sequential allylic C–H mines 673 was accomplished by the group of Yu in 2020
amination and intramolecular Diels–Alder (IMDA) reaction (Scheme 162).308 Key to the success of this reaction was the
(Scheme 160). This method was a highly reliable transforma- use of a chiral bidentate thioether ligand, characterized by its
tion as it was used as the key step in the synthesis of letermovir. privileged bidentate coordination mode and a thioether motif.
Recently, an interesting intermolecular [4+2] cycloaddition Cyclopropylmethylamines could react smoothly with aryl and
involving the direct Pd(0)-catalyzed allylic C–H functionaliza- heteroaryl iodide to afford various chiral g-(hetero)aryl free
tion to provide straightforward access to a broad range of chiral amines through a Pd(II)/Pd(IV) catalytic cycle. Notably, employ-
hydroquinolines 670 was established by the group of Li and Liu ing the same chiral ligand, a series of g-olefinated free amines
(Scheme 160).306 Utilizing a chiral alkylphosphine ligand was and g-lactams were efficiently synthesized through C(sp3)–H
the key for the success of the reaction. This reaction was carbonylation and olefination reactions via Pd(II)/Pd(0)
thought to proceed via the key palladium-containing 1,4- catalytic cycle.
dipolar intermediate. The investigation into the effect of the 11.2.3. Pd(II)/Pd(IV) catalytic cycle. A streamlined method
oxidant indicated that the oxidant as well as the corresponding for synthesizing b-aryl b-lactams 679 was described by Chen,
hydroquinones in combination with palladium played an Liu and He in 2019, involving a Pd(II)-catalyzed enantioselective
essential role in the stereocontrol of C–C bond formation. intramolecular C(sp3)–H amidation reaction (Scheme 163).309
Control experiments suggested that allylic C–H functionaliza- Various substituents at meta and para positions of aryl groups
tion might take place through the concerted proton and two- reacted smoothly whereas ortho-substituted or electron-
electron transfer process. deficient aryl groups resulted in a significantly lower yield
In 2017, Gaunt and co-workers reported a palladium- and ee. Intramolecular amination of the unactivated C(sp3)–H
catalyzed enantioselective C–H activation of aliphatic amines bond was found to be less efficient, yielding the desired
671 employing a chiral BINOL phosphoric acid ligand, provid- product with low yield and moderate ee. Mechanistic studies
ing efficient access to a series of synthetically valuable aziri- indicated that employing 2-methoxy-5-chlorophenyl iodide as
dines 672 (Scheme 161).307 It was found that the electronic an oxidant played a vital role in controlling the competing C–N
properties of the N-aryl group in amines had a considerable versus C–C reductive elimination pathways of the PdIV inter-
effect on the enantioselectivity. The authors proposed two mediate. Soon afterwards, using 3,3 0 -substituted BINOL ligands
possible pathways for the enantioselective C–H activation. in combination with a 2-pyridinylisopropyl (PIP) auxiliary, the
straightforward synthesis of chiral b-lactams 682 through a
Pd(II)-catalyzed enantioselective amidation of methylene
C(sp3)–H bonds was investigated by Shi and co-workers
(Scheme 163).310 It was found that both benzylic and unbiased
methylene C(sp3)–H bonds from aliphatic carboxamides could
be easily activated. Notably, tuning the steric and electronic
properties of aryl iodide as an oxidant was essential for both
high stereocontrol and selectivity for C–N reduction, with 2-
Scheme 161 Pd-Catalyzed enantioselective C–H activation of aliphatic fluoro-1-iodo-4-nitrobenzene being the optimal choice. Subse-
amines. quent studies by the same group showed that the similar

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chiral g-lactam, and the Pd(0) species was reoxidized to Pd(II)

with the assistance of vinyl iodide.

12. Cyclization via a-,b- or c-

functionalization of carbonyl
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containing compounds
12.1. Cyclization via a-arylation of aldehydes or ketones
Utilizing their newly developed C1-symmetric chiral phos-
phino–pyridine ligands based on the atropoisomeric binepine
scaffold, a highly enantioselective Pd-catalyzed intramolecular
a-arylation of a-branched aldehydes 687, providing convenient
access to a series of bicyclic aldehydes 688 bearing a quaternary
stereogenic center, was established by the group of Mazet in
2012 (Scheme 164).313 It was found that aryl chloride or iodide
in place of aryl bromide led to significantly diminished yield
while maintaining a very high level of enantioselectivity. a-
Methyl or ethyl substituent proved to be amenable to this
transformation, whereas a phenyl or secondary alkyl substitu-
ent had a detrimental effect on either activity or the selectivity.
In the presence of the Pd(OAc)2/achiral PPh3 ligand com-
bined with L-proline, Jia and co-workers in 2016 described an
enantioselective a-arylative desymmetrization of cyclohexa-
nones 689, providing a simple route to a series of optically
active morphan 690 derivatives bearing a-carbonyl tertiary
stereocenters (Scheme 165).314 Examining the effect of halogen
suggested that the bromo substrate was more favorable than
the iodo or chloro substrate. It was found that the N-protecting
group had a remarkable effect on the reaction outcome, and
substrates bearing methyl or benzyl protecting groups pro-
ceeded smoothly whereas remarkably lower yields and

Scheme 163 Pd-Catalyzed enantioselective C(sp3)–H functionalization

through a Pd(II)/Pd(IV) catalytic cycle.

catalytic system was also applied to a Pd(II)-catalyzed enantio-

selective aliphatic methylene C(sp3)–H alkenylation–aza-
Wacker cyclization of aliphatic amides 683 with vinyl iodides
370 for the facile synthesis of various chiral b-stereogenic g-
lactams 684 (Scheme 163).311 Notably, the use of 3,3 0 -F2-BINOL
and 3,3 0 -CN2-BINOL as chiral ligands proved to be crucial for
the reaction. Control experiments suggested that the stereo-
chemistry of olefin was controlled by the syn-aminopalladation
in the aza-Wacker cyclization, and this cascade reaction invol- Scheme 164 Pd-Catalyzed intramolecular a-arylation of a-branched
ving an enantioselective C–H alkynylation–cyclization pathway aldehydes.
was ruled out. The authors further extended this cascade
reaction for the synthesis of a,b-stereospecific g-lactams 686
with high enantio- and diastereoselectivities (Scheme 163).312
The mechanism was proposed to be initiated with the desym-
metric C–H alkenylation of gem-dialkyl C(sp3)–H bonds to
generate intermediate Int-I, followed by an oxidative addition
of vinyl iodide yielding PdIV intermediate Int-II, which under-
went reductive elimination to produce the alkenylation product
intermediate Int-III. The subsequent intramolecular syn- Scheme 165 Pd-Catalyzed enantioselective a-arylative desymmetriza-
aminopalladation and b-H elimination would furnish the final tion of cyclohexanones.

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enantioselectivities were achieved using N-benzoyl and N- DFT calculations indicated that benzylamine played a vital
ethoxycarbonyl substituted substrates. Besides, bridged ring role in accelerating the reaction rate and enhancing the
products bearing tetrasubstituted stereocenters could also be enantioselectivities.
prepared efficiently when 1,6-bis(diphenylphosphino)hexane In addition to synergistic co-catalysis, transition-metal cata-
(dpph) was used as the achiral ligand instead of PPh3. More- lysts were also found to be efficient for enantioselective a-
over, control experiments indicated that L-proline was more arylation of ketones. In 2017, Shi and co-workers established
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likely to act as an enamine catalyst to activate the ketone. This an intramolecular asymmetric a-arylative desymmetrization of
transformation was proposed to proceed through the formation 1,3-diketones 699 with the use of a catalyst composed of
of enamine intermediates and subsequent Heck arylation. Pd(OAc)2 and the FOXAP ligand that provided expedient access
Later, an enantioselective desymmetrization of cyclobuta- to highly oxygenated and densely substituted bicyclo[m.n.1]
nones enabled by combining the palladium/phosphorous skeletons 700 of different sizes (Scheme 167).317 It was notable
ligand with enamine catalyst systems was established by Lu’s that both molecular sieves and Cs2CO3 were essential for
group in 2018 (Scheme 166).315 The authors showed that the
Pd-(S,S)-BDPP complex as a transition-metal catalyst and com-
mercially available (S)-indoline-2-carboxylic acid as a chiral
aminocatalyst were effective for the intramolecular arylation
of O-tethered cyclobutanone 692. For the arylation of N-
tethered substrate 695, palladium catalysts containing a chiral
phosphoramidite ligand and achiral pyrrolidine were needed.
These two distinct modes of asymmetric induction were proved
to be highly efficient for synthesizing enantiomerically
enriched cyclobutanones fused to an O- or N-heterocyclic ring.
Further studies by the Liu group demonstrated that using
commercially available tBuPhox as the chiral ligand and cheap
benzylamine as the cocatalyst, palladium-catalyzed desymme-
trization of g-quaternary carbon-containing cyclohexanones
697 was a useful method for the construction of various
complex bicyclo[3.3.1]nonanones 698 with a quaternary
carbon bridgehead (Scheme 166).316 Notably, aryl and alkenyl
bromides as well as less reactive triflates proved to be
amenable to this transformation. Mechanistic studies and

Scheme 166 Enantioselective desymmetrization of cyclobutanones and

cyclohexanones employing synergistic co-catalysis. Scheme 167 Pd-Catalyzed enantioselective a-arylation of ketones.

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facilitating the reaction. The significance of this method was

demonstrated by the efficient asymmetric total synthesis of
()-parvifoline. Later, a catalytic system consisting of Pd(dba)2
and a strongly donating Josiphos ligand was shown to be
effective for the enantioselective arylation of racemic ketones
701 to construct bridged bicyclic rings 702 via dynamic kinetic
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resolution, which was disclosed by Zhou’s group in 2018

(Scheme 167).318 Key to the success of the reaction was the
use of a moderately strong base which could promote rapid
racemization at the a 0 -position of the ketone via reversible
enolization. When DMSO-d6 was used, extensive deuteration
was observed at both a- and a 0 -positions in the products, which
demonstrated that this transformation involved a rapid, rever-
sible deprotonation of ketones. The Tang group further found
an effective catalytic system employing the chiral monopho-
sphorus ligand BI-DIME for the enantioselective palladium-
catalyzed a-arylation with sterically hindered substrates 703,
providing a novel and useful method for the construction of a
Scheme 169 Pd-Catalyzed enantioselective a-carbonylative arylation reaction.
chiral all-carbon quaternary center (Scheme 167).319 Notably, this
reaction was a highly reliable transformation as it was used as one
of the key steps in the total syntheses of various natural products DFT calculations and the results suggested that this transfor-
and drugs, such as (S)-nafenodone, (+)-sceletium A-4, ()-coryno- mation proceeded through reductive elimination rather than a
line and ()-DeN-corynoline. The same group in 2020 extended the nucleophilic addition pathway. The mechanism of this reaction
enantioselective palladium-catalyzed a-arylation to construct spiro was proposed to proceed via an oxidative addition of aryl
quaternary carbon stereocenters using a sterically hindered and bromine to Pd(0) to produce palladium(II) species Int-I, fol-
electron-rich P-chiral monophosphorus biaryl ligand, leading to a lowed by CO coordination and insertion to generate an
wide range of [4.4], [4.5], and [4.6]-spirocycles 706 (Scheme 167).320 acylpalladium(II) complex Int-II, which underwent ligand
Notably, the addition of water was of utmost importance to exchange and isomerization under basic conditions to form
enhance the enantioselectivity. a-pallado ketone intermediate Int-III and subsequent reductive
elimination, yielding the final cyclization product.
12.2. Cyclization via a-arylation of ketimino amides
12.4. Cyclization via b-arylation of enamines
In 2012, Ley and co-workers applied the Pd-(R)-DiFluorPhos
system for the asymmetric intramolecular arylation of a- In 2021, Jia, Yang and co-workers established an enantio-
ketimino amides 707, providing access to various enantiomeri- selective palladium-catalyzed intramolecular b-arylation of tet-
cally enriched 3-amino-2-oxindoles 708 (Scheme 168).321 It was rasubstituted endocyclic and exocyclic enamines, offering an
found that the electronic nature of the imine substituent played unprecedented efficient route for the selective synthesis of
important roles in enantioselectivity of this transformation, optically active fused- or spiro-indolenines and 1H-indole deri-
with electron-donating substituents leading to lower enantios- vatives (Scheme 170).323 In the presence of chiral palladium
electivity than electron-withdrawing substituents. catalysts ligated by (S,Sp)-PhOSFERROX with Cs2CO3 as the
base, a series of endocyclic enamines 711 reacted smoothly to
12.3. Cyclization via a-carbonylative arylation of ketones afford medium-ring fused indolenines 712 with high enantios-
An efficient method for synthesizing a diverse set of chiral spiro electivity. Besides, the catalytic system with Pd(OAc)2 and
b,b 0 -diketones 710 bearing various ring sizes was described by (S)-tBuPHOX was found to work well for b-arylation of exocyclic
Tang et al. in 2021 (Scheme 169), which involved enantio- enamines 713, affording various chiral 3,3 0 -spiroindolenines
selective Pd-catalyzed a-carbonylative arylation employing an 714 using K3PO4 as a base. For the facile synthesis of enan-
ethylene-bridged chiral bisphospholane (R,R)-Ph-BPE as a tioenriched 1H-indoles 716 from endocyclic enamines 715, a Pd
chiral ligand under CO (1.5 atm).322 The authors carried out catalytic system derived from (S)-DIFLUORPHOS and the use of
Ag3PO4 as a base were required. Moreover, DFT calculations
revealed that this reaction probably proceeded via a domino
enamine-isomerization/b-arylation sequence, forming the 1H-
indole product.

12.5. Cyclization via c-arylation of b,c-unsaturated

butenolides
Scheme 168 Pd-Catalyzed enantioselective a-arylation of ketimino Employing a catalyst composed of Pd(dba)2 and Antphos, an
amides. enantioselective g-arylation of b,g-unsaturated butenolides 717

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intramolecular ipso-Friedel–Crafts allylic alkylation of phenols

721 (Scheme 172).325 In the presence of 5 mol% Pd(dba)2, 6
mol% of a Trost ligand, and 1 equiv. of Li2CO3 as an additive,
spirocyclohexadienone 722 could be prepared efficiently in
80% yield with 89% ee. Later, You’s group showed that palla-
dium catalysts containing a chiral Trost ligand were also
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effective for the intermolecular asymmetric allylic dearomatiza-

tion reaction of naphthol derivatives 723, providing straightfor-
ward access to various chiral b-naphthalenones 725 bearing an
all-carbon quaternary chiral center with high performance
(Scheme 172).326 The reaction was quite general and efficient,
tolerating a wide range of substituents, in both b-naphthol and
allylic carbonates. In 2016, a preliminary exploration of

Scheme 170 Pd-Catalyzed enantioselective intramolecular b-arylation of

tetrasubstituted endocyclic and exocyclic enamines.

Scheme 171 Pd-Catalyzed enantioselective g-arylation of b,g-

unsaturated butenolides with aryl bromides.

with aryl bromides 370 was accomplished by the group of

Zhang and Yang, allowing convenient access to a series of
chiral quaternary arylated g-butenolide 718 with high g-
selectivity and excellent enantioselectivity (Scheme 171).324
Strikingly, the authors further applied this protocol for the
efficient synthesis of tricyclic tetrahydroindolines and tetrahy-
droisoquinolinones 720 in one step. The application of this
methodology was underscored by the efficient synthesis of the
natural product (R)-(+)-boivinianin A. Moreover, DFT calcula-
tions revealed that g-arylation was more favorable than a-
arylation, which was consistent with the experimental results.

13. Cyclization via catalytic

asymmetric dearomatization
13.1. Dearomatization reaction of naphthol or phenol
derivatives
13.1.1. Via allylic substitutions. In 2012, Hamada and co-
workers reported the synthesis of spirocyclohexadienones 722 Scheme 172 Pd-Catalyzed dearomatization reaction of naphthol or phe-
with an all-carbon quaternary spirocenter via the Pd-catalyzed nol derivatives via allylic substitutions.

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enantioselective Pd(0)-catalyzed dearomatization of naphthol- chiral biaryl monophosphorus ligand AntPhos. Recently,
based biaryl 726 with 1,3-dienes 129 enabled by a chiral another example of asymmetric palladium-catalyzed dearoma-
phosphoramidite ligand was presented by the group of tization using a Pd-(S)-BI-DIME catalyst, allowing convenient
Luan, affording a chiral spirocarbocycle in 76% yield with access to various enantioenriched bridged tetracyclic skeletons
80% ee (Scheme 172).327 This transformation involved an 737, was demonstrated by the same group (Scheme 173).335
oxidative addition/olefin insertion/allylative dearomatization In 2015, Luan and co-workers reported that a Pd-NHC
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sequence. Recently, an interesting method for synthesizing system was an effective catalyst for the dynamic kinetic asym-
bicyclo[3.3.1]alkenone 730 through the enantioselective dear- metric spiroannulation of racemic biaryl substrates 726 with
omative allylic annulation of allyl desoxyhumulones 728 with internal alkynes 202, opening a new avenue for the synthesis of
allylic decarbonates 729 catalyzed by a Pd catalytic system enantioenriched spirocyclic products containing an all-carbon
derived from a chiral phosphoramidite ligand was described quaternary stereocenter with excellent enantioselectivities
by Zhang, Yang and co-workers (Scheme 172).328 The synthetic (Scheme 174).336 This reaction, which involved an axial-to-
application of the reaction process was illustrated with central chirality transfer process, tolerated a wide range of
the diversity-oriented synthesis of polycyclic polyprenylated biaryl substrates, such as 4-(2-bromoaryl)-naphthalen-1-ols
acylphloroglucinol (PPAP) analogues and variants. Soon and 2 0 -bromo-[1,1 0 -biphenyl]-4-ols. The authors also found that
afterwards, a catalytic system employing [Pd(allyl)Cl]2 and the use of configurationally labile biaryls was essential for the
a N-allyl phosphoramidite ligand was shown to be effective success of this novel DYKAT method. Besides symmetrical
for the construction of chiral indole–terpenoid frameworks 731 alkynes, unsymmetrical alkynes also reacted smoothly, forming
through the enantioselective domino Heck cyclization/dearo- products where the alkyl group was close to the spirocyclic
matization reaction between b-naphthols 723 and N-(2- carbon center. Employing (1,n)-diynes as reaction partners, the
iodophenyl)allenamides 572, which was established by the same group reported their preliminary studies on the
group of Guo and Wang (Scheme 172).329 It was notable that palladium(0)-catalyzed dearomative cyclization reaction with
both nitrogen protecting groups of allenamides and substitu- bromophenols to construct new polycyclic architectures bear-
ents at the 3-position of b-naphthol had a significant influence ing an all-carbon quaternary center (Scheme 174).337 In the
on the enantioselectivity of the products. Moreover, the linear presence of chiral palladium catalysts ligated by TADDOL-
relationship between the ee value of the ligand and product derived phosphoramidite, 4-bromonaphthalen-1-ol 739 reacted
indicated the possible existence of a monomeric chiral catalyst with a dialkyl-diaryl mixed diyne 740 to afford 741 in 83% yield
in this reaction.
13.1.2. Via cross-coupling. In 2014, the group of You
reported their preliminary studies on the asymmetric Pd-
catalyzed dearomatization of 5-hydroxyl indoline 732 for direct
access to chiral erythrinane skeleton 733 with a promising
enantioselectivity albeit in moderate yield (31% yield, 86% ee)
with the use of a TADDOL-derived phosphoramidite ligand
(Scheme 173).330 This transformation was proposed to proceed
through an oxidative addition of aryl bromine to Pd(0), followed
by a ligand exchange with the para-aminophenol moiety
assisted by a base and subsequent reductive elimination,
yielding the product. Employing their newly developed P-
chiral monophosphine ligand with a 2,5-diphenylpyrrole
moiety, versatile synthesis of chiral phenanthrenone derivatives
735 bearing an all-carbon quaternary center via a novel enantio-
selective palladium-catalyzed dearomative cyclization was rea-
lized by Tang’s group in 2015 (Scheme 173).331 Various
functional groups including substituted aryl or heteroaryl bro-
mines and vinyl triflate were amenable to this transformation.
The alkyl substituent at the 4a-position, including methyl, ethyl
and butyl, were well tolerated, whereas a phenyl substituent at
the 4a-position failed to give the desired product. Application of
this methodology was underscored by the efficient synthesis of
a kaurene intermediate, the skeleton of the anabolic steroid
boldenone and the antimicrobial diterpene natural product
()-totaradiol. The authors further extended this method to
the synthesis of triptoquinone H,332 immunosuppressants
(+)-dalesconol A and B,333 ()-crinine, indole alkaloid ()-aspi-
dospermidine as well as ()-minensine,334 with the use of P- Scheme 173 Pd-Catalyzed dearomative cyclization via cross-coupling.

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Scheme 175 Pd-Catalyzed dearomative cyclization of indoles via allylic

substitutions.

13.2.2. Via cross-coupling. A preliminary exploration of the

palladium(0)-catalyzed dearomative arylation of 3-substituted
indole 749 to synthesize chiral spiroindolenine 750 in 71%
yield with 61% ee was described by You et al. in 2012, employ-
Scheme 174 Pd-Catalyzed dearomative cyclization of naphthol or phe- ing [Pd(C3H5)Cl]2 as a precatalyst and a spiro phosphoramidate
nol derivatives with internal alkynes.
as a chiral ligand (Scheme 176).340 In their subsequent studies,
a convenient synthesis of spiroindolenines 752 bearing two
with 66% ee via a [2+2+1] spiroannulation. For an asymmetric stereogenic centers with excellent diastereo- and enantio-
[2+2+2] dearomative reaction of 3-bromo-4-methylphenol 742 selectivities via dearomative arylation of 3-substituted indole
with simple diyne 743, palladium catalysts containing a Feringa 751 through a desymmetrization strategy was established by
ligand were needed, leading to the desired product in 73% yield the same group in 2022 (Scheme 176).341 It was found that a
with 84% ee. BINOL-derived chiral phosphoramidite ligand was essential for
controlling the stereoselectivity of this reaction. Besides,
monoindole-derived substrates also reacted smoothly to afford
13.2. Dearomatization reaction of indoles chiral spiroindolenines with high performance.
13.2.1. Via allylic substitutions. By using palladium com-
plexes generated in situ from [Pd(C3H5)Cl]2 and a planar chiral
ferrocene-based ligand as a catalyst, asymmetric allylic dearo-
matization of 3-substituted indoles 745 to provide interesting
fused ring structures 746 bearing a stereogenic quaternary
carbon center with up to 78% ee was reported by You’s group
in 2013 (Scheme 175).338 A remarkable example of this type of
dearomatization was the formation of the tetracyclic core
structure of the indole alkaloid (+)-minfiensine, a transforma-
tion pioneered by Jiao and co-workers in 2016 (Scheme 175).339
The reaction, which was catalyzed by palladium catalysts con-
taining a chiral ligand with a dihydro-9,10-ethanoanthracene
(ANDEN) backbone, was proposed to proceed through an
asymmetric indole dearomatization/iminium cyclization cas-
cade. The electronic nature of the indole core was found to
have a significant effect on the enantioselectivity of this trans-
formation, in which electron-donating substituents led to
higher enantioselectivity than electron-withdrawing substitu-
ents. The significance of this method was demonstrated by the
efficient asymmetric total synthesis of the indole alkaloid Scheme 176 Pd-Catalyzed dearomative cyclization of indoles via cross-
(+)-minfiensine. coupling.

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14. Miscellaneous cyclization reaction

14.1. Denitrogenative annulation
In past decades, the denitrogenative annulation of benzotria-
zoles with suitable coupling partners has emerged as a valuable
strategy for the synthesis of diverse N-heterocyclic compounds
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of biological importance. In 2019, the first example of enantio-

selective denitrogenative cyclization of benzotriazoles 753 with
either allenes or N-allenamines 754 to provide a direct route to
a series of optically active 3-methyleneindolines was reported
by Zhang and co-workers (Scheme 177), using their developed
chiral sulfinamidephosphine(Sadphos)-type ligand (PC-
Phos).342 The hypothesized mechanism for this transformation
involved the generation of diazonium Int-I through a Dimroth-
type equilibrium of benzotriazoles, followed by an oxidative
addition process to produce Pd(II) intermediates. Subsequent Scheme 178 Denitrogenative cyclization of benzotriazoles with cyclic
insertion of allene or allenamide leads to the formation of a p- and acyclic 1,3-dienes.
allylpalladium complex, which then undergoes allylic substitu-
tion to produce the desired products and regenerate the Pd(0)
catalyst. hexahydrocarbazoles with the same absolute configuration. As
In addition to allenes and allenamides, it has been shown for acyclic 1,3-diene, PC-Phos was the optimal choice after
that 1,3-dienes could also undergo mechanistically related several attempts by the authors. Moreover, various transforma-
denitrogenative annulation. Two year later, the same group tions of the optically active hexahydrocarbazoles, such as
demonstrated that benzotriazoles could react with cyclic and hydrogenation, epoxidation, selective oxidative, etc., were also
acyclic 1,3-dienes 757 in the presence of Pd and Sadphos, showcased to demonstrate the synthetic value of the method.
yielding a variety of hexahydrocarbazoles and indolines in good
yields with high ee values (Scheme 178).343 It is worth mention- 14.2. Cyclization via C–C bond activation cascade reaction
ing the use of Xu-Phos and PC-Phos, which are optimum chiral Enantioselective palladium-catalyzed tandem reactions invol-
ligands for cyclic 1,3-dienes, can yield a pair of enantiomers of ving the nucleophilic capture of transient s-alkylpalladium
species generated by intramolecular carbopalladation of double
bonds, namely, Heck cascade reactions, has emerged as a
powerful tool. Alternatively, formal carbopalladation of the C–
C s-bond of cyclobutanones due to the inherent high ring
strain, also represents an elegant approach for generating the
key intermediate s-alkylpalladium species. In this regard, Xu,
Cao and co-workers have reported a series of studies on C–C
bond activation cascade reactions and established a practical
and robust Pd/TADDOL-derived phosphoramidite catalytic sys-
tem. The authors proposed two possible pathways for the ring-
opening process of cyclobutanones to form s-alkylpalladium
species (Scheme 179). The nucleophilic addition of the arylpal-
ladium species Int-I to the carbonyl group resulted in the
formation of an alkoxypalladium intermediate Int-II, which
underwent enantioselective b-carbon elimination, leading to

Scheme 177 Denitrogenative cyclization of benzotriazoles with allenes Scheme 179 Two possible pathways for the ring-opening process of
and N-allenamines. cyclobutanones to form s-alkylpalladium species.

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Scheme 180 Pd-Catalyzed enantioselective cyclization via C–C bond activation cascade reaction.

s-alkylpalladium species Int-II. In another pathway, the aryl- tandem C–C bond activation/Cacchi reaction between cyclobu-
palladium species Int-I underwent a second enantioselective tanones and o-ethynylanilines 767 to provide expedient access
oxidative addition to form the PdIV intermediate Int-IV, fol- to chiral indanone-substituted indoles 768 with high perfor-
lowed by a facile reductive elimination, producing the s- mance, was also accomplished by the same group.347 The
alkylpalladium species Int-III. authors further applied this cascade process to construct axially
As shown in Scheme 180, employing aryl or alkenyl boronic chiral indoles using naphthyl-substituted o-ethynylaniline 256
acids 9 as coupling reagents, they disclosed an enantioselective as substrates. Additionally, control experiments revealed that
ring opening/cross-coupling of cyclobutanones 760 in 2019, this transformation was unlikely to involve C–H activation of
allowing convenient access to a series of chiral indanones 762 indole intermediates.
bearing C3-quaternary stereocenters.344 It was found that cyclo-
butanones bearing various alkyl groups at the R1 position were 14.3. Oxidative carbocyclization of allenes
well-tolerated, whereas those bearing a phenyl group or hydro- In 2015, employing biphenol-type chiral phosphoric acid as a
gen led to the desired products in trace amount. Notably, in the superior co-catalyst, a palladium(II)-catalyzed enantioselective
absence of external coupling reagents, chiral cyclopropane- oxidative carbocyclization–borylation of enallenes 769 for the
fused indanones 761 were efficiently synthesized through a synthesis of to a number of chiral borylated carbocycles 770 was
ring-opening/cyclopropanation sequence. They further synthe- presented by Bäckvall and co-workers (Scheme 181).348 It was
sized various chiral indanones 765 bearing an alkyl iodide found that cycloalkylideneallenes provided a significant
group and an all-carbon quaternary stereocenter through a improvement in enantioselectivity compared to diethyl malo-
sequential C–C bond activation/alkyl iodide reductive elimina- nate. Notably, the terminal disubstitution of the allene played a
tion of cyclobutanones.345 Using KI as the source of iodide, aryl crucial role in facilitating the reaction and controlling the
bromides were also compatible. Moreover, DFT calculation enantioselectivity. Modifications on the alkene moiety were
indicated that this transformation proceeded through the unfavorable for this transformation, and aza-enallene was
involvement of the PdIV species. In their subsequent studies, incompatible with standard conditions perhaps due to its
the coupling reagent was extended to terminal alkynes 298.346 sensitivity to the acidic environment. They further investigated
Various chiral alkynylated indanones 766 bearing an all-carbon the reaction mechanism by means of DFT calculations.349 The
quaternary stereocenter were prepared efficiently by the reaction was proposed to be initiated with the deprotonation of
sequential C–C bond activation/Sonogashira reaction of cyclo- an allylic position of the allene coordinated to palladium(II),
butanones in the presence of the newly designed ligand with resulting in the formation of a vinylpalladium species Int-II,
bulky aryl groups bearing TMS and a fluorine atom. Recently, a followed by the alkene insertion to produce complex Int-III,

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(Scheme 181).351 It was found that heteroaryl acetylenes as well

as aliphatic acetylenes were all amenable to this transforma-
tion, whereas alkyne bearing a trimethylsilyl group resulted in
low yield and ee. Soon afterwards, utilizing a catalyst composed
of Pd(OAc)2 and biphenol-type phosphoric acid, preliminary
attempt to develop an enantioselective carbocyclization–boryla-
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tion of enallenes with B2Pin2 was studied by the group of

Bäckvall (Scheme 181), producing the cyclohexene 778 with a
reasonably moderate ee value (66%).352

14.4. Cyclization based on rearrangement reaction

Using (R)-BINAP as a chiral ligand, a palladium(II)-catalyzed
enantioselective tandem Claisen rearrangement/cyclization of
propargyloxy-indoles 779 for the efficient formation of spiro-
cyclic lactones 780 was investigated by Kozlowski and co-
workers in 2012 (Scheme 182).353 This reaction involved the
generation of allenyl-substituted oxindoles Int-I via Claisen
rearrangements of proparyloxy-substituted indoles, followed
by hydration to form a carbocation intermediate Int-III, which
was stabilized via the b-silyl effect. The subsequent palladium-
catalyzed cyclization resulted in the formation of lactone.
Notably, substrates bearing silyl groups played a vital role in
facilitating the reaction.
In 2016, the group of Morgan reported that a cationic
palladium(II)–(R)-DTBM-Segphos system was an effective
catalyst for the enantioselective Heine reaction of N-
acylaziridines 781 to produce highly enantioenriched oxazo-
lines 782 with up to 98% ee (Scheme 183).354 Various substi-
tuted 5-isoxazoles, 6-membered ring carbocyclic aziridines as
well as acyclic meso-aziridine substrates were proved to be
amenable to this transformation, while a 7-membered carbo-
cyclic backbone led to a lower conversion albeit with high
enantioselectivity. It was proposed that the Pd catalyst binds
to both nitrogen atoms of aziridine to form intermediate Int-I,
followed by bond reorganization step to generate complex Int-II
and subsequent dissociation of the palladium catalyst leading
to the final product. It was suggested that enantioselectivity was
introduced at the bond reorganization step.
Scheme 181 Pd-Catalyzed enantioselective oxidative carbocyclization
reaction of allenes.

which underwent transmetallation with B2Pin2 to afford inter-

mediate Int-IV. The subsequent C–B reductive elimination
resulted in the formation of the target product, and
palladium(0) was reoxidized to palladium(II) by benzoquinone.
Later, the same group reported their preliminary studies on
palladium-catalyzed oxidative cascade carbonylative spirolacto-
nization of enallenols with the use of (R)-VAPOL phosphoric
acid as a co-catalyst under atmospheric pressure of CO, leading
to spirolactone 773 bearing an all-carbon quaternary center
with 66% ee (Scheme 181).350 In their subsequent studies,
VAPOL phosphoric acid was also found to be an optimal co-
catalyst for the enantioselective palladium(II)-catalyzed carbo-
nylative carbocyclization of enallenes terminated with a cross- Scheme 182 Pd-Catalyzed enantioselective tandem Claisen rearrange-
dehydrogenative coupling (CDC) using a terminal alkyne 308 ment/cyclization of propargyloxy-indoles.

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vital role in controlling the enantioselectivity. Recently, in the

presence of chiral palladium catalysts ligated by their devel-
oped GF-Phos, the asymmetric carbenylative amination
between N-tosylhydrazones 791 and (E)-vinyl iodides 790 which
contain an amine moiety through a carbene migratory inser-
tion/Tsuji–Trost sequence that opened a new avenue for the
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synthesis of a variety of chiral 2-substituted pyrrolidines and

piperidines with high chemo-, regio-, enantioselectivities was
accomplished by the group of Zhang and Li (Scheme 185).357
This reaction involved the key intermediate palladium carbene
Int-I, which underwent migratory insertion to form the p-
Scheme 183 Pd-Catalyzed enantioselective Heine reaction of N- allylpalladium intermediate Int-II, followed by the nucleophilic
acylaziridines. attack by the nitrogen atom, yielding the desired product. The
significance of this method was further demonstrated by the rapid
asymmetric synthesis of natural product ()-norruspoline.
14.5. Cyclization based on carbene insertion reaction
Using b-isocupreidine (b-ICD) as a co-catalyst, an asymmetric 14.6. Cyclization through intramolecular asymmetric
Pd(II)-catalyzed cascade reaction between diazoacetamides 783 reductive amination
and MBH carbonates 784 that allowed convenient access to a An interesting method for synthesizing a wide spectrum of
series of multifunctional oxindoles 785 bearing a C-3 quatern- chiral sultams 794 was described by Zhou et al. in 2017, which
ary stereocenter, was disclosed by Hu’s group in 2016 involved a palladium-catalyzed intramolecular asymmetric
(Scheme 184).355 This tandem reaction tolerated a wide range reductive amination of ketones with weakly nucleophilic sulfo-
of substituents on both the aromatic rings, leading to chiral namides with the use of a Brønsted acid (Scheme 186).358 In the
oxindoles with up to 86% ee. Notably, this reaction involved the presence of chiral palladium catalysts ligated by (S,S)-f-
formation of two key intermediates: one was zwitterion inter- Binaphane, g-sultams were efficiently synthesized in excellent
mediate Int-A generated by C–H insertion reaction, and the yields with high ee values. Using D-camphorsulfonic acid (D-
other was a chiral MBH ammonium cation intermediate Int-B CSA) as the additive and (R,Sp)-Cy-JosiPhos as the chiral ligand,
via nucleophile attack of b-ICD on MBH carbonate. higher temperatures were required to promote the reductive
In 2021, Wang, Lan and co-workers presented a highly amination for the facile synthesis of chiral d-sultams. Besides, a
efficient palladium-catalyzed carbene insertion into carbon– catalytic system consisting of a Pd(II) complex, (R,Sp)-tBu-
silicon bonds of silacyclobutanes 788 for expedient access to JosiPhos, TsOHH2O was shown to be effective for allowing
a wide range of silacyclopentanes 789 with a three- or four- convenient access to chiral e-sultams. Subsequent studies by
substituted stereocenter with excellent enantioselectivity the same group showed that chiral d-sultams 796 with two
(Scheme 185).356 It was notable that the presence of matched contiguous stereogenic centers could also be prepared effi-
chirality in the BINOL-phosphoramidite ligand was essential ciently by a palladium-catalyzed intramolecular asymmetric
for the reaction. Trisylhydrazones derived from aldehydes and reductive amination of racemic a-branched ketones bearing
ketones proved to be amenable to this transformation. More-
over, DFT calculations indicated that this transformation pro-
ceeded via oxidative addition, carbene migratory insertion, and
reductive elimination. It was also found that oxidative addition
was likely the enantioselectivity-determining step, with the
chiral phosphoramidite bearing bulky substituents playing a

Scheme 184 Pd-Catalyzed enantioselective cascade reaction between

diazoacetamides and MBH carbonates. Scheme 185 Pd-Catalyzed enantioselective carbene insertion reaction.

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Scheme 187 Pd-Catalyzed asymmetric C–N coupling for easy access to

chiral hemiaminals.

starting material to produce the Pd(II) complex, followed by

deprotonation leading to the stereodefined imido–Pd complex,
and the subsequent reductive elimination, yielding the target
product. The synthetic application of the reaction process was
illustrated with a new 6-step synthesis of the HCV drug candi-
date elbasvir.
A catalytic system consisting of Pd(OAc)2 and a SPINOL-
derived phosphoramidite chiral ligand was shown to be
effective for imidoylative cycloamidation of N-alkyl-2-isocyano-
benzamides 802 with 2,6-disubstituted aryl iodides 801, provid-
Scheme 186 Pd-Catalyzed intramolecular asymmetric reductive
ing a novel and useful method for the construction of axially
amination. chiral 2-arylquinazolinones 803, which was accomplished by
the group of Zhu and Luo in 2021 (Scheme 188).362 It was found
that the ortho ester group was crucial for this transformation, as
sulfonamides via dynamic kinetic resolution (Scheme 186).359 replacing the ester with N,N-dimethylamide or N-methoxy-N-
Mechanistic studies indicated that this reaction involved a methylamide had a significant influence on both yield and
deprotection/cyclodehydration/dynamic kinetic asymmetric atroposelectivity, and the use of the ketone analog could
hydrogenation sequence. Notably, Brønsted acid played a cru- completely inhibit the reaction. Moreover, 2,3-diarylquinazo-
cial role in promoting the first step of deprotection and linones containing two stereogenic axes could also be efficiently
cyclodehydration to form the enesulfonamide, as well as the synthesized with moderate diastereoselectivity and good enantios-
tautomerization of the enesulfonamide to highly reactive N- electivities employing N-(2,4-dimethoxyphenyl)-2-isocyanobenzamide
sulfonylimine intermediates. It was later demonstrated by Zhou as a substrate. Mechanistic investigations revealed that the Pd(II)
et al. that tert-butyl(2-(2-oxo-3-phenylpropyl)phenyl)carbamates intermediate generated by oxidative addition favors the isocyanide
797 could undergo a similar transformation involving a intra- insertion process, supporting that the reaction proceeds through a
molecular condensation/N-Boc deprotection/palladium-catalyzed sequence of coupling–cyclization.
asymmetric hydrogenation sequence to yield chiral 2-substituted Recently, an unprecedented method for synthesizing N–N
indolines 798 with high performance (Scheme 186).360 It was bisindole atropisomers 807 was described by Liu, Li and co-
notable that the presence of a strong Brønsted acid was essential workers, which involved the palladium-catalyzed de novo
for the formation of indoles and the following asymmetric hydro-
genation process.

14.7. Cyclization via intramolecular C–N coupling

In 2015, Belyk, Li and co-workers presented an asymmetric Pd-
catalyzed C–N coupling for easy access to chiral hemiaminals
800 using in situ generated chiral bisphosphine mono-oxides
from (R,R)-QuinoxP* (Scheme 187).361 This reaction tolerated
various aryl and heteroaryl substituents on racemic hemiam-
inals, whereas better enantioselectivities were achieved employ-
ing alkyl substituted hemiaminals in the presence of the more
electron-rich Josiphos ligand. A plausible catalytic cycle for this
transformation included the generation of the active BPMO– Scheme 188 Pd-Catalyzed asymmetric imidoylative cycloamidation of
Pd(0) catalyst, which underwent oxidative addition with N-alkyl-2-isocyanobenzamides with 2,6-disubstituted aryl iodides.

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Scheme 189 Pd-Catalyzed asymmetric cascade condensation/N-

Scheme 191 Pd-Catalyzed [4+2] annulation of cyclopropenes with
arylation reaction between a-arylketones and 1-amine indoles.
benzosilacyclobutanes.

construction of one indole skeleton via a cascade condensation/ insertion/reductive elimination. The mechanism of this transfor-
N-arylation reaction between a-arylketones 804 and 1-amine mation was further elucidated by Xu et al. in 2016 by means of DFT
indoles 805 enabled by the more hindered DTBM-Segphos calculations.365
(Scheme 189).363 In addition to bisindole atropisomers, the In 2020, Xu’s group described an unusual palladium-
cascade reaction was also applied to efficiently prepare struc- catalyzed [4+2] annulation of cyclopropenes 810 with benzosi-
turally diverse indole-pyrrole, indole-carbazole, and non-biaryl- lacyclobutanes 809 using TADDOL-based phosphoramidites as
indole atropisomers containing a chiral N–N axis. DFT calcula- a chiral ligand, providing easy access to a wide range of chiral
tions indicated that this transformation proceeded through bicyclic silaheterocycle derivatives 811 with up to 91% ee
oxidative addition, N–H deprotonation, intramolecular rearran- (Scheme 191).366 The reaction involved chemoselective Si–
gement to form a six-membered palladacycle and reductive C(sp2) bond activation in combination with ring expansion/
elimination sequence, and indicated that the deprotonation insertion of cyclopropenes. Mechanistic studies and DFT cal-
step was the rate-limiting step. culations suggested that the directing ester group on cyclopro-
14.8. Cyclization initiated by Si–C bond activation pane played a vital role in the activation of both CQC bonds
and Si–C bonds.
In the presence of chiral palladium catalysts ligated by
H8–BINOL-derived phosphoramidite, an enantioselective
14.9. Cyclization via Catellani reaction
desymmetrization of silacyclobutanes 788 with alkyne 202
for the convenient synthesis of silicon-stereogenic 1-sila-2- In 2018, Dong and co-workers showed their initial efforts in
cyclohexenes 808 with high enantioselectivity was disclosed developing a Pd-catalyzed asymmetric annulation between aryl
by the group of Hayashi and Shintani in 2012 (Scheme 190).364 iodides 370 and racemic epoxides 183 using a chiral norbor-
This reaction tolerated various substituents on the silicon atom of nene as a cocatalyst (Scheme 192).367 The authors also provided
silacyclobutane, including alkyl, aryl and hetroaryl groups. In a novel and useful method for the construction of various
addition to various symmetrical alkynes, unsymmetrical alkynes enantiopure ester-, amide- and imide-substituted norbornenes,
were also found to be amenable to this transformation, leading to in which isopropyl ester- and amide-substituted norbornene
products as single regioisomers. Based on mechanistic studies, the could lead to the formation of chiral 2,3-dihydrobenzofurans
authors thought that this reaction favored proceeding through an with promising enantioselectivities.
alkyne coordination/transmetallation/reductive elimination A modular and convergent method for synthesizing C–N
sequence, rather than a sequence of oxidative addition/alkyne axially chiral phenanthridinones 816 was described by Zhou,
Hong and co-workers in 2021, which involved an axial-to-axial
chirality transfer strategy enabled by Pd/chiral norbornene

Scheme 190 Pd-Catalyzed enantioselective desymmetrization of silacy- Scheme 192 Pd-Catalyzed asymmetric annulation between aryl iodides
clobutanes with alkyne. and racemic epoxides.

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Scheme 195 Pd-Catalyzed asymmetric ring-opening reaction between

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iodobenzoate derivatives and azabenzonorbornadienes.

other possibility via Pd(0)-catalyzed intramolecular amidation

could not be ruled out.

14.11. Cyclization via ring-opening reaction

In 2013, Zhu, Xu and co-workers reported the synthesis of
Scheme 193 Axial-to-axial chirality transfer reaction enabled by Pd/chiral
enantiomerically enriched cis-dihydrobenzo[c] phenanthridi-
norbornene cooperative catalysis.
nones 822, which are the core structures of numerous chiral
natural products, via palladium-catalyzed asymmetric ring-
cooperative catalysis (Scheme 193).368 This method was also opening (ARO) reaction between iodobenzoate derivatives 821
found to be effective for the construction of two vicinal axes and azabenzonorbornadienes 820 enabled by a chiral spiropho-
through double atroposelective C–H arylation, and remote sphine ligand (Scheme 195).370 This reaction required zinc
stereogenic axes via axial-to-axial diastereoinduction of C–N powder as a reducing reagent and I2 as an additive. The
axially chiral phenanthridinones. Mechanistic experiments and significance of this method was further demonstrated by the
DFT calculations suggested that a sterically bulky substituent at efficient asymmetric total synthesis of natural product
the ortho-position of the aniline motif played a crucial role in (+)-chelidonine with the ARO reaction serving as the key step.
stabilizing the C–N axial configuration. The reaction mecha-
14.12. Asymmetric Nazarov-type cyclization
nism initiated via oxidative addition of aryl iodide, followed by
insertion of chiral NBE and a base-assisted arene C–H bond Employing a TADDOL-derived phosphoramidite bearing a
activation to generate intermediate Int-I, which underwent the weakly coordinating pyridine ring as a chiral ligand, a Pd(0)-
secondary oxidative addition, reductive elimination and subse- catalyzed asymmetric Nazarov-type cyclization that provided a
quent b-carbon elimination to produce intermediate Int-II with novel and useful method for the construction of cyclopente-
C–C axial chirality. Subsequently, an intramolecular amidation nones 824 with two contiguous asymmetric centers, was
occurs to yield the amino Pd(II) intermediate Int-III, which demonstrated by the group of Tiu and Ates- in in 2015
undergoes C–N reductive elimination, producing the final (Scheme 196).371 It was found that small or large aliphatic
product. groups at the C2 position were well-tolerated, whereas the C2
position bearing a phenyl group resulted in a moderate ee
14.10. Asymmetric 6-endo type cyclization value. Substitution at the C5 position had a significant influ-
Using a BINAP-Pd catalyst system, an asymmetric 6-endo type ence on the results of reactions. Replacing the methyl group
cyclization of dienamide 818 to synthesize chiral 2- with an ethyl or phenyl group led to decreases in yield and ee
piperidinone compounds 819 was described by Katsumura, values, and an ethoxy substituent resulted in the formation of
Tsuchikawa and co-workers in 2012 (Scheme 194).369 It was the racemic product. Notably, various aryl or alkyl substitutions
notable that both N-p-toluenesulfonyl and C-3 ester substitu- at C6 position were amenable to this transformation, which
ents were essential for activating this cyclization reaction. This indicated that aryl substitution at C6 position was not
transformation was proposed to proceed via the key activated 1-
azatriene intermediate Int-A, followed by an immediate aza-
electrocyclization to give the 2-piperidinone compound, but the

Scheme 194 Pd-Catalyzed asymmetric 6-endo-type cyclization of

dienamide. Scheme 196 Pd-Catalyzed asymmetric Nazarov-type cyclization.

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necessary to activate the cyclization. The tentative mechanism

involved initial coordination of Pd to the alkene group followed
by enol tautomerization of the diketoester to generate inter-
mediate Int-I, which could undergo concerted proton transfer
from the enol to the carbonyl forming a key p-allylpalladium
intermediate Int-II and the subsequent intramolecular nucleo-
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philic attack leading to the formation of the final product.

Further investigation of the mechanism of this transformation
was conducted by the same group by means of DFT calculations
in 2017.372

14.13. Cyclization via intramolecular B–H arylation reaction

In 2018, Xie, Qiu and co-workers found an efficient catalytic
system employing a chiral phosphine ligand (R)-BI-DIME for
palladium-catalyzed asymmetric intramolecular B–H arylation
of o-carboranes 835, opening a new avenue for the synthesis of
chiral-at-cage compounds with new skeletons (Scheme 197).373
Various electron-donating or electron-withdrawing group sub-
stituted aryl bromides were well-tolerated, whereas heteroaryl
Scheme 198 Pd-Catalyzed enantioselective intramolecular cycloaddi-
bromides, such as 2-acylthienyl-3-bromide, 1-acylthienyl-2- tions of alkylidenecyclopropanes (ACPs).
bromide and 2-acylthienyl-1-bromide, resulted in moderate to
low ee values, perhaps due to the chelation of sulfur atoms to
the Pd center. This reaction was proposed to proceed through Alder reaction of acetylenic dienophiles (Scheme 199).375 Var-
the oxidative addition of the C(sp2)–Br bond to palladium(0), ious terminal silyl, alkyl and aryl substituted ynones were well-
followed by intramolecular B–H palladation and reductive tolerated to afford chiral cycloadducts. Notably, the steric
elimination. Moreover, the DFT calculation results were con- effects of aryl groups on phosphine ligands were essential for
sistent with the excellent enantioselectivity observed the enantioselectivity of products. DFT calculations indicated
experimentally. that the steric demand of ligands did not affect the endo/exo-
selectivity, but had a significant influence on the enantioface
14.14. Cycloadditions of alkylidenecyclopropanes selectivity of dienes. Employing Pd(II)-(S)-BINAP complexes as a
A remarkable example involving enantioselective intra- catalyst resulted in the formation of (1R,4S)-cycloadducts, while
molecular cycloadditions of alkylidenecyclopropanes (ACPs) (1S,4R)-cycloadducts were obtained in the presence of chiral
was disclosed by López, Mascareñas and co-workers in 2018, palladium catalysts ligated by (S)-DTBM-Segphos.
offering an unprecedented efficient route for the selective
synthesis of chiral bicyclic systems (Scheme 198).374 A Pd
14.16. Asymmetric cross-cyclotrimerization reaction
catalytic system derived from a sterically demanding Vapol-
based chiral phosphoramidite ligand was found to be optimal In the presence of the palladium complex generated in situ
for the [3+2] cycloaddition reaction using alkenes as subatrates, from [Pd2(dba)3]CHCl3 and (S)-QUINAP as a catalyst, the
leading to the formation of chiral bicyclo[3.3.0]octanes 828 with straightforward synthesis of optically active triple helicenes
high efficiency. Besides, employing dienes in place of alkenes, a 837 through cross-cyclotrimerization of the helicenylaryne pre-
wide range of bicyclo[5.3.0]decenes 830 were prepared effi- cursor 836 with acetylenedicarboxylates 202 via dynamic
ciently via the [4+3] cycloaddition reaction using less bulky kinetic resolution, was accomplished by the group of
phosphoramidite as a chiral ligand. Kamikawa and Tsurusaki in 2020 (Scheme 200).376 This cross-
cyclotrimerization involved the formation of the
14.15. Asymmetric Diels–Alder reaction
In 2018, Mikami et al. reported that cationic chiral palladium
complexes served as an effective catalyst for asymmetric Diels–

Scheme 197 Pd-Catalyzed asymmetric intramolecular B–H arylation of Scheme 199 Pd-Catalyzed asymmetric Diels–Alder reaction of acetyle-
o-carboranes. nic dienophiles.

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Scheme 200 Pd-Catalyzed cross-cyclotrimerization of the helicenylaryne

precursor with acetylenedicarboxylates.

palladacyclopentadiene intermediate (M,P,M)-A from Pd(0)/(S)-

QUINAP and two helicenyl arynes generated in situ from 836
with the assistance of CsF, followed by the insertion of alkyne
202 to produce the palladacycloheptatriene intermediate,
which underwent reductive elimination, resulting in the for-
mation of (M,P,M)-837. Notably, DFT calculations indicated
that this reaction proceeded via the dynamic kinetic resolution Scheme 202 Plausible catalytic cycle of asymmetric decarboxylative
aldol cyclization.
of the palladacyclopentadiene intermediate, whose several
stereoisomers were initially formed and they eventually isomer-
ized into the thermodynamically most stable form (M,P,M)-A. were treated directly with DMP to furnish the desired enan-
Moreover, the authors also examined the photophysical and tioenriched 1,3-diketospiranes 839. However, the diastereo-
chiroptical properties of 837. mers of spirocyclic b-hydroxy lactams obtained from
aldehyde-containing N-benzoyl lactams 840 could be readily
14.17. Asymmetric decarboxylative aldol cyclization separated by flash column chromatography on silica. Impor-
Stoltz and co-workers in 2020 disclosed an asymmetric tantly, the application of this chemistry was evidenced by the
decarboxylative aldol cyclization of racemic allyl b-ketoesters, synthesis of ()-isonitramine in 7 steps from commercially
providing unprecedented access to enantioenriched 1,3- available starting materials. As shown in Scheme 202, the
diketospiranes of several sizes as well as spirocyclic b-hydroxy authors envisioned that the catalytic cycle initiated with the
lactams (Scheme 201).377 Employing cyclic allyl b-ketoesters oxidative deallylation of b-ketoester furnishing Pd(II) carboxy-
838 as substrates, spirocyclic b-hydroxyketones were obtained late Int-I, which underwent transmetallation with another Pd(II)
with moderate diastereoselectivity, which were generally diffi- species, generating a new Pd(II) carboxylate Int-III. The subse-
cult to separate by flash chromatography, so these mixtures quent decarboxylative enolate process resulted in the formation
of enolate intermediate Int-IV. The following intramolecular
aldol cyclization and protonolysis with the aid of Brønsted acid
resulted in the formation of the product and regenerated Pd(II)
species Int-VI. Finally, the conjugate base acted as a nucleo-
phile, leading to the reductive deallylation of Int-II and regen-
erating Pd(0) species.

14.18. Cyclization via acyl-carbamoylation reaction

In 2021, the group of Dai and Xu achieved success in Pd-
catalyzed asymmetric acyl-carbamoylation of an alkene using
thioesters as acyl electrophiles and tBuNC as the carbamoyl
reagent, allowing convenient access to a series of chiral cyclo-
ketone 846 bearing an a-quaternary stereogenic center
(Scheme 203).378 Employing (R)-Segphos as the chiral ligand,
various indanone derivatives were efficiently synthesized with
Scheme 201 Pd-Catalyzed asymmetric decarboxylative aldol cyclization excellent enantioselectivity, while a palladium/modified BINAP
of racemic allyl b-ketoesters. catalyst was proved to be effective for the facile synthesis of

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of alkene to produce an alkyl palladium intermediate. Then,

coordination and migratory insertion of CO into the alkyl
palladium intermediate yielded an acyl palladium intermedi-
ate, which was subsequently captured by the nucleophile and
reductive elimination occurred, leading to the formation of the
product.
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Scheme 203 Pd-Catalyzed asymmetric acyl-carbamoylation reaction.

chiral 1-tetralone derivatives. The mechanism of this transfor- 15. Conclusions

mation was proposed to proceed via oxidative addition of Pd(0)
with thioester to generate acyl-Pd intermediates, followed by an Due to the ability of palladium to cycle efficiently among
asymmetric 1,2-migratory insertion into alkene to produce the different oxidation states and its compatibility with a wide
C(sp3)–Pd species, which underwent migratory insertion of range of ligands and functional groups, it is not surprising
isocyanides, hydrolysis, and reductive elimination and subse- that palladium catalysts are a widely studied family of
quently tautomerized to furnish the desired product. The transition-metal catalysts. This review illustrates that asym-
recrystallized optically pure indanones could be readily deriva- metric palladium catalysis has contributed to the development
tized to the acid product, spiro-ring compound, aldehyde and of enantioselective cyclization reactions, providing powerful
ketones with the retention of enantiopurity. and practical avenues for the synthesis of a huge variety of
carbo- and hetero-cyclic compounds with high stereocontrol,
14.19. Cyclization via cascade imidoyl-carbamoylation including fused, bridged, or spiro rings. Various palladium
reaction catalysts ligated by diverse chiral ligands have been proven to
be effective in asymmetric cyclization reactions with impressive
Recently, utilizing a catalyst composed of a Pd(II) complex and
levels of stereoselective control, and some of these protocols
monodentate phosphoramidite ligands, a preliminary attempt
have found potential applications in the enantioselective synth-
to develop an enantioselective four-component cascade
esis of related natural products and bioactive compounds.
imidoyl-carbamoylation of inactivated alkenes was made by
Undoubtedly, further exploration of different types of reactions
Zhu, Luo and co-workers (Scheme 204).379 An acetamide sub-
and the development of novel chiral catalysts to continue
stituted with five-membered cyclic ketoimine 848 was obtained
expanding the scope of asymmetric cyclization reactions and
with 52% ee using a SPINOL-derived phosphoramidite ligand,
applying these powerful strategies in the synthesis of biologi-
and the BINOL-derived phosphoramidite ligand led to the
cally interesting molecules including natural products, phar-
formation of a seven-membered cyclic ketoimine 850 with
maceuticals and functional materials are the future direction in
77% ee. The hypothesized mechanism for the reaction involved
this field.
the oxidative addition of aryl iodide to Pd(0), generating an aryl
palladium species, followed by coordination and migratory
insertion of the isocyano moiety to form an imidoyl palladium Conflicts of interest
complex, which underwent intramolecular migratory insertion
There are no conflicts to declare.

Acknowledgements
We gratefully acknowledge the funding support of the National
Key R&D Program of China (2021YFF0701600), NSFC (22031004
and 21921003), the Shanghai Municipal Education Commis-
sion (20212308), STCSM (23ZR1445600) and the China Post-
doctoral Science Foundation (2022M713667).

Notes and references

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3 R. D. Taylor, M. MacCoss and A. D. G. Lawson, J. Med.
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Scheme 204 Pd-Catalyzed enantioselective four-component cascade 4 F. Hemmerling and F. Hahn, Beilstein J. Org. Chem., 2016,
imidoyl-carbamoylation of inactivated alkenes. 12, 1512–1550.

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