Metal-Mediated Synthesis

2. Palladium-Catalysed Cross
Coupling for C-C Bond Formation
How do we couple C(sp2) centres?
Palladium-catalysed cross-coupling

[Pd0] – a Pd(0) source, usually with ligands

X – halide or pseudohalide (e.g. OTf)
[M] – metal or metalloid:

 Mg Corriu-Kumada
 Zn Negishi
 Sn Migita-Kosugi-Stille
 B Suzuki-Miyaura
 Si Hiyama-Denmark

later: Mizoroki-Heck coupling, Sonogashira coupling,

Tsuji-Trost allylation
Palladium-catalysed cross-coupling
Catalysts

Pd(PPh3)4 – tetrakis(triphenylphosphine)palladium(0)

18-electron complex – ligand loss necessary

air and moisture sensitive

18e 16e 14e 12e

Fewer donor ligands – less electron-rich Pd

Bulkier, more coordinatively saturated

Equilibrium is solvent- and ligand-dependent

Palladium-catalysed cross-coupling
Catalysts

Coordination number increases by 2

Valence electron count increases by 2

16e, low-spin d8 complexes (e.g. PdII)

are stable

18e 16e 14e 12e

saturated unreactive reactive highly

reactive
major species
in solution
(L = PPh3)
Palladium-catalysed cross-coupling
Catalysts – generation of Pd(0) from Pd(II)
Palladium-catalysed cross-coupling
The β-hydride problem

Alkyl electrophiles are

challenging substrates for
Pd-catalysed coupling
Palladium-catalysed cross-coupling
Negishi coupling

Selective for Ar-I over Ar-Cl

Knochel, Chem. Commun. 2009, 3536

Palladium-catalysed cross-coupling
Stille coupling

Configuration of both double bonds retained in product

Rates of transmetalation from Sn:

alkynyl > alkenyl > aryl > allyl ~ benzyl >> alkyl

RSnMe3 and RSnBu3 most commonly used coupling partners

Stille, J. Am. Chem. Soc. 1987, 813; Smith, J. Am. Chem. Soc. 1995, 5407.
Palladium-catalysed cross-coupling
Stille coupling

Copper(I) salts often employed in

challenging couplings – possible
transmetalation of R[Sn] to R[Cu]

Stille, J. Am. Chem. Soc. 1984, 4630; Corey, J. Am. Chem. Soc. 1999, 7600
Palladium-catalysed cross-coupling
Carbonylative Stille coupling

Stille, J. Am. Chem. Soc. 1984, 7500

Palladium-catalysed cross-coupling
Suzuki coupling

Suzuki coupling favoured over Stille

coupling in presence of base

Addition of base (MeOLi) required for

Suzuki reaction to proceed

Suzuki, Synlett 1991, 687; Suzuki, Chem. Lett. 1989, 1959

Palladium-catalysed cross-coupling
Suzuki coupling - reagents

Some organoboron
reagents commonly
used in Suzuki
couplings:

Varying levels of activity in Suzuki couplings:

 Protecting groups for boronic acids
 “bench stable” boronic acid equivalents

Review of organoboron reagents in Suzuki coupling: Lloyd-Jones, Chem. Soc. Rev. 2014, 412
Palladium-catalysed cross-coupling
Hiyama coupling

Review of Hiyama coupling: Nakao/Hiyama, Chem. Soc. Rev. 2011, 4893

Review of C-C Cross-Coupling
“Textbook” mechanism for Pd(0/II) cross-couplings

 Evidence based on studies

of isolated complexes
(1970s onwards)

 Oversimplified view of
mechanism – dependent on:
 ligands L
 (pseudo)halide X
 metal M
 organic groups R1, R2
 additives, solvent…
Oxidative addition at Pd(0)
Mechanism of oxidative addition to C(sp2)-X

Oxidative addition of Positive value of reaction constant ρ

p-CNPhBr approximately 5000 indicates build-up of negative charge on
times slower than p-CNPhI the aromatic ring in the transition state.
𝒓 (𝒑 − 𝐍 𝐎 )
Rule-of-thumb: 𝟐
≈ 𝟏𝟎
𝝆
𝒓 (𝒑 − 𝐎𝐌𝐞 )
p-NO2 reacts about 100x faster than
p-OMe

Fauvarque et al., J. Organomet. Chem. 1981, 208, 419

Oxidative addition at Pd(0)
Mechanism of oxidative addition to C(sp2)-X

(Ph3P)2Pd0 oxidative addition into

Ph–Br

Concerted, cyclic transition state

Fey/Harvey, Dalton Trans. 2014, 13545

Oxidative addition at Pd(0)
Mechanism of oxidative addition to C(sp2)-X

Ion pairing: PhMe > THF > DMF

ArX krel
No evidence for covalent bond between Pd and PhBr 1
OTf, even in PhMe
PhOTf 1.7
P NMR and MS support 14e cationic Pd species
31
PhI 17000

Jutand, Organometallics 1995, 14, 1810

Oxidative addition at Pd(0)
Oxidative addition to difficult substrates

Rates of oxidative addition with (Ph3P)2Pd

ArX krel
PhBr 1
PhOTf 1.7
PhI 17000

Use bulky, electron-rich phosphines – oxidative

addition of Pd(PR3) or Pd(PR3)2/Pd(P~P)
Oxidative addition at Pd(0)
Diphosphine ligands
Pre-distortion of L2Pd accelerates
oxidative addition

Small bite angle phosphines do

not allow cis-trans isomerisation

L-Pd-L : “bite angle” – ligand-dependent

For a discussion of bite angle effects, see van Leeuwen, Chem. Rev. 2000, 2741
Oxidative addition at Pd(0)
Diphosphine ligands
Pre-distortion of L2Pd accelerates
oxidative addition

Small bite angle phosphines do

not allow cis-trans isomerisation

transmetalation

For a discussion of bite angle effects, see van Leeuwen, Chem. Rev. 2000, 2741
Oxidative addition at Pd(0)
Bulky ligands

Steric bulk of phosphorus

substituents increases energy
required to close L-Pd-L angle

Oxidative addition of LPd more

favourable

Electron-rich phosphines give more

nucleophilic Pd – faster oxidative
additions
Isomerisation of Pd(II) complexes
Cis-trans isomerisation of L2Pd(Ar)X

Berry pseudorotation – exchanges

the two axial (A) ligands with two
equatorial (E) ligands

Espinet, Organometallics 1998, 17, 954

Transmetalation in Suzuki coupling
Oxo-palladium vs. boronate pathways

Review: Lloyd-Jones, Angew. Chem. Int. Ed. 2015, 7362

Transmetalation in Suzuki coupling
Oxo-palladium vs. boronate pathways

X K(X)
I 0.17
Br 1.3
Cl 3.2

ArB(OH)2 + L2Pd(Ph)OH react approximately

104 times faster than ArB(OH)3– + L2Pd(Ph)Br

HO– also accelerates reductive elimination

Hartwig, J. Am. Chem. Soc. 2011, 2116; Amatore/Jutand, Chem. Eur. J. 2011, 2492
Transmetalation in Suzuki coupling
Finding the pre-transmetalation intermediate

Denmark, Science 2016, 352, 329

Reductive elimination at Pd(II)
Reductive elimination is the microscopic reverse of oxidative addition

sp2-hybridised carbons undergo faster reductive elimination than sp 3

reduced electron density at PdII favours reductive elimination

(LPd faster than L2Pd)

Brown, Inorg. Chim. Acta. 1994, 220, 249; Goddard, J. Am. Chem. Soc. 1986, 6115
Sonogashira reaction
Alkyne synthesis

Takahashi, Synthesis 1980, 627; Plenio, Angew. Chem. Int. Ed. 2003, 1056
Sonogashira reaction
Alkyne synthesis

Crisp, Synth. Commun. 1989, 19, 1745

Sonogashira reaction
Catalytic cycle

 2º/3º amine bases commonly

used: not strong enough to
deprotonate alkyne – Cu(I)
complexed alkyne more acidic

 In presence of air, alkyne-alkyne

coupling (Glaser coupling)
competes with Sonogashira
coupling

Reviews: Chinchilla/Nájera, Chem. Rev. 2007, 874; Chem. Soc. Rev. 2011, 5084
Heck reaction
Alkene synthesis

Fu, J. Org. Chem. 1999, 10

Heck reaction
Catalytic cycle
Heck reaction
Alkene isomerisation

Larock, J. Org. Chem. 1990, 407

Heck reaction
Alkene isomerisation

Larock, J. Org. Chem. 1990, 407

Heck reaction
Regioselectivity – neutral Pd

Electron-deficient alkenes: arylation at less hindered site favoured

Electron-rich alkenes: arylation at most electron-deficient site favoured

Heck reaction
Regioselectivity – cationic Pd

Electronic factors dominate in reactions with cationic Pd

Tsuji-Trost allylic substitution
Soft nucleophiles, pKa(HNu) < 25

Trost, J. Org. Chem. 1976, 3215

Tsuji-Trost allylic substitution
Soft nucleophiles

Some leaving groups may be basic enough to

deprotonate the neutral pronucleophiles (RHXY)

BSA
Tsuji-Trost allylic substitution
Enolate nucleophiles: decarboxylative allylic alkylation from β-ketoesters

Use of preformed enolates

possible, but poor selectivity
and over-reaction common

In situ, irreversible enolate

formation in coordination
sphere of allylpalladium cation

Similar reactivity possible with allyl enol carbonates:

Tsuji, Tetrahedron Lett. 1980, 21, 3199; Saegusa, J. Am. Chem. Soc. 1980, 6381
Tsuji-Trost allylic substitution
Dynamic equilibria of (π-allyl)palladium complexes: η 3-η1-η3/π-σ-π

syn - anti isomerisation: minimise A1,3 strain

Pd(Ph2PN(iPr)PPh2)
complexes
Tsuji-Trost allylic substitution
Dynamic equilibria of (π-allyl)palladium complexes: η 3-η1-η3/π-σ-π
Wacker oxidation
Palladium-catalysed alkene hydration

Tsuji, Org. Synth. 1984, 62, 9.

Pd(II)-catalysed nucleopalladation
Oxypalladation

Stoltz, J. Am. Chem. Soc. 2005, 17778; Pd(II) Nu-Pd review: Stahl, Chem. Rev. 2011, 2981
Pd(II)-catalysed nucleopalladation
Oxypalladation

Reoxidation of Pd(0) by O2 is
relatively slow – pyridine acts
as a ligand to stabilise Pd(0),
preventing decomposition

Stoltz, J. Am. Chem. Soc. 2005, 17778; Pd(II) Nu-Pd review: Stahl, Chem. Rev. 2011, 2981
Pd(II)-catalysed nucleopalladation
Indole cyclisation

Stoltz, J. Am. Chem. Soc. 2003, 9578

Oxidative Heck reaction (Fujiwara-Moritani)
Pd(II)-catalysed alkene synthesis

Yu/Jiao, Chem. Asian. J. 2010, 1090; Stoltz, Angew. Chem. Int. Ed. 2004, 6144
Oxidative Heck reaction (Fujiwara-Moritani)
Pd(II)-catalysed alkene synthesis

Review: Muzart, Chem. Rev. 2011, 1170

Oxidative Heck reaction (Fujiwara-Moritani)
C-H activation

C-H activation occurs by

concerted metalation-
deprotonation (CMD)
mechanism

Gorelsky/Fagnou, J. Am. Chem. Soc. 2008, 10848;

Davies/Macgregor, J. Am. Chem. Soc. 2005, 13754
Oxidative Heck reaction (Fujiwara-Moritani)
Selective pyrrole functionalisation

Bulky TIPS group

sterically shields C2

Boc group can direct C-H

activation and stabilise
C2 intermediate by
chelation

Gaunt, J. Am. Chem. Soc. 2006, 2528

Catellani reaction
Interrupted Heck reaction
Catellani reaction
Ipso,ortho-functionalisation of aryl iodides

Review: Catellani, Acc. Chem. Res. 2016, 1389

Catellani reaction
Catalytic cycle
Catellani reaction
C-H activation

Originally interpreted as SEAr –

possibly CMD?
Catellani reaction
Pd(II/IV) oxidative addition

Reductive elimination from

octahedral PdIV fast when
groups are cis

Ar-R2 reductive elimination

faster than norbornene-R2
(sp2 vs sp3)
Catellani reaction
Intramolecular Catellani
Summary

 Palladium(II) can act as a catalyst for the activation of alkenes:

Wacker oxidation (~ 106 tonnes acetaldehyde in 2003). Cu co-
catalyst + O2 re-oxidises Pd(0)

 Subsequently adapted into lab-scale system for alkene hydration

 Pd(II) can activate alkenes towards nucleophilic attack

 Oxidative Heck (Fujiwara-Moritani) – activation of aromatic C-H

bonds in place of more expensive aryl (pseudo)halides:
achieving selectivity can be difficult – use directing groups

 Catellani reaction uses norbornene to direct reaction ortho to

aryl iodides, allowing one-pot triple functionalisation via
Pd(0/II/IV) catalytic cycle