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of pyrroles
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Cite this: RSC Adv., 2021, 11, 13585

Biplob Borah, Kartikey Dhar Dwivedi and L. Raju Chowhan *

Organocatalysis has emerged as one of the most important tools for the synthesis of diverse structural
scaffolds, and has become one of the most important hot topics of current research. Construction of
the pyrrole ring has gained much attention from the last few decades due to its remarkable biological
activities, pharmaceutical application, intermediate in the synthesis of many natural products, and
material science application. With access to these 5-membered aza heterocycles, organocatalytic
approaches have provided a new alternative from the perspective of synthetic efficiency, as well as from
Received 3rd March 2021
Accepted 24th March 2021
the green chemistry point of view, and a vast array of synthetic procedures has been developed.
Enlightened by the significance of this growing research area, we aim to describe the recent
DOI: 10.1039/d1ra01690c
organocatalytic approaches developed for the construction of pyrroles, and organized them based on
rsc.li/rsc-advances substrates employed.

a signicant role in the eld of medicinal and pharmaceutical

1. Introduction chemistry because of their wide-ranging biological activities6
Pyrroles are the most well-known ve-membered nitrogen- (Fig. 1). These tremendous biological activities, pharmaceutical
containing heterocyclic aromatic compounds, and are the key applications, use as a synthetic intermediate in many natural
structural unit of heme and related porphinoid co-factors,1 such products synthesis and material science application have
as heme b, chlorophyll a, vitamin B12, and factor 430. Besides stimulated interest in the synthesis of pyrroles starting from
these, the pyrrole ring commonly exists in marine natural a traditional one, such as the Hantzsch pyrrole synthesis,7 van
products,2 non-natural products,3 drug candidates,4 synthetic Leusen,8 Knorr,9 Paal–Knorr pyrrole synthesis10 to non-classical
intermediates,5 and optoelectronic materials,1b and plays one,11 and vast arrays of the synthetic pathway have been
developed.
Over the last decade, the use of small organic molecules
School of Applied Material Sciences, Centre for Applied Chemistry, Central University
called organocatalysts in organic transformation has received
of Gujarat, Gandhinagar, 382030, India. E-mail: [email protected]

Biplob Borah was born in 1995 Kartikey Dhar Dwivedi was born
in Garukhunda, a small village in 1992 in Barouhin, a small
in the Nagaon District of Assam, village in the Rewa District of
India. He graduated with a BSc Madhya Pradesh, India. He ob-
degree in Chemistry from Now- tained his BSc degree from
gong College (Gauhati Univer- Swami Sharddhanand College
sity), Assam in 2017, and (Delhi University), Delhi in
received his Master's degree in 2014, and MSc degree in Chem-
Industrial Chemistry from the istry from the Central University
Central University of Gujarat, of Punjab, Bathinda, India in
India in 2019. Currently, he has 2017. Since August 2017, he has
joined as a PhD Scholar in the been a doctoral fellow (PhD
School of Applied Material student) in the research group of
Science at the Central University of Gujarat under the guidance of Dr L. Raju Chowhan at the Central University of Gujarat, Gan-
Dr L. Raju Chowhan. His research interest includes organo- dhinagar. His research interests include catalysis in organic
catalysis, multicomponent reactions (MCRs), green chemistry, and synthesis, heterogeneous catalysis, and cycloaddition reactions in
the synthesis of medicinally privileged heterocycles in aqueous aqueous medium.
medium.

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Fig. 1 Some natural (A–E)1,2 and non-natural compounds (F–G)3,4 with

biological activity containing the pyrrole moiety.

increased attention12 due to their remarkable properties,

including high stability, lower activation energy, high efficiency,
transition metal-free nature, reduced toxicity, cost-
effectiveness, ready availability and easy recoverability; avoid-
ing expensive catalysts, simple handling in reaction, and the
possibility of performing reactions through different activation
modes.13 In addition, the utilization of chiral organic molecules
has emerged as a new platform for the synthesis of enantio-
merically enriched compounds.14 Various types of organo-
catalysts employed for the synthesis of pyrroles are listed in
Fig. 2. Encouraged by the growth in the area of organocatalysis
in organic transformation and the increased application of the
pyrrole heterocycle in many branches of chemistry, an interest
was born in our mind to highlight the recent developments for
the synthesis of pyrroles by systematically using the different
organocatalytic systems in this review. Although several reviews
have covered the synthesis of pyrroles based on multicompo-
nent reactions,15 metal-catalyzed syntheses,16 and others,17 the
organocatalytic approaches toward its synthesis have not been
covered with all details until now. This current review aims to Fig. 2 Organocatalyst used for the synthesis of pyrroles.
provide access to the works on the synthesis of pyrroles by using
various organocatalytic strategies and their development to the
present state. On behalf of the appropriate understanding and
a convenient presentation, the article is classied according to
the nature of the substrates used.
Dr L. Raju Chowhan obtained his
BSc degree from Osmania
University, Master's degree from 2. Synthesis of pyrroles by two-
Hyderabad Central University, component cascade reactions
Hyderabad, and PhD from the
CSIR-Indian Institute of Chem- 2.1 From dicarbonyl compounds and amines
ical Technology, in association In 2012, Darabi et al. discovered a practical eco-friendly method
with Hyderabad Central Univer- for the Paal–Knorr pyrrole synthesis based on the metal-free
sity. He joined as an Assistant catalyst (Scheme 1).18 Treatment of hexane-2,5-dione 32 with
Professor in the Centre for several substituted aromatic amines 33 in ethanol in the pres-
Applied Chemistry, Central ence of vitamin B1 (25) as an organocatalyst at room tempera-
University of Gujarat, Gan- ture for 1 hour gave the corresponding N-substituted pyrroles 34
dhinagar in September 2012. His in moderate to excellent yield (25–94%). Aromatic amines pos-
research interests include the stereoselective synthesis of natural sessing different electron-withdrawing and electron-donating
products and the development of novel methodologies for asym- substituents at the C-2, C-3, and C-4 position could react with
metric synthesis. hexane-2,5-dione smoothly to give the desired product in high

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Scheme 1 Vitamin B1-catalyzed synthesis of substituted pyrroles 34.

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Scheme 4 Mechanochemical method for the synthesis of pyrroles.

bonds with the carbonyl oxygen. Substitution of different alkyl

groups in 1,4-dione 37 and amines 38 leads to a wide-ranging
substrate scope with high yields.
A very efficient straightforward method for the synthesis of
N-substituted pyrroles 39 under solvent-free conditions by using
Scheme 2 Squaric acid-catalyzed synthesis of pyrrole derivatives 36. mechanochemical activation and biomass-derived organic acid
in a very short reaction time has been developed by Akelis et al.
(Scheme 4).21 The synthesis involving the reaction of diketones
yield. However, amines possessing substitution at the C-2 37 with various aliphatic and aromatic amines 38 in the pres-
position by the –NO2 group had a detrimental effect on the ence of citric acid 22 at 30 Hz ball-mill frequency for 15–30
reactivity, and the desired product was not formed due to the minutes was found to lead to corresponding pyrroles 39 in 23–
existence of the steric hindrance. 84% yield. In addition, they further extended the methodology
In 2013, Azizi et al.19 reported a novel two-component for the desymmetrization of amines or to access bis(pyrroles) 41
strategy that affords N-substituted pyrroles 36 from the reac- by using various aromatic and aliphatic diamines 40 as the
tion of hexane-2,5-dione 32 with several aromatic amines 35 in reactants under the same reaction condition. The formation of
water by introducing squaric acid 23 as an organocatalyst at mono-pyrroles 39, i.e., desymmetrization of amines and bis(-
60
C for 5 hours in 40–95% yields (Scheme 2). The reaction pyrroles) 41 depends on the reactant diketones 37 and diamines
performed under the ultrasound irradiation condition also 40 (Scheme 5).
afforded the product in good yield. Although the role of squaric In 2015, Bhandari and Gaonkar synthesized a series of N-
acid 23 in this transformation is not clear, it was believed that substituted 2,5-dimethylpyrroles 43 through the two-
the Brønsted acidity is the main reason for which the reaction component Paal–Knorr cyclo-condensation reaction of hexane-
has proceeded. 2,5-dione 32 with several aromatic hydrazides 42 in methanol
The combination of urea as an organocatalyst with choline catalyzed by 25 mol% of saccharin (8) at room temperature for
chloride (CC) provided an effective solvent/catalyst system for 30 minutes (Scheme 6).22 The methodology offers several
several organic transformations. In this context, Handy and signicant advantages, including non-toxicity, low cost,
Lavender in 2013 demonstrated an environmentally friendly ecological safety, easy isolation of the product, and reusability
protocol for the synthesis of N-substituted pyrroles 39 in 56– of the catalyst that could be applicable to a wide-ranging
99% yield via the reaction of 1,4-diones 37 with several amines substrate scope in good to excellent yield. All heterocyclic, as
38 in the presence of choline chloride/urea (24) at 80
C for 12–
24 hours (Scheme 3).20 In this reaction, the use of urea as an
organocatalyst activates the carbonyl compound for the Paal–
Knorr cycloaddition reaction with amine by forming two H-

Scheme 3 Synthesis of pyrroles 39 from 1,4-diones and amines. Scheme 5 Synthesis of pyrroles by using diamines as the reactants.

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Scheme 6 Saccharin-catalyzed synthesis of pyrroles 43.

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well as aromatic hydrazides, react equally well with hexane-2,5-

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dione 32 under the standard condition to afford the product 36.

In 2016, Aghapoor et al.23 reported that the treatment of
hexane-2,5-dione 32 with several aromatic amines 35 in the
presence of the natural primary amino acid L-tryptophan 1 as an
organocatalyst at 70
C under solvent-free condition afforded
the corresponding N-substituted pyrroles 36 in 86–97% yield in
1–2 hours (Scheme 7). The proposed mechanism for this
transformation initiated by the double condensation of hexane- Scheme 8 Nano-FGT catalyzed synthesis of pyrroles 45.
2,5-dione 32 with amines 35 under the presence of catalyst 1.
The catalyst 1 activates the dicarbonyl compound by forming
hydrogen bond between the carbonyl oxygen and its amino acid naturally abundant tripeptide glutathione as an organocatalyst
group, and thereby facilitating the nucleophilic attack of N- on the nano-ferrite surfaces. The catalytic activity of the
atom of aromatic amines to the carbonyl carbon. In the nal prepared nanoparticle-supported organocatalyst was found to
stage, the subsequent removal of water molecules followed by be very efficient for the two-component Paal–Knorr condensa-
detachment of the catalyst leads to the formation of product 36. tion reaction of tetrahydro-2,5-dimethoxyfuran 44 with different
amines 35 in aqueous medium under microwave irradiation at
2.2 From tetrahydro-2,5-dimethoxyfurans and amines 140
C. The corresponding pyrrole 45 was obtained in 72–92%
In 2009, Polshettiwar et al. reported the synthesis of a novel within 20 minutes (Scheme 8).24 Under the standard reaction
nanoparticle-supported organocatalyst, namely, Nano-Ferrite condition, as mentioned, various aryl, heteroaryl, and alkyl
supported Glutathione (Nano-FGT) for the synthesis of amines worked well and a total of 16 compounds were synthe-
pyrroles. The catalyst was prepared via the immobilization of sized in good to excellent yield.
Another organocatalytic route for the synthesis of N-
substituted pyrroles 45 in 85–97% yield has been accomplished
via the treatment of tetrahydro-2,5-dimethoxyfuran 44 with
several aryl amines 35 in the presence of 23 as an organocatalyst

Scheme 9 Preparation of N-substituted pyrroles 45 from tetrahydro-

Scheme 7 Synthesis of pyrroles via double-condensation reaction. 2,5-dimethoxyfuran and amines.

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Scheme 11 One-pot synthesis of 3-acyl pyrrole from an unsaturated

ketone by cooperative catalysis.
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pyrroles 51 in 20–85% yield (Scheme 11).26 The reaction has

proceeded through the iminium activation of unsaturated
ketones 49 by 3, followed by aza-Michael addition with
substituted propargylamine that undergoes alkyne carbo-
cyclization reaction, which leads to the formation of corre-
sponding 3-acyl pyrroles 51 aer the oxidation reaction.
Scheme 10 Synthesis of N-hydroxypyrroles 48 via Michael addition/
aldol condensation reaction.

2.4 Other two-component reactions

in the aqueous medium at 60 C for 3–6 hours (Scheme 9). The 19 In 2015, Adhikary et al.27 reported a practical one-pot conversion
suggested way for this transformation starts with the formation procedure for the synthesis of N-substituted pyrrole-2-
of anilinium squarate salt by the reversible acid–base treatment carbaldehydes 53 in 21–53% yields via the reaction of carbo-
of aniline with squaric acid 23. The hydrolysis of tetrahydro-2,5- hydrates 52 with primary amines 38 in the presence of oxalic
dimethoxyfuran in the presence of a catalytic amount of 23 gave acid in DMSO at 90
C for 30 minutes (Scheme 12). The reaction
the active 1,4-dicarbonyl compound, which could undergo of D-ribose with amino-ester, resulting from the N-Boc-protected
a cyclo-condensation reaction with aniline to afford the corre- b-amino-ester, led to the formation of N-substituted pyrroles 54
sponding product 45 (Scheme 9). in 54% yield. In the case of D-xylose under the same condition,
the corresponding product was obtained in 51% yield.
2.3 From a,b-unsaturated carbonyl compounds A plausible mechanism for this practical conversion is
depicted in Scheme 13. Initially, the N-glycosylation of amines
Due to the attractive advantages, organocatalytic domino reac-
38 from carbohydrates 52a produces the ring-opened enamine
tions have been considered as a powerful tool in organic
tautomer that facilitates removal of the protonated 3-hydroxyl
synthesis from the last decade. In 2009, Tan and his co-workers
group to give the imine intermediate. Addition of another
demonstrated that the one-pot domino reaction of a,b-unsatu-
amine 38 to the imine intermediates, and then cyclization fol-
rated aldehydes 46 and a-carbonyl oximes 47 by using 7 as an
lowed by removal of the protonated 4-hydroxyl group, and
organocatalyst in toluene at room temperature for 18–48 hours
further aromatization afforded the corresponding pyrrole 53a.
afforded N-hydroxy pyrroles 48 in 58–83% yield (Scheme 10).25
The reaction has proceeded via the domino Michael addition/
aldol condensation reaction, and oximes were utilized as N-
selective nucleophiles for the Michael addition reaction step.
The proposed mechanism involves the initial iminium activa-
tion of a,b-unsaturated aldehydes by secondary amine catalyst 7
that undergo Michael addition reaction by experiencing
a nucleophilic attack from the N-selective nucleophile oximes.
The subsequent intramolecular aldol condensation reaction
and aromatization reaction afforded the nal N-hydroxypyrroles
48 in good yield.
Similar to the a,b-unsaturated aldehydes, the reactivity of
unsaturated ketones was also explored for the synthesis of
polysubstituted pyrroles via cooperative catalysis. In recent
years, cooperative catalysis has drawn much more attention for
the production of useful structural units by combining both
metal-catalyst and organocatalyst. Treatment of unsaturated
ketones 49 with N-substituted propargylated amines 50 by using
3 as the organocatalyst in the presence of copper salt at room Scheme 12 Conversion of carbohydrates into N-substituted pyrrole-
temperature or 40
C produces the polysubstituted 3-acyl 2-carbaldehydes.

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produces the N-heterocyclic carbene/zwitterionic catalyst,

which facilitate the preferential acyl anion conjugate addition
of acylsilanes 58 to more electrophilic a,b-unsaturated ketones
59, which leads to the formation of the 1,4-dicarbonyl
compound that undergoes the Paal–Knorr condensation reac-
tion upon treatment with amines 38, acid and dehydrating
agent to produce the corresponding pyrroles 60.
In 2005, a very efficient one-pot four-component reaction of a,b-
unsaturated aldehydes 46, 2,4-diones 61, acetic acid, and sodium
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nitrite in the presence of secondary amine 7 in aqueous medium at

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room temperature was found to provide the green construction of

polyfunctionalized N-hydroxypyrroles 48 aer 24 hours. By using
water as a green solvent, the products were isolated in moderate
yield ranging from 52–65% (Scheme 16).25 This protocol displayed
various advantages, including mild reaction condition, environ-
mentally friendly nature, simple isolation process, low cost and the
catalyst could be easily recovered.
Scheme 13 Plausible mechanism for the conversion of D-glucose 52a
to pyrrole 53a. Dawande et al. established the direct synthesis of substituted
pyrroles 64 with a new stereogenic center in good yield via the
one-pot three-component reaction of enaldiazo compounds 62,
several substituted aromatic aldehydes 63, and amines 33 (Ar ¼
Aryl, Boc) by introducing the cooperative catalyst Rh2(OAc)4 and
()-BINOL phosphoric acid 18 in DCM at 10
C for 4 hours
(Scheme 17).30 It is interesting to note that due to the steric
hindrance, the amine 2-(triuoromethyl)-aniline produces the
pyrrole in lower yield, whereas the amine 2,4,6-trimethylaniline
did not produce the corresponding pyrrole. The methodology

Scheme 14 Cu–NHC catalyzed synthesis of N-unsubstituted pyrroles.

N-Heterocyclic carbenes (NHC) as a Lewis base organo-

catalyst have had a widespread impact on the organic chemistry
community due to their several modes of activation. Saturated
imidazolium carbene precursors 13, in combination with CuBr,
catalyzed the two-component reaction of ketones 55 and b-
amino alcohols 56 in the presence of base LiOtBu at 140
C for
the synthesis of N-unsubstituted pyrroles 57 in 48–64% yield
aer 24 hours (Scheme 14).28

3. Synthesis of pyrroles via

multicomponent reactions (MCRs)
3.1 From a,b-unsaturated compounds
In recent times, multicomponent reactions (MCRs) have
increasingly gained favor in organic synthesis due to the
formation of diverse molecular structures in a single step with
enhanced efficiency, reduced waste, and high atom economy. In
this perspective, a one-pot three-component reaction of acylsi-
lanes 58, a,b-unsaturated carbonyl compounds 59 and amines
38 catalyzed by thiazolium salt 15 in the presence of DBU for the
synthesis of highly substituted pyrroles 60 via the Sila-Stetter/
Paal–Knorr approach was developed by Ashwin and Karl in 2004
(Scheme 15).29 The reaction proceeded through the combina- Scheme 15 Synthesis of highly substituted pyrroles 60 via Sila-Stetter/
tion of thiazolium salt 15 with an amine base DBU that Paal–Knorr strategy.

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Scheme 16 Four-component synthesis of N-hydroxypyrroles 48 in

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the presence of a secondary amine catalyst.

Scheme 18 NHC-catalyzed synthesis of trisubstituted pyrroles 67.

3.2 From alkynes

In 2001, Braun et al. successfully synthesized a series of diverse
1,2,3,5-tetrasubstituted pyrroles 70 in 49–59% yield by exploring
Scheme 17 Access to pyrroles via ammonium ylide/Mannich reaction/
cyclization cascade sequence.
(hetero)aryl halides 68, such as 4-bromo benzonitrile or 2-
bromo pyridine, terminal propargyl alcohols 69, aromatic
aldehydes 63, and primary amines 38 as starting materials in
the presence of thiazolium salt 14 (Scheme 19).32 This one-pot
was found to be very efficient in the diastereoselective synthesis
four-component method initiated by the coupling-
of the binaphthyl-based chiral pyrrole. The transient protic
isomerization of aryl halides 68 with propargyl alcohols 69 fol-
ammonium ylide generated from the rhodium enalcarbenoid
lowed by addition of aldehydes 63 via Stetter reaction afforded
allowing for the vinylogous nucleophilic addition to the imi-
the 1,4-dicarbonyl compound, and then the subsequent Paal–
nium species afforded the Mannich product with a new ster-
Knorr reaction with amines 38 furnished the tetrasubstituted
eogenic center that underwent [4 + 1] cyclo-condensation
pyrroles 70.
reaction to give the desired pyrroles 64.
A highly efficient one-pot treatment of primary amines 38
Recently, it has been shown that the N-heterocyclic carbene
with acetylene dicarboxylates 71 and propiolates 72 in aqueous
catalyzed synthesis of 1,2,4-trisubstituted pyrroles could also be
applicable in the synthesis of diverse structural precursors of ator-
vastatin. The direct one-pot three-component coupling of a,b-unsat-
urated ketones 65, glycolaldehyde dimer 66 as a novel C1 building
block, and amines 38 using thiazolium salt 14 and K3PO4 at 120
C in
MeCN for 16 hours produced the 1,2,4-trisubstituted pyrroles 67 in
28–85% yield (Scheme 18).31 The mechanism proposed for this
reaction sequence involves the addition of thiazol carbene (produces
from the reaction of thiazolium salt 14 with K3PO4) to the carbonyl
carbon of glycolaldehyde, furnishes the anionic intermediate that
could undergo retro-benzoin C–C bond cleavage reactions aer
proton transfer, and thereby the formation of a carbon nucleophile
along with formaldehyde. The conjugate addition of a carbon
nucleophile with a,b-unsaturated ketones 65 as Michael acceptor via
Stetter reaction leads to the 1,4-dicarbonyl compound that provides
the corresponding pyrroles 67 aer subsequent Paal–Knorr cyclo-
Scheme 19 Coupling-isomerization-Stetter–Paal–Knorr strategy for
condensation reaction with the amines 38.
the preparation of tetrasubstituted pyrroles.

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Scheme 21 Synthesis of disubstituted pyrroles by domino MCRs.

The highly efficient one-pot construction of several poly-

substituted pyrroles 78 in acceptable to good yield (42–87%) has
been obtained via the environmentally benign multicomponent
Scheme 20 N-Methylimidazole catalyzed three-component reaction of 1,2-diones 77, aryl amines 38, and aldehydes 63 in
synthesis of 2,3,4-trisubstituted pyrroles.
the presence of 4-methylbenzenesulfonic acid monohydrate
(TsOH$H2O) as an organocatalyst in acetonitrile at room
temperature for 10–20 hours (Scheme 22).35 The reaction pro-
medium by using 5 mol% N-methylimidazole as an organo- ceeded with the formation of an iminium ion from aryl amines
catalyst at room temperature for 1 hour afforded the function- 38 and aldehydes 63 that experiences a nucleophilic attack from
alized pyrroles 73 in 70–87% yield (Scheme 20).33 The the enamine intermediate, generated from aryl amines 38 and
mechanism proposed to explain this reaction begins with the 1,2-diones 77, followed by an intramolecular cyclization and
addition of N-methylimidazole with propiolates 72, produces tautomerization to afford the imine form amino alcohol
the zwitterionic intermediate, which undergoes addition reac-
tion with an enamine-ester formed in situ from 71 and 38, fol-
lowed by subsequent proton transfer and intramolecular
cyclization to give the dihydropyrrole derivatives with simulta-
neous regeneration of the catalyst. The nal elimination of
hydrogen from the dihydropyrrole intermediate yielded the
corresponding product 73.

3.3 From carbonyl compounds

In 2012, Martı́n-Santos et al.34 performed the domino three-
component reaction of aldehydes 74, (Z)-b,b-bromo-
nitroalkenes 75, and amines 38 in the presence of organo-
catalyst 6 in CH2Cl2 at room temperature to form the 3,4-
disubstituted pyrroles 76 in good to excellent yield (Scheme 21).
The mechanism involved in this reaction starts with the
formation of an enamine from the addition of 6 with aldehydes
74 that undergoes Michael addition to (Z)-b,b-bromo-
nitroalkenes 75, and produces the g-bromo-g-nitro-aldehyde
intermediate aer the hydrolysis and regeneration of organo-
catalyst 6. The reaction of this intermediate with amines 38,
followed by tautomerization and intramolecular cyclization,
and the subsequent syn-elimination of the nitro group afforded Scheme 22 Synthesis of polysubstituted pyrroles from 1,2-diones,
the nal product 76. aldehydes, and aryl amines.

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substituted pyrroles 85 in 76–91% yields within 4–7 hours

(Scheme 24).36
The mechanistic pathway for this solvent-free synthesis
involves the initial reaction of dicarbonyl compounds 83 with
amines 38 in the presence of 2 to give the enamine intermedi-
ates 86, which react with the nitroalkenes 87 generated from the
reaction of aldehydes 63 and nitromethane 84 to afford the
Scheme 23 Synthesis of pyrroles by using the Cu–NHC catalyst imine 88. In both cases, the carbonyl groups were activated by
system. the catalyst through hydrogen bonding. Through tautomeriza-
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tion and intermolecular cyclization, the imine 88 forms the

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corresponding pyrroles 85, aer a subsequent loss of a water

(Scheme 30).25 The loss of one molecule of water from the imine molecule and nitrosyl hydride.
amino alcohol produces the conjugate iminium ion interme- A highly convergent multi-catalytic multicomponent reac-
diate that yields the nal product 78 via deprotonation. tion (MCR) strategy to access very constructive symmetrical and
Dang et al.28 noted that the combination of CuBr with car- unsymmetrical 2-aryl substituted 1,4-diketone building blocks
bene precursors benzimidazolium salts 13 lead to the formation from readily available aldehydes and nitroalkenes as latent 1,2-
of a Cu–NHC complex as an efficient non-noble metal catalyst in dication synthons and their utilization for the one-pot four-step
the presence of a base, and was found to be a very effective synthesis of polysubstituted pyrroles 92 by using carbene
catalyst in the preparation of a variety of 1,2-, 1,2,3-, variety of precursor 17 and K2CO3 as N-heterocyclic carbene (NHC)-
1,2-, 1,2,3-, 1,2,3,5- and fully substituted pyrroles (Scheme 23). catalyst has been developed (Scheme 25) by Fuchs et al.37 For
This Cu–NHC catalyzed one-pot protocol begins with the three- the synthesis of symmetrical 1,4-diketones, the reaction of
component reaction of different substituted ketones 79, amines aldehydes 89 and nitroalkenes 90 was carried out in the pres-
80, and diols 81 at 140
C for 24 hours to produce the corre- ence of 10 mol% of NHC-precursors 17 and 100 mol% of K2CO3
sponding pyrroles 82 in 40–95% yields. in Et2O at room temperature for 16 hours, followed by the
Hassani et al. reported an operationally simple and eco- addition of a second aldehyde 91 at 50
C for another 8 hours.
friendly one-pot four-component reaction of 1,3-dicarbonyl This 1,4-diketone on treatment with amines 38 in acetic acid
compounds 83, amines 38, aldehydes 63, and nitromethane 84 under heating condition afforded the corresponding symmet-
in the presence of chitosan 2 as an organocatalyst under the rical pyrroles 92 in 40–98% yield. However, for the synthesis of
solvent-free and microwave-irradiation condition to afford the unsymmetrical 1,4-diketones, the amount of NHC-precursors
17 was increased to 20 mol% and the amount of base was
reduced to 30 mol% in the rst step, and increased to 120 mol%
in the elimination step. Its nal addition with amines 38 in
heating acetic acid produced the unsymmetrical pyrroles 92 in
21–84% yield. In the case of reactive aldehydes, only NHC was
found to be very sufficient to promote the reaction. However, in
the case of aldehydes with lower reactivity, an additional thio-
urea derivative 29 as the H-bonding catalyst is required for the
activation of 1,2-bis-electrophilic nitroalkenes.

Scheme 25 Synthesis of pyrroles via four-step one-pot multicom-

Scheme 24 Solvent-free microwave-assisted synthesis of pyrroles. ponent reaction.

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In 2018, Singh et al. reported an efficient sequential multi-

component strategy toward the synthesis of N-aryl pyrrole-3-
carbaldehydes 95 via the secondary amine 4 catalyzed reaction
of aldehydes 89, arylamines 33, and succinaldehyde 93 in DMSO
by using IBX as the oxidant (Scheme 26).38 Not only the aryl
aldehydes, but also heteroaryl/indole-aldehydes worked well
with this methodology, and a total of 37 compounds were
synthesized in moderate to good yield. The suggested mechanism
for this transformation starts with the in situ formation of enamine
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from the reaction of succinaldehyde 93 and catalyst 4, which can

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then react with the N-PMP-imines 94 generated in situ from alde-

hydes 89 and amines 33, via a direct Mannich reaction, resulting in
the formation of Mannich product 96. The intermediate 96 then
undergoes intramolecular cyclization reaction with subsequent
removal of the catalyst, followed by IBX-promoted oxidative
aromatization to form the nal product 95.

4. Synthesis of pyrroles via multistep

reactions
Scheme 27 L-Proline catalyzed synthesis of trisubstituted pyrroles.
In 2012, Kumar et al. developed a robust two-step strategy
involving the reaction of succinaldehyde 93 with N-PMP aldi-
mines 94 in the presence of organocatalyst 4 in DMSO at room
aromatization under the inuence of DDQ in toluene at 70
C
temperature, followed by acid-catalyzed cyclization and
for the synthesis of substituted pyrroles 95 in 58–82% yield
(Scheme 27).39 This transformation was completed through the
formation of an enamine intermediate 96 from the reaction of
succinaldehyde 93 and amine catalyst 4, which reacts with the
N-PMP aldimines 94 via a direct Mannich reaction, followed by
intramolecular cyclization with the simultaneous regeneration
of 4, acid-catalyzed dehydration and nal aromatization by DDQ
with a subsequent loss of the water molecule to provide the
pyrroles 95.
In 2013, Jean et al. reported the regioselective construction of
2-heteroarylmethylene decorated N-aryl pyrroles 101 via two-
step sequence from readily available aldehydes, imines, and
phosphonium 99 in the presence of organocatalyst 5 in DMF at
40
C. The Mannich coupling of aldehydes 97 and imines 98,
followed by Wittig olenation with phosphonium 99 along with
proton mediated hydroamination, leads to the rapid access of
pyrrolidine 100 (Scheme 28).40 Isomerization of pyrrolidine 100
by simply using the amine base DBU in CH2Cl2 at room
temperature afforded the substituted pyrroles 101 in 41–98%
yield aer 1 hour. The formation of pyrrolidine 100 and
subsequent isomerization steps to 101 is shown in Scheme 28.
Aer the formation of pyrrolidine 100, the deconjugation of the
acrylate moiety followed by aromatization in the presence of the
DBU base yielded the nal product 101.
In 2016, Niknam et al. synthesized a variety of 2,3,4,5-tetra-
substituted pyrroles 103 in 85–91% yield through the one-pot
multistep reaction of substituted aldehydes 63, NH4OAc 102,
and 1,3-dicarbonyl compound 83 by using carbene precursors
16 in the presence of NaOH in absolute ethanol under reux
condition (Scheme 29).41 The reaction of aldehydes 63 in the
presence of N-heterocyclic carbene 16a (generated in situ from
Scheme 26 L-Proline catalyzed synthesis and mechanism of pyrroles
via sequential multicomponent reaction.
16 and NaOH) produced the corresponding benzoin 104 via in

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Scheme 28 Synthesis of 2-heteroarylmethylene decorated pyrroles.

cycloaddition reactions has been developed for the organo-

catalytic synthesis of pyrroles. In 2005, Kamijo and co-workers
developed an organophosphine 11 catalyzed formal [3 + 2]
cycloaddition reaction for the synthesis of 2,3-di-EWG-
substituted pyrroles 108 from activated alkynes 106 and iso-
cyanides 107 in dioxane at 100
C for 0.5–24 hours in 18–79%
yield (Scheme 30).42 The mechanism for this [3 + 2] cycloaddi-
tion reaction begins with the 1,4-addition of a nucleophilic
catalyst 11 to the activated alkynes 106. It then produces the
zwitterionic intermediate, which aer abstraction of acidic
proton in the isocyanides 107, afforded the cationic interme-
diate 109 and the carbanion 110 that undergoes [3 + 2]

Scheme 29 NHC-catalyzed tandem sequence to access pyrroles 103.

situ condensation reactions aer 30 minutes, which reacts with

the imine 105 formed in situ from the NHC-mediated addition
of 1,3-dicarbonyl compound 83 and NH4OAc 102. An intra-
molecular cyclization and aromatization by loss of a water
molecule gave the desired product 103.

5. Synthesis of pyrroles via formal [3 +

2] cycloaddition reactions
For the construction of ve-membered heterocyclic scaffolds,
the [3 + 2] cycloaddition reaction has emerged as one of the Scheme 30 Synthesis of pyrroles from alkynes and isocyanides via [3 +
most promising approaches, and a vast array of [3 + 2] 2] cycloaddition reaction.

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Scheme 31 Secondary amine-catalyzed [3 + 2] annulation to pyrroles.

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cycloaddition reaction via the attack of carbanion 110 to the

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carbon of cationic intermediate 109 bearing the EWG1 and

thereby facilitates the generation of a new anionic center in the
cationic intermediate 109 to attack the isocyanide carbon of
110, leading to the 5-membered cyclic intermediate. Its intra-
molecular proton relocation and removal of the catalyst fol- Scheme 33 [3 + 2] Annulation/elimination/isomerization process to
lowed by 1,5-hydrogen shi yields the nal product 108. access substituted pyrroles 118.
A straightforward route to access densely substituted 3-
formyl pyrroles 112 in 45–70% yield via formal [3 + 2] cycload- iminonitriles 113 through the amino-catalyzed [3 + 2] annula-
dition reaction has been demonstrated by Kumar et al. in 2014. tion (Scheme 32). The reaction was carried out in the presence
The protocol is mainly based on the one-pot cascade reaction of of the secondary amine 4 in DMSO, along with PhCO2H as
substituted 1,4-ketoaldehydes 111 and imines 94 in the pres- additive under microwave heating at 70
C for 40–60 minutes,
ence of the amine catalyst 4 in aqueous DMSO at room followed by the addition of cold MeOH, AcOH at 0
C to room
temperature in 24–38 hours (Scheme 31).43 This transformation temperature, and then the addition of NaBH4 for 2 hours fur-
can be completed via the chemoselective Mannich reaction of nished the pyrrole-3-methanols 114 up to 75% yield. The process
1,4-keto aldehydes 111 with imine 94, followed by intra- started with the direct Mannich reaction of an enamine interme-
molecular cyclization and aerobic oxidative aromatization. diate generated from the reaction of 4 and 93, with iminonitriles
In 2016, Mir et al.44 reported a microwave-assisted synthesis 113, followed by intramolecular cyclization and then dehydration
of substituted pyrrole-3-methanols 114 in good yield from the afforded the enamine intermediate 115. The simultaneous
one-pot two-step reaction of succinaldehyde 93 and a- removal of the catalyst occurred for the next cycle. Its nal in situ
dehydrocyanation and reduction lead to the desired product 114.
In 2016, Ni et al. reported the [3 + 2] cycloaddition reaction to
form the trisubstituted pyrroles 118 by the cascade reaction of 2-
aminoketone derivatives 116 with allenoate 117 in the presence
of tertiary amine 9, along with Na2CO3 in dioxane at 50
C for 12
hours in 37–75% yield. It is pertinent to note that the 2-tosyla-
mino ketone derivatives 116 were found to be a very efficient
1N,2C-bis-nucleophile partner for the [3 + 2] annulation with
allenoate 117 (Scheme 33).45 However, the reaction efficiency
was found to be somewhat lower due to the lower nucleophi-
licity of 116, and results in a moderate yield of the product, as
well as incomplete reaction. The overall process involves the
amino catalyzed [3 + 2] annulation of allenoate 117 and 2-ami-
noketone 116 that undergo 1,2-elimination of the Ts group in
the presence of a base, followed by isomerization route to afford
the corresponding pyrroles 118.
Also, several substituted pyrrole-2,4-dialdehydes 119 were
obtained in 60–80% yield through the one-pot reaction of
glutaraldehyde 93 and imines 94 using the amine catalyst 4 in
aqueous DMSO in the presence of oxidant IBX at 95
C for 8–9
hours (Scheme 34).46 This was an unprecedented pseudo-[3 + 2]
annulation reaction that proceeded under a metal-free condi-
tion, in which not only the substituted and unsubstituted aryl
imines, but also heteroaryl imines were well tolerated in the
pyrrole synthesis. The mechanism involves the direct Mannich
reaction of glutaraldehyde 93 with imines 94, and then cycli-
Scheme 32 Microwave-assisted [3 + 2] annulation for the preparation zation in presence of organocatalyst 4, followed by
of pyrroles 114.

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6. Synthesis of axially chiral pyrroles

The existence of organocatalysis has led to a chiral revolution in
the eld of asymmetric synthesis.48–51 The growth of asymmetric
organocatalysis in the synthesis of pyrroles has drawn much
more attention due to the inexpensive, metal-free, and non-
toxic reaction conditions. In this context, Zhang et al. re-
ported a very efficient strategy for the synthesis of axially chiral
aryl pyrroles 125 with high enantioselectivity by introducing
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a chiral phosphoric acid (S)-20 as the organocatalyst and

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Fe(OTf)3 as the Lewis acid. The combination of two acid systems

enhances the enantioselectivity of the corresponding aryl
pyrroles 125 (Scheme 36).52 The reaction of various 1,4-dike-
tones 124 with aromatic amines 35 using the combined acid
catalyst system in CCl4 and cyclohexane at 0
C afforded the
chiral aryl pyrroles 125 in 85–95% yield with 86–97% ee aer 4
days. This highly atroposelective transformation of the chiral
Scheme 34 Regioselective access to pyrroles via pseudo-[3 + 2]
aryl pyrroles initially involves the formation of the key enamine
annulation reaction.
intermediate 126 from 1,4-diketones 124 and amine 35, which
then undergo acid-catalyzed dehydrative cyclization to produce
the desired product 125.
The chiral phosphine-catalyzed synthesis of enantioenriched
1H-pyrroles via formal [3 + 2] cycloaddition reaction has been
reported by Zhao and co-workers in 2018. Treatment of allenoates
127 and activated isocyanides 128 in the presence of 12 in CHCl3 at
24
C for 24 hours afforded the enantioenriched pyrroles 129 in
17–50% yield with 81–97% ee (Scheme 37).53 Several electron-
withdrawing and electron-donating substituents on the benzyl
ring of allenoate affected the yield and enantioselectivity of the
corresponding products. When electron-withdrawing groups were
substituted at the ortho or 2,6-position, the yield of the product was
found to be very low with good enantioselectivity. Whereas, for the
Scheme 35 Organocatalytic formal [3 + 2] cycloaddition reaction for electron-donating groups, substitution at the ortho position fur-
the asymmetric construction of dihydropyrroles 122. nished moderate yield with good ee. Also, the electron-donating
groups at the para position of the benzyl ring were well tolerated
regioselective oxidation under the inuence of oxidant IBX to by this method.
produce 1,2-dihydropyridines (DHPs). The oxidation, ring- In 2019, the synthesis of axially chiral 2-aryl pyrroles 132
opening, and IBX-promoted intramolecular cyclization affor- from enantioenriched atropisomeric alkenes via direct chirality
ded the dihydropyrrole intermediate that undergoes nal
oxidative aromatization to give the pyrroles 119.
Guo et al. developed the rst organocatalytic asymmetric
construction of optically active 2,3-dihydropyrroles by means of
the formal [3 + 2] cycloaddition reaction. Treatment of several
isocyanoesters 120 and nitroalkenes 121 in the presence of
cinchona alkaloid 26 in CH2Cl2 at 35
C was found to lead to 2,3-
dihydropyrroles 122 in 51–99% yield (Scheme 35).47 Not only the
aromatic ring bearing various electron-donating and electron-
withdrawing substituents, but also aliphatic nitroalkenes were
well tolerated, and resulted in the formation of the products
with high diastereoselectivities of up to >20 : 1 with 91 to >99%
ee. The process was initiated with the activation of the acidic a-
carbon atom of isocyanoesters 120 by the catalyst 26 to undergo
enantioselective Michael addition with nitroalkenes 121,
thereby providing the intermediate 123. The subsequent intra-
molecular cyclization of 123 followed by protonation afforded
the nal product 122. Scheme 36 Atroposelective construction of pyrroles 125 via Paal–
Knorr reaction strategy.

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Scheme 39 Synthesis of axially chiral aryl pyrroles 135 via desym-

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metrization/kinetic resolution strategy.

Scheme 37 Enantioselective synthesis of substituted pyrroles 129 via

[3 + 2] cycloaddition sequence.

transfer strategy was developed by Wang et al.54 The atropiso- Scheme 40 PTC-catalyzed asymmetric construction of chiral
meric alkenes 131 were produced through the asymmetric bisphosphine 138 bearing a 3-pyrrole unit.
reaction of substituted enamines 129 with N-alkylating reagents
130 in the presence of the cinchonine-derived organocatalyst 27
and Cs2CO3 in toluene at 0
C for 6 days. Treatment of 131 in the
presence of the strong base lithium diisopropylamide (LDA) in
THF at 78
C for 1–2 hours afforded the corresponding axially
chiral 2-aryl pyrrole scaffolds 132 in 54–96% yield with 83–94%
ee (Scheme 38).
Zhang et al.55 reported an atroposelective synthesis of axially
chiral aryl pyrroles 135 from 1H-pyrrole 133 and diethyl keto-
malonates 134 in the presence of chiral phosphoric acid (S)-21
in cyclohexane at room temperature via desymmetrization/
kinetic resolution strategy. Products were formed in very high
yield (82–99%) with 83–96% ee (Scheme 39).
The reaction of nitroolen of type 136 with a-iso- Scheme 41 Kinetic resolution of 141 via enantioselective aromatiza-
cyanomethyldiphenylphosphine oxide 137 in the presence of tion sequence to access 3-aryl pyrroles 142.
the cinchona-derived phase transfer catalyst 28 and CsOH in
toluene at 20
C aer 24 hours afforded the corresponding of the racemic intermediate of the Barton–Zard reaction via
axially chiral pyrrole 138 in 99% yield with high enantiose- the enantioselective aromatization reaction. The process
lectivity (Scheme 40).56 However, when the same reaction was starts with the base potassium hexamethyldisilazide
carried out in a Ag2O/quinine-derived aminophosphine ligand (KHMDS)-catalyzed diastereoselective reaction of nitro-
catalytic system, the corresponding product 138 was formed in olens 139 with a-isocyano substrates 140 bearing an
75% yield with 21% ee. electron-withdrawing group to produce the Barton–Zard
In 2019, Zheng et al.57 also noted that the enantioenriched intermediate 3,4-dihydro-2H-pyrroles 141 as a racemic
3-aryl pyrroles would be obtained from the kinetic resolution product (Scheme 41). This diastereomerically pure ()-3,4-
dihydro-2H-pyrroles [()-141] on treatment with quinine-
derived thiourea 30 and 5 Å MS (molecular sieves) in
toluene at 30
C underwent enantioselective aromatization,
thereby providing (+)-3-aryl pyrroles [(+)-142] in good yield
with 76–93% ee, and recovered (+)-3,4-dihydro-2H-pyrroles
[(+)-141] in 50–98% ee. The subsequent aromatization of the
resolved (+)-141 in the presence of another quinidine-derived
catalyst 31 in toluene at 30
C furnishes the ()-3-aryl
pyrroles [()-142] in 93–100% yield with excellent central-to-
Scheme 38 Synthesis of axially chiral 2-aryl pyrroles via chirality axial chirality transfer.
transfer approaches.

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Scheme 43 Organocatalytic hydride transfer strategy to access

pyrroles 150 & 152.

ketoesters 149 provided the corresponding b-functionalized

pyrroles 150 in 35–78% yields (Scheme 43).59 This reaction
proceeded through the intramolecular [1,5]-hydride transfer
Scheme 42 Organocatalytic cycloisomerization reactions to access (HT) initiated cascade reaction sequence. It is pertinent to note
substituted pyrroles 144. that various halogens present on the aromatic rings and other
aromatic rings, such as naphthalene, acenaphthene, biphenyl,
furan, and thiophene, were well tolerated with this trans-
7. Other strategies for the synthesis of formation. They also expanded the methodology for the
synthesis of other pyrrole derivatives 152, and the desired
pyrroles product was obtained in 19–77% yield. To obtained the best
In 2019, Meng et al.58 reported that the substrates Z-1-iodo-4-N- yield of the product, the solvent system was replaced by toluene
methylbenzenesulfonyl-1,6-enynes 143 bearing vinyl iodide and instead of DCE, and the transformation was carried out via
N-propargylamine underwent a cycloisomerization reaction in intermolecular HT-initiated b-C(sp3)–H functionalization/
the presence of organocatalyst 10 and KOtBu in THF at 10
C, aromatization sequence.
and thereby provided the functionalized pyrroles 144 from non-
aromatic to aromatic systems in 44–79% yield within 10
minutes (Scheme 42), although the effect of the organocatalyst 8. Conclusion
in this radical initiation transformation is not clearly described
in the report. However, the author suggested a mechanistic In this review, we have summarized the up-to-date advances on
pathway for this reaction, which initially involves the homolytic the utilization of organocatalysts for the synthesis of various
cleavage of the C–I bond of 143 under the inuence of complex pyrroles over the last decades. On behalf of the appropriate
145 (10 and t-BuOK), leading to the formation of a vinyl radical understanding and a convenient presentation, the article is
143a and complex 146 with subsequent removal of the iodide classied according to the two-component synthesis, multi-
anion. The abstraction of hydrogen by 146 from the propargylic component synthesis, multistep synthesis, formal [3 + 2]
position furnishes the complex 147 that reconverted into the cycloaddition, synthesis of axially chiral pyrroles, as well as
catalyst 145 by treating with iodide. The double radical 143b other synthetic strategies. Aer the renaissance of organo-
undergoes intramolecular cyclization followed by isomerization catalysis, the growth in the eld of organic synthetic chemistry
in the presence of KOtBu and aromatization to yield the corre- for the construction of diverse biologically active building
sponding pyrroles 144. blocks in asymmetric, as well as non-asymmetric fashion, has
In 2020, Zhou and his co-workers demonstrated an unprec- reached an exceptional level in this century. It can be catego-
edented cascade b-functionalization/aromatization reaction of rized into several activation modes, including amine catalysis,
N-aryl pyrrolidines for the synthesis of diverse b-substituted aryl phase-transfer catalysis, hydrogen-bonding catalysis, and
pyrroles embedded with triuoromethyl groups by using others. In sharp contrast devoted towards its development, the
20 mol% of 1,1&-binaphthyl-2,2-diyl hydrogen phosphate 19 as synthesis of pyrrole molecules by organocatalytic strategy is
the Brønsted acid catalyst in 1,2-dichloroethane (DCE) as the limited. However, several metal-free approaches have been
solvent at 100
C. The reaction of N-aryl pyrrolidines 148 with discovered, even though they all are not considered organo-
catalytic routes. Although remarkable results were obtained, the

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development of very effective and concise organocatalytic 7 (a) A. Hantzsch, Chem. Ber., 1890, 23, 1474; (b) M. W. Roomi
methods for the pyrrole synthesis is still desired. We hope these and S. F. MacDonald, Can. J. Chem., 1970, 48, 1689–1697.
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Springer, Berlin, Heidelberg, 2009, pp. 411–412; (b)

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There are no conicts to declare. B. K. Banik, I. Banik, M. Renteria and S. K. Dasgupta,

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