Синтез піролів з нітроолефінів
The synthesis of pyrroles occupies a key place in synthetic organic chemistry due to the numerous biological properties of pyrrole derivatives, in particular antimicrobial, antibacterial, antifungal, antimalarial, anticancer activities, etc. Therefore, pyrroles serve as building blocks in the creati...
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| author | Hotynchan, Andrii H. Kovtun, Olena M. Kovtun, Yuriy P. |
| author_facet | Hotynchan, Andrii H. Kovtun, Olena M. Kovtun, Yuriy P. |
| author_institution_txt_mv | [
{
"author": "Andrii H. Hotynchan",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Olena M. Kovtun",
"institution": "Dragomanov Ukrainian State University",
"orcid": ""
},
{
"author": "Yuriy P. Kovtun",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
}
] |
| author_sort | Hotynchan, Andrii H. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 58 |
| container_issue | 2 |
| container_start_page | 48 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 23 |
| datestamp_date | 2026-08-22T19:54:27Z |
| description | The synthesis of pyrroles occupies a key place in synthetic organic chemistry due to the numerous biological properties of pyrrole derivatives, in particular antimicrobial, antibacterial, antifungal, antimalarial, anticancer activities, etc. Therefore, pyrroles serve as building blocks in the creation of potential pharmaceuticals and also serve as the basis for the synthesis of boradipyrromethene dyes. One of the most well-known approaches to the synthesis of pyrroles is the reaction between nitroolefins, 1,3-dicarbonyl compounds, and amines, also known as the Grob-Camenisch reaction. This review is devoted to the historical chronology from the discovery of this transformation dating back to 1950s to the present, and covers the development of various modifications of the above reaction in the synthesis of pyrroles. |
| doi_str_mv | 10.24959/ophcj.25.323775 |
| first_indexed | 2025-07-23T04:43:39Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 48
Review Article
http://ophcj.nuph.edu.ua
UDC 547.74:547.232
A. H. Hotynchan1, O. M. Kovtun2, Yu. P. Kovtun1
1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academik Kukhar str., 02094 Kyiv, Ukraine
2 Dragomanov Ukrainian State University, 9 Pyrohova str., 01601 Kyiv, Ukraine
The Synthesis of Pyrroles from Nitroolefins
Abstract
The synthesis of pyrroles occupies a key place in synthetic organic chemistry due to the numerous biological properties of
pyrrole derivatives, in particular antimicrobial, antibacterial, antifungal, antimalarial, anticancer activities, etc. Therefore,
pyrroles serve as building blocks in the creation of potential pharmaceuticals and also serve as the basis for the synthesis
of boradipyrromethene dyes. One of the most well-known approaches to the synthesis of pyrroles is the reaction between
nitroolefins, 1,3-dicarbonyl compounds, and amines, also known as the Grob-Camenisch reaction. This review is devoted
to the historical chronology from the discovery of this transformation dating back to 1950s to the present, and covers the
development of various modifications of the above reaction in the synthesis of pyrroles.
Keywords: pyrrole; Grob–Camenisch reaction; nitroolefines
А. Г. Готинчан1, О. М. Ковтун2, Ю. П. Ковтун1
1 Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02094, Україна
2 Український державний університет імені Михайла Драгоманова,
вул. Пирогова, 9, м. Київ, 01601, Україна
Синтез піролів з нітроолефінів
Анотація
Синтез піролів займає ключове місце в синтетичній органічній хімії завдяки численним біологічним властивостям по-
хідних піролу, зокрема антимікробній, антибактеріальній, протигрибковій, антималярійній, протираковій тощо. Саме тому
піроли слугують будівельними блоками у створенні потенційних фармацевтичних препаратів, а також є основою для
синтезу барвників бордипірометенового ряду. Одним із найвідоміших підходів до синтезу піролів є реакція між ні-
троолефінами, 1,3-дикарбонільними сполуками та амінами, відома як реакція Гроба-Каменіша. Цей огляд висвітлює
історичну хронологію від відкриття цього перетворення, датованого 1950-ми роками, до сьогодення та охоплює роз-
робку різноманітних модифікацій вищезгаданої реакції в синтезі піролів.
Ключові слова: пірол; реакція Гроба-Каменіша; нітроолефіни
Citation: Hotynchan, A. H.; Kovtun, O. M.; Kovtun, Yu. P. The synthesis of pyrroles from nitroolefins. Journal of Organic
and Pharmaceutical Chemistry 2025, 23 (2), 48 – 58.
https://doi.org/10.24959/ophcj.25.323775
Received: 26 February 2025; Revised: 4 June 2025; Accepted: 7 June 2025
Copyright© 2025, A. H. Hotynchan, O. M. Kovtun, Yu. P. Kovtun. This is an open access article under the CC BY license
(http://creativecommons. org/licenses/by/4.0).
Funding: The authors received no specific funding for this work.
Conflict of interests: The authors have no conflict of interests to declare.
■ Introduction
Heterocyclic compounds are very important
in the field of organic chemistry as they are wide-
ly spread in nature and commonly used as build-
ing blocks in pharmacology. Among heterocycles,
pyrrole is of great interest due to its presence in
a variety of medicines, such as atorvastatin [1],
tolmetin [2], ketorolac [3] etc., and its application
in the dye synthesis, for example, BODIPY [4].
Therefore, the pyrrole core synthesis methods play
a key role in contemporary organic chemistry.
There are some well-known synthetic routes
for the pyrrole synthesis. The first one is the
Hantzsch reaction, including the transforma-
tion between β-ketoesters, ammonia source, and
ISSN 2308-8303 (Print) / 2518-1548 (Online) 49
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
haloketones [5]. Alternatively, the Knorr synthe-
sis (the reaction between α-amino-ketones and
1,3-dicarbonyl compounds) [6] or the Paal-Knorr
synthesis (the reaction between 1,4-diketones and
different ammonia sources) [7] can be employed.
Due to increased interest, other methods of the
pyrrole synthesis were developed. One of them
is based on the aza-Wittig reaction, involving the
interaction between l-aza-l,3-bis(triphenylphos-
phoranylidene)propane and 1,2-diketo-com-
pounds [8], and another one includes the reac-
tion between 3-formylchromones and amines
under TMSCl-mediated conditions [9].
Nitroolefins are an efficient initial material
for the synthesis of organic compounds. Their syn-
thetic attractiveness refers to the simplicity of
their preparation via the condensation between
nitroalkanes and aldehydes, known as the Hen-
ry reaction [10]. In β-nitrostyrene, the conjugation
of the double bond with the nitro group enables
it to participate in the Michael addition [11],
a reaction that plays a crucial role in the syn-
thesis of heterocycles. For example, nitroolefins
are widely used in the synthesis of aziridines,
pyrrolidines, oxazoles, indoles, etc. [12].
Taking the aforementioned information into
account, the aim of this review is to discuss the
historical development and progress in the pyr-
role synthesis methods from nitroolefin deriva-
tives.
Discovery of the Grob-Camenisch reac-
tion
The first literary mention of the pyrroles syn-
thesis from nitro compounds refers to the work
of Grob and Kamenisch, dating back to 1953 [13].
Using 1-nitro-2-methylaminopropane and ace-
toacetic ester, the authors synthesized ethyl
1,2,4-trimethyl-2-pyrrolecarboxylate with a yield
of 31 %. They suggested the following mechanism
(Scheme 1). In the solution, 1-nitro-2-methyl-
aminopropane (1) exists in equilibrium with me-
thylamine (2) and 1-nitropropene (3). After the
addition of acetoacetic ester, the latter under-
goes the condensation to form the corresponding
enamine 4, which further reacts with 1-nitropro-
pene, resulting in Michael’s product 5. This pro-
duct 5 cyclizes into dihydropyrrole 6, eliminat-
ing a molecule of nitrous acid, which, in turn,
oxidizes intermediate 6, forming pyrrole 7.
The further development of the reaction in-
volving nitroolefins, 1,3-dicarbonyl compounds,
and amines focused on identifying alternative
synthetic approaches to increase pyrrole yields
and expand the range of substrates that could
be used. Currently, several variants of this reac-
tion are known, including two-, three-, and four-
component Grob-Camenisch-type reactions.
A two-component Grob-Camenisch-type
reaction
The two-component Grob-Camenisch-type
synthesis of pyrroles involves the reaction of
β-enaminoesters or ketones with nitrostyrenes.
First reported in 1981, this method utilized
enamines 8, derived from acetoacetic ester and
(E)-(2-nitroprop-1-en-1-yl)benzene (9) [14]. Reflux-
ing the reaction mixture in ethanol for four to
six hours allows the pyrroles 10 to be obtained
with yields ranging from 16 % to 80 % (Scheme 2).
The authors also found that using N-unsub-
stituted enamine 11 in the reaction with nitro
Me
H
N NO2
Me
Me
NH2 +
Me
NO2
Me
O
CO2Et
Me
NH2
Me
NHMe
CO2Et
Me
NO2
Me
NO2
EtO2C
NHMe
- HNO2
N
MeEtO2C
HNO2
N
MeEtO2C
1 2 3
4 5
67
MeMe
Me
MeMe
32
Scheme 1. The synthesis of pyrrole by Grob–Camenisch
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Журнал органічної та фармацевтичної хімії 2025, 23 (2)
compound 9 by refluxing in ethanol for 14 hours
could produce pyrrole 12 with a yield of 51 %
(Scheme 3).
Enaminoketones can also be used in a Grob-
Camenisch-type reaction. However, harsher con-
ditions are required, delivering the products with
lower yields compared to standard substrates.
Specifically, the reaction of enamine 13 with ni-
trostyrene 10 in a melt at 150°C produces pyr-
role 14 with a yield of only 26 % (Scheme 4) [14].
Further studies of the pyrrole synthesis from
nitrostyrenes and β-enaminoesters or β-enami-
noketones showed that enaminones 15 reacted
with nitrostyrene or p-tolylnitrostyrene (16) un-
der solvent-free conditions, yielding pyrroles in
70 – 90 % yield (Scheme 5) [15]. The mechanism
proposed involves the Michael-type addition of
β-enaminones to nitroolefins, forming interme-
diate 17, which cyclizes to pyrroline 18 with the
elimination of nitrous acid. The subsequent oxi-
dation results in the production of the final pyr-
role 19.
The scope and diversity of pyrroles synthe-
sized from β-enaminones or esters and nitroole-
fins can be enhanced by using solvents or cata-
lysts. For instance, the reaction of N-phenyl-
substituted enamine 20 with substituted nitro-
propene 21 in methanol at 120°C yields penta-
substituted pyrroles 22 (Scheme 6) [16].
The authors observed that catalytic amounts
of bases (e.g., sodium acetate or piperidine) and
polar aprotic solvents (e.g., DMSO or acetonitrile)
H
N
R
Me
H
CO2Et
N
CO2Et
MeMe
Ph
R
+
Ph
Me
NO2
8 9 10
R = Me ( ), cyclopropyl ( )80 % 16 %
EtOH
Scheme 2. The synthesis of pyrroles from methyl- and cyclopropyl-derived enaminoesters
H2N
Me
H
CO2Et
N
H
CO2Et
MeMe
Ph
+
Ph
Me
NO2
11 9 12
EtOH
51 %
Scheme 3. The synthesis of pyrrole from N-unsubstituted enaminoester
O
HN
R
N
Ph
Me
O
13 14
R =
OMe
OMe
+
R
Ph
Me
NO2
9
neat
150 Cº
26 %
Scheme 4. The synthesis of pyrrole from enaminone based on dimedone
+ R
O
Me
N
Ar
NO2
R
O Me
Ar
NO2
N
H
R'
- HNO2
N
Me
R'
O
R
Ar
17 18
[Ox]
R
O
Me
HN
R'
Ar
NO2
N
Ar
O
R
Me
R'
R = Me, OEt
R' = Bn, Bu, -Hexn c
Ar = Ph, Tolp-
15 16
19
R'
neat
70 95 %–
Scheme 5. The reaction mechanism of the pyrrole formation in the reaction between enamines and nitrostyrenes
ISSN 2308-8303 (Print) / 2518-1548 (Online) 51
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
significantly decreased pyrrole yields. Electron-
donating substituents on the aryl groups of ni-
trostyrenes and β-enaminoesters substantially
improve yields compared to electron-withdraw-
ing ones. It is noteworthy that the use of [2-ni-
troprop-1-en-1-yl]furan made it possible to syn-
thesize pyrrole with a furyl group in position 3,
yielding 79 % of the product. Additionally, the
application of nitrostyrene as a reagent facilitates
the production of α-CH pyrrole with good yields.
Catalytic reactions provide an effective pre-
parative method for synthesizing pyrroles from
β-enaminoesters and nitroolefins. For instance,
using iodine as a catalyst allows the formation
of N-substituted pyrroles from nitrostyrene and
β-enaminoesters derived from the acetoacetic
ester. It is noteworthy that nitrostyrenes bearing
electron-donating substituents result in pyrroles
with significantly higher efficiency, whereas
N-alkyl-substituted 3-aminobut-2-enoates lead
to slightly lower yields due to competing side re-
actions [17].
The Ph3PAuCl catalyst combined with AgO-
Tf significantly enhances the pyrrole synthe-
sis via a two-component reaction. Reactions of
N-substituted enamines 23 obtained from ace-
toacetic ester or acetylacetone with substituted
nitrostyrenes 24 lead to pyrroles 25 with yields
exceeding 80 % (Scheme 7) [18]. It is noteworthy
that the nature of substituents in aryl groups has
minimal impact on pyrrole yields, and N-alkyl-
substituted enamines react without side reactions,
also giving pyrroles in high yields.
The PEG-400 catalyst demonstrated a high
effectiveness for synthesizing isoxazole deriva-
tives bearing a pyrrole moiety in position 4 [19].
The reaction of ethyl 3-((3-methyl-5-((E)-styryl)-
isoxazol-4-yl)amino)but-2-enoate derivatives (26)
with nitrostyrenes 27 gave the corresponding pyr-
roles 28 with yields from 70 to 90 % (Scheme 8).
A solid-phase method for the pyrrole synthe-
sis was also developed [20]. Initially, Rink Amide
resin (29) is acetoacetylated with diketene to form
amide 30, which is subsequently converted to
polymer-bound enaminone 31 upon the treatment
with primary amines. Further reaction of polymer-
bound 31 with nitroolefins in a DMF/EtOH sol-
vent mixture at 60°C yielded pyrroles 32, which
upon the treatment with trifluoroacetic acid pro-
duced final amides 33. In this method, the pyr-
role yield exceeds 80 % when using both alipha-
tic and aromatic amines, as well as aliphatic ni-
troolefins (Scheme 9).
A three-component Grob-Camenisch-type
reaction
The three-component Grob-Camenisch syn-
thesis of pyrroles involves the reaction of amines,
1,3-dicarbonyl compounds, and nitrostyrenes,
R
2
R
1
NO2Me
NHPh
CO2Me
MeOH, 120 ºC
N
CO2Me
Me
Ph
R
2
R
3
2120 22
R
1
= H, Me
R
2
= Ph, 4-Me-C6H4, 3-Me-C6H4, 4-OMe-C6H4, 4-Me-C6H4, 4-NMe2-C6H4,
4-F-C6H4, 2-furfuryl
+
75 85 %–
Scheme 6. The synthesis of N-substituted pyrroles 22
Me
NH
R
2
O
O2N
Ar
R
1
Ph3PAuCl
AgOTf
NO2
Ar
OR
2
NH
Me
R
1
N
Ar
OR
2
NH
Me
R
1
OH
O
N
Ar
O
R
2
N
Me
R
1
OH
HO - H2O
- HNO
N
R
1
Me
Ar
O
R
2
R
1
R
2
= Me, OEt
23 24
25
+
75 95 %–
Scheme 7. The reaction mechanism of the pyrrole formation in the reaction between enamines and nitrostyrenes catalyzed with Ph3PAuCl
ISSN 2308-8303 (Print) / 2518-1548 (Online) 52
Журнал органічної та фармацевтичної хімії 2025, 23 (2)
which make it possible to prepare pyrroles with
catalytic activity. For instance, research [21] de-
monstrates that lactic acid serves as an effective
medium for synthesizing tetrasubstituted pyr-
roles from acetylacetone and substituted ani-
lines, achieving yields of approximately 70 – 90 %.
The study indicates that neither electron-with-
drawing nor electron-donating substituents on
the aniline significantly influence pyrrole yields.
Iron-based catalysts, such as FeCl3, are wide-
ly employed in the catalytic synthesis of pyrroles
from nitroolefins and 1,3-dicarbonyl compounds.
For instance, FeCl3 facilitates a three-component
reaction, yielding pyrroles at 70 – 80 % using
1,3-dicarbonyl compounds like acetoacetic es-
ter, acetylacetone, or ethylbenzyl acetate [22].
As a Lewis acid, FeCl3 promotes the formation
of β-enaminoester 34, which undergoes the Mi-
chael-type addition to nitrostyrene, followed by
the cyclization of the resulting adduct 35 into
pyrrole via the nitro group conversion to its aci-
nitro form (Scheme 10).
Interestingly, iron(III) chloride makes it pos-
sible to synthesize pyrroles from nitrostyrene
bearing ethynyl substituents in the ortho-position,
obtaining the target products with a yield of
about 50 % [23]. Additionally, the catalyst facili-
tates the pyrrole synthesis from peptides with a
free amino group [24].
An alternative to FeCl3 is the use of Fe3O4 na-
noparticles, in particular Fe3O4@SiO2-CPTMS-
guanidine-SO3H, which contain a terminal sulfo
group [24]. This catalyst allows the synthesis of
tetrasubstituted pyrroles from acetoacetic ester,
acetylacetone, and para-chloro- or para-bromo-
anilines with yields of approximately 90 %
(Scheme 11). The sulfo group is supposed to ca-
talyze the reaction similarly to FeCl3.
Cerium(III) chloride serves as an alternative
catalyst to FeCl3, effective in the microwave-as-
sisted synthesis using nitromethane as a solvent
[26]. This method allows the synthesis of tet-
rasubstituted pyrroles from acetoacetic ester or
acetylacetone, nitrostyrenes, and anilines, with
yields of about 80 %. However, when para-chlo-
ronitrostyrene is used, the yield decreases to
about 50 %.
An alternative to CeCl3 is cerium(IV) ammo-
nium nitrate (CAN), which catalyzes the reac-
tion of nitrostyrene 38, acetoacetic ester (36),
N
O
HN
Ar
1
Me
Me
O
EtO
Ar
NO2
R
PEG-400 (10 mol%)
H2
N
O
Ar
1
Me
N
Me
R
Ar
CO2Et
26 27 28
R
1
= H, Me, Ph
+
70 90 %–
O, reflux, 3–4 h
Scheme 8. The synthesis of pyrroles 28
NH2
O
O
CH2Cl2
-15 C to rt, 2.5 hº
N
H
O
Me
O
rt, 48 h
N
H
O
Me
HN
R
1
DMF/EtOH (1:1)
60 C, 2hº
R
3
H
NO2
R
2
NMe R
2
R
3
R
1
N
H
O
20 % TFA/CH2Cl2, 30 min
NMe R
2
R
3
R
1
H2N
O
31
32 33
29 30
R
1
NH2
R
1
= 2-phenylethyl, pyperonyl, cyclopropyl, 2-furfuryl, thiophene-2-ethyl,
R
2
= H, Me
R
3
= H, Ph, -Cl-Cp 6H4, 4-OMe-C6H4, 3-OMe-C6H4, 4-bromothienyl, cyclohexyl
45 90 %–
Scheme 9. The solid-phase synthesis of pyrroles from nitroolefins
ISSN 2308-8303 (Print) / 2518-1548 (Online) 53
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
and benzylamine (37) at room temperature in me-
thanol [27]. This method produces pyrroles with
yields ranging from 50 to 75 % (Scheme 12).
In addition to other metal-containing cata-
lysts, Ph3PAuCl combined with AgOTf [28] and
zirconyl dichloride complexes [29] makes it pos-
sible to use acetoacetic ester and various β-dike-
toamides as 1,3-dicarbonyl compounds, yielding
pyrroles at approximately 70 %.
Furthermore, diacetoxyiodobenzene serves as
an effective non-metal catalyst for the pyrrole syn-
thesis, producing pyrroles from acetoacetic ester
and acetylacetone with yields of about 70 %, un-
affected by substituents on nitrostyrene or ani-
line [30, 31].
The combination of oxone and iodobenzene
makes it possible to synthesize pyrroles from ni-
trostyrenes, acetylacetone, or acetoacetic ester,
and anilines, yielding 80 – 90 % of the desired
product. Notably, neither electron-donating nor
electron-withdrawing substituents on nitrosty-
rene or aniline impact the pyrrole yield [31].
R
1
NO2
R
2
R
3
O O
R
4
R
5
NH2
FeCl3 (5 mol%)
N R
2R
3
R
5
R
1R
4
O
FeCl3
- H2O
R
3
NH O
R
4
R
5 R
1
NO2
R
2
FeCl3
NH
R
2
R
3
R
5
R
1
R
4
O
N
OH
O
- HNO
- H2O
34 35
+ +
R
1
= Ph, 4-Me-C6H4, 4-Me-C6H4, 4-OMe-C6H4, 4-Cl-C6H4, Br-C6H4, 2-thiophenyl, 2-naphtyl
R
2
= H, Me
R
3
= Me, Ph
R
4
= Me, OEt
R
5
= 4-Me-C6H4, 4-Me-C6H4, 4-OMe-C6H4, 4-F-C6H4, 4-Cl-C6H4, Br-C6H4, 2-naphtyl
60 90 %–
Scheme 10. The reaction mechanism of the three-component synthesis of pyrroles from nitroolefins catalyzed with FeCl3
O O
R
2
Me
R
1
NH2
HO3S
NH
Me
O
R
2
NO2 N
O
R
2
Me
NH
OH
O
HO3S N
Me
N
HO
OH
R
2
O
H
- HNO
- H2O
N
Me
R
2
O
5
+
R
1
R
3
R
1
R
3
R
3
R
1
R
3
R
1
R
1
= Ph, 4-Cl, 4-Br
R
2
= Me, OEt
R
3
= H, 4-Me, 4-Cl, 4-OMe
85 90 %–
Scheme 11. The reaction mechanism of the three-component synthesis of pyrroles from nitroolefins catalyzed
with Fe3O4@SiO2-CPTMS-guanidine-SO3H
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Журнал органічної та фармацевтичної хімії 2025, 23 (2)
Ionic liquids, such as N-methyl-2-pyrrolido-
nium methyl sulfonate, serve as effective catalysts
for the three-component synthesis of pyrrole in-
volving nitroolefins, amines, and 1,3-dicarbonyl
compounds. Notably, the yields of pyrroles from
substituted nitrostyrenes and anilines, ranging
from 70 to 90 %, show no correlation with the sub-
stituent effects. However, using aliphatic nitro-
olefins and amines decreases yields to 30 % [32].
A four-component Grob-Camenisch-type
reaction
Another convenient option for the synthesis
of pyrroles is a four-component reaction involv-
ing aldehydes, nitroalkanes, 1,3-dicarbonyl com-
pounds, and amines. Currently, only catalytic va-
riants of this transformation have been developed
using FeCl3 [32], palladium [34], and tungsten-
based complexes [35], CuO nanoparticles [36],
ionic liquids [37, 38], iodine [39], clay [40],
NiCl2·6H2O [41], as well as organic acids – lactic
and gluconic [42] (Scheme 13).
The reaction mechanism includes the cata-
lyzed formation of a β-enaminone from a nitro-
olefin, followed by the Michael addition to form
an intermediate. This intermediate undergoes eli-
mination of a hyponitrous acid molecule, result-
ing in the formation of pyrrole.
The synthesis of N-unsubstituted α-CH
pyrroles
The synthesis of N-H α-CH pyrroles is of sig-
nificant interest in the Grob cyclization, as these
compounds serve as precursors for luminescent
BODIPY borofluoride complexes and porphyrins.
The earliest reported attempt to synthesize such
Me
O
CO2Et
Bn NH2 EtO2C
Ph
OAc
NO2
CAN
(15 mol%)
MeOH, rt
CAN
Bn
N
H
Me
CO2Et
CO2Et
OAc
Ph
O2N
- OAc, - H
+
SN2'
N
Me
Bn
O OEt
NO2
Ph
EtO2C H
5-exo-trig N
OEt
O
O2N
Ph
H
CO2Et
Me
Bn
N
EtO2C
Ph
CO2EtMe
Bn
- HNO2
36 37 38
+ +
+
H
+
65 %
Scheme 12. The reaction mechanism of the three-component synthesis of pyrroles from nitroolefin 38
R
1
NH2
R
2
CHO
R
3
O O
R
4
R
5
NO2 N R
5R
3
R
1
R
2R
4
O
Lewis
acid
R
3
NH O
R
4
R
2
NO2
R
5
R
2
H
NO
R
4
R
2
N
R
5
R
1
R
3
OHO
N
R
5
R
3
R
1
R
2
R
4
O
H
N
OH
OH
- HNO
- H2O
+ +
+
Lewis acid 40 85 %–
R
1
= benzyl, cycloxehyl
R
2
= Ph, 4-Me-C6H4, 4-OMe-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-CN-C6H4, 4-NO2-C6H4,
2-thiophenyl, 2- furfuryl, 2-naphtyl
R
3
=Ph, Me
R
4
= OMe, OEt
R
5
= H, Me
Scheme 13. The reaction mechanism of the four-component synthesis of pyrroles from nitroolefins catalyzed by Lewis acids
ISSN 2308-8303 (Print) / 2518-1548 (Online) 55
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
pyrroles was by Grob [13] where 1-nitropropan-
2-amine 39 and acetoacetic ester were used.
However, instead of the expected N-H pyrrole,
an N-substituted derivative 44 was obtained.
This outcome was attributed to intermediate 41
possessing two nucleophilic centers: a carbon atom
and a nitrogen one. Hence, two Michael additions
occur, leading to intermediate 42, which under-
goes further cyclization, thus yielding N-isopro-
pyl derivative 44 instead of the expected N-H one
(Scheme 14).
In order to synthesize the corresponding
N-H α-CH pyrrole, Grob first isolated interme-
diate 45, which failed to transform into pyrrole
46 under different conditions (Scheme 15). The
author attributed this to the conjugation of the
nitrogen atom lone pair in intermediate 45 with
the ethoxycarbonyl group reducing its nucleo-
philicity. However, interestingly, upon the treat-
ment of 45 with methylamine, pyrrole 48 could
be isolated, assuming that the transamination
occurred with the formation of 47, which then
cyclized to 48. From this observation, it could be
suspected that the presence of even weak elec-
tron-donating groups favors the pyrrole synthe-
sis by the Grob cyclization.
In the subsequent study, Gómez-Sánchez [43]
investigated the synthesis of N-H α-CH pyrro-
les using nitro compounds, with a focus on the for-
mation of anomalous Michael products from ni-
trostyrene and acetylacetone. By employing non-
catalytic amounts of sodium methoxide with ace-
tylacetone and nitrostyrene 49, the authors obtain-
ed anomalous Michael products 50 (Scheme 16).
The latter product, upon the treatment with sa-
turated methanolic ammonia solution at 0°C, gives
rise to pyrrole 51 (Scheme 16).
Based on this observation, the authors deve-
loped a one-pot procedure of the pyrrole synthe-
sis, including the treatment of nitrostyrene 49
with acetylacetone, acetoacetic ester, or methyl
acetoacetate in methanol with a non-catalytic
H2N
Me
NO2
+
Me
NO2
Me
O
CO2Et +
Me
NH2
CO2Et
Me
HN
CO2Et
Me
NO2
N
Me
EtO2C Me
N
Me
EtO2C Me
39 40
41 42
43
Me
NO2
NH3
NH3
Me
NO2
Me
NO2
Me
NO2
2-step addition
-HNO2
HNO2
44, 55 %
Scheme 14. The synthesis of pyrrole by Grob-Camenisch
NH2Me
EtO2C
Me
NO2
N
H
Me
EtO2C
Me
45 46
MeNH2
N
H
Me
EtO2C
Me
NO2
47
N
Me
EtO2C
Me
48, 31 %
Me
Me
Scheme 15. Transformations of intermediate 45
ISSN 2308-8303 (Print) / 2518-1548 (Online) 56
Журнал органічної та фармацевтичної хімії 2025, 23 (2)
amount of sodium methoxide at 0°C for 1 hour
with further addition of an ammonia source, such
as aniline, benzylamine or saturated methano-
lic ammonia solution. This synthetic procedure
allowed obtaining pyrroles 52 with yields of up
to 80 % (Scheme 17).
Two additional literature references describe
similar methods for synthesizing N-H α-CH pyr-
roles, involving the initial formation of the Mi-
chael addition product between nitrostyrenes 53
and acetoacetic ester, followed by the treatment
with ammonia (Scheme 18). Using this approach,
pyrroles 54 were obtained, though in low yields,
from 25 to 30 % [44, 45].
■ Conclusions
The Grob-Camenisch synthesis of pyrroles is
highly valued for its straightforward methods
and procedures, as evidenced by numerous pub-
lications. The main advantage of this reaction is
the possibility of obtaining tetra- and three-sub-
stituted pyrrole derivatives. This reaction also
allows the synthesis of pyrroles in multi-gram
amounts. It is noteworthy that for this method,
it is possible to use catalysts of different types
(Lewis and Brønsted acids, nanoparticles, etc.),
which broadens the synthetic possibilities of the
pyrrole synthesis.
■ References
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Ph
NO2
+
Me
O
Me
O
N
H
Ph
O
Me
Me
49
MeONa
NH3
51, 93 %
O
Ph
Me
Ph
Me
OH
N
O
MeOH, 0 Cº
MeOH, 0 Cº
50, 92 %
Me
O
Me
O
-HNO2, -H2O
Scheme 16. The synthesis of anomalous Michael’s product 50 and pyrrole 51
52
N
Ph
R
2
O
R
1
Me
a: R
1
= OMe, R
2
= H
b: R
1
= OEt, R
2
= H
c: R
1
= Me, R
2
= H
d: R
1
= OMe, R
2
= CH2Ph
e: R
1
= OMe, R
2
= Ph
f: R
1
= O Bu, Rt 2
= H
Ph
NO2
+
Me
O
R
1
O
49
1. MeONa / MeOH, 0 Cº
2. R
2
-NH2 / MeOH, 0 Cº
50 80 %–
Scheme 17. The one-pot pyrrole synthesis by Gómez-Sánchez
52
N
H
O
EtO
Me
R
1
= 4-NC-C6H4, 2-O2N-C6H4
NO2 +
Me
O
OEt
O
49
1. MeONa / MeOH, 0 Cº
2. NH3 / MeOH, 0 Cº
25 30 %–
R
1
R
1
Scheme 18. The synthesis of other pyrrole derivatives by the Gómez-Sánchez-like procedure
ISSN 2308-8303 (Print) / 2518-1548 (Online) 57
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
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Information about the authors:
Andrii H. Hotynchan (corresponding author), Ph.D. student of the Department of Colour and Structure of Organic Compounds,
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine. https://orcid.org/0000-0002-1569-8590;
e-mail for correspondence: ahotynchan@gmail.com.
Olena M. Kovtun, Associate Professor of the Chemistry Department, Natural Faculty, Dragomanov Ukrainian State University.
Yuriy P. Kovtun, Dr. Sci. in Chemistry, Professor, Leading Researcher of the Department of Colour and Structure of Organic Compounds,
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine. https://orcid.org/0000-0002-2673-5342.
|
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| spelling | oai:ojs.journals.uran.ua:article-3237752026-08-22T19:54:27Z The Synthesis of Pyrroles from Nitroolefins Синтез піролів з нітроолефінів Hotynchan, Andrii H. Kovtun, Olena M. Kovtun, Yuriy P. pyrrole Grob–Camenisch reaction nitroolefines пірол реакція Гроба-Каменіша нітроолефіни The synthesis of pyrroles occupies a key place in synthetic organic chemistry due to the numerous biological properties of pyrrole derivatives, in particular antimicrobial, antibacterial, antifungal, antimalarial, anticancer activities, etc. Therefore, pyrroles serve as building blocks in the creation of potential pharmaceuticals and also serve as the basis for the synthesis of boradipyrromethene dyes. One of the most well-known approaches to the synthesis of pyrroles is the reaction between nitroolefins, 1,3-dicarbonyl compounds, and amines, also known as the Grob-Camenisch reaction. This review is devoted to the historical chronology from the discovery of this transformation dating back to 1950s to the present, and covers the development of various modifications of the above reaction in the synthesis of pyrroles. Синтез піролів займає ключове місце в синтетичній органічній хімії завдяки численним біологічним властивостям похідних піролу, зокрема антимікробній, антибактеріальній, протигрибковій, антималярійній, протираковій тощо. Саме тому піроли слугують будівельними блоками у створенні потенційних фармацевтичних препаратів, а також є основою для синтезу барвників бордипірометенового ряду. Одним із найвідоміших підходів до синтезу піролів є реакція між нітроолефінами, 1,3-дикарбонільними сполуками та амінами, відома як реакція Гроба-Каменіша. Цей огляд висвітлює історичну хронологію від відкриття цього перетворення, датованого 1950-ми роками, до сьогодення та охоплює розробку різноманітних модифікацій вищезгаданої реакції в синтезі піролів. National University of Pharmacy 2025-06-11 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/323775 10.24959/ophcj.25.323775 Journal of Organic and Pharmaceutical Chemistry; Vol. 23 No. 2 (2025); 48-58 Журнал органической и фармацевтической химии; Том 23 № 2 (2025); 48-58 Журнал органічної та фармацевтичної хімії; Том 23 № 2 (2025); 48-58 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/323775/322354 Copyright (c) 2025 Andrii H. Hotynchan, Olena M. Kovtun, Yuriy P. Kovtun http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | пірол реакція Гроба-Каменіша нітроолефіни Hotynchan, Andrii H. Kovtun, Olena M. Kovtun, Yuriy P. Синтез піролів з нітроолефінів |
| title | Синтез піролів з нітроолефінів |
| title_alt | The Synthesis of Pyrroles from Nitroolefins |
| title_full | Синтез піролів з нітроолефінів |
| title_fullStr | Синтез піролів з нітроолефінів |
| title_full_unstemmed | Синтез піролів з нітроолефінів |
| title_short | Синтез піролів з нітроолефінів |
| title_sort | синтез піролів з нітроолефінів |
| topic | пірол реакція Гроба-Каменіша нітроолефіни |
| topic_facet | pyrrole Grob–Camenisch reaction nitroolefines пірол реакція Гроба-Каменіша нітроолефіни |
| url | https://ophcj.nuph.edu.ua/article/view/323775 |
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