Organic catalytic multicomponent one-pot synthesis of highly substituted pyrroles

Article abstract of DOI:10.1080/00397910902838953

A multicomponent synthesis of highly substituted pyrroles catalyzed by thiazolium salts has been disclosed. The reaction employs an acyl anion conjugate addition reaction of aldegyde and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. Th

Full text of DOI:10.1080/00397910902838953

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Organic Catalytic
Multicomponent One-Pot
Synthesis of Highly Substituted
Pyrroles
Xiaobi Jing a , Xin Pan a , Zhen Li a , Xiaoxin Bi a
Chaoguo Yan a & Hongxiang Zhu b
,
a Department of Chemistry, Yangzhou University,
Yangzhou, Jiangsu, China
b School of Light Industrial and Food Engineering,
Guangxi University, Nanning, Guangxi, China
Version of record first published: 07 Oct 2009
To cite this article: Xiaobi Jing, Xin Pan, Zhen Li, Xiaoxin Bi, Chaoguo Yan &
Hongxiang Zhu (2009): Organic Catalytic Multicomponent One-Pot Synthesis of Highly
Substituted Pyrroles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:21, 3833-3844
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Synthetic Communications1, 39: 3833–3844, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902838953
Organic Catalytic Multicomponent One-Pot
Synthesis of Highly Substituted Pyrroles
Xiaobi Jing,1 Xin Pan,1 Zhen Li,1 Xiaoxin Bi,1
Chaoguo Yan,1 and Hongxiang Zhu2
1Department of Chemistry, Yangzhou University,
Yangzhou, Jiangsu, China
2School of Light Industrial and Food Engineering,
Guangxi University, Nanning, Guangxi, China
Abstract: A multicomponent synthesis of highly substituted pyrroles catalyzed by
thiazolium salts has been disclosed. The reaction employs an acyl anion conjugate
addition reaction of aldegyde and unsaturated ketones to generate 1,4-dicarbonyl
compounds in situ. The subsequent addition of various amines promotes a
Paal–Knorr reaction, affording the desired pyrrole nucleus in an efficient one-pot
process.
Keywords: Highly substituted pyrroles, Paal–Knorr reaction, thiazolium salts
catalysts
INTRODUCTION
The pyrrole heterocycle is an important structural attribute in many
bioactive natural products,[1] therapeutic compounds,[2] and new organic
materials.[3] Consequently, the efficient assembly of this class of molecule
is a significant objective in synthetic chemistry. The construction of the
pyrrole ring system typically involves a multistep approach from pre-
formed intermediates, such as the classic Paal–Knorr cyclization reaction
of 1,4-dicarbonyl compounds and amines.[4] More contemporary
Received December 3, 2008.
Address correspondence to Xiaobi Jing, College of Chemistry and Chemical
Engineering, Yangzhou University, Yangzhou 225002, China. E-mail: jingxiaobi@
yahoo.com.cn
3833

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X. Jing et al.
Scheme 1. Scheidt’s general multicomponent pyrrole synthesis.
transition-metal-based strategies include the addition of chromium
carbenes to dipolarophiles,[5a] the copper(I)-catalyzed cycloisomerization
of alkynyl imines,[5b] and rhodium-catalyzed reactions, either N-H
insertions[5c] or the combination of isonitriles and 1,3-diketones.[5d]
However, an alternate and more direct strategy is the combination of
multiple reactants in a single flask to afford the pyrrole core.
In 2004, Bharadwaj and Scheidt reported[6] a one-pot, multi-
component assembly of highly substituted pyrroles (3) utilizing a sila-
Stetter=Paal–Knorr sequence of acylsilanes (1), unsaturated carbonyl
compounds (2), and amines catalyzed by thiazolium salt (4) (Scheme 1).
However, they only focused on the starting material of expensive
acylsilanes, and also in their paper the synthesis of only highy phenyl sub-
stituted pyrroles was reported. Herein, we report the realization of an
improved one-pot, multicomponent assembly of not only highly phenyl
but also highly heterocycle-substituted pyrroles utilizing a Stetter=Paal–
Knorr sequence of cheaper and more common aldehydes (instead of
acylsilabes), unsaturated carbonyl compounds, and amines catalyzed by
thiazolium salt.
RESULTS AND DISCUSSION
At first, we found that under Bharadwaj and Scheidt’s conditions, using
aldehydes instead of acylsilanes, the pyrroles were the main products, but
when we used heterocycle-substituted unsaturated ketones instead of
phenyl unsaturated ketones, the yield was very poor. Perhaps the yield
is poor because the heterocycle-substituted unsaturated ketones in the
solvent of tetrahydrofuran (THF) are not very soluble. We found that
the yield of the competitive reaction of 1,4-dikitones (benzoin condensa-
tion) is also very poor, which means there is much that can be improved
in the reaction.
To improve the yield, we scanned different solvents and acid
(Scheme 2). At last, we found that MeOH=HOAc is the best condition
instead of THF=TsOH. The result is listed in Table 1.

Highly Substituted Pyrroles
3835
Scheme 2. Highly heterocycle-substituted pyrrole synthesis in different
conditions.
To study the efficiency of the procedure we found, we synthesized
different heterocycle-substituted pyrroles (Scheme 3). The result is listed
in Table 2.
According to the literatures,[6] we also proposed the working
catalytic cycle (Scheme 4). Our proposed working catalytic cycle involves
the addition of a neutral carbene=zwitterionic species (I, generated in situ
from the exposure of thiazolium salt I to DBU) to an aldehyde.[7] This
nucleophilic attack of the carbonyl function of an aldehyde then gener-
ates the thiazolium salt adduct II. Deprotonation=reprotonation leads to
the active aldehyde in the form of the resonance-stabilized enaminol-type
Breslow intermediate III.[8] Then this nucleophilic acylation reagent III
undergoes preferential addition to the more electrophilic a,b-unsaturated
ketone. The resulting intermediate IV reforms the acyl anion carbonyl,
which liberates the heterocyclic catalyst I and subsequently produces
the 1,4-dicarbonyl compound V. Once the starting a,b-unsaturated
ketone is consumed, the direct addition of a primary amine and acid to
Table 1. Highly heterocycle-substituted pyrrole synthesis in different
conditionsa
Entry
R1
Solvent
Catalyst
Acid
Yieldb (%)
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
propyl
THF
1,4-Dioxane
C2H5OH
CH3OH
CH3OH
CH3OH
CH3OH
A
A
A
A
A
A
B
TsOH
TsOH
TsOH
TsOH
HCl
20
5
65
70
60
75
70
HOAc
HOAc
aReaction conditions: 25 mol% of A or B and 30 mol% of DBU
and 10 mL methanol, reflux for 1–3 h. Amine and the acid were then
added. The mixture was refluxed for an additional 1–3 h.
bIsolated yield after purification.

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X. Jing et al.
Scheme 3. Synthesis of pyrroles in the best condition.
the reaction followed by heating generates the desired pyrroles via the
standard Paal–Knorr reaction manifold.
In conclusion, the process described herein is an efficient one-pot
catalytic assembly of pyrroles via the thiazolium-catalyzed acyl anion
conjugate addition of aldehyde. This approach utilizes a neutral
organic molecule as a catalyst, is multicomponent in nature, and
can rapidly install substitution at multiple positions of the pyrrole
nucleus.
EXPERIMENTAL
General Information
Melting points were obtained on a hot-plate microscope apparatus and
were uncorrected. Infrared (IR) spectra were obtained on a Nicolet
1
Fourier transform (FT)-IR 740 spectrometer in KBr discs. H NMR
(600 MHz) spectroscopies were recorded on a Bruker AV-600 spectro-
photometer in CDCl3 or dimethysulfoxide (DMSO-d6).
Typical Experimental Procedure
a,b-Unsaturated ketone (1.0 equiv), aldehyde (1.5 equiv), thiazolium salt
(A or B 25 mol%), and DBU (30 mol%) were added to methanol, and
the mixture was refluxed untill the completion of the reaction, which was
indicated by thin-layer chromatography (TLC). After that, amine (2.0
equiv) and HOAc (3.0 equiv) were added to the solution. The solution
was refluxed for another 1–3 h. After completion of the reaction, the reac-
tion mixture was diluted with dichloromethane (20 mL) and washed with
water (30 mL). The aqueous layer was washed with dichloromethane

3837

3838

3839

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X. Jing et al.
Scheme 4. Proposed catalytic cycle.
(3 ꢀ 10mL) and dried over sodium sulfate. Removal of the solvent under
reduced pressure followed by purification on silica gel (Merck, 100–200
mesh, ethyl acetate–hexane 1:5) afforded the corresponding pure highly
substituted pyrroles.
Spectral Data for Selected Compounds
1-Phenyl-2-phenyl-3-(2-furanyl)-5-(1-methyl-benzimidazolyl)-
1H-pyrrole (4a)
Off-white solid; mp 193–195ꢁC; IR (KBr): 3041, 3049, 1596, 1496, 1445,
1
1399, 1324, 1281, 1244, 1071, 1005, 792, 741 cmꢂ1; H NMR (600 MHz,
CDCl3) d: 3.5(s, 3H), 5.89 (s, 1H), 6.28 (s, 1H), 6.99 (d, J ¼ 5.59 Hz, 2H),
7.07–7.08 (d, J ¼ 6.04 Hz, 4H), 7.24–7.25 (m, 7H), 7.33–7.47 (m, 2H),
7.71–7.72 (d, J ¼ 6.04 Hz, 1H); 13C NMR (150 MHz, CDCl3) d: 30.9,
104.2, 107.7, 109.5, 111.0, 112.4, 115.3, 120.0, 122.2, 122.7, 127.3,
127.8, 128.1, 128.6, 128.9, 131.2, 1331.8, 132.9, 135.4, 137.9, 140.5,
146.4, 150.1.

Highly Substituted Pyrroles
3841
2-(2-Furanyl)-3-(2-furanyl)-5-(1-methyl-benzimidazolyl)-1H-pyrrole (4b)
White solid, mp 232–235ꢁC; IR (KBr): 3440, 3106, 2915, 2572, 1631, 1591,
1523, 1465, 1294, 1089, 1017, 824, 736 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d: 4.16 (s, 3H), 6.47 (s, 1H), 6.54 (s, 1H), 6.83 (d, J ¼ 2.81 Hz, 1H),
7.36–7.37 (d, J ¼ 2.13 Hz, 2H), 7.39–7.46 (m, 4H), 7.56 (s, 1H),
7.73–7.74 (d, J ¼ 7.67 Hz, 1H), 13.07 (brs, 1H); 13C NMR (150 MHz,
CDCl3) d: 31.3, 105.7, 108.6, 109.2, 109.7, 110.4, 112.0, 112.3, 113.7,
114.6, 123.7, 124.3, 125.7, 128.2, 130.7, 139.4, 139.8, 141.0, 143.4, 146.0.
1-(2-Hydroxyethyl)-2-(2-furanyl)-3-(2-furanyl)-5-(1-methyl-
benzimidazolyl)-1H-pyrrole (4c)
Brick red solid; mp 122–124ꢁC; IR (KBr): 3421, 3202, 3111, 2845, 1603,
;
1563, 1449, 1401, 1365, 1324, 1076, 1014, 807, 741 cmꢂ1 1H NMR
(600 MHz, CDCl3) d: 3.98 (m, 5H), 4.35–4.36 (t, J ¼ 4.61 Hz, 2H), 5.96
(d, J ¼ 2.97 Hz, 1H), 6.34 (d, 1H), 6.57 (s, 1H), 6.65 (d, J ¼ 2.93 Hz,
1H), 6.89 (s, 1H), 7.31–7.36 (m, 3H), 7.41–7.42 (d, J ¼ 7.67 Hz, 2H),
7.61 (s, 1H), 7.77–7.78 (d, J ¼ 7.58 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d: 30.9, 47.3, 62.5, 103.7, 109.0, 109.7, 110.4, 112.3, 117.1, 118.5, 122.0,
122.1, 122.4, 122.5, 134.9, 139.8, 140.3, 142.7, 143.8, 144.8, 148.6.
2-(4-Methylphenyl)-3-(2-furanyl)-5-(1-methyl-benzimidazolyl)-
1H-pyrrol (4d)
Brown solid; mp 123–125ꢁC; IR (KBr): 3428, 2930, 1620, 1529, 1406,
1
1400, 1291, 1068, 1010, 826, 738 cmꢂ1; H NMR (600 MHz, CDCl3) d:
2.12 (s, 3H), 4.03 (s, 3H), 6.25 (d, J ¼ 2.31 Hz, 1H), 6.39 (d, J ¼ 1.31 Hz,
Hz, 1H), 7.26 (s, 1H), 7.28–7.32 (m, 2H), 7.36–7.37 (d, J ¼ 7.05 Hz, 1H),
7.39 (s, 1H), 7.47–7.49 (d, J ¼ 8.09 Hz, 2H), 7.52–7.53 (d, 8.17 Hz, 2H),
7.69–7.70 (d, J ¼ 7.36 Hz, 1H), 11.4 (brs, 1H); 13C NMR (150 MHz,
CDCl3) d: 21.5, 31.9, 105.2, 109.3, 111.1, 111.6, 114.7, 117.9, 120.9,
122.1, 123.0, 123.1, 130.1, 130.6, 131.5, 132.0, 135.6, 140.8, 145.9, 149.7.
2-(4-Chlorophenyl)-3-(4-methoxyphenyl)-5-(1-methyl-benzimidazolyl)-
1H-pyrrole (4f)
White solid; mp 218–220ꢁC; IR (KBr): 3448, 3062, 2935, 1604, 1517,
1477, 1405, 1288, 1248, 1173, 1096, 1025, 834, 744 cmꢂ1
;
1H
NMR (600 MHz, CDCl3) d: 3.83 (s, 3H), 4.12 (s, 3H), 6.85–6.87 (d,
J ¼ 8.48 Hz, 2H), 7.10–7.11 (d, J ¼ 8.48 Hz, 1H), 7.21–7.22 (d,

3842
X. Jing et al.
J ¼ 8.47 Hz, 2H), 7.29–7.31 (d, J ¼ 8.47 Hz, 2H), 7.36–7.42 (m, 2H),
7.48–7.49 (d, J ¼ 8.04 Hz, 1H), 7.59–7.61 (d, J ¼ 8.41 Hz, 2H), 7.73–7.74
(d, J ¼ 7.90 Hz, 1H), 13.00 (brs, 1H); 13C NMR (150 MHz, CDCl3) d:
33.1, 55.3, 110.6, 113.7, 114.1, 118.8, 125.9, 126.1, 126.7, 128.6, 129.0,
129.5, 130.0, 130.1, 132.6, 134.4, 136.3, 142.2, 158.9.
1-(4-Hydroxyphenyl)-2-amyl-(4-methylphenyl)-5-(1-hydrogen-
benzimidazolyl)-1H-pyrrole (4h)
White solid; mp 265–270ꢁC; IR (KBr): 3430, 3170, 2960, 2925, 2864, 1641,
1555, 1508, 1467, 1328, 1228, 1181, 822, 741, 619 cmꢂ1; 1H NMR (600MHz,
DMSO-d6) d: 0.85 (m, 3H), 1.28 (m, 4H), 1.70 (m, 2H), 2.34 (s, 3H), 2.79 (m,
2H), 7.12–7.66 (m, 13H), 12.36 (brs, 1H), 14.46 (brs, 1H).
1-Phenyl-2-(2-pyridinyl)-3-(4-methylphenyl)-5-(1-hydrogen-
benzimidazolyl)-1H-pyrrole (4i)
White solid; mp 243–244ꢁC; IR (KBr): 3430, 3054, 2875, 1625, 1590,
;
1499, 1458, 1458, 1404, 1344, 1274, 1225, 817, 745 cmꢂ1 1H NMR
(600 MHz, CDCl3) d: 2.30 (s, 3H), 7.04–7.16 (m, 9H), 7.37–7.42 (m,
7H), 7.70–8.25 (m, 2H), 8.43 (brs, 1H); 13C NMR (150 MHz, CDCl3)
d: 21.1, 113.9, 122.0, 122.5, 125.7, 126.0, 126.8, 128.2, 128.8, 129.1,
129.2, 132.0, 133.7, 135.9, 138.5, 145.2, 149.3, 151.2.
1-(1-Phenylethyl)-2-propyl-3-(4-methylphenyl)-5-(1-hydrogen-
benzimidazolyl)-1H-pyrrole (4j)
Yellow solid; mp 180–182ꢁC; IR (KBr): 3422, 2963, 2870, 1589, 1500,
;
1443, 1406, 1338, 1275, 1223, 1118, 806, 748, 670 cmꢂ1 1H NMR
(600 MHz, CDCl3) d: 0.66 (t, J ¼ 7.18 Hz, 3H), 0.91–0.97 (m, 1H),
1.01–1.10 (m, 1H), 1.31–1.36 (m, 1H), 1.94–1.95 (d, J ¼ 7.12 Hz, 2H),
2.36 (s, 3H), 2.55–2.58 (m, 2H), 6.77 (s, 1H), 7.02 (s, 1H), 7.16–7.17 (d,
J ¼ 7.66 Hz, 4H), 7.23–7.24 (d, J ¼ 7.60 Hz, 3H), 7.29–7.33 (m, 4H),
7.68 (s, 1H), 8.89 (brs, 1H); 13C NMR (150 MHz, CDCl3) d: 14.2, 19.6,
21.1, 23.0, 28.3, 53.4, 112.8, 121.9, 123.7, 126.2, 127.0, 128.6, 129.1,
133.9, 135.1, 135.3, 142.8, 146.6.
2-Amyl-3-(4-chlorophenyl)-5-(1-hydrogen-benzimidazolyl)-1H-
pyrrole (4k)
White solid; mp 245–249ꢁC; IR (KBr): 3423, 3179, 2924, 2866, 1641,
;
1561, 1523, 1469, 1329, 1271, 1229, 808, 741, 617 cmꢂ1 1H NMR

Highly Substituted Pyrroles
3843
(600 MHz, DMSO-d6) d: 0.85 (m, 3H), 1.29 (m, 4H), 1.72 (m, 2H), 2.83
(m, 2H), 7.44–7.73 (m, 9H), 12.61 (brs, 1H), 14.88 (brs, 1H).
1-(4-Methylphenyl)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-
5-(1-hydrogen-benzimidazolyl)-1H-pyrrole (4l)
White solid; mp 226–228ꢁC; IR (KBr): 3436, 3057, 2961, 1626, 1593,
1510, 1453, 1407, 1348, 1273, 1097, 822, 743 cmꢂ1
;
1H NMR
(600 MHz, CDCl3) d: 2.41 (s, 3H), 6.95–6.96 (d, J ¼ 7.48 Hz, 1H), 7.06
(s, 1H), 7.10–7.12 (t, J ¼ 7.85 Hz, 1H), 7.15–7.23 (m, 11H), 7.25 (m,
1H), 7.69 (s, 1H), 8.15 (brs, 1H); 13C NMR (150 MHz, CDCl3) d: 20.5,
112.6, 121.8, 123.0, 124.9, 127.2, 127.8, 128.0, 128.5, 128.7, 129.6,
130.3, 131.2, 132.5, 132.6, 133.2, 134.3, 138.9, 144.2.
ACKNOWLEDGMENTS
This research was supported by the National Natural Science Foundation
of China (20572091; 20576111) and the Cultivation and Construction
Fund for the State Key Subject of Physical Chemistry.
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