A solvent-free synthesis of 1,2,3,5-tetrasubstituted pyrroles from enaminones and α-haloketones

Article abstract of DOI:10.1016/j.cclet.2011.05.026

A simple synthesis of 1,2,3,5-tetrasubstituted pyrrole derivatives from the reaction of enaminone with α-haloketones, under solvent-free conditions, is described.

Full text of DOI:10.1016/j.cclet.2011.05.026

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1219–1222
www.elsevier.com/locate/cclet
A solvent-free synthesis of 1,2,3,5-tetrasubstituted pyrroles
from enaminones and a-haloketones
*
Issa Yavari , Maryam Ghazvini, Leila Azad, Tayebeh Sanaeishoar
Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
Received 3 March 2011
Available online 18 July 2011
Abstract
A simple synthesis of 1,2,3,5-tetrasubstituted pyrrole derivatives from the reaction of enaminone with a-haloketones, under
solvent-free conditions, is described.
# 2011 Issa Yavari. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 1H-Pyrrole; Enaminone; a-Haloketone; 1,3-Dicarbonyl compound; Solvent-free
Simple N-heterocycles received considerable attention in the literature as a consequence of their exciting biological
properties and their role as pharmacophores [1]. Of these heterocycles, the synthesis, reactions, and biological
activities of pyrrole derivatives stand as an area of research in heteroaromatic chemistry, and this structural motif
appears in a large number of pharmaceutical agents and natural products [2]. Accordingly, many strategies have been
developed for the preparation of pyrroles [3–7]. Despite these new developments, the classical Paal-Knorr [8] reaction
remains the most attractive method for the synthesis of pyrroles [9]. Enaminones were employed in several new
preparations of the pyrrole derivatives [9,10]. As a part of our current studies on the development of new routes in
pyrrole synthesis [10–14], we wish to report a convenient catalyst-free synthesis of 1,2,3,5-tetrasubstituted pyrrole
derivatives from the reaction of enaminone with a-haloketones, under solvent-free conditions (Scheme 1).
1. Experimental
Enaminones 1 were prepared by known methods [15] and a-haloketones 2 were obtained from Merck; IR spectra:
1
Shimadzu IR-460 spectrometer; H- and 13C NMR spectra: Bruker DRX-300AVANC instrument; in CDCl3 at
300 MHz and 75 MHz, respectively, ( in ppm J in Hz; EI-MS (70 eV): Finningan-MAT-8430 mass spectrometer, in m/
z. Elemental analyses (C, H, and N) were performed with a Heraeus CHN-O-Rapid analyzer.
* Corresponding author.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
1001-8417/$ – see front matter # 2011 Issa Yavari. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.05.026

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I. Yavari et al. / Chinese Chemical Letters 22 (2011) 1219–1222
R
O
NHR'
O
O
+
Solvent-free
r.t., 3 h
Br
R
R"
R"
N
2
1
3
R'
Yiled (%) of 3
R'
R"
R
a
b
c
d
e
f
4-Br-C6H4
CO2Et
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
n-Bu
n-Bu
n-Bu
89.2
91.0
93.4
88.2
85.0
74.1
94.3
65.3
83.2
71.1
69.0
76.1
4-MeO-C6H4
CO2Et
c-Hexyl
c-Hexyl
c-Hexyl
Bn
4-MeO-C6H4
4-Br-C6H4
CO2Et
g
h
i
4-MeO-C6H4
4-Br-C6H4
CO2Et
Bn
Bn
j
k
l
Bn
4-MeO-C6H4
4-Br-C6H4
Me
Bn
Me
Bn
Scheme 1.
1.1. Typical procedure for the preparation of compounds 3
A mixture of enaminone 1 (2 mmol) and the a-haloketone 2 (2 mmol) was stirred at r.t. After completion of the
reaction (about 3 h); TLC (AcOEt/hexane 2:1)], the reaction mixture was purified by column chromatography [silica
gel (230–240 mesh; Merck), hexane/AcOEt 4:1].
1.1.1. Ethyl 5-(4-bromophenyl)-1-butyl-2-methyl-1H-pyrrole-3-carboxylate (3a)
1
Pale yellow oil; 0.66 g (89.2%). IR: 1689, 1429, 1388, 1270 cmÀ1. H NMR (300 MHz, CDCl3): d 0.82 (t, 3H,
J = 7.3 Hz, Me), 1.16 (m, 2H, CH2), 1.35 (t, 3H, J = 7.1 Hz, Me), 1.51 (m, 2H, CH2), 2.61 (s, 3H, Me), 3.84 (t, 2H,
J = 7.7 Hz, CH2N), 4.28 (q, 2H, J = 7.1 Hz, CH2O), 6.55 (s, 1H, CH), 7.22 (d, 2H, J = 7.7 Hz, 2 CH), 7.53 (d, 2H,
J = 7.7 Hz, 2 CH). 13C NMR (75 MHz, CDCl3): d 11.9 (Me), 13.9 (Me), 14.9 (Me), 20.1 (CH2), 33.1 (CH2), 44.3
(CH2N), 59.7 (CH2O), 110.5 (CH), 112.5 (C), 121.9 (C), 131.2 (2 CH), 132.0 (2 CH), 132.5 (C), 134.1 (C), 137.1 (C),
165.9 (CO). MS (EI, 70 eV): m/z (%) 365 (M++2, 10), 363 (M+, 9), 336 (23), 334 (100), 322 (20), 320 (17). Anal.
Calcd. for C18H22BrNO2 (364.28): C, 59.35; H, 6.09; N, 3.85%. Found: C, 59.68; H, 6.13; N, 3.69%.
1.1.2. Diethyl 1-butyl-5-methyl-1H-pyrrole-2,4-dicarboxylate (3b)
1
Yellow oil; 0.51 g (91.0%). IR: 1691, 1401, 1393, 1289 cmÀ1. H NMR (300 MHz, CDCl3): d 0.95 (t, 3H,
J = 7.3 Hz, Me), 1.32 (m, 8H, 2 Me, CH2), 1.68 (m, 2H, CH2), 2.38 (s, 3H, Me), 3.79 (t, 2H, J = 7.2 Hz, CH2N), 4.28
(m, 4H, 2 CH2O), 7.10 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d 11.1 (Me), 14.0 (Me), 14.6 (Me), 14.7 (Me), 20.1
(CH2), 33.0 (CH2), 47.2 (CH2N), 60.4 (CH2O), 60.6 (CH2O), 113.6 (C), 115.3 (C), 126.1 (CH), 134.9 (C), 164.6 (CO),
165.9 (CO). MS (EI, 70 eV): m/z (%) 281 (M+, 7), 252 (100), 238 (19). Anal. Calcd. for C15H23NO4 (281.35): C, 64.03;
H, 8.24; N, 4.98%. Found: C, 63.88; H, 8.11; N, 4.89%.
1.1.3. Ethyl 1-butyl-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylate (3c)
1
Yellow oil; 0.58 g (93.4%). IR: 1697, 1373, 1244, 1189 cmÀ1. H NMR (300 MHz, CDCl3): d 0.81 (t, 3H,
J = 7.2 Hz, Me), 1.17 (m, 2H, CH2), 1.35 (t, 3H, J = 7.1 Hz, Me), 1.51 (m, 2H, CH2), 2.66 (s, 3H, Me), 3.83 (m, 2H,
CH2N), 3.86 (s, 3H, MeO), 4.72 (q, 2H, 3J 7.1, CH2O), 6.49 (s, 1H, CH), 6.94 (d, 2H, 3J 8.6, 2 CH), 7.26 (d, 2H, 3J 8.6,
2 CH). 13C NMR (75 MHz, CDCl3): d 11.9 (Me), 13.9 (Me), 14.9 (Me), 20.1 (CH2), 33.1 (CH2), 44.2 (CH2N), 55.6
(MeO), 56.9 (CH2O), 109.6 (CH), 112.0 (C), 114.2 (2 CH), 126.0 (C), 131.1 (2 CH), 133.5 (C), 136.3 (C), 159.4 (C),
166.1 (CO). MS (EI, 70 eV): m/z (%) 315 (M+, 11), 286 (100), 272 (22). Anal. Calcd. for C19H25NO3 (315.41): C,
72.35; H, 7.99; N, 4.44%. Found: C, 71.88; H, 7.86; N, 4.39%.
1.1.4. Diethyl 1-cyclohexyl-5-methyl-1H-pyrrole-2,4-dicarboxylate (3d)
Yellow oil; 0.54 g (88.2%). IR: 1681, 1311, 1265, 1209 cmÀ1. 1H NMR (300 MHz, CDCl3): d 1.33–1.35 (m, 6H, 2
Me), 1.27–2.00 (m, 10H, 5 CH2), 2.04 (s, 3H, Me), 3.66 (m, 1H, CHN), 4.28–4.62 (m, 4H, 2 CH2O), 7.28 (s. 1H, CH).

I. Yavari et al. / Chinese Chemical Letters 22 (2011) 1219–1222
1221
O
O
O
R'
_
R
NR'
O
N
H
O
R
R
HBr
_
H2O
1
NR'
OH
+
2
3
R"
R"
4
R"
5
6
Scheme 2.
13C NMR (75 MHz, CDCl3): d 11.9 (Me), 14.0 (Me), 14.3 (Me), 24.9 (CH2), 29.3 (2 CH2), 31.1(2 CH2), 54.4 (CH2O),
55.1 (CH2O), 57.8 (CHN), 112.2 (C), 115.9 (C), 126.1 (CH), 133.9 (C), 164.6 (CO), 165.9 (CO). MS (EI, 70 eV): m/z
(%) 307 (M+, 12), 224 (100). Anal. Calcd. for C17H25NO4 (307.38): C, 66.43; H, 8.20; N, 4.56%. Found: C, 66.88; H,
8.09; N, 4.51%.
1.1.5. Ethyl 1-cyclohexyl-5-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylate (3e)
Yellow oil; 0.58 g (85.0%). IR: 1700, 1319, 1255, 1222 cmÀ1. 1H NMR (300 MHz, CDCl3): d 1.20–2.07 (m, 10H, 5
CH2), 1.26 (t, 3H, J = 7.1 Hz, Me), 2.71 (s, 3H, Me), 3.72 (m, 1H, CHN), 3.91 (s, 3H, MeO), 4.12 (q, 2H, J = 7.1 Hz,
CH2O), 6.31 (s, 1H, CH), 6.98 (d, 2H, J = 8.8 Hz, 2 CH), 7.23 (d, 2H, J = 8.8 Hz, 2 CH). 13C NMR (75 MHz, CDCl3):
d 12.8 (Me), 14.4 (Me), 25.4 (CH2), 26.5 (2 CH2), 32.4 (2 CH2), 55.0 (MeO), 57.7 (CH2O), 58.8 (CHN), 110.1 (CH),
112.5 (C), 113.9 (2 CH), 131.0 (C), 131.7 (2 CH), 132.4 (C), 135.7 (C), 159.8 (C), 165.2 (CO). MS (EI, 70 eV): m/z
(%) 341 (M+, 8), 258 (100). Anal. Calcd. for C21H27NO3 (341.44): C, 73.87; H, 7.97; N, 4.10%. Found: C, 73.58; H,
8.09; N, 3.96%.
1.1.6. Ethyl 5-(4-bromophenyl)-1-cyclohexyl-2-methyl-1H-pyrrole-3-carboxylate (3f)
Yellow oil; 0.57 g (74.1%). IR: 1717, 1345, 1258, 1227 cmÀ1. 1H NMR (300 MHz, CDCl3): d 1.14–2.07 (m, 10H, 5
CH2), 1.24 (t, 3H, J = 7.1 Hz, Me), 2.73 (s, 3H, Me), 4.10 (m, 1H, CHN), 4.21 (q, 2H, J = 7.1 Hz, CH2O), 6.40 (s, 1H,
CH), 7.31 (d, 2H, J = 8.3, 2 CH), 7.63 (d, 2H, J = 8.3 Hz, 2 CH). 13C NMR (75 MHz, CDCl3): d 12.8 (Me), 14.3 (Me),
25.4 (CH2), 26.4 (2 CH2), 32.4 (2 CH2), 58.0 (CH2O), 58.9 (CHN), 110.8 (CH), 112.9 (C), 121.6 (C), 131.8 (2 CH), 132.1
(2CH), 132.8(C), 135.1(C), 136.7(C), 165.0(CO). MS (EI, 70 eV):m/z(%) 391(M++2, 10), 389(M+, 9), 308(100), 306
(23). Anal. Calcd. for C20H24BrNO2 (390.31): C, 61.54; H, 6.20; N, 3.59%. Found: C, 62.05; H, 6.41; N, 3.64%.
2. Results and discussion
The reaction of enaminones (1) and a-haloketones (2) proceeds at room temperature after 12 h to produces (3) in good
yields (Scheme 1). The structures of compounds (3a–3l) were deduced from their elemental analyses and their IR, 1H
NMR, and 13C NMR. The mass spectra of these compounds displayed molecular ion peaks at appropriate m/z values. The
1H NMR spectrum of 3a in CDCl3 showed one singlet for methyl (d 2.61), together with characteristic multiplets for the
butylethoxy groups, onesingletsignal (d 6.55)formethineandtwodoublet(d 7.22, 7.53)forthearomaticproton. The13
C
NMR spectrum of 3a showed 16 signals in agreement with the proposed structure. Partial assignments of these
resonancesaregiveninSection1. The1H-and13CNMRspectraof3b–3laresimilartothoseof3aexceptforthealkyland
aryl substituents, which exhibit characteristic signals in the appropriate regions of the NMR spectra.
A plausible rationalization may be advanced to explain the product formation (Scheme 2). Presumably, the
enaminone 1 attacks a-haloketones 2 and undergoes HBr elimination to produce 4. Elimination of water from
intermediate 6 leads to product 3.
In conclusion, we report a simple synthesis of 1,2,3,5-tetrasubstituted pyrroles from the reaction of enaminone with
a-haloketones, under solvent-free conditions. The advantage of the present procedure is that the reaction is performed
under neutral conditions by simple mixing of the starting materials. The procedure described here provides an
acceptable method for the preparation of new derivatives of 1H-pyrrole.
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