Solvent-free synthesis of pyrrole derivatives

Article abstract of DOI:10.1002/jhet.785

A one-pot synthesis of pyrrole derivatives via reaction between activated carbonyl compounds, primary amines, and 1,3-dicarbonyls under solvent-free conditions is described..

Full text of DOI:10.1002/jhet.785

January 2012
Solvent-Free Synthesis of Pyrrole Derivatives
Faramarz Rostami-Charati,a* Zinatossadat Hossaini,b
Mohammad A. Khalilzadeh,b and Hojatollah Jafaryana
217
aGonbad Kavous University, PO Box 163, Gonbad, Iran
bDepartment of Chemistry, Islamic Azad University, Qaemshahr Branch, Mazandaran, Iran
*E-mail: f_rostami_ch@yahoo.com
Received August 30, 2010
DOI 10.1002/jhet.785
Published online 17 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
A one-pot synthesis of pyrrole derivatives via reaction between activated carbonyl compounds,
primary amines, and 1,3-dicarbonyls under solvent-free conditions is described.
J. Heterocyclic Chem., 49, 217 (2012).
INTRODUCTION
primary amines (3) under solvent-free conditions at
70ꢀC (Scheme 1).
Multicomponent reactions have been frequently used
by synthetic chemists as a facile means to generate mo-
lecular diversity from bifunctional substrates that react
sequentially in an intramolecular fashion [1]. Five mem-
bered, nitrogen-containing heterocycles are important
building blocks in an extensive number of biologically
active compounds [2]. Among them, pyrroles are hetero-
cycles of great importance because of their presence in
numerous natural products such as heme, chlorophyll,
vitamin B12, and various cytochrome enzymes [3].
Some of the recently isolated pyrrole-containing marine
natural products have been found to exhibit considerable
cytotoxicity and function as multidrug resistant reversal
agents [4]. Many of these biologically active compounds
have emerged as chemotherapeutic agents. In addition,
polysubstituted pyrroles are molecular frameworks hav-
ing immense importance in material science [5]. They
have also been used as antioxidants, antibacterial,
ionotropic, antitumor, anti-inflammatory, and antifungal
agents [6–11]. Moreover, they are a highly versatile
class of intermediates in the synthesis of natural prod-
ucts and in heterocyclic chemistry [12]. As part of our
current studies on the development of new routes in het-
erocyclic synthesis [13], we report an efficient procedure
for direct synthesis of tetrahydroindeno [2,1-b]pyrrole-3-
dicarboxylates (4) from the reaction of ninhydrin (1)
and 1,3-carbonyl compounds 2 in the presence of
RESULTS AND DISCUSSION
The presence of two or more different heterocyclic
moieties in a single molecule often enhances the biocide
profile remarkably [14]. Therefore, we investigated a
multicomponent reaction of ninhydrin 1 and 1,3-dicar-
bonyls 2 in the presence of primary amines 3 under sol-
vent-free conditions, which afforded pyrrole-3-carboxy-
late derivatives in good isolated yields (Scheme 1).
The procedure was simple and easy to handle. Structures
of compounds 4a–4d were assigned by infrared (IR),
1H-NMR, 13C-NMR, and mass spectral data [15]. The
1H-NMR spectrum of 4a exhibited one triplet at d ¼
1.35 (3J ¼ 7.4), two singlet at d ¼ 2.21 and 3.25 ppm
for the methyl protons, and two singlet at d ¼ 4.61 and
4.72 for OH protons, along with characteristic signals
for aromatic protons at (7.56–7.87 ppm). The carbonyl
group resonances in 13C-NMR spectra of 4a appear at
165.7 and 190.1 ppm. The mass spectra of 4a displayed
the molecular ion peaks at 303.
A tentative mechanism for this transformation is pro-
posed in Scheme 2. It is conceivable that the reaction
involves the initial formation of enaminones 5 between
1,3-dicarbonyls 2 and primary amines 3. Enaminones
that are formed under solvent-free conditions react with
C
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F. Rostami-Charati, Z. Hossaini, M. A. Khalilzadeh, and H. Jafaryan
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Scheme 1. Three-component reactions of 1,3-dicarbonyls, ninhydrin, and primary amines.
obtained with a Bruker FT-500 spectrometer in chloroform-d1,
and tetramethylsilane was used as an internal standard. Mass
spectra were recorded with a Finnigan Mat TSQ-70 spectrome-
ter. IR spectra were acquired on a Nicollet Magna 550-FT spec-
trometer. Elemental analyses were carried out with a Perkin-
Elmer model 240-C apparatus. The results of elemental analyses
(C, H, N) were within 60.4% of the calculated values.
General procedure for preparation of compounds 4a–d
and 7a–b. A mixture of primary amines 3 (2 mmol) and 1,3-
dicarbonyls 2 (2 mmol) was warmed at about 70ꢀC for 30
min. Then, activated carbonyl compounds 1 (2 mmol) was
added slowly. The reaction mixture was stirred for 8 h at 70ꢀC
and then poured into 15 mL of water. The resulting precipitate
was separated by filtration and using EtOH to afford the pure
title compounds.
carbonyl group of 1 and produced 6. Cyclization of this
intermediate leads to the compound 4.
Under similar conditions, the reaction of 1,3-dicarbon-
yls 2 with another activated carbonyl compounds such
as benzyl or acenaphthoquinone in the presence of pri-
mary amines led to pyrrole derivatives in good yields
(see Table 1).
In summary, the reaction of 1,3-dicarbonyls and acti-
vated carbonyl compounds such as ninhydrin, benzyl, or
acenaphthoquinone in the presence of primary amines
under solvent-free conditions, which afforded pyrrole
derivatives in excellent yields. The advantages of our
work are as follows: (1) the reaction is performed under
solvent-free conditions and mild condition. (2) No cata-
lyst is required for this reaction. (3) The simplicity of
the present procedure makes it an interesting alternative
to the complex multistep approaches.
Ethyl 3a,8b-dihydroxy-1,2-dimethyl-4-oxo-1,3a,4,8b-tetra-
hydroindeno[1,2-b]-pyrrole-3carboxylate (4a). Yellow crystal,
mp 150–152ꢀC, yield: 0.57 g (95%). IR (KBr) (mmax/cmꢁ1):
3403, 1716, 1650, 1564, 1480, 1379, 1326, 1208, and 1140
1
3
cmꢁ1. H-NMR: 1.35 (3 H, t, JHH ¼ 7.4 Hz, Me), 2.21 (3 H,
3
s, Me), 3.25 (3 H, s, NMe), 4.26 (2 H, t, JHH ¼ 7.4 Hz,
OCH2), 4.61 (1 H, s, OH), 4.72 (1 H, s, OH), 7.56 (1 H, t,
EXPERIMENTAL
3JHH ¼ 7.5 Hz, CH), 7.78 (2 H, d, JHH ¼ 7.4 Hz, 2 CH),
3
7.87 (1 H, t, JHH ¼ 7.6 Hz, CH) ppm. 13C-NMR: 14.1 (Me),
3
All chemicals were obtained from commercial sources.
Melting points were measured on a Kofler hot stage apparatus
and are uncorrected. 1H-NMR and 13C-NMR spectra were
14.4 (Me), 28.5 (NMe), 58.6 (CH2O), 85.4 (C), 91.9 (C), 96.1
(C), 123.5 (CH), 124.8 (CH), 130.3 (CH), 135.5 (C), 135.9
Scheme 2. Possible mechanism for the formation of products 4.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012
Solvent-Free Synthesis of Pyrrole Derivatives
219
Table 1
Tetrahydroindeno[1,2-b]pyrrole-3-carboxylate derivatives.
Entry
1,3-Dicarbonyl
Activated carbonyl compound
Product
Yield (%)
95
1
2
89
(CH), 150.5 (C), 159.9 (C), 165.7 (C¼¼O), 190.1 (C¼¼O) ppm.
EI-MS: 303 (Mþ, 30), 271 (62), 243(92), 225 (97), 198 (30),
104(40),76 (30). Anal. Calcd for C16H17NO5 (303.31): C,
63.36, H, 5.65, N, 4.62; Found: C, 63.42, H, 5.72, N, 4.75%.
3-Acetyl-3a,8b-dihydroxy-1,2-methyl-3a,8b-dihydroindeno[1,2-
b]-pyrrole-4(1H)-one (4b). White powder, mp 210–212ꢀC, yield:
0.50 g (92%). IR (KBr) (mmax/cmꢁ1): 3361, 3271, 1709, 1603,
CH) ppm. 13C-NMR: 27.6 (Me), 28.7 (Me3C), 57.8 (C), 85.2 (C),
92.4 (C), 115.1 (C), 118.2 (CH), 119.3 (C), 124.9 (CH), 125.2 (2
CH), 128.8 (CH), 129.3 (CH), 131.1 (2 CH), 132.4 (C), 134.5
(CH), 142.5 (C), 150.1 (C), 185.2 (C¼¼O), 190 (C¼¼O) ppm. EI-
MS: 377 (Mþ, 20), 303 (62), 289 (90), 226 (78), 213 (45), 186
(35), 104 (50), 76 (40). Anal. Calcd for C23H23NO4 (377.44): C,
73.19, H, 6.14, N, 3.71; Found: C, 73.25, H, 6.23, N, 3.80%.
Ethyl 4,5-dihydroxy-1,3-dimethyl-4,5-diphenyl-4,5-dihydro-
1H-pyrrole-2-carboxylate (7a). Pale yellow powder, mp 118–
120ꢀC, yield: 0.67 g (95%). IR (KBr) (mmax/cmꢁ1): 3353, 3056,
2398, 1734, 1713, 1682, 1602, 1191, and 1088 cmꢁ1 .1H-NMR:
1.12 (3 H, t, 3JHH ¼ 7.2 Hz, Me), 2.37 (3 H, s, Me), 3.38 (3 H, s,
NMe), 4.09 (2 H, q, 3JHH ¼ 7.2 Hz, OCH2), 5.26 (2 H, s, 2 OH),
7.09–7.35 (10 H, m, 10 CH) ppm. 13C-NMR: 14.2 (Me), 19.3
(Me), 35.4 (NMe), 61.0 (OCH2), 93.4 (C), 98.2 (C), 113.2 (C),
123.3 (CH), 126.3 (2 CH), 127.1 (CH), 127.9 (2 CH), 128.3 (2
CH), 130.3 (2 CH), 136.5 (C), 138.3 (C), 151.7 (C), 170 (C¼¼O)
ppm. EI-MS: 353 (Mþ, 15), 321 (58), 293 (90), 275 (95), 248 (25),
171 (30), 76 (25). Anal. Calcd for C21H23NO4 (353.42): C, 71.37,
H, 6.56, N, 3.96; Found: C, 71.28, H, 6.47, N, 3.88%.
1
1578, 1482, 1441, and 1385 cmꢁ1. H-NMR: 2.23 (3 H, s, Me),
2.40 (3 H, s, Me), 3.38 (3 H, s, NMe), 4.12 (1 H, s, OH), 4.15
3
(1 H, s, OH), 7.59 (1 H, t, JHH ¼ 7.3 Hz, CH), 7.79 (1 H, t,
3
3JHH ¼ 7.5 Hz, CH), 7.81 (2 H, d, JHH ¼ 7.5 Hz, 2 CH) ppm.
13C-NMR: 15.3 (Me), 27.9 (Me), 29.0 (NMe), 85.8 (C), 92.1 (C),
106.4 (C), 123.5 (CH), 124.6 (CH), 130.4 (CH), 135.1 (C), 136.3
(CH), 150.2 (C), 151.3 (C), 163.4 (C¼¼O), 196.5 (C¼¼O) ppm.
EI-MS: 273 (Mþ,40), 241(60), 227 (90),199 (35), 104 (50), 76
(33). Anal. Calcd for C15H15NO4 (273.29): C, 65.93, H, 5.53, N,
5.13; Found: C, 65.85, H, 5.48, N, 5.00%.
Ethyl2-ethyl-3a,8b-dihydroxy-4-oxo-1-propyl-1,3a,4,8b-tetra-
hydroindeno[1,2-b]-pyrrole-3-carboxylate (4c). Yellow pow-
der, mp 195–197ꢀC, yield: 0.60 g (87%). IR (KBr) (mmax/cmꢁ1):
1
3200,1772, 1726, 1514, and 1260 cmꢁ1. H-NMR: 0.92 (3 H, t,
Ethyl 6b,9a-dihydroxy-7,8-dimethyl-7,9a-dihydro-6bH-ace-
naphtho[1,2-b]-pyrrole-9-carboxylate (7b). Yellow powder,
mp 165–167ꢀC, yield: 0.58 g (89%). IR (KBR) (vmax/cmꢁ1):
3
3JHH ¼ 7.2, Me), 1.28 (3 H, t, JHH ¼ 7.2 Hz, Me), 1.32 (3 H, t,
3JHH ¼ 7.3 Hz, Me), 1.69–1.72 (2 H, m, CH2), 2.52 (2 H, q,
3412, 1733, 1685, 1522, 1370, 1187, 1090, and 1014 cmꢁ1
.
3JHH ¼ 7.3 Hz, CH2), 3.39–3.41 (1 H, m, CH), 3.62–3.64 (1 H,
3
1H-NMR: 1.48 (3 H, t, JHH ¼ 7.2 Hz, Me), 2.23 (3 H, s,
3
m, CH), 4.12 (2 H, q, JHH ¼ 7.5 Hz, OCH2), 4.56 (1 H, s, OH),
3
3
Me), 3.57 (3 H, s, NMe), 4.25 (2 H, q, JHH ¼ 7. 2 Hz,
4.70(1 H, s, OH), 7.74 (1 H, t, JHH ¼ 7.6 Hz, CH), 7.89(2 H, d,
3
3JHH ¼ 7.4 Hz, 2 CH), 8.08 (1 H, t, JHH ¼ 7.5 Hz, CH) ppm.
OCH2), 4.15 (1 H, s, OH), 4.45 (1 H, s, OH), 7.12–7.82 (6 H,
m, 6 CH) ppm.13C-NMR: 13.7 (Me), 17.5 (Me), 35.4 (NMe),
61.4 (CH2O), 90.4 (C), 95.0 (C), 110.3 (C), 116.1 (CH), 117.2
(CH), 124.7 (CH), 126.5 (CH), 127.5 (CH), 128.1 (CH), 130.2
(C), 131.4 (C), 132.3 (C), 140.0 (C), 144.1 (C), 166.7 (C¼¼O)
ppm. EI-MS: 325 (Mþ, 25), 293 (49), 265 (85), 247 (95),
220(33). Anal. Calcd for C19H19NO4 (325.36): C, 70.14, H,
5.89, N, 4.30: Found: C, 70.23, H, 5.95, N, 4.42.
13C-NMR: 11.4 (Me), 14.1 (Me), 14.5 (Me), 24.4 (CH2), 45.4
(CH2), 60.2 (OCH2), 82.4 (C), 95.2 (C), 109.1 (C), 122.7 (CH),
124.4 (CH), 129.2 (CH), 133.4 (C), 135.5 (CH), 136.6 (C), 140.2
(C), 160.2 (C), 165.4 (C¼¼O), 183.2 (C¼¼O) ppm. EI-MS: 345
(Mþ,15), 301(60), 273 (88), 245 (78), 218 (25), 104 (50), 76
(33). Anal. Calcd for C19H23NO5 (345.39): C, 66.07, H, 6.71, N,
4.06; Found: C, 66.15, H, 6.82, N, 4.12%.
3-Acetyl-1-(tert-butyl)-3a,8b-dihydroxy-2-phenyl-3a,8b-dihy-
droindeno[1,2-b]-pyrroel-4(1H)-one (4d). Yellow powder,
yield: mp 182–184ꢀC, 0.68 g (90%). IR (KBr) (mmax/cmꢁ1): 3648,
3462, 3217, 1731, 1715, 1602, 1548, and 1472 cmꢁ1 .1H-NMR:
1.48 (9 H, s, Me3C), 1.65 (3 H, s, Me), 3.51 (2 H, s, 2 OH), 7.37 (2
H, d, 3JHH ¼ 7.5 Hz, 2 CH), 7.5 (3 H, m, 3 CH), 7.6 (1 H, t, 3JHH
¼ 7.6 Hz, CH), 7.81 (2 H, m, 2 CH), 7.91 (1 H, d, 3JHH ¼ 7.6 Hz,
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DOI 10.1002/jhet