Synthesis of highly functionalized pyrroles from primary amines and activated acetylenes in water

Article abstract of DOI:10.1016/j.cclet.2012.06.042

Stable derivatives of pyrroles were prepared using multicomponent reactions of dialkyl acetylenedicarboxylate, primary amine and propiolate in the presence of N-methylimidazole in water at room temperature in good yields.

Full text of DOI:10.1016/j.cclet.2012.06.042

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1119–1121
www.elsevier.com/locate/cclet
Synthesis of highly functionalized pyrroles from primary
amines and activated acetylenes in water
b
c
S. Zahra Sayyed-Alangi a, , Zinatossadat Hossaini , Faramarz Rostami-Charati
*
a Department of Chemistry, Azadshahr Branch, Islamic Azad University, Azadshahr, Iran
b Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
c Department of Chemistry, Faculty of Science, Gonbad Kavous University, P.O. Box 163, Gonbad, Iran
Received 14 May 2012
Available online 23 September 2012
Abstract
Stable derivatives of pyrroles were prepared using multicomponent reactions of dialkyl acetylenedicarboxylate, primary amine
and propiolate in the presence of N-methylimidazole in water at room temperature in good yields.
# 2012 S. Zahra Sayyed-Alangi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Propiolate; Dialkyl acetylenedicarboxilates; Multicomponent reactions; N-methylimidazole
Water is an ideal solvent and reagent for biochemical transformations. In the past, water was not used as a solvent
for synthetic organic chemistry due to the poor solubility and, in some cases, the instability of organic reagents in
aqueous solutions. Now, it has been recognized that chemical reactions in mixed aqueous solutions or two-phase
systems often give better results than in organic solvents and often the insolubility of the final products facilitates their
isolation [1,2]. Five-membered, nitrogen-containing heterocycles, such as pyrroles are important building blocks in an
extensive number of biologically active compounds [3]. Pyrroles are heterocycles of great importance because of their
presence in numerous natural products like heme, chlorophyll, vitamin B12, and various cytochrome enzymes [4].
Polysubstituted pyrroles are molecular frameworks having immense importance in material science [5]. They have
been also employed as antioxidants, antibacterial, ionotropic, antitumor, anti-inflammatory, and antifungal agents [6].
Moreover, they are a highly versatile class of intermediates in the synthesis of natural products as well as in
heterocyclic chemistry [7,8]. Herein, we examined the reaction between primary alkylamine, dimethyl
acetylenedicarboxylate and propiolate in the presence of catalytic amount of N-methylimidazole in water at room
temperature. The reaction proceeded smoothly to give pyrrole derivatives 4 in good yield (Scheme 1).
The structures of compounds 4a–g were deduced from their IR, 1H and 13C NMR spectra [9]. The mass spectra of
these compounds displayed the molecular ion peaks at the appropriate m/z values. The 1H and 13C NMR spectroscopic
data, as well as IR spectra, were in agreement with the proposed structures. For example, the 1H NMR spectrum of 4a
in CDCl3 exhibited five sharp singlets readily recognized as arising from methoxy (d 3.72, 3.80, 3.92), methyl (d 3.85),
and vinyl (d 6.78) protons. The 13C NMR spectrum of 4a exhibited 11 signals in agreement with the proposed
* Corresponding author.
E-mail address: zalangi_szalangi@yahoo.com (S.Z. Sayyed-Alangi).
1001-8417/$ – see front matter # 2012 S. Zahra Sayyed-Alangi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.042

1120
S.Z. Sayyed-Alangi et al. / Chinese Chemical Letters 23 (2012) 1119–1121
CO2R
H
N
R''O2C
CO2R
CO2R
(5 mol%)
NMe
H2O,
R' NH2
+
+
r.t., 1h
N
CO2R
CO2R''
R'
1
2
3
4
Yield (%) of4
R'
Me
Me
1, 2, 3, 4
a
R
Me
Et
R''
Me
Et
80
75
78
70
b
c
Et
Et
Me
Et
Me
Et
d
e
87
85
80
Me
Me
Me
Me
Me
Bn
f
4-MeC6H4CH2
4-MeOC6H4CH2
g
Me
Scheme 1.
CO2R
CO2R''
_
H2
3
4
CO2R
N
N
CO2R''
H
N
Me
R'
_
1 + 2
+
11
N
N
Me
6
CO2R
RO2C
R'HN
CO2R''
H
5
CO2R
CO2R
_
H
+
N
CO2R''
H
H
+
N
CO2R
RO2C
_
R'N
CO2R''
N
R'
N
H
+
+
CO2R
CO2R
_
Me
10
N
N
Me
8
7
N
R'
9
N
Me
Scheme 2.
structure. Presumably, the zwitterionic intermediate 6, formed from N-methylimidazole and propiolate 3, is protonated
by the enaminoester 5, generated in situ from primary amine 2 and acetylenic ester 1, to produce intermediates 7 and 8
(Scheme 2). Nucleophilic attack of the conjugate base 7 on intermediate 8 leads to adduct 9, which undergoes proton
shifts to afford new zwitterionic intermediate 10. Finally, intramolecular cyclization affords 11 by elimination of N-
methylimidazole, which is converted into 4 by elimination of hydrogen [10].
In summary, we have developed a simple, one-pot synthesis of highly functionalized pyrroles from reactions of
primary amines with acetylenic esters in the presence N-methylimidazole in water at room temperature. Short reaction
times, readily available starting materials and water as the green solvent are the main advantages of this methodology.
References
[1] P.A. Grieco, Organic Synthesis in Water, Blackie Academic & Professional, Glasgow, 1998.
[2] .P. Anastas, T.C. Williamson, Green Chemistry Frontiers in Benign Chemical Synthesis and Processes, Oxford University Press, New York, 1998
[3] (a) G.W. Gribble, J. Chem. Soc. Perkin Trans. 1 (2000) 1045;
(b) G.W. Gribble, J. Chem. Soc. Perkin Trans. 1 (1998) 615;
(c) A. Nobuyoshi, O. Akihiko, M. Chikara, et al. J. Med. Chem. 42 (1999) 2946;

S.Z. Sayyed-Alangi et al. / Chinese Chemical Letters 23 (2012) 1119–1121
1121
(d) P.S. Baran, J.M. Richter, D.W. Lin, Angew. Chem. Int. Ed. 44 (2005) 609;
(e) M. Torok, M. Abid, S.C. Mhadgut, B. Torok, Biochemistry 45 (2006) 5377.
[4] R.J. Sundberg, in: A. Katritzky, C.W. Rees, E.F.V. Scriven (Eds.), Comprehensive Heterocyclic Chemistry, vol. 2, Pergamon, Oxford, 1996, p.
119.
[5] (a) M. Baumgarten, N. Tyutyulkov, Chem. Eur. J. 4 (1998) 987;
(b) A. Deronzier, J.C. Moutet, Curr. Top. Electrochem. 3 (1994) 159;
(c) G.A. Pagani, Heterocycles 37 (1994) 2069.
[6] (a) J. Lehuede, B. Fauconneau, L. Barrier, et al. Eur. J. Med. Chem. 34 (1999) 991;
(b) R.W. Burli, D. McMinn, J.A. Kaizerman, et al. Bioorg. Med. Chem. Lett. 14 (2004) 1253;
(c) R.W. Burli, P. Jones, D. McMinn, et al. Bioorg. Med. Chem. Lett. 14 (2004) 1259;
(d) R. Jonas, M. Klockow, I. Lues, et al. Eur. J. Med. Chem. 28 (1993) 129.
[7] D.L. Boger, C.W. Boyce, M.A. Labrili, et al. J. Am. Chem. Soc. 121 (1999) 54.
[8] C.M. Sharland, J. Singkhonrat, M.N. Ullah, et al. Tetrahedron Lett. 52 (2011) 2320.
[9] General procedure for preparation of compounds 4a–g. To a stirred solution of amine 2 (2 mmol) and acetylenic esters 1 (2 mmol) in water
(5 mL), was added propiolate 3 (2 mmol) and N-methylimidazole (0.1 mmol) at r.t. After completion of the reaction [1 h; TLC (AcOEt/hexane
1:5) monitoring], the mixture of reaction was purified by preparative TLC on silica gel column chromatography (Merck 230-400 mesh) using n-
hexane-EtOAc as eluent to give compound 4. Trimethyl 1-methyl-1H-pyrrole-2,3,4-tricarboxylate (4a). Yellow oil; yield: 0.41 g (80%). IR
(KBr, cmÀ1): 1720, 1587, 1454, 1256. 1H NMR (500.1 MHz, CDCl3): d 3.72 (s, 3H, MeO), 3.80 (s, 3H, MeO), 3.85 (s, 3H, NMe), 3.92 (s, 3H,
MeO), 6.78 (s, 1H, CH). 13C NMR (125.7 MHz, CDCl3): d 38.2 (NMe), 52.2 (MeO), 52.8 (MeO), 53.4 (MeO), 108.2 (C), 130.2 (C), 134.2
(CH), 147.2 (C), 165.2 (C O), 165.6 (C O), 166.0 (C O). MS m/z: 255 (M+, 15), 240 (68), 224 (88), 31 (100). Anal. Calcd. for C11H13NO6
(255.22): C, 51.77; H, 5.13; N, 5.49. Found: C, 51.85; H, 5.24; N, 5.58. Triethyl 1-methyl-1H-pyrrole-2,3,4-tricarboxylate (4b). Yellow oil;
yield: 0.45 g (75%). IR (KBr, cmÀ1): 1727, 1547, 1485, 1372, 1264. 1H NMR (500.1 MHz, CDCl3): d 1.12 (t, 3H, 3J = 7.2 Hz, Me), 1.32 (t, 3H,
3J = 7.3 Hz, Me), 1.42 (t, 3H, 3J = 7.2 Hz, Me), 3.86 (s, 3H, NMe), 4.12 (q, 2H, 3J = 7.2 Hz, CH2O), 4.25 (q, 2H, 3J = 7.2 Hz, CH2O), 4.32 (q,
2H, 3J = 7.2 Hz, CH2O), 6.85 (s, 1H, CH). 13C NMR (125.7 MHz, CDCl3): d 13.8 (Me), 14.2 (Me), 14.5 (Me), 37.8 (NMe), 62.4 (CH2O), 63.0
(CH2O), 63.4 (CH2O), 107.8 (C), 131.0 (C), 135.4 (CH), 148.2 (C), 165.2 (C O), 165.5 (C O), 165.8 (C O). MS m/z: 297 (M+, 20), 282 (46),
252 (82), 45 (100). Anal. Calcd. for C14H19NO6 (297.30): C, 56.56; H, 6.44; N, 4.71. Found: C, 56.67; H, 6.52; N, 4.78. Trimethyl 1-ethyl-1H-
pyrrole-2,3,4-tricarboxylate (4c). Pale yellow oil; yield: 0.42 g (78%). IR (KBr, cmÀ1): 1735, 1547, 1474, 1367, 1263, 1195. 1H NMR
(500.1 MHz, CDCl3): d 1.24 (t, 3H, 3J = 7.2 Hz, Me), 3.75 (s, 3H, MeO), 3.84 (q, 2H, 3J = 7.2 Hz, CH2), 3.87 (s, 3H, MeO), 3.93 (s, 3H, MeO),
6.87 (s, 1H, CH). 13C NMR (125.7 MHz, CDCl3): d 14.0 (Me), 42.0 (CH2N), 52.3 (MeO), 53.4 (MeO), 53.7 (MeO), 108.6 (C), 124.5 (CH),
129.6 (C), 147.8 (C), 163.4 (C O), 163.7 (C O), 164.2 (C O). Anal. Calcd. for C12H15NO6 (269.25): C, 53.53; H, 5.62; N, 5.20. Found: C,
53.64; H, 5.73; N, 5.28. Triethyl 1-ethyl-1H-pyrrole-2,3,4-tricarboxylate (4d). Yellow oil; yield: 0.44 g (70%). IR (KBr, cmÀ1): 1722, 1567,
1456, 1382, 1247. 1H NMR (500.1 MHz, CDCl3): d 1.14 (t, 3H, 3J = 7.4 Hz, Me), 1.18 (t, 3H, 3J = 7.2 Hz, Me), 1.27 (t, 3H, 3J = 7.5 Hz, Me),
1.37 (t, 3H, 3J = 7.2 Hz, Me), 3.85 (q, 2H, 3J = 7.2 Hz, CH2N), 4.10 (q, 2H, 3J = 7.4 Hz, CH2O), 4.26 (q, 2H, 3J = 7.5 Hz, CH2O), 4.34 (q, 2H,
3J = 7.5 Hz, CH2O), 6.80 (s, 1H, CH). 13C NMR (125.7 MHz, CDCl3): d 13.9 (Me), 14.0 (Me), 14.3 (Me), 14.6 (Me), 38.9 (NCH2), 62.2
(CH2O), 62.8 (CH2O), 63.5 (CH2O), 108.2 (C), 126.4 (CH), 130.4 (C), 148.5 (C), 161.2 (C O), 161.5 (C O), 162.2 (C O). Anal. Calcd. for
C15H21NO6 (311.33): C, 57.87; H, 6.80; N, 4.50. Found: C, 57.76; H, 6.72; N, 4.39. Trimethyl 1-benzyl-1H-pyrrole-2,3,4-tricarboxylate (4e).
Pale yellow oil; yield: 0.57 g (87%). IR (KBr, cmÀ1): 1732, 1684, 1558, 1467, 1394, 1268. 1H NMR (500.1 MHz, CDCl3): d 3.75 (s, 3H, MeO),
3.83 (s, 3H, MeO), 3.90 (s, 3H, MeO), 5.32 (2H, s, CH2N), 6.84 (s, 1H, CH), 7.22 (d, 2H, 3J = 7.2 Hz, 2CH), 7.32–7.36 (m, 3H, 3CH). 13C NMR
(125.7 MHz, CDCl3): d 48.7 (CH2N), 52.6 (MeO), 53.2 (MeO), 53.5 (MeO), 108.2 (C), 121.4 (CH), 127.2 (C), 127.8 (2CH), 128.6 (CH), 129.4
(2CH), 135.4 (C), 145.3 (C), 163.2 (C O), 164.3 (C O), 164.6 (C O). Anal. Calcd. for C17H17NO6 (331.32): C, 61.63; H, 5.17; N, 4.23.
Found: C, 61.72; H, 5.24; N, 4.30. Trimethyl 1-(4-methylbenzyl)-1H-pyrrole-2,3,4-tricarboxylate (4f). Yellow oil; yield: 0.59 g (85%). IR (KBr,
cmÀ1): 1728, 1678, 1536, 1458, 1385, 1265. 1H NMR (500.1 MHz, CDCl3): d 2.45 (s, 3H, Me), 3.72 (s, 3H, MeO), 3.80 (s, 3H, MeO), 3.87 (s,
3
3
3H, MeO), 5.34 (s, 2H, CH2N), 6.87 (s, 1H, CH), 7.28 (d, 2H, J = 7.6 Hz, 2CH), 7.34 (d, 2H, J = 7.6 Hz, 2CH). 13C NMR (125.7 MHz,
CDCl3): d 23.4 (Me), 48.5 (CH2N), 52.4 (MeO), 52.8 (MeO), 53.2 (MeO), 108.2 (C), 121.5 (CH), 127.6 (C), 128.2 (2CH), 128.7 (2CH), 132.4
(C), 137.6 (C), 147.2 (C), 163.4 (C O), 164.6 (C O), 165.2 (C O). Anal. Calcd. for C18H19NO6 (345.35): C, 62.60; H, 5.55; N, 4.06. Found:
C, 62.73; H, 5.64; N, 4.17. Trimethyl 1-(4-methoxybenzyl)-1H-pyrrole-2,3,4-tricarboxylate (4g). Yellow oil; yield: 0.58 g (80%). IR (KBr,
cmÀ1): 1735, 1686, 1557, 1462, 1423, 1274. 1H NMR (500.1 MHz, CDCl3): d 3.74 (s, 3H, MeO), 3.82 (s, 3H, MeO), 3.88 (s, 3H, MeO), 3.93 (s,
3H, MeO), 5.30 (s, 2H, CH2N), 6.87 (s, 1H, CH), 7.32 (d, 2H, 3J = 7.6, 2CH), 7.78 (d, 2H, 3J = 7.6, 2CH). 13C NMR (125.7 MHz, CDCl3): d
49.2 (CH2N), 52.2 (MeO), 52.7 (MeO), 53.4 (MeO), 54.6 (MeO), 108.5 (C), 115.4 (2CH), 121.6 (CH), 127.3 (C), 133.4 (2CH), 134.3 (C), 146.4
(C), 158.2 (C), 163.4 (C O), 163.8 (C O), 164.5 (C O). Anal. Calcd. for C18H19NO7 (361.35): C, 59.83; H, 5.30; N, 3.88. Found: C, 59.75;
H, 5.23; N, 3.79.
[10] I. Yavari, Z.S. Hossaini, M. Sabbaghan, Tetrahedron Lett. 47 (2006) 6037.