A novel synthesis of tetrasubstituted pyrroles via tandem benzylic oxidative cyclization

Article abstract of DOI:10.1055/s-0033-1339757

A new method for the synthesis of tetrasubstituted pyrroles from a domino reaction between primary benzylamines and dialkyl acetylenedicarboxylates, in the presence of potassium cyanide without using a metal or oxidant, is described. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339757

LETTER
▌2279
letter
A Novel Synthesis of Tetrasubstituted Pyrroles via Tandem Benzylic Oxidative
Cyclization
Tetrasubstituted Pyrroles
Issa Yavari,* Mohammad J. Bayat
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: yavarisa@modares.ac.ir
Received: 17.07.2013; Accepted after revision: 18.08.2013
presence of different amounts of KCN in MeCN, and the
Abstract: A new method for the synthesis of tetrasubstituted pyr-
best result was obtained with one equivalent of KCN.
Subsequently, the reaction was tested in other solvents
roles from a domino reaction between primary benzylamines and
dialkyl acetylenedicarboxylates, in the presence of potassium cya-
such as dichloromethane (52% yield), N,N-dimethyl-
formamide (40% yield), polyethylene glycol (50% yield),
and a mixture of H2O–MeCN (1:1, 58% yield) at room
temperature, and the best result was obtained in MeCN
(66% yield).
nide without using a metal or oxidant, is described.
Key words: pyrrole, acetylenic ester, primary benzylamine, potas-
sium cyanide
The generality of this transformation was demonstrated
by applying various primary benzylamines 1 and acetyle-
nic esters 2 under optimized conditions (1 equiv of KCN,
MeCN, 24 h), and the results are summarized in Table 1.
Sequential
multiple-bond-forming transformations,
which include tandem reactions, are of interest in the de-
velopment of synthetic organic chemistry.1,2 Carbon–car-
bon and carbon–heteroatom bond formation through C–H
bond functionalization is another important strategy in or-
ganic synthesis.3–5 Herein, a new method for the synthesis
of tetrasubstituted pyrroles via tandem benzylic oxidative
cyclization without using any metal or oxidant is de-
scribed. The pyrrole ring system is present in a large num-
ber of natural products and pharmaceuticals and materials
having desirable properties.6–11 Although there are many
reports for the synthesis of pyrroles,12–17 the number of
methods for synthesizing substituted pyrroles through
benzylic oxidative cyclization is limited.18 In recent years,
several reports of benzylic C–H functionalization have
been published.18–28
1
The structures of compounds 3a–j were verified by H
NMR, 13C NMR, and IR spectroscopic and mass spectro-
metric analysis.34
Table 1 Synthesis of Compounds 3a–j from the Reaction of Benzyl-
amines and Acetylenic Esters in the Presence of KCNa
CO2R
RO2C
CO2R
Ar
KCN
2
Ar
NH2
+
MeCN, r.t
RO2C
N
CO2R
H
1
2
3
Amine 1 Ar
Acetylenic R
ester 2
Product 3 Yield
(%)b
As part of our current studies on the development of new
multicomponenent reactions to synthesize novel function-
al heterocycles,29–32 we herein report a domino reaction
between primary benzylamines and dialkyl acetylenedi-
carboxylates, in the presence of potassium cyanide for the
synthesis of tetrasubstituted pyrroles. This work is an ex-
tension of our recent report that the reaction between ben-
zylamine (1 mmol) and dialkyl acetylenedicarboxylates
(2 mmol) in the presence of N-methylimidazole (0.05
mmol) as an organocatalyst gives trialkyl 1-benzyl-6-oxo-
1a
1b
1c
1d
1e
1f
Bn
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
Me
Me
3a
3b
3c
3d
3e
3f
61
66
63
59
57
51
54
56
49
45
4-MeC6H4CH2
4-MeOC6H4CH2
2-ClC6H4CH2
4-ClC6H4CH2
1-naphthyl
Me
Me
Me
Me
Et
1,6-dihydro-2,3,4-pyridinetricarboxylates
in
good
yields.33
1a
Bn
3g
3h
3i
Initially, the reaction between 4-methylbenzylamine (1b, 1b
4-MeC6H4CH2
4-MeOC6H4CH2
1-naphthyl
Et
1 mmol) and dimethyl acetylenedicarboxylate (2a,
DMAD, 2 mmol) in the presence of potassium cyanide (1
1c
Et
mmol) was examined. The reaction proceeded smoothly 1f
and afforded trimethyl 5-(4-methylphenyl)-1H-pyrrole-
2,3,4-tricarboxylate (3b) in 66% yield. In an attempt to
optimize the reaction, the reaction was carried out in the
Et
3j
a Reaction conditions: benzylamines 1 (1 mmol), acetylenic ester 2, (2
mmol), KCN (1 mmol), and MeCN (5 mL).
b Yield of isolated pure product after column chromatography.
SYNLETT 2013, 24, 2279–2281
Advanced online publication: 13.09.2013
DOI: 10.1055/s-0033-1339757; Art ID: ST-2013-D0666-L
© Georg Thieme Verlag Stuttgart · New York
A possible mechanism for this transformation is outlined
in Scheme 1. The initial event involves protonation of the
zwitterionic intermediate 6, formed from KCN and 2 by
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2280
I. Yavari, M. J. Bayat
LETTER
the enaminoester intermediate 7, which itself is generated
in situ from the primary amine 1 and acetylenic ester 2, to
produce intermediates 8 and 9. Then, nucleophilic attack
of the conjugate base 9 on intermediate 8 leads to adduct
10, which undergoes intramolecular proton-transfer reac-
tions to afford 11. Intermediate 11 undergoes intramolec-
ular cyclization28 by elimination of salt 12 to generate 13,
which is converted into the desired product 3 by a formal
[1,3]-H shift and air oxidation.
CO2Me
MeO2C
N
CO2R
CO2R
KCN
+
+
1a 2a
MeCN, r.t.
4a: R = Me
4b: R = Et
5a: R = Me
5b: R = Et
Scheme 2 Synthesis of compounds 5
HN
Ar
+
1
2
CO2R
References and Notes
CO2R
CO2R
RO2C
CN
K
N
Ar
7
(1) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions
in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(2) Multicomponent Reactions; Zhu, J.; Bienayme, H., Eds.;
Wiley-VCH: Weinheim, 2005.
CO2R
KCN
2
+
NC
CO2R
RO2C
K
CO2R
6
8
9
(3) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624.
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K
NC
CO2R
12
CO2R
CN
CO2R
CN
RO2C
RO2C
RO2C
CO2R
CO2R
K
K
N
Ar
RO2C
N
Ar
10
11
(9) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. F. Chem. Rev. 2008,
108, 264.
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RO2C
RO2C
CO2R
Ar
CO2R
Ar
RO2C
RO2C
[1,3]-H shift
air
3
N
H
N
13
14
Scheme 1 A plausible mechanism for the formation of compounds 3
The same reaction was tested using aliphatic amines such
as butylamine or allylamine instead of benzylamines, but
no tetrasubstituted pyrroles were detected in the reaction
mixtures. The reaction of propargylamine with DMAD af-
forded pyrrole derivatives.35
(18) Hong, D.; Zhu, Y.; Li, Y.; Lin, X.; Lu, P.; Wang, Y. Org.
Lett. 2011, 13, 4668.
(19) Hikawa, H.; Ino, Y.; Suzuki, H.; Yokoyama, Y. J. Org.
Chem. 2012, 77, 7046.
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C.; She, N. F.; Wu, A. X. Tetrahedron 2013, 69, 22.
(22) Karnakar, K.; Kumar, A. V.; Murthy, S. N.; Ramesh, K.;
Nageswar, Y. V. D. Tetrahedron Lett. 2012, 53, 4613.
(23) Liu, P.; Li, Y.; Wang, H.; Wang, Z.; Hu, X. Tetrahedron
Lett. 2012, 53, 6654.
(24) Rachkonda, S.; Pratap, P. S.; Basaveswara Rao, M. V.
Synthesis 2012, 44, 2065.
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(26) Patil, R. D.; Adimurthy, S. Adv. Synth. Catal. 2011, 353,
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13, 1274.
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2010, 12, 4376.
To extend our knowledge of this transformation, we per-
formed the same reaction with equimolar amounts of 4-
methylbenzylamine (1b), DMAD, and alkyl propiolates 4.
These reactions led to the formation of dimethyl 2-{N-
[(E)-2-(alkoxycarbonyl)vinyl]-N-benzylamino}maleates
5 in good yields (Scheme 2). This reaction afforded only
3
the E isomer of 5, as evidenced from the JHH value of
about 13.3 Hz for the vicinal olefinic protons. Compounds
5 were again fully characterized with their IR, 1H NMR,
and 13C NMR spectra.34
In conclusion, we have designed a new strategy for the
syntheses of tetrasubstituted pyrroles using a tandem
three-component reaction between benzylamines and
acetylenic esters.
(29) Yavari, I.; Souri, S.; Sirouspour, M. Synlett 2008, 1633.
(30) Yavari, I.; Souri, S. Synlett 2007, 2969.
(31) Yavari, I.; Nematpour, M. Synlett 2013, 24, 165.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
Synlett 2013, 24, 2279–2281
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrasubstituted Pyrroles
2281
(32) Yavari, I.; Nematpour, M. Synlett 2012, 23, 2215.
(33) Yavari, I.; Bayat, M. J. Tetrahedron Lett. 2011, 52, 6649.
(34) General Procedure for the Synthesis of Compounds 3
To a stirred solution of amine 1 (1 mmol) and acetylenic
ester 2 (2 mmol) in MeCN (5 mL) was added KCN (1 mmol)
at r.t. After completion of the reaction [about 24 h; TLC
(EtOAc–hexane, 1:5) monitoring], the solvent was
evaporated, and the residue was purified by column
chromatography [silica gel (230–400 mesh; Merck);
EtOAc–hexane, 1:5] to give pure product.
General Procedure for the Synthesis of Compounds 5
To a stirred solution of 4-methylbenzylamine (1b, 1 mmol),
DMAD (1 mmol), and methyl propiolate (4a, 1 mmol) in
MeCN (5 mL) was added KCN (1 mmol) at r.t. After
completion of the reaction [about 24 h; TLC (EtOAc–
hexane, 1:5) monitoring], the solvent was evaporated, and
the residue was purified by column chromatography [silica
gel (230–400 mesh; Merck); EtOAc–hexane, 1:5] to give
pure product.
Dimethyl 2-{[(E)-3-Methoxy-3-oxoprop-1-enyl](4-
methylbenzyl)amino}maleate (5a)
Trimethyl 5-Phenyl-1H-pyrrole-2,3,4-tricarboxylate
(3a)
Pale yellow powder; mp 94–96 °C; yield 0.22 g (63%). IR
(KBr): 3415, 2952, 1712, 1590 cm–1. 1H NMR (500.1 MHz,
CDCl3): δ = 2.36 (3 H, s, Me), 3.62, 3.67, 4.02 (9 H, s, MeO),
4.83 (2 H, s, CH2N), 5.17 (1 H, d, 3J = 13.3 Hz, CH), 5.24 (1
H, s, CH), 7.03 (2 H, d, 3J = 7.8 Hz, CH), 7.16 (2 H, t, 3J =
7.8 Hz, CH), 7.59 (2 H, t, 3J = 13.3 Hz, CH) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 21.0 (Me), 51.1 (CH2N), 51.5,
51.6, 53.4 (3 MeO), 97.1 (CH), 98.8 (CH), 125.7 (2 CH),
129.8 (2 CH), 130.0 (C), 137.7 (C), 143.4 (CH), 150.1 (C),
164.4 (C=O), 166.2 (C=O), 167.5 (C=O) ppm. MS (EI): m/z
(%) = 347 (3) [M+], 332 (8), 288 (11), 105 (25), 77 (13), 59
(7). Anal. Calcd for C18H21NO6 (347.36): C, 62.24; H, 6.09;
N, 4.03. Found: C, 62.51; H, 6.14; N, 4.08.
Pale yellow oil; yield 0.19 g (61%). IR (KBr): 3421, 3000,
1728, 1610 cm–1. 1H NMR (500.1 MHz, CDCl3): δ = 3.76,
3.79, 4.04 (9 H, s, 3 MeO), 7.45–7.47 (3 H, m, CH), 7.06 (2
H, d, 3J = 7.8 Hz, CH), 9.24 (1 H, br s, NH) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 51.5, 52.3, 52.7 (3 MeO), 122.4
(C), 126.3 (C), 128.3 (2 CH), 128.6 (C), 129.9 (2 CH), 129.6
(CH), 131.9 (C), 142.6 (C), 161.7 (C=O), 164.9 (C=O),
167.8 (C=O) ppm. MS (EI): m/z (%) = 317 (3) [M+], 302 (4),
258 (23), 91 (14), 77 (6), 59 (7). Anal. Calcd for C16H15NO6
(317.29): C, 60.57; H, 4.56; N, 4.41. Found: C, 60. 75; H,
4.52; N, 4.47.
(35) Schmidt, G.; Winterfeldt, E. Chem. Ber. 1971, 104, 2483.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2279–2281

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