A novel approach to the synthesis of highly functionalized pyrroles

Article abstract of DOI:10.1055/s-0028-1088224

A new and efficient one-pot synthesis of polysubstituted pyrrole derivatives by a three-component reaction between dialkyl acetylenedicarboxylates, aromatic amines, triphenylphosphine, and arylglyoxals is described. The reactions were performed in dichlor

Full text of DOI:10.1055/s-0028-1088224

LETTER
1115
A Novel Approach to the Synthesis of Highly Functionalized Pyrroles
S
ynthesis of Polyfunct
o
h
role
D
eriva
t
a
ive
s
mmad Anary-Abbasinejad,* Khadije Charkhati, Hossein Anaraki-Ardakani
Department of Chemistry, Islamic Azad University, Yazd Branch, P. O. Box 89195-155, Yazd, Iran
Fax +98(351)8211109; E-mail: mohammadanary@yahoo.com
Received 2 January 2009
Ph3P
PPh3
CO2Me
Abstract: A new and efficient one-pot synthesis of polysubstituted
pyrrole derivatives by a three-component reaction between dialkyl
1
PhHN
+
MeO2C
CO2Me
acetylenedicarboxylates, aromatic amines, triphenylphosphine, and
arylglyoxals is described. The reactions were performed in dichloro-
methane at room temperature and neutral conditions and afforded
high yields of products.
CO2Me
PhNH2
3
2
4
Scheme 1 Synthesis of 2-aminophosphoranes by reaction of Ph3P-
Key words: pyrrole derivatives, dialkyl acetylenedicarboxylates,
triphenylphosphine, multicomponent reaction, intramolecular
Wittig reaction
DMAD zwitterion with aniline
an equimolar amount of 4-nitrophenylglyoxal in dichlo-
romethane, a smooth reaction took place. After comple-
tion of the reaction (monitored by TLC) dimethyl 5-(4-
nitrophenyl)-1-phenylpyrrole-2,3-dicarboxylate (6a) was
obtained in 90% yield. As shown in Scheme 2, it is rea-
sonable to assume that the Wittig reaction of phosphorane
4 with 4-nitrophenylglyoxal (5) affords intermediate 6
which then cyclizes to dihydropyrrole intermediate 7 that
subsequently loses water to produce pyrrole derivative 6a.
Simple nitrogen-containing heterocycles receive consid-
erable attention in the literature as a consequence of their
exciting biological properties and their role as pharma-
cophores of historical importance.1 Of these heterocycles,
the synthesis, reactions, and biological activities of
pyrrole-containing molecules stand as an area of research
in heteroaromatic chemistry, and this structural motif ap-
pears in a large number of pharmaceutical agents and nat-
ural products.2 Accordingly, many strategies have been
developed for the preparation of pyrroles.2,3
PPh3
O
– Ph3PO
PhHN
H
+
CO2Me
CO2Me
Ar
CH2Cl2, r.t., 24 h
O
Addition reaction between phosphines and activated
carbon–carbon triple bonds is well known to produce a
reactive zwitterionic intermediate, which may be trapped
by various electrophiles.4–8 Reaction of triphenylphos-
phine with dimethyl acetylenedicarboxylate (DMAD) has
been studied in the presence of a variety of organic acidic
compounds, in order to trap the zwitterionic intermediate.
Trapping of Ph3P-DMAD zwitterion by an organic acidic
compound containing a carbonyl group has been used as
a one-pot and efficient route for the synthesis of a variety
of heterocyclic and carbocyclic compounds.7–11 Treat-
ment of triphenylphosphine with DMAD in the presence
of primary amines has been reported to produce b-amino
phosphoranes 4 (Scheme 1).8 Recently, we reported the
reaction of these ylides with ethyl chlorooxoacetate for
the synthesis of dimethyl N-aryl-4-ethoxy-5-oxo-2,5-di-
hydro-1H-pyrrole-2,3-dicarboxylates.12 In continuation
of our previous works on the reaction between phosphorus
nucleophiles and acetylenic esters in the presence of or-
ganic acids,6,9,11,12 we decided to investigate the reaction
of these phosphorus ylides with arylglyoxals.
4
5
Ar
Ar
HO
H
H
H
N
O
N
Ph
H
CO2Me
Ph
CO2Me
CO2Me
MeO2C
7
6
H
CO2Me
– H2O
Ar = 4-O2NC6H4
Ar
CO2Me
N
Ph
6a
Scheme 2 Reaction of 2-aminophosphorane 4 with 4-nitrophenyl-
glyoxal for the synthesis of pyrrole derivative 6a
Being successful in this reaction, we decided to investi-
gate the one-pot synthesis of dimethyl 5-(4-nitrophenyl)-
1-phenylpyrrole-2,3-dicarboxylate (6a, Table 1). Thus,
equimolar amounts of triphenylphosphine, aniline, and
DMAD were mixed in dichloromethane as solvent. After
stirring for one minute at room temperature, 4-nitrophe-
nylglyoxal was added, and the progress of the reaction
was monitored by TLC. After 24 hours the TLC of the
mixture of the reaction showed only the presence of pyr-
role derivative 6a and triphenylphosphine oxide. Silica
gel chromatography afforded the product dimethyl 5-(4-
Ylide 4 was prepared by the reaction between triphe-
nylphosphine, DMAD, and aniline by the previously re-
ported procedure.8 When phosphorane 4 was stirred with
SYNLETT 2009, No. 7, pp 1115–1117
x
x.
x
x.
2
0
0
9
Advanced online publication: 20.03.2009
DOI: 10.1055/s-0028-1088224; Art ID: D00409ST
© Georg Thieme Verlag Stuttgart · New York

1116
M. Anary-Abbasinejad et al.
LETTER
nitrophenyl)-1-phenylpyrrole-2,3-dicarboxylate (6a) in
References and Notes
85% yield.13
(1) Yates, F. S. In Comprehensive Heterocyclic Chemistry, Vol.
2; Boulton, A. J.; McKillop, A., Eds.; Pergamon: Oxford,
1984, 511.
(2) Jones, R. A. In Pyrroles: The synthesis, Reactivity, and
Physical Properties of Substituted Pyrroles, Part 2; Wiley:
New York, 1992.
(3) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491.
(4) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119,
7595.
(5) Nair, V.; Nair, J. S.; Vinod, A. U.; Rath, N. P. J. Chem. Soc.,
Perkin Trans. 1 1997, 329.
(6) Anary-Abbasinejad, M.; Anaraki-Ardakani, H.; Hosseini-
Mehdiabad, H. Phosphorus, Sulfur Silicon Relat. Elem.
2008, 183, 1440.
(7) Yavari, I.; Hekmat-Shoar, R.; Zonouzi, A. Tetrahedron Lett.
1998, 39, 2391.
To investigate the scope of the reaction, different aryl
amines and arylglyoxals were reacted with triphenylphos-
phine and dialkyl acetylenedicarboxylates (DAAD) and
the corresponding pyrroles were obtained in good yields
(Table 1).
Table 1 Three-Component Reaction between Anilines, DAAD, and
Arylglyoxals Promoted by Ph3P
E
Ph3P
O
1
– Ph3PO
Ar
+ E
E +
Ar
E
H
CH2Cl2, r.t., 24 h
N
R
RNH2
2
O
3
5
6
(8) Yavari, I.; Adib, M.; Hojabri, L. Tetrahedron 2002, 58,
7213.
(9) Anary-Abbasinejad, M.; Mosslemin, M. H.; Hassanabadi,
A.; Tabatabaee, M. Synth. Commun. 2008, 38, 3700.
(10) Evans, L. A.; Griffiths, K. E.; Guthmann, H.; Murphy, P. J.
Tetrahedron Lett. 2002, 43, 299.
2, 6
a
R
E
Ar
Yield of 6 (%)a
Ph
CO2Me
CO2Me
4-O2NC6H4
4-O2NC6H4
4-ON2C6H4
4-BrC6H4
4-BrC6H4
4-O2NC6H4
4-BrC6H4
4-BrC6H4
85
85
85
84
85
86
90
85
b
c
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
CO2t-Bu
CO2Me
CO2Et
(11) Mosslemin, M. H.; Yavari, I.; Anary-Abbasinejad, M.;
Nateghi, M. R. Synthesis 2004, 1029.
d
e
(12) Anary-Abbasinejad, M.; Anaraki-Ardakani, H.; Dehghan,
A.; Hassanabadi, A.; Seyedmir, M. R. J. Chem. Res. 2007,
574.
(13) General Procedure for the Preparation of Compounds
6a–h
f
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
CO2Me
CO2Et
g
To a magnetically stirred solution of Ph3P (1 mmol) and
aniline derivative (1 mmol) in CH2Cl2 (10 mL) was added
dropwise a mixture of dialkyl acetylenedicarboxylate (1
mmol) in CH2Cl2 (3 mL) at r.t. over 2 min. The reaction
mixture was then stirred for one more minute. Arylglyoxal
(1 mmol) was added, and the reaction mixture was stirred for
more 24 h. Solvent was evaporated, and the residue was
purified by column chromatography on SiO2 using EtOAc–
hexane (1:4) mixture as eluent.
h
CO2Me
a Isolated yields.
The structure of compounds 6a–h was deduced from their
elemental analyses and their IR, 1H NMR, and 13C NMR
spectra.14–21 The mass spectrum of compound 6a dis-
played the molecular ion peak at m/z = 380 as the base
(14) Dimethyl 5-(4-Nitrophenyl)-1-(phenyl)-pyrrole-2,3-
dicarboxylate (6a)
1
peak. The 500 MHz H NMR spectrum of 6a exhibited
Yellow powder, mp 115–117 °C. IR (KBr): nmax = 1716,
1720 (C=O) cm–1. Anal. Calcd (%) for C20H16N2O6 (380.35):
C, 63.16; H, 4.24; N, 7.37. Found: C, 63.27; H, 4.19; N, 7.65.
1H NMR (500 MHz, CDCl3): d = 3.72 and 3.85 (6 H, 2 s, 2
OCH3), 7.09 (1 H, s, CH of pyrrole), 7.34 (2 H, m, 2 CH of
C6H5), 7.48 (3 H, m, 3 CH of C6H5), 7.58 (2 H, d, J = 9 Hz,
2 CH of C6H4NO2), 8.20 (2 H, d, J = 9 Hz, 2 CH of
C6H4NO2). 13C NMR (125.8 MHZ, CDCl3): d = 52.6 and 52.9
(2 OCH3), 121.2, 123.3, 124.3, 125.4, 126.3, 126.6, 128.8,
129.3, 129.6, 139.3, 140.5, 147.1 (arom.), 160.8 and 166.3 (2
C=O, ester). MS: m/z (%) = 380 (100) [M+].
three sharp signals at d = 3.72, 3.85, and 7.09 ppm for two
methoxy group protons and the proton of pyrrole ring, re-
spectively. Aromatic protons resonated between d = 7.34
13
and 8.20 ppm. The C NMR spectrum of compound 6a
showed sixteen distinct resonances in agreement with the
proposed structure. The structural assignments made on
the basis of the NMR spectra of compound 6a were sup-
ported by its IR spectrum. The ester carbonyl groups ex-
hibited strong absorption bands at 1716 and 1720 cm–1.
(15) Dimethyl 1-(4-Methylphenyl)-5-(4-nitrophenyl)-pyrrole-
2,3-dicarboxylate (6b)
In conclusion, we report a three-component reaction be-
tween dialkyl acetylenedicarboxylates, aromatic amines,
and arylglyoxals promoted by triphenylphosphine to pro-
duce functionalized pyrrole derivatives in high yields. The
present method carries the advantage that not only the re-
action is performed under neutral conditions but also that
the substances can be mixed without any activation or
modification.
Yellow powder, mp 148–150 °C. IR (KBr): nmax = 1717
(C=O) cm–1. Anal. Calcd (%) for C21H18N2O6 (394.38): C,
63.96; H, 4.60; N, 7.10. Found: C, 63.67; H, 4.71; N, 7.29.
1H NMR (500 MHz, CDCl3): d = 2.24 (3 H, s, CH3), 3.55 and
3.67 (6 H, 2 S, 2 OCH3), 6.87 (1 H, s, CH pyrrol), 7.07 (4 H,
m, arom.), 7.41 (2 H, d, J = 9 Hz, 2 CH arom.), 8.05 (2 H, d,
J = 9 Hz, 2 CH arom.). 13C NMR (500 MHz, CDCl3): d =
21.2 (CH3), 52.2 and 52.5 (2 OCH3), 120.6, 122.7, 123.9,
125.7, 126.2, 128.3, 129.7, 131.1, 136.4, 139.0, 140.1, 146.7
(arom.), 160.4, 166.7 (2 C=O, ester). MS: m/z (%) = 394
(100) [M+].
Synlett 2009, No. 7, 1115–1117 © Thieme Stuttgart · New York

LETTER
Synthesis of Polyfunctionalized Pyrrole Derivatives
1117
(16) Di(tert-butyl) 1-(4-Methylphenyl)-5-(4-nitrophenyl)-
pyrrole-2,3-dicarboxylate (6c)
(19) Dimethyl 1-(4-Methoxyphenyl)-5-(4-nitrophenyl)-
pyrrole-2,3-dicarboxylate (6f)
Yellow oil. IR (KBr): nmax = 1709 (C=O, ester) cm–1. Anal.
Calcd (%) for C27H30N2O6 (478.54): C, 67.77; H, 6.32; N,
5.85. Found: C, 67.92; H, 6.10; N, 5.97. 1H NMR (500 MHz,
CDCl3): d = 1.31 (9 H, s, t-Bu), 1.48 (9 H, s, t-Bu), 2.41 (3
H, s, CH3), 6.91 (1 H, s, CH pyrrole(, 7.19 (4 H, m, arom.),
7.58 and 8.20 (4 H, 2 d, 3JHH = 8 Hz, arom.). 13C NMR (125
MHz, CDCl3): d = 21.5 (CH3), 28.2 and 28.4 (6 CH3 of 2
t-Bu), 82.3 and 82.7 (2 C of 2 t-Bu), 121.5, 123.2, 124.0,
125.1, 126.2, 128.1, 129.2, 130.0, 137.5, 139.0, 141.4, 146.9
(arom.), 159.6 and 164.5 (2 C=O, ester). MS: m/z (%) = 478
(90) [M+].
Yellow powder; mp 159–161 °C. IR (KBr): nmax = 1731,
1729 (C=O, ester) cm–1. Anal. Calcd (%) for C21H18N2O7
(410.38): C, 61.46; H, 4.42; N, 6.83. Found: C, 61.52; H,
4.19; N, 7.07. 1H NMR (500 MHz, CDCl3): d = 3.73 and
3.85 (6 H, 2 s, 2 OCH3), 3.86 (3 H, s, OCH3), 7.05 (1 H, s,
CH pyrrole), 6.95 (2 H, d, J = 8 Hz, 2 CH arom.), 7.28 (2 H,
d, J = 8 Hz, 2 CH arom.), 7.60 (2 H, d, J = 8 Hz, 2 CH
arom.), 8.22 (2 H, d, J = 8 Hz, 2 CH arom.). 13C NMR (125
MHz, CDCl3): d = 52.6 and 52.9 (2 OCH3), 56.0 (OCH3),
114.6, 116.9, 120.9, 123.0, 124.3, 126.9, 127.6, 128.7,
132.2, 140.6, 147.1, 160.23 (arom.), 160.8 and 166.4 (2
C=O, ester). MS: m/z (%) = 410 (61) [M+].
(17) Dimethyl 5-(4-Bromophenyl)-1-(4-methylphenyl)-
pyrrole-2,3-dicarboxylate (6d)
(20) Diethyl 5-(4-Bromophenyl)-1-(4-methoxyphenyl)-
pyrrole-2,3-dicarboxylate (6g)
Yellow oil. IR (KBr): nmax = 1719 (C=O, ester) cm–1. Anal.
Calcd (%) for C21H18BrNO4 (428.28): C, 58.89; H, 4.24; N,
3.27. Found: C, 58.97; H, 4.19; N, 3.55. 1H NMR (500 MHz,
CDCl3): d = 2.41 (3 H, s, CH3), 3.72 and 3.83 (6 H, 2 s, 2
OCH3), 6.95 (1 H, s, CH pyrrole), 7.22 (4 H, m, 4 CH arom.),
7.30 (2 H, d, J = 9 Hz, 2 CH arom.), 7.49 (2 H, d, J = 9 Hz,
2 CH arom.). 13C NMR (125 MHz, CDCl3): d = 21.6 (CH3),
52.5 and 52.8 (2 OCH3), 121.4, 121.6, 124.1, 124.4, 126.1,
126.2, 129.9, 130.0, 132.1, 132.7, 137.2, 139.1 (arom.),
160.9 and 166.8 (2 C=O, ester). MS: m/z (%) = 427 (95)
[M+].
Yellow powder; mp 149–151 °C. IR (KBr): nmax = 1714,
1711 (C=O, ester) cm–1. Anal. Calcd (%) for C23H22BrNO5
(472.33): C, 58.49; H, 4.69; N, 2.97. Found: C, 58.25; H,
4.51; N, 3.11. 1H NMR (500 MHZ, CDCl3): d = 1.16 and 1.27
(6 H, 2 t, 3JHH = 7 Hz, 2 CH3), 3.82 (3 H, s, OCH3), 4.15 and
4.29 (4 H, 2 q, 3JHH = 7 Hz, 2 OCH2), 6.91 (1 H, s, CH
pyrrole), 6.92, 7.24, 7.30 and 7.46 (8 H, 4 d, 3JHH = 8 HZ,
arom.). 13C NMR (125 MHz, CDCl3): d = 14.3 and 14.5 (2
CH3), 55.9 (OCH3), 61.3 and 61.8 (2 OCH2), 114.4, 116.9,
121.4, 123.8, 124.6, 126.2, 127.7, 129.9, 132.0, 132.7, 132.8
and 160.1 (arom.), 160.4 and 166.4 (2 C=O, ester). MS:
m/z (%) = 471 (73) [M+].
(18) Diethyl 5-(4-Bromophenyl)-1-(4-methylphenyl)-pyrrole-
2,3-dicarboxylate (6e)
Yellow oil. IR (KBr): nmax = 1720 (C=O, ester) cm–1. Anal.
Calcd (%) for C23H22BrNO4 (456.33): C, 60.54; H, 4.86; N,
3.07. Found: C, 60.29; H, 4.69; N, 3.31. 1H NMR (500 MHz,
CDCl3): d = 1.17 and 1.30 (6 H, 2 t, 3JHH = 7 Hz, 2 CH3), 2.42
(3 H, s, CH3), 4.16 and 4.31 (4 H, 2 q, 3JHH = 7 Hz, 2 OCH2),
6.93 (1 H, s, CH pyrrole), 7.22 (4 H, m, 4 CH arom.), 7.32 (2
H, d, J = 9 Hz, 2 CH arom.), 7.48 (2 H, d, J = 9 Hz, 2 CH
arom.). 13C NMR (125 MHz, CDCl3): d = 14.3, 14.6 and 21.6
(3 CH3), 61.4 and 61.7 (2 OCH2), 121.5, 121.6, 124.0, 124.5,
126.0, 126.3, 128.9, 130.2, 132.0, 132.8, 137.3, 139.0
(arom.), 160.4 and 166.3 (2 C=O, ester). MS: m/z (%) = 455
(77) [M+].
(21) Dimethyl 5-(4-Bromophenyl)-1-(4-chlorophenyl)-
pyrrole-2,3-dicarboxylate (6h)
Yellow oil. IR (KBr): nmax = 1718 (C=O) cm–1. Anal. Calcd
(%) for C20H15BrClNO4 (448.69): C, 53.54; H, 3.37; N, 3.12.
Found: C, 53.20; H, 3.19; N, 3.35. 1H NMR (500 MHz,
CDCl3): d = 3.72 and 3.84 (6 H, 2 s, 2 OCH3), 6.94 (1 H, s,
CH of pyrrole), 7.29 (4 H, m, 4 CH arom.), 7.42 (2 H, d,
J = 9 Hz, 2 CH arom.), 7.50 (2 H, d, J = 9 Hz, 2 CH arom.).
13C NMR (125.8 MHz, CDCl3): d = 52.5 and 52.9 (2 OCH3),
121.8, 122.3, 123.9, 124.5, 126.1, 127.9, 129.6, 129.8,
132.3, 132.6, 135.0, 138.2 (arom.), 160.6 and 166.7 (2 C=O,
ester). MS: m/z (%) = 447 (37) [M+].
Synlett 2009, No. 7, 1115–1117 © Thieme Stuttgart · New York

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