Synthesis of 5H-pyrrolo[1,2-c]imidazoles by intramolecular wittig reaction

Article abstract of DOI:10.2174/157017811794557840

The intermediate phosphorus ylides which were prepared by reaction between triphenylphosphine and imidazole-4-carbaldehyde in the presence of acetylenic diesters produce dialkyl 5H-pyrrolo[1,2-c]imidazole-5,6-dicarboxylate derivatives via intramolecular Wittig reaction.

Full text of DOI:10.2174/157017811794557840

12
Letters in Organic Chemistry, 2011, 8, 12-15
Synthesis of 5H-pyrrolo[1,2-c]imidazoles by Intramolecular Wittig
Reaction
Nourallah Hazeri, Ghasem Marandi, Malek T. Maghsoodlou* and Sayyed M.H. Khorassani
Department of Chemistry, The University of Sistan & Baluchestan, P. O. Box 98135-674, Zahedan, Iran
Received June 25, 2010: Revised November 05, 2010: Accepted December 15, 2010
Abstract: The intermediate phosphorus ylides which were prepared by reaction between triphenylphosphine and
imidazole-4-carbaldehyde in the presence of acetylenic diesters produce dialkyl 5H-pyrrolo[1,2-c]imidazole-5,6-
dicarboxylate derivatives via intramolecular Wittig reaction.
Keywords: Dialkyl 5H-pyrrolo[1,2-c]imidazole-5,6-dicarboxylates, imidazole-4-carbaldehyde, Acetylenic esters,
Triphenylphosphine.
INTRODUCTION
carbonyl region (1735 and 1685 cm-1) in agreement with
proposed structure. The H NMR spectrum of 3a exhibited
1
Imidazole-containing compounds have been widely
reported in the mainstream as well as in the patent literature
because of their potential such as anti-inflammatory,
analgesic, antimicrobial and anti-fungicidal properties [1-4].
The interest in bicyclic 5:5 systems with one ring junction
nitrogen atom between the five-membered rings and no extra
heteroatoms, stems from the appearance of saturated and
partially saturated pyrrolo[1,2-c]imidazole ring systems in
many biologically active compounds [5-8]. For example,
six singlets for the methoxy (ꢀ = 3.84 and 3.99 ppm) and
methine (ꢀ = 6.34, 6.67, 7.70 and 7.82 ppm) protons. The
1
absence of methylene signal in the H NMR spectrum of 3a
rules out structure 6 (see Fig. 1). The 13C-NMR spectrum of
3a showed ten signals in agreement with the proposed
structure. In this spectrum, the carbonyl groups were
discernible at ꢀ = 162.54 and 165.66 ppm. Partial assign-
ments of these resonances are given in the experimental
1
section. The H- and 13C-NMR spectra of 3b and 3c are
pyrrolo[1,2-c]imidazole-1,3-diones,
imidazo[1,5-a]indole
similar to those of 3a, except for the ester moieties, which
exhibit characteristic signals at appropriate chemical shifts.
and pyrrolo[1,2-c]imidazol-5-one have anti-diabetic, aldose
reductase inhibitory and immunosuppressive activity [9-11].
The Wittig reaction is a well known method for achieving
alkenylation in these systems. Recently we have described
the synthesis of many stable phosphorus ylides [12]. Now we
report the preparation of pyrrolo[1,2-c]imidazole derivatives
3, in the reaction of imidazole-4-carbaldehyde 1 and dialkyl
acetylenedicarboxylates 2 in the presence of triphenyl-
phosphine.
CO2R
OHC
CO2R
C
N
CO2R
dry diethyl ether
r.t.
+
+
Ph3P
C
N
N
H
CO2R
3
1
N
2
3
% yield
R
a
b
c
Me
Et
t-butyl
95
93
98
RESULTS AND DISCUSSION
Scheme 1.
The reaction between triphenylphosphine and imidazole-
4-carbaldehyde 1 in the presence of the dialkyl acetylenedi-
carboxylates 2 was carried out in dry diethyl ether and was
completed at room temperature in a few hours to produce
dialkyl 5H-pyrrolo[1,2-c]imidazole-5,6-dicarboxylate 3a-c in
high yields (see Scheme 1).
On the basis of the well established chemistry of trivalent
phosphorus nucleophiles [6, 7, 13-18], it is reasonable to
assume that zwitterionic specie 4 results from the initial
addition of triphenylphosphine to the acetylenic ester and
subsequent protonation of the 1:1 adduct by the NH
compound 1. Then the positively charged ion is attacked by
the nitrogen atom of the conjugated base of the imidazolyl
anion to form intermediate phosphoranes 5 (see Scheme 2).
A speculative mechanistic explanation for this reaction is
provided in Scheme 2.
Structures of compounds 3a-c were characterized by their
IR, 1H- and 13C-NMR and mass spectrometry data. The
elemental analysis data are satisfactory favorable with
calculated values.
The mass spectra of these compounds displayed
molecular ion peak at appropriate m/z values. The IR
spectrum of compound 3a showed strong absorption peak at
The presence of three olefinic protons signals and
methine proton signal in the 1H NMR spectrum confirms the
proposed structure 3.
Absence of the methylen signal in the 13C DEPT analysis
confirms the structure 3 (Fig. 1).
*Address correspondence to this author at the Department of Chemistry,
The University of Sistan & Baluchestan, P. O. Box 98135-674, Zahedan,
Iran; Tel/Fax: +98-541-2416586; E-mail: mt_maghsoodlou@yahoo.com
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Synthesis of 5H-pyrrolo[1,2-c]imidazoles by Intramolecular
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
13
OHC
OHC
OHC
N
CO2R
N
N
H
Ph3P
RO2C
Ph3P
H
1
C
N
+
Ph3P
C
CO2R
RO2C
CO2R
CO2R
N
4
2
N
N
H
O
N
N
O
Ph3P+
RO2C
N
- Ph3PO
N
N
Ph3P
RO2C
CO2R
3
CO2R
RO2C
CO2R
5
Scheme 2.
EXPERIMENTAL
N
Melting points were taken on an Electrothermal 9100
apparatus and IR spectra of all compounds were recorded in
a JASCO FT-IR spectrometer respectively. The 1H- and 13C-
NMR spectra were measured with a Bruker DRX-300
AVANCE instrument with CDCl3 as solvent at 300.1 and
75.5 MHz, respectively. The C, H and N elemental analyses
were determined using a Heraeus CHN-O-Rapid analyzer. In
addition, the mass spectra were recorded on a Shimadzu
GCMS-QP5050A mass spectrometer operating at an
ionization potential of 70 eV. All chemicals were purchased
from (Fluka and Acros), and used without further
purifications.
N
RO2C
CO2R
6
Fig. (1). Compound 6 was ruled out as a possible structure.
It is noticeable that when imidazol-2-carbaldehyde 7 was
replaced instead of imidazol-4-carbaldehyde 1 at the same
reaction (Scheme 3) no reaction was observed.
In additional work, reaction carried out with other
acetylenic esters such as methyl and ethyl propiolate 10
instead of acetylenic diesters 2, but unfortunately other
analogous of compound 3 were not obtained (see Scheme 4).
General Procedure (Preparation of Compound 3a)
In summary, intramolecular Wittig reaction was
employed for the preparation of dialkyl 5H-pyrrolo[1,2-
c]imidazole-5,6-dicarboxylates under neutral condition at
room temperature.
To a magnetically stirred solution of imidazole-4-
carbaldehyde (0.096 g, 1 mmol) and triphenylphosphine
(0.26 g, 1 mmol) in dry diethyl ether was added, dropwise, a
mixture of dimethyl acetylenedicarboxylate (0.14 g, 1 mmol)
in diethyl ether (3 mL) at -5 °C over 10 min. After
RO2C
CHO
RO2C
CO2R
C
C
dry diethyl ether
r.t
HN
N
+
RO2C
+
Ph3P
or
N
N
RO2C
N
N
CO2R
7
8
9
2
not formed
not formed
Scheme 3.
OHC
CO2R
CO2R
N
C
C
dry diethyl ether
r.t
R =Me, Et
+
+
Ph3P
N
N
N
11
H
H
1
10
not formed
Scheme 4.

14
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
Hazeri et al.
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dicarboxylate
Light yellow crystal, yield (95%), m.p. 98-101°C. IR
1
(KBr) (ꢀmax,cm-1): 1686 and 1735 (C=O); H NMR (300
MHz, CDCl3): ꢁH 3.84 and 3.99 (2s, 6 H, 2 OCH3), 6.34 (s, 1
H, NCH), 6.67 (s, 1 H, CH), 7.70 (s, 1 H, CH), 7.82 (s, 1 H,
CH); 13C NMR (75.5 MHz, CDCl3): ꢁC 52.29 and 52.33 (2s,
2 OCH3), 129.74 (NCH), 131.70 (Cpyr), 131.74 (CHpyr),
132.38 (CHimi), 133.12 (NCfus), 133.40 (NCN), 165.37 and
165.66 (2 C=O); MS m/z (%): 222 (M+, 1), 201 (25), 199
(27), 183 (28), 154 (7), 107 (8), 77 (40), 59 (14), 43 (100).
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°
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1
(KBr) (ꢀmax,cm-1): 1685 and 1735 (C=O); H NMR (300
related
to
the
metabolites
of
(E)-4-[1-[4-[2-
MHz, CDCl3): ꢁH 1.28 (t, 3H, J = 7.1 Hz, OCH2CH3), 1.30
(t, 3H, J = 7.1 Hz, OCH2CH3), 4.22 (q, 2H, J = 7.1 Hz,
OCH2CH3), 4.24 (q, 2H, J = 7.1 Hz, OCH2CH3), 6.23 (s, 1
H, NCH), 6.33 (s, 1 H, CH), 7.48 (s, 1 H, CH), 7.83 (s, 1 H,
CH). 13C NMR (75.5 MHz, CDCl3): ꢁC 13.83 and 14.08 (2s,
2 OCH2CH3), 61.22 and 62.21 (2s, 2 OCH2CH3), 129.15
(NCH), 131.72 (Cpyr), 132.00 (CHpyr), 132.67 (CHimi), 133.10
(NCfus), 133.61 (NCN), 164.99 and 165.25 (2 C=O); MS m/z
(%): 250 (M+, 2), 203 (3), 199 (100), 183 (17), 153 (6), 107
(5), 77 (19), 57 (3), 43 (2). Anal. Calcd for C12H14N2O4
(250.25): C, 57.60; H, 5.64; N, 11.20. Found: C, 57.71; H,
5.58; N, 11.23.
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Di
tert-butyl
5H-pyrrolo[1,2-c]imidazole-5,6-
dicarboxylate
Pale white crystal, yield (98%), m.p. 122-125 C, IR
°
1
(KBr) (ꢀmax,cm-1): 1687 and 1734 (C=O); H NMR (300
MHz, CDCl3): ꢁH 1.49 and 1.50 (2s, 18 H, 2 OCMe3), 6.05
(s, 1 H, NCH), 6.66 (s, 1 H, CH), 7.44 (s, 1H, CH), 7.67 (s, 1
H, CH); 13C NMR (75.5 MHz, CDCl3): ꢁC 28.00 and 28.15
(2s, 2 OCMe3), 81.64 and 81.76 (2s, 2 OCMe3), 130.11
(NCH), 131.91 (Cpyr), 131.96 (CHpyr), 132.01 (CHimi), 132.94
(NCfus), 134.56 (NCN), 164.40 and 164.46 (2 C=O); MS m/z
(%): 308 (M++2, 4), 306 (M+, 13), 227 (6), 201 (36), 199
(43), 183 (39), 154 (7), 107 (5), 77 (100), 57 (70), 43 (83).
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9.14. Found: C, 62.78; H, 7.30; N, 9.22.
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ACKNOWLEDGEMENT
We gratefully acknowledge financial support from the
Research Council of the University of Sistan & Baluchestan.
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