Annellation of triazole and tetrazole systems onto pyrrolo[2,3-d] pyrimidines: Synthesis of tetrazolo[1,5-c]-pyrrolo[3,2-e]-pyrimidines and triazolo[1,5-c]pyrrolo-[3,2-e]pyrimidines as potential antibacterial agents

Article abstract of DOI:10.3390/70700554

Syntheses of several novel 4-chloropyrrolo[2,3-d]pyrimidines (1), 4-hydrazinopyrrolo[2,3-d]pyrimidines (2) and 3-amino-4-iminopyrrolo[2,3-d] pyrimidines (7) and their use in the synthesis of tetrazolo[1,5-c]pyrrolo[3,2-e] pyrimidines (3) and triazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (4) required for biological screening are reported.

Full text of DOI:10.3390/70700554

Molecules 2002, 7, 554-565
molecules
ISSN 1420-3049
http://www.mdpi.org
Annellation of Triazole and Tetrazole Systems onto
Pyrrolo[2,3-d]pyrimidines: Synthesis of Tetrazolo[1,5-c]-
pyrrolo[3,2-e]-pyrimidines and Triazolo[1,5-c]pyrrolo-
[3,2-e]pyrimidines as Potential Antibacterial Agents
Chaitanya G. Dave* and Rina D. Shah
Organic Syntheses Laboratory, M.G. Science Institute, Navrangpura, Ahmedabad 380 009, India.
*Author to whom correspondence should be addressed; e-mail: drdave@icenet.net
Received: 5 May 2002; in revised form: 12 July 2002 / Accepted: 28 July 2002 / Published: 31 July
2002
Abstract: Syntheses of several novel 4-chloropyrrolo[2,3-d]pyrimidines (1), 4-
hydrazinopyrrolo[2,3-d]pyrimidines (2) and 3-amino-4-iminopyrrolo[2,3-d]pyrimidines
(7) and their use in the synthesis of tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (3) and
triazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (4) required for biological screening are
reported.
Keywords: Tetrazolopyrrolopyrimidines, triazolopyrrolopyrimidines, pyrrolo[2,3-d]-
pyrimidines, antibacterial activity
Introduction
It is well known that organofluorine compounds display a variety of interesting pharmacological
and agrochemical properties [1-7]. Moreover, pyrimidines having halogen groups at positions 2 or 4
appear to be more labile, displaying powerful reactivity in nucleophilic substitution reactions with
reagents such as piperidine, piperazine, morpholines, hydrazines, azides, etc. These replacements also
permit the combination of two active moieties [8-9] forming potent bi- and triheterocycles [8-12].
Further, the resulting compounds were found to undergo reactions with carbon or nitrogen donor

Molecules 2002, 7
555
moieties giving triazole or tetrazole ring formation [10-11] onto the pyrimidine rings. In addition,
many fused triazolopyrimidines, tetrazolopyrimidines and fluoropyrimidines are well known for their
antibacterial and antifungal activities [1,13,14]. Studies of nucleophilic substitution reactions of
pyrrolopyrimidines are scarce [15-17]. Herein, we wish to report the synthesis of 7,9-disubstituted 7H-
tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (3) and 7,9-disubstituted 7H-triazolo[1,5-c]pyrrolo-
[3,2-e]pyrimidines (4) from 5,7-disubstituted 4-chloro-7H-pyrrolo[2,3-d]pyrimidines (1) [17-19].
Results and Discussion
Reaction between 1 and sodium azide in presence of ammonium chloride and DMSO as a solvent
afforded the target tetrazolopyrrolopyrimidines 3. Ammonium chloride was used for in situ generation
of ammonium azide and the reaction was found to be incomplete in the absence of ammonium
chloride. The same 7,9-disubstituted 7H-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (3) can also be
synthesized by the diazotization of 5,7-disubstituted 4-hydrazino-7H-pyrrolo[2,3-d]pyrimidines (2)
[17-19], obtained from 1 on treatment with hydrazine hydrate in hot alcohol. Thus obtained
compounds 2 were reacted with sodium nitrite in acetic acid under cooling (0-5 °C) to give the same
tetrazolopyrrolopyrimidines 3. The complete reaction sequences leading to compounds 3 is depicted in
Scheme 1.
Scheme 1
Cl
N
NHNH
2
R
R
2.H2O
N
N
N
NH2NH
N
R
N
R
1
1
1
2
AcOH
+
NaN3
+
NaNO2
0
0-5
NH4Cl
N
N
N
N
R
N
N
R
1
3
R
R1
R
R1
1,2,3
1,2,3
a
b
c
d
e
f
C6H5
C6H5
C6H5
C6H5
C6H5
g
h
i
4-OCH3C6H4
4-OCH3C6H4
4-ClC6H4
4-FC6H4
4-ClC6H4
4-FC6H4
3-Cl-4-FC6H3
C6H5
3-Cl-4-FC6H3
C6H5
j
4-ClC6H4
4-ClC6H4
4-FC6H4
4-OCH3C6H4
4-OCH3C6H4
k
l
4-ClC6H4
4-OCH3C6H4
4-ClC6H4
3-Cl-4-FC6H3

Molecules 2002, 7
556
The synthesis of novel 7,9-disubstituted 7H-triazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (4) has also
been carried out from 2 upon reaction with hot formic acid. The same triazolopyrrolopyrimidines 4
have been prepared by another method, starting from 2-amino-3-cyanopyrroles (5) [17-21], whereby
compounds 5 were treated with triethyl orthoformate giving 1,4-disubstituted N-ethoxymethylene 2-
amino-3-cyanopyrroles (6), which on condensation with hydrazine hydrate afforded 5,7-disubstituted
3-amino-4-imino-7H-pyrrolo[2,3-d]pyrimidines (7). Cyclocondensation of 7 with hot formic acid or
triethyl orthoformate resulted in the formation of the same 7,9-disubstituted 7H-triazolo[1,5-
c]pyrrolo[3,2-e]pyrimidines 4 (Scheme 2).
Scheme 2
R
CN
R
CN
HC(OC2H5)3
N
R1
5
N
NH2
N CHOC2H5
R1
6
NH2NH2.EtOH
NH
N NH2
N
R
R
N
N
OR
HC(OC2H5)3
HCOOH
N
N
N
N
R1
R1
7
HCOOH
4
2
R
R1
2,4,5,6,7
a
b
c
d
e
C6H5
4-ClC6H4
C6H5
4-OCH3C6H4
4-OCH3C6H4
4-ClC6H4
4-OCH3C6H4
C6H5
4-ClC6H4
4-ClC6H4
The identity of compounds 3 and 4 obtained by both methods was proven on the basis of melting
points (mp), thin layer chromatography (TLC) and spectral data. The IR spectra of compounds 3 and 4
exhibited C=C and C=N stretching vibrations near 1624-1488 cm-1. The absence of absorptions near
2100 cm-1 excluded the possibility of azide formation [22] in case of compounds 3. The formation of 3
from 2, and 4 from 2 as well as of 4 from 7 was also supported by absence in their IR spectra of bands
at 3400-3150 and at 1648-1640 cm-1 for the respective stretching and bending vibrations of NH in
imino, amino as well hydrazino functionalities, which were found to be present in case of compounds 2

Molecules 2002, 7
557
[17, 18] and 7. In the IR spectra of compounds 6 the cyano and ester carbonyl groups exhibited bands
in the 2210-2200 and 1720-1710 cm-1 regions, respectively. The 1H-NMR spectra of the compounds 3
and 4 displayed resonances due to aromatic protons near δ 8.3-6.95, and, in case of 4, the C2 proton
1
resonated at δ 9.15−9.1. In the H-NMR spectra of the compounds 6 and 7 the aromatic protons
appeared as a multiplet near δ 6.9-7.95. Amino protons appeared as a broad peak in the δ 5.46-5.43
region, integrating for 2H, while the imino proton appeared at δ 8.1-8.0 in the spectra of compounds 6.
Both imino and amino protons were found to be D2O exchangeable. The CH proton of the NCH=OEt
group in 6 also appeared downfield at δ 8.5-8.45, whereas a triplet (3H) at δ 1.42-1.2 and quartet (2H)
at δ 4.3-4.2 were assigned to the methyl and methylene protons of the ethyl group in the same
functionality. The mass spectra of tetrazolopyrrolopyrimidine 3e was found to show a regular
fragmentation pattern [22] giving a molecular ion peak at m/e 342 along with the fragments at 314, 287
and 286, resulting from successive elimination of nitrogen and hydrogen cyanide or subsequent
elimination of two nitrogen molecules (Scheme 3).
Scheme 3
+
+
.
.
H3CO
H3CO
N
N
N
N
N3
N
N
N
N
N
m/z=342
m/z=342
3e
-N (28)
2
H3CO
H3CO
+
.
N
N
+
.
N
N
-HCN(27)
N
N
N
-N (28)
2
m/z=314
m/z=287
H3CO
+
.
N
N
m/z=286

Molecules 2002, 7
558
The mass fragmentation pattern of triazolopyrrolopyrimidine 4b was also in agreement with that
reported for fused triazolopyrimidines [23-24], showing a M+ peak at 341 together with signals at m/e
313, 314 and 286 resulting from subsequent removal of nitrogen and hydrogen cyanide or hydrogen
cyanide and nitrogen molecules (Scheme 4).
Scheme 4
+
.
+
.
H3CO
H3CO
N
N
N
N
N
N
-HCN(27)
N
N
N
m/z=314
m/z=341
4b
-N (28)
2
-N (28)
2
H3CO
+
.
H3CO
+
.
N
N
-HCN(27)
N
N
N
m/z=313
m/z=286
Antibacterial activity
The antibacterial activity of all the newly synthesized compounds 3 and 4 was investigated. Assays
against different bacterial cultures comprising E. coli, E. entericus, P. aeruginosa, S. aureous and B.
subtilis were carried out by the agar plate diffusion method [25-26]. The bacterial cultures were
streaked across grooves filled with 0.6 mL of a 1 % solution in DMSO of each compound 3 and 4,
which were then allowed to diffuse in the agar nutrient plate. The antibiotic ampicillin and the DMSO
solvent were used as positive and negative controls, respectively. The results are recorded in Table 1 as
the relative extent of inhibition observed around the grooves compared to the negative control. Against
E. coli all the compounds tested displayed comparable activities except for 3e and 3j. Compounds 4
were found to be moderately active. Compounds 3c and 3j exhibited better activity than ampicillin
against E. entericus while the remaining compounds were found to be either less active or inactive.
Activity against P. aeruginosa was similar for all active compounds, while 3g, 3k and 4d failed to give

Molecules 2002, 7
559
any inhibition. Against S. typhi better to good activity was shown by most of the derivatives 3 and 4,
except 3l and 4a, which were inactive. 3h and 3k gave better inhibition than the positive control
against S. aureous species while 4c and 4d showed remarkable activity against B. subtilis.
Table 1: Antibacterial activity data of compounds 3 and 4. Inhibition in mm after 48 hr
Compd.
E. coli E. entericus P. aeruginosa S. typhi S. aureous B. subtilis
15.0
15.5
15.0
15.0
10.0
15.5
15.0
15.0
15.0
5.0
5.0
5.0
15.0
3.0
-
5.0
10.0
15.0
10.0
10.0
5.0
-
10.0
5.0
-
-
-
3.0
5.0
-
3a
3b
15.0
5.0
-
3c
5.0
10.0
-
3d
15.0
10.0
15.0
10.0
5.0
-
3e
-
-
3f
-
-
-
3g
10.0
-
5.0
15.0
10.0
-
15.0
-
-
3h
-
3i
5.0
15.0
5.0
5.0
5.0
3.0
-
10.0
-
15.0
-
-
3j
15.0
15.0
5.0
3.0
-
3k
10.0
5.0
15.0
15.5
-
15.0
-
3.0
5.0
-
3l
4a
5.0
5.0
3.5
10.0
10.0
0.5
-
-
10.0
5.5
4b
5.0
-
4c
5.0
5.0
5.0
5.0
15.5
-
4d
10.0
15.0
-
-
10.0
12.0
-
10.5
11.0
-
4e
Ampicillin
DMSO
11.0
-
Conclusions
A series of novel tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (3) and triazolo[1,5-c]pyrrolo[3,2-e]-
pyrimidines (4) have been synthesized by two different routes and their antimicrobial activity
investigated. Compound 3c exhibited better activity than ampicillin against all the tested cultures
except S. aureous.
Acknowledgements
Thanks are due to RSIC, Chandigarh for the NMR data, CDRI, Lucknow for mass spectral analysis
and Dishman Pharmaceuticals and Chemicals Ltd, Ahmedabad, for the IR spectral data.

Molecules 2002, 7
560
Experimental Section
General
Melting points were determined on an Electrothermal apparatus in an open capillary tube and are
uncorrected. The IR spectra were recorded in cm-1 for KBr pellets on a Buck Scientific
1
spectrophotometer. H-NMR spectra were recorded on a Varian 300MHz spectrometer using
DMSO-d6 or CDCl3 as the solvent and TMS as the internal reference standard. Chemical shifts are
expressed in δ ppm. Mass spectra were taken on a LKB 9000 mass spectrometer. The purity of the
compounds was routinely checked by TLC using Silica G and the spots were exposed in iodine vapour
for visualization.
Synthesis of 7,9-disubstituted 7H-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 3a-l: General Procedure.
Method A: A mixture of sodium azide (0.011 mole, 0.072 g) and ammonium chloride (0.011 mole,
0.059 g) in DMSO (20 mL) was stirred for five min. at 90°C and the 5,7-disubstituted 4-chloro-7H-
pyrrolo[2,3-d]pyrimidine (1, 0.01 mole) was added in portions with stirring. After the addition the
reaction mixture was further stirred for 2.0-2.5 hr at the same temperature and for 1 hr at room
temperature. Then it was decomposed on ice. The solid obtained was filtered, washed with water, dried
and crystallized from toluene or a mixture of ethanol-chloroform (8:2) to give the title compounds 3.
Method B: An aqueous solution of sodium nitrite (20% w/v, 4.2 mL) was slowly added in portions to
a stirred mixture of 5,7-disubstituted 4-hydrazino-7H-pyrrolo[2,3-d]pyrimidine (2, 0.01 mole) in acetic
acid (40 mL) at 0-5°C. The reaction mixture was then further stirred for 2 hr at the same temperature,
then it was diluted with cold water and the solid obtained was filtered, washed with water, sodium
bicarbonate (20 % w/v), followed by water, dried and crystallized to furnish compounds 3.
7,9-Diphenyltetrazolo[1,5-c]pyrrolo-7H-[3,2-e]pyrimidine (3a): Yield: 61 % (Method A), 60 %
(Method B); mp: 215-17°C; IR: 1608, 1504 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.0-7.1 (m, 12H,
ArH); MS: 312 m/z (M+); Anal. Calcd. for C19H12N6: C 73.06, H 3.87, N 26.11 %, found: C 73.26, H
3.71, N 26.60 %.
7-(4-Fluorophenyl)-9-phenyltetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3b): Yield: 70 % (Method
A), 56 % (Method B); mp: 217-19°C; IR: 1604, 1516 (C=C, C=N ring); 1H NMR (DMSO-d6): 8.0-7.2
(m, 11H, ArH); MS: 330 m/z (M+); Anal. Calcd. for C18H11FN6: C 65.45, H 3.36, N 25.45 %, found: C
65.66, H 3.27, N 25.09 %.
7-(4-Chlorophenyl)-9-phenyl-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3c): Yield: 70 %
1
(Method A), 64 % (Method B); mp: 218-20°C; IR: 1612, 1492 (C=C, C=N ring); H-NMR

Molecules 2002, 7
561
(DMSO-d6): 8.0-7.3 (m, 11H, ArH); MS: 347 m/z (M+); Anal. Calcd. for C18H11ClN6: C 62.34, H 3.20,
N 24.24 %, found: C 62.46, H 3.27, N 24.56 %.
7-(3-Chloro-4-fluorophenyl)-9-phenyl-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3d): Yield:
1
64 % (Method A), 63 % (Method B); mp: 212-14°C; IR: 1604, 1492 (C=C, C=N ring); H-NMR
(DMSO-d6): 8.1-7.2 (m, 10H, ArH); MS: 365 m/z (M+); Anal. Calcd. for C18H10ClFN6: C 59.27, H
2.76, N 23.04 %, found: C 59.54, H 2.50, N 22.86 %.
7-Phenyl-9-(4-methoxyphenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3e): Yield: 70
%
1
(Method A), 56 % (Method B); mp: 216-18°C; IR: 1604, 1516 (C=C, C=N ring); H-NMR
(DMSO-d6): 3.9 (s, 3H, OCH3), 8.0-7.2 (m, 11H, ArH); MS: 342 m/z (M+); Anal. Calcd. for
C19H14N6O: C 66.65, H 4.12, N 24.55 %, found: C 66.46, H 4.27, N 24.78 %.
7,9-Di(4-methoxyphenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3f): Yield: 77 % (Method A),
75 % (Method B); mp: 237-39°C; IR: 1596, 1500 (C=C, C=N ring); 1H-NMR (DMSO-d6): 3.95 (s, 6H,
OCH3), 8.1-7.3 (m, 10H, ArH); MS: 372 m/z (M+); Anal. Calcd. for C20H16FN6O2: C 64.50, H 4.33, N
22.57 %, found: C 64.39, H 4.28, N 22.33 %.
7-(4-Fluoropheny)l-9-(4-methoxyphenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3g): Yield: 63
1
% (Method A), 61 % (Method B); mp: 245-47°C; IR: 1600, 1504 (C=C, C=N ring); H-NMR
(DMSO-d6): 4.0 (s, 3H, OCH3), 8.1-7.3 (m, 10H, ArH); MS: 360 m/z (M+); Anal. Calcd. for
C19H13FN6O: C 63.33, H 3.64, N 23.33 %, found: C 63.09, H 3.45, N 23.44 %.
7-(3-Chloro-4-fluorophenyl)-9-(4-methoxyphenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3h):
Yield: 56 % (Method A), 58 % (Method B); mp: 219-21°C; IR: 1608, 1504 (C=C, C=N ring);
1H-NMR (DMSO-d6): 3.95 (s, 3H, OCH3), 8.3-7.3 (m, 9H, ArH); MS: 395 m/z (M+); Anal. Calcd. for
C19H12ClFN6O: C 57.80, H 3.07, N 21.29 %, found: C 57.45, H 3.25, N 21.60 %.
7-(4-Phenyl)-9-(4-chlorophenyl)-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3i): Yield: 80 %
1
(Method A), 71 % (Method B); mp: 233-35°C; IR: 1608, 1508 (C=C, C=N ring); H-NMR (DMSO-
d6): 8.0-7.2 (m, 11H, ArH); MS: 347 m/z (M+); Anal. Calcd. for C18H10ClN6: C 62.45, H 3.36, N 24.24
%, found: C 62.46, H 3.27, N 24.56 %.
7-(4-Fluorophenyl)-9-(4-chlorophenyl)-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3j): Yield:
1
67 % (Method A), 66 % (Method B); mp: 226-28°C; IR: 1612, 1496 (C=C, C=N ring); H-NMR
(DMSO-d6): 8.2-7.1 (m, 10H, ArH); MS: 365 m/z (M+); Anal. Calcd. for C18H12ClFN6: C 59.27, H
2.76, N 23.04 %, found: C 59.06, H 2.49, N 23.46 %.

Molecules 2002, 7
562
7,9-Di(4-chlorophenyl)-7H-tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (3k): Yield: 77 % (Method
A), 70 % (Method B); mp: 224-25°C; IR: 1608, 1500 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.2-7.1
(m, 11H, ArH); MS: 381 m/z (M+); Anal. Calcd. for C18H10Cl2N6: C 56.70, 2.64, N 22.05 %, found: C
56.49, H 2.39, N 21.88 %.
7-(3-Chloro-4-fluoropheny)l-9-(4-chlorophenyl)tetrazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine
(3l):
Yield: 65 % (Method A), 63 % (Method B); mp: 220-22°C; IR: 1604, 1508 (C=C, C=N ring);
1H-NMR (DMSO-d6): 8.3-7.2 (m, 9H, ArH); MS: m/z 399 (M+); Anal. Calcd. for C18H9Cl2FN6: C
54.15, H 2.27, N 21.05 %, found: C 54.01, H 2.11, N 20.88 %.
Synthesis of 1,4-disubstituted N-ethoxymethylene-2-amino-3-cyanopyrroles 6a-e: General Procedure.
A mixture of 1,4-disubstituted 2-amino-3-cyanopyrrole (5, 0.01 mole) in triethylorthoformate (10
mL) was refluxed for 3-4 hr, then the excess reagent was distilled in vacuo. The solid thus obtained
was treated with ice water, filtered, washed with water, dried and crystallized from ethanol.
1-(4-Chlorophenyl)-N-ethoxymethylene-2-amino-3-cyano-4-phenylpyrrole (6a): Yield: 70 %; mp:
130-31°C; IR: 2210 (CN), 1720 (C=O), 1616, 1504 (C=C, C=N ring); 1H-NMR (CDCl3): 1.4-1.2 (J =
6Hz, t, 3H, OCH2CH3), 4.3-4.2 (J = 6Hz, q, 2H, OCH2CH3), 7.8-7.2 (m, 10H, ArH), 8.5 (s, 1H,
N=CHOEt); Anal. Calcd. for C20H16ClN3O: C 68.67, H 4.61, N 12.01 %, found: C 68.77, H 4.62, N
12.23 %.
1-Phenyl-N-ethoxymethylene-2-amino-3-cyano-4-(4-methoxyphenyl)pyrrole (6b): Yield: 72 %; mp:
159-60°C; IR: 2220 (CN), 1716 (C=O), 1632, 1520 (C=C, C=N ring); 1H-NMR (CDCl3): 1.4-1.25 (J =
5.9Hz, t, 3H, OCH2CH3), 3.9 (s, 3H, OCH3), 4.3-4.2 (J = 5.9Hz, q, 2H, OCH2CH3), 7.8-7.1 (m, 10H,
ArH), 8.45 (s, 1H, N=CHOEt); Anal. Calcd. for C21H19N3O2: C 72.88, H 5.55, N 12.17 %, found: C
73.02, H 5.32, N 12.02 %.
1,4-Di(4-methoxyphenyl)-N-ethoxymethylene-2-amino-3-cyanopyrrole (6c): Yield: 73 %; mp:
117-18°C; IR: 2210 (CN), 1712 (C=O), 1616, 1504 (C=C, C=N ring); 1H-NMR (CDCl3): 1.41-1.2 (J =
6Hz, t, 3H, OCH2CH3), 3.95 (s, 6H, OCH3), 4.32-4.2 (J = 6Hz, q, 2H, OCH2CH3), 7.9-7.2 (m, 9H,
ArH), 8.5 (s, 1H, N=CHOEt); Anal. Calcd. for C22H21N3O3: C 70.38, H 5.64, N 11.19 %, found: C
70.28, H 5.44, N 11.01 %.
1-Phenyl-N-ethoxymethylene-2-amino-3-cyano-4-(4-chlorophenyl)pyrrole (6d): Yield: 70 %; mp: 167-
1
68°C; IR: 2210 (CN), 1710 (C=O), 1616, 1504 (C=C, C=N ring); H-NMR (CDCl3): 1.42-1.2 (J =
6.5Hz, t, 3H, OCH2CH3), 4.32-4.2 (J = 6.5Hz, q, 2H, OCH2CH3), 7.9-7.2 (m, 10H, ArH), 8.5 (s, 1H,
N=CHOEt); Anal. Calcd. for C20H16ClN3O: C 68.67, H 4.61, N 12.01 %, found: C 68.77, H 4.62, N
12.23 %.

Molecules 2002, 7
563
1,4-Di(4-chlorophenyl)-N-ethoxymethylene-2-amino-3-cyanopyrrole (6e): Yield: 81 %; mp: 200-01°C;
1
IR: 2200 (CN), 1720 (C=O), 1600, 1508 (C=C, C=N ring); H-NMR (CDCl3): 1.41-1.22 (J = 6Hz, t,
3H, OCH2CH3), 4.3-4.21 (J = 6Hz, q, 2H, OCH2CH3), 7.9-7.1 (m, 9H, ArH), 8.45 (s, 1H, N=CHOEt);
Anal. Calcd. for C20H15Cl2N3O: C 62.50, H 3.93, N 10.93 %, found: C 62.81, H 3.81, N 11.09 %.
Synthesis of 5,7-Disubstituted 3-amino-4-imino-7H-pyrrolo[2,3-d]pyrimidines 7a-e: General
Procedure.
1,4-Disubstituted N-ethoxymethylene-2-amino-3-cyanopyrroles (6, 0.01 mole) were treated with
refluxing hydrazine hydrate (99 %, 10 mL) for 3-4 hr. The reaction mixture was allowed to cool,
poured onto crushed ice and neutralized with 50 % acetic acid. The solid obtained was filtered, washed
with water, dried and recrystallized from benzene or dioxane.
3-Amino-4-imino-5-phenyl-7-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (7a): Yield: 89 %; mp:
1
201-02°C; IR: 3380, 3270, 3170, 1640 (NH), 1600, 1504 (C=C, C=N ring); H-NMR (DMSO-d6):
5.45 (s, 2H, NH2), 7.9-7.2 (m, 11H, ArH), 8.0 (s, 1H, NH); Anal. Calcd. for C18H14ClN5: C 64.38, H
4.20, N 20.86 %, found: C 64.49, H 4.33, N 20.99 %.
3-Amino-4-imino-5-(4-methoxyphenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (7b): Yield: 88 %; mp:
193-95°C; IR: 3400, 3320, 3280, 1648 (NH), 1624, 1508 (C=C, C=N ring); 1H-NMR (CDCl3): 3.9 (s,
3H, OCH3), 5.43 (s, 2H, NH2), 7.85-7.2 (m, 11H, ArH), 8.05 (s, 1H, NH); Anal. Calcd. for C19H17N5O:
C 68.886, H 5.17, N 21.123 %, found: C 68.53, H 5.27, N 21.01 %.
3-Amino-4-imino-5,7-di(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (7c): Yield: 84 %: mp: 154-
55°C; IR: 3330, 3380, 3150, 1644 (NH), 1620, 1488 (C=C, C=N ring); 1H-NMR (CDCl3): 3.95 (s, 6H,
OCH3), 5.44 (s, 2H, NH2), 7.8-7.1 (m, 10H, ArH), 8.1 (s, 1H, NH); Anal. Calcd. for C20H19N5O2: C
66.47, H 5.29, N 19.39 %, found: C 66.27, H 5.14, N 19.11 %.
3-Amino-4-imino-5-(4-chlorophenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (7d): Yield: 86 %; mp:
204-06°C; IR: 3380, 3270, 3170, 1644 (NH), 1620, 1504 (C=C, C=N ring); 1H-NMR (DMSO-d6): 5.44
(s, 2H, NH2), 7.9-7.1 (m, 11H, ArH), 8.05 (s, 1H, NH); Anal. Calcd. for C18H14ClN5: C 64.38, H 4.20,
N 20.86 %, found: C 64.21, H 4.01, N 20.49 %.
3-Amino-4-imino-5,7-di(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (7e): Yield: 70 %; mp: 224-
25°C; IR: 3340, 3280, 3190, 1648 (NH), 1620, 1516 (C=C, C=N ring); 1H-NMR (DMSO-d6): 5.46 (s,
2H, NH2), 7.95-7.2 (m, 10H, ArH), 8.0 (s, 1H, NH); Anal. Calcd. for C18H13ClN5: C 58.39, H 3.54, N
18.92 %, found: C 58.09, H 3.44, N 18.62 %.

Molecules 2002, 7
564
Synthesis of 7,9-disubstituted 7H-triazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 4a-e: General Procedure.
Method A. A mixture of 5,7-disubstituted 4-hydrazino-7H-pyrrolo[2,3-d]pyrimidine (2, 0.01 mole) in
formic acid (20 mL) was heated under reflux for 7-8 hr. The reaction mixture was poured onto crushed
ice, neutralized with 1N sodium hydroxide solution and the solid obtained was filtered off, washed
with water, dried and recrystallized from toluene or a mixture of DMF-EtOH (6:4) to give the title
compounds.
Method B: A mixture of 5,7-disubstituted 3-amino-4-imino-7H-pyrrolo[2,3-d]pyrimidine (7, 0.01
mole) in formic acid (15 mL) was heated under reflux for 3-4 hr. The cold reaction mixture was poured
onto crushed ice, treated with 1N sodium hydroxide solution and the solid obtained was filtered,
washed with water, dried and recrystallized to give the identical compounds 4.
7-(4-Chorophenyl)-9-phenyl-7H-triazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4a): Yield: 69 %
1
(Method A), 57 % (Method B); mp: 256-58°C, IR: 1616, 1504 (C=C, C=N ring); H-NMR (DMSO-
d6): 8.4-7.3 (m, 11H, ArH), 9.12 (s, 1H, H at C2); MS: 346 (M+); Anal. Calcd. for C19H12ClN5: C
65.99, H 3.50, N 20.26 %, found: C 66.17, H 3.30, N 20.01 %.
7-Phenyl-9-(4-methoxyphenyl)triazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4b): Yield: 55 % (Method
A), 62 % (Method B); mp: 225-26°C; IR: 1616, 1498 (C=C, C=N ring); 1H-NMR (DMSO-d6): 3.82 (s,
3H, OCH3), 8.3-6.95 (m, 11H, ArH), 9.1 (s, 1H, H at C2); MS: 341 m/z (M+); Anal. Calcd. for
C20H15N5O: C 72.42, H 4.56, N 20.51 %, found: C 72.09, H 4.36, N 20.31 %.
7,9-Di(4-methoxyphenyltriazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4c): Yield: 85 % (Method A),
75 % (Method B); mp: 204-05°C; IR: 1608, 1496 (C=C, C=N ring); 1H-NMR (DMSO-d6): 3.8 (s, 6H,
OCH3), 8.2-7.0 (m, 10H, ArH), 9.1 (s, 1H, H at C2); MS: 371 m/z (M+); Anal. Calcd. for C21H17N5O2:
C 67.91, H 4.62, N 18.86 %, found: C 67.71, H 4.50, N 18.66 %.
7-(4-Phenyl)-9-(4-chlorophenyl)-7H-triazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4d): Yield: 70 %
1
(Method A), 72 % (Method B); mp: 240-42°C; IR: 1616, 1500 (C=C, C=N ring); H-NMR
(DMSO-d6): 8.3-7.3 (m, 11H, ArH), 9.12 (s, 1H, H at C2); MS: 346 m/z (M+); Anal. Calcd. for
C19H12ClN5: C 65.99, H 3.50, N 20.26 %, found: C 66.17, H 3.66, N 20.06 %.
7,9-Di(4-chlorophenyl)-7H-triazolo[1,5-c]-7H-pyrrolo[3,2-e]pyrimidine (4e): Yield: 85 % (Method
A), 82 % (Method B); mp: 237-39°C; IR: 1616, 1500 (C=C, C=N ring); 1H-NMR (DMSO-d6): 8.3-7.2
(m, 10H, ArH), 9.15 (s, 1H, H at C2); MS: 380 m/z (M+); Anal. Calcd. for C19H11Cl2N5: C 60.01, H
2.92, N 18.42 %, found: C 60.11, H 3.08, N 18.31 %.

Molecules 2002, 7
565
References
1. Wilkinson, J.A. Chem. Rev. 1992, 92, 505.
2. Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Irikura, T. J. Med. Chem. 1980, 23, 1358.
3. Wise, R.; Andrews, J.M.; Edwards, L.J. Antimicrob. Agents Chemother. 1983, 23, 559.
4. Hayakawa, I.; Hiramitsu, T.; Tanka, Y. Chem. Pharm. Bull. 1984, 32, 4907.
5. Matsumoto, J.; Miyamoto, T.; Minamada, A.; Mishimuna, Y.; Egawa, H.; Nisimira, H. J. Med.
Chem. 1984, 27, 292.
6. Goueffon, Y.; Montay, G.; Roquot, F.; Pesson, M. C.R. Acad. Sci., Ser. III 1981, 292, 37.
7. Hagen, S.E.; Domagala, J.M. Hiefetz, C.L.; Johnson, J. J. Med. Chem. 1991, 34, 1155.
8. Peinador, C.; Ojea, V.; Quintela, J.M. J. Heterocycl. Chem. 1992, 29, 1698.
9. Schneller, S.W.; Clough, F.W. J. Heterocycl. Chem. 1992, 11, 975.
10. Robba, M.; Lecomte, J.M.; Cugnon de M. J. Heterocycl. Chem. 1975, 12, 525.
11. Bourgurgnon, J.; Gougeon, E.; Queguiner, G.; Pastor, B. Bull. Soc. Chem. Fr. 1975, 3-4, 815.
12. Liu, K.C.; Hu, M.K. Ching-hua Yao Hsueh Tsa Chih 1988, 40, 117 [Chem. Abstr. 1989, 111,
57667].
13. Omer, A.; Mohson, M.; Shams, A.; Labouta, I. Alexandria J. Pharm. Sci. 1991, 5, 213.
14. Schram, K.L.; Manning, S.J.; Townsend, L.B. J. Heterocycl. Chem. 1975, 12, 1020.
15. Ali, A.S.; Swealan, S.A. Egypt. J. Pharm. Sci. 1992, 33, 473.
16. Bhat, G.A.; Schram, K.L.; Townsend, L.B. J. Carb-Nucleos-Nucl. 1981, 8, 145.
17. Dave, C.G.; Shah, R.D. J. Heterocycl. Chem. 1998, 35, 1295.
18. Dave, C.G.; Desai, N.D. J. Heterocycl. Chem. 1999, 36, 729.
19. Dave, C.G. Unpublished work.
20. Gewald, K.; Henschel, M. J. Prakt. Chem. 1976, 318, 663.
21. Dave, C.G.; Upadhyaya, S.P.; Shah, P.R. J. Indian Chem. Soc. 1987, LXIV, 713.
22. Shishoo, C.J.; Devani, M.B.; Karvekar, M.D.; Ullas, G.V.; Ananthan, S.; Bhadti, V.S.; Patel, R.B.;
Gandhi, T.P. Indian J. Chem. 1982, 21B, 666.
23. Shishoo, C.J.; Devani, M.B.; Ullas, G.V.; Ananthan, S.; Bhadti, V.S. J. Heterocycl. Chem. 1981,
24, 1125.
24. Shishoo, C.J.; Devani, M.B.; Ullas, G.V.; Ananthan, S.; Bhadti, V.S. J. Heterocycl. Chem. 1981,
18, 43.
25. Bentley’s Textbook of Pharmaceutics, 6th Edition; Davis, H.; Bean, H.S.; Carless, J.E.; Fishburn,
A.C.; Hanis, N.D.; Sarynb, C.L., Eds; Bailliáere Tindall and Co.: London, 1961; pp.723.
26. Abbott, W.S. J. Econ. Entomol. 1925, 18, 801.
Sample Availability: Available from the authors
© 2002 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

Molecules 2002, 7
566