Synthesis of fused tetrazolo[1,5- c]pyrrolo[3,2-e]pyrimidines and their reductive conversion to new 4-aminopyrrolo[2,3-d]pyrimidines

Article abstract of DOI:10.1080/00397910600638846

Some new 7,9-substituted 7 H -1,2,3,4-tetrazolo[1,5- c ]pyrrolo[3,2- e ]pyrimidines 5 have been synthesized either by diazotization of 4-hydrazino-5,7-disubstituted- 7H -pyrrolo[2,3- d ]pyrimidines 4 obtained by hydrazinolysis of 4-chloro-5,7-disubstitute

Full text of DOI:10.1080/00397910600638846

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Synthesis of Fused Tetrazolo[1,5‐c]
pyrrolo[3,2‐e]pyrimidines and
Their Reductive Conversion to New
4‐Aminopyrrolo[2,3‐d]pyrimidines
Nirmal D. Desai a
a Loyola Center for Research and Development, St. Xavier's College,
Navrangpura, Ahmedabad, India
Published online: 16 Feb 2007.
To cite this article: Nirmal D. Desai (2006): Synthesis of Fused Tetrazolo[1,5‐c] pyrrolo[3,2‐e]pyrimidines
and Their Reductive Conversion to New 4‐Aminopyrrolo[2,3‐d]pyrimidines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:15, 2169-2182
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Synthetic Communicationsw, 36: 2169–2182, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600638846
Synthesis of Fused Tetrazolo[1,5-c]
pyrrolo[3,2-e]pyrimidines and Their
Reductive Conversion to New
4-Aminopyrrolo[2,3-d]pyrimidines
Nirmal D. Desai
Loyola Center for Research and Development, St. Xavier’s College,
Navrangpura, Ahmedabad, India
Abstract: Some new 7,9-substituted 7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimi-
dines 5 have been synthesized either by diazotization of 4-hydrazino-5,7-disubstituted-
7H-pyrrolo[2,3-d]pyrimidines 4 obtained by hydrazinolysis of 4-chloro-5,7-disubstituted
7H-pyrrolo[2,3-d]pyrimidines 3 or via a substitution reaction between 3 and sodium
azide. 5,7-Disubstituted-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-ones 2 were obtained by
cyclocondensation of 1,4-disubstituted 2-amino-3-cyanopyrroles 1 with formic acid,
which, on chlorination using phosphorus oxychloride, afforded 3. 2-Amino-3-cyanopyr-
roles 1 were synthesized from the reaction between (2-bromo-1-(4-fluorophenyl) ethyli-
dene) propanedinitrile and substituted aromatic amines under Gewald reaction
conditions. A novel route for the synthesis of 4-amino-5,7-disubstituted-7H-
pyrrolo[2,3-d]pyrimidines 6 by the reductive ring cleavage of 5 has been reported.
Keywords: Aminopyrrolo[2,3-d]pyrimidine, reductive conversion, tetrazolo-
pyrrolopyrimidine
INTRODUCTION
The investigation of fused tetrazolopyrimidine as a potent antagonist
contributed to a wide range of biological activities such as analgesic,[1]
Received in the USA January 5, 2006
Dedicated to the memory of Dr. Chaitanya G. Dave.
Address correspondence to Nirmal D. Desai, Department of Chemistry, Loyola
Center for Research and Development, St. Xavier’s College, Navrangpura,
Ahmedabad 380009, India. Tel.: 91-79-26308057; E-mail: nirmaldesai_3@yahoo.com
2169

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N. D. Desai
antiinflammatory[1] anticonvulsant,[2] antiulcer,[3] antiallergic,[3] anticancer,[4,5]
antifolate,[6] antihypertensive,[7] antimalarial,[8] and, antitumor[9] activities.
Moreover, the capability of fused tetrazolopyrimidines to undergo reductive
ring cleavage to form fused aminopyrimidines,[6,10] known for their valuable
pharmacological properties and as intermediates in the construction of variety
of triheterocycles, was also studied.[11] Therefore, we thought to undertake
the synthesis of novel 7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines
and to study their transformation to 4-amino-5,7-disubstituted-7H-pyrrolo[2,3-
d]pyrimidines via reductive ring opening of tetrazolopyrrolopyrimidines. The
target triheterocyclic 7,9-disubstituted-7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,
2-e]pyrimidines 5 were constructed by the annelation of the tetrazole ring
onto the existing 4-chloro-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 3
and 4-hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 4.
RESULTS AND DISCUSSION
2-Amino-3-cyanopyrroles 1 were obtained by the reaction of (2-bromo-1-(4-
fluorophenyl)ethylidene)propanedinitrile and substituted aromatic amine
under Gewald reaction conditions.[12]
Compounds 1 were refluxed in boiling formic acid to obtain 5,7-
disubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-(3H)-ones 2. The reaction is
believed to proceed through the formation of the corresponding 2-amino-3-
carboxamidopyrroles followed by cyclization. Compounds 2 were refluxed
in phosphorus oxychloride to obtain 4-chloro-5,7-disubstituted-7H-
pyrrolo[2,3-d]pyrmidines 3 (Scheme 1).
The chloro group present at position-4 in the pyrrolo[2,3-d]pyrimidine
ring was found to be highly reactive toward nucleophilic substitution
reactions with sodium azide and hydrazine hydrate. The desired tetrazolo-
pyrrolopyrimidines 5 have been prepared by two different routes. In the
first route, 4-chloro-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrmidines 3 were
converted to 4-hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 4
by a substitution reaction with hydrazine hydrate (99%) in ethanol, which in
turn was diazotized with sodium nitrite in glacial acetic acid to obtain tetrazo-
lopyrrolopyrimidines 5 (method A). In the second route, 4-chloropyrrolo[2,3-
d]pyrimidines 3 were reacted with sodium azide in the presence of ammonium
chloride in which in situ generation of ammonium azide facilitated the
reaction in dimethyl sulfoxide with stirring at 908C (method B) (Scheme 2).
Because the reductive ring cleavage of the tetrazole moiety constituted a
synthetically important process for the preparation of amines, 4-amino-5,7-
disubstituted-7H-pyrrolo[2,3-d]pyrimidines 6 have been synthesized for the
first time from tetrazolopyrrolopyrimidines 5, employing zinc in acetic acid as
a reducing agent under boiling conditions, and it was found that the
compounds obtained were identical with those synthesized by condensation of
2-amino-3-cyanopyrroles 1 and formamide at reflux temperature[13] (Scheme 3).

Tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines
2171
Scheme 1.
The attempted ring cleavage using agents such as sodiumborohydride[14]
and zinc–nickel chloride hexahydrate[15] were unsuccessful, and in both the
cases the starting compound 5 was recovered.
EXPERIMENTAL
Melting points were determined by the electrothermal method in an open
capillary tube and are uncorrected. The IR spectra were recorded in cm21
1
for KBr pellets on a Buck-500 spectrophotometer. The H NMR spectra
were recorded on Varian 300-MHz spectrophotometer in CDCl3 or

2172
N. D. Desai
Scheme 2.
DMSO-d6 using TMS as internal standard, and the chemical shifts are
expressed in d ppm. MS spectra were recorded on an LKB 9000 mass spectro-
photometer. The purity of the compounds was routinely checked by TLC
using silica gel G, and spots were exposed in iodine vapor.
General Procedure for the Synthesis of 1,4-Disubstituted 2-amino-3-
cyanopyrroles[12,13] 1a–e
Substituted aromatic amine (0.02 mol) dissolved in n-propanol (10 ml) was
added portionwise to the solution of (2-bromo-l-(4-fluorophenyl)ethylidene)-
propanedinitrile (0.02 mol) in n-propanol (50 ml) with constant stirring at
60–658C over a period of 40 min. After the completion of addition, the
reaction mixture was stirred for 1 h at the same temperature and 1 h at room
temperature. The reaction mixture was poured onto crushed ice, and the
solid separated was filtered, dried, and crystallized from petroleum ether.
Data
1-Phenyl-2-amino-3-cyano-4-(4-fluorophenyl)pyrrole (1a): Yield, 58%, mp
142–1448C; IR (KBr): n ¼ 3480, 3360 (NH), 2210 (CN), 1616, 1504 cm21

Tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines
2173
Scheme 3.
(C55C, C55N ring); 1H NMR (CDCl3): d ¼ 5.44 (s, 2H, NH), 6.85 (s, 1H, H at
C5), 7.18–7.68 (m, 9H, Ar-H); anal. calcd. for C17H12FN3 (277.30): C, 73.63;
H, 4.36; N, 15.15%. Found: C, 73.56; H, 4.12; N, 15.31%.
1-(4-Methoxyphenyl)-2-amino-3-cyano-4-(4-fluorophenyl)pyrrole (1b): Yield,
62%, mp 122–1248C; IR (KBr): n ¼ 3460, 3330 (NH), 2210 (CN), 1612,
1
150 cm21 (C55C, C55N ring); H NMR (CDCl3): d ¼ 3.90 (s, 3H, OCH3),
5.46 (s, 2H, NH), 6.87 (s, 1H, H at C5), 7.12–7.68 (m, 8H, Ar-H); anal.
calcd. for C18H14FN3O (307.32): C, 70.35; H, 4.59; N, 13.67%. Found: C,
70.26; H, 4.77; N, 13.49%.
1-(4-Chlorophenyl)-2-amino-3-cyano-4-(4-fluorophenyl)pyrrole (1c): Yield,
68%, mp 252–2548C; IR (KBr): n ¼ 3480, 3340 (NH), 2220 (CN), 1612,
1508 cm21 (C55C, C55N ring); 1H NMR (CDCl3): d ¼ 5.40 (s, 2H,
NH), 6.82 (s, 1H, H at C5), 7.20–7.74 (m, 8H, Ar-Hg; anal. cald. for
C17H11ClFN3 (311.74): C, 65.50; H, 3.56; N, 13.48%. Found: C, 65.38; H,
3.64; N, 13.61%.

2174
N. D. Desai
1,4-Bis(4-fluorophenyl)-2-amino-3-cyanopyrrole (1d): Yield, 52%, mp
112–1148C; IR (KBr): n ¼ 3470, 3380 (NH), 2210 (CN), 1620, 1512 cm21
1
(C55C, C55N ring); H NMR (CDCl3): d ¼ 5.47 (s, 2H, NH), 6.85 (s, 1H,
H at C5), 7.14–7.68 (m, 8H, Ar-H); anal. calcd. for C17H11F2N3 (295.29):
C, 69.15; H, 3.75; N, 14.23%. Found: C, 69.26; H, 3.98; N, 14.02%.
1-(3-Chloro-4-fluorophenyl)-2-amino-3-cyano-4-(4-fluorophenyl)pyrrole (1e):
Yield, 66%, mp 196–1988C; IR (KBr): n ¼ 3460, 3340 (NH), 2210 (CN),
1
1616, 1500cm21 (C55C, C55N ring); H NMR (CDCl3): d ¼ 5.46 (s, 2H,
NH), 6.86 (s, 1H, H at C5), 7.20–7.78 (m, 7H, Ar-H); anal. calcd. for
C17H10ClF2N3 (329.73): C, 61.92; H, 3.06; N, 12.74%. Found: C, 61.86; H,
2.98; N, 12.67%.
General Procedure for the Synthesis of 5,7-Disubstituted-7H-
pyrrolo[2,3-d]pyrimidin-4(3H)-ones 2a–e
A mixture of 1,4-disubstituted-2-amino-3-cyanopyrrole (1, 0.01 mol) and
formic acid (25 ml) was stirred at reflux temperature for 7–8 h. The reaction
mixture was then allowed to cool, poured onto crushed ice (50 g), neutralized
with sodium hydroxide solution (5 N), filtered, dried, and crystallized from a
mixture of N,N-dimethylformamide and ethanol (6 : 4 v/v).
Data
5-(4-Fluorophenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
(2a)
nomenclature. Yield, 60%, mp 238–2408C; IR (KBr): n ¼ 3240 (NH), 1680
(C55O), 1586, 1508 cm21 (C55C, C55N ring); 1H NMR (DMSO-d6):
d ¼ 7.20–8.10 (m, 11H, Ar-H), 11.65 (s, 1H, NH); anal. calcd. for
C18H12FN3O (305.31): C, 70.81; H, 3.96; N, 13.76%. Found: C, 70.66; H,
3.90; N, 13.67%.
5-(4-Fluorophenyl)-7-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-
one (2b). Yield, 60%, mp 286–2888C; IR (KBr): n ¼ 3250 (NH), 1682 (C550),
1
1590, 1504cm21 (C55C, C55N ring); H NMR (DMSO-d6): d ¼ 3.88 (s, 3H,
OCH3), 7.16–8.14 (m, 10H, Ar-H), 11.58 (s, 1H, NH); anal. calcd. for
C19H14FN3O2 (335.33): C, 68.05; H, 4.21; N, 12.53%. Found: C, 68.10; H,
4.44; N, 12.67%.
5-(4-Fluorophenyl)-7-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one
(2c). Yield, 70%, mp 297–2998C; IR (KBr): n ¼ 3260 (NH), 1676 (C55O),
1
1584, 1512 cm21 (C55C, C55N ring); H NMR (DMSO-d6): d ¼ 7.24–8.06
(m, 10H, Ar-H), 11.63 (s, 1H, NH); anal. calcd. for C18H11FN3O (339.75): C,
63.63; H, 3.26; N, 12.37%. Found: C, 63.42; H, 3.12; N, 12.10%.

Tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines
2175
5,7-Bis(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (2d). Yield,
52%, mp 217–2198C; IR (KBr): n ¼ 3290 (NH), 1672 (C55O), 1588,
1496 cm21 (C55C, C55N ring); 1H NMR (DMSO-d6): d ¼ 7.16–8.14
(m, 10H, Ar-H), 11.67 (s, 1H, NH); anal. calcd. for C18H11F2N3O (323.30):
C, 66.87; H, 3.43; N, 13.00%. Found: C, 67.01; H, 3.50; N, 12.88%.
5-(4-Fluorophenyl)-7-(3-chloro-4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-
4(3H)-one (2e). Yield, 65%, mp 275–2778C; IR (KBr): n ¼ 3210 (NH), 1680
(C55O), 1586, 1500 cm21 (C55C, C55N ring); 1H NMR (DMSO-d6):
d ¼ 7.16–8.14 (m, 9H, Ar-H), 11.62 (s, 1H, NH); anal. calcd. for
C18H10ClF2N3O (357.74): C, 60.43; H, 2.82; N, 11.75%. Found: C, 60.12; H,
3.02; N, 11.69%.
General Procedure for the Synthesis of 4-Chloro-5,7-disubstituted-
7H-pyrrolo[2,3-d]pyrimidines 3a–e
A mixture of 5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (2,
0.01 mol) and phosphorus oxychloride (25 ml) was refluxed for 16–17 h.
After the completion of reaction, the excess of phosphorus oxychloride was
removed under vacuum. The cooled reaction mixture was then added to
crushed ice (25 g). The resulting solid was filtered, washed with sodium bicar-
bonate (5% w/v) followed by cold water, dried, and crystallized from ethanol
and chloroform (8 : 2 v\v).
Data
4-Chloro-5-(4-fluorophenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (3a): Yield
78%, mp 138–1408C; IR (KBr): n ¼ 1612, 1504 cm21 (C55C, C55N ring); 1H
NMR (CDCl3): d ¼ 7.16–8.14 (m, 11H, Ar-H); anal. calcd. for C18H11ClFN3
(323.75): C, 66.78; H, 3.42; N, 12.98%. Found: C, 66.52; H, 3.50; N, 12.88%.
4-Chloro-5-(4-fluorophenyl)-7-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimi-
dine (3b): Yield; 81%, mp 166–1678C; IR (KBr): n ¼ 1608, 1512 cm21
1
(C55C, C55N ring), H NMR (CDCl3): d ¼ 3.90 (s, 3H, OCH3); 7.20–8.22
(m, 10H, Ar-H); anal. calcd. for C19H13ClFN3O (353.78): C, 64.50; H,
3.70; N, 11.88%. Found: C, 64.38; H, 3.52; N, 12.03%.
4-Chloro-5-(4-fluorophenyl)-7-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine
(3c): Yield, 75%, mp 179–1818C; IR (KBr): n ¼ 1616, 1500 cm21 (C55C,
1
C55N ring); H NMR (CDCl3): d ¼ 7.12–8.00 (m, 10H, Ar-H); anal. calcd.
for C18H10Cl2FN3 (358.20): C, 60.36; H, 2.81; N, 11.73%. Found: C, 60.18;
H, 3.04; N, 11.96%.

2176
N. D. Desai
4-Chloro-5,7-bis(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (3d): Yield,
68%, mp 118–1198C; IR (KBr): n ¼ 1604, 1512 cm21 (C55C, C55N ring);
1H NMR (CDCl3): d ¼ 7.18–8.16 (m, 10H, Ar-H); anal. calcd. for
C18H10ClF2N3 (341.74): C, 63.26; H, 2.95; N, 12.30%. Found: C, 63.18; H,
3.04; N, 12.19%.
4-Chloro-5-(4-fluorophenyl)-7-(3-chloro-4-chlorophenyl)-7H-pyrrolo[2,3-d]
pyrimidine (3e): Yield, 85%, mp 153–1558C; IR (KBr): n ¼ 1612,
1
1504 cm21 (C55C, C55N ring); H NMR (CDCl3): d ¼ 7.12–8.08 (m, 9H,
Ar-H); anal. calcd. for C18H9Cl2F2N3 (376.19): C, 57.47; H, 2.41; N,
11.17%. Found: C, 57.22; H, 2.24; N, 10.96%.
General Procedure for the Synthesis of 4-Hydrazino-5,7-
disubstituted-7H-pyrrolo[2,3-d]pyrimidines 4a–e
4-Chloro-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidine (3, 0.01mol) was
added to a mixture of hydrazine hydrate (99%, 15ml) and absolute ethanol
(30 ml) and heated under reflux conditions for 3–4 h. Then the reaction
mixture was allowed to attain the room temperature, poured onto the crushed
ice, and neutralized with acetic acid (pH 7) to obtain the solid, which was
filtered, washed with water, dried, and crystallized from chlorofrorm.
Data
4-Hydrazino-5-(4-fluorophenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (4a):
Yield, 76%, mp 196–1988C; IR (KBr): n ¼ 3420, 3320, 3260 (NH), 1612,
1
1504 cm21 (C55C, C55N ring); H NMR (CDCl3): d ¼ 4.12 (s, 2H, NH2),
6.15 (s, 1H, NH), 7.28–8.46 (m, 11H, Ar-H); anal. calcd. for C18H14FN5
(319.34): C, 67.70; H, 4.42; N, 21.93%. Found: C, 67.53; H, 4.55; N, 21.89%.
4-Hydrazino-5-(4-fluorophenyl)-7-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyr-
imidine (4b): Yield, 65%, mp 178–1808C; IR (KBr): n ¼ 3440, 3330, 3250
1
(NH), 1608, 1508 cm21 (C55C, C55N ring); H NMR (CDCl3): d ¼ 3.89
(s, 3H, OCH3), 4.14 (s, 2H, NH2), 6.17 (s, 1H, NH), 7.30–8.48 (m, 10H,
Ar-H); anal. calcd. for C19H16FN5O (349.36): C, 65.32; H, 4.62; N,
20.05%. Found: C, 65.22; H, 4.73; N, 19.99%.
4-Hydrazino-5-(4-fluorophenyl)-7-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyri-
midine (4c): Yield, 79%, mp 203–2058C; IR (KBr): n ¼ 3440, 3340, 3240
1
(NH), 1604, 1500 cm21 (C55C, C55N ring); H NMR (CDCl3): d ¼ 4.10
(s, 2H, NH2), 6.19 (S, 1H, NH) 7.32–8.44 (m, 10H, Ar-H); anal. calcd. for
C18H13ClFN5 (353.78): C, 61.11; H, 3.70; N, 19.80%. Found: C, 61.23; H,
3.58; N, 19.89%.

Tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines
2177
4-Hydrazino-5,7-bis(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine
(4d):
Yield, 61%, mp 157–1598C; IR (KBr): n ¼ 3420, 3320, 3260 (NH), 1616,
1
1508 cm21 (C55C, C55N ring); H NMR (CDCl3): d ¼ 4.12 (s, 2H, NH2),
6.13 (s, 1H, NH), 7.30–8.50 (m, 10H, Ar-H); anal. calcd. for C18H13F2N5
(337.33): C, 64.09; H, 3.88; N, 20.76%. Found: C, 64.28; H, 3.78; N,
20.90%.
4-Hydrazino-5-(4-fluorophenyl)-7-(3-chloro-4-fluorophenyl)-7H-pyrrolo[2,3-
d]pyrimidine (4e): Yield 72%, mp 212–2148C; IR (KBr): n ¼ 3440, 3310,
3250 (NH), 1604, 1512 cm21 (C55C, C55N ring); 1H NMR (CDCl3):
d ¼ 4.15 (s, 2H, NH2), 6.13 (s, 1H, NH), 7.32–8.46 (m, 9H, Ar-H); anal.
calcd. for C18H12ClF2N5 (371.17): C, 58.15; H, 3.25; N, 18.84%. Found: C,
58.24; H, 3.20; N, 18.96%.
General Procedure for the Synthesis of 7,9-Disubstituted-7H-
1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 5a–e
Method A
4-Hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidine (4, 0.01mol) was
dissolved in glacial acetic acid (40 ml), and an aqueous solution of sodium
nitrite (20% w/v, 4.2 ml) was added in small portions with cooling (0–58C)
and constant stirring. The reaction mixture was further stirred for 1–1.5 h at
this temperature and poured onto crushed ice (25 g). The solid obtained was
filtered, washed with sodium bicarbonate (20% w/v) followed by water,
dried, and crystallized from 1,4-dioxane.The physical and analytical data
are represented in (Table 1).
Method B
4-Chloro-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidine (3, 0.01 mol) was
added in portions with constant stirring to the well-stirred solution of
ammonium chloride (0.011 mol, 0.059 g.) and sodium azide (0.011 mol,
0.072 g) in dimethyl sulfoxide (25 ml). The reaction mixture was stirred for
2 h at 908C and 1 h at room temperature. The cold solution was poured on
to crushed ice (25 g), and the obtained solid was filtered, washed with
water, dried, and crystallized (Table 1).
Data
5-(4-Fluorophenyl)-7-phenyl-7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyri-
midines (5a). IR (KBr): n ¼ 1604, 1508 cm21 (C55C, C55N ring); 1H NMR
(CDCl3): d ¼ 7.18–8.10 (m, 11H, Ar-H); MS: m/z ¼ 330 (Mþ).

Table 1. Physical and analytical data of 7,9-disubstituted-7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 5a–e
Reaction time (h)
Yielda (%)
Analysis calcd. (found)
H N
Compound
no.
Molecular formula
(molecular wt.)
Method A Method B Method A Method B
Mp (8C)
C
5a
5b
5c
5d
5e
2
2
2
2
2
3
3
3
3
3
65
68
58
66
70
55
63
55
60
64
218–220
C18H11FN6
(330.32)
65.45(65.64) 3.36(3.33) 25.44(25.64)
63.33(63.17) 3.64(3.85) 23.32(23.06)
59.27(59.09) 2.76(2.90) 23.04(22.85)
62.07(62.20) 2.89(3.08) 24.13(24.40)
56.48(56.33) 2.37(2.08) 21.96(21.99)
245–247
226–228
201–202
234–236
C19H13FN6O
(360.34)
C18H10ClFN6
(364.76)
C18H10F2N6
(348.31)
C18H9ClF2N6
(382.75)
aOverall yields for method A from compound 4 and for method B from compound 3.

Tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines
2179
5-(4-Fluorophenyl)-7-(4-methoxyphenyl)-7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo-
[3,2-e]pyrimidine (5b): IR (KBr): n ¼ 1600, 1500 cm21 (C55C, C55N ring);
1H NMR (CDCl3): d ¼ 3.88 (s, 3H, OCH3), 7.16–8.20 (m, 10H, Ar-H); MS:
m/z ¼ 360(Mþ).
5-(4-Fluorophenyl)-7-(4-chlorophenyl)-7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo-
[3,2-e]pyrimidine (5c): IR (KBr): n ¼ 1608, 1496 cm21 (C55C, C55N ring);
1H NMR (CDCl3): d ¼ 7.24–8.30 (m, 10H, Ar-H); MS: m/z ¼ 364 (Mþ).
5,7-Bis(4-fluorophenyl)-7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo-[3,2-e]pyrimi-
1
dine (5d): IR (KBr): n ¼ 1600, 1504 cm21/(C55C, C55N ring); H NMR
(CDCl3): d = 7.10–8.14 (m, 10H, Ar-H); MS: m/z ¼ 348 (Mþ).
5-(4-Fluorophenyl)-7-(3-chloro-4-fluorophenyl)-7H-pyrrolo-1,2,3,4-tetrazolo-
[1,5-c]pyrrolo[3,2-e]pyrimidine (5e): IR (KBr): n ¼ 1608, 1504 cm21 (C55C,
C55N ring); 1H NMR (CDCl3): d ¼ 7.16–8.24 (m, 9H, Ar-H); MS:
m/z ¼ 382 (Mþ).
General Procedure for the Synthesis of 4-Amino-5,7-disubstituted-
7H-pyrrolo[2,3-d]pyrimidines 6a–e
Method C
Powdered zinc (0.5 g) was added cautiously to the mixture of 7,9-disub-
stituted-7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidine (5, 0.002 mol)
in glacial acetic acid (10 ml) over a period of 30 min. (An exothermic
reaction was observed.) The reaction mixture was then refluxed for 1–1.5 h,
cooled, and poured onto crushed ice (25 g). The resulting mixture was neutral-
ized to (pH 7) with ammonia solution (6 N) and extracted with chloroform
(2 ꢀ 30 ml). The total chloroform layer was dried over anhydrous
magnesium sulfate, concentrated in vacuo, and crystallized from a mixture
of ethanol and chloroform (8 : 2 v/v). The physical and analytical data are
given in Table 2.
Method D
A mixture of 1,4-disubstituted 2-amino-3-cyanopyrrole (1, 0.01 mol),
formamide (15 ml), N,N-dimethylformamide (5 ml), and formic acid
(2 ml) was heated under reflux for 6–8 h. The reaction mixture was
allowed to stand overnight at room temperature. The solid thus
obtained was filtered, washed with cold methanol, dried, and crystallized
(Table 2).

Table 2. Physical and analytical data of 4-amino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 6a–e
Yielda (%)
Reaction time (h)
Analysis calcd. (found)
H
Compound
no.
Molecular formula
(molecular wt.)
Method C Method D Method C Method D
Mp (8C)
C
N
6a
6b
6c
6d
6e
2
6
65
68
58
66
70
55
63
55
60
64
185–187
C18H13FN4
(304.32)
71.04(71.12)
68.25(68.37)
63.82(63.90)
67.08(67.28)
60.77(60.83)
4.31(4.33) 18.41(18.64)
2.5
3
7
153–154
276–278
163–165
241–243
C19H15FN4O
(334.35)
4.52(4.65) 16.76(16.96)
3.57(3.48) 16.54(16.65)
3.75(3.95) 17.38(17.40)
2.83(2.86) 15.75(15.99)
6.5
8
C18H12ClFN4
(338.77)
2
C18H12F2N4
(322.31)
2
7
C18H11ClF2N4
(355.75)
aOverall yields for method C from compound 5 and for method D from compound 1.

Tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines
2181
Data
4-Amino-5-(4-fluorophenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (6a). IR
(KBr): n ¼ 3470, 3290 (NH), 1585, 1500 cm21 (C55C, C55N ring); 1H
NMR (CDCI3): d ¼ 5.30 (s, 2H, NH2), 7.10–8.38 (m, 11H, Ar-H).
4-Amino-5-(4-fluorophenyl)-7-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimi-
dine (6b): IR (KBr): n ¼ 3480, 3270 (NH), 1580, 1510 cm21 (C55C, C55N
1
ring); H NMR (CDCl3): d ¼ 3.91 (s, 3H, OCH3), 5.20 (s, 2H, NH2), 7.20–
8.40 (m, 10H, Ar-H).
4-Amino-5-(4-fluorophenyl)-7-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine
(6c): IR (KBr): n ¼ 3465, 3280 (NH), 1580, 1510 cm21 (C55C, C55N ring);
1H NMR (CDCl3): d ¼ 5.24 (s, 2H, NH2), 7.12–8.36 (m, 10H, Ar-H).
4-Amino-5,7-bis(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine change (6d):
1
IR (KBr): n ¼ 3480, 3300 (NH), 1580, 1485 cm21 (C55C, C55N ring); H
NMR (CDCl3): d ¼ 5.28 (s, 2H, NH2), 7.20–8.38 (m, 10H, Ar-H).
4-Amino-5-(4-fluorophenyl)-7-(3-chloro-4-chlorophenyl)-7H-pyrrolo[2,3-
d]pyrimidine (6e): IR (KBr): n ¼ 3460, 3280 (NH), 1580, 1500 cm21
1
(C55C, C55N ring); H NMR (CDCl3): d ¼ 5.30 (s, 2H, NH2), 7.18–8.34
(m, 9H, Ar-H).
ACKNOWLEDGMENT
We thank the Regional Sophisticated Instrumentation Center, Central Drug
1
Research Institute, Lucknow and Chandigarh, India, for H NMR and mass
spectral analysis and the director of the Loyola Center for Research and
Development, St. Xavier’s College, Ahmedabad, India, for the facility to
carry out this work.
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