Synthesis and interconversion of isomeric pyrrolotriazolopyrimidines

Article abstract of DOI:10.1002/hc.20295

4-Hydrazino-7H-pyrrolo[2,3-d]pyrimidines 4 were cyclocondensed with formic acid or triethyl orthoformate to give 7H-pyrrolo[3,2-e][1,2,4] triazolo[1,5-c]pyrimidines 6 and 7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c] pyrimidines 7,respectively. The [4,3-c] isom

Full text of DOI:10.1002/hc.20295

Heteroatom Chemistry
Volume 18, Number 3, 2007
Synthesis and Interconversion of Isomeric
Pyrrolotriazolopyrimidines
Nirmal D. Desai
Loyola Center of R&D, St. Xavier’s College, Navrangpura, Ahmedabad 380009, India
Received 6 November 2005; revised 13 March 2006
and their related compounds. Triazolopyrimidines
ABSTRACT: 4-Hydrazino-7H-pyrrolo[2,3-d]pyrimi-
dines 4 were cyclocondensed with formic acid or tri-
ethyl orthoformate to give 7H-pyrrolo[3,2-e][1,2,4]
are extensively reviewed as adenosine receptor
antagonists [1]. They are also associated with
potent biological activity, such as antitumor [2],
antihypertensive [3], anti-inflammatory [4], anti-
asthmatic [5], anxiolytic [6], and antifungal [7].
A number of reports have been published for
the synthesis of fused triazolopyrimidines by cy-
clocondensation of 4-hydrazinopyrimidines with
various one-carbon donor moieties [8–15]. In many
instances, formic acid was used as a cyclizing
agent, in which the possibility of the formation
of isomeric triazole was overlooked [15–18]. How-
ever, the possibility of isomeric rearrangement
was taken into consideration in the reaction of 4-
hydrazinothienopyrimidines, 4-hydrazinopyrazolo-
pyrimidines, and 4-hydrazinoquinazolines with
one-carbon donor moieties yielding respec-
tive isomeric triazolothienopyrimidines [19,20],
triazolopyrazolopyrimidines [21], and triazolo-
quinazolines [22], respectively. So far, there has
not been any report on isomeric conversion in
the pyrrolotriazolopyrimidine system. Few works
have been found in which a triazole ring was
annellated onto existing pyrrolo[2,3-d]pyrimidines
[23–25]. Therefore, in continuation of our inter-
est in fused triheterocyclic pyrimidines [26–29],
it was interesting to report the synthesis of
7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines
and 7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimi-
dines by the annellation of the triazole ring
triazolo[1,5-c]pyrimidines
6 and 7H-pyrrolo[3,2-
e][1,2,4]triazolo[4,3-c]pyrimidines 7,respectively. The
[4,3-c] isomers 7 were rearranged into thermody-
namically more stable [1,5-c] isomers 6. The iden-
tical compounds 6 were prepared using another
route by reacting 3-amino-4-imino-7H-pyrrolo[2,3-
d]pyrimidines 3 with formic acid or triethyl ortho-
formate. The reaction of 2-amino-3-cyanopyrroles 1
with triethyl orthoformate gave N-ethoxymethylene-
2-amino-3-cyanopyrroles 2. Further reaction with an
equivalent of hydrazine hydrate provided 3-amino-4-
imino-7H-pyrrolo[2,3-d]pyrimidines 3, whereas treat-
ment with excess of hydrazine hydrate, 3 rearranged
to 4-hydrazino-7H-pyrrolo[2,3-d]pyrimidines 4. Com-
pounds 4 were also obtained by the treatment of
N-ethoxymethylene-2-amino-3-cyanopyrroles 2 in ex-
ꢀ
C
cess of hydrazine hydrate.
2007 Wiley Periodicals,
Inc. Heteroatom Chem 18:265–273, 2007; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20295
INTRODUCTION
In the past years, the literature is enriched with
progressive finding about the synthesis and phar-
macological actions of fused triazolopyrimidines
onto
the
existing
pyrrolo[2,3-d]pyrimidine
Dedicated to the memory of Dr. Chaitanya G. Dave.
Correspondence to: Nirmal D. Desai; e-mail: nirmalde-
sai 3@yahoo.com.
2007 Wiley Periodicals, Inc.
ring systems. Furthermore, the conversion of
N-ethoxymethylene-2-amino-3-cyanopyrroles and
3-amino-4-imino-7H-pyrrolo[2,3-d]pyrimidines to
c
ꢀ
265

266 Desai
4-hydrazino-7H-pyrrolo[2,3-d]pyrimidines and an
isomeric rearrangement of pyrrolotriazolopyrim-
idines to the more stable form have also been
studied.
5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines
3
rather than the expected 4-hydrazino-5,7-disubs-
tituted-7H-pyrrolo[2,3-d]pyrimidines 4; these re-
sults are in accordance with Hosmane et al. [31].
Products 4 were obtained by the Dimroth rear-
rangement of 2 (method A) and 3 (method B) upon
prolonged heating in excess of hydrazine hydrate in
aqueous ethanol [32]. Structure 4 was confirmed
by unambiguous synthesis between 4-chloro-
5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines
RESULTS AND DISCUSSION
1,4-Disubstituted-2-amino-3-cyanopyrroles 1 [30]
were reacted in boiling triethyl orthoformate to
give 1,4-disubstituted-N-ethoxymethylene-2-amino-
3-cyanopyrroles 2. The reaction of 2 with an equiva-
lent of hydrazine hydrate afforded 3-amino-4-imino-
5
(method C) and hydrazine hydrate [30]
(Scheme 1).
R
R
CN
CN
( i )
N
NH2
CHOC2H5
N
N
R1
R1
1
2
NH
N NH2
NH
R
R
( ii )
( iii )
N NH2
H
N
N
N
N
R1 CHOH
R1
R
A
CN
3
CHOC2H5
N
N
R1
NHNH2
NH
2
NHNH2
N
R
R
( iv )
N
N
N
N
R1
CHOH
R1
4
B
( v )
Cl
N
R
N
N
R1
5
1,2,3,4,5
R
R1
a
b
c
d
e
f
C6H5
C6H5
4-OCH3-C6H4
4-OCH3-C6H4
4-Cl-C6H4
4-F-C6H4
3-Cl-4-F-C6H3
4-F-C6H4
3-Cl-4-F-C6H3
4-F-C6H4
3-Cl-4-F-C6H3
4-Cl-C6H4
SCHEME 1 Reagent and conditions (i) CH(OC2H5)3, reflux 3–4 h.; (ii) equivalent NH2NH2 · H2O, EtOH, 40–50 min.; (iii)
NH2NH2 · H2O in excess, EtOH, 60–65◦C, 12–13 h.; (iv) NH2NH2 · H2O in excess, EtOH, reflux, 13–14 h.; (v) NH2NH2 · H2O,
reflux, 3–4 h.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Interconversion of Isomeric Pyrrolotriazolopyrimidines 267
N
N
NH
R
R
N
N
NH2
N
( vi )
N
N
N
R1
R1
6
3
3, 6
R
R1
a
b
c
d
e
f
C6H5
C6H5
4-OCH3-C6H4
4-OCH3-C6H4
4-Cl-C6H4
4-F-C6H4
3-Cl-4-F-C6H3
4-F-C6H4
3-Cl-4-F-C6H3
4-F-C6H4
3-Cl-4-F-C6H3
4-Cl-C6H4
SCHEME 2 Reagent and conditions (vi) CH(OC2H5)3 or HCOOH, Reflux, 5–6 h.
The cyclocondensation of 3-amino-4-imino-5,7-
disubstituted-7H-pyrrolo[2,3-d]pyrimidines 3 with
one-carbon donor moiety, such as triethyl or-
thoformate or formic acid, under reflux con-
ditions yielded 7,9-disubstituted-7H-pyrrolo[3,2-
e][1,2,4]triazolo[1,5-c]pyrimidines 6 (method D)
(Scheme 2).
–CH proton of ethoxymethylene functionality ap-
pears in the downfield region at δ 8.45–8.85 as a
singlet.
The UV (methylene chloride) spectra of
3-amino-4-imino-5,7-disubstituted-7H-pyrrolo[2,3-
d]pyrimidines 3 show two λmax near 293 and 246 nm,
respectively. The IR (potassium bromide) spectra of
3-amino-4-imino-5,7-disubstituted-7H-pyrrolo[2,3-
d]pyrimidines 3 exhibited stretching vibrations
in the region of 3440–3140 cm−1 together with a
bending vibration at 1648–1632 cm−1 because of
imino and amino functionalities. A broad singlet at
δ 5.41–5.48 and a multiplet at δ 7.20–8.10 were as-
signed to amino and aromatic protons, respectively,
while δ 8.34–8.59 was attributed to an imino proton
in the 1H NMR (DMSO-d6) spectra of 3.
The UV (methylne chloride) spectra of 7,9-
disubstituted-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-
c]pyrimidines 6 displayed two λmax at 247 and
257–293 nm. The IR (potassium bromide) spectra of
6 and 7 exhibited absorption bands in the region of
1628–1496 cm−1 for aromatic C C, C N stretching
vibrations, whereas the resonance due to aromatic
protons as a multiplet was obtained at δ 7.0–8.43
in the 1H NMR (DMSO-d6) spectra of 6 and 7.
The more deshilded triazole proton in the [1,5-c]
isomers 6 present at position 2 appears as a singlet
at δ 8.9–9.22, whereas the proton at position 3 in
the [4,3-c] isomer 7 was found to appear at little
downfield in the region of δ 9.39–9.49 in the form of
a singlet [19–22].
The identical pyrrolotriazolopyrimidines 6 were
synthesized by another route (method E) in which 4-
hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyri-
midines 4 were condensed with formic acid un-
der boiling condition. The attempted reaction
was believed to initiate with the formation of 7
that was rearranged to more stable isomers 6
in the presence of acidic reagent under thermal
conditions. The reaction between 4 and triethyl
orthoformate at 70◦ C provided 7,9-disubstituted-
7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines
7. The [4,3-c] isomers 7 on heating with formic acid
were isomerized to thermodynamically more stable
unsymmetrical [1,5-c] isomers 6 via the Dimroth
rearrangement (method F) [19,20] (Scheme 3).
The UV (methylene chloride) spectra of 1,4-
disubstituted-N-ethoxymethylene-2-amino-3-cyano-
pyrroles 2 show two prominent λmax near 297 and
249 nm. The IR (potassium bromide) spectra of 1,4-
disubstituted-N-ethoxymethylene-2-amino-3-cyano-
pyrroles 2 exhibit a sharp absorption near 2210 cm−1
due to a cyano group. 1H NMR (CDCl3) spectra
of 2 display a triplet at δ 1.20–1.46 and a quar-
tet at δ 4.20–4.35 integrating for three and two
protons, respectively, because of ethyl protons of
ethoxymethylene group. A multiplet responsible
for aromatic protons appeared near δ 7.10–7.86,
the proton resonance of the pyrrole ring is ob-
served as a singlet at δ 6.85–6.91, and an aliphatic
The mass fragmentation pattern of 7a is depicted
in Scheme 4, which is in agreement with the pattern
of fused triazolopyrimidine [19,20] giving a molecu-
lar ion peak at 329. The fragments 301, 302, and 274
were obtained because of subsequent elimination of
Heteroatom Chemistry DOI 10.1002/hc

268 Desai
N
N
N
NHNH2
R
R
N
N
N
(vii)
N
N
R1
R1
4
7
(viii)
(ix)
N
N
R
N
N
N
R1
6
4,6,7
R
R1
a
b
c
d
e
f
C6H5
C6H5
4-OCH3-C6H4
4-OCH3-C6H4
4-Cl-C6H4
4-F-C6H4
3-Cl-4-F-C6H3
4-F-C6H4
3-Cl-4-F-C6H3
4-F-C6H4
3-Cl-4-F-C6H3
4-Cl-C6H4
SCHEME 3 Reagent and conditions (vii) CH(OC2H5)3, 70◦C, 1–1.5 h.; (viii) HCOOH, Reflux, 6–8 h.; (ix) HCOOH, reflux,
3–4 h.
nitrogen and hydrogen cyanide or hydrogen cyanide
and nitrogen molecules.
EXPERIMENTAL
Melting points were determined by electrothermal
method in an open capillary tube and are uncor-
rected. The UV (methylene chloride) spectra were
taken on Backman Du-64 spectrophotometer. The
IR spectra were recorded in cm−1 for KBr pellets on
+
.
+
.
N
N
N
N
1
Buck-500 spectrophotometer. The H NMR spectra
N
−HCN (27)
N
were recorded on Varian 300 MHz spectrophotome-
ter in deuteriochloroform or deuteriodimethyl sul-
foxide using TMS as an internal standard, and the
chemical shifts are expressed in δ ppm. MS spec-
tra were recorded on LKB 9000 mass spectropho-
tometer. The purity of the compounds was routinely
checked by TLC using silica gel G, and spots were
exposed in iodine vapor.
N
N
F
N
F
7a
m\ e = 329
m\ e = 302
−N2 (28)
−N2 (28)
+
.
+
.
N
N
−HCN (27)
General Procedure for the Synthesis of 1,4-Disu-
bstituted-N-ethoxymethylene-2-amino-3-cyano-
pyrroles 2a–f
N
N
F
N
F
1,4-disubstituted-2-amino-3-cyanopyrrole (1, 0.01
mol) was refluxed with triethyl orthoformate (10
mL) for 3.0–4.0 h. After completion of the reaction,
excess of triethyl orthoformate was recovered in
m\ e = 301
m\ e = 274
SCHEME 4 Mass fragmentation pattern of 7a.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Interconversion of Isomeric Pyrrolotriazolopyrimidines 269
vacuo. The solid thus obtained was treated with cold
water, filtered, dried, and crystallized from ethanol
to give 2a–f.
1-(3-Chloro-4-fluorophenyl)-N-ethoxymethylene-
2-amino-3-cyano-4-(4-chlorophenyl)pyrrole
(2f).
Yield, 85%, mp 181–183◦C; IR (KBr): ν = 2210 (CN),
1620, 1508 cm−1 (C C, C N ring); 1H NMR (CDCl3):
δ = 1.28 (t, J = 6.82 Hz 3H, OCH2CH3), 4.27 (q,
J = 6.98 Hz 2H, OCH2CH3), 6.89 (s, 1H, H at C5),
7.22–7.73 (m, 7H, Ar-H), 8.56 (s, 1H, N CHOC2H5);
Anal. calcd for C20H14Cl2FN3O (402.25): C, 59.72; H,
3.51; N, 10.45; found: C, 59.58; H, 3.44; N, 10.70.
1-(4-Fluorophenyl)-N-ethoxymethylene-2-amino-
3-cyano-4-phenylpyrrole (2a). Yield, 68%; mp
109–110◦ C; IR (KBr): ν = 2210 (CN), 1616, 1504
1
cm−1 (C C, C N ring); H NMR (CDCl3): δ = 1.34
(t, J = 6.72 Hz 3H, OCH2CH3), 4.27 (q, J = 7.02 Hz
2H, OCH2CH3), 6.85 (s, 1H, H at C5), 7.18–7.68 (m,
9H, Ar-H), 8.53 (s, 1H, N CHOC2H5); Anal. calcd
for C20H16FN3O (333.36): C, 72.06; H, 4.84; N, 12.61;
found: C, 72.26; H, 4.98; N, 12.67.
General Procedure for the Synthesis of
3-Amino-4-imino-5,7-disubstituted-7H-
pyrrolo[2,3-d]pyrimidines 3a–f
1-(3-Chloro-4-fluorophenyl)-N-ethoxymethylene-
2-amino-3-cyano-4-phenylpyrrole (2b). Yield, 70%,
mp 127–128◦C; IR (KBr): ν = 2220 (CN), 1612, 1504
cm−1 (C C, C N ring); 1H NMR (CDCl3): δ = 1.28 (t,
J = 6.78 Hz 3H, OCH2CH3), 4.27 (q, J = 6.9 Hz 2H,
OCH2CH3), 6.87 (s, 1H, H at C5), 7.21–7.76 (m, 8H,
Ar-H), 8.45 (s, 1H, N CHOC2H5); Anal. calcd for
C20H15ClFN3O (367.80): C, 65.31; H, 4.11; N, 11.42;
found: C, 65.38; H, 4.32; N 11.27.
1,4-Disubstituted- N-ethoxymethylene-2-amino-3-
cyanopyrrole (2, 0.01 mol) was treated with
hydrazine hydrate (99%, 0.01 mol) in absolute
methanol (25 mL) under gentle reflux condition
for 40–50 min. The mixture was allowed to cool;
precipitates thus formed were filtered, dried, and
crystallized from benzene.
3-Amino-4-imino-5-phenyl-7-(4-fluorophenyl)-7H-
pyrrolo[2,3-d]pyrimidine 3a. Yield, 58%, mp 119–
120◦C; IR (KBr): ν = 3380, 3270, 3170 (NH), 1620,
1-(4-Fluorophenyl)-N-ethoxymethylene-2-amino-
1
3-cyano-4-(4-methoxyphenyl)pyrrole
(2c). Yield,
1508 cm−1 (C C, C N ring); H NMR (DMSO-d6):
63%, mp 156–158◦C; IR (KBr): ν = 2210 (CN), 1624,
1500 cm−1 (C C, C N ring); 1H NMR (CDCl3):
δ = 1.34 (t, J = 6.84 Hz 3H, OCH2CH3), 3.90 (s, 3H,
OCH3), 4.27 (q, J = 6.78 Hz 2H, OCH2CH3), 6.89
(s, 1H, H at C5), 7.22–7.74 (m, 8H, Ar-H), 8.48 (s,
1H, N CHOC2H5); Anal. calcd for C21H18FN3O2
(363.38): C, 69.41; H, 4.99; N 11.56; found: C, 69.63;
H, 5.10; N, 11.39.
δ = 5.45 (br s, 2H, NH2,exchangeable), 7.20–7.89 (m,
11H, Ar-H), 8.32 (br s, 1H, NH, exchangeable); MS:
m/z = 319 (M+). Anal. calcd for C18H14FN5 (319.34):
C, 67.70; H, 4.42; N, 21.93; found: C, 67.58; H, 4.62;
N, 21.70.
3-Amino-4-imino-5-phenyl-7-(3-chloro-4-fluoro-
phenyl)-7H-pyrrolo[2,3-d]pyrimidine
3b. Yield,
70%, mp 158–160◦C; IR (KBr): ν = 3400, 3280, 3190
1
1-(3-Chlorophenyl-4-fluorophenyl)-N-ethoxy-
methylene-2-amino-3-cyano-4-(4-methoxyphenyl)-
pyrrole (2d). Yield, 75%, mp 165–167◦C; IR (KBr):
ν = 2210 (CN), 1620, 1508 cm−1 (C C, C N ring); 1H
NMR (CDCl3): δ = 1.3 (t, J = 6.84 Hz 3H, OCH2CH3),
3.92 (s, 3H, OCH3), 4.27 (q, J = 7.14 Hz 2H,
OCH2CH3), 6.88 (s, 1H, H at C5), 7.12–7.68 (m, 7H,
Ar-H), 8.52 (s, 1H, N CHOC2H5); Anal. calcd for
C21H17ClFN3O2 (397.83): C, 63.40; H, 4.31; N, 10.56;
found: C, 63.62; H, 4.11; N, 10.48.
(NH), 1620, 1508 cm−1 (C C, C N ring); H NMR
(DMSO-d6): δ = 5.43 (br s, 2H, NH2,exchangeable),
7.18–7.82 (m, 10H, Ar-H), 8.39 (br s, 1H, NH,
exchangeable); MS: m/z = 353 (M+). Anal. calcd for
C18H13ClFN5 (353.78): C, 61.11; H, 3.70; N, 19.80;
found: C, 60.95; H, 3.68; N, 19.75.
3-Amino-4-imino-5-(4-methoxyphenyl)-7-(4-fluoro-
phenyl)-7H-pyrrolo[2,3-d]pyrimidine
3c. Yield,
58%, mp 167–169◦C; IR (KBr): ν = 3370, 3300, 3170
(NH), 1608, 1512 cm−1 (C C, C N ring); H NMR
1
1-(4-Fluorophenyl)-N-ethoxymethylene-2-amino-
3-cyano-4-(4-chlorophenyl)pyrrole (2e). Yield, 80%,
mp 193–195◦C; IR (KBr): ν = 2220 (CN), 1608, 1512
cm−1 (C C, C N ring); 1H NMR (CDCl3): δ = 1.32 (t,
J = 6.78 Hz 3H, OCH2CH3), 4.27 (q, J = 7 Hz 2H,
OCH2CH3), 6.85 (s, 1H, H at C5), 7.24–7.82 (m, 8H,
Ar-H), 8.48 (s, 1H, N CHOC2H5); Anal. calcd for
C20H15ClFN3O (367.80): C, 65.31; H, 4.11; N, 11.42;
found: C, 65.26; H, 4.08; N, 11.69.
(DMSO-d6): δ = 3.91 (s, 3H, OCH3), 5.47 (br s, 2H,
NH2, exchangeable), 7.15–7.77 (m, 10H, Ar-H), 8.34
(br s, 1H, NH, exchangeable); MS: m/z = 349 (M+).
Anal. calcd for C19H16FN5O (349.36): C, 65.32; H,
4.62; N, 20.05; found: C, 65.49; H, 4.47; N, 20.17.
3-Amino-4-imino-5-(4-methoxyphenyl)-7-(3-chloro-
4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine
3d.
Yield, 77%, mp 192–194◦C; IR (KBr): ν = 3360, 3290,
Heteroatom Chemistry DOI 10.1002/hc

270 Desai
3150 (NH), 1612, 1500 cm−1 (C C, C N ring); H
NMR (DMSO-d6): δ = 3.93 (s, 3H, OCH3), 5.42 (br
s, 2H, NH2,exchangeable), 7.23–7.78 (m, 9H, Ar-H),
8.41 (br s, 1H, NH, exchangeable); MS: m/z = 383
(M+). Anal. calcd for C19H15ClFN5O (383.81): C,
59.46; H, 3.94; N, 18.25; found: C, 59.51; H, 4.21; N,
18.18.
1
N-ethoxymethylene-2-amino-3-cyanopyrrole
(2,
1.0 g) in absolute ethanol (25 mL), hydrazine
hydrate (99%, 5 mL) was added. The solution was
stirred at 60–65◦C for 12–13 h. The precipitated
solid was filtered in vacuo, dried, and crystallized
to obtain 4a–f. The physical and analytical data are
represented in Table 1.
Method B: Reaction of 3 with Excess of Hy-
drazine Hydrate. A mixture of 3-amino-4-imino-
5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidine (3,
1.0 g), absolute ethanol (25 mL), and hydrazine
hydrate (99%, 5 mL) was refluxed for 12–14 h. The
precipitated solid was filtered, dried, and crystal-
lized to obtain 4a–f (Table 1). The spectral data of
these compounds were identical with those of 4
obtained by method A or C [30].
3-Amino-4-imino-5-(4-chlorophenyl)-7-(4-fluoro-
phenyl)-7H-pyrrolo[2,3-d]pyrimidine
3e. Yield,
80%, mp 200–202◦C; IR (KBr): ν = 3390, 3270, 3160
(NH), 1620, 1508 cm−1 (C C, C N ring); H NMR
1
(DMSO-d6): δ = 5.46 (br s, 2H, NH2,exchangeable),
7.20–7.89 (m, 10H, Ar-H), 8.30 (br s, 1H, NH,
exchangeable); MS: m/z = 353 (M+). Anal. calcd for
C18H13ClFN5 (353.78): C, 61.11; H, 3.70; N, 19.80;
found: C, 61.01; H, 3.56; N, 19.71.
3-Amino-4-imino-5-(4-chlorophenyl)-7-(3-chloro-
4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine 3f. Yield,
85%, mp 233–235◦C; IR (KBr): ν = 3360, 3270, 3150
Method
C. 4-Chloro-5,7-disubstituted-7H-
pyrrolo[2,3-d]pyrimidine [30] (5, 0.01 mol) was
reacted with hydrazine hydrate (99%, 15 mL) in
boiling ethanol (30 mL) for 3–4 h. The cooled
reaction mixture was then added onto crushed ice
and neutralized with aqueous acetic acid (pH 7); the
solid thus obtained was filtered, washed with water,
and crystallized to get 4a–f (Table 1).
1
(NH), 1624, 1512 cm−1 (C C, C N ring); H NMR
(DMSO-d6): δ = 5.42 (br s, 2H, NH2, exchangeable)
7.22–7.76 (m, 9H, Ar-H), 8.44 (br s, 1H, NH, ex-
changeable); MS: m/z = 388 (M+). Anal. calcd for
C18H12Cl2FN5 (388.23): C, 55.69; H, 3.12; N, 18.04;
found: C, 55.80; H, 3.16; N, 17.88.
General Procedure for the Synthesis of 7,9-Disub-
stituted-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]-
pyrimidines 6a–f
General Procedure for the Preparation of 4-Hydr-
azino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrim-
idines 4a–f
Method D. 3-Amino-4-imino-5,7-disubstituted-
7H-pyrrolo[2,3-d]pyrimidine (3, 0.01 mol) was
heated with boiling formic acid (15 mL) for 5–6 h.
Method A: Reaction of 2 with Excess of Hydrazine
Hydrate. To a stirring solution of 1,4-disubstituted-
TABLE 1 Physical and Analytical Data of 4-Hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 4a–f
Yield a (%)
Method
Analysis
Calcd.\(Found)
Compound
No.
mp ( ◦C)\Solvent for
Molecular Formula
(Molecular Wt.)
A
B
Cb
69
78
63
72
79
77
Crystallizationc
C
H
N
4a
4b
4c
4d
4e
4f
65
68
58
66
70
68
55
198–200
C18H14FN5
(319.34)
C18H13ClFN5
(353.78)
C19H16FN5O
(349.36)
C19H15ClFN5O
(383.80)
C18H13ClFN5
(353.78)
C18H12ClFN5
(388.23)
67.70
67.64
61.11
60.97
65.32
65.09
59.46
59.58
61.11
61.33
55.69
55.82
4.42
4.33
3.70
3.85
4.62
4.48
3.94
4.12
3.70
3.82
3.12
2.96
21.93
21.74
19.80
19.96
20.05
19.85
18.25
18.40
19.80
19.99
18.04
17.86
G
63
55
60
64
62
240–242
H
172–173
H
202–204
H
210–212
G
243–245
H
aOverall yield for methods A and B from 2 and for method C from 5.
bMethod reported in [30].
cG = chloroform; H = N,N-dimethyl formamide.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Interconversion of Isomeric Pyrrolotriazolopyrimidines 271
TABLE 2 Physical and Analytical Data of 7,9-Disubstituted-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines 6a–f
Yield a (%)
Method
Analysis
Calcd \(Found)
Compound
No.
mp ( ◦C)\Solvent for
Molecular Formula
(Molecular Wt.)
D
E
F
Crystallization b
C
H
N
6a
6b
6c
6d
6e
6f
65
68
63
60
68
66
55
60
61
58
65
63
68
66
69
64
70
70
207–209
C19H12FN5
(329.33)
C19H11ClFN5
(363.78)
C20H14FN5O
(359.36)
C20H13ClFN5O
(393.80)
69.29
69.34
62.73
62.92
66.85
67.09
61.00
61.22
62.73
61.61
57.31
57.41
3.67
3.52
3.05
2.87
3.93
4.05
3.33
3.57
3.05
3.10
2.53
2.48
21.27
21.39
19.25
19.44
19.49
19.57
17.78
17.66
19.25
19.48
17.59
17.67
J
249–250
H
197–199
H
219–221
H
230–232
J
259–261
H
C
19H11ClFN5
(363.78)
C19H10Cl2FN5
(398.22)
aOverall yields for method D from 3, for method E from 4, and for method F overall yields from 7.
bJ = dioxane; H = N,N-dimethyl formamide.
The mixture was then cooled, poured onto crushed
ice, and neutralized with sodium hydroxide solution
(1N). The solid obtained was filtered, washed with
water, dried, and crystallized in order to get 6a–f.
The physical and analytical data for 6a–h are given
in Table 2.
7-(3-Chloro-4-fluorophenyl)-9-(4-methoxyphenyl)-
7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine 6d.
IR (KBr): ν = 3070, 2880 (CH), 1616, 1508 cm−1
1
(C C, C N ring); H NMR (DMSO-d6): δ = 3.89 (s,
3H,OCH3), 7.0–8.29 (m, 9H, Ar-H), 9.12 (s, 1H, H at
C2); MS: m/z = 393 (M+).
Method E. A mixture of 4-hydrazino-5,7-
7-(4-Fluorophenyl)-9-(4-chlorophenyl)-7H-pyrrolo-
[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine 6e. IR (KBr):
ν = 3080, 2860 (CH), 1624, 1512 cm−1 (C C, C N
disubstituted-7H-pyrrolo[2,3-d]pyrimidine
(4,
0.01 mol) and formic acid (20 mL) was refluxed for
6–8 h. The resulting mixture was cooled, poured
onto crushed ice, and neutralized with sodium
hydroxide solution (1N). The obtained solid was
filtered, washed with water, dried, and crystallized
to get the title compounds (Table 2).
1
ring); H NMR (DMSO-d6): δ = 7.18–8.26 (m, 10H,
Ar-H), 9.18 (s, 1H, H at C2); MS: m/z = 363 (M+).
7-(3-Chlorophenyl-4-fluorophenyl)-9-(4-chloro-
phenyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyri-
midine 6f. IR (KBr): ν = 3090, 2880 (CH), 1620,
1
1512 cm−1 (C C, C N ring); H NMR (DMSO-d6):
7-(4-Fluorophenyl)-9-phenyl-7H-pyrrolo[3,2-e][1,-
2,4]triazolo[1,5-c]pyrimidine 6a. IR (KBr): ν =
3090, 2860 (CH), 1624, 1512 cm−1 (C C, C N ring);
1H NMR (DMSO-d6): δ = 7.22–8.22 (m, 11H, Ar-H),
9.05 (s, 1H, H at C2); MS: m/z = 329 (M+).
δ = 7.18–8.26 (m, 9H, Ar-H), 9.20 (s, 1H, H at C2);
MS: m/z = 398 (M+).
General Procedure for the Synthesis of
7,9-Disubstituted-7H-pyrrolo[3,2-
e][1,2,4]triazolo[4,3-c]pyrimidines
7a–f
7-(3-Chloro-4-fluorophenyl)-9-phenyl-7H-pyrrolo-
[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine 6b. IR (KBr):
ν = 3060, 2840 (CH), 1612, 1508 cm−1 (C C, C N
1
ring); H NMR (DMSO-d6): δ = 7.10–8.20 (m, 10H,
A
mixture of 4-hydrazino-5,7-disubstituted-7H-
Ar-H), 9.12 (s, 1H, H at C2); MS: m/z = 363 (M+).
pyrrolo[2,3-d]pyrimidine (4, 0.01 mol) and triethyl
orthoformate (20 mL) was stirred at 70◦C for 1–1.5
h. The excess of reagent was distilled under pres-
sure, and to the cold reaction mixture n-hexane
(10 mL) was added. Thus obtained solid was fil-
tered, dried, and crystallized from a mixture of N,N-
dimethylformamide: ethanol (4:6 v/v) to get the title
compounds 7a–f.
7-(4-Fluorophenyl)-9-(4-methoxyphenyl)-7H-py-
rrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine 6c. IR
(KBr): ν = 3070, 2880 (CH), 1616, 1508 cm−1 (C C,
C N ring); 1H NMR (DMSO-d6): δ = 3.89 (s, 3H,
OCH3), 7.0–8.29 (m, 10H, Ar-H), 9.12 (s, 1H, H at
C2); MS: m/z = 359 (M+).
Heteroatom Chemistry DOI 10.1002/hc

272 Desai
7-(4-Fluorophenyl)-9-phenyl-7H-pyrrolo[3,2-e][1,
General Procedure for Conversion of 7a–f to
2,4]triazolo[4,3-c]pyrimidine 7a. Yield, 62%, mp
6a–f
216–218◦C; IR (KBr): ν = 3090, 2950 (CH), 1620,
Method F. 7,9-Disubstituted-7H-pyrrolo[3,2-e]-
[1,2,4]triazolo[4,3-c]pyrimidine (7, 1.0 g) and formic
acid (10 mL) was heated under reflux condition for
3–4 h. The reaction mixture was allowed to cool,
poured onto crushed ice, and the obtained solid was
filtered, washed with water, dried, and crystallized
to get 6a–f. The IR and 1H NMR data were superim-
posed on those of 6 obtained from either method D
or E as described above.
1
1512 cm−1 (C C, C N ring); H NMR (DMSO-d6):
δ = 7.22–8.22 (m, 11H, Ar-H), 9.46 (s, 1H, H at C2);
Anal. calcd for C19H12FN5 (329.33): C, 67.29; H, 3.67;
N, 21.27; found: C, 67.45; H, 3.56; N, 21.08.
7-(3-Chloro-4-fluorophenyl)-9-phenyl-7H-pyrrolo-
[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine
7b. Yield,
67%, mp 258–260◦C; IR (KBr): ν = 3070, 2870
(CH), 1612, 1504 cm−1 (C C, C N ring); H NMR
1
(DMSO-d6): δ = 7.00–8.16 (m, 10H, Ar-H), 9.45 (s,
1H, H at C2); Anal. calcd or C19H11ClFN5 (363.78): C,
62.73; H, 3.05; N, 19.25; found: C, 62.56; H, 3.19; N,
19.38.
ACKNOWLEDGMENTS
We thank the Regional Sophisticated Instrumen-
tation Center, Central Drug Research Institute,
Lucknow and Chandigarh, India for H NMR and
1
mass spectral analysis and to the Director, Loyola
Center for R&D, St. Xavier’s College, Ahmedabad,
India for providing the facility to carry out this work.
7-(4-Fluorophenyl)-9-(4-methoxyphenyl)-7H-pyr-
rolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine 7c. Yield,
50%, mp 203–205◦C; IR (KBr): ν = 3090, 2930
1
(CH), 1620, 1504 cm−1 (C C, C N ring); H NMR
(DMSO-d6): δ = 3.90 (s, 3H, OCH3), 7.12–8.26 (m,
10H, Ar-H), 9.43 (s, 1H, H at C2); Anal. calcd for
C20H14FN5O (359.36): C, 66.85; H, 3.93; N, 19.49;
found: C, 66.74; H, 4.12; N, 19.17.
REFERENCES
[1] (a) Baraldi, P. G.; Cacciari, B.; Spalluto, G.; Pineda
de las Infantas y Villatoro, M. J.; Zocchi, C.;
Dionisotti, S.; Ongini, E. J Med Chem 1996, 39(5),
1164–1171; (b) Baraldi, P. G.; Cacciari, B.; Ro-
magnoli, R.; Spalluto, G.; Moro, S.; Klotz, K.
N.; Leung, E.; Varani, K.; Gessi, S.; Merighi, S.;
Borea, P. A. J Med Chem 2000, 43(25), 4768–
4780; (c) Baraldi, P. G.; Cacciari, B.; Romagnoli, R.;
Spalluto, G.; Monopoli, A.; Ongini, E.; Varani, K.;
Borea, P. A. J Med Chem 2002, 45(1), 115–126; (d)
Pastorin, G.; Da Ros, T; Bolcato, C.; Montopoli, C.;
Moro, S.; Cacciari, B.; Baraldi, P. G.; Varani, K.;
Borea, P. A.; Spalluto, G. J Med Chem 2006, 49(5),
1720–1729.
7-(3-Chloro-4-fluorophenyl)-9-(4-methoxyphenyl)-
7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine 7d.
Yield, 65%, mp 256–258◦C; IR (KBr): ν = 3070, 2880
1
(CH), 1608, 1500 cm−1 (C C, C N ring); H NMR
(DMSO-d6): δ = 3.89 (s, 3H, OCH3), 7.11–8.26 (m,
9H, Ar-H), 9.45 (s, 1H, H at C2); Anal. calcd for
C20H13ClFN5O (393.80): C, 61.00; H, 3.33; N, 17.78;
found: C, 59.80; H, 3.16; N, 17.88.
[2] Navarro, J. A. R.; Salas, J. M.; Romero, M. A.;
Vilaplana, R.; Gonzalez-Vilchez, F.; Faure, R. J Med
Chem 1998, 41(3), 332–338.
[3] (a) Kathwala, F. G.; Hardtmanm, G. E. Gre Offen
214076; Chem Abstr 1972, 77, 48501f; (b) Hardtman,
G. E.; Kathawala F. G. Ger Offen 2261095; Chem
Abstr 1973, 79, 66385.
7-(4-Fluorophenyl)-9-(4-chlorophenyl)-7H-pyrrolo-
[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine 7e.
Yield,
60%, mp 250–252◦C; IR (KBr): ν = 3060, 2940
1
(CH), 1620, 1512 cm−1 (C C, C N ring); H NMR
(DMSO-d6): δ = 7.14–8.08 (m, 10H, Ar-H), 9.43 (s,
1H, H at C2); Anal. calcd for C19H11ClFN5 (363.78):
C, 62.73; H, 3.05; N, 19.25; found: C, 62.80; H, 3.16;
N, 19.30.
[4] Hardtmann, G. E.; Kathawala, F. G. U.S. Patent
4053600; Chem Abstr 1978, 89, 22970k.
[5] Francis, J. E.; Bennett, D. A.; Hyun, J. L.; Rovinski,
S. L.; Amrick, C. L.; Loo, P. S.; Murphy, D.; Neale, R.
F.; Wilson, D. E. J Med Chem 1991, 34(9), 2899–2906.
[6] Francis, J. E.; Gelotte, K. O. Eur Pat 263071; Chem
Abstr 1988, 109, 159546j.
7-(3-Chlorophenyl-4-fluorophenyl)-9-(4-chloro-
phenyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyri-
midine 7f. Yield, 68%, mp 290–292◦C; IR (KBr):
ν = 3090, 2880 (CH), 1612, 1516 cm−1 (C C, C N
ring); 1H NMR (DMSO-d6): δ = 7.20–8.24 (m, 9H, Ar-
H), 9.45 (s, 1H, H at C2); Anal. calcd for C19H10Cl2FN5
(398.22): C, 57.31; H, 2.53; N, 17.59; found: C, 57.14;
H, 2.47; N, 17.81.
[7] Pees, K. J.; Albert, G. Eur Pat Appl EP 550113 1993;
Chem Abstr 1993, 119, 271190k.
[8] Kottke, K.; Kuchsmedt, H. Pharmazie 1978, 33, 507;
Chem Abstr 1978, 89, 215340.
[9] Sidhu, G . S.; Tyagrajan, G.; Nagabhushan, R.
Naturewissenschaften 1963, 50, 732; Chem Abstr
1964, 60, 6841.
[10] Kottke, K.; Kuchsmedt, H. Pharmazie 1980, 35, 800;
Chem Abstr 1980, 92, 765150.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Interconversion of Isomeric Pyrrolotriazolopyrimidines 273
[11] Shaban, M. A. E.; Taha, M. A. M.; Sharshira, E. E.
M. Alexandria J Pharm Sci 1992, 6, 219; Chem Abstr
1993, 118, 95458.
[12] Bourguignon, J.; Gougeon, E.; Queguiner, G.;
Pastour, P. Bull Soc Chem Fr (3, 4 pt-2) 1975, 815;
Chem Abstr 1975, 83, 114329.
[13] Michihio, Y.; Masao, K.; Hisao, Y. German Patent
1978, 124, 280; Chem Abstr 1978, 89, 197593.
[14] Hiedo, K.; Yasuo, M. Japan Patent 1959, 5577; Chem
Abstr 1960, 54, 14280.
[15] Robba, M.; Cugnon, M.; Lecomte, J. M. J Heterocyclic
Chem 1975, 12, 525.
[21] Bhatt, G. A.; Schram, K. H.; Townsend, L. B. J Chem.
Soc, Perkin Trans 1 1981, 2387.
[22] Breuer, H. Tetrahedron Lett 1976, 23, 1935–1938.
[23] Basyouni, W. M.; Hosni, M. H.; El-Bayouki, A. M. Kh.
J Chem. Res (s) 1997, 452.
[24] Ali, A. S.; Swelam, S. A.; Abdel-Megeid, F. M. E. Egypt
J Pharma Sci 1992, 33(3,4), 473; Chem Abstr 1994,
120, 323463.
[25] Bhatt, G. A.; Schram, K. H.; Townsend L. B. Carbo-
hydr Nucleoside Nucleotide 1981, 8(2), 145.
[26] Dave, C. G.; Shah, R. D. J Heterocycl Chem 1998, 35,
1295.
[16] Robba, M.; Touzot, P.; Lacomte, J. M. C R Acad Sci
1975, 53, 276; Chem Abstr 1975, 78, 111243.
[17] Arya, V. P. Indian J Chem 1972, 10, 1141.
[18] Sauter, F.; Stanetty, P. Monatsh Chem 1975, 106,
1111.
[19] Shishoo, C. J.; Devani, M. B.; Ullas, G. V.; Ananthan,
S.; Bhadti, V. S. J Heterocycl Chem 1981, 18,
43.
[27] Dave, C. G.; Shah, A. B.; Shah, H. C. J Heterocycl
Chem 1997, 34, 937.
[28] Dave, C. G.; Shah, R. D. Heterocycles 1999, 51, 1999.
[29] Dave, C. G.; Shukla, M. C. J Heterocycl Chem 1997,
34, 1805.
[30] Dave, C. G.; Desai, N. D. J Heterocycl Chem 1999, 36,
729.
[31] Hosmane, R. S.; Lim, B. B.; Burnett, F. N. J Org Chem
1988, 53, 382.
[20] Shishoo, C. J.; Devani, M. B.; Ullas, G. V.; Ananthan,
S.; Bhadti, V. S. J Heterocycl Chem 1987, 24,
1125.
[32] Taylor, E. C.; Leoffler, P. K. J Am Chem Soc 1960, 82,
3147.
Heteroatom Chemistry DOI 10.1002/hc