Synthesis and regioselective N- and O-alkylation of 3-alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones and 2-phenyl-9-propyl-9H-purin-6(1H)-one with evaluation of antiviral and antitumor activities

Article abstract of DOI:10.1016/j.tet.2008.08.014

3-Alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones were prepared by nitrosative cyclization of the appropriate 5,6-diamino-2-phenylpyrimidin-4(3H)-ones with nitrous acid and were subjected to regioselective alkylation with several alkylating a

Full text of DOI:10.1016/j.tet.2008.08.014

Tetrahedron 64 (2008) 9885–9894
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and regioselective N- and O-alkylation of 3-alkyl-5-phenyl-3H-
[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones and 2-phenyl-9-propyl-9H-purin-
6(1H)-one with evaluation of antiviral and antitumor activities
,
Rafiqul Islam a, Noriyuki Ashida b, Tomohisa Nagamatsu a
*
a Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
Okayama University, Tsushima-naka, Okayama 700-8530, Japan
b Biology Laboratory, Research and Development Division, Yamasa Shoyu Co., Choshi, Chiba 288-0056, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 June 2008
Received in revised form 3 August 2008
Accepted 6 August 2008
Available online 9 August 2008
3-Alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones were prepared by nitrosative cycliza-
tion of the appropriate 5,6-diamino-2-phenylpyrimidin-4(3H)-ones with nitrous acid and were subjected
to regioselective alkylation with several alkylating agents in aprotic solvent at different temperature.
Simultaneous 6-N- and 7-O-alkylation were observed and the regioselectivity varied remarkably with
size and shape of the alkylating agents as well as with the reaction temperature. Similarly, N- and
O-alkylation as well as selectivity was also observed in the case of 2-phenyl-9-propyl-9H-purin-6(1H)-
one. Some of the synthesized compounds showed moderate antiviral and antitumor activities.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Regioselective alkylation
Triazolopyrimidinone
Antiviral activity
Antitumor activity
1. Introduction
purine derivatives may lead to achieve the highly expected effective
antiviral and antitumor drugs. Hence, our laboratory has designed
The fused pyrimidine derivatives such as naturally occurring
purine bases and their analogues have been focused of great
interest over many years by reason of their diversified biological
activities.1–5 Particular interests are the structural modification of
purine bases as well as introduction of different functional groups
into these bases in the view of searching potential antineoplastic
and antiviral agents. Introduction of different functional groups,
e.g., amino, oxo, thioxo, alkylthio, alkyl/aryl groups, into purine
bases at different positions has been assessed for potency and
selectivity for the biological system.2,6–11 6-Chloro, thioxo, alkylthio,
amino purine derivatives as well as 9-substituted purine derivatives
have been reported for good antitumor and antiviral activities.2,6,7,11
A few effective and clinically applicable antineoplastic and antiviral
agents have been reported so far. Therefore, continuous efforts have
been conducted for the synthesis of purines and their analogues for
searching the effective biological agents. To be biologically active for
any compound needs some active sites to interact with DNA or RNA.
A minor modification of a biologically active compound can greatly
alter its potentiality. Thus, more modifications of biologically active
the program for the synthesis of fused pyrimidines,12–19 especially
purine and modified purine derivatives, by introducing different
substituents at different positions accompanied the alternation of
natural sugar at the 3/9-position with alkyl/aryl groups in order to
observe the change of antiviral and antitumor activities. Study of
regioselective N- and O-alkylation of purine and modified purine
derivatives is a part of the program since much attention has not
been directed toward the selective O-alkylation for the synthesis of
biologically active compounds in this area.
We reported19 the synthesis of 1H-, 2H-, and 3H-[1,2,3]tri-
azolo[4,5-d]pyrimidine-5,7(4H,6H)-diones and their first regiose-
lective 5-O-alkylation along with 4-N-alkylation. There are some
reports20–22 of preparation of 6-O-alkyl purine derivatives from
6-chloropurines and the conversion of 6-cyanopurines into 6-O-al-
kylpurine derivatives. Although there are many reports of alkylation
of xanthine and hypoxanthine, all of them are involved in either
N-alkylation23–25 or S-alkylation.26,27 The interest of most alkylation
for xanthines, 8-azaxanthines, and 8-azahypoxanthines has been
turned to the imidazole23,24 and triazole rings.25 In connection with
the program of synthesis and regioselective alkylation of 8-azapur-
ines, we report herein the synthesis of 3-alkyl-5-phenyl-3H-
[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones and 2-phenyl-9-pro-
pyl-9H-purin-6(1H)-one, and their regioselective N- and
* Corresponding author. Tel./fax: þ81 86 251 7931.
E-mail address: nagamatsu@pheasant.pharm.okayama-u.ac.jp (T. Nagamatsu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.014

9886
R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
O-alkylation along with the evaluation of their antiviral and anti-
tumor activities.
2. Results and discussion
2.1. Chemistry
The requisite key starting materials, 5,6-diamino-2-phenyl-
pyrimidin-4(3H)-ones 1a–g, were prepared from 6-chloro-2-
phenylpyrimidin-4(3H)-one in simple three steps following the
standard methods.19,23,28 The nitrosative cyclization of these
5,6-diaminopyrimidine derivatives 1a–g with nitrous acid at room
temperature led to the formation of 3-alkyl-5-phenyl-3H-
[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones 2a–g in 63–86% yields
(Scheme 1). The methylation of 2a–g with methyl iodide in the
presence of anhydrous potassium carbonate in N,N-dime-
thylformamide at room temperature afforded the mixture of 6-N-
methylated 3a–g (44–52% yields) and 7-O-methylated derivatives
4a–g (30–37% yields). The same methylation of 2a–g with methyl
iodide at boiling temperature gave the 6-N-methylated derivatives
3a–g in 71–81% yields, exclusively. The methylation of 2b with
methyl iodide in the presence of sodium hydride in N,N-dime-
thylformamide at 0 ꢀC gave 3b and 4b in 52% and 28% yields,
respectively.
Figure 1. Relative yields of 6-N-methyl 3b (dotted line) and 7-O-methyl 4b (solid line)
isomers yielded by the methylation of 2b with MeI at different temperature.
temperature can be explained by the following fact. That is to say,
an adequate energy is supplied at high temperature to conquer the
steric interaction of 5-phenyl group with methyl iodide to give the
comparatively more stable N-methylated products.29
The O-methylation was verified by another synthetic route.
Namely, treatment of compounds 2a–d with phosphoryl chloride in
the presence of N,N-dimethylaniline gave the corresponding
7-chloro derivatives 5a–d in quantitative yields, which on sub-
sequent treatment with sodium methoxide in methanol at room
temperature yielded the 7-methoxy derivatives 4a–d in excellent
yields (Scheme 2). The physical and spectral data of 4a–d prepared
by the second route were quite identical in all respects with the first
fraction isolated by column chromatography from a mixture of
products gained by methylation of 2a–d with methyl iodide at
room temperature. The IR, 1H NMR, and UV spectra of the O- and
N-methyl isomers provided satisfactory evidence for their dis-
crimination and identification. Usually IR spectra of the 7-oxo de-
rivatives 2a–g, 3a–g showed the characteristic absorption band in
the region of 1690–1720 cmꢁ1 for C]O group. In the case of the
O-methylated derivatives, the absorption band based on the 7-C]O
in the region of 1690–1720 cmꢁ1 disappeared. Hence, this evidently
revealed the disappearance of the 7-oxo group due to the formation
of the 7-O-methylated derivatives 4a–g. In addition, the 1H NMR
spectra displayed considerable confirmation exhibiting chemical
shifts for 7-O-CH3 protons (
more down field than that of 6-N-CH3 protons (
d
4.37–4.40 for compounds 4a–g) in
3.53–3.55 for
d
compounds 3a–g) due to the inductive effect. The UV spectra of
Scheme 1.
The acquit effect of temperature on methylation was examined
by carrying out the reaction of 2b with methyl iodide at different
temperature from 0 to 153 ꢀC as shown in Figure 1. It was observed
that there was no effect of temperature between 0 and 100 ꢀC on
the ratio of yields, but at over 100–153 ꢀC the 6-N-methylation was
in preference to the 7-O-methylation. Thus, the 6-N-methylated
derivative 3b was prevailed exclusively at 153 ꢀC. The priority for
the formation of the N-methylated derivatives at higher
Scheme 2.

R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
9887
these regioisomers also provided the confirmation to assign the 7-
O-methylation along with 6-N-methylation. The UV spectra of all
O-methyl isomers in ethanol exhibited six maxima absorption
bands (238, 245–246, 275–276, 284, 293–294, and 304 nm), while
N-methyl isomers showed two maxima absorption bands (266–267
and 271–272 nm). It is also notable that the physical and spectral
properties of the 7-O-methyl 4a–g and 7-chloro derivatives 5a–
d are about quite analogous due to their structural resemblance.
Thus, we distinguished and established the 7-O-methylation along
with the 6-N-methylation by comparing several spectral data.
Chlorination of 3-(2-hydroxyethyl)- 2f and 3-(3-hydroxy
propyl)-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-one 2g
was achieved in an analogous way to compounds 2a–d (Scheme 3).
Initially, it was expected that the chlorination might take place only
at the 7-position, but actually, the alcoholic hydroxyl group of both
compounds was also replaced by a chlorine to afford the corre-
sponding 7-chloro-3-(2-chloroethyl)- 6 and 7-chloro-3-(3-chlor-
or benzyl bromide in the presence of anhydrous potassium car-
bonate in N,N-dimethylformamide at room temperature afforded
the 7-O-alkylated derivatives 4b, 4ba, and 4bb as the major prod-
ucts (61–66% yields) along with the 6-N-alkylated derivatives 3b,
3ba, and 3bb (10–17% yields) (Scheme 4). Even the methylation as
well as ethylation of 2b with dimethyl sulfate and ethyl iodide at
boiling temperature led to the 7-O-methyl 4b (39% yield) and 7-O-
ethyl 4ba (41% yield) derivatives as the major products accompa-
nied with 6-N-methyl 3b (16% yield) and 6-N-ethyl 3ba (18% yield)
derivatives, respectively. In the case of benzylation of 2b at boiling
temperature two regioisomers 3bb and 4bb were obtained almost
in equal quantity. Hence, it is apparent that the 7-O-alkylation fa-
vored preference over the 6-N-alkylation for bulkier alkylating
agents19 due to the steric interaction of the alkylating agents with
the phenyl group at the 5-position. That is, the energy produced at
boiling temperature in N,N-dimethylformamide is not sufficient
enough to overcome the steric interaction force for bulkier alky-
lating agents to give only the more stable 6-N-alkyl derivatives. For
confirmation of the 7-O-alkylation, compound 4ba was also pre-
pared by treating 5b with sodium ethoxide in ethanol at room
temperature, which was identical in all respects with the 7-ethoxy
derivative obtained by ethylation of 2b. IR, 1H NMR, and UV spectra
as well as microanalyses for these 6-N-alkylated and 7-O-alkylated
derivatives were also quite satisfactory to assign and differentiate
the regioisomers as discussed for 6-N-methyl 3a–g and 7-O-methyl
4a–g regioisomers.
On the other hand, the similar regioselective N- and O-alkyl-
ation was also observed in the alkylation on purine ring. 2-Phenyl-
9-propyl-9H-purin-6(1H)-one 10 was prepared by treating free
5,6-diaminopyrimidine derivative 1b with 85% formic acid in order
to observe the alkylation position on the pyrimidine ring of it
(Scheme 5). The methylation of 10 with 1 equiv methyl iodide in the
presence of anhydrous potassium carbonate in N,N-dime-
thylformamide at 0 ꢀC gave the 1-N-methyl 11a and 6-O-methyl
isomer 11b in 26% and 45% yields, respectively. The same methyl-
ation with excess methyl iodide at room temperature gave 11b and
6,9-dihydro-1,7-dimethyl-6-oxo-2-phenyl-9-propyl-1H-purin-7-
ium hydroxide 12 in 44% and 30% yields, respectively. Similar
methylation of 10 with 1 equiv dimethyl sulfate at room
opropyl)-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine
7 in 87%
and 84% yields, respectively. The absence of the alcoholic
absorption band in the IR spectra as well as the broad singlet signal
attributable to the alcoholic OH proton in the 1H NMR spectra of
these two derivatives 6 and 7 showed the substitution of hydroxyl
group to chlorine. When the dichlorinated derivatives 6 and 7 were
treated with sodium methoxide in methanol at room temperature,
the nucleophilic substitution took place only at the 7-position to
give the corresponding 3-(2-chloroethyl)-7-methoxy- 8 and 3-(3-
chloropropyl)-7-methoxy-5-phenyl-3H-[1,2,3]triazolo[4,5-d]py-
rimidine 9 in 81% and 88% yields, respectively. 1H NMR spectra of
these two methoxy derivatives showed only one singlet signal (
4.38) attributable to the 7-O-methyl protons, which was consistent
with the other 7-O-methyl derivatives ( 4.37–4.40 for 4a–g).
d
d
Besides, the physical and spectral data of 3-(2-hydroxyethyl)-7-
methoxy 4f and 3-(3-hydroxypropyl)-7-methoxy-5-phenyl-3H-
[1,2,3]triazolo[4,5-d]pyrimidine 4g obtained by methylation of 2f
and 2g were different from that of 8 and 9, respectively. Hence, it is
obvious that the replacement of chlorine by methoxy group took
place selectively at the 7-position without the side chain of 6 and 7.
To examine the effect of size and shape of the alkylating agents
on the O- and N-alkylation, compound 2b was chosen as the model
compound. The alkylation of 2b with dimethyl sulfate, ethyl iodide,
Scheme 3.
Scheme 4.

9888
R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
Table 1
temperature gave only 11b in 76% yield. Therefore, it is obvious that
the O-methylation of 2-phenylhypoxanthine 10 takes place more
preferentially over the N-methylation compared with that of
2-phenyl-8-axahypoxanthine 2. Besides, the 1,9-disubstituted hy-
poxanthine 11a forms the 1,7,9-trisubstituted quaternary salt 12
with excess alkylating agent. The quaternary salt was obtained as
hydroxide salt. IR, 1H NMR, and microanalysis data were quite
satisfactory with the hydroxide salt 12.
Evaluation of antiviral and antitumor activities in vitro of compounds (2a–g, 3a–
g,bb, 4a–g,bb, 5a–d, 6, and 8)
Compd No.
Inhibitory concentration
against Herpes Simplex
Inhibitory concentration
against tumor cell
lines [IC50 (mg/mL)]
Virus [ED50
(
mg/mL)]
HSV-1
HSV-2
CCRF-HSB-2
KB
2a
2b
2c
2d
2e
>20
>20
42.3
51.0
>100
80.7
17.5
92.6
61.0
>100
n.d.
70.5
57.8
67.5
74.3
11.0
>100
70.1
>100
n.d.
>100
>100
>20
>100
>100
>20
>4
>4
2f
>100
>100
>100
n.d.
>100
>100
>100
n.d.
2g
3a
3b
3c
3d
3e
>100
>100
>20
>100
>100
>20
82.3
97.6
25.9
86.2
60.4
>100
>100
n.d.
>100
>100
29.0
>100
41.0
>100
>100
n.d.
3f
>100
>100
>20
>100
>100
>20
3g
3bb
4a
4b
4c
>100
n.d.
>100
n.d.
>100
>20
>100
>20
>100
39.4
n.d.
>100
32.1
n.d.
4d
4e
n.d.
n.d.
4f
>100
>100
>100
>0.8
>20
>0.8
>20
>20
>100
>100
>100
>0.8
>20
>0.8
>20
>20
77.7
>100
>100
32.6
1.9
8.4
8.3
6.5
97.9
>100
72.2
43.4
8.9
36.4
30.9
17.4
4g
4bb
5a
5b
5c
5d
6
8
>20
0.16
n.d.
>20
0.16
n.d.
2.3
n.d.
0.07
8.8
n.d.
0.09
ACVa
Ara-Cb
The n.d. means not done.
Scheme 5.
a
ACV¼acyclovir.
b
Ara-C¼arabinosylcytidine.
2.2. Biological activity
(8.8–36.4
midin-7(6H)-one 2e showed potential activity against CCRF-HSB-2
and KB cells at the concentration of 17.5 g/mL and 11.0 g/mL,
respectively, while 6-N-methyl-3-octyl derivative 3e exhibited
about similar activity (25.9 g/mL and 29.0 g/mL) against both
cells. Other compounds were too low toxic to exhibit potential
activity. Thus, it is apparent that the presence of electronegative
chlorine atom at the 7-position is significant for antitumor activ-
ity. Besides, among the alkyl groups at the 9-position, octyl group
is responsible for increased activity due to its hydrophobic char-
acter. 6-N-Alkyl and 7-O-alkyl groups do not enhance antitumor
activity.
mg/mL). 3-Octyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyri-
2.2.1. Antiviral activity
Compounds 2a–g, 3a–g,bb, 4a–g,bb, 5a–d, 6, and 8 were eval-
uated for antiviral activity in vitro against herpes simplex virus type
1 (HSV-1) and type 2 (HSV-2) according to the methods developed
by Machida et al.30,31 The results are summarized in Table 1. The
potency of antiviral activity of each compound is expressed as
a minimum inhibitory concentration (ED50) required to reduce
virus plaque formation by 50% under experimental conditions.
Among the tested compounds, 5a and 5c were more potential
m
m
m
m
(>0.8
activity at the concentration of >4
2a,d, 3e,bb, 4d, 5b,d, 6, and 8, showed activity against both herpes
viruses at the concentration of >20 g/mL and some did not exhibit
any activity up to 100 g/mL. 7-Chloro derivatives are compara-
mg/mL) against both viruses. Compound 2e showed its
m
g/mL. Some compounds, e.g.,
m
m
3. Conclusion
tively more active than 6-N-alkyl or 7-O-alkyl derivatives.
Thus, this can be concluded that the NH proton on the pyrimi-
dine ring of 5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-
ones and 2-phenyl-9-propyl-9H-purin-6(1H)-one remains as
lactam–lactim tautomers. Therefore, the N- and O-alkylation
(electrophilic substitution) takes place simultaneously. The selec-
tivity for the alkylation position onto 5-phenyl-3H-[1,2,3]tri-
azolo[4,5-d]pyrimidin-7(6H)-ones is highly controllable by
temperature as well as by the size and shape of the alkylating agents
(electrophiles). A few of the synthesized compounds have moderate
antiviral and antitumor activities. Therefore, this simple and facile
methodology for simultaneous N- and O-alkylation of lactam–
lactim tautomers might be used in future for the preparation of
analogous compounds for searching potential biological agents.
2.2.2. Antitumor activity
The modified32 3-(3,4-dimethylthiazol-2-yl)-2,5-diphenylte-
trazolium bromide (MTT) assay for cellular growth and survival
application method developed by Mosmann33 was used to de-
termine the growth inhibitory effects (antitumor activity) of the
synthesized compounds against CCRF-HSB-2 (human T-cell acute
lymphoblastoid leukemia) and KB (human oral epidermoid car-
cinoma) cells in vitro. The results, i.e., 50% inhibitory concentra-
tion [IC50 (mg/mL)] of each compound against the both cells are
summarized in Table 1. 7-Chloro-5-phenyl-3H-[1,2,3]triazolo
[4,5-d]pyrimidines (5b–d, 6, and 8) showed better activity against
CCRF-HSB-2 cancer cells (1.9–8.4 mg/mL) than against KB cells

R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
9889
4. Experimental
4.1. General
4.2.4. 5-Amino-6-isobutylamino-2-phenylpyrimidin-4(3H)-one
hemisulfate (1d)
Yield 1.61 g (6.24 mmol, 78%); mp 205–206 ꢀC (decomp.); Rf 0.31
(n-hexane/EtOAc,1:3);IR(Nujol):3280, 3070(NH),1630(C]O) cmꢁ1
1H NMR (CDCl3):
CH2CH), 3.30(s,2H, N-CH2), 6.31(brs,1H,6-NH), 7.43–7.52(m, 3H, Ph-
m,pH), 8.12–8.21 (m, 2H, Ph-oH). Anal. Calcd for C14H18N4O$1/2H2SO4:
C, 54.71; H, 6.23; N, 18.23. Found: C, 55.07; H, 6.18; N, 18.58.
;
Mps were determined on a Yanagimoto micro-melting point hot
stage apparatus and were uncorrected. IR spectra were obtained
using a JASCO FT/IR-200 spectrophotometer in Nujol mulls. UV
spectra were recorded with a Beckman DU-68 spectrophotometer
in ethanol. IR and UV absorption values in italic refer to wave
numbers and wave length, respectively, at which shoulders or in-
flexions occur in the absorption. 1H NMR spectra were measured
using a VXR 300 MHz spectrometer and chemical shift values were
d
0.94 (d, J¼6.6 Hz, 6H, 2ꢂCH3), 1.83–1.96 (m, 1H, N-
4.2.5. 5-Amino-6-octylamino-2-phenylpyrimidin-4(3H)-one
hemisulfate (1e)
Yield 1.91 g (6.08 mmol, 76%); mp 158–159 ꢀC (decomp.); Rf 0.49
(n-hexane/EtOAc, 1:3); IR (Nujol): 3345, 3070 (NH), 1635
expressed in d values (ppm) relative to TMS as an internal standard.
Coupling constants are given in hertz and signals are quoted as
follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet;
sext, sextet; sept, septed; br, broad; m, multiplet. Microanalyses
were measured by a Yanako CHN Corder MT-5 apparatus. Reaction
progress was monitored by analytical thin-layer chromatography
(TLC) on pre-coated glass plates (silica gel 60 F254 Plate-Merck) and
products were visualized by UV light. Column chromatography was
(C]O) cmꢁ1 1H NMR (CDCl3):
; d 0.85 (s, 3H, CH3), 1.25 (br s, 10H,
[CH2]5CH3), 1.50–1.66 (m, 2H, N-CH2CH2), 3.45 (br s, 2H, N-CH2),
6.16 (br s, 1H, 6-NH), 7.40–7.52 (m, 3H, Ph-m,pH), 8.01–8.13 (m, 2H,
Ph-oH). Anal. Calcd for C18H26N4O$1/2H2SO4: C, 59.48; H, 7.49; N,
15.41. Found: C, 59.87; H, 7.39; N, 15.45.
4.2.6. 5-Amino-6-(2-hydroxyethylamino)-2-phenylpyrimidin-
4(3H)-one hemisulfate (1f)
accomplished on Daisogel IR-60 (63/210 mm, Daiso Co.).
Yield 1.64 g (6.64 mmol, 83%); mp 215–216 ꢀC (decomp.); Rf 0.45
(EtOAc/EtOH, 4:1); IR (Nujol): 3320 (OH), 3200 (NH), 1640
4.2. General procedure for the synthesis of 6-alkylamino-5-
amino-2-phenylpyrimidin-4(3H)-one hemisulfates (1a–g)
(C]O) cmꢁ1; 1H NMR (CDCl3):
(br s, 2H, N-CH2), 4.29 (br s, 1H, OH), 5.97 (br s, 1H, 6-NH), 7.38–7.45
d
3.44 (q, J¼6.9 Hz, 2H, O-CH2), 3.57
A mixture of an appropriate 6-alkylamino-5-nitroso-2-phenyl-
pyrimidin-4(3H)-ones (8.0 mmol), acetic acid (5 mL), water (50 mL),
and methanol (50 mL) was heated to ca. 60 ꢀC and to it was added
Na2S2O4 (25–32 mmol) by portions with stirring. Then, the mixture
was heated at 70 ꢀC for 0.5–1.0 h. After the reaction was complete,
the solutionwas concentrated to ca. 20 mL and to it was added water
(25 mL). Upon keeping the mixture at room temperature (rt) for
several hours, the solid deposited was collected by filtration to give
the corresponding 5,6-diamino hemisulfate derivatives 1a–g as pale
yellow powdery crystals. For analysis a portion of these products
were recrystallized from dilute H2SO4 except 1e, which was
recrystallized from a mixture of ethanol and dilute H2SO4.
(m, 3H, Ph-m,pH), 8.00–8.13 (m, 2H, Ph-oH). Anal. Calcd for
C
12H14N4O2$(1/2H2SO4þ1/8H2O): C, 48.44; H, 5.17; N, 18.83. Found:
C, 48.37; H, 5.37; N, 18.59.
4.2.7. 5-Amino-6-(3-hydroxypropylamino)-2-phenylpyrimidin-
4(3H)-one hemisulfate (1g)
Yield 1.56 g (6.0 mmol, 75%); mp 210–211 ꢀC (decomp.); Rf 0.47
(EtOAc/EtOH, 4:1); IR (Nujol): 3310 (OH), 3200 (NH), 1640
(C]O) cmꢁ1
;
1H NMR (CDCl3):
d
1.73 (quin, J¼6.6 Hz, 2H, N-
CH2CH2), 3.44 (q, J¼6.9 Hz, 2H, O-CH2), 3.51 (t, J¼5.7 Hz, 2H, N-CH2),
4.18 (br s,1H, OH), 6.27 (br s,1H, 6-NH), 7.40–7.54 (m, 3H, Ph-m,pH),
8.01–8.13 (m, 2H, Ph-oH). Anal. Calcd for C13H16N4O2$1/2H2SO4: C,
50.48; H, 5.54; N, 18.11. Found: C, 50.54; H, 5.62; N, 17.91.
4.2.1. 5-Amino-6-ethylamino-2-phenylpyrimidin-4(3H)-one
hemisulfate (1a)
4.3. General procedure for the synthesis of 3-alkyl-5-phenyl-
3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones (2a–g)
Yield 1.28 g (5.52 mmol, 69%); mp 217–218 ꢀC (decomp.); Rf 0.26
(n-hexane/EtOAc, 1:3); IR (Nujol): 3345, 3070 (NH), 1635
(C]O) cmꢁ1; 1H NMR (CDCl3):
s, 2H, CH2), 6.40 (br s, 1H, 6-NH), 7.43–7.52 (m, 3H, Ph-m,pH), 8.03–
8.13 (m, 2H, Ph-oH). Anal. Calcd for C12H14N4O$(1/2H2SO4þ2/
3H2O): C, 49.47; H, 5.65; N, 19.23. Found: C, 49.53; H, 5.44; N, 19.23.
d
1.21 (t, J¼7.2 Hz, 3H, CH3), 3.49 (br
A cooled solution of NaNO2 (10.0 mmol) in water (5 mL) on ice
was added to a solution of an appropriate 1a–g (6.0 mmol) in 10%
HCl (20 mL) at 0–5 ꢀC with stirring over 20 min. Then, the reaction
solution was brought to rt and stirred for 3–5 h. The solid deposited
was collected by filtration, washed with water, and dried to afford
the corresponding [1,2,3]triazolo derivatives 2a–g.
4.2.2. 5-Amino-2-phenyl-6-propylaminopyrimidin-4(3H)-one
hemisulfate (1b)
Yield 1.58 g (6.48 mmol, 81%); mp 215–216 ꢀC (decomp.); Rf 0.29
(n-hexane/EtOAc, 1:3); IR (Nujol): 3340, 3065 (NH), 1640
4.3.1. 3-Ethyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-
one (2a)
(C]O) cmꢁ1
;
1H NMR (CDCl3):
d
0.96 (t, J¼7.5 Hz, 3H, CH3), 1.57–
Pale yellow powdery crystals; yield 1.25 g (5.16 mmol, 86%); mp
257–258 ꢀC (EtOAc); Rf 0.38 (n-hexane/EtOAc, 1:2); IR (Nujol): 3180
1.66 (m, 2H, N-CH2CH2), 3.44 (br s, 2H, N-CH2), 6.38 (br s,1H, 6-NH),
7.41–7.53 (m, 3H, Ph-m,pH), 8.02–8.14 (m, 2H, Ph-oH). Anal. Calcd
for C13H16N4O$(1/2H2SO4þ1/2H2O): C, 51.64; H, 6.00; N, 18.53.
Found: C, 51.67; H, 5.87; N, 18.38.
(NH), 1695 (CO) cmꢁ1; 1H NMR (CDCl3):
d
1.67 (t, J¼7.2 Hz, 3H, CH3),
4.66 (q, J¼7.2 Hz, 2H, CH2), 7.51–7.60 (m, 3H, Ph-m,pH), 8.21 (dd,
Jo,p¼2.1 Hz, Jo,m¼7.8 Hz, 2H, Ph-oH), 12.36 (br s, 1H, NH); UV (EtOH):
lmax (log 3) 238 (4.44), 268 (4.35), 274 (4.37), 283 nm (4.36). Anal.
4.2.3. 5-Amino-6-isopropylamino-2-phenylpyrimidin-4(3H)-one
hemisulfate (1c)
Calcd for C12H11N5O: C, 59.74; H, 4.60; N, 29.03. Found: C, 59.60; H,
4.56; N, 28.83.
Yield 1.51 g (6.16 mmol, 77%); mp 208–210 ꢀC (decomp.); Rf 0.29
(n-hexane/EtOAc, 1:3); IR (Nujol): 3270, 3060 (NH), 1655
4.3.2. 5-Phenyl-3-propyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7(6H)-one (2b)
(C]O) cmꢁ1
;
1H NMR (CDCl3):
d
1.23 (d, J¼6.3 Hz, 6H, 2ꢂCH3),
4.24–4.41 (m, 1H, CH), 6.18 (br s, 1H, 6-NH), 7.49–7.64 (m, 3H,
Ph-m,pH), 8.05–8.14 (m, 2H, Ph-oH). Anal. Calcd for C13H16N4O$(1/
2H2SO4þ1/4H2O): C, 52.42; H, 5.92; N, 18.81. Found: C, 52.60; H,
5.90; N, 18.44.
Pale yellow needles; yield 1.26 g (4.92 mmol, 82%); mp 206–
207 ꢀC (EtOAc); Rf 0.41 (n-hexane/EtOAc, 1:2); IR (Nujol): 3180
(NH), 1700 (CO) cmꢁ1; 1H NMR (CDCl3):
2.10 (m, 2H, N-CH2CH2), 4.60 (t, J¼7.2 Hz, 2H, N-CH2), 7.61–7.63 (m,
d
1.03 (t, J¼7.5 Hz, 3H, CH3),

9890
R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
3H, Ph-m,pH), 8.29 (dd, Jo,p¼2.4 Hz, Jo,m¼7.5 Hz, 2H, Ph-oH), 12.04
(s, 1H, NH); UV (EtOH): lmax (log ) 238 (4.43), 268 (4.34), 274
(4.36), 284 nm (4.34). Anal. Calcd for C13H13N5O: C, 61.16; H, 5.13; N,
27.43. Found: C, 61.28; H, 5.28; N, 27.11.
for 5–6 h. Then, the solutionwas evaporated to dryness in vacuo and
water (15 mL) was added to the residue. The solid deposited was
collected by filtration and washed with water. The two regioisomers
cropped were separated by column chromatography on silica gel
using an appropriate mixture of n-hexane and EtOAc as eluting
solvent to afford the corresponding 7-methoxy 4a–g and 6-methyl
derivatives 3a–g as the first and second fractions, respectively.
3
4.3.3. 3-Isopropyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7(6H)-one (2c)
Pale yellow powdery crystals; yield 1.20 g (4.68 mmol, 78%); mp
261–262 ꢀC (EtOAc); Rf 0.42 (n-hexane/EtOAc, 1:2); IR (Nujol): 3180
4.4.1.1. 3-Ethyl-6-methyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyr-
imidin-7(6H)-one (3a). Colorless needles; yield 0.31 g (1.23 mmol,
49%); mp 221–222 ꢀC (n-hexane/EtOAc); Rf 0.43 (n-hexane/EtOAc,
(NH),1690 (CO) cmꢁ1;1HNMR(CDCl3):
d
1.75 (d, J¼7.2 Hz, 6H, 2ꢂCH3),
5.20 (sept, J¼7.2 Hz, 1H, CH), 7.52–7.61 (m, 3H, Ph-m,pH), 8.21 (dd,
Jo,p¼2.4 Hz, Jo,m¼7.5 Hz, 2H, Ph-oH), 12.12 (s,1H, NH); UV (EtOH): lmax
1:2); IR (Nujol): 1720 (CO) cmꢁ1
;
1H NMR (CDCl3):
d
1.62 (t,
J¼7.2 Hz, 3H, CH2CH3), 3.53 (s, 3H, N-CH3), 4.60 (q, J¼7.2 Hz, 2H,
CH2), 7.53–7.59 (m, 5H, Ph-H); UV (EtOH): lmax (log ) 267 (4.29),
(log 3) 237 (4.4), 268 (4.31), 275 (4.34), 284 nm (4.34). Anal. Calcd for
C13H13N5O: C, 61.16; H, 5.13; N, 27.43. Found: C, 61.48; H, 5.19; N, 27.51.
3
272 nm (4.28). Anal. Calcd for C13H13N5O: C, 61.16; H, 5.13; N, 27.43.
4.3.4. 3-Isobutyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7(6H)-one (2d)
Found: C, 60.91; H, 4.98; N, 27.26.
Pale yellow prisms; yield 1.39 g (5.16 mmol, 86%); mp 203–
204 ꢀC (EtOAc); Rf 0.45 (n-hexane/EtOAc, 1:2); IR (Nujol): 3170
4.4.1.2. 6-Methyl-5-phenyl-3-propyl-3H-[1,2,3]triazolo[4,5-d]pyr-
imidin-7(6H)-one (3b). Pale yellow prisms; yield 0.34 g (1.28 mmol,
51%); mp 170–171 ꢀC (n-hexane/EtOAc); Rf 0.49 (n-hexane/EtOAc,
(NH), 1700 (CO) cmꢁ1
;
1H NMR (CDCl3):
d
1.02 (d, J¼6.9 Hz, 6H,
2ꢂCH3), 2.40–2.53 (m, 1H, N-CH2CH), 4.45 (d, J¼7.2 Hz, 2H, N-CH2),
7.58–7.65 (m, 3H, Ph-m,pH), 8.26 (dd, Jo,p¼2.4 Hz, Jo,m¼7.2 Hz, 2H,
1:2); IR (Nujol): 1715 (CO) cmꢁ1; 1H NMR (CDCl3):
d
0.99 (t, J¼7.5 Hz,
3H, CH2CH3), 2.04 (sext, J¼7.5 Hz, 2H, N-CH2CH2), 3.53(s, 3H, N-CH3),
4.50 (t, J¼7.8 Hz, 2H, N-CH2), 7.52–7.57 (m, 5H, Ph-H); UV (EtOH):
Ph-oH), 11.79 (s, 1H, NH); UV (EtOH): lmax (log 3) 237 (4.47), 268
(4.38), 275 (4.40), 284 nm (4.39). Anal. Calcd for C14H15N5O: C,
62.44; H, 5.61; N, 26.01. Found: C, 62.62; H, 5.66; N, 26.04.
lmax (log 3) 267 (4.41), 272 nm (4.39). Anal. Calcd for C14H15N5O: C,
62.44; H, 5.61; N, 26.01. Found: C, 62.13; H, 5.60; N, 26.02.
4.3.5. 3-Octyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-
one (2e)
4.4.1.3. 3-Isopropyl-6-methyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyr-
imidin-7(6H)-one (3c). Colorless prisms; yield 0.30 g (1.10 mmol,
44%); mp 200–201 ꢀC (n-hexane/EtOAc); Rf 0.51 (n-hexane/EtOAc,
Colorless powdery crystals; yield 1.51 g (4.62 mmol, 77%); mp
132–133 ꢀC (n-hexane/EtOAc); Rf 0.53 (n-hexane/EtOAc, 1:2); IR
1:2); IR (Nujol): 1720 (CO) cmꢁ1
;
1H NMR (CDCl3):
d
1.69 (d,
J¼6.6 Hz, 6H, CH3CHCH3), 3.53 (s, 3H, N-CH3), 5.11 (sept, J¼6.6 Hz,
1H, CH), 7.53–7.59 (m, 5H, Ph-H); UV (EtOH): lmax (log ) 266 (4.33),
(Nujol): 3190 (NH), 1690 (CO) cmꢁ1 1H NMR (CDCl3):
; d 0.86 (t,
J¼7.2 Hz, 3H, CH3), 1.26 (br s, 6H, CH2[CH2]3CH3), 1.38 (br s, 4H, N-
CH2CH2[CH2]2), 2.03–2.23 (m, 2H, N-CH2CH2), 4.63 (t, J¼7.52 Hz, 2H,
N-CH2), 7.61–7.65 (m, 3H, Ph-m,pH), 8.25 (dd, Jo,p¼2.1 Hz, Jo,m¼7.5 Hz,
3
272 nm (4.32). Anal. Calcd for C14H15N5O: C, 62.44; H, 5.61; N, 26.01.
Found: C, 62.35; H, 5.62; N, 25.87.
2H, Ph-oH), 11.55 (s, 1H, NH); UV (EtOH): lmax (log 3) 238 (4.44), 268
(4.36), 273 (4.36), 284 nm (4.34). Anal. Calcd for C18H23N5O: C, 66.44;
H, 7.12; N, 21.52. Found: C, 66.52; H, 7.21; N, 21.42.
4.4.1.4. 3-Isobutyl-6-methyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyr-
imidin-7(6H)-one (3d). Colorless needles; yield 0.35 g (1.23 mmol,
49%); mp 159–160 ꢀC (n-hexane/EtOAc); Rf 0.52 (n-hexane/EtOAc,
4.3.6. 3-(2-Hydroxyethyl)-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7(6H)-one (2f)
1:2);IR (Nujol):1720 (CO) cmꢁ1; 1HNMR (CDCl3):
d
0.97 (d, J¼6.6 Hz,
6H, CH3CHCH3), 2.34–2.48 (m, 1H, N-CH2CH), 3.54 (s, 3H, N-CH3),
4.35 (d, J¼7.2 Hz, 2H, N-CH2), 7.52–7.59 (m, 5H, Ph-H); UV (EtOH):
Colorless powdery crystals; yield 1.16 g (4.50 mmol, 75%); mp
270–271 ꢀC (EtOAc/EtOH); Rf 0.43 (EtOAc); IR (Nujol): 3360 (OH),
lmax (log 3) 267 (4.38), 272 nm (4.37). Anal. Calcd for C15H17N5O: C,
3185 (NH), 1715 (CO) cmꢁ1; 1H NMR (DMSO-d6):
d
3.94 (q, J¼5.7 Hz,
63.59; H, 6.05; N, 24.72. Found: C, 63.69; H, 6.09; N, 24.48.
2H, O-CH2), 4.61 (t, J¼5.7 Hz, 2H, N-CH2), 4.98 (t, J¼5.7 Hz, 1H, OH),
7.54–7.63 (m, 3H, Ph-m,pH), 8.15 (d, J¼7.5 Hz, 2H, Ph-oH), 12.77 (s,
4.4.1.5. 6-Methyl-3-octyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyr-
imidin-7(6H)-one (3e). Colorless powdery crystals; yield 0.38 g
(1.13 mmol, 45%); mp 102–103 ꢀC (n-octane/EtOAc); Rf 0.60 (n-hex-
1H, NH); UV (EtOH): lmax (log 3) 237 (4.46), 268 (4.37), 274 (4.39),
283 nm (4.38). Anal. Calcd for C12H11N5O2: C, 56.03; H, 4.31; N,
27.22. Found: C, 56.09; H, 4.38; N, 27.42.
ane/EtOAc, 1:2); IR (Nujol): 1720 (CO) cmꢁ1; 1H NMR (CDCl3):
d 0.86
(t, J¼6.9 Hz, 3H, CH2CH3),1.24 (br s, 6H, CH2[CH2]3CH3),1.34 (br s, 4H,
N-CH2CH2[CH2]2),1.94–2.04 (m, 2H, N-CH2CH2), 3.53 (s, 3H, N-CH3),
4.52 (t, J¼7.5 Hz, 2H, N-CH2), 7.52–7.57 (m, 5H, Ph-H); UV (EtOH):
4.3.7. 3-(3-Hydroxypropyl)-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7(6H)-one (2g)
Colorless prisms; yield 1.03 g (3.78 mmol, 63%); mp 193–194 ꢀC
(EtOAc); Rf 0.42 (EtOAc); IR (Nujol): 3375 (OH), 3180 (NH), 1700
lmax (log 3) 266 (4.32), 271 nm (4.30). Anal. Calcd for C19H25N5O: C,
67.23; H, 7.42; N, 20.63. Found: C, 67.57; H, 7.53; N, 20.43.
(CO) cmꢁ1; 1H NMR (CDCl3):
d
2.25 (quin, J¼6.3 Hz, 2H, N-CH2CH2),
2.66 (br s,1H, OH), 3.66 (t, J¼6.0 Hz, 2H, O-CH2), 4.76 (t, J¼6.9 Hz, 2H,
4.4.1.6. 3-(2-Hydroxyethyl)-6-methyl-5-phenyl-3H-[1,2,3]triazolo-
[4,5-d]pyrimidin-7(6H)-one (3f). Colorless powdery crystals; yield
0.35 g (1.30 mmol, 52%); mp 212–213 ꢀC (EtOAc); Rf 0.50 (EtOAc); IR
N-CH2), 7.50–7.59 (m, 3H, Ph-m,pH), 8.18 (dd, Jo,p¼1.5 Hz, Jo,m¼7.8 Hz,
2H, Ph-oH), 12.41 (s, 1H, NH); UV (EtOH): lmax (log 3) 237 (4.38), 268
(4.29), 273 (4.31), 284 nm (4.32). Anal. Calcd for C13H13N5O2: C, 57.56;
H, 4.83; N, 25.82. Found: C, 57.63; H, 4.96; N, 25.55.
(Nujol): 3440 (OH), 1695 (CO) cmꢁ1 1H NMR (CDCl3):
; d 3.35 (t,
J¼6.6 Hz, 1H, OH), 3.54 (s, 3H, N-CH3), 4.17 (q, J¼6.0 Hz, 2H, O-CH2),
4.72 (t, J¼5.1 Hz, 2H, N-CH2), 7.54–7.59 (m, 5H, Ph-H); UV (EtOH):
4.4. General procedure for the methylation of 2a–g with
methyl iodide
lmax (log 3) 267 (4.38), 271 nm (4.37). Anal. Calcd for C13H13N5O2: C,
57.56; H, 4.83; N, 25.82. Found: C, 57.85; H, 4.80; N, 26.20.
4.4.1. At room temperature (A)
A mixture of an appropriate 2a–g (2.5 mmol), anhydrous K2CO3
(5.0 mmol), and MeI (7.5 mmol) in dry DMF (25 mL) was stirred at rt
4.4.1.7. 3-(3-Hydroxypropyl)-6-methyl-5-phenyl-3H-[1,2,3]triazolo-
[4,5-d]pyrimidin-7(6H)-one (3g). Pale yellow powdery crystals;
yield 0.34 g (1.20 mmol, 48%); mp 146–147 ꢀC (n-hexane/EtOAc); Rf

R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
9891
0.49 (EtOAc); IR (Nujol): 3395 (OH), 1705 (CO) cmꢁ1
(CDCl3):
2.17 (quin, J¼6.0 Hz, 2H, N-CH2CH2), 2.73 (br s, 1H, OH),
3.55 (s, 3H, N-CH3), 3.61 (br s, 2H, O-CH2), 4.73 (t, J¼6.3 Hz, 2H, N-
CH2), 7.53–7.59 (m, 5H, Ph-H); UV (EtOH): lmax (log ) 267 (4.33),
;
1H NMR
1:2); IR (Nujol): 3360 (OH), 1250, 1060 (C–O–C) cmꢁ1
(CDCl3):
;
1H NMR
d
d
4.08 (t, J¼6.6 Hz, 1H, OH), 4.28 (q, J¼6.6 Hz, 2H, O-CH2),
4.37 (s, 3H, O-CH3), 4.90 (t, J¼4.8 Hz, 2H, N-CH2), 7.49–7.55 (m, 3H,
Ph-m,pH), 8.49 (dd, Jo,p¼2.1 Hz, Jo,m¼7.5 Hz, 2H, Ph-oH); UV (EtOH):
3
271 nm (4.31). Anal. Calcd for C14H15N5O2: C, 58.94; H, 5.30; N,
lmax (log 3) 238 (4.70), 245 (4.67), 276 (4.67), 284 (4.69), 293 (4.65),
24.55. Found: C, 58.79; H, 5.29; N, 24.24.
304 nm (4.41). Anal. Calcd for C13H13N5O2: C, 57.56; H, 4.83; N, 25.82.
Found: C, 57.66; H, 4.75; N, 26.11.
4.4.1.8. 3-Ethyl-7-methoxy-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrim-
idine (4a). Colorless needles; yield 0.23 g (0.90 mmol, 36%); mp
135–136 ꢀC (n-octane/EtOAc); Rf 0.32 (n-hexane/EtOAc, 5:1); IR
4.4.1.14. 3-(3-Hydroxypropyl)-7-methoxy-5-phenyl-3H-[1,2,3]triazolo-
[4,5-d]pyrimidine (4g). Colorless needles; yield 0.21 g (0.75 mmol,
30%); mp 138–139 ꢀC (n-octane/EtOAc); Rf 0.36 (n-hexane/EtOAc,
(Nujol): 1250, 1080 (C–O–C) cmꢁ1 1H NMR (CDCl3):
; d 1.72 (t,
J¼7.2 Hz, 3H, CH2CH3), 4.37 (s, 3H, O-CH3), 4.76 (q, J¼7.2 Hz, 2H,
1:2); IR (Nujol): 3355 (OH), 1245, 1050 (C–O–C) cmꢁ1 1H NMR
;
N-CH2), 7.47–7.51 (m, 3H, Ph-m,pH), 8.53 (dd, Jo,p¼2.1 Hz,
(CDCl3):
d
2.24 (quin, J¼6.3 Hz, 2H, N-CH2CH2), 3.17 (br s, 1H, OH),
Jo,m¼7.8 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3
) 238 (4.66), 245
3.59 (t, J¼5.7 Hz, 2H, O-CH2), 4.40 (s, 3H, O-CH3), 4.91 (t, J¼6.3 Hz,
(4.62), 276 (4.63), 284 (4.65), 294 (4.60), 304 nm (4.36). Anal. Calcd
for C13H13N5O: C, 61.16; H, 5.13; N, 27.43. Found: C, 61.12; H, 5.20; N,
27.21.
2H, N-CH2), 7.48–7.53 (m, 3H, Ph-m,pH), 8.48 (dd, Jo,p¼1.8 Hz,
Jo,m¼7.8 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 238 (4.54), 246
(4.50), 276 (4.49), 284 (4.49), 294 (4.45), 304 nm (4.23). Anal. Calcd
for C14H15N5O2: C, 58.94; H, 5.30; N, 24.55. Found: C, 58.66; H, 5.29;
N, 24.65.
4.4.1.9. 7-Methoxy-5-phenyl-3-propyl-3H-[1,2,3]triazolo[4,5-d]pyrim-
idine (4b). Colorless needles; yield 0.22 g (0.80 mmol, 32%); mp
119–120 ꢀC (n-octane/EtOAc); Rf 0.35 (n-hexane/EtOAc, 5:1); IR
4.4.2. At boiling temperature (B)
(Nujol): 1245, 1080 (C–O–C) cmꢁ1
;
1H NMR (CDCl3):
d
1.02 (t,
A mixture of an appropriate 2a–g (1.8 mmol), anhydrous K2CO3
(3.6 mmol), and MeI (7.2 mmol) in dry DMF (20 mL) was refluxed
for 1 h. Then, the solution was evaporated to dryness in vacuo and
water (12 mL) was added to the residue. The solid deposited was
filtered, washed with water, and recrystallized from an appropriate
organic solvent to give the corresponding 6-N-methyl derivatives
3a–g in 81%, 76%, 73%, 81%, 71%, 76%, and 74% yields, respectively.
J¼7.2 Hz, 3H, CH2CH3), 2.13 (sext, J¼7.2 Hz, 2H, N-CH2CH2), 4.38 (s,
3H, O-CH3), 4.68 (t, J¼7.2 Hz, 2H, N-CH2), 7.48–7.52 (m, 3H, Ph-
m,pH), 8.55 (dd, Jo,p¼2.4 Hz, Jo,m¼7.5 Hz, 2H, Ph-oH); UV (EtOH):
lmax (log 3) 238 (4.61), 245 (4.58), 276 (4.57), 284 (4.58), 293 (4.54),
304 nm (4.31). Anal. Calcd for C14H15N5O: C, 62.44; H, 5.61; N, 26.01.
Found: C, 62.28; H, 5.62; N, 25.94.
4.4.1.10. 3-Isopropyl-7-methoxy-5-phenyl-3H-[1,2,3]triazolo[4,5-d]py-
rimidine (4c). Colorless needles; yield 0.23 g (0.85 mmol, 34%); mp
139–140 ꢀC (n-octane/EtOAc); Rf 0.37 (n-hexane/EtOAc, 5:1); IR
4.5. Methylation of 2b with methyl iodide in the presence
of NaH
(Nujol): 1245, 1065 (C–O–C) cmꢁ1
;
1H NMR (CDCl3):
d
1.80 (d,
A mixture of 2b (0.4 g, 1.57 mmol), NaH (0.12 g, 5.0 mmol), and
MeI (0.61 g, 4.3 mmol) in dry DMF (25 mL) was stirred at 0 ꢀC for
7 h. After the usual work-up like above general method as de-
scribed in Section 4.4.1, compounds 3b and 4b were obtained in 52%
and 28% yields, respectively.
J¼6.9 Hz, 6H, CH3CHCH3), 4.37 (s, 3H, O-CH3), 5.32 (sept, J¼6.9 Hz,
1H, CH), 7.50–7.52 (m, 3H, Ph-m,pH), 8.55 (dd, Jo,p¼2.1 Hz,
Jo,m¼7.8 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 238 (4.62), 245
(4.58), 276 (4.58), 284 (4.61), 293 (4.57), 304 nm (4.32). Anal. Calcd
for C14H15N5O: C, 62.44; H, 5.61; N, 26.01. Found: C, 62.13; H, 5.48;
N, 25.96.
4.6. General procedure for the chlorination of 2a–d
4.4.1.11. 3-Isobutyl-7-methoxy-5-phenyl-3H-[1,2,3]triazolo[4,5-d]py-
rimidine (4d). Pale yellow plates; yield 0.26 g (0.93 mmol, 37%); mp
104–105 ꢀC (n-octane/EtOAc); Rf 0.40 (n-hexane/EtOAc, 5:1); IR
To a cooled mixture of an appropriate 2a–d (3.0 mmol) and
phosphoryl chloride (POCl3) (12 mL) was added N,N-dimethylani-
line (0.7 mL) with stirring and the reaction mixture was refluxed
gently for 3 h. Then, the excess POCl3 was evaporated in vacuo and
the residue was treated with cracked ice (20 g). Thus, the solid
deposited was filtered, washed well with water, and dried to give
the corresponding 7-chloro derivatives 5a–d.
(Nujol): 1245, 1085 (C–O–C) cmꢁ1 1H NMR (CDCl3):
; d 1.02 (d,
J¼6.6 Hz, 6H, CH3CHCH3), 2.47–2.59 (m, 1H, N-CH2CH), 4.38 (s, 3H,
O-CH3), 4.52 (d, J¼7.2 Hz, 2H, N-CH2), 7.49–7.54 (m, 3H, Ph-m,pH),
8.56 (dd, Jo,p¼2.1 Hz, Jo,m¼7.5 Hz, 2H, Ph-oH); UV (EtOH): lmax
(log 3) 238 (4.60), 246 (4.57), 276 (4.58), 284 (4.60), 293 (4.56),
304 nm (4.32). Anal. Calcd for C15H17N5O: C, 63.59; H, 6.05; N,
24.72. Found: C, 63.56; H, 6.08; N, 24.75.
4.6.1. 7-Chloro-3-ethyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidine (5a)
Pale yellow powdery crystals; yield 0.65 g (2.52 mmol, 84%); mp
116–117 ꢀC (n-hexane); Rf 0.41 (n-hexane/EtOAc, 5:1); IR (Nujol):
4.4.1.12. 7-Methoxy-3-octyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrim-
idine (4e). Pale yellow powdery crystals; yield 0.26 g (0.75 mmol,
30%); mp 58–59 ꢀC (n-octane); Rf 0.47 (n-hexane/EtOAc, 5:1); IR
1590, 1560, 1460, 1400, 1155, 705 cmꢁ1 1H NMR (CDCl3):
; d 1.74 (t,
J¼7.2 Hz, 3H, CH3), 4.85 (q, J¼7.2 Hz, 2H, CH2), 7.50–7.55 (m, 3H,
(Nujol): 1245, 1080 (C–O–C) cmꢁ1 1H NMR (CDCl3):
; d 0.86 (t,
Ph-m,pH), 8.56 (dd, Jo,p¼2.4 Hz, Jo,m¼8.1 Hz, 2H, Ph-oH); UV (EtOH):
J¼6.9 Hz, 3H, CH2CH3), 1.25 (br s, 6H, CH2[CH2]3CH3), 1.38 (br s, 4H,
N-CH2CH2[CH2]2), 2.05–2.13 (m, 2H, N-CH2CH2), 4.38 (s, 3H, O-
CH3), 4.70 (t, J¼7.2 Hz, 2H, N-CH2), 7.49–7.52 (m, 3H, Ph-m,pH), 8.55
lmax (log 3) 246 (4.68), 252 (4.66), 265 (4.42), 273 (4.41), 289 (4.44),
302 nm (4.48). Anal. Calcd for C12H10ClN5: C, 55.50; H, 3.88; N,
26.97. Found: C, 55.71; H, 4.01; N, 26.79.
(dd, Jo,p¼1.8 Hz, Jo,m¼7.5 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 238
(4.55), 246 (4.52), 275 (4.50), 284 (4.51), 293 (4.47), 304 nm (4.25).
Anal. Calcd for C19H25N5O: C, 67.23; H, 7.42; N, 20.63. Found: C,
66.98; H, 7.22; N, 20.85.
4.6.2. 7-Chloro-5-phenyl-3-propyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidine (5b)
Pale yellow needles; yield 0.76 g (2.79 mmol, 93%); mp 98–99 ꢀC
(n-hexane); Rf 0.51 (n-hexane/EtOAc, 5:1); IR (Nujol): 1590, 1555,
4.4.1.13. 3-(2-Hydroxyethyl)-7-methoxy-5-phenyl-3H-[1,2,3]triazolo-
[4,5-d]pyrimidine (4f). Colorless needles; yield 0.24 g (0.88 mmol,
35%); mp 163–164 ꢀC (n-hexane/EtOAc); Rf 0.39 (n-hexane/EtOAc,
1465, 1400, 1160, 710 cmꢁ1; 1H NMR (CDCl3):
CH2CH3), 2.16 (sext, J¼7.5 Hz, 2H, N-CH2CH2), 4.73 (t, J¼7.5 Hz, 2H,
N-CH2), 7.52–7.56 (m, 3H, Ph-m,pH), 8.56 (dd, Jo,p¼1.8 Hz,
d
1.04 (t, J¼7.5 Hz, 3H,

9892
R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
Jo,m¼8.1 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3
) 247 (4.61), 253
4.10. 3-(2-Chloroethyl)-7-methoxy-5-phenyl-3H-
[1,2,3]triazolo[4,5-d]pyrimidine (8)
(4.60), 265 (4.38), 272 (4.36), 290 (4.37), 302 nm (4.39). Anal. Calcd
for C13H12ClN5: C, 57.04; H, 4.42; N, 25.59. Found: C, 56.82; H, 4.39;
N, 25.61.
To
a solution of sodium methoxide (from 0.03 g of Na,
1.30 mmol) in methanol (25 mL) was added 6 (0.15 g, 0.51 mmol)
and the mixture was stirred at rt for 1 h. Then, the solvent was
removed in vacuo and water (10 mL) was added to the residue.
Thus, the solid deposited was collected by filtration, washed with
water to give product 8 as pale yellow needles; yield 0.12 g (81%);
mp 182–183 ꢀC (n-octane/EtOAc); Rf 0.16 (n-hexane/EtOAc, 5:1); IR
4.6.3. 7-Chloro-3-isopropyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidine (5c)
Colorless needles; yield 0.71 g (2.61 mmol, 87%); mp 118–119 ꢀC
(n-hexane); Rf 0.52 (n-hexane/EtOAc, 5:1); IR (Nujol): 1590, 1560,
1460,1380,1160, 710 cmꢁ1; 1H NMR (CDCl3):
d
1.83 (d, J¼6.6 Hz, 6H,
2ꢂCH3), 5.36 (sept, J¼6.6 Hz, 1H, CH), 7.48–7.53 (m, 3H, Ph-m,pH),
8.55 (dd, Jo,p¼2.4 Hz, Jo,m¼7.8 Hz, 2H, Ph-oH); UV (EtOH): lmax
(Nujol): 1245, 1085 (C–O–C) cmꢁ1 1H NMR (CDCl3):
; d 4.15 (t,
J¼6.3 Hz, 2H, Cl-CH2), 4.38 (s, 3H, O-CH3), 5.03 (t, J¼6.3 Hz, 2H,
(log 3) 247 (4.56), 252 (4.55), 265 (4.33), 272 (4.31), 290 (4.31),
N-CH2), 7.49–7.53 (m, 3H, Ph-m,pH), 8.56 (dd, Jo,p¼1.8 Hz,
301 nm (4.36). Anal. Calcd for C13H12ClN5: C, 57.04; H, 4.42; N,
25.59. Found: C, 57.15; H, 4.45; N, 25.54.
Jo,m¼7.8 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 237 (4.54), 244
(4.49), 276 (4.48), 284 (4.50), 292 (4.47), 304 nm (4.23). Anal. Calcd
for C13H12ClN5O: C, 53.89; H, 4.17; N, 24.17. Found: C, 53.84; H, 4.22;
N, 24.10.
4.6.4. 7-Chloro-3-isobutyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidine (5d)
Colorless needles; yield 0.81 g (2.82 mmol, 94%); mp 107–
108 ꢀC (n-octane); Rf 0.55 (n-hexane/EtOAc, 5:1); IR (Nujol): 1590,
4.11. 3-(3-Chloropropyl)-7-methoxy-5-phenyl-3H-
[1,2,3]triazolo[4,5-d]pyrimidine (9)
1560, 1465, 1400, 1155, 710 cmꢁ1 1H NMR (CDCl3):
; d 1.04 (d,
J¼6.6 Hz, 6H, 2ꢂCH3), 2.47–2.61 (m, 1H, N-CH2CH), 4.58 (d,
Compound 9 was prepared from 7 (0.15 g, 0.49 mmol) in an
analogous way to 8 as colorless needles; yield 0.13 g (88%); mp 115–
116 ꢀC (n-octane/EtOAc); Rf 0.18 (n-hexane/EtOAc, 5:1); IR (Nujol):
J¼7.2 Hz, 2H, N-CH2), 7.49–7.56 (m, 3H, Ph-m,pH), 8.56 (dd,
Jo,p¼2.1 Hz, Jo,m¼7.5 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 247
(4.62), 253 (4.61), 265 (4.42), 272 (4.40), 289 (4.39), 303 nm (4.42).
Anal. Calcd for C14H14ClN5: C, 58.44; H, 4.90; N, 24.34. Found: C,
58.29; H, 4.91; N, 24.09.
1250, 1085 (C–O–C) cmꢁ1; 1H NMR (CDCl3):
d
2.58 (quin, J¼6.3 Hz,
2H, N-CH2CH2), 3.64 (t, J¼6.3 Hz, 2H, Cl-CH2), 4.38 (s, 3H, O-CH3),
4.90 (t, J¼6.6 Hz, 2H, N-CH2), 7.50–7.53 (m, 3H, Ph-m,pH), 8.56 (dd,
Jo,p¼1.8 Hz, Jo,m¼8.1 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 238
4.7. General procedure (C) for the synthesis of 4a–d from 5a–d
(4.63), 245 (4.59), 276 (4.59), 285 (4.62), 292 (4.60), 304 nm (4.35).
Anal. Calcd for C14H14ClN5O: C, 55.36; H, 4.65; N, 23.06. Found: C,
55.27; H, 4.63; N, 22.91.
Sodium (0.05 g, 2.17 mmol) was dissolved in absolute methanol
(30 mL) and to it was added an appropriate 5a–d (1.0 mmol). The
resulting solution was stirred at rt for 1–2 h. Then, the solution was
evaporated in vacuo to dryness and water (10 mL) was added to the
residue. Thus, the solid deposited was filtered, washed with water,
and recrystallized from a mixture of n-octane and EtOAc to afford
the corresponding products 4a–d in 91%, 94%, 93%, and 87% yields,
respectively.
4.12. Methylation of 2b with dimethyl sulfate
4.12.1. At room temperature
A mixture of 2b (0.5 g, 1.96 mmol), anhydrous K2CO3 (0.54 g,
3.92 mmol), and dimethyl sulfate (0.37 g, 2.94 mmol) in dry DMF
(25 mL) was stirred at rt for 8 h. After the usual work-up like the
general method as described in Section 4.4.1, compounds 3b and 4b
were obtained in 17% and 61% yields, respectively.
4.8. 7-Chloro-3-(2-chloroethyl)-5-phenyl-3H-
[1,2,3]triazolo[4,5-d]pyrimidine (6)
4.12.2. At boiling temperature
Compound 6 was prepared from 2f (0.50 g, 1.94 mmol) accord-
ing to the general procedure for chlorination of 2a–d as pale yellow
needles; yield 0.50 g (87%); mp 129–130 ꢀC (n-octane/EtOAc); Rf
0.22 (n-hexane/EtOAc, 5:1); IR (Nujol): 1590, 1555, 1460, 1160,
The above methylation of 2b with dimethyl sulfate at boiling
temperature for 3 h gave 3b and 4b in 16% and 39% yields,
respectively.
710 cmꢁ1; 1H NMR (CDCl3):
d
4.17 (t, J¼6.3 Hz, 2H, Cl-CH2), 5.09 (t,
J¼6.3 Hz, 2H, N-CH2), 7.51–7.58 (m, 3H, Ph-m,pH), 8.56 (dd,
) 246
4.13. Ethylation of 2b with ethyl iodide
Jo,p¼2.1 Hz, Jo,m¼7.8 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3
4.13.1. At room temperature
(4.67), 252 (4.66), 265 (4.45), 273 (4.43), 290 (4.45), 302 nm (4.48).
Anal. Calcd for C12H9Cl2N5: C, 49.00; H, 3.08; N, 23.81. Found: C,
48.90; H, 3.35; N, 23.57.
A mixture of 2b (0.62 g, 2.43 mmol), anhydrous K2CO3 (0.67 g,
4.86 mmol), and ethyl iodide (1.04 g, 7.3 mmoL) in dry DMF (25 mL)
was stirred at rt for 8 h. Then, the solution was evaporated to
dryness in vacuo and water (20 mL) was added to the residue. The
solid deposited was collected by filtration and washed with water.
The two regioisomers cropped were separated by column chro-
matography using n-hexane/EtOAc (6:1/1:1) as eluting solvent to
afford the 7-O-ethyl 4ba and 6-N-ethyl derivatives 3ba as the first
and second fractions, respectively.
4.9. 7-Chloro-3-(3-chloropropyl)-5-phenyl-3H-
[1,2,3]triazolo[4,5-d]pyrimidine (7)
Compound 7 was prepared from 2g (0.60 g, 2.21 mmol) in the
similar way to 6 as colorless prisms; yield 0.57 g (84%); mp 120–
121 ꢀC (n-hexane); Rf 0.30 (n-hexane/EtOAc, 5:1); IR (Nujol): 1590,
1560, 1460, 1160, 710 cmꢁ1; 1H NMR (CDCl3):
d
2.60 (quin, J¼6.3 Hz,
4.13.1.1. 6-Ethyl-5-phenyl-3-propyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7(6H)-one (3ba). Pale yellow needles; yield 0.07 g (10%); mp 145–
146 ꢀC (n-hexane/EtOAc); Rf 0.48 (n-hexane/EtOAc, 1:2); IR (Nujol):
2H, N-CH2CH2), 3.65 (t, J¼6.3 Hz, 2H, Cl-CH2), 4.96 (t, J¼6.6 Hz, 2H,
N-CH2), 7.51–7.56 (m, 3H, Ph-m,pH), 8.57 (dd, Jo,p¼2.4 Hz,
Jo,m¼7.8 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 247 (4.53), 252
1710 (CO) cmꢁ1
;
1H NMR (CDCl3):
d
0.98 (t, J¼7.5 Hz, 3H, 3-
(4.53), 264 (4.37), 272 (4.38), 290 (4.31), 303 nm (4.33). Anal. Calcd
for C13H11Cl2N5: C, 50.67; H, 3.60; N, 22.73. Found: C, 51.00; H, 3.74;
N, 22.54.
CH2CH2CH3), 1.22 (t, J¼7.2 Hz, 3H, 6-CH2CH3), 2.03 (sext, J¼7.5 Hz,
2H, 3-CH2CH2), 4.08 (q, J¼7.2 Hz, 2H, 6-CH2), 4.49 (t, J¼7.2 Hz, 2H,
3-CH2), 7.48–7.59 (m, 5H, Ph-H); UV (EtOH): lmax (log 3) 265 (4.33),

R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
9893
272 nm (4.30). Anal. Calcd for C15H17N5O: C, 63.59; H, 6.05; N, 24.72.
4.15.2. At boiling temperature
Found: C, 63.89; H, 6.17; N, 24.58.
The above benzylation of 2b with benzyl bromide at boiling
temperature for 1 h gave 3bb and 4bb in 37% and 35% yields,
respectively.
4.13.1.2. 7-Ethoxy-5-phenyl-3-propyl-3H-[1,2,3]triazolo[4,5-d]pyrim-
idine (4ba). Colorless needles; yield 0.45 g (66%); mp 73–74 ꢀC (n-
octane/EtOAc); Rf 0.40 (n-hexane/EtOAc, 5:1); IR (Nujol): 1245,
1085 (C–O–C) cmꢁ1
;
1H NMR (CDCl3):
d
1.01 (t, J¼7.2 Hz, 3H, 3-N-
4.16. Preparation of 2-phenyl-9-propyl-9H-purin-6(1H)-
one (10)
CH2CH2CH3), 1.61 (t, J¼7.2 Hz, 3H, O-CH2CH3), 2.13 (sext, J¼7.2 Hz,
2H, N-CH2CH2), 4.67 (t, J¼7.2 Hz, 2H, N-CH2), 4.87 (q, J¼7.2 Hz, 2H,
O-CH2), 7.48–7.54 (m, 3H, Ph-m,pH), 8.54 (dd, Jo,p¼2.1 Hz,
A solution of free 5,6-diaminopyrimidine derivative 1b (1.0 g,
4.09 mmol) in 85% aqueous formic acid (15 mL) was heated under
reflux for overnight. Then, the solution was concentrated to ca.
2 mL and to it was added water (15 mL). Thus, the solid deposited
was collected by filtration and washed with water to afford 10 as
pale yellow powdery crystals; yield 0.78 g (75%); mp 265–267 ꢀC
(EtOAc/EtOH); Rf 0.47 (EtOAc/EtOH, 4:1); IR (Nujol): 3175 (NH),
Jo,m¼7.5 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 239 (4.48), 246
(4.45), 277 (4.44), 285 (4.45), 292 (4.42), 304 nm (4.15). Anal. Calcd
for C15H17N5O: C, 63.59; H, 6.05; N, 24.72. Found: C, 63.49; H, 6.10;
N, 24.67.
4.13.2. At boiling temperature
The above ethylation of 2b with little more excess ethyl iodide
(ca. 5 equiv) at boiling temperature for 4 h gave 3ba and 4ba in 18%
and 41% yields, respectively.
1690 (CO) cmꢁ1
;
1H NMR (CDCl3):
d
1.0 (t, J¼7.5 Hz, 3H, CH3), 1.98
(sext, J¼7.4 Hz, 2H, N-CH2CH2), 4.21 (t, J¼7.4 Hz, 2H, N-CH2),
7.52–7.62 (m, 3H, Ph-m,pH), 7.81 (s, 1H, N]CH), 8.22–8.25 (m, 2H,
Ph-oH), 11.90 (s, 1H, NH); UV (EtOH): lmax (log 3) 261 (3.99), 302 nm
(4.14). Anal. Calcd for C14H14N4O$1/8H2O: C, 65.55; H, 5.60; N,
21.84. Found: C, 65.49; H, 5.64; N, 21.89.
4.14. Preparation of 4ba from 5b
To a solution of sodium ethoxide (from 0.02 g of Na, 0.87 mmol)
in absolute ethanol (20 mL) was added 5b (0.11 g, 0.40 mmol) and
the solution was stirred at rt for 1 h. The solvent was removed in
vacuo and water (10 mL) was added to the residue. Thus, the solid
deposited was collected by filtration, washed with water to give
4ba (0.09 g, 79%), which was identical in all respects with authentic
sample prepared by another method.
4.17. Methylation of 10
4.17.1. With 1 equiv MeI at 0 ꢀC
A mixture of 10 (0.4 g, 1.57 mmol), anhydrous K2CO3 (0.4 g,
2.89 mmol), and MeI (0.23 g, 1.62 mmol) in dry DMF (20 mL) was
stirred at 0 ꢀC for 1.5 days. Then, the solution was evaporated to
dryness in vacuo and water (10 mL) was added to the residue. The
products were extracted with CH2Cl2 and the extract was dried over
anhydrous MgSO4. Solvent was removed in vacuo and the residue
was subjected to column chromatography on silica gel column
using n-hexane/EtOAc (2:1/1:10) as eluting solvent to give 11b
and 11a as the first and second fractions, respectively.
4.15. Benzylation of 2b with benzyl bromide
4.15.1. At room temperature
A mixture of 2b (0.55 g, 2.16 mmol), anhydrous K2CO3 (0.60 g,
4.32 mmol), and benzyl bromide (0.55 g, 3.24 mmol) in dry DMF
(25 mL) was stirred at rt for 8 h. Then, the solution was evaporated
to dryness in vacuo and water (20 mL) was added to the residue.
The solid deposited was collected by filtration and washed with
water. The two regioisomers cropped were separated by column
chromatography using n-hexane/EtOAc (6:1/1:1) as eluting sol-
vent to afford the 7-O-benzyl 4bb and 6-N-benzyl derivatives 3bb
as the first and second fractions, respectively.
4.17.1.1.
Colorless needles; yield 0.11 g (26%); mp 169–170 ꢀC (n-hexane/
EtOAc); Rf 0.53 (EtOAc/EtOH, 4:1); IR (Nujol): 1685 (CO) cmꢁ1 1H
NMR (CDCl3):
0.96 (t, J¼7.5 Hz, 3H, CH2CH3), 1.90 (sext, J¼7.4 Hz,
2H, N-CH2CH2), 3.53 (s, 3H, N-CH3), 4.12 (t, J¼7.4 Hz, 2H, N-CH2),
7.53 (s, 5H, Ph-H), 7.77 (s, 1H, N]CH); UV (EtOH): lmax (log ) 254
1-Methyl-2-phenyl-9-propyl-9H-purin-6(1H)-one (11a).
;
d
3
(4.02), 282 nm (4.01). Anal. Calcd for C15H16N4O: C, 67.15; H, 6.01; N,
20.88. Found: C, 67.29; H, 6.11 N, 20.77.
4.15.1.1. 6-Benzyl-5-phenyl-3-propyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
7(6H)-one (3bb). Colorless needles; yield 0.10 g (13%); mp 156–
157 ꢀC (n-hexane/EtOAc); Rf 0.55 (n-hexane/EtOAc, 1:2); IR (Nujol):
4.17.1.2. 6-Methoxy-2-phenyl-9-propyl-9H-purine (11b). Pale yel-
low powdery crystals; yield 0.19 g (45%); mp 115 ꢀC (n-hexane/
EtOAc); Rf 0.22 (n-hexane/EtOAc, 1:1); IR (Nujol): 1240, 1080 (C–O–
1715 (CO) cmꢁ1; 1H NMR (CDCl3):
d
0.99 (t, J¼7.5 Hz, 3H, CH3), 2.04
C) cmꢁ1; 1H NMR (CDCl3):
d
1.0 (t, J¼7.5 Hz, 3H, CH2CH3), 2.01 (sext,
(sext, J¼7.5 Hz, 2H, N-CH2CH2), 4.50 (t, J¼7.5 Hz, 2H, N-CH2), 5.30 (s,
2H, CH2Ph), 6.84–6.88 (m, 2H, Ph-H), 7.17–7.27 (m, 5H, Ph-H), 7.42
(t, J¼7.8 Hz, 2H, Ph-H), 7.49–7.55 (m, 1H, Ph-H); UV (EtOH): lmax
J¼7.4 Hz, 2H, N-CH2CH2), 4.26 (t, J¼7.4 Hz, 2H, N-CH2), 4.29 (s, 3H,
O-CH3), 7.43–7.52 (m, 3H, Ph-m,pH), 7.89 (s, 1H, N]CH), 8.53 (dd,
Jo,p¼2.1 Hz, Jo,m¼7.8 Hz, 2H, Ph-oH); UV (EtOH): lmax (log
3) 231
(log
3) 265 (4.36), 272 nm (4.33). Anal. Calcd for C20H19N5O: C,
(4.30), 237 (4.28), 282 (4.37), 290 (4.34), 305 nm (3.97). Anal. Calcd
for C15H16N4O: C, 67.15; H, 6.01; N, 20.88. Found: C, 66.93; H, 6.12;
N, 20.80.
69.55; H, 5.54; N, 20.28. Found: C, 69.73; H, 5.65; N, 20.06.
4.15.1.2. 7-Benzyloxy-5-phenyl-3-propyl-3H-[1,2,3]triazolo[4,5-d]pyr-
imidine (4bb). Colorless needles; yield 0.47 g (63%); mp 105–106 ꢀC
(n-octane/EtOAc); Rf 0.40 (n-hexane/EtOAc, 5:1); IR (Nujol): 1250
4.17.2. With 1 equiv Me2SO4 at room temperature
A mixture of 10 (0.3 g, 1.18 mmol), anhydrous K2CO3 (0.3 g,
2.17 mmol), and Me2SO4 (2.3 g, 1.62 mmol) in dry DMF (20 mL)
was stirred at rt for 1 day. Then, the solution was evaporated to
dryness in vacuo and water (10 mL) was added to the residue.
The products were extracted with CH2Cl2 and the extract
was dried over anhydrous MgSO4. Solvent was removed in vacuo
and the residue was recrystallized from n-hexane to give 11b
(0.24 g, 76%).
(C–O–C) cmꢁ1
;
1H NMR (CDCl3):
d
1.02 (t, J¼7.5 Hz, 3H, CH3), 2.12
(sext, J¼7.2 Hz, 2H, N-CH2CH2), 4.67 (t, J¼7.2 Hz, 2H, N-CH2), 5.86 (s,
2H, CH2Ph), 7.34–7.43 (m, 3H, Ph-H), 7.50–7.53 (m, 3H, Ph-H), 7.61
(d, J¼7.2 Hz, 2H, Ph-H), 7.55 (dd, J¼2.1 Hz, J¼7.5 Hz, 2H, Ph-H); UV
(EtOH): lmax (log 3) 240 (4.60), 247 (4.57), 276 (4.51), 284 (4.53), 293
(4.49), 304 nm (4.26). Anal. Calcd for C20H19N5O: C, 69.55; H, 5.54; N,
20.28. Found: C, 69.59; H, 5.63; N, 20.12.

9894
R. Islam et al. / Tetrahedron 64 (2008) 9885–9894
5. Daly, J. W.; Padgett, W. L.; Shamim, M. T. J. Med. Chem. 1986, 29, 1305.
4.17.3. With excess MeI at room temperature
6. Thomson, R. L.; Price, M. L.; Minton, S. A., Jr.; Elion, G. B.; Hitchings, G. H.
J. Immunol. 1950, 65, 529.
7. Sugiyama, T.; Fujita, M.; Koide, N.; Mori, I.; Yoshida, T.; Mori, H.; Yokochi, T.
Microbiol. Immunol. 2004, 48, 957.
8. De Simone, C.; Famularo, G.; Foresta, P.; Albertoni, C.; Arrigoni Martelli, E. Ann.
N.Y. Acad. Sci. 1993, 685, 344.
9. Clarke, D. A.; Elion, G. B.; Hitchings, G. H.; Stock, C. C. Cancer Res. 1958, 18, 445.
10. Bowden, K.; Wooldridge, K. R. H. Biochem. Pharmacol. 1973, 22, 1015.
11. Noell, C. W.; Robins, R. K. J. Med. Pharm. Chem. 1962, 5, 558.
12. Nagamatsu, T.; Yamasaki, H.; Akiyama, T.; Hara, S.; Mori, K.; Kusakabe, H.
Synthesis 1999, 655.
A mixture of 10 (0.4 g, 1.57 mmol), anhydrous K2CO3 (0.45 g,
3.26 mmol), and MeI (0.60 g, 4.23 mmol) in DMF (20 mL) was
stirred at rt for 15 h. Then, another portion of MeI (0.50 g,
3.52 mmol) was added to the reaction mixture and the mixture was
stirred at rt for additional 15 h. The usual work-up like method as
described in Section 4.17.1 gave 12 and 11b as the first and second
fractions in 30% and 44% yields, respectively.
4.17.3.1. 6,9-Dihydro-1,7-dimethyl-6-oxo-2-phenyl-9-propyl-1H-pu-
rin-7-ium hydroxide (12). Colorless prisms; mp 147 ꢀC (n-hexane);
Rf 0.48 (n-hexane/EtOAc, 1:1); IR (Nujol): 3350 (OH), 1680
13. Nagamatsu, T.; Fujita, T.; Endo, K. J. Chem. Soc., Perkin Trans. 1 2000, 33.
14. Nagamatsu, T.; Yamasaki, H.; Hirota, T.; Yamato, M.; Kido, Y.; Shibata, M.;
Yoneda, F. Chem. Pharm. Bull. 1993, 41, 362.
15. Nagamatsu, T.; Yamagishi, Y.; Yoneda, F. Jpn. Kokai Tokkyo koho JP 09 255,681,
1977; Chem. Abstr. 1997, 127, 336635w.
16. Ali, H. I.; Ashida, N.; Nagamatsu, T. Bioorg. Med. Chem. 2008, 16, 922.
17. Nagamatsu, T.; Kuroda, K.; Mimura, N.; Yanada, R.; Yoneda, F. J. Chem. Soc.,
Perkin Trans. 1 1994, 1125.
18. Nagamatsu, T.; Islam, R.; Ashida, N. Heterocycles 2007, 72, 573.
19. Islam, R.; Nagamatsu, T. Synthesis 2006, 4167.
(CO) cmꢁ1
;
1H NMR (CDCl3):
d
0.99 (t, J¼7.5 Hz, 3H, CH2CH3), 1.68
(sext, J¼7.4 Hz, 2H, N-CH2CH2), 3.08 (s, 3H, 1-N-CH3), 3.54–3.61 (m,
2H, N-CH2), 4.04 (s, 3H, 7-N-CH3), 4.95 (br s, 1H, OH), 7.43–7.48 (m,
3H, Ph-m,pH), 8.0 (s, 1H, N]CH), 8.43 (dd, Jo,p¼2.1 Hz, Jo,m¼7.5 Hz,
2H, Ph-oH); UV (EtOH): lmax (log 3) 240 (4.67), 246 (4.69), 262
20. Huber, G. Chem. Ber. 1957, 90, 698.
(4.40), 299 nm (4.02). Anal. Calcd for C16H20N4O2: C, 63.98; H, 6.71;
N, 18.65. Found: C, 63.59; H, 6.65; N, 18.61.
21. Ovcharova, I. M.; Golovchinskaya, E. S. Khim.-Farm. Zh. 1974, 8, 26.
22. Carvalho, M. A.; Esteves, T. M.; Proenca, M. F.; Booth, B. L. Org. Biomol. Chem.
2004, 2, 1019.
23. Yoneda, F.; Nagamatsu, T. J. Chem. Soc., Perkin Trans. 1 1976, 1547.
24. Bram, G.; Decodts, G.; Bensaid, Y.; Farnoux, C. C.; Galons, H.; Miocque, M.
Synthesis 1985, 543.
Acknowledgements
25. Nu¨bel, G.; Pfleiderer, W. Chem. Ber. 1965, 98, 1060.
26. Koppel, H. C.; O’Brien, D. E.; Robins, R. K. J. Org. Chem. 1959, 24, 259.
27. Montgomery, J. A.; Holum, L. B.; Johnston, T. P. J. Am. Chem. Soc. 1959, 81, 3963.
28. Nagamatsu, T.; Yamada, H.; Shiromoto, K. Heterocycles 2004, 63, 9.
29. Bohle, D. S.; McQuade, L. E.; Perepichka, I.; Zhang, L. J. Org. Chem. 2007,
72, 3625.
The authors are grateful to the SC-NMR Laboratory of Okayama
University, Japan for the NMR experiments.
References and notes
30. Machida, H.; Sakata, S.; Kuninaka, A.; Yoshino, H.; Nakayama, C.; Saneyoshi, M.
Antimicrob. Agents Chemother. 1979, 16, 158.
31. Machida, H.; Sakata, S.; Kuninaka, A.; Yoshino, H. Antimicrob. Agents Chemother.
1981, 20, 47.
32. Miura, S.; Yoshimura, Y.; Endo, M.; Machida, H.; Matsuda, A.; Tanaka, M.;
Sasaki, T. Cancer Lett. 1998, 129, 103.
33. Mosmann, T. J. Immunol. Methods 1983, 65, 55.
1. Smith, K. O.; Galloway, K. S.; Kennell, W. L.; Ogilvie, K. K.; Radatus, B. K. Anti-
microb. Agents Chemother. 1982, 22, 55.
2. Skipper, H. E.; Montgomery, J. A.; Thomson, J. R.; Schabel, F. M., Jr. Cancer Res.
1959, 19, 425; Cancer Res. 1959, 19, 287 (supplement).
3. Kidder, G. W.; Dewey, V. C.; Parks, R. E., Jr.; Woodside, G. L. Cancer Res. 1949,
11, 204.
4. Baker, B. R.; Wood, W. F. J. Med. Chem. 1967, 10, 1101.