A solution-phase parallel synthesis of 5-substituted 3,6-dihydro-7H-1,2,3- triazolo[4,5-d]pyrimidin-7-ones

Article abstract of DOI:10.1002/cjoc.201190201

5-Substituted 7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones (4) were rapidly prepared by a solution-phase parallel synthetic method, which includes aza-Wittig reaction of iminophosphorane (1) with phenyl isocynate to give carbodiimide (2) and subsequent reacti

Full text of DOI:10.1002/cjoc.201190201

FULL PAPER
A Solution-Phase Parallel Synthesis of 5-Substituted
3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones
Sun, Shaofa*(孙绍发)
Chen, Li(陈莉)
Yang, Xuhong(杨绪红)
Department of Chemistry and Life Science, Xianning College, Xianning, Hubei 437000, China
5-Substituted 7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones (4) were rapidly prepared by a solution-phase parallel
synthetic method, which includes aza-Wittig reaction of iminophosphorane (1) with phenyl isocynate to give car-
bodiimide (2) and subsequent reaction of 2 with various amine and alcohols in the presence of catalytic amount of
sodium alkoxide in a parallel fashion.
Keywords aza-Wittig reaction, triazolo[4,5-d]pyrimidin-7-one, parallel synthesis, isocyanate
Introduction
apparatus (Beijing Taike Company) and were uncor-
rected. MS were measured on Finnigan Trace MS spec-
trometer. IR spectra were recorded on a PE-983 infrared
7H-1,2,3-Triazolo[4,5-d]pyrimidin-7-ones, also
named as 8-azaguanines, are of great importances be-
cause of their remarkable biological properties and their
structural similarity with guanines. For example, some
derivatives of them show significant antitumor, antiviral,
and anti-HIV activities,1-3 whereas others exhibited
good fungicidal activities.4 There are many known
methods for the synthesis of 7H-1,2,3-triazolo[4,5-
d]pyrimidin-7-ones,5-8 however, there were few reports
on the synthesis of 5-amino or 5-alkoxy substituted
7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones.9
－1
spectrometer as KBr pellets with absorption in cm .
NMR were recorded in CDCl3 on a Varian Mercury 400
spectrometer and resonances are given relative to TMS.
Elementary analyses were taken on a Vario EL III ele-
mentary analysis instrument. Iminophosphorane (1) was
prepared by the literature report.16
Parallel synthesis of 2-substituted 7H-1,2,3-triazolo-
[4,5-d]pyrimidin-7-ones (4)
To a solution of iminophosphorane 1 (13.7 g, 26
mmol) in dry methylene dichloride (100 mL) was added
phenyl isocyanate (3.09 g, 26 mmol) under nitrogen at
r.t. After the reaction mixture was stood for 24 h, the
solvent was removed off under reduced pressure and
ether/petroleum ether (V∶V＝1∶2, 200 mL) was
added to precipitate triphenylphosphine oxide. After
filtration, the filtrate was condensed and methylene di-
chloride was added to make a solution of carbodiimide
(2) (130 mL), which was divided into thirteen parts (10
mL every part). To each part of 2 prepared above (10
mL) was added separately di-n-propylamine (0.20 g, 2
mmol), or di-n-butylamine (0.26 g, 2 mmol), or
di-iso-butylamine (0.26 g, 2 mmol), or di-n-pentylamine
(0.31 g, 2 mmol), or di-n-hexylamine (0.37 g, 2 mmol),
or piperidine (0.17 g, 2 mmol), or morpholine (0.17 g, 2
mmol), or methol (0.04 g, 2 mmol), or n-propanol (0.12
g, 2 mmol), or iso-propanol (0.12 g, 2 mmol), or
n-butanol (0.15 g, 2 mmol), or prop-2-en-1-ol (0.12 g, 2
mmol), or prop-2-yn-1-ol (0.11 g, 2 mmol). After the
reaction mixture was stood for 1—2 h, anhydrous alco-
hol (10 mL) with several drops of RONa in ROH was
added. The mixture was stirred for 2—5 h at room tem-
perature (r.t.). The solution was condensed and the re-
sidual was recrystallized from ethanol to give
Recently, combinatorial synthesis of libraries con-
taining small organic molecules has become a rapid
evolving area of research.10-12 It includes solid-phase
and solution-phase synthetic techniques. Solution-phase
synthetic techniques have the advantages of nonlimiting
scale and can be easily manipulated as well, but purifi-
cation of the reaction products is difficult.
The aza-Wittig reactions of iminophosphoranes have
received increased attention in view of their utility in
the synthesis of nitrogen heterocyclic compounds.13-15
Annelation of ring systems with N-heterocycles by
means of an aza-Wittig reaction has been widely util-
ized because of the availability of functionalized
iminophosphoranes. Here we wish to report a solu-
tion-phase parallel synthesis of some new derivatives of
5-substituted 7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones
(4). By using this parallel synthetic method, 4 was rap-
idly obtained and the separation of 4 from the reaction
mixture was easily carried out by simple recrystalliza-
tion.
Exeperimental
Melting points were determined using a X-4 model
*
E-mail: sfsun10@126.com
Received October 26, 2010; revised November 30, 2010; accepted December 13, 2010.
Chin. J. Chem. 2011, 29, 991— 994
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Sun, Chen & Yang
FULL PAPER
7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones 4a — 4m
406 (M＋, 100), 378 (45), 349 (12), 212 (26), 77 (93).
Anal. calcd for C21H19ClN6O: C 61.99, H 4.71, N 20.66;
found C 61.74, H 4.90, N, 20.46.
separately.
3-(4-Chlorophenyl)-5-di(n-propyl)amino-6-phenyl-
3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one
(4a) White solid, m.p. 212 — 214 ℃ ; 1H NMR
(CDCl3, 400 MHz) δ: 8.20—7.27 (m, 9H, ArH), 3.07 (t,
J＝7.6 Hz, 4H, 2NCH2), 1.37—1.28 (m, 4H, 2CH2),
0.76 (t, J＝7.2 Hz, 6H, 2CH3); IR (KBr) ν: 1720, 1595,
3-(4-Chlorophenyl)-5-(4-morpholinyl)-6-phenyl-
3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one
(4g) White solid, m.p. 259 — 261 ℃ ; 1H NMR
(CDCl3, 400 MHz) δ: 8.13—7.38 (m, 9H, ArH), 3.47 (t,
J＝3.2 Hz, 4H, 2OCH2), 3.24 (t, J＝3.2 Hz, 4H,
－1
－1
＋
1526, 1360 cm ; MS m/z (%): 423 (M , 20), 323 (13),
137 (59), 111 (45), 77 (100). Anal. calcd for
C22H23ClN6O: C 62.48, H 5.48, N 19.87; found C 62.23,
H 5.54, N 19.96.
2NCH2); IR (KBr) ν: 1717, 1596, 1533, 1118 cm ; MS
m/z (%): 408 (M＋, 100), 379 (28), 323 (15), 214 (11),
137 (34), 77 (98). Anal. calcd for C20H17ClN6O: C
58.75, H 4.19, N 20.56; found C 58.54, H 4.11, N 20.80.
3-(4-Chlorophenyl)-5-methoxy-6-phenyl-3,6-dihy-
3-(4-Chlorophenyl)-5-di(n-butyl)amino-6-phenyl-
3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one
(4b) White solid, m.p. 118 — 120 ℃ ; 1H NMR
(CDCl3, 400 MHz) δ: 8.19—7.30 (m, 9H, ArH), 3.11 (t,
J＝7.6 Hz, 4H, 2NCH2), 1.29—1.12 (m, 8H, 4CH2),
0.85 (t, J＝7.2 Hz, 6H, 2CH3); IR (KBr) ν: 2961, 1727,
dro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one
(4h)
White solid, m.p.＞300 ℃; 1H NMR (CDCl3, 400 MHz)
δ: 8.13—7.23 (m, 9H, ArH), 4.04 (s, 3H, OCH3); IR
－1
(KBr) ν: 1737, 1598, 1558, 1257 cm ; MS m/z (%):
353 (M＋, 50), 325 (26), 303 (64), 137 (75), 91(100).
Anal. calcd for C17H12ClN5O2: C 57.72, H 3.42, N 19.80;
found C 57.58, H 3.45, N 19.69.
－1
＋
1533, 1361 cm ; MS m/z (%): 450 (M , 10), 422 (8),
366 (4), 323 (25), 287 (16), 137 (65), 77 (100). Anal.
calcd for C24H27ClN6O: C 63.92, H 6.03, N 18.64;
found C 63.81, H 6.24, N 18.80.
3-(4-Chlorophenyl)-6-phenyl-5-(n-propoxy)-3,6-
dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one (4i)
1
3-(4-Chlorophenyl)-5-di(iso-butyl)amino-6-phen-
yl-3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-
White solid, m.p. 198—200 ℃; H NMR (CDCl3, 400
MHz) δ: 8.12—7.23 (m, 9H, ArH), 4.40 (t, J＝6.4 Hz,
2H, OCH2), 1.69—1.63 (m, 2H, CH2), 0.81 (t, J＝7.2
1
one (4c) White solid, m.p. 192—194 ℃; H NMR
－1
(CDCl3, 400 MHz) δ: 8.19—7.32 (m, 9H, ArH), 2.92 (d,
J＝7.2 Hz, 4H, 2NCH2), 1.93—1.85 (m, 2H, 2CH), 0.82
(d, J＝6.4 Hz, 6H, 2CH3); IR (KBr) ν: 2962, 1720, 1526,
Hz, 3H,CH3); IR (KBr) ν: 1733, 1598, 1558, 1258 cm ;
MS m/z (%): 383 (20), 381 (M＋, 76), 311 (50), 248 (33),
111 (57), 43 (100). Anal. calcd for C19H16ClN5O2: C
59.77, H 4.22, N 18.34; found C 59.57, H 4.36, N 18.12.
3-(4-Chlorophenyl)-6-phenyl-5-(iso-propoxy)-3,6-
dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one (4j)
－1
＋
1386 cm ; MS m/z (%): 450 (M , 10), 422 (5), 323
(50), 137 (40), 41 (100). Anal. calcd for C24H27ClN6O:
C 63.92, H 6.03, N 18.64; found C 63.98, H 6.18, N
18.46.
1
White solid, m.p. 192—194 ℃; H NMR (CDCl3, 400
3-(4-Chlorophenyl)-5-di(iso-pentyl)amino-6-phen-
yl-3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-
MHz) δ: 8.12—7.20 (m, 9H, ArH), 5.41—5.35 (m, 1H,
OCH), 1.29 (d, J＝6.4 Hz, 6H, 2 CH3); IR (KBr) ν:
1
－1
one (4d) White solid, m.p. 115—117 ℃; H NMR
1727, 1596, 1541, 1250 cm ; MS m/z (%): 383 (17),
(CDCl3, 400 MHz) δ: 8.19—7.31 (m, 9H, ArH), 3.09 (t,
J＝7.6 Hz, 4H, 2NCH2), 1.30—1.09 (m, 12H, 6CH2),
0.86 (t, J＝7.2 Hz, 6H, 2CH3); IR (KBr) ν: 2954, 1720,
381 (M＋, 67), 367 (12), 339 (30), 77 (30), 43 (100);
Anal. calcd for C19H16ClN5O2: C 59.77, H 4.22, N 18.34;
found C 59.90, H 4.12, N 18.18.
－1
＋
1596, 1536 cm ; MS m/z (%): 478 (M , 10), 450 (16),
323 (19), 287 (17), 77 (78), 43 (100). Anal. calcd for
C26H31ClN6O: C 65.19, H 6.52, N 17.54; found C 65.02,
H 6.74, N 17.67.
5-(n-Butoxy)-3-(4-chlorophenyl)-6-phenyl-3,6-di-
hydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one (4k)
White solid, m. p. 188—190 ℃; 1H NMR (CDCl3, 400
MHz) δ: 8.13—7.22 (m, 9H, ArH), 4.44 (t, J＝6.4 Hz,
2H, OCH2), 1.64—1.60 (m, 2H, CH2), 1.26—1.20 (m,
2H, CH2), 0.84 (t, J＝7.2 Hz, 3H, CH3); IR (KBr) ν:
3-(4-Chlorophenyl)-5-di(iso-hexyl)amino-6-phen-
yl-3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-
＋
1
－1
one (4e) White solid, m.p. 113—114 ℃; H NMR
1731, 1597, 1559, 1258 cm ; MS m/z (%): 395 (M ,
100), 367 (6), 311 (33), 282 (20), 248 (22), 77 (22).
Anal. calcd for C20H18ClN5O2: C 60.68, H 4.58, N 17.69;
found C 60.53, H 4.71, N 17.45.
(CDCl3, 400 MHz) δ: 8.19—7.27 (m, 9H, ArH), 3.09 (t,
J＝7.6 Hz, 4H, 2NCH2), 1.32—1.10 (m, 16H, 8CH2),
0.87 (t, J＝7.2 Hz, 6H, 2CH3); IR (KBr) ＋ν: 2956, 1720,
－1
1600, 1526 cm ; MS m/z (%): 506 (M , 6), 478 (9),
5-Allyloxy-3-(4-chlorophenyl)-6-phenyl-3,6-di-
hydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one (4l)
323 (22), 287 (16), 137 (37), 43 (100). Anal. calcd for
C28H35ClN6O: C 66.32, H 6.96, N 16.57; found C 66.17,
H 6.84, N 16.78.
1
White solid, m.p. 210—212 ℃; H NMR (CDCl3, 400
MHz) δ: 8.12—7.24 (m, 9H, ArH), 5.91—5.84 (m, 1H,
＝CH), 5.24—5.13 (m, 2H, ＝CH2), 4.93 (t, J＝5.2 Hz,
3-(4-Chlorophenyl)-6-phenyl-5-(1-piperidinyl)-
3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one
(4f) White solid, m.p.: 208 — 210 ℃ ; 1H NMR
(CDCl3, 400 MHz) δ: 8.19—7.36 (m, 9H, ArH), 3.22 (t,
J＝5.2 Hz, 4H, 2NCH2), 1.51—1.28 (m, 6H, 3CH2); IR
－1
2H, OCH2); IR (KBr) ν: 3095, 1730, 1550, 1249 cm ;
MS m/z (%): 379 (M＋, 8), 334 (12), 306 (8), 276 (6),
146 (23), 41 (100). Anal. calcd for C19H14ClN5O2: C
60.09, H 3.72, N 18.44; found C 60.33, H 3.56, N 18.57.
3-(4-Chlorophenyl)-6-phenyl-5-(prop-2-yn-1-yl
－1
(KBr) ν: 1720, 1596, 1532, 1358 cm ; MS m/z (%):
992
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Chin. J. Chem. 2011, 29, 991— 994

Synthesis of 5-Substituted 3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones
oxy)-3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-
Table 1 Preparation of 7H-1,2,3-triazolo[4,5-d]pyrimidin-7-
ones 4
1
7-one (4m) White solid, m.p. 238—240 ℃; H NMR
(CDCl3, 400 MHz) δ: 8.16—7.25 (m, 9H, ArH), 5.01 (s,
2H, OCH2), 2.56 (s, H, ≡CH); IR (KBr) ν: 3296, 2129,
Compound
Y
Condition Yielda/%
＋
－1
4a
4b
4c
4d
4e
4f
N(n-Pr)2
r.t./2 h
r.t./2 h
r.t./3 h
r.t./3 h
r.t./3 h
r.t./2 h
r.t./2 h
r.t./2 h
r.t./2 h
r.t./2 h
r.t./3 h
r.t./4 h
r.t./5 h
85
84
89
88
83
90
91
92
78
88
80
86
55
1727, 1249 cm ; MS m/z (%): 377 (M , 23), 311 (7),
179 (6), 91 (20), 39 (100). Anal. calcd for
C19H12ClN5O2: C 60.41, H 3.20, N 18.54; found C
60.56, H 3.02, N 18.75.
N(n-Bu)2
N(iso-Bu)2
N(n-C5 H11)2
N(n-C6H13)2
1-Piperidinyl
4-Morpholinyl
MeO
Results and discussion
4g
4h
4i
Iminophosphorane 1 reacted with phenyl isocyanate
to give carbodiimide 2. After removing the by-product
Ph3PO by recrystallization, the solution of 2 was di-
vided equally into several parts to which were added
various amines and alcohols separately. The resulted
solution was stood at room temperature for 1—2 h and
catalytic amount of sodium alkoxide was added. After
reaction at room temperature for further 2—5 h, the
solvent was removed in reduced pressure and the resi-
due was recrystallized to give various 5-amino or
5-alkoxy substituted 7H-1,2,3-triazolo[4,5-d]pyrimidin-
7-ones (4) in satisfactory yields. The formation of 4 can
be rationalized in terms of an initial nucleophilic addi-
tion to give the intermediate 3, which cyclized to give 4
in the basic condition. When HY (Table 1) is an amine,
the reaction can be carried out at r.t. even as Y is bulky
di-iso-propylamine. The yields of products 4 are related
to the N-substituents of the secondary amines. High
yields are obtained as the N-substituents are cyclic alkyl
group (4f, 4g, Table 1), however, relatively lower yield
is gotten when the N-substituent is long chain alkyl
group (4e, Table 1). When HY is an alcohol, the cycli-
zation was also achieved at room temperature and 4 can
be isolated from the reaction mixture in moderate to
good yields. The relatively lower yield of the compound
4m might be due to the influence of the alkynyl group
n-PrO
4j
iso-PrO
4k
4l
n-BuO
CH2＝CHCH2O
4m
HC≡CCH2O
a Isolated yields based on iminophosphorane 1.
of the alcohol under the basic condition. The results are
listed in Table 1.
The structure of 4 has been confirmed by spectral
data of 1H NMR, IR and MS. For example, the 1H NMR
spectral data of 4a show the signals of —NCH2 at δ
3.07 as triplets, signals of CH2 at δ 1.37—1.28 as multi-
plets, and signals of CH3 at δ 0.76 as triplets. The
phenyl signals appeared at δ 8.20—7.27 as multiplets.
The IR of 4a showed the strong stretching resonance
－1
peak of pyrimidinone C＝O at 1720 cm . The MS of
4a showed M＋ at m/z 423 with 20% abundance.
In summary, the above solution-phase parallel syn-
thetic method provides a high-speed synthesis of
5-substituted 7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones.
Due to the easily accessible and versatile starting mate-
rial, this method has the potential in synthesis of many
biologically and pharmaceutically active 7H-1,2,3-
triazolo[4,5-d]pyrimidin-7-one derivatives.
Scheme 1
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Chin. J. Chem. 2011, 29, 991— 994