Microwave irradiation for accelerating synthesis of [1,2,4]Triazole[4,3-a ]-pyrimidines based on isoflavones

Article abstract of DOI:10.1055/s-0030-1258105

Microwave irradiation was used to accelerate the cyclocondensation of isoflavones and 3-amino-1,2,4-triazoles in the presence of sodium methoxide to produce 6,7-diphenyl[1,2,4]-triazolo[4,3-a]pyrimidines in good to moderate yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258105

LETTER
1825
Microwave Irradiation for Accelerating Synthesis of [1,2,4]Triazole[4,3-a]-
pyrimidines Based on Isoflavones
M
icrowave Irra
u
diation for
A
n
ccelerating
S
-
ynthesis
T
of
[
1,2,4]triazo
i
le[4,3-
n
a
]pyrimidine
g
s
Zhang,* Juan Xie, Mu-Lin Zhu, Dong Xue
Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Labo-
ratory for Resource Development of Endangered Crude Drugs in Northwest of China, and School of Chemistry and Materials Science,
Shaanxi Normal University, Xi’an 710062, P. R. of China
Fax +86(29)85303940; E-mail: zhangzt@snnu.edu.cn
Received 9 February 2010
hours afforded 6-phenyl-7-(2-hydroxy-4-isopropoxyphe-
Abstract: Microwave irradiation was used to accelerate the cyclo-
nyl)-[1,2,4]trizolo[4,3-a]pyrimidine (3a) in 25% yield
condensation of isoflavones and 3-amino-1,2,4-triazoles in the pres-
(Scheme 1).18 On the other hand, treatment of 1a with 2a
ence of sodium methoxide to produce 6,7-diphenyl[1,2,4]-
(1:1 equiv) in ethanol in the presence of NaOH (3 equiv)
under microwave irradiation for 10 minutes afforded 3a in
slightly better yield (34%).
triazolo[4,3-a]pyrimidines in good to moderate yields.
Key words: isoflavone, triazole, [1,2,4]triazolo[4,3-a]pyrimidine,
microwave
We then started to optimize the conditions by using 1a and
2a as model compounds (Table 1). First, NaOH was used
as a base in different solvents such as MeOH, EtOH, n-BuOH,
glycol, and DMSO, and DMSO was found to give the
highest product yield (entry 5). A comparative study of
different bases showed that NaOMe was the most effec-
tive (entry 8). Further studies using variable amount of
NaOMe revealed that highest product yield could be ob-
tained with 3 equivalents of base (entry 7). The ratio of 1a
and 2a was also evaluated. With a ratio of 1a/2a (1:1.4),
the yield of 3a was the highest (entry 11).
The 1,2,4-triazolopyrimidine skeleton, although virtually
unknown as a component in natural products, is an impor-
tant pharmaceutical target (Figure 1).1 It has been report-
ed that 1,2,4-triazolopyrimidine can show a broad
spectrum of pharmacological and medicinal properties,
such as antibacterial,2 antifungal, antiviral,1 antihyperten-
sion, and others.3
N
N
N
N
Table 1 Optimization of Cyclocondensation of Isoflavone 1a with
3-Amino-1,2,4-triazoles 2aa
OH
1
Entry
Solvent
Base
Molar ratios
1a/2a/base
Yield (%)b
3a
Figure 1
1
2
MeOH
EtOH
NaOH
1:1:3
1:1:3
1:1:3
1:1:3
1:1:3
1:1:3
1:1:2
1:1:3
1:1:4
1:1.2:3
1:1.4:3
1:1.6:3
17
34
38
29
42
29
51
64
48
66
72
69
The conventional synthesis of triazolopyrimidines in-
volves cyclizations of 2-hydrazinopyrimidines with ali-
phatic carboxylic acids, their esters, anhydrides, and
chlorides,4–8 as well as with ortho esters,9–11 or phosgene.6
Recently, we have reported the high-throughput synthesis
of 3,4-diarylpyrazoles, 4,5-diphenyl-2-pyrimidinylguani-
dine, and 2,3-diarylpyrimido[1,2-a]-benzimidazole by us-
ing one-step reaction of hydrazine,12 biguanidine,13 and 2-
aminobenzimidazole14 with isoflavones. To the best of
our knowledge, there is no report on the synthesis of 6,7-
diphenyl[1,2,4]triazolo-[4,3-a]pyrimidine. Herein, we
report a new strategy for the preparation of 6,7-di-
phenyl[1,2,4]triazolo[4,3a]-pyrimidine (3) by cyclo-
condensation of isoflavones 1 with 3-amino-1,2,4-tria-
zoles 2a or 3-amino-5-hydroxy-1,2,4-triazoles 2b by
microwave irradiation.15–17
NaOH
3
n-BuOH
glycol
NaOH
4
NaOH
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NaOH
6
K2CO3
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
7
8
9
10
11
12
Treatment of ipriflavone (1a) with 2a (1:1 equiv) in re-
fluxing ethanol in the presence of NaOH (3 equiv) for 72
a All reactions were carried out in the appropriate solvent (8 mL) us-
ing 1a (1.5 mmol), 2a, and base until complete disappearance of 1a
(microwave irradiation for 10–20 min). Reaction temperature:
MeOH, EtOH at boiling; n-BuOH, glycol, DMSO at 100 °C. Micro-
wave output = 240 W.
SYNLETT 2010, No. 12, pp 1825–1828
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258105; Art ID: W02310ST
© Georg Thieme Verlag Stuttgart · New York
b Isolated yield after silica chromatography.

1826
Z.-T. Zhang et al.
LETTER
HO
O
H
N
O
O
O
N
N
MW
+
NH2
N
solvent, base
Ph
N
Ph
N
N
1a
3a
2a
Scheme 1
Table 2 Synthesis of [1,2,4]Triazolo[4,3-a]pyrimidine by Cyclocondensation of Various Isoflavones with 3-Amino-1,2,4-triazole 2a or 3-
Amino-5-hydroxy-1,2,4-triazole 2b in DMSOa
H
R1
N
X
NH2
HO
R2
R1
R1
N
N
R7
R7
R2
R3
O
O
R2
R3
O
O
O
N
N
2a X = H
2b X = OH
R3
R5
N
OH
R4
R6
R6
N
X
R4
R4
R5
R5
R6
1
3
R7
Entry
1
Productb R1
R2
R3
R4
H
R5
R6
R7
H
Time (min)
Yield (%)c
72
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
Br
H
H
H
H
Oi-Pr
OMe
OMe
OMe
Os-Bu
OMe
Oi-Pr
OBn
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
10
10
10
12
12
15
12
12
10
15
15
10
10
15
10
10
15
10
10
15
2
OMe
H
H
OMe
OMe
H
H
74
3
H
H
68
4
Me
H
H
H
54
5
H
OMe
OMe
H
H
69
6
H
iPr
H
i-Pr
H
52
7
3g
3h
3i
H
67
8
H
H
OMe
OMe
OH
OH
OMe
OMe
H
H
70
9
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Oi-Pr
OMe
OBn
H
Br
H
H
58
10
11
12
13
14
15
16
17
18
19
20
3j
H
H
47
3k
3l
H
i-Pr
H
iPr
H
43
OMe
H
65
3m
3n
3o
3p
3q
3r
3s
3t
H
H
62
Me
H
H
H
50
H
H
H
56
H
H
H
H
64
H
i-Pr
H
OMe
OMe
H
i-Pr
H
47
H
62
Oi-Pr
OMe
H
H
H
67
H
H
OH
H
38
a Isoflavones 1 (1.5 mmol), 2b (2.1 mmol), NaOMe (4.5, 6.0, and 7.5 mmol are used for 0, 1, and 2 free hydroxyl groups in 1 and 2b, respec-
tively), 100 °C.
b Compounds 3a–k compounds are synthesized with isoflavones 1 and 3-amino-1,2,4-triazole (2a), compounds 3i–t are synthesized with isofla-
vones 1 and 3-amino-5-hydroxy-1,2,4-triazole (2b).
c Isolated yield after silica chromatography.
Synlett 2010, No. 12, 1825–1828 © Thieme Stuttgart · New York

LETTER
Microwave Irradiation for Accelerating Synthesis of [1,2,4]triazole[4,3-a]pyrimidines
1827
OH
O
2a or 2b
1. – H2O
CH
N
O
– MeOH
2. + H
N
H2N
OMe
H
N
O
O
O
X
N
C
N
X
N
N
OMe
3
OMe
O
OH
O
O
C
OMe
H
1
4
OMe
1. OMe
2. – HC(OMe)3
3. H
O
5
Scheme 2 Proposed mechanism for the formation of 3
(6) Kottke, K.; Kuhmstedt, K.; Knoke, D. Pharmazie 1983, 38,
25.
With the optimized reaction conditions in hand, conden-
sation of a variety of structurally divergent 1 with 2a were
studied (Table 2).19 Due to the presence of an unprotected
acidic phenol functionalities in isoflavones 1j,k,t and in
compound 2b, 4 or 5 equivalents of NaOMe were required
in the synthesis of 3j–t.19 All substrates react smoothly to
give compound 3 in high yields for 10–15 minutes. All
(7) El-Sherief, H. A.; Abdel-Rachman, A. E.; El-Naggar, G. M.;
Mahmoud, A. M. Bull. Chem. Soc. Jpn. 1983, 56, 1227.
(8) Bower, J. D.; Doyle, F. P. J. Chem. Soc. 1957, 727.
(9) Oganisyan, A. Sh.; Noravyan, A. S.; Karapetyan, A. A.;
Aleksanyan, M. S.; Struchkov, Yu. T. Khim. Geterotsikl.
Soedin. 2004, 85.
1
13
(10) Lalezari, I.; Jabari-Sahbari, M. H. J. Heterocycl. Chem.
products were characterized by IR, H NMR, C NMR,
and elemental analysis.
1978, 15, 873.
(11) Vas’kevich, R. I.; Savitskii, P. V.; Zborovskii, Yu. L.;
Staninets, V. I.; Rusanov, E. B.; Chernega, A. N. Russ. J.
Org. Chem. 2006, 42, 1403.
The reaction possible underwent a mechanism as shown
in Scheme 2. It was reported that isoflavone underwent
ring-opening reaction to form an a,b-unsaturated ketone
intermediate 4 in the presence of a base. The nitrogen
atom at position 4 of 2a or 2b then attacked the b-carbon
in 4. Ring-closure reaction between primary amine and
the carbonyl carbon then afforded product 3. On the other
hand, intermediate 4 may eliminate HC(OMe)3 to gener-
ate a byproduct 5.20
(12) Zhang, Z.-T.; Tan, D.-J.; Xue, D. HeIv. Chim. Acta 2007, 90,
2096.
(13) Zhang, Z.-T.; Xu, F.-F.; Gao, M.-X.; Qiu, L. J. Comb. Chem.
2009, 11, 880.
(14) Zhang, Z.-T.; Qiu, L.; Xue, D.; Wu, J.; Xu, F.-F. J. Comb.
Chem. 2010, 12, 225.
(15) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(16) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20,
1.
(17) Abramovitch, R. A. Org. Prep. Proced. Int. 1991, 23, 683.
(18) 6-Phenyl-7-(2-hydroxy-4-isopropoxyphenyl)[1,2,4]-
triazolo[4,3-a]pyrimidine (3a)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Mp 228–230 °C. IR (KBr): n = 3083, 2982, 2679, 2586,
1610, 1504, 1440, 1381, 1292, 1264, 1180, 1115, 989, 921,
846, 791, 757, 703, 652, 573, 506, 461 cm–1. 1H NMR (300
MHz, DMSO-d6): d = 1.26 (d, J = 5.9 Hz, 6 H), 4.56 (m, 1
H), 6.39 (d, J = 8.2 Hz, 2 H), 7.03 (d, J = 8.2 Hz, 1 H), 7.33
(m, 5 H), 8.60 (s, 1 H), 8.95 (s, 1 H), 9.86 (s, 1 H) ppm.
13C NMR (75 MHz, DMSO-d6): d = 21.8, 69.4, 102.6, 106.4,
118.7, 125.0, 127.8, 128.3, 129.4, 131.6, 134.4, 144.2,
154.3, 155.5, 155.9, 156.9, 160.2 ppm. MS (EI): m/z (rel
intensity) = 369 (62) [M + Na], 347 (100) [M + 1], 305 (66).
Anal. Calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17.
Found: C, 69.18; H, 5.31; N, 16.25.
Acknowledgments
This research is supported by the National Natural Science Founda-
tion of China (No: 20772076) and Science and Technology Key
Project of Xi’an of Shaanxi province (No: FY07075).
References and Notes
(1) Yang, G.-L. CN 200710301577.6, 2007.
(2) Prakash, O.; Bhardwaj, V.; Kumar, R.; Tyagi, P.; Aneja,
K. R. Eur. J. Med. Chem. 2004, 39, 1073.
(3) Bradbury, R. H.; Major, O. S.; Oldham, A. A.; Rivett, J. E.;
Roberts, D. A.; Slater, A. M.; Timms, D.; Waterson, D.
J. Med. Chem. 1990, 33, 2335.
(19) Representative Procedure for the Preparation of
6-Phenyl-7-(2-hydroxy-4-isopropoxy-phenyl)[1,2,4]-
triazolo[4,3-a]-pyrimidine (3a) and 3-Hydroxy-6-phenyl-
7-(2-hydroxy-4-isopropoxyphenyl)[1,2,4]triazolo[4,3-
a]pyrimidine (3s)
(4) Babichev, F. S.; Kovtunenko, V. A. Khim. Geterotsikl.
Soedin. 1977, 147.
The ipriflavone (1a, 1.5 mmol, 420 mg), 2a (2.1 mmol, 118
mg) and NaOMe (4.5 mmol, 3 equiv) were mixed in DMSO
(8 mL). The mixture was heated by the microwave
irradiation (output 240 W, 100 °C) for 10 min. Reaction was
(5) Allen, C. F. H.; Beilfuss, H. R.; Burness, D. M.; Reynolds,
G. A.; Tinker, J. F.; Van Allan, J. A. J. Org. Chem. 1959, 24,
787.
Synlett 2010, No. 12, 1825–1828 © Thieme Stuttgart · New York

1828
Z.-T. Zhang et al.
LETTER
monitored by TLC, in which the disappearance of 1a
indicated the completeness of reaction. The mixture was
added into H2O (30 mL) and adjusted to neutrality with the
solution of 5% HCl. Precipitate appeared and was filtered.
Finally, 3a (374mg, 72%) was obtained by purifying the
precipitate on silica gel column chromatography (PE 60–90–
EtOAc = 2:1); 3s was obtained by the same way, except that
the equivalent of NaOMe (6.0 mmol, 4 equiv) was different
when 2b was instead of 2a.
(20) Varga, M.; Bátori, S.; Kövári-Rádkai, M.; Prohászka-
Német, I.; Vitányi-Morvai, M.; Böcskey, Z.; Bokotey, S.;
Simon, K.; Hermecz, I. Eur. J. Org. Chem. 2001, 20, 3911.
Synlett 2010, No. 12, 1825–1828 © Thieme Stuttgart · New York

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