New efficient synthesis of 5,6-disubstituted-3-phenyl-1,2,3-triazolo[4,5-d] pyrimidin-7-ones via a tandem aza-Wittig reaction

Article abstract of DOI:10.1080/00397911.2010.535940

Twelve novel 5,6-disubstituted-3-phenyl-1,2,3-triazolo[4,5-d]pyrimidine-7- ones 5a-5l were designed and successfully synthesized via tandem aza-Wittig and annulation reactions of the corresponding iminophosphorances 2, aromatic isocyanate, and substituted

Full text of DOI:10.1080/00397911.2010.535940

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New Efficient Synthesis of 5,6-
Disubstituted-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidin-7-ones via a
Tandem Aza-Wittig Reaction
Tao Wang a , Xi Xian Ke a , Shui Tao Zhou a & Hui Zong Chen a
a Key Laboratory of Functional Organic Small Molecules, Ministry of
Education, College of Chemistry and Chemical Engineering, Jiangxi
Normal University, Nanchang, China
Accepted author version posted online: 17 Nov 2011.Published
online: 25 Jan 2012.
To cite this article: Tao Wang , Xi Xian Ke , Shui Tao Zhou & Hui Zong Chen (2012): New Efficient
Synthesis of 5,6-Disubstituted-3-phenyl-1,2,3-triazolo[4,5-d]pyrimidin-7-ones via a Tandem Aza-Wittig
Reaction, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:10, 1393-1400
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Synthetic Communications1, 42: 1393–1400, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.535940
NEW EFFICIENT SYNTHESIS OF 5,6-DISUBSTITUTED-
3-PHENYL-1,2,3-TRIAZOLO[4,5-d]PYRIMIDIN-7-ONES
VIA A TANDEM AZA-WITTIG REACTION
Tao Wang, Xi Xian Ke, Shui Tao Zhou, and Hui Zong Chen
Key Laboratory of Functional Organic Small Molecules, Ministry of
Education, College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang, China
GRAPHICAL ABSTRACT
Abstract Twelve novel 5,6-disubstituted-3-phenyl-1,2,3-triazolo[4,5-d]pyrimidine-7-ones
5a–5l were designed and successfully synthesized via tandem aza-Wittig and annulation
reactions of the corresponding iminophosphorances 2, aromatic isocyanate, and substituted
thiophenols in satisfactory yields. The results from the preliminary bioassay indicated that
some of these compounds possess inhibitory activities against the root and stalk of Brassica
napus(rape) as well as Echinochloa crusgalli (barnyard grass) at the dosages of 100 mg=L
and 10 mg=L, respectively.
Keywords Aza-Wittig reaction; herbicidal activity; synthesis; 1,2,3-triazolo[4,5-d]-
pyrimidine-7-ones
INTRODUCTION
The synthesis of triazolopyrimidine derivatives has become a topic of
particular interest recently because of the broad spectrum of biological properties
of these compounds. Some of these derivatives have shown remarkable biological
properties such as antitumor, antiviral, adenosine A2A receptor antibacterial, and
anti-HIV activities,[1–6] whereas others exhibited good insecticidal, growth
regulatory, herbicidal, fungicidal, and anti-inflammatory activities.[7–15] However,
so far few reports are available on the herbicidal activities of 1,2,3-triazolo
[4,5-d]pyrimidine derivatives.
Received November 5, 2009.
Address correspondence to Tao Wang, Key Laboratory of Functional Organic Small Molecules,
Ministry of Education, College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, China. E-mail: wangtao1962@sohu.com
1393

1394
T. WANG ET AL.
The aza-Wittig reactions of iminophosphoranes have received increasing atten-
tion in view of their wide utilities in the synthesis of N-heterocyclic compounds.[16–22
]
Recently, we have become interested in the synthesis of new bioactive heterocycles
such as triazolo[4,5-d]pyrimidine-7-ones using various iminophosphoranes, with
the aim of discovering bioactive compounds by evaluating their biological activities.
Herein, we present the facile synthesis of a class of 5,6-disubstituted-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidine-7-ones via the tandem aza-Wittig and cyclization reaction.
The results of the bioassay indicated that these compounds possess herbicidal
activity against the root and stalk of brassica napus (rape) and echinochloa crusgalli
(barnyard grass).
RESULTS AND DISCUSSION
Synthesis
Iminophosphorane 2 was obtained in satisfactory yield when 1[23] was treated
with triphenylphosphine, hexachloroethane, and Et3N. Iminophosphorane 2 reacted
with arylisocyanate to give carbodiimides 3. The direct reaction of 3 with substituted
thiophenols did not produce 6-aryl-5-arylthio-3,6-dihydro-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidin-7-ones 5; however, the reaction took place to give 5a–5l in
good yields under the condition of heating for 2–3 h in the presence of a catalytic
amount of K2CO3. The formation of 5 could be initiated by the selective nucleophilic
addition of thiophenols to carbodiimides 3, which produced intermediate 4. Target
products 5 were finally furnished via the intramolecular cyclization of 4 and Table 1.
Both electron-withdrawing and electron-donating group functionalized thiophenols
were well tolerated.
Herbicidal Activity
The herbicidal activity of all compounds 5 against rape and barnyard grass has
been investigated at the dosages of 100 mg=L and 10 mg=L using a known pro-
cedure[24] and compared with distilled water. The results of the bioassay showed that
Scheme 1. Synthesis of the title compounds 5a–l.

SYNTHESIS VIA TANDEM AZA-WITTIG REACTION
1395
Table 1. Synthesis of 5a–l
Compound5
a
b
c
d
e
f
g
h
i
j
k
l
Ar1
Ph Ph
Ph
Ph
4-Cl 4-Cl 4-Cl
4-Cl
Ph
3-Cl 3-Cl 3-Cl
3-Cl
Ph
4-Cl 2-Cl 4-CH3
Ph Ph Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ar2
Ph 4-Cl 2-Cl 4-CH3
Ph Ph Ph
4-Cl 2-Cl 4-CH3
Ph Ph Ph
Table 2. Herbicidal activity of compounds 5
Relative inhibition root (%)=Stalk (%)
Compound Rape 100 mg=L Rape 10 mg=L Barnyard grass 100 mg=L Barnyard grass 10 mg=L
5a
5b
5c
71.0=48.0
97.6=98.7
67.6=59.7
64.2=46.3
98.5=96.5
97.6=95.3
98.3=96.5
98.7=97.6
76.5=56.5
92.5=90.7
79.5=54.2
87.2=654
92.6=90.2
52.1=3.50
85.1=33.1
32.7=3.70
33.2=9.40
85.1=89.2
93.3=90.2
92.1=89.2
95.3=83.0
51.4=9.50
85.2=81.4
72.7=38.7
70.5=44.6
94.1=90.2
69.3=83.2
97.8=92.8
54.8=34.8
52.8=34.7
100=100
51.4=28.0
92.6=90.5
51.1=16.4
47.5=17.8
98.6=89.6
95.6=92.5
94.3=95.7
90.4=91.2
52.8=40.0
94.4=89.8
48.6=38.6
57.3=13.4
85.8=38.8
5d
5e
5f
100=100
100=100
100=100
5g
5h
5i
63.2=73.2
98.6=92.3
68.5=56.7
77.5=34.8
95.3=38.3
5j
5k
5l
2,4-D
many of these compounds exhibit good herbicidal activity (the inhibition rates are
listed in Table 2). It showed that most of compounds 5 in Table 2 exhibit good inhi-
bition rates (90–100%) against the root and stalk of barnyard grass at 10 mg=L. For
example, 5b, 5e, 5f, 5g, 5h, and 5j showed >90% inhibitory rate to root and stalk of
barnyard grass. Most of compounds 5 in Table 2 exhibit good inhibition rates
(97–100%) against the root of rape and barnyard grass at 100 mg=L. For example,
5b, 5e, 5f, 5g, and 5h showed >97% inhibitory rate to root of rape and barnyard
grass.
EXPERIMENTAL
Melting points were measured on an Electrothermal melting-point apparatus
and are uncorrected. Mass spectra were measured on a Finnigan Trace MS 2000
spectrometer. Infrared (IR) spectra were recorded on an FTS-185 IR spectrometer
as KBr pellets with absorption in cmꢀ1. 1H NMR were recorded in CDCl3 as solvent
on a Bruker AC-P400 spectrometer, and resonances are given in parts per million (d)
relative to tetramethylsilane (TMS). Elementary analyses were taken on a Vario EL
III elementary analysis instrument. All of the solvents and materials were reagent
grade and purified as required.

1396
T. WANG ET AL.
Synthesis of Iminophosphorane 2
Ph3P (7.86 g, 30 mmol), C2Cl6(7.11 g, 30 mmol), and Et3N (6.06 g, 60 mmol)
were added in this order to a solution of 1 (2.26 g, 10 mmol) in CH3CN (60 mL).
The mixture was stirred for 3 h at rt. Then, the solution was concentrated, and the
residue was recrystallized from EtOH to give 2 in 90.7% yield. Mp: 196–198 ꢁC.
1H NMR (400 MHz, CDCl3) d 1.04 (t, 3 H, CH2CH3, J ¼ 6.8 Hz), 3.91 (q, 2 H,
CH2CH3, J ¼ 7.2 Hz), 7.37–7.75 (m, 20 H, Ar-H); Elemental anal. calcd. for
C29H25N4O2P: C, 70.72; H, 5.12; N, 11.38. Found: C, 70.47; H, 5.23; N, 11.57.
Preparation of 6-Aryl-5-arylthio-3,6-dihydro-3-phenyl-1,2,3-triazolo
[4,5-d]pyrimidin-7-ones 5
Phenylisocyanate (3 mmol) was added to a solution of iminophosphorane 2
(3 mmol) in dry methylene chloride (15 mL) under nitrogen at room temperature.
After the reaction mixture was left unstirred for 2–3 h, the solvent was removed
under vacuum, and anhydrous ethanol (10 mL) was added to precipitate triphenyl-
ꢁ
phosphineoxide. Removal of the solvent gave carbodiimides 3 [mp: 121–123 C,
1H NMR (TMS, CDCl3): d 1.07 (t, 3 H, CH2CH3, J ¼ 6.8 Hz), 4.12 (q, 2 H,
CH2CH3, J ¼ 7.2 Hz), 7.38–7.78 (m, 10 H, Ar-H)], which were used directly without
further purification.
Substituted thiophenol (3 mmol) and cat. solid K2CO3(0.24 g, 2 mmol) was
added to the solution of 3 prepared in CH3CN (15 mL). The mixture was stirred
for 2–3 h at 50 ꢁC and filtered; the filtrate was condensed and the residue was recrys-
tallized from dichloromethane = petroleum ether to give pure 6-aryl-5-arylthio-
3,6-dihydro-3-phenyl-1,2,3-triazolo[4,5-d]pyrimidin-7-ones.
3,6-Dihydro-3,6-diphenyl-5-phenylthio-1,2,3-triazolo[4,5-d]pyrimidine-
7-ones (5a). White solid, yield 84.5%, mp: 252–254 ꢁC; IR (KBr, t=cmꢀ1): 1733
1
=
(C O), 1566, 1524, 714; H NMR (CDCl3, 400 MHz): 7.26–7.84 (m, 15 H, Ar-H);
MS (EI, m=z, %): 397 (Mþ, 8), 369 (16), 341 (12), 196 (24), 129 (45), 91 (51), 77
(100). Anal. calcd. (%) for C22H15N5OS: C, 66.48; H, 3.80; N, 17.62. Found: C,
66.21; H, 3.69; N, 17.57.
5-[(4-Chlorophenyl)thio]-3,6-dihydro-3,6-diphenyl-1,2,3-triazolo[4,5-d]
pyrimidine-7-ones (5b). White solid, yield 82.3%, mp: 248–250 ꢁC; IR (KBr, t=
1
cmꢀ1): 1743 (C O), 1567, 1523, 713; H NMR (CDCl3, 400 MHz): 7.26–7.81 (m,
=
14 H, Ar-H); MS (EI, m=z, %): 431 (Mþ, 6), 403 (12), 375 (21), 231 (17), 129 (30),
91 (23), 77 (100), Anal. calcd. (%) for C22H14ClN5OS: C, 61.18; H, 3.27; N, 16.22.
Found: C, 61.31; H, 3.24; N, 16.47.
5-[(2-Chlorophenyl)thio]-3,6-dihydro-3,6-diphenyl-1,2,3-triazolo[4,5-d]
pyrimidine-7-ones (5c). White solid, yield 76.5%, mp 218–219 ꢁC; IR (KBr,
1
t=cmꢀ1): 1733 (C O); 1564, 1524, 714; H NMR (CDCl3, 400 MHz): 7.26–7.80
=
(m, 14 H, Ar-H); MS (EI, m=z, %): 431 (Mþ, 4), 403 (14), 375 (17), 231 (11), 129
(32), 91 (37), 77 (100). Anal. calcd. (%) for C22H14ClN5OS: C, 61.18; H, 3.27; N,
16.22. Found: C, 61.33; H, 3.42; N, 16.43.

SYNTHESIS VIA TANDEM AZA-WITTIG REACTION
1397
3,6-Dihydro-3,6-diphenyl-5-[(4-methylphenyl)thio]-1,2,3-triazolo[4,5-d]
pyrimidine-7-ones (5d). White solid, yield 77.7%, mp 263–265 ꢁC; IR (KBr, t=
1
cmꢀ1): 1739 (C O), 1567, 1523, 714; H NMR (CDCl3, 400 MHz): 2.50 (s, CH3Ph),
=
7.26–7.87 (m, 14 H, Ar-H); MS (EI, m=z, %): 411 (Mþ, 5), 383 (23), 355 (14), 210
(21), 128 (32), 91 (43), 77 (100). Anal. calcd. (%) for C23H17N5OS: C, 67.13; H,
4.16; N, 17.02. Found: C, 67.30; H, 4.22; N, 17.16.
6-(4-Chlorophenyl)-3,6-dihydro-3-phenyl-5-phenylthio-1,2,3-triazolo[4,5-
d]pyrimidine-7-ones (5e). White solid, yield 76.2%, mp 230–232 ꢁC; IR (KBr, t=
1
cmꢀ1): 1737 (C O), 1564, 1524, 733; H NMR (CDCl3, 400 MHz): 7.26–7.82 (m, 14
=
H, Ar-H); MS (EI, m=z, %): 431 (Mþ, 11), 403 (3), 375 (21), 231 (13), 129 (26), 91
(42), 77 (100); Anal. calcd. (%) for C22H14ClN5OS: C, 61.18; H, 3.27; N, 16.22.
Found: C, 61.21; H, 3.32; N, 16.36.
6-(4-Chlorophenyl)-5-[(4-chlorophenyl)thio]-3,6-dihydro-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidine-7-ones (5f). White solid, yield 74.3%, mp 195–197 ꢁC;
1
IR (KBr, t=cmꢀ1): 1736 (C O); 1562, 1524, 735; H NMR (CDCl3, 400 MHz):
=
7.26–7.79 (m, 13 H, Ar-H); MS (EI, m=z, %): 465 (Mþ, 6), 437 (16), 409 (9), 267
(23), 128 (22), 91 (36), 77 (100). Anal. calcd. (%) for C22H13Cl2N5OS: C, 56.66; H,
2.81; N, 15.02. Found: C, 56.40; H, 3.02; N, 15.28.
6-(4-Chlorophenyl)-5-[(2-chlorophenyl)thio]-3,6-dihydro-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidine-7-ones (5g). White solid, yield 78.2%, mp 221–223 ꢁC;
1
IR (KBr, t=cmꢀ1): 1736 (C O), 1563, 1523, 733; H NMR (CDCl3, 400 MHz):
=
7.26–7.82 (m, 13 H, Ar-H); MS (EI, m=z, %): 465 (Mþ, 9), 437 (18), 409 (5), 267
(11), 128 (25), 91(29), 77 (100). Anal. calcd. (%) for C22H13Cl2N5OS: C, 56.66; H,
2.81; N, 15.02. Found: C, 56.42; H, 3.01; N, 15.27.
6-(4-Chlorophenyl)-3,6-dihydro-5-[(4-methylphenyl)thio]-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidine-7-ones (5h). White solid, yield 73.5%, mp 203–205 ꢁC;
1
IR (KBr, t=cmꢀ1): 1738 (C O), 1563, 1524, 735; H NMR (CDCl3, 400 MHz): 2.51
=
(s, CH3Ph), 7.26–7.85 (m, 13 H, Ar-H); MS (EI, m=z, %): 445 (Mþ, 4), 417 (22), 389
(15), 245 (12), 128 (29), 91 (16), 77 (100); Anal. calcd. (%) for C23H16ClN5OS: C,
61.95; H, 3.62; N, 15.71. Found: C, 61.83; H, 3.43; N, 15.56.
6-(3-Chlorophenyl)-3,6-dihydro-3-phenyl-5-phenylthio-1,2,3-triazolo[4,
5-d]pyrimidine-7-ones (5i). White solid, yield 77.9%, mp 235–237 ꢁC; IR (KBr,
1
t=cmꢀ1): 1741 (C O), 1563, 1525, 732; H NMR (CDCl3, 400 MHz): 7.26–7.82
=
(m, 14 H, Ar-H); MS (EI, m=z, %): 431 (Mþ, 7), 403 (28), 375 (19), 231 (30), 128
(21), 91 (14), 77 (100). Anal. calcd. (%) for C22H14ClN5OS: C, 61.18; H, 3.27; N
16.22. Found: C, 61.24; H, 3.36; N, 16.11.
6-(3-Chlorophenyl)-5-[(4-chlorophenyl)thio]-3,6-dihydro-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidine-7-ones (5j). White solid, yield 78.6%, mp 245–247 ꢁC;
1
IR (KBr, t=cmꢀ1): 1751 (C O), 1571, 1524, 734; H NMR (CDCl3, 400 MHz):
=
7.26–7.81 (m, 13 H, Ar-H); MS (EI, m=z, %): 465 (Mþ, 5), 437 (17), 409 (32), 267
(15), 129 (22), 91 (41), 77 (100). Anal. calcd. (%) for C22H13Cl2N5OS: C, 56.66; H,
2.81; N, 15.02. Found: C, 56.78; H, 3.00; N, 15.22.

1398
T. WANG ET AL.
6-(3-Chlorophenyl)-5-[(2-chlorophenyl)thio]-3,6-dihydro-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidine-7-ones (5k). White solid, yield 72.8%, mp 243–245 ꢁC;
1
IR (KBr, t=cmꢀ1): 1729 (C O), 1565, 1523, 735; H NMR (CDCl3, 400 MHz):
=
7.26ꢂ7.79 (m, 13 H, Ar-H); MS (EI, m=z, %): 465 (Mþ, 5), 437 (16), 409 (34), 267
(13), 129 (42), 91 (34), 77 (100); Anal. calcd. (%) for C22H13Cl2N5OS: C, 56.66; H,
2.81; N, 15.02. Found: C, 56.49; H, 3.03; N, 15.19.
6-(3-Chlorophenyl)-3,6-dihydro-5-[(4-methylphenyl)thio]-3-phenyl-1,2,3-
triazolo[4,5-d]pyrimidine-7-ones (5l). White solid, yield 75.2%, mp 238–240 ꢁC;
1
IR (KBr, t=cmꢀ1): 1737 (C O); 1567, 1524, 714; H NMR (CDCl3, 400 MHz):
=
2.51 (s, CH3Ph), 7.26–7.85 (m, 13 H, Ar-H); MS (EI, m=z, %): 445 (Mþ, 7), 417
(19), 389 (32), 245 (16), 129 (39), 91 (42), 77 (100). Anal. calcd. (%) for
C23H16ClN5OS: C, 61.95; H, 3.62; N, 15.71. Found: C, 61.86; H, 3.39; N, 15.93.
Herbicidal Testing
Herbicidal testing of the newly synthesized compounds 5 was carried out in a
plant growth room. Temperature 23 ꢃ 1 ꢁC, RH 60 ꢃ 5%, light intensity 10 Klux,
photoperiod 8 h=day. Twenty seeds of each weed species including rape and barn-
yard grass were chosen for testing. Seedlings were grown in the test plate 9 cm in
diameter containing two pieces of filter paper and 9 mL solution of the tested
compound (100 mg=L and 10 mg=L, respectively). Distilled water and 2,4-dichloro-
phenoxyl acetic acid (2, 4-D), a commercially available herbicide, were used as com-
parison compounds. The herbicidal activity was assessed as the inhibition rate in
comparison with the distilled water. The herbicidal rating score is based on visual
observation. Range is from 0% to 100%; 0% means no effect, and 100% means
complete killing.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (No. 20862007)
and the Natural Science Foundation of Jiangxi Province in China (No.
2007GZH1399) for financial support.
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