Synthesis of [1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-b]pyrimidin- 9(10H)-ones via 1,3-dipolar cycloaddition of nitrile oxide to thiazolo[3,2-a]pyrimidin-3-one derivatives

Article abstract of DOI:10.1002/cjoc.201090181

A new class of [1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-b]pyrimidin-9(10H)-one was prepared in moderate yields by the reaction of nitrile oxide with 2-arylmethylidene-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-3-one. The reaction site of dipolarphile is the C=N of thiazolo[3,2-a]pyrimidin-3-one rather than the expected C=C of aryl-methylidene. The structures of the products were characterized thoroughly by IR, elemental analysis, MS, and NMR analysis.

Full text of DOI:10.1002/cjoc.201090181

FULL PAPER
Synthesis of [1,2,4]Oxadiazolo[4,5-a]thiazolo[2,3-b]pyrimidin-
9(10H)-ones via 1,3-Dipolar Cycloaddition of Nitrile Oxide to
Thiazolo[3,2-a]pyrimidin-3-one Derivatives
Li, Xiaofang(李筱芳)
Zheng, Aiting(郑爱庭)
Liu, Bin(刘彬)
Yu, Xianyong(于贤勇)
Yi, Pinggui*(易平贵)
Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education & Hunan Province,
College Key Laboratory of QSAR/QSPR, School of Chemistry and Chemical Engineering, Hunan University of
Science and Technology, Xiangtan, Hunan 411201, China
A new class of [1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-b]pyrimidin-9(10H)-one was prepared in moderate yields
by the reaction of nitrile oxide with 2-arylmethylidene-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-3-one. The reac-
tion site of dipolarphile is the C＝N of thiazolo[3,2-a]pyrimidin-3-one rather than the expected C＝C of aryl-
methylidene. The structures of the products were characterized thoroughly by IR, elemental analysis, MS, and NMR
analysis.
Keywords thiazolo[3,2-a]pyrimidine, 1,3-dipolar cycloaddition, nitrile oxide, [1,2,4]oxadiazolo[4,5-a]thiazolo-
[2,3-b]pyrimidin-9(10H)-one
Introduction
tially bioactive triheterocyclic systems. Such an ap-
proach resulted in a synthesis of various [1,2,4]oxadi-
Nitrile oxides are important intermediates as 1,3-
dipoles in cycloaddition reaction.1 Reaction of nitrile
oxides with alkenes dipolarophiles can obtain iso-
xazolines which often have important bioactivities.2-5
the C, N double bond of pyridine, quinoline, isoquino-
line and 1,5-benzothiazepine as heterodipolarophile can
also react with nitrile oxides to obtain oxadiazoles.6,7
Oxadiazoles, the important bioisosters for esters and
amides in drug discovery, have been reported to have
muscarinic agonist, benzodiazepine receptor agonist,
5-HT agonist, and antirhinoviral activities.8-11
Thiazolo[3,2-a]pyrimidin-3-one derivatives are
found to be associated with various biological activities
such as antibacterial, antimicrobial and anticancer ac-
tivities.12-14
The incorporation of isoxazoline (or oxadiazole) and
thiazolo[3,2-a]pyrimidin-3-one into a triheterocyclic
system, which we believe could be a useful framework
with potential biological activities, has not been inves-
tigated yet. In the present work, we wish to report the
preliminary results of our attempt to apply the
1,3-dipolar cycloaddition reaction involving nitrile ox-
azolo[4,5-a]thiazolo[2,3-b]pyrimidin-9(10H)-ones
instead of the spiroisoxazoline 3, as shown in Scheme 1.
4
Experimental
Materials and instruments
114 and 215 were prepared according to the reported
procedures. All NMR spectra were recorded on a
Bruker AV-II 500 MHz NMR spectrometer, operating
1
at 500 MHz for H, and 125 MHz for 13C. TMS was
1
used as an internal reference for H and 13C chemical
shifts and CDCl3 was as solvent. Elemental analysis was
measured by an Elementar analyzer (varioEL II). MS
was conducted by a Finnigan LCQ Advantage MAX
mass spectrometer. IR spectra were recorded on a
Perkin-Elmer spectrometer (Spectrum One). Melting
points were measured by a Yanaco MP500 melting
point apparatus and uncorrected.
General procedure for the synthesis of 3-(2,6-di-
chlorophenyl)-10-arylmethylidene-6,7-dihydro-5H-
[1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-b]pyrimidin-
ide
2
and 2-arylmethylidene-6,7-dihydro-5H-thia-
9(10H)-ones
zolo[3,2-a]pyrimidin-3-one 1, which contain two possi-
ble dipolarophile sites (C＝N and C＝C). Our aim was
not only to study the chemoselectivity of the reaction
but also to develop a rapid access to new types of poten-
A mixture of 1 (1 mmol) and 2 (0.19 g, 1 mmol) in
dioxane (30 mL) were reflux for 24 h. The solvent was
evaporated in vacuum. The residue was purified by
*
E-mail: fine_chem@163.com
Received November 13, 2009; revised January 18, 2010; accepted February 5, 2010.
Project supported by the National Natural Science Foundation of China (Nos. 20971041, 20803020, 20772027), and Scientific Research Fund of
Hunan Provincial Education Department (Nos. 09B032, 09K081).
Chin. J. Chem. 2010, 28, 977— 980
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977

Li et al.
FULL PAPER
Scheme 1
column chromatography on silica gel using petroleum
ether and ethyl acetate (V∶V＝5∶1) as eluent to afford
the corresponding 4a—4h.
14.2 Hz, 1H, Hc), 7.40—7.48 (m, 7H), 7.65 (s, 1H, Hf);
13C NMR (CDCl3, 125 MHz) δ: 22.99 (CH2), 34.26
(CH2), 36.46 (CH2), 118.80 (Cd), 122.55 (Cf), 124.74,
126.66, 128.73, 128.85, 129.08, 130.96, 132.96, 134.81,
136.17, 136.69, 152.39 (C＝N), 163.68 (C＝O); IR
3-(2,6-Dichlorophenyl)-10-benzylidene-6,7-dihy-
dro-5H-[1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-b]pyrim-
idin-9(10H)-one (4a) White solid, yield 52%; m.p.
－1
(KBr) v: 1698.8 (C＝O) cm ; ESI MS m/z: 466 [M＋
178—180 ℃; H NMR (CDCl3, 500 MHz) δ: 1.99—
H]＋. Anal. calcd for C20H14Cl3N3O2S: C 51.46, H 3.02,
N 9.00; found C 51.62, H 3.15, N 8.95.
1
2.09 (m, 2H, Hb), 3.05 (ddd, J＝1.7, 9.1, 15.4 Hz, 1H,
Ha), 3.14 (ddd, J＝1.7, 9.1, 15.4 Hz, 1H, Ha), 3.41 (ddd,
J＝1.4, 9.4, 14.2 Hz, 1H, Hc), 4.41 (ddd, J＝1.4, 9.4,
14.2 Hz, 1H, Hc), 7.35—7.37 (m, 1H), 7.43—7.49 (m,
5H), 7.52—7.54 (m, 2H), 7.72 (s, 1H, Hf); 13C NMR
(CDCl3, 125 MHz) δ: 23.03 (CH2), 34.17 (CH2), 36.45
(CH2), 118.74 (Cd), 122.65 (Cf), 124.01, 128.11, 128.72,
128.81, 128.84, 129.05, 129.85, 132.90, 134.40, 136.18,
136.72, 152.35 (C＝N), 163.91 (C＝O); IR (KBr) v:
3-(2,6-Dichlorophenyl)-10-(4-nitrobenzylidene)-6,
7-dihydro-5H-[1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-b]-
pyrimidin-9(10H)-one (4d) White solid, yield 55%;
m.p. 217—219 ℃; 1H NMR (CDCl3, 500 MHz) δ: 1.99
—2.04 (m, 1H, Hb), 2.10—2.15 (m, 1H, Hb), 3.07 (ddd,
J＝1.3, 9.1, 15.2 Hz, 1H, Ha), 3.18 (ddd, J＝1.3, 9.1,
15.2 Hz, 1H, Ha), 3.42 (ddd, J＝1.4, 9.2, 14.0 Hz, 1H,
Hc), 4.43 (ddd, J＝1.4, 9.2, 14.0 Hz, 1H, Hc), 7.46—
7.50 (m, 3H), 7.67 (d, J＝8.5 Hz, 2H), 7.73 (s, 1H, Hf),
8.29 (d, J＝8.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ:
22.93 (CH2), 34.49 (CH2), 36.51 (CH2), 118.96 (Cd),
122.39 (Cf), 124.09, 125.01, 128.77, 128.87, 129.11,
130.24, 133.07, 136.20, 136.72, 140.80, 147.05, 152.51
(C＝N), 163.12 (C＝O); IR (KBr)＋v: 1698.2 (C＝O)
＋
－1
1693.7 (C＝O) cm ; ESI MS m/z: 432 [M＋H] . Anal.
calcd for C20H15Cl2N3O2S: C 55.56, H 3.50, N 9.72;
found C 55.48, H 3.57, N 9.78.
3-(2,6-Dichlorophenyl)-10-(4-methoxybenzylid-
ene)-6,7-dihydro-5H-[1,2,4]oxadiazolo[4,5-a]thia-
zolo[2,3-b]pyrimidin-9(10H)-one (4b) White solid,
1
－1
yield 58%; m.p. 221—223 ℃; H NMR (CDCl3, 500
cm ; ESI MS m/z: 477 [M＋H] . Anal. calcd for
MHz) δ: 1.96—2.02 (m, 1H, Hb), 2.04—2.10 (m, 1H,
Hb), 3.05 (ddd, J＝1.5, 9.1, 15.2 Hz, 1H, Ha), 3.13 (ddd,
J＝1.5, 9.1, 15.2 Hz, 1H, Ha), 3.40 (ddd, J＝1.3, 9.4,
14.4 Hz, 1H, Hc), 3.85 (s, 3H, OCH3), 4.40 (ddd, J＝1.3,
9.4, 14.4 Hz, 1H, Hc), 6.96—6.98 (m, 2H), 7.43—7.50
(m, 5H), 7.67 (s, 1H, Hf); 13C NMR (CDCl3, 125 MHz)
δ: 23.04 (CH2), 34.11 (CH2), 36.44 (CH2), 55.38
(OCH3), 118.76 (Cd), 122.70 (Cf), 127.10, 127.95,
128.71, 128.79, 131.58, 132.88, 136.17, 136.70, 152.31
(C＝N), 164.14 (C＝O); IR (KBr)＋v: 1693.3 (C＝O)
C20H14Cl2N4O4S: C 50.33, H 2.96, N 11.74; found C
50.55, H 3.11, N 11.63.
3-(2,6-Dichlorophenyl)-10-(4-fluorobenzylidene)-
6,7-dihydro-5H-[1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-
b]pyrimidin-9(10H)-one (4e) White solid, yield 48%;
m.p. 180—181 ℃; 1H NMR (CDCl3, 500 MHz) δ: 1.97
—2.13 (m, 2H, Hb), 3.05 (ddd, J＝1.5, 9.0, 15.3 Hz, 1H,
Ha), 3.15 (ddd, J＝1.5, 9.0, 15.3 Hz, 1H, Ha), 3.41 (ddd,
J＝1.25, 7.3, 14.2 Hz, 1H, Hc), 4.40 (ddd, J＝1.3, 7.3,
14.2 Hz, 1H, Hc), 7.13 (t, J＝8.5 Hz, 2H), 7.44—7.53
(m, 5H), 7.67 (s, 1H, Hf);13C NMR (CDCl3, 125 MHz) δ:
23.00 (CH2), 34.21 (CH2), 36.46 (CH2), 118.81 (Cd),
122.61 (Cf), 123.71, 123.73, 126.87, 128.73, 128.81,
131.75, 132.93, 136.19, 136.71, 152.37－(C＝N), 163.78
－1
cm ; ESI MS m/z: 462 [M＋H] . Anal. calcd for
C21H17Cl2N3O3S: C 54.55, H 3.71, N 9.09; found C
54.40, H 3.88, N 9.18.
3-(2,6-Dichlorophenyl)-10-(4-chlorobenzylidene)-
6,7-dihydro-5H-[1,2,4]oxadiazolo[4,5-a]thiazolo[2,3-
b]pyrimidin-9(10H)-one (4c) White solid, yield 55%;
m.p. 182—183 ℃; 1H NMR (CDCl3, 500 MHz) δ: 1.97
—2.09 (m, 2H, Hb), 3.05 (ddd, J＝1.3, 9.4, 14.2 Hz, 1H,
Ha), 3.16 (ddd, J＝1.3, 9.4, 14.2 Hz, 1H, Ha), 3.40 (ddd,
J＝1.4, 9.4, 14.2 Hz, 1H, Hc), 4.40 (ddd, J＝1.4, 9.4,
1
(C＝O); IR (KBr) v: 1703.7 (C＝O) cm ; ESI MS m/z:
450 [M＋H]＋. Anal. calcd for C20H14Cl2FN3O2S: C
53.34, H 3.13, N 9.33; found C 53.20, H 3.29, N 9.24.
3-(2,6-Dichlorophenyl)-10-(4-methylthiobenzylid-
ene)-6,7-dihydro-5H-[1,2,4]oxadiazolo[4,5-a]thiazolo-
-
978
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Chin. J. Chem. 2010, 28, 977— 980

Synthesis of [1,2,4]Oxadiazolo[4,5-a]thiazolo[2,3-b]pyrimidin-9(10H)-ones
1
[2,3-b]pyrimidin-9(10H)-one (4f) White solid, yield
55%; m.p. 173—175 ℃; 1H NMR (CDCl3, 500 MHz) δ:
1.96—2.03 (m, 1H, Hb), 2.05—2.11 (m, 1H, Hb), 2.52 (s,
3H, SCH3), 3.05 (ddd, J＝1.5, 9.1, 15.2 Hz, 1H, Ha),
3.14 (ddd, J＝1.5, 9.1, 15.2 Hz, 1H, Ha), 3.41 (ddd, J＝
1.3, 9.4, 14.4 Hz, 1H, Hc), 4.40 (ddd, J＝1.3, 9.4, 14.4
Hz, 1H, Hc), 7.27—7.29 (m, 2H), 7.44—7.48 (m, 5H),
7.66 (s, 1H, Hf); 13C NMR (CDCl3, 125 MHz) δ: 15.17
(SCH3), 23.04 (CH2), 34.18 (CH2), 36.47 (CH2), 118.79
(Cd), 122.69 (Cf), 122.91, 125.94, 127.62, 128.72,
128.81, 130.21, 130.90, 132.89, 136.21, 136.75, 140.55,
152.34 (C＝N), 164.00 (C＝O); IR (KBr) v: 1693.9
2-a]pyrimidin-3-one. The H NMR spectrum of 4g re-
vealed several multiplets in the range of δ 1.96—4.44
resulting from 1,4,5,6-tetrahydropyrimidine ring for the
six protons of three methylenes, several multiplets in the
range of δ 7.31—7.57 for aromatic protons. The exis-
tence of a singlet at δ 7.97 resulting from benzylidene
proton indicates the C＝C of benzylidene was not in-
volved in the cycloaddition reaction. Furthermore, the
absence of any singlet downfield of δ 6.5 that is assign-
able for the methine proton of 3g excluded the presence
of product 3g.2,3
The 13C NMR spectrum of the product 4g exhibits
the presence of three methylene carbons at δ 22.98,
34.35 and 36.50, carbonyl carbons at δ 163.19, ben-
zylidene carbon at δ 122.89 (based on HMQC). The
absence of any signal between δ 70—100 that is as-
signable for the methine and spiro carbon of 3g ex-
cluded the presence of 3g.2 1H-13C HMBC spectrum of
4g adds conclusive support for the proposed structure.
＋
－1
(C＝O) cm ; ESI MS m/z: 478 [M＋H] . Anal. calcd
for C21H17Cl2N3O2S2: C 52.72, H 3.58, N 8.78; found C
52.64, H 3.63, N 8.70.
3-(2,6-Dichlorophenyl)-10-(2,4-dichlorobenzylid-
ene)-6,7-dihydro-5H-[1,2,4]oxadiazolo[4,5-a]thiazolo-
[2,3-b]pyrimidin-9(10H)-one (4g) White solid, yield
50%; m.p. 214—215 ℃; 1H NMR (CDCl3, 500 MHz) δ:
1.96—2.12 (m, 2H, Hb), 3.05 (ddd, J＝1.5, 9.4, 15.2 Hz,
1H, Ha), 3.16 (ddd, J＝1.5, 9.4, 15.2 Hz, 1H, Ha), 3.41
(ddd, J＝1.4, 9.4, 14.4 Hz, 1H, Hc), 4.42 (ddd, J＝1.4,
9.4, 14.4 Hz, 1H, Hc), 7.31—7.34 (m, 1H), 7.44—7.50
(m, 4H), 7.55 (d, J＝8.0Hz, 1H), 7.97 (s, 1H, Hf); 13C
NMR (CDCl3, 125 MHz) δ: 22.98 (CH2), 34.35 (CH2),
36.50 (CH2), 118.84 (Cd), 122.89 (Cf), 127.34, 127.68,
128.79, 128.86, 129.74, 129. 96, 131.41, 133.05, 135.04,
135.87, 116.19, 136.68, 152.46 (C＝N), 163.19 (C＝O);
In the H-13C HMBC map of 4g both Ha and Hc corre-
1
late with Cd (δ 118.84), Hc and benzylidene proton Hf
correlate with a carbonyl carbon Cg (δ 163.1). The cor-
relation of Ha and Ce (δ 152.46) indicates the carbon
atom of nitrile oxide was connected with the nitrogen
atom of C＝N in 1,4,5,6-tetrahydropyrimidine ring
(Figure 1). This kind of regioselectivity was general in
the 1,3-dipolar cycloaddition reaction of nitrile oxide
and C＝N.6,7
－1
IR (KBr) v: 1700.2 (C＝O) cm ; ESI MS m/z: 500
[M＋H]＋. Anal. calcd for C20H13Cl4N3O2S: C 47.93, H
2.61, N 8.38; found C 48.15, H 2.50, N 8.31.
3-(2,6-Dichlorophenyl)-10-(3,4,5-trimethoxybenz-
ylidene)-6,7-dihydro-5H-[1,2,4]oxadiazolo[4,5-a]thia-
zolo[2,3-b]pyrimidin-9(10H)-one (4h) White solid,
1
yield 53%; m.p. 186—188 ℃; H NMR (CDCl3, 500
MHz) δ: 1.89—2.10 (m, 2H, Hb), 3.06 (ddd, J＝1.4, 9.1,
15.3 Hz, 1H, Ha), 3.15 (ddd, J＝1.4, 9.1, 15.3 Hz, 1H,
Ha), 3.41 (ddd, J＝1.3, 9.4, 14.3 Hz, 1H, Hc), 3.89 (s,
3H, OCH3), 3.92 (s, 6H, OCH3), 4.41 (ddd, J＝1.3, 9.4,
14.3 Hz, 1H, Hc), 6.78 (s, 2H), 7.44—7.49 (m, 3H),
7.64 (s, 1H, Hf); 13C NMR (CDCl3, 125 MHz) δ: 23.08
(CH2), 34.17 (CH2), 36.46 (CH2), 56.16 (OCH3), 56.21
(OCH3), 60.97 (OCH3), 118.91 (Cd), 122.58 (Cf),
123.12, 128.32, 128.80, 128.84, 130.00, 132.95, 136.21,
136.64, 138.84, 153.34 (C＝N), 163.81 (C＝O); IR
Figure 1 Part HMBC diagram of 4g.
Conclusion
A novel series of heterocycle compounds, [1,2,4]-
oxadiazolo[4,5-a]thiazolo[2,3-b]pyrimidin-9(10H)-ones,
were synthesized by the reaction of nitrile oxide with
the C＝N of thiazolo[3,2-a]pyrimidine derivatives in
moderate yields. The reaction shows high chemoselec-
tivity which only the C＝N involved in the cycloaddi-
tion and the C＝C was inert. This chemoselectivity of-
fers an easy way to synthesize new complicated hetero-
cycles which is difficult to synthesize by common
methods.
－1
(KBr) v: 1698.5 (C＝O) cm ; ESI MS m/z: 522 [M＋
H]＋. Anal. calcd for C23H21Cl2N3O5S: C 52.88, H 4.05,
N 8.04; found C 52.94, H 3.95, N 7.91.
Results and discussion
References
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Chin. J. Chem. 2010, 28, 977— 980