New efficient synthesis of 1,2,4-triazolo[5,1-b]quinazolin-9(3h)-ones via a tandem aza-Wittig/heterocumulene-mediated annulation

Article abstract of DOI:10.1002/ejoc.200400185

The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, react with hydrazine to give, selectively, the 3-amino-2-arylaminoquinazolin-4(3H)-ones 4. Reaction of 4 with triphenylphosphane, hexachloroethane and

Full text of DOI:10.1002/ejoc.200400185

FULL PAPER
New Efficient Synthesis of 1,2,4-Triazolo[5,1-b]quinazolin-9(3H)-ones via a
Tandem Aza-Wittig/Heterocumulene-Mediated Annulation
Ming-Wu Ding,*[a] Yun-Feng Chen,[a] and Nian-Yu Huang[a]
Keywords: aza-Wittig reaction / Carbodiimide / Iminophosphorane / Nitrogen heterocycles / Synthetic methods
The carbodiimides 2, obtained from aza-Wittig reactions of
iminophosphorane 1 with aromatic isocyanates, react with
satisfactory yield. The aza-Wittig reaction of iminophosphor-
ane 5 with CS2 or CO2 gives the 1,2,4-triazolo[5,1-b]quinaz-
hydrazine to give, selectively, the 3-amino-2-arylaminoquin- olin-9(3H)-ones 14 or 17, respectively. Further S-alkylation of
azolin-4(3H)-ones 4. Reaction of 4 with triphenylphosphane,
hexachloroethane and triethylamine produces iminophos-
phoranes 5. A tandem aza-Wittig reaction of iminophosphor-
ane 5 with isocyanate or acyl chloride generates the 1,2,4-
triazolo[5,1-b]quinazolin-9(3H)-ones 7 or 9, respectively, in
14 produces the 2-alkylthio-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one 15.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
ones, which are of considerable interest as potential biologi-
cally active compounds or pharmaceuticals, has been re-
ported.
The synthesis of derivatives of quinazolinone has been
the focus of great interest recently. This is due, in part, to
the broad spectrum of biological properties of these com-
pounds. Some of these activities include antimicrobial,[1,2]
anti-inflammatory,[3,4] antifungal,[5Ϫ7] anticancer[8] and
AMPA receptor antagonistic properties.[9,10] The range of
biological activities and characteristic chemical structures
have made synthetic studies of quinazolinones very attract-
ive.
Heterocycles containing the 1,2,4-triazole nucleus also
exhibit various biological activities, and several of them
have been used as fungicidal, bactericidal, insecticidal, anti-
tumor and anti-inflammatory agents.[11Ϫ17] The introduc-
tion of a triazole ring to the quinazolinone system is ex-
pected to influence the biological activities significantly. In
fact, some 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones have
been reported to exhibit good antifungal, antihistaminic
and antirheumatic activities.[18,19]
Over the past twenty years, the aza-Wittig reactions of
iminophosphoranes have received increasing attention in
view of their utility in the synthesis of nitrogen heterocyclic
compounds.[23] Annelation of ring systems with N-hetero-
cycles by means of an aza-Wittig reaction has been widely
utilized because of the availability of functionalized imino-
phosphoranes. Consequently, the discovery of novel func-
tionalized iminophosphoranes is important in this respect.
Recently we have become interested in the synthesis of qui-
nazolinones, thienopyrimidinones and imidazolinones by
an aza-Wittig reaction, with the aim of evaluating their
fungicidal activities.[24Ϫ30] Here we wish to report a funda-
mentally new approach to the synthesis of 1,2,4-tri-
azolo[5,1-b]quinazolin-9(3H)-ones by tandem aza-Wittig/
heterocumulene-mediated annulation of easily accessible
N-(2-arylamino-3H-quinazolin-4-on-3-yl)iminotriphenyl-
phosphorane with isocyanates, acyl chloride, CS2 or CO2.
The methods described so far for the preparation of some
representative derivatives of this ring system involve either
reaction of anthranilic acid with 3-mercapto-s-triazoles[18]
or cyclization of 3-amino-2-arylaminoquinazolin-4(3H)-
ones with carboxylic acids, acyl chlorides or alde-
hydes.[20Ϫ22] However, these methods often require relatively
harsh acid, dehydrating conditions or heating at high tem-
perature. Until now, no general and simple approach to
2-amino-substituted 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-
Results and Discussion
Iminophosphorane 1 reacts with aromatic isocyanates to
give carbodiimides 2, which were allowed to react with hy-
drazine to give, selectively, the 2-arylamino-3-aminoquin-
azolin-4(3H)-ones 4 in 72Ϫ81% yield (Scheme 1). It is
worth noting that the reaction between carbodiimides 2 and
aliphatic primary amine gives mainly abnormal 2-alkyl-
amino-3-arylquinazolin-4(3H)-ones; this might be due to
the geometry of the guanidine intermediate.[28] The normal
formation of 4 can be rationalized in terms of an initial
nucleophilic addition of hydrazine to give the guanidine in-
termediate 3, which cyclizes to give 4 across the strong
nucleophilic hydrazine group rather than the arylamine one.
[a]
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal
University,
Wuhan, 430079, P. R. China
E-mail: ding5229@yahoo.com.cn
mwding@mail.ccnu.edu.cn
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400185
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Efficient Synthesis of 1,2,4-Triazolo[5,1-b]quinazolin-9(3H)-ones
FULL PAPER
It has been reported that 4a (Ar1 ϭ Ph) can be obtained by
a rearrangement of hydrazine with 2-alkylthioquinazolin-
4(3H)-one.[31a] The structure of 4 obtained by our new syn-
thetic method was confirmed by comparison with the litera-
ture. Compounds 4 were easily converted into novel func-
tionalized iminophosphoranes 5 upon reaction with tri-
phenylphosphane, hexachloroethane and triethylamine in
good yields (76Ϫ85%, Scheme 1).
Table 1. Preparation of 2-arylamino-1,2,4-triazolo[5,1-b]quinaz-
olin-9(3H)-ones 7
Compd.
Ar1
Ar2
Yield (%)
7a
7b
7c
7d
7e
7f
Ph
Ph
Ph
Ph
4-Me-C6H4
3-Me-C6H4
Ph
4-Cl-C6H4
3-Cl-C6H4
4-Me-C6H4
3-Me-C6H4
Ph
90
90
92
94
92
93
92
91
87
86
Ph
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
7g
7h
7i
4-Cl-C6H4
3-Cl-C6H4
7j
Scheme 2. Reaction conditions: (i) Ar2NCO, CH2Cl2, room temp.,
1Ϫ2 h
Scheme 1. Reaction conditions: (i) Ar1NCO, CH2Cl2, 0Ϫ5 °C,
6Ϫ12 h; (ii) NH2NH2, EtOH, room temp., 10 min; (iii) PPh3,
C2Cl6, CH2Cl2, NEt3, room temp., 4Ϫ6 h
at temperatures slightly higher than its melting point
(Scheme 4).[32] This unsuccessful cyclization by an intramol-
ecular aza-Wittig reaction of 11 has been ascribed to the
restricted conformation of the side chain at the 3-position,
which could be entropically unfavourable for the cycliza-
tion. This phenomenon has also been found in other
cases.[33Ϫ36] The easy transformation of 8 to 9 reveals the
preferential reactivity of the iminophosphorane group of
compound 5, compared to the amino moiety, towards elec-
trophilic reagents. Consequently, the formation of 9 can be
viewed as an initial aza-Wittig reaction between the imino-
phosphorane 5 and acyl chloride in the presence of triethyl-
amine, affording the intermediate imidoyl chloride 8, which
undergoes cyclization to give 9.
When solutions of iminophosphoranes 5 in dry dichloro-
methane were treated with aromatic isocyanate at room
temperature, the colour of the reaction mixture quickly
turned red. This colour disappeared after a few minutes,
and 2-arylamino-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones
7 were subsequently isolated as crystalline solids in excellent
yields (86Ϫ94%, Table 1, Scheme 2). Presumably, the con-
version of 5 into 7 involves initial aza-Wittig reaction be-
tween the iminophosphorane 5 and the isocyanate to give
a carbodiimide 6 as a highly reactive intermediate, which
easily undergoes ring closure across the arylamino group to
give the otherwise not readily available 2-arylamino-substi-
tuted 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones 7. It is
noteworthy that the reaction can be easily carried out at
room temperature under mild neutral condition and the
Table 2. Preparation of 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones 9
separation of 7 from the reaction mixture was also easily Compd.
Ar1
R
Yield (%)
carried out by simple filtration.
Iminophosphoranes 5 react with acyl chlorides in the
presence of triethylamine in dichloromethane at room tem-
perature to give the 2-substituted 1,2,4-triazolo[5,1-b]quin-
azolin-9(3H)-ones 9 in good yield (63Ϫ88%, Table 2,
Scheme 3). It is interesting to note that a similar iminophos-
phorane 10 reacts with acyl chloride at room temperature
to give the corresponding N-acyl derivative 11, which does
not cyclize to give 12 even in refluxing toluene for 24 h or
9a
Ph
Ph
Ph
Ph
Me
Ph
73
88
67
63
78
68
81
73
67
9b
9c
4-Cl-C6H4
ClCH2
4-Cl-C6H4OCH2
Me
Ph
4-Cl-C6H4
ClCH2
9d
9e
9f
Ph
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
9g
9h
9i
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M.-W. Ding, Y.-F. Chen, N.-Y. Huang
FULL PAPER
Scheme 3. Reaction conditions: (i) RCOCl, CH2Cl2, NEt3, room
temp., 2Ϫ4 h
Scheme 5. Reaction conditions: (i) CS2, CH2Cl2, 40 °C, 20 h; (ii)
RX, CH3CN, K2CO3 (s), room temp. or 50Ϫ60 °C, 1Ϫ4 h
Table 3. Composition of compounds 14, 15 and 17
Compd.
Ar1
RX
Yield (%)
14a
14b
15a
15b
15c
15d
15e
15f
15g
15h
15i
Ph
4-Cl-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
Ph
87
83
92
81
76
84
88
83
91
82
74
80
84
78
77
84
43
MeI
EtBr
nPrBr
nBuBr
PhCH2Cl
ClCH2CN
ClCH2COOEt
MeI
EtBr
nPrBr
Scheme 4. Literature conditions for the reaction of iminophos-
phorane 10 with acyl chloride: (i) R2COCl, THF, NEt3, room
temp.; (ii) toluene, reflux, 24 h or heating above the melting point
15j
15k
15l
15m
15n
17
nBuBr
PhCH2Cl
ClCH2CN
ClCH2COOEt
Iminophosphoranes 5 react with CS2 in refluxing di-
chloromethane to give the 2-thioxo-1,2,4-triazolo[5,1-b]quin-
azolin-9(3H)-ones 14 in good yield (83Ϫ87%, Scheme 5,
Table 3). The formation of 14 can be viewed as an initial
aza-Wittig reaction between the iminophosphorane 5 and
CS2 affording the intermediate isothiocyanate 13, which un-
dergoes cyclization to give 14. S-Alkylation of 14 with alkyl
halide in the presence of solid potassium carbonate gave the
2-alkylthio-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones 15 in
satisfactory yields. With alkylating reagents such as RI and
BrCH2COR, the alkylation could be carried out at room
temperature. With other reagents, the alkylation had to be
carried out at 50 °C.
The 1,3-dihydro-1,2,4-triazolo[5,1-b]quinazolin-2,9-dione
17 was obtained in moderate yield (43%, Scheme 6) when
iminophosphoranes 5 were allowed to react with CO2 in
dichloromethane. The formation of 17 can be viewed as an
initial aza-Wittig reaction between the iminophosphorane 5
and CO2, affording the intermediate isocyanate 16, which
undergoes cyclization to give 17. The significantly low yield
of the reaction might be due to the low solubility of CO2
gas in the organic solvent.
Scheme 6. Reaction conditions: (i) CO2, CH2Cl2, room temp., 30 h
1
tively. The H NMR spectrum of 7a shows two singlets at
The structure of 1,2,4-triazolo[5,1-b]quinazolin-9(3H)- δ ϭ 6.12 and 2.33 ppm due to the NH and CH3 groups,
ones 7, 9, 14, 15 and 17 was confirmed by their spectro- respectively. The signals attributable to the 8-H and other
scopic data. For example, the IR spectra of 7a reveals NϪH aromatic protons are found at δ ϭ 8.44 and 7.17Ϫ7.72 ppm
and CϭO absorption bands at 3295 and 1675 cmϪ1, respec- as a doublet and multiplets, respectively. The 13C NMR
3874
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Efficient Synthesis of 1,2,4-Triazolo[5,1-b]quinazolin-9(3H)-ones
FULL PAPER
1H NMR (CDCl3, 400 MHz): δ ϭ 7.05Ϫ8.03 (m, 24 H, Ar-H),
9.16 (s, 1 H, N-H) ppm. 31P NMR (CDCl3, 162 MHz): δ ϭ
43.70 ppm. IR (KBr): ν˜ ϭ 3367 (NϪH), 1699 (CϭO), 1587, 1473,
1115, 690 cmϪ1. MS: m/z ϭ 512 (81) [Mϩ], 420 (15), 276 (96), 262
(83), 183 (100), 108 (74). C32H25N4OP (512.6): calcd. C 74.99, H
4.92, N 10.93; found C 74.84, H 4.81, N 10.96.
spectroscopic data for 7a show the signals of CϭO and CH3
at δ ϭ 154.8 and 20.6 ppm, respectively. The mass spectrum
of 7a shows a strong molecular ion peak at m/z ϭ 367 with
100% abundance.
N-[2-(4-Chlorophenyl)amino-3H-quinazolin-4-on-3-yl]iminotri-
phenylphosphorane (5b): White crystals (yield 3.33 g, 76%); m.p.
Conclusion
1
278Ϫ280 °C. H NMR (CDCl3, 400 MHz): δ ϭ 7.06Ϫ8.01 (m, 23
H, Ar-H), 9.42 (s, 1 H, N-H) ppm. 31P NMR (CDCl3, 162 MHz):
δ ϭ 43.67 ppm. IR (KBr): ν˜ ϭ 3372 (NϪH), 1698 (CϭO), 1583,
1472, 1113, 755 cmϪ1. MS: m/z ϭ 548/546 (25/77) [Mϩ], 277 (100),
261 (65), 183 (80), 107 (22). C32H24ClN4OP (547.0): calcd. C 70.27,
H 4.42, N 10.24; found C 70.32, H 4.28, N 10.37.
We have developed an efficient synthesis of 2-substituted
1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones by aza-Wittig re-
actions. This method utilizes easily accessible starting mate-
rials and allows mild reaction conditions, straightforward
product isolation and good yields. We think that the syn-
thetic approach discussed here compares very favourably
with existing methods.
2-Arylamino-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones 7a؊7j: Aro-
matic isocyanate (2 mmol) was added under nitrogen, at room tem-
perature, to a solution of iminophosphorane 5 (2 mmol) in dry di-
chloromethane (15 mL). The colour of the reaction mixture turned
red, disappearing after a few minutes. The colourless solution was
stirred at room temperature for 1Ϫ2 h. The white precipitate was
collected by filtration and recrystallized from CH2Cl2/ethanol to
give 7 as a crystalline solid.
2-[(4-Methylphenyl)amino]-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (7a): White crystals (yield 664 mg, 90%); m.p. Ͼ300 °C.
1H NMR (CDCl3, 400 MHz): δ ϭ 2.33 (s, 3 H, CH3), 6.12 (s, 1 H,
NH), 7.17Ϫ7.72 (m, 12 H, Ar-H), 8.44 (d, J ϭ 8.0 Hz, 1 H, H-8)
ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 20.6 (CH3), 114.9, 118.6,
121.1, 125.8, 128.1, 128.2, 128.6, 130.4, 132.1, 132.2, 134.3, 136.6,
137.1, 137.8, 143.4, 149.9 (Ar-C), 154.8 (CϭO) ppm. IR (KBr):
ν˜ ϭ 3295 (NϪH), 1675 (CϭO), 1579, 1474, 760 cmϪ1. MS: m/z ϭ
367 (100) [Mϩ], 351 (22), 248 (14), 221 (34), 119 (38). C22H17N5O
(367.4): calcd. C 71.92, H 4.66, N 19.06; found C 71.81, H 4.69,
N 19.25.
2-[(3-Methylphenyl)amino]-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (7b): White crystals (yield 661 mg, 90%); m.p. Ͼ300 °C.
1H NMR (CDCl3, 400 MHz): δ ϭ 2.31 (s, 3 H, CH3), 6.32 (s, 1 H,
NH), 7.17Ϫ8.00 (m, 12 H, Ar-H), 8.43 (d, J ϭ 8.4 Hz, 1 H, H-8)
ppm. IR (KBr): ν˜ ϭ 3238 (NϪH), 1676 (CϭO), 1584, 1473, 689
cmϪ1. MS: m/z ϭ 367 (100) [Mϩ], 351 (32), 248 (23), 221 (32), 119
(43). C22H17N5O (367.4): calcd. C 71.92, H 4.66, N 19.06; found C
71.76, H 4.57, N 19.18.
Experimental Section
General Remarks: Melting points are uncorrected. Mass spectra
were measured on a Finnigan Trace MS spectrometer. IR were re-
corded on a PE-983 infrared spectrometer as KBr pellets with ab-
sorptions given in cmϪ1. NMR were recorded in CDCl3 or
[D6]DMSO on a Varian Mercury 400 spectrometer and resonances
are given in ppm (δ) relative to TMS. Elementary analyses were
determined on a PerkinϪElmer CHN 2400 elementary analysis in-
strument.
3-Amino-2-arylamino-4(3H)-quinazolinones (4): Aromatic isocyan-
ate (5 mmol) was added under nitrogen, at room temperature, to a
solution of iminophosphorane 1[27] (2.12 g, 5 mmol) in dry di-
chloromethane (15 mL). After leaving the reaction mixture to stand
for 6Ϫ12 hours at 0Ϫ5 °C, the solvent was removed under reduced
pressure and diethyl ether/petroleum ether (1:2, 20 mL) was added
to precipitate the triphenylphosphane oxide. The mixture was then
filtered and the solvent was removed to give carbodiimide 2, which
was used directly without further purification. A solution of hydra-
zine hydrate (0.35 g, 6 mmol, 85%) in EtOH (5 mL) was added to
the solution of 2 prepared above, in EtOH (15 mL). The mixture
was stirred for 10 min at room temperature and filtered to give 3-
amino-2-arylamino-4(3H)-quinazolinone 4.
2-(Phenylamino)-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one
(7c):
White crystals (yield 652 mg, 92%); m.p. Ͼ300 °C. 1H NMR
(CDCl3, 400 MHz): δ ϭ 6.18 (s, 1 H, NH), 7.12Ϫ7.73 (m, 13 H,
Ar-H), 8.45 (d, J ϭ 6.8 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ 3277
(NϪH), 1673 (CϭO), 1579, 1474, 686 cmϪ1. MS: m/z ϭ 353 (100)
[Mϩ], 337 (22), 235 (37), 221 (54), 77 (85). C21H15N5O (353.4):
calcd. C 71.38, H 4.28, N 19.82; found C 71.45, H 4.22, N 19.71.
2-[(4-Chlorophenyl)amino]-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (7d): White crystals (yield 728 mg, 94%); m.p. Ͼ300 °C.
1H NMR (CDCl3, 400 MHz): δ ϭ 6.23 (s, 1 H, NH), 7.10Ϫ7.78
(m, 12 H, Ar-H), 8.44 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. IR (KBr):
ν˜ ϭ 3279 (NϪH), 1672 (CϭO), 1576, 1474, 763 cmϪ1. MS:
m/z ϭ 389/387 (35/100) [Mϩ], 371 (11), 236 (9), 221 (22), 77 (32).
C21H14ClN5O (387.8): calcd. C 65.04, H 3.64, N 18.06; found C
65.23, H 3.53, N 18.13.
3-Amino-2-(phenylamino)-4(3H)-quinazolinone (4a): White solid
(yield 1.02 g, 81%), m.p. 149Ϫ150 °C; ref.[31a] m.p. 150 °C.
3-Amino-2-[(4-chlorophenyl)amino]-4(3H)-quinazolinone (4b): White
solid (yield 1.03 g, 72%); m.p. 232Ϫ233 °C. 1H NMR (CDCl3,
400 MHz): δ ϭ 4.65 (s, 2 H, NH2), 7.09Ϫ8.08 (m, 8 H, Ar-H), 8.71
(s, 1 H, N-H) ppm. IR (KBr): ν˜ ϭ 3324, 3296, 3219 (NϪH), 1677
(CϭO), 1613, 1544, 763 cmϪ1. MS: m/z ϭ 288/286 (35/100) [Mϩ],
269 (41), 255 (61), 220 (39), 161 (43), 90 (73). C14H11ClN4O (286.7):
calcd. C 58.65, H 3.87, N 19.54; found C 58.82, H 3.75, N 19.58.
N-(2-Arylamino-3H-quinazolin-4-on-3-yl)iminotriphenylphos-
phoranes 5a and 5b): NEt3 (2.42 g, 24 mmol) was added dropwise,
at room temperature, to a mixture of 4 (8 mmol), PPh3 (3.14 g,
12 mmol) and C2Cl6 (2.84 g, 12 mmol) in dry CH2Cl2 (40 mL). The
colour of the reaction mixture quickly turned yellow. After stirring
for 4Ϫ6 h, the solvent was removed under reduced pressure and
the residue was recrystallized from EtOH to give iminophos-
phoranes 5.
2-[(3-Chlorophenyl)amino]-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (7e): White crystals (yield 714 mg, 92%); m.p. Ͼ300 °C.
1H NMR (CDCl3, 400 MHz): δ ϭ 6.18 (s, 1 H, NH), 7.08Ϫ7.74
(m, 12 H, Ar-H), 8.45 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. IR (KBr):
N-(2-Phenylamino-3HϪquinazolin-4-on-3-yl)iminotriphenylphos- ν˜ ϭ 3264 (NϪH), 1675 (CϭO), 1578, 1475, 767 cmϪ1. MS: m/z ϭ
phorane (5a): White crystals (yield 3.49 g, 85%); m.p. 209Ϫ211 °C.
389/387 (1/3) [Mϩ], 371 (1), 235 (2), 221 (14), 102 (100).
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M.-W. Ding, Y.-F. Chen, N.-Y. Huang
FULL PAPER
C21H14ClN5O (387.8): calcd. C 65.04, H 3.64, N 18.06; found C
65.15, H 3.79, N 17.98.
3-(4-Chlorophenyl)-2-[(4-methylphenyl)amino]-1,2,4-triazolo[5,1-b]-
quinazolin-9(3H)-one (7f): White crystals (yield 745 mg, 93%); m.p.
H-8) ppm. IR (KBr): ν˜ ϭ 1699 (CϭO), 1628, 1552, 1470, 770 cmϪ1
.
MS: m/z ϭ 338 (5) [Mϩ], 219 (4), 180 (35), 102 (100). C21H14N4O
(338.4): calcd. C 74.54, H 4.17, N 16.56; found C 74.58, H 4.26,
N 16.41.
Ͼ300 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 2.32 (s, 3 H, CH3), 2-(4-Chlorophenyl)-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-
6.18 (s, 1 H, NH), 7.14Ϫ7.69 (m, 11 H, Ar-H), 8.42 (d, J ϭ 8.0 Hz, one (9c): White crystals (yield 500 mg, 67%); m.p. 194Ϫ195 °C. 1H
1 H, H-8) ppm. IR (KBr): ν˜ ϭ 3287 (NϪH), 1673 (CϭO), 1577, NMR (CDCl3, 400 MHz): δ ϭ 7.35Ϫ7.76 (m, 12 H, Ar-H), 8.49
1472, 761 cmϪ1. MS: m/z ϭ 403/401 (37/100) [Mϩ], 385 (9), 256 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ 1701 (CϭO), 1608,
(14), 221 (12), 102 (44). C22H16ClN5O (401.9): calcd. C 65.76, H 1591, 1470, 743 cmϪ1. MS: m/z ϭ 374/372 (28/81) [Mϩ], 371 (100),
4.01, N 17.43; found C 65.58, H 4.16, N 17.48.
3-(4-Chlorophenyl)-2-[(3-methylphenyl)amino]-1,2,4-triazolo[5,1-b]-
308 (5), 235 (6), 102 (42), 77 (83). C21H13ClN4O (372.8): calcd. C
67.66, H 3.51, N 15.03; found C 67.82, H 3.35, N 15.14.
quinazolin-9(3H)-one (7g): White crystals (yield 740 mg, 92%); m.p. 2-Chloromethyl-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one
Ͼ300 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 2.35 (s, 3 H, CH3), (9d): White crystals (yield 390 mg, 63%); m.p. 221Ϫ223 °C. 1H
6.10 (s, 1 H, NH), 6.93Ϫ7.69 (m, 11 H, Ar-H), 8.44 (d, J ϭ 8.0 Hz, NMR (CDCl3, 400 MHz): δ ϭ 4.62 (s, 2 H, ClCH2), 7.38Ϫ7.71
1 H, H-8) ppm. IR (KBr): ν˜ ϭ 3276 (NϪH), 1673 (CϭO), 1589, (m, 8 H, Ar-H), 8.40 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. IR (KBr):
1473, 759 cmϪ1. MS: m/z ϭ 403/401 (10/29) [Mϩ], 385 (6), 256 (12), ν˜ ϭ 1705 (CϭO), 1628, 1610, 1473, 764 cmϪ1. MS: m/z ϭ 312/310
221 (10), 102 (100). C22H16ClN5O (401.9): calcd. C 65.76, H 4.01,
N 17.43; found C 65.64, H 3.95, N 17.54.
3-(4-Chlorophenyl)-2-(phenylamino)-1,2,4-triazolo[5,1-b]quinazolin-
(35/100) [Mϩ], 275 (70), 236 (34), 208 (21), 102 (93). C16H11ClN4O
(310.8): calcd. C 61.84, H 3.57, N 18.03; found C 61.76, H 3.63,
N 18.26.
9(3H)-one (7h): White crystals (yield 704 mg, 91%); m.p. Ͼ300 °C. 2-[(4-Chlorophenoxy)methyl]-3-phenyl-1,2,4-triazolo[5,1-b]-
1H NMR (CDCl3, 400 MHz): δ ϭ 6.16 (s, 1 H, NH), 7.14Ϫ7.70
quinazolin-9(3H)-one (9e): White crystals (yield 626 mg, 78%); m.p.
(m, 12 H, Ar-H), 8.44 (d, J ϭ 6.8 Hz, 1 H, H-8) ppm. IR (KBr): 175Ϫ176 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 5.18 (s, 2 H,
ν˜ ϭ 3263 (NϪH), 1673 (CϭO), 1576, 1473, 757 cmϪ1. MS: m/z ϭ
OCH2), 6.80Ϫ7.82 (m, 12 H, Ar-H), 8.44 (d, J ϭ 7.6 Hz, 1 H, H-
389/387 (11/31) [Mϩ], 371 (5), 242 (7), 207 (7), 102 (100). 8) ppm. IR (KBr): ν˜ ϭ 1705 (CϭO), 1627, 1609, 1473, 769 cmϪ1
.
C21H14ClN5O (387.8): calcd. C 65.04, H 3.64, N 18.06; found C
65.23, H 3.56, N 18.16.
MS: m/z ϭ 404/402 (30/85) [Mϩ], 275 (100), 235 (22), 218 (26), 102
(85). C22H15ClN4O2 (402.8): calcd. C 65.60, H 3.75, N 13.91; found
3-(4-Chlorophenyl)-2-[(4-chlorophenyl)amino]-1,2,4-triazolo[5,1-b]- C 65.45, H 3.84, N 13.83.
quinazolin-9(3H)-one (7i): White crystals (yield 733 mg, 87%); m.p.
3-(4-Chlorophenyl)-2-methyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-
Ͼ300 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 6.18 (s, 1 H, NH), one (9f): White crystals (yield 424 mg, 68%); m.p. Ͼ300 °C. 1H
7.18Ϫ7.72 (m, 11 H, Ar-H), 8.44 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. NMR (CDCl3, 400 MHz): δ ϭ 2.48 (s, 3 H, CH3), 7.37Ϫ7.72 (m,
IR (KBr): ν˜ ϭ 3271 (NϪH), 1670 (CϭO), 1575, 1471, 764 cmϪ1
.
7 H, Ar-H), 8.46 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ
MS: m/z ϭ 423/421 (4/6) [Mϩ], 255 (5), 241 (4), 144 (17), 102 (100). 1688 (CϭO), 1628, 1609, 1473, 770 cmϪ1. MS: m/z ϭ 312/310 (33/
C21H13Cl2N5O (422.3): calcd. C 59.73, H 3.10, N 16.58; found C 93) [Mϩ], 309 (100), 275 (18), 235 (64), 152 (46), 111 (92).
59.78, H 3.23, N 16.41.
C16H11ClN4O (310.8): calcd. C 61.84, H 3.57, N 18.03; found C
3-(4-Chlorophenyl)-2-[(3-chlorophenyl)amino]-1,2,4-triazolo[5,1-b]- 61.90, H 3.36, N 18.17.
quinazolin-9(3H)-one (7j): White crystals (yield 726 mg, 86%); m.p.
3-(4-Chlorophenyl)-2-phenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-
Ͼ300 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 6.16 (s, 1 H, NH), one (9g): White crystals (yield 604 mg, 81%); m.p. 284Ϫ286 °C. 1H
7.16Ϫ7.70 (m, 11 H, Ar-H), 8.44 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. NMR (CDCl3, 400 MHz): δ ϭ 7.38Ϫ7.74 (m, 12 H, Ar-H), 8.49
IR (KBr): ν˜ ϭ 3281 (NϪH), 1656 (CϭO), 1586, 1477, 767 cmϪ1
.
(d, J ϭ 8.0 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ 1704 (CϭO), 1629,
MS: m/z ϭ 423/421 (1.3/2) [Mϩ], 255 (5), 241 (4), 145 (21), 102 1608, 1403, 754 cmϪ1. MS: m/z ϭ 374/372 (31/90) [Mϩ], 371 (100),
(100). C21H13Cl2N5O (422.3): calcd. C 59.73, H 3.10, N 16.58;
found C 59.94, H 3.21, N 16.43.
336 (34), 279 (16), 214 (22), 102 (97). C21H13ClN4O (372.8): calcd.
C 67.66, H 3.51, N 15.03; found C 67.57, H 3.46, N 15.27.
2,3-Bis(4-Chlorophenyl)-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one
1
1,2,4-Triazolo[5,1-b]quinazolin-9(3H)-ones 9a؊9i: Acyl chloride
(2 mmol) and triethylamine (0.20 g, 2 mmol) were added under ni-
trogen, at room temperature, to a solution of iminophosphorane 5
(2 mmol) in dry CH2Cl2 (15 mL). The solution was stirred at room
temperature for 2Ϫ4 h. The white precipitated ammonium salt was
separated by filtration and the filtrate was concentrated to dryness.
The residue was recrystallized from CH2Cl2/ethanol to give 9 as a
crystalline solid.
2-Methyl-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one (9a):
White crystals (yield 404 mg, 73%); m.p. 290Ϫ291 °C. 1H NMR
(CDCl3, 400 MHz): δ ϭ 2.47 (s, 3 H, CH3), 7.26Ϫ7.71 (m, 8 H,
Ar-H), 8.46 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. 13C NMR (CDCl3,
100 MHz): δ ϭ 20.6 (CH3), 114.6, 118.9, 127.3, 127.8, 128.1, 129.0,
131.7, 133.7, 137.2, 138.4, 145.3, 153.4 (Ar-C), 154.3 (CϭO) ppm.
IR (KBr): ν˜ ϭ 1698 (CϭO), 1608, 1593, 1471, 764 cmϪ1. MS:
m/z ϭ 276 (100) [Mϩ], 247 (13), 236 (14), 219 (12), 118 (27), 77
(85). C16H12N4O (276.3): calcd. C 69.55, H 4.38, N 20.28; found C
69.72, H 4.30, N 20.33.
(9h): White crystals (yield 592 mg, 73%); m.p. Ͼ300 °C. H NMR
(CDCl3, 400 MHz): δ ϭ 7.38Ϫ7.76 (m, 11 H, Ar-H), 8.47 (d, J ϭ
8.0 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ 1684 (CϭO), 1606, 1586,
1474, 763 cmϪ1. MS: m/z ϭ 410/408/406 (8/46/72) [Mϩ], 370 (11),
248 (12), 137 (31), 102 (100). C21H12Cl2N4O (407.3): calcd. C 61.93,
H 2.97, N 13.76; found C 61.81, H 2.95, N 13.88.
2-Chloromethyl-3-(4-chlorophenyl)-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (9i): White crystals (yield 465 mg, 67%); m.p. 205Ϫ207
°C. 1H NMR (CDCl3, 400 MHz): δ ϭ 4.62 (s, 2 H, ClCH2),
7.40Ϫ7.73 (m, 7 H, Ar-H), 8.43 (d, J ϭ 8.4 Hz, 1 H, H-8) ppm.
IR (KBr): ν˜ ϭ 1695 (CϭO), 1635, 1611, 1472, 766 cmϪ1. MS:
m/z ϭ 348/346/344 (4/22/34) [Mϩ], 313 (96), 270 (54), 255 (86), 90
(100). C16H10Cl2N4O (345.2): calcd. C 55.67, H 2.92, N 16.23;
found C 55.41, H 2.76, N 16.38.
2-Thioxo-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones 14a, and 14b:
An excess of CS2 (10 mL) was added under nitrogen, at room tem-
perature, to a solution of iminophosphorane 5 (30 mmol) in dry
dichloromethane (15 mL). After refluxing the reaction mixture for
2,3-Diphenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one (9b): White
crystals (yield 595 mg, 88%); m.p. Ͼ300 °C. 1H NMR (CDCl3, 400 20 h, the white precipitated solid was collected by filtration to
MHz): δ ϭ 7.19Ϫ7.65 (m, 13 H, Ar-H), 8.42 (d, J ϭ 8.0 Hz, 1 H, give 14.
3876
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3872Ϫ3878

Efficient Synthesis of 1,2,4-Triazolo[5,1-b]quinazolin-9(3H)-ones
FULL PAPER
3-Phenyl-2-thioxo-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one (14a):
White crystals (yield 7.67 g, 87%); m.p. 278Ϫ280 °C. 1H NMR
7.32Ϫ7.72 (m, 13 H, Ar-H), 8.46 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm.
IR (KBr): ν˜ ϭ 1702 (CϭO), 1631, 1510, 1468, 764 cmϪ1. MS:
([D6]DMSO, 400 MHz): δ ϭ 7.40Ϫ7.79 (m, 8 H, Ar-H), 8.26 (d, m/z ϭ 384 (57) [Mϩ], 324 (7), 293 (23), 236 (12), 148 (58), 91 (100).
J ϭ 8.4 Hz, 1 H, 8-H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ
114.7, 118.8, 127.4, 128.1, 128.8, 131.6, 134.0, 136.8, 138.2, 145.2
153.6 (Ar-C), 154.1 (CϭO) ppm. IR (KBr): ν˜ ϭ 3423 (NϪH), 1702
(CϭO), 1657, 1578, 1126, 685 cmϪ1. MS: m/z ϭ 294 (2) [Mϩ], 265
(2), 235 (4), 144 (26), 77 (100). C15H10N4OS (294.3): calcd. C 61.21,
H 3.42, N 19.03; found C 61.14, H 3.35, N 19.24.
3-(4-Chlorophenyl)-2-thioxo-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-
one (14b): White crystals (yield 8.18 g, 83%); m.p. 267Ϫ268 °C. 1H
NMR ([D6]DMSO, 400 MHz): δ ϭ 7.39Ϫ7.79 (m, 7 H, Ar-H), 8.25
(d, J ϭ 8.0 Hz, 1 H, 8-H) ppm. IR (KBr): ν˜ ϭ 3424 (NϪH), 1718
(CϭO), 1663, 1579, 1134, 756 cmϪ1. MS: m/z ϭ 330/328 (32/100)
[Mϩ], 265 (17), 235 (12), 101 (12), 77 (11). C15H9ClN4OS (328.7):
calcd. C 54.80, H 2.76, N 17.04; found C 54.96, H 2.62, N 17.08.
C22H16N4OS (384.5): calcd. C 68.73, H 4.19, N 14.57; found C
68.54, H 4.32, N 14.74.
2-(Cyanomethylthio)-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-
1
one (15f): White crystals (yield 1.11 g, 83%); m.p. 251Ϫ253 °C. H
NMR (CDCl3, 400 MHz): δ ϭ 4.25 (s, 2 H, SCH2), 7.42Ϫ7.73 (m,
8 H, Ar-H), 8.45 (d, J ϭ 7.6 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ
2246 (CN), 1698 (CϭO), 1631, 1511, 1468, 770 cmϪ1. MS: m/z ϭ
333 (87) [Mϩ], 293 (84), 235 (24), 130 (97), 102 (100). C17H11N5OS
(333.4): calcd. C 61.25, H 3.33, N 21.01; found C 61.10, H 3.22,
N 21.07.
2-(Ethoxycarbonylmethylthio)-3-phenyl-1,2,4-triazolo[5,1-b]-
quinazolin-9(3H)-one (15g): White crystals (yield 1.38 g, 91%); m.p.
230Ϫ231 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 1.33 (t, J ϭ 7.2 Hz,
3 H, CH3), 4.24Ϫ4.29 (m, 4 H, SCH2 and OCH2), 7.37Ϫ7.73 (m,
8 H, Ar-H), 8.44 (d, J ϭ 7.6 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ
1723 and 1699 (CϭO), 1632, 1512, 1467, 765 cmϪ1. MS: m/z ϭ
380 (96) [Mϩ], 335 (11), 307 (12), 293 (100), 221 (14), 102 (83).
C19H16N4O3S (380.4): calcd. C 59.99, H 4.24, N 14.73; found C
60.03, H 4.10, N 14.67.
2-Alkylthio-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones 15a؊15n: A
mixture of 14 (4 mmol), alkyl halide (5 mmol) and solid potassium
carbonate (1.11 g, 8 mmol) in CH3CN (30 mL) was stirred for 1Ϫ4
h at room temperature or 50Ϫ60 °C and then filtered. The filtrate
was condensed and the residue was recrystallized from dichloro-
methane/petroleum ether (1:2) to give 2-alkylthio-1,2,4-tri-
azolo[5,1-b]quinazolin-9(3H)-ones 15.
2-(Methylthio)-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one
(15a): White crystals (yield 1.13 g, 92%); m.p. 296Ϫ298 °C. 1H
NMR (CDCl3, 400 MHz): δ ϭ 2.81 (s, 3 H, CH3), 7.40Ϫ7.71 (m,
8 H, Ar-H), 8.45 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ
1696 (CϭO), 1607, 1510, 1469, 762 cmϪ1. MS: m/z ϭ 308 (77)
[Mϩ], 293 (100), 265 (9), 221 (7), 102 (40), 77 (42). C16H12N4OS
(308.4): calcd. C 62.32, H 3.92, N 18.17; found C 62.17, H 3.84,
N 18.30.
2-(Ethylthio)-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one
(15b): White crystals (yield 1.05 g, 81%); m.p. 233Ϫ235 °C. 1H
NMR (CDCl3, 400 MHz): δ ϭ 1.48 (t, J ϭ 7.2 Hz, 3 H, CH3), 3.43
(q, J ϭ 7.2 Hz, 2 H, SCH2), 7.37Ϫ7.69 (m, 8 H, Ar-H), 8.45 (d,
J ϭ 8.4 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ 1693 (CϭO), 1633,
1506, 1470, 767 cmϪ1. MS: m/z ϭ 322 (94) [Mϩ], 293 (100), 265
(8), 236 (17), 221 (35), 102 (76), 77 (79). C17H14N4OS (322.4): calcd.
C 63.34, H 4.38, N 17.38; found C 63.42, H 4.21, N 17.32.
3-Phenyl-2-(n-propylthio)-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one
(15c): White crystals (yield 1.02 g, 76%); m.p. 218Ϫ220 °C. 1H
NMR (CDCl3, 400 MHz): δ ϭ 1.07 (t, J ϭ 7.2 Hz, 3 H, CH3),
1.80Ϫ1.89 (m, 2 H, CH2), 3.41 (t, J ϭ 7.2 Hz, 2 H, SCH2),
7.37Ϫ7.69 (m, 8 H, Ar-H), 8.45 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm.
IR (KBr): ν˜ ϭ 1695 (CϭO), 1632, 1508, 1469, 768 cmϪ1. MS: m/
z ϭ 336 (59) [Mϩ], 293 (58), 236 (11), 221 (15), 102 (62), 41 (100).
C18H16N4OS (336.4): calcd. C 64.27, H 4.79, N 16.65; found C
64.21, H 4.85, N 16.52.
3-(4-Chlorophenyl)-2-(methylthio)-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (15h): White crystals (yield 1.12 g, 82%); m.p. 274Ϫ275
°C. 1H NMR (CDCl3, 400 MHz): δ ϭ 2.80 (s, 3 H, CH3),
7.36Ϫ7.73 (m, 7 H, Ar-H), 8.44 (d, J ϭ 8.4 Hz, 1 H, H-8) ppm.
IR (KBr): ν˜ ϭ 1679 (CϭO), 1630, 1510, 1462, 771 cmϪ1. MS:
m/z ϭ 344/342 (35/100) [Mϩ], 327 (97), 292 (29), 255 (43), 130 (94).
C16H11ClN4OS (342.8): calcd. C 56.06, H 3.23, N 16.34; found C
56.13, H 3.21, N 16.57.
3-(4-Chlorophenyl)-2-(ethylthio)-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (15i): White crystals (yield 1.06 g, 74%); m.p. Ͼ300 °C.
1H NMR (CDCl3, 400 MHz): δ ϭ 1.50 (t, J ϭ 7.2 Hz, 3 H, CH3),
3.45 (q, J ϭ 7.2 Hz, 2 H, SCH2), 7.38Ϫ7.70 (m, 7 H, Ar-H), 8.45
(d, J ϭ 7.2 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ 1690 (CϭO), 1646,
1501, 1473, 769 cmϪ1. MS: m/z ϭ 358/356 (31/98) [Mϩ], 327 (100),
292 (17), 255 (31), 102 (75). C17H13ClN4OS (356.8): calcd. C 57.22,
H 3.67, N 15.70; found C 57.36, H 3.41, N 15.59.
3-(4-Chlorophenyl)-2-(n-propylthio)-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (15j): White crystals (yield 1.18 g, 80%); m.p. 188Ϫ189
°C. 1H NMR (CDCl3, 400 MHz): δ ϭ 1.08 (t, J ϭ 7.2 Hz, 3 H,
CH3), 1.81Ϫ1.89 (m, 2 H, CH2), 3.42 (t, J ϭ 7.2 Hz, 2 H, SCH2),
7.38Ϫ7.71 (m, 7 H, Ar-H), 8.44 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm.
IR (KBr): ν˜ ϭ 1689 (CϭO), 1636, 1511, 1473, 770 cmϪ1. MS:
m/z ϭ 372/370 (30/83) [Mϩ], 327 (100), 292 (20), 235 (27), 102 (66).
C18H15ClN4OS (370.9): calcd. C 58.30, H 4.08, N 15.11; found C
58.15, H 4.13, N 15.17.
2-(n-Butylthio)-3-(4-chlorophenyl)-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (15k): White crystals (yield 1.29 g, 84%); m.p. 166Ϫ168
°C. 1H NMR (CDCl3, 400 MHz): δ ϭ 0.96 (t, J ϭ 7.2 Hz, 3 H,
CH3), 1.43Ϫ1.81 (m, 4 H, CH2CH2), 3.45 (t, J ϭ 7.2 Hz, 2 H,
SCH2), 7.38Ϫ7.70 (m, 7 H, Ar-H), 8.45 (d, J ϭ 8.0 Hz, 1 H, H-8)
ppm. IR (KBr): ν˜ ϭ 1694 (CϭO), 1633, 1608, 1510, 1472, 768
cmϪ1. MS: m/z ϭ 386/384 (27/75) [Mϩ], 237 (36), 327 (100), 255
(28), 235 (31), 102 (72). C19H17ClN4OS (384.9): calcd. C 59.29, H
4.45, N 14.56; found C 59.14, H 4.67, N 14.48.
2-(n-Butylthio)-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-9(3H)-one
(15d): White crystals (yield 1.18 g, 84%); m.p. 191Ϫ192 °C. 1H
NMR (CDCl3, 400 MHz): δ ϭ 0.95 (t, J ϭ 7.2 Hz, 3 H, CH3),
1.44Ϫ1.81 (m, 4 H, CH2CH2), 3.43 (t, J ϭ 7.2 Hz, 2 H, SCH2),
7.37Ϫ7.69 (m, 8 H, Ar-H), 8.45 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm.
13C NMR (CDCl3, 100 MHz): δ ϭ 13.4 (CH3), 21.7 (CH2), 30.4
(CH2), 31.2 (SCH2), 117.7, 123.5, 126.0, 127.2, 129.8, 130.1, 131.3,
133.8, 147.1, 148.4, 154.3 (Ar-C), 155.5 (CϭO) ppm. IR (KBr):
ν˜ ϭ 1704 (CϭO), 1627, 1509, 1466, 763 cmϪ1. MS: m/z ϭ 350 (3)
[Mϩ], 293 (18), 236 (4), 221 (4), 102 (57), 41 (100). C19H18N4OS 3-(4-Chlorophenyl)-2-(phenylmethylthio)-1,2,4-triazolo[5,1-b]-
(350.5): calcd. C 65.12, H 5.18, N 15.99; found C 65.06, H 5.03,
N 16.17.
quinazolin-9(3H)-one (15l): White crystals (yield 1.30 g, 78%); m.p.
191Ϫ193 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 4.65 (s, 2 H,
SCH2), 7.31Ϫ7.72 (m, 12 H, Ar-H), 8.46 (d, J ϭ 8.0 Hz, 1 H, H-
3-Phenyl-2-(phenylmethylthio)-1,2,4-triazolo[5,1-b]quinazolin-
9(3H)-one (15e): White crystals (yield 1.35 g, 88%); m.p. 216Ϫ218
8) ppm. IR (KBr): ν˜ ϭ 1689 (CϭO), 1628, 1508, 1471, 766 cmϪ1
.
°C. 1H NMR (CDCl3, 400 MHz): δ ϭ 4.65 (s, 2 H, SCH2), MS: m/z ϭ 420/418 (4/12) [Mϩ], 372 (12), 296 (67), 270 (96), 235
Eur. J. Org. Chem. 2004, 3872Ϫ3878
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3877

M.-W. Ding, Y.-F. Chen, N.-Y. Huang
FULL PAPER
R. Guinn, D. Critchett, J. Lazzaro, A. H. Ganong, K. M.
Devries, T. L. Staigers, B. L. Chenard, Bioorg. Med. Chem.
Lett. 2001, 11, 177Ϫ181.
B. L. Chenard, F. S. Menniti, W. M. Jr. Welch, EP 900568
(1999) [Chem. Abstr. 1999, 130, 218317h].
J. Onodera, S. Sato, S. Kumazawa, A. Ito, S. Saishoji, Y. Nii-
zeki, JP 96127568 (1996) [Chem. Abstr. 1996, 125, 142713h].
H. Mikamo, X. H. Yin, Y. Hayasaki, M. Satoh, T. Tamaya,
Chemotherapy 2001, 47, 377Ϫ380.
R. P. Dickinson, A. W. Bell, C. A. Hitchcock, S. Narayana-
Swami, S. J. Ray, K. Richardson, P. F. Troke, Bioorg. Med.
Chem. Lett. 1996, 6, 2031Ϫ2036.
N. Ulusoy, A. Gursoy, G. Otuk, Farmaco 2001, 56, 947Ϫ952.
V. B. Hegde, S. J. Bis, E. C. Heo, C. T. Hamilton, P. L. Johnson,
L. L. Karr, T. P. Martin, P. A. Neese, N. Orr, F. E. Tisdell,
M. C. H. Yap, Y. Zhu, US 20020019370 [Chem. Abstr. 2002,
136, 146541].
S.-I. Nagai, S. Takemoto, T. Ueda, K. Mizutani, Y. Uozumi,
H. Tokuda, J. Heterocycl. Chem. 2001, 38, 1097Ϫ1101.
E. Palaska, G. Sahin, P. Kelicen, N. T. Durlu, G. Altinok, Far-
maco 2002, 57, 101Ϫ107.
S. Giri, Nizamuddin, K. K. Singh, Indian J. Chem. Sect B 1982,
21, 377Ϫ378.
R. Westwood, W. R. Tully, R. Murdoch, EP 34529 (1981).
[Chem. Abstr. 1981, 96, 20114a].
(68), 145 (97), 91 (100). C22H15ClN4OS (418.9): calcd. C 63.08, H
3.61, N 13.37; found C 63.25, H 3.45, N 13.24.
3-(4-Chlorophenyl)-2-(cyanomethylthio)-1,2,4-triazolo[5,1-b]-
quinazolin-9(3H)-one (15m): White crystals (yield 1.13 g, 77%); m.p.
238Ϫ240 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 4.25 (s, 2 H,
SCH2), 7.40Ϫ7.75 (m, 7 H, Ar-H), 8.44 (d, J ϭ 8.0 Hz, 1 H, H-8)
ppm. IR (KBr): ν˜ ϭ 2238 (CN), 1685 (CϭO), 1637, 1518, 1471,
767 cmϪ1. MS: m/z ϭ 369/367 (20/53) [Mϩ], 327 (50), 292 (41), 130
(61), 102 (100). C17H10ClN5OS (367.8): calcd. C 55.51, H 2.74, N
19.04; found C 55.43, H 2.79, N 19.16.
3-(4-Chlorophenyl)-2-(ethoxycarbonylmethylthio)-1,2,4-triazolo[5,1-b]-
quinazolin-9(3H)-one (15n): White crystals (yield 1.40 g, 84%); m.p.
191Ϫ193 °C. 1H NMR (CDCl3, 400 MHz): δ ϭ 1.33 (t, J ϭ 7.2 Hz,
3 H, CH3), 4.24Ϫ4.29 (m, 4 H, SCH2 and OCH2), 7.37Ϫ7.71 (m,
7 H, Ar-H), 8.43 (d, J ϭ 8.0 Hz, 1 H, H-8) ppm. IR (KBr): ν˜ ϭ
1739 and 1689 (CϭO), 1635, 1508, 1470, 767 cmϪ1. MS: m/z ϭ
416/414 (33/98) [Mϩ], 369 (16), 327 (98), 292 (29), 130 (62), 102
(100). C19H15ClN4O3S (414.9): calcd. C 55.01, H 3.64, N 13.50;
found C 55.07, H 3.53, N 13.42.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
1,3-Dihydro-3-phenyl-1,2,4-triazolo[5,1-b]quinazolin-2,9-dione (17):
Dry CO2 was bubbled through a solution of iminophosphorane 5a
(1.54 g, 3 mmol) in dry dichloromethane (30 mL) at room tempera-
ture. After allowing the reaction mixture to stand for 24 h, the
white precipitate was collected by filtration to give 17. White crys-
tals (yield 357 mg, 43%); m.p. Ͼ300 °C. 1H NMR ([D6]DMSO, 400
MHz): δ ϭ 7.39Ϫ7.75 (m, 8 H, Ar-H), 8.15 (d, J ϭ 8.0 Hz, 1 H,
8-H) ppm. 13C NMR (CDCl3, 100 MHz): δ ϭ 115.4, 120.6, 126.9,
127.6, 128.1, 128.6, 131.0, 132.9, 138.2, 138.8, 142.9 150.1 (Ar-C),
152.6 (CϭO) ppm. IR (KBr): ν˜ ϭ 3448 (NϪH), 1735 and 1698
(CϭO), 1637, 1442, 1139, 762 cmϪ1. MS: m/z ϭ 278 (100) [Mϩ],
236 (11), 221 (21), 194 (12), 102 (18). C15H10N4O2 (278.3): calcd.
C 64.74, H 3.62, N 20.13; found C 64.57, H 3.54, N 20.18.
[20]
[21]
[22]
K. Kottke, H. Kuehmstedt, Pharmazie 1985, 40, 55.
G. A. -R. El-Hiti, Bull. Chem. Soc. Jpn. 1997, 70, 2209Ϫ2213.
N. R. El-Brollosy, M. F. Abdel-Megeed, A. R. Genady, Mon-
atsh. Chem. 2001, 132, 1063Ϫ1073.
[23]
For recent examples of application of aza-Wittig reaction in
heterocyclic synthesis see: [23a] C. Bonini, M. D’Auria, M. Fun-
[23b]
icello, G. Romaniello, Tetrahedron 2002, 58, 3507Ϫ3512.
R. Alvarez-Sarandes, C. Peinador, J. M. Quintela, Tetrahedron
[23c]
2001, 57, 5413Ϫ5420.
P. Molina, P. M. Fresneda, S.
Delgado, J. A. Bleda, Tetrahedron Lett. 2002, 43, 1005Ϫ1007.
[23d]
F. Palacios, C. Alonso, P. Amezua, G. Rubiales, J. Org.
[23e]
Chem. 2002, 67, 1941Ϫ1946.
Synthesis 1994, 1197Ϫ1218.
P. Molina, M. J. Vilaplana,
[24]
[25]
M. W. Ding, S. J. Yang, J. Zhu, Synthesis 2004, 75Ϫ79.
M. W. Ding, Y. Sun, Z. J. Liu, Synth. Commun. 2003, 33,
1267Ϫ1274.
M. W. Ding, Y. Sun, S. J. Yang, X. P. Liu, Z. J. Liu, Synth.
Commun. 2003, 33, 1651Ϫ1658.
M. W. Ding, G. P. Zeng, T. J. Wu, Synth. Commun. 2000, 30,
1599Ϫ1604.
Y. Liang, M. W. Ding, Z. J. Liu, X. P. Liu, Synth. Commun.
2003, 33, 2843Ϫ2848.
M. W. Ding, G. P. Zeng, Z. J. Liu, Phosphorus Sulfur Silicon
Relat. Elem. 2002, 177, 1315Ϫ1321.
Acknowledgments
We gratefully acknowledge financial support of this work by the
National Key Project for Basic Research (2003CB114400,
2003CB114406) and the National Natural Science Foundation of
China (Project No.20102001).
[26]
[27]
[28]
[29]
[30]
[1]
S. N. Pandeya, D. Sriram, G. Nath, E. De Clercq, Pharm. Acta
Helv. 1999, 74, 11Ϫ17.
S. A. Shiba, A. A. El-Khamry, M. E. Shaban, K. S. Atia, Phar-
[2]
mazie 1997, 52, 189Ϫ194.
N. A. Santagati, E. Bousquet, A. Spadaro, G. Ronsisvalle, Far-
M. W. Ding, Y. L. Shu, X. P. Liu, Z. J. Liu, Acta Chim. Sin.
2002, 60, 1893Ϫ1898.
[3]
[31] [31a]
maco 1999, 54, 780Ϫ784.
M. A. Badawy, S. A. L. Abdel-Hady, Y. A. Ibrahim, J.
[4]
[31b]
A. A. Bekhit, M. A. Khalil, Farmaco 1998, 53, 539Ϫ543.
Heterocycl. Chem. 1985, 22, 1535Ϫ1536.
K. Kottke, H.
[5]
J. F. Bereznak, Z. Y. Chang, T. P. Selby, C. G. Sternberg, US
Kuhmstedt, I. Grafe, D. Knoke, Pharmazie 1990, 45, 285Ϫ286.
P. Molina, A. Arques, M. V. Vinader, J. Org. Chem. 1990, 55,
4724Ϫ4731.
P. Molina, A. Arques, M. V. Vinader, Synthesis 1990, 469Ϫ473.
P. Molina, M. Alajarin, A. Vidal, J. Elguero, R. M. Claramunt,
Tetrahedron 1988, 44, 2249Ϫ2259.
[32]
5945423 (1999). [Chem. Abstr. 1999, 131, 170360h].
J. F. Bereznak, Z. Y. Chang, C. G. Sternberg, PCT Int. Appl.
[6]
[33]
[34]
WO 9702262 (1997) [Chem. Abstr. 1998, 129, 132536w].
J. Bartroli, E. Turmo, M. Alguero, E. Boncompte, M. L. Ver-
[7]
icat, L. Conte, J. Ramis, M. Merlos, J. Garcia-Rafanell, J. Forn,
[35]
[36]
J. Med. Chem. 1998, 41, 1869Ϫ1882.
L. Skelton, V. Bavetsias, A. Jackman, WO 0050417 (2000)
P. Molina, A. Alias, A. Balado, A. Arques, Liebigs Ann. Chem.
1994, 745Ϫ749.
[8]
[Chem. Abstr. 2000, 133, 207917q].
W. M. Welch, F. E. Ewing, J. Huang, F. S. Menniti, M. J. Pag-
P. Molina, C. Conesa, M. D. Velasco, Liebigs Ann./Recueil
1997, 107Ϫ110.
[9]
nozzi, K. Kelly, P. A. Seymour, V. Guanowsky, S. Guhan, M.
Received March 22, 2004
3878
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3872Ϫ3878