Synthesis and characterization of a novel heterocycle: 1-Substituted-4- arylazamethylene-6-arylpyrazolo[5,4-d]-1,3-oxazine

Article abstract of DOI:10.1002/jhet.5570450211

(Chemical Equation Presented) A series of novel heterocycles 1-aryl- or alkyl-substituted-4-arylazamethylene-6-arylpyrazolo[5,4-d]-1,3-oxazines were synthesized from the acylation of (5-amino-1-substituted-pyrazol-4-yl)-N- carboxamide in 63-89% isolated y

Full text of DOI:10.1002/jhet.5570450211

Mar-Apr 2008
365
Synthesis and Characterization of a Novel Heterocycle:
1-Substituted-4-arylazamethylene-6-arylpyrazolo[5,4-d]-1,3-oxazine
Kunlun Hea*, Houjun Lv b, Junbo Wang b, Guofu Qiua, Xianming Hua
[a]College of Pharmacy, Wuhan University, Wuhan, Hubei Province, 430072, China
*e-mail: hkl80@hotmail.com
[b]Sundia Meditech Company Ltd., Shanghai, 201203, China
Received April 3, 2007
R2
O
N
N
R2
R3COCl/ pyridine
rt.
N
O
N
H
N
N
NH2
N
R3
R1
R1= akyl or aryl
R2, R3= aryl
R1
A series of novel heterocycles 1-aryl- or alkyl-substituted-4-arylazamethylene-6-arylpyrazolo[5,4-d]-
1,3-oxazines were synthesized from the acylation of (5-amino-1-substituted-pyrazol-4-yl)-N-carboxamide
in 63-89% isolated yields at room temperature within 12 hours. The structure was confirmed by X-ray
crystal analysis.
J. Heterocyclic Chem., 45, 365 (2008).
the ester group in 5 by preformed aniline anions. These
were then reacted with more than two equivalents of aroyl
chlorides at room temperature in pyridine to give the
target products 4 [19] in good yields. The results are
shown in Table 1.
INTRODUCTION
As shown in Figure 1, quinazolinones 1 have been
investigated synthetically [1-4], pharmacologically [2,4],
and corresponding rearrangement isomers 2 were also
studied for applications in medicinal chemistry [3,5-14] as
well as in plant pest control [15]. The 1-aryl- or alkyl-
substituted-5-hydropyrazolo[5,4-d]pyrimidin-4-one
3
Scheme 1
were also well known synthetically [16-18]. These
compounds have also been used to treat or prevent
diseases or disorders associated with the activity of
cannabinoid receptor 1 (CB1) [18]. Here we report the
synthesis and characterization of the novel heterocycles 1-
aryl- or alkyl-substituted-4-arylazamethylene-6-arylpyr-
azolo[5,4-d]-1,3-oxazines 4.
R2
O
N
N
O
R2
R2NH2
R3COCl
pyridine
N
O
O
N
N
H
N
n-BuLi
N
N
N
NH2
R3
NH2
R1
R1
R1
5
6
4
R4
O
N
N
N
In all cases, dry solvent and freshly redistilled
R4
R5
aroyl chlorides were necessary in order to obtain 4 in
N
N
O
good yields. If less strict conditions were used, a
R5
X
X
large amount of bis-amides
7 [20] formed as
1
2
intermediates, which after further treatment with
more than 1 equivalent of aroyl chloride, were
converted to 4 smoothly with high yields as shown
in Scheme 2. Interestingly, when bis-amides 7 were
treated with TiCl4 in 1,2-dichloroethane, the
isomeric structures 3 were obtained. Compounds 3
have also known to be synthesized from 7 by the
action of TMSCl/TEA [18].
R2
O
N
N
4
3
R2
R3
5
O
N
2 N
6
N
N
N
7
R3
1
R1
R1
3
4
Figure 1 R1, R2, R3, R4, R5 = aryl or alkyl; X = H, halogen or other
groups.
The structure of compound 4c was confirmed by the X-
ray crystallography (Figure 2) [21].
RESULTS AND DISCUSSION
The stability of 4 was also investigated. It was
stable towards dilute hydrochloric acid at room
temperature.
The synthesis of 4 is shown in Scheme 1. The
precursors 6 were readily obtained through replacement of

366
K. He, H. Lv, J. Wang, G. Qiu, X. Hu
Vol 45
Table 1
Synthesis of Compounds 4
Reaction
time (h)a
Entry
4a
4b
4c
4d
4e
4f
R1
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
2-pyridyl
cyclohexyl
R2
R3
Yield (%)b
4-chlorophenyl
4-methoxylphenyl
4-chlorophenyl
6-chloro-(3-pyridyl)
4-methylphenyl
4-methylphenyl
4-methoxylphenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
6-chloro-(3-pyridyl)
4-chlorophenyl
4-chlorophenyl
6-chloro-(3-pyridyl)
6-chloro-(3-pyridyl)
6-chloro-(3-pyridyl)
6-chloro-(3-pyridyl)
8
5
5
5
5
5
5
12
3
89
80
74
65
68
77
80
63
85
4g
4h
4i
4-methoxylphenyl
[a] Reaction conditions have not been optimized. [b] Isolated by chromatography on silica gel.
Scheme 2
However, these decomposed at higher temperature in
acidic condition to give acyclic compounds 7. On the
other hand, compounds 4 were stable under neutral or
basic conditions even at higher temperature.
It is worth noting that the methodology works well for
4a-i; however, it failed in case of R3 = 2,4-dichlorophenyl.
The acylation of substrate 6a with 2,4-dichlorobenzoyl
chloride only afforded 8 as shown in Scheme 3. The
structure of compound 8 was confirmed by X-ray
crystallography (Figure 3) [21].
O
R2
N
H
N
N
NH2
R1
6
R3COCl/
pyridine
O
O
N
R2
R2
R3
N
H
TMSCl/ TEA
N
Scheme 3
N
N
N
O
N
Cl
or:TiCl4/ ClC2H4Cl
HN
Cl
Cl
R1
R1
R3
3
7
O
O
NH
O
R3COCl/
pyridine
Cl
NH
Cl
N
O
Cl
N
N
NH2
N
Cl
N
R2
pyridine
N
N
O
O
Cl
N
N
Cl
R3
6a
8
R1
4
Figure 3 X-ray crystal structure of 8.
Figure 2 X-ray crystal structure of 4c.

Mar-Apr 2008
Synthesis and Characterization of a Novel Heterocycle
367
7.56 (m, 1H), 7.12 (d, J = 8.4, 2H), 6.49 (br, 2H), 2.26 (s, 3H)
ppm; 13C nmr: δ 162.6, 149.7, 138.6, 138.1, 136.7, 131.8, 129.4
(2C), 128.9 (2C), 127.2, 123.2 (2C), 120.0 (2C), 97.6, 20.4 ppm;
ms (esi): m/z 293 (M+H)+. Anal. Calcd. for C17H16N4O, C, 69.85;
H, 5.52; N, 5.47. Found: C, 69.47; H, 5.60; N, 5.58.
(5-Amino-1-(2-pyridyl)pyrazol-4-yl)-N-(4-chlorophenyl)
carboxamide (6e). This compound was obtained as a brown
solid from 5-amino-1-(2-pyridyl)-1H-pyrazole-4-carboxylic acid
5b and 4-chloroaniline with 65% yield. ir (KBr): 3410, 3302
(NH2), 1653 (CO-NH) cm-1; 1H nmr (DMSO-d6): δ 9.72 (s, 1H),
8.48 (dd, J = 4.8, 1.2, 1H), 8.24 (s, 1H), 8.02 (td, J = 7.5, 1.8,
1H), 7.90 (d, J = 8.1), 7.38-7.73 (m, 4H), 7.40-7.32 (m, 3H)
ppm; 13C nmr: δ 162.3, 153.5, 151.4, 147.1, 139.7, 139.6, 138.3,
128.5 (2C), 126.4, 121.3 (2C), 120.8, 113.1, 96.8 ppm; ms (esi):
m/z 314 (M+H)+. Anal. Calcd. for C15H12ClN5O, C, 57.42; H,
3.86; N, 22.32. Found: C, 57.56; H, 3.74; N, 22.60.
(5-Amino-1-cyclohexylpyrazol-4-yl)-N-(4-methoxylphenyl)
carboxamide (6f). This compound was prepared analogously
from 5-amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (5c)
and 4-methoxylaniline with 82% yield: ir (KBr): 3415, 3296
(NH2), 2931, 2854 (C6H11), 1610 (CO-NH), 1236 (OCH3) cm-1;
1H nmr (DMSO-d6): δ 9.28 (s, 1H), 7.88 (s, 1H), 7.55 (m, 2H),
6.87(m, 2H), 6.30 (s, 2H), 4.02 (m, 1H), 3.72 (s, 3H), 2.50 (m,
2H), 1.81-1.64 (m, 7H), 1.43-1.30 (m, 2H), 1.23-1.15 (m, 1H)
ppm; 13C nmr: δ 162.7, 154.9, 148.7, 136.3, 132.5, 121.5 (2C),
113.6 (2C), 96.6, 55.1, 54.0, 31.6 (2C), 25.0 (2C), 24.9 ppm; ms
(esi): m/z 315.1 (M+H)+. Anal. Calcd. for C17H22N4O, C, 64.95;
H, 7.05; N, 17.82. Found: C, 64.78; H, 7.24; N, 17.99.
General procedure of synthesis of compounds 4. To a
solution of 6 (1 mmol) in dry pyridine (10 mL), was added
dropwise aroyl chloride (3 mmol) at room temperature. The
mixture was stirred for 3-12 hours. Next 2/3 of solvent was
evaporated off, 10 mL of water was added and stirred for 10
minutes at room temperature. The suspension was filtered and
the resulting crude solid was purified by flash chromatography
on silica gel to give the target product.
EXPERIMENTAL
General Methods. Tetrahydrofuran (THF) was distilled
freshly from calcium hydride immediately prior to use. Aroy
chlorides were distilled prior to use. Pyridine was dried with
calcium hydride. Unless otherwise indicated, all other reagents
and solvent were purchased from commercial sources and were
used without further purification. All the pyroreactions were
performed by microwave synthesizer, Initiator, Biotage. The
data of melting points (mp) are uncorrected. The nuclear
magnetic resonance (nmr) spectra were recorded at 300 MHz
and the coupling constant are reported in Hz.
General Procedure of synthesis of 6 from 5. A solution of
aniline (11 mmol) in dry THF (15 mL) was cooled to -78 °C. A
2.5 M solution of n-butyllithium in hexane (4 mL, 10 mmol) was
added dropwise via syringe over 5 minutes. The resulting
brownish mixture was stirred for 10 minutes, then compound 5 (6
mmol) was added as a solid under a positive purge of nitrogen.
The reaction mixture was warmed to room temperature within 30
minutes and quenched with saturated aqueous ammonium
chloride, extracted with ethyl acetate. The combined organic phase
was washed with saturated brine and dried. Removal of the
solvent gave the crude product as a dark-brown solid and
recrystallization from methanol afforded 6. The starting materials
5 were synthesized according to the literature [18].
(5-Amino-1-phenylpyrazol-4-yl)-N-(4-chlorophenyl) car-
boxamide (6a). This compound was obtained as a grey solid
from 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (5a) and
4-chloroaniline with 93% yield. mp 237.0 °C (decomposed); ir
(KBr): 3475, 3325 (NH2), 1647 (CO-NH) cm-1; 1H nmr (DMSO-
d6): δ 9.72 (s, 1H), 8.20 (s, 1H), 7.79-7.74 (m, 2H), 7.62-7.52
(m, 4H), 7.48-7.36 (m, 3H), 6.55 (s, 2H) ppm; 13C nmr: δ 162.8,
149.8, 138.6, 138.8, 138.0, 129.4 (2C), 128.5 (2C), 127.3, 126.4,
123.3 (2C), 121.4 (2C), 97.4 ppm; ms (esi): m/z 313 (M+H)+.
Anal. Calcd. for C16H13ClN4O, C, 61.44; H, 4.19; N, 17.91.
Found: C, 61.2; H, 4.23; N, 18.20.
6-(4-Chlorophenyl)-4-[(4-chlorophenyl)azamethylene]-1-
phenylpyrazolo[5,4-d]1,3-oxazine (4a) was prepared from 6a
(5-Amino-1-phenylpyrazol-4-yl)-N-(4-methoxylphenyl)
carboxamide (6b): This compound was obtained as a grey solid
from 5a and 4-methoxylaniline with 88% yield. mp 209.0-210.0
°C, ir (KBr): 3419, 3290 (NH2), 1649 (CO-NH), 1245 (OCH3)
cm-1; 1H nmr (DMSO-d6): δ 7.67 (br, 1H), 7.58-7.49 (m, 4H),
7.46-7.41 (m, 3H), 7.21 (br, 1H), 6.91-6.88 (m, 2H), 5.60 (br,
1H), 3.81 (s, 3H) ppm; 13C nmr: δ 162.8, 156.5, 149.2, 137.6,
137.0, 130.7, 129.8 (2C), 128.2 (2C), 123.8 (2C), 122.6, 114.2
(2C), 98.0, 55.5l ppm; ms (esi): m/z 309 (M+H)+. Anal. Calcd.
for C17H16N4O2, C, 66.22; H, 5.23; N, 18.17. Found: C, 66.40; H,
5.34; N, 18.02.
(5-Amino-1-phenylpyrazol-4-yl)-N-(6-chloro(3-pyridyl))
carboxamide (6c). This compound was obtained as a brown
solid from 5a and 5-chloro-3-pyridylamine with 66% yield. ir
(KBr): 3412, 3303 (NH2), 1660 (CO-NH) cm-1; 1H nmr (DMSO-
d6): δ 9.92 (s, 1H), 8.17 (d, J = 3.3, 1H), 8.18 (m, 2H), 7.60-7.41
(m, 6H), 6.57 (br, 2H) ppm; 13C nmr: δ 162.2, 150.0, 143.2,
140.9, 138.6, 137.9, 135.7, 130.3, 129.5 (2C), 127.4, 124.0,
123.4 (2C), 97.0 ppm; ms (esi): m/z 314 (M+H)+. Anal. Calcd.
for C15H12ClN5O, C, 57.42; H, 3.86; N, 22.32. Found: C, 57.34;
H, 3.87; N, 22.69.
and 4-chlorobenzoylchloride with
8 hours as a yellow
amorphous solid (89% yield): mp 208.5-209.0 °C; ir (KBr):
1720 (C=N) cm-1; 1H nmr (CDCl3): δ 8.26 (d, J = 8.7, 1H), 8.19
(s, 0.6H), 8.03 (dd, J = 8.1, 1.2, 1H), 7.97-7.90 (m, 2H), 7.58-
7.48 (m, 3H), 7.43-7.35 (m, 4H), 7.17-7.14 (m, 1H), 7.00-7.98
(d, J = 8.4, 1H), 6.85 (s, 0.4H) ppm; ms (esi): m/z 433 (M+H)+.
Anal. Calcd. for C23H14Cl2N4O, C, 63.76; H, 3.26; N, 12.93.
Found: C, 63.69; H, 3.27; N, 12.90.
6-(4-Chlorophenyl)-4-[(4-methoxylphenyl)azamethylene]-
1-phenylpyrazolo[5,4-d]1,3-oxazine (4b) was prepared from 6b
and 4-chlorobenzoylchloride with 5 hours as a yellow solid
(80% yield). mp 198.0-200.0 °C; ir (KBr): 1713 (C=N), 1245
(OCh3) cm-1; 1H nmr (CDCl3): δ 8.30 (d, J = 2.1, 0.5H), 8.27 (d,
J = 2.1, 0.5H), 8.19 (d, J = 2.7, 0.5H), 8.06-7.95 (m, 2H), 8.00
(d, J = 2.4, 0.5H), 7.98 (s, 0.5H), 7.58-7.48 (m, 3H), 7.44-7.40
(m, 2H), 7.23 (dd, J = 6.9, 2.4,1H), 6.99-6.95 (m, 3H), 6.82 (s,
0.5H), 3.87 (s, 1.5H), 3.86 (s, 1.5H) ppm; ms (esi): m/z 429
(M+H)+. Anal. Calcd. for C24H17ClN4O2, C, 67.21; H, 4.00; N,
13.06. Found: C, 67.20; H, 4.11; N, 12.87.
6-(6-Chloro(3-pyridyl))-4-[(4-chlorophenyl)azamethylene]-
1-phenylpyrazolo[5,4-d]1,3-oxazine (4c) was prepared from 6a
and 6-chloropyridine-3-carbonyl chloride with 5 hours as a
yellow solid (74% yield). mp 184.0-185.0 °C; ir (KBr): 1713
(C=N) cm-1; 1H nmr (CDCl3): δ 9.31 (d, J = 2.1, 0.4H), 8.95 (d, J
(5-Amino-1-phenylpyrazol-4-yl)-N-(4-methylphenyl) car-
boxamide (6d). This compound was obtained as a white solid
from 5a and 4-methyl-aniline with 90% yield. mp 255.5-256.5 °C;
ir (KBr): 3467, 3313 (NH2), 1647 (CO-NH), 1404 (CH3) cm-1; 1H
nmr (DMSO-d6): δ 9.50 (s, 1H), 8.17 (s, 1H), 7.60-7.56 (m, 6H),

368
K. He, H. Lv, J. Wang, G. Qiu, X. Hu
Vol 45
= 2.1, 0.6H), 8.51 (dd, J = 8.4, 2.4, 0.4H), 8.22 (s, 0.6H), 8.19
(dd, J = 8.4, 2.4, 0.6H), 8.00 (d, 1.2H), 7.92 (d, J = 7.8, 0.8H),
7.58-7.49 (m, 2.4H), 7.46-7.35 (m, 3.6H), 7.13 (d, J = 8.7,
1.2H), 7.99 (d, J = 8.7, 0.8H), 6.88 (s, 0.4H) ppm ; ms (esi): m/z
434 (M+H)+. Anal. Calcd. for C22H13Cl2N5O, C, 60.84; H, 3.02;
N, 16.13. Found: C, 60.81; H, 3.03; N, 16.10.
0.45H), 7.42 (d, J = 8.4, 0.55H), 7.15 (dd, J = 6.9, 2.4, 1H), 6.94-
6.91 (m, 3H), 6.67 (s, 0.45H), 4.58-4.55 (m, 1H), 3.85 (s, 1.65H),
3.83 (s, 1.35H), 2.07-1.90 (m, 6H), 1.78-1.31 (m, 4H) ppm; ms
(esi): m/z 436 (M+H)+. Anal. Calcd. for C23H22ClN5O2, C, 63.37;
H, 5.09; N, 16.07. Found: C, 63.18; H, 5.14; N, 16.33.
Synthesis procedure for 4b from 5-(4-chlorobenzamido)-N-
(4-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxamide (7b)
is typical: To a solution of 7b (223.2 mg, 0.5 mmol) in dry
pyridine (5 mL), was added dropwise 4-chlorobenzoylchloride
(175.0 mg, 1 mmol) at room temperature. The mixture was
stirred for 4 hours. Next 2/3 of solvent was evaporated off, 5 mL
of water was added and stirred for 10 minutes at room
temperature. The suspension was filtered and washed with water
for several times. Purification by flash chromatography on silica
gel gave 201.0 mg (94%) of 4b as a yellow solid.
4-[(6-Chloro(3-pyridyl))azamethylene]-6-(4-chlorophenyl)
-1-phenylpyrazolo[5,4-d]1,3-oxazine (4d) was prepared from
6c and 4-chlorobenzoylchloride with 5 hours as a yellow solid
(65% yield). mp 178.5-179.5 °C, ir (KBr): 1713 (C=N) cm-1; 1H
nmr (CDCl3): δ 8.39 (d, J = 2.4, 1H), 8.22 (s, 0.53H), 8.03 (dd, J
= 6.9, 1.2, 2H), 7.02 (d, J = 8.7, 2H), 7.56-7.52 (m, 5H), 7.46-
7.39 (m, 2H), 7.18 (s, 0.47H) ppm; ms (esi): m/z 434 (M+H)+.
Anal. Calcd. for C22H13Cl2N5O, C, 60.84; H, 3.02; N, 16.13.
Found: C, 60.61; H, 3.05; N, 15.87.
In addition, synthesis of 4a, 4h was tried by this method. The
yields were 88%, 90% respectively.
6-(4-Chlorophenyl)-4-[(4-methylphenyl)azamethylene]-1-
phenylpyrazolo[5,4-d]1,3-oxazine (4e) was prepared from 6d
and 4-chlorobenzoylchloride with 5 hours as a yellow solid
(68% yield). mp 186.0-187.4 °C; ir (KBr): 1713 (C=N) cm-1; 1H
nmr (CDCl3): δ 8.28 (d, J = 8.7, 1H), 8.21 (s, 0.5H), 8.04 (dd, J
= 8.7, 1.2, 1H), 7.96 (dd, J = 8.7, 2.1, 2H), 7.55-7.48 (m, 3H),
7.43-7.40 (m, 2H), 7.25-7.13 (m, 3H), 6.94 (d, J = 8.4, 1H), 6.75
(d, J = 8.4, 1H), 2.40 (s, 3H) ppm; ms (esi): m/z 413 (M+H)+.
Anal. Calcd. for C24H17ClN4O, C, 69.82; H, 4.15; N, 13.57.
Found: C, 69.46; H, 4.04; N, 13.45.
The intermediate 5-(4-chlorobenzamido)-N-(4-chlorophenyl)-
1-phenyl-1H-pyrazole-4-carboxamide (7a) was obtained from
decyclization of 4a; 7b was synthesized according to the
reported [18,20a]; 7h was isolated as shown in Scheme 2.
Procedure of decyclization of 4a to 7a is typical: A mixture of
4a (108.2 mg, 0.25 mmol) in 5 mL of saturated HCl-ClC2H4Cl
and 50 mg of water was placed in a sealed microwave tube, then
heated to 120 °C for 3 hours. Lcms showed 83% conversion. mp
227.0-228.2 °C; 1H nmr (CDCl3): δ 9.82 (br, 1H), 8.16 (br, 1H),
7.92 (s, 1H), 7.80 (d, J = 8.7, 2H), 7.518-7.477 (m, 5H), 7.446-
7.34 (m, 4H), 7.304-7.258 (m, 2H) ppm; 13C nmr: δ 164.8,
161.8, 139.6, 139.5, 138.2, 137.7 (2C), 135.9, 130.6, 129.9,
129.3 (2C), 129.2 (2C), 129.1 (2C), 128.3, 123.0 (2C), 121.7
(2C), 117.7, 109.1 ppm; ms (esi): m/z 451 (M+H)+. Anal. Calcd.
for C23H16Cl2N4O2, C, 61.21; H, 3.57; N, 12.41. Found: C, 61.33;
H, 3.61; N, 12.57.
95% conversion of decyclization of 4b to 7b: 1H nmr
(CDCl3): δ 10.07 (s, 1H), 8.55 (s, 1H), 7.85 (s, 1H), 7.75 (m,
2H), 7.43 (m, 2H), 7.35-7.28 (m, 7H), 6.76 (d, J = 9.0, 2H), 3.75
(s, 3H) ppm; 13C nmr: δ 165.5, 161.7, 156.7, 139.2 (2C), 139.1,
138.4, 136.8, 130.4, 130.2, 129.3 (2C), 129.1 (2C), 129.0 (2C),
128.2, 123.2 (2C), 122.5, 114.1 (2C), 110.87, 55.4 ppm; ms
(esi): m/z 467 (M+H)+. Anal. Calcd. for C24H19ClN4O3, C, 64.50;
H, 4.29; N, 12.54. Found: C, 64.32; H, 4.30; N, 12.64.
6-(6-Chlro(3-pyridyl))-4-[(4-methylphenyl)azamethylene]-
1-phenylpyrazole[5,4-d]-1,3-oxazine (4f) was prepared from
6d and 6-chloropyridine-3-carbonyl chloride with 5 hours as a
yellow solid (77% yield). mp 194.4-195.0 °C; ir (KBr): 1697
1
(C=N), 1462 (CH3) cm-1; H nmr to see [19]; ms (esi): m/z 414
(M+H)+. Anal. Calcd. for C23H16ClN5O, C, 66.75; H, 3.90; N,
16.92. Found: C, 66.36; H, 3.93; N, 16.57.
6-(6-Chloro(3-pyridyl))-4-[(4-methoxylphenyl)azamethyl-
ene]-1-phenylpyrazolo[5,4-d]1,3-oxazine (4g) was prepared
from 6b and 6-chloropyridine-3-carbonyl chloride with 5 hours
as a yellow solid (80% yield). mp 181.0-183.7 °C; ir (KBr):
1
1709 (C=N), 1250 (OCH3) cm-1; H nmr (CDCl3): δ 9.31 (d, J =
2.4, 0.4H), 9.00 (d, J = 2.1, 0.6H), 8.51 (dd, J = 8.4, 2.4, 0.4H),
8.24 (dd, J = 8.4, 2.4, 0.6H), 8.20 (s, 0.6H), 8.00 (d, J = 8.1,
1.2H), 7.92 (d, J = 8.1, 0.8H), 7.57-7.39 (m, 4H), 7.21-7.38 (m,
1H), 6.98-6.93 (m, 3H), 6.85 (s, 0.4H), 3.85 (s, 3H) ppm; ms
(esi): m/z 430 (M+H)+. Anal. Calcd. for C23H16ClN5O2, C, 64.26;
H, 3.75; N, 16.29. Found: C, 63.95; H, 3.79; N, 15.98.
99% conversion of decyclization of 4h to N-(4-(4-chloro-
phenylcarbamoyl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl)-6-chloro-
pyridine-3-carboxamide (7h): mp 229.5-230.0 °C; 1H nmr
(DMSO-d6): δ 11.14 (s, 1H), 10.14 (s, 1H), 8.90 (d, J = 2.7, 1H),
8.44-8.42 (m, 1H), 8.37 (s, 1H), 8.29 (dd, J = 8.1, 2.4, 1H), 8.04
(td, J = 7.8, 1.8, 1H), 7.82 (d, J = 8.4, 1H), 7.75-7.71 (m, 3H),
7.44-7.37 (m, 3H) ppm; 13C nmr: δ 163.0, 160.0, 153.4, 151.7,
149.4, 148.1, 140.0, 139.5, 139.1, 137.9, 137.1, 128.6 (2C),
128.5, 127.1, 124.5, 123.2 (2C), 121.5, 116.8, 113.0 ppm; ms
(esi): m/z 453 (M+H)+. Anal. Calcd. for C21H14Cl2N6O2, C,
55.64; H, 3.11; N, 18.54. Found: C, 55.34; H, 3.14; N, 18.69.
General procedure of synthesis of Compounds 3 from 7.
To a solution of 7 (0.25 mmol) in dry 1,2-dichloroethane (4 mL) was
added TiCl4 (0.11 mL, 1 mmol). The mixture was heated at 120 °C
for 25 minutes in a microwave, cooled down and diluted with
dichloroethane and quenched with water. The organic layer was
separated and washed with water for several times, dried and
concentrated. Recrystallization from acetonitrile afforded 3 as a solid.
5,6-Bis(4-chlorophenyl)-1-phenyl-5-hydropyrazolo[5,4-d]-
pyrimidin-4-one 3a. (60% yield), white solid: mp 222.2-223.5
6-(6-Chloro(3-pyridyl))-4-[(4-chlorophenyl)azamethylene]-
1-(2-pyridyl)pyrazolo[5,4-d]-1,3-oxazine (4h) was prepared
from 6e and 6-chloropyridine-3-carbonyl chloride in undried
pyridine with 12 hours as a yellow solid (63% yield). mp 211.0-
1
211.5 °C; ir (KBr): 1713 (C=N) cm-1; H nmr (CDCl3): δ 9.30
(d, J = 2.1, 0.33H), 8.98 (d, J = 2.1, 0.67H), 8.7-8.66 (m, 1H),
8.54 (dd, J = 8.7, 2.7, 0.33H), 8.28 (s, 0.67H), 8.23 (dd, J = 8.4,
2.4, 0.67H), 8.04-7.92 (m, 2H), 7.46-7.37 (m, 4H), 7.51 (d, J =
8.4, 0.33H), 7.17 (d, J = 0.9, 0.67H), 7.13 (d, J = 0.9, 0.33H),
6.94 (s, 0.33H) ppm; ms (esi): m/z 435 (M+H)+. Anal. Calcd. for
C21H12Cl2N6O, C, 57.95; H,2.78; N, 19.31. Found: C, 57.76; H,
2.85; N, 18.95.
6-(6-Chloro(3-pyridyl))-4-[(4-methoxylphenyl)azamethyl-
ene]-1-cyclohexylpyrazolo[5,4-d]1,3-oxazine (4i) was prepared
from 6f and 6-chloropyridine-3-carbonyl chloride with 3 hours as
a yellow solid (85% yield). mp 94.0-95.0 °C, ir (KBr): 2933, 2858
(C6H11), 1707 (C=N), 1244 (OCH3) cm-1; 1H nmr (CDCl3): δ 9.31
(d, J = 2.4, 0.45H), 8.99 (d, J = 2.4, 0.55H), 8.54 (dd, J = 8.4, 2.4,
0.45H), 8.27 (dd, J = 8.4, 0.55H), 8.03 (s, 0.55H), 7.50 (d, J = 8.4,
1
°C; H nmr (CDCl3): δ 8.32 (s, 1H), 8.15-8.11 (m, 2H), 7.54-

Mar-Apr 2008
Synthesis and Characterization of a Novel Heterocycle
369
5288.
7.49 (m, 2H), 7.39-7.32 (m, 3H), 7.30-7.23 (m, 4H), 7.11-7.07
(m, 2H) ppm; 13C nmr: δ 156.2, 150.3, 139.1, 138.5, 136.7,
136.3, 135.6, 134.9, 133.3, 130.7 (2C), 130.6 (2C), 130.5 (2C),
129.5 (2C), 129.1 (2C), 128.5 (2C), 127.2, 121.9 (2C), 105.7
ppm; ms (esi): m/z 433 (M+H)+. Anal. Calcd. for C23H14Cl2N4O,
C, 63.76; H, 3.26; N, 12.93. Found: C, 63.57; H, 3.30; N, 12.70.
5-(4-Methoxyphenyl)-6-(4-chlorophenyl)-1-phenyl-5-hydro-
pyrazolo[5,4-d]pyrimidin-4-one 3b. ( 77% yield), grey solid: 1H
nmr (CDCl3): δ 8.31 (s, 1H), 8.15-8.12 (m, 2H), 7.50 (m, 2H),
7.37-7.26 (m, 3H), 7.23-7.20 (m, 2H), 7.05-7.01 (m, 2H) 6.85
(m, 2H), 3.79 (s, 3H) ppm; 13C nmr: δ 159.5, 158.3, 157.6,
150.5, 138.6, 136.6, 135.9, 133.8, 130.7 (2C), 130.2 (2C), 129.6,
129.1 (2C), 128.3 (2C), 127.1, 121.8 (2C), 114.5 (2C), 105.9,
55.4 ppm; ms (esi): m/z 429 (M+H)+. Anal. Calcd. for
C24H17ClN4O2, C, 67.21; H, 4.00; N,13.06. Found: C, 67.40; H,
4.11; N, 13.27.
[13] (a) Liu, J.-F.; Lee, J. Dalton, A. M.; Bi, G.; Baldino, C. M.;
MCElory, E.; Brown, M. Tetrahedron. Lett. 2005, 46, 1241-1244; (b) Liu, J.-
F.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C.
M. J. Org. Chem. 2005, 70, 6339-6345.
[14] Zhichikin, P.; Kesicki, E.; Treiberg, J.; Bourdon, L.; Ronsheim,
M.; Ooi, H, C.; White, S.;Judkins, A.; Fairfax, D. Org. Lett. 2007, 9, 1415-
1418
[15] Selby, T. P.; Birch, L. D. WO Patent 03/032731 A1, 2003; Chem.
Abstr. 2003, 138: 316207.
[16] Pathak, U. S.; Gandhi, S.; Rathod,I. S. Indian J. Chem. Sect. B.
1994, 33, 734-737.
[17] Reddy, P, S, N.; Reddy, P.; Reddy, G. J.; Rao, K. S. Heterocycl.
Commun. 2003, 9, 503-506.
[18] Liu, H; He, X. H.; Choi, H. S.; Yang, K.Y.; Woodmansee, D.;
Wang, Z. C.; Ellis, D. A.; Wu, B. G.; He, Y. ; Nguyen, T. N. WO Patent
06/047516 A1, 2006 ; Chem. Abstr. 2006, 144: 450725.
[19] We noticed that compounds 4 exist as a mixture of cis- and trans-
isomers in solution, and the ratio of isomers depended on the solvents. For
example, the ratio of the two isomers changed from about 1:1 in CDCl3 to
about 3:1 in DMSO-d6. The 1H nmr spectrum data are attached here: 4f
(CDCl3): δ 9.31 (d, J = 2.1, 0.44H), 8.95 (d, J = 2.1, 0.56H), 8.51 (dd, J = 8.4,
2.4, 0.44H), 8.23 (dd, J = 8.4, 2.4, 0.56H), 8.21 (s, 0.56H), 8.00 (d, J = 8.1,
1.12H), 7.82 (d, J = 8.1, 0.88H), 7.57-7.40 (m, 4H), 7.23-7.09 (m, 3H), 6.93
(d, J = 8.1, 1H), 6.78 (s, 0.44H), 2.40 (s, 1.32H), 2.38 (s, 1.68H) ppm; 4f
(DMSO-d6): δ 9.15 (d, J = 2.1, 0.25H), 8.81 (d, J = 2.1, 0.75H), 8.53 (dd, J =
8.4, 2.4, 0.25H), 8.31 (dd, J = 8.4, 2.4, 0.75H), 8.39 (s, 0.75H), 8.05 (d, J =
8.1, 1.5H), 7.82 (d, J = 8.1, 0.5H), 7.81-7.74 (m, 1H), 7.65-7.58 (m, 2H),
7.50-7.43 (m, 1H), 7.30-7.18 (m, 3.5H), 6.91 (d, J = 8.1, 0.5H), 6.58 (s,
0.25H), 2.37 (s, 0.75H), 2.38 (s, 2.25H) ppm.
[20] (a) Daidone, G.; Plascia, F.; Maggio, B.; Raffa, D.; Cutuli, V. M.
C.; Mangano,NG.;Caruso,A. Arch. Pharm. Pharm. Med. Chem. 2001, 334,
153-156; (b) Daidone,G.; Plascia, F.; Maggio,B.; Raffa,D.; Caruso,A.; Cutuli,
V. M. C.; Amico-Roxas,M. Eur. J. Med. Chem. 1994, 29, 707-711; (c)
Daidone, G.; Maggio, B.; Plescia, S.; Raffa, D.; Schilliaci,D.; Caruso, A.;
Cutuli, V. M. C.; Amico- Roxas, M. Farmaco. 1998, 53, 350-356; (d)
Daidone, G.; Raffa, D.; Maggio, B.; Plescia, F.; Cutuli, V. M. C.; Mangano,
N. G.; Caruso,A.; Arch. Pharm. Pharm. Med. Chem. 1999, 332, 50-54.
[21] Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDC
639095 (4c) & 635094 (8). Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
+44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgement. We thank Sundia Meditech Company
Ltd. for support of the work.
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