A facile and selective synthesis of 2-alkylamino-4(3H)-quinazolinones

Article abstract of DOI:10.1081/SCC-120022173

The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with aliphatic primary amines to give mainly 2-alkylamino-4(3H)-quinazolinones 4 with unusual selectivity.

Full text of DOI:10.1081/SCC-120022173

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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 16, pp. 2843–2848, 2003
A Facile and Selective Synthesis of
-Alkylamino-4(3H )-quinazolinones
2
Yi Liang,Ming-Wu Ding, * Zhao-Jie Liu,and Xiao-Peng Liu
Institute of Organic Synthesis,
Central China Normal University, Wuhan, P.R. China
ABSTRACT
The carbodiimides 2, obtained from aza–Wittig reactions of imino-
phosphorane 1 with aromatic isocyanates, reacted with aliphatic
primary amines to give mainly 2-alkylamino-4(3H )-quinazolinones
4
with unusual selectivity.
4
(3H )-Quinazolinones are important heterocycles bearing good anti-
1–4]
[
microbial, antiinflammatory, antifungal activities.
showed significant anticancer and AMPA receptor antagonistical activ-
Some of them
[5–7]
ities.
4(3H )-quinazolinones,
Although there are many known methods for the synthesis of
the 2-alkylamino derivatives were not easily
[8–12]
*Correspondence: Ming-WuDing, Instit ut e of Organic Synthesis, Central China
Normal University, Wuhan, 430079, P.R. China.
2
843
DOI: 10.1081/SCC-120022173
Copyright & 2003 by Marcel Dekker, Inc.
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2
844
Liang et al.
accessible by general routes. We have reported a facile and selective
synthesis of 2-alkylamino-3,5-dihydro-4H-imidazol-4-ones via the reac-
tion of aliphatic primary amine with functionalized carbodiimides under
[13]
mild conditions. This method was further utilized to synthesis 2-alkyl-
amino-4(3H )-quinazolinones 4.
[12]
Iminophosphorane 1
reacted with aromatic isocyanates to give
carbodiimides 2, which were allowed to react with aliphatic primary
amines to provide mainly quinazolinone 4, one of the possible regio-
isomers. We obtained pure 4 from the reaction mixture by recrystalliza-
tion; isomers 5 were found to exist in minor amount by GC-MS
detection. The structure of quinazolinones 4 is mainly deduced from
1
1
their H NMR data. For example, the H NMR spectrum in 4a shows
the signals of NH at 4.02 ppm as a wide absorption and NCH2 at
3.42–3.32 ppm as multiple absorption, which strongly suggest the exis-
tence of NHCH CH CH group in 4a. Moreover, when the sample was
2
2
3
1
treated with deuterated water, the H NMR spectrum in 4a shows the
absorption of NCH at 3.37 ppm as triplets with the disappearance of
2
signals of NH absorption. Whenever the primary amine used is small
(
R ¼ n-Pr) or bulky (R ¼ t-Bu), the cyclization was achieved all in mod-
erate to good yields with the same selectivity. The results are listed in
Table 1.
The formation of 4 can be rationalized in terms of an initial nucleo-
philic addition to give the guanidine intermediate 3 which cyclized to
give 4 across the arylamino group rather than the alkylamino one. This
will probably due to the geometry of the intermediate 3 which might
mainly be Z-form suitable for arylamino group to cyclize. It is guessed
that the configurations of carbodiimide 2 are mainly coplanar 2a and 2b
due to the resonance effect. When the aliphatic primary amines react

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2
-Alkylamino-4(3H)-quinazolinones
2845
Table 1. Preparation of 2-alkylamino-4(3H )-quinazolinones 4.
a
Yield (%)
Compound
Ar
Ph
R
Conditions
4a
4b
4c
4d
4e
4f
n-C H
3
r.t./12 h
r.t./12 h
r.t./12 h
r.t./24 h
r.t./24 h
r.t./24 h
52
56
58
67
81
80
7
Ph
Ph
Ph
Ph
Ph
4
n-C H
9
PhCH
i-C H
2
3
7
t-C H
4
9
4
4
4
4
4
4
g
h
i
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
n-C H
3
r.t./12 h
r.t./12 h
r.t./12 h
r.t./24 h
r.t./24 h
r.t./24 h
56
50
53
70
84
78
7
n-C
PhCH
i-C
t-C H
4
H
9
2
j
H
3 7
k
l
4
9
a
Isolated yields based on iminophosphorane 1.
with 2a, Z-3a will be formed for the amine will attack 2a mainly from
the down direction due to the steric hindrance of COOEt group. When
the amines react with 2b, Z-3b will be formed for the amine will attack
2b mainly from the right direction due to the steric hindrance of phenyl
hydrogen. Actually Z-3a is equivalent to Z-3b through the C–N single
bond rotation.

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846
Liang et al.
EXPERIMENTAL
Melting points were uncorrected. MS were measured on a HP5988A
spectrometer. IR were recorded on a ShimadzuIR-408 infrared spectrom-
eter. NMR were taken on a Varian XL-200 spectrometer. Elementary
analysis were taken on a CHN 2400 elementary analysis instrument.
General Preparation of 2-Alkylamino-4(3H )-quinazolinones 4
To a solution of iminophosphorane 1 (2.12 g, 5 mmol) in dry methy-
lene dichloride (15 mL) was added aromatic isocyanate (5 mmol) under
nitrogen at room temperature. After the reaction mixture was stood for
ꢁ
6
ꢀ12 h at 0ꢀ5 C, the solvent was removed off under reduced pressure
and diethyl ether/petroleum ether (1:2, 20 mL) was added to precipitate
triphenylphosphine oxide. Filtered, the solvent was removed to give
carbodiimide 2, which was used directly without further purification.
To a solution of 2 prepared above in methylene dichloride (15 mL)
was added primary amine (5 mmol). After the reaction mixture was
stirred for 12–24 h, the solvent was removed off under reduced pressure
and the residual was recrystallized from methylene dichloride/diethyl
ether to give 2-alkylamino-4(3H )-quinazolinones 4.
ꢁ
a. White crystals, m.p. 127–128 C. H NMR (CDCl , 200 MHz) ꢀ
3
1
4
8
1
.09–7.09 (m, 9H, Ar-H), 4.02 (s, 1H, NH), 3.42–3.32 (m, 2H, NCH2),
.57–1.46 (m, 2H, CH ), 0.85 (t, 3H, J ¼ 7.3 Hz, CH ). MS (m/z, %): 279
2
3
þ
(M , 15), 264 (6), 236 (100), 221 (16), 145 (11), 90 (23). Anal. calcd. for
C H N O: C, 73.10; H, 6.13; N, 15.04. Found: C, 73.23; H, 6.05;
1
7
17
3
N, 15.12.
b. White crystals, m.p. 148–150 C. H NMR (CDCl , 200 MHz) ꢀ
ꢁ
1
4
.09–7.09 (m, 9H, Ar-H), 3.99 (s, 1H, NH), 3.45–3.36 (m, 2H, NCH2),
3
8
1
2
.50–1.20 (m, 4H, CH CH ), 0.88 (t, 3H, J ¼ 6.8 Hz, CH ). MS (m/z, %):
2
2
3
þ
93 (M , 22), 264 (13), 251 (27), 236 (100), 221 (25), 145 (19), 106 (42).
Anal. calcd. for C H N O: C, 73.69; H, 6.53; N, 14.32. Found: C,
3
1
8
19
7
3.62; H, 6.65; N, 14.18.
4
ꢁ
1
c. White crystals, m.p. 140–142 C. H NMR (CDCl , 200 MHz) ꢀ
3
8
1
.10–7.02 (m, 14H, Ar-H), 4.64 (d, 2H, J ¼ 5.8 Hz, NHCH Ph), 4.38 (s,
2
þ
H, NH). MS (m/z, %): 327 (M , 44), 250 (3), 222 (14), 167 (36), 91
(
100). Anal. calcd. for C H N O: C, 77.04; H, 5.23; N, 12.84. Found: C,
21 17 3
7
6.87; H, 5.13; N, 12.96.
4
.09–7.09 (m, 9H, Ar-H), 4.40–4.20 (m, 1H, NCH), 3.81 (s, 1H, NH),
ꢁ
1
d. White crystals, m.p. 118–120 C. H NMR (CDCl , 200 MHz) ꢀ
3
8
1
þ
.12 (d, 6H, J ¼ 5.8 Hz, 2CH ). MS (m/z, %): 279 (M , 29), 236 (100),
3

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2
-Alkylamino-4(3H)-quinazolinones
2847
2
21 (18), 145 (16), 90 (28). Anal. calcd. for C H N O: C, 73.10; H, 6.13;
1
7
17
3
N, 15.04. Found: C, 73.31; H, 6.21; N, 14.87.
ꢁ
e. White crystals, m.p. 145–147 C. H NMR (CDCl , 200 MHz) ꢀ
3
1
4
8.09–7.10 (m, 9H, Ar-H), 3.89 (s, 1H, NH), 1.37 (s, 9H, 3CH ). MS (m/z,
%
3
þ
): 293 (M , 10), 236 (100), 221 (7), 145 (12), 77 (16). Anal. calcd. for
C H N O: C, 73.69; H, 6.53; N, 14.32. Found: C, 73.53; H, 6.64; N,
1
8
19
3
1
4.39.
f. White crystals, m.p. 133–135 C. H NMR (CDCl , 200 MHz) ꢀ
ꢁ
1
4
.09–7.07 (m, 9H, Ar-H), 4.10–3.80 (m, 2H, NCH and NH), 1.96–1.00
3
8
þ
(
m, 10H, 5CH ). MS (m/z, %): 319 (M , 19), 262 (8), 236 (100), 221 (24),
2
145 (23), 90 (33). Anal. calcd. for C H N O: C, 75.21; H, 6.63; N, 13.16.
20 21 3
Found: C, 75.47; H, 6.55; N, 13.27.
ꢁ
g. White crystals, m.p. 149–151 C. H NMR (CDCl , 200 MHz) ꢀ
3
1
4
8.08–7.10 (m, 8H, Ar-H), 3.97 (s, 1H, NH), 3.43–3.33 (m, 2H, NCH2),
1
.59–1.48 (m, 2H, CH ), 0.87 (t, 3H, J ¼ 7.3 Hz, CH ). MS (m/z, %): 315
2
3
þ
(8), 313 (M , 23), 298 (9), 270 (100), 255 (17), 192 (9), 145 (29), 90 (54).
Anal. calcd. for C H ClN O: C, 65.07; H, 5.14; N, 13.39. Found: C,
1
7
16
3
6
5.14; H, 5.11; N, 13.43.
4
.08–7.10 (m, 8H, Ar-H), 3.95 (s, 1H, NH), 3.47–3.38 (m, 2H, NCH2),
ꢁ
1
h. White crystals, m.p. 126–127 C. H NMR (CDCl , 200 MHz) ꢀ
3
8
1
3
.53–1.23 (m, 4H, CH CH ), 0.91 (t, 3H, J ¼ 7.3 Hz, CH ). MS (m/z, %):
2
2
3
þ
29 (6), 327 (M , 20), 298 (12), 285 (25), 270 (100), 255 (17), 140 (47), 90
(
58). Anal. calcd. for C H ClN O: C, 65.95; H, 5.53; N, 12.82. Found:
18 18 3
C, 65.76; H, 5.64; N, 12.75.
i. White crystals, m.p. 183–184 C. H NMR (CDCl , 200 MHz) ꢀ
ꢁ
1
4
3
8
1
9
.20–7.04 (m, 13H, Ar-H), 4.65 (d, 2H, J ¼ 6.4 Hz, NHCH Ph), 4.38 (s,
2
þ
H, NH). MS (m/z, %): 363 (9), 361 (M , 26), 256 (6), 201 (17), 145 (9),
1 (100). Anal. calcd. for C H ClN O: C, 69.71; H, 4.46; N, 11.61.
2
1
16
3
Found: C, 69.84; H, 4.51; N, 11.47.
ꢁ
j. White crystals, m.p. 120–122 C. H NMR (CDCl , 200 MHz) ꢀ
3
1
4
8
1
.07–7.09 (m, 8H, Ar-H), 4.38–4.20 (m, 1H, NCH), 3.76 (s, 1H, NH),
þ
.14 (d, 6H, J ¼ 6.8 Hz, 2CH ). MS (m/z, %): 315 (12), 313 (M , 36), 270
3
(
100), 255 (18), 145 (39), 90 (59). Anal. calcd. for C H ClN O: C, 65.07;
17 16 3
H, 5.14; N, 13.39. Found: C, 65.22; H, 5.08; N, 13.34.
ꢁ
k. White crystals, m.p. 176–177 C. H NMR (CDCl , 200 MHz) ꢀ
3
1
4
8.07–7.11 (m, 8H, Ar-H), 3.81 (s, 1H, NH), 1.39 (s, 9H, 3CH ). MS (m/z,
%
3
þ
): 329 (3), 327 (M , 8), 270 (100), 235 (6), 145 (32), 90 (31). Anal. calcd.
for C H ClN O: C, 65.95; H, 5.53; N, 12.82. Found: C, 65.84; H, 5.42;
1
8
18
3
N, 12.98.
l. White crystals, m.p. 103–104 C. H NMR (CDCl , 200 MHz) ꢀ
ꢁ
1
4
.06–7.08 (m, 8H, Ar-H), 4.12–3.78 (m, 2H, NCH and NH), 1.98–0.98
3
8
(
þ
m, 10H, 5CH ). MS (m/z, %): 355 (4), 353 (M , 11), 270 (100), 192 (9),
2

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2
848
Liang et al.
1
1
45 (26), 90 (33). Anal. calcd. for C H ClN O: C, 67.89; H, 5.70; N,
3
1.88. Found: C, 67.72; H, 5.75; N, 11.97.
2
0
20
ACKNOWLEDGMENT
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (Project No. 20102001).
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Received in Japan September 21, 2002

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