364 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Abdel-Jalil et al.
N-H), 7.40 (1H, d, J = 9.3 Hz, H-5), 7.04 (1H, d, J = 13.2
Hz, H-8), 3.01, 2.45 (each 4H, each bs, piperazine), 2.23
(3H, s, N-CH3), 1.88 (1H, s, S-H); 13C (DMSO-d6): ꢀ 173.89
(C=O), 161.39 (C=N), 113.80, 116.14, 137.53, 138.86,
158.05 and 159.85 (Ar), 54.97, 50.57 (piperazine), 46.15 (N-
CH3); IR (KBr) ꢁ 3347 (NH), 1673 (C=O), 1626 (C=N) cm-1;
MS m/z: 294 (M+). Anal. Calcd. for C13H15FN4OS: C, 53.05;
H, 5.14; N, 19.03; S, 10.89. Found: C, 53.12; H, 5.09; N,
19.17; S, 10.81 %.
3.05, 2.50 (each bs, each 4H, piperazine), 2.22 (s, 3H, N-
CH3), 3.17 (t, J = 7.2 Hz, 2H, CH3CH2CH2CH2), 1.59-1.69
(m, 2H, CH3CH2CH2CH2), 1.34-1.46 (m, 2H, CH3CH2CH2
CH2), 0.82 (t, J = 15.4 Hz, 3H, CH3CH2CH2CH2). 13C
(DMSO-d6): ꢀ 161.33 (C=O), 157.96 (C=N), 112.64, 115.02,
117.30, 139.10, 145.36, 155.83 (Ar), 54.98, 50.53
(piperazine), 46.16 (N-CH3), 31.26 (CH3CH2CH2CH2-),
29.69 (CH3CH2CH2CH2-), 21.80 (CH3CH2CH2CH2-), 13.95
(CH3CH2CH2CH2-). IR (KBr): 34057, 1687, 1574 cm-1; MS
m/z: 350 (M+). Anal. Calcd. for C17H23FN4OS: C, 58.26; H,
6.62; N, 15.99; S, 9.15. Found: C, 58.33; H, 6.65; N, 16.07;
S, 9.09 %.
7-Fluoro-6-(4-methyl-1-piperazinyl)-2-thiosubstituted-
4(3H)-quinazolinones 5a-e
General Procedure
7-Fluoro-6-(4-methyl-1-piperazinyl)-2-sec-butylthio-4(3H)-
quinazolinone 5d
To
a
stirred solution of 7-fluoro-6-(4-methyl-1-
piperazinyl)-2-mercapto-4(3H)-quinazolinone (4) (0.5 g, 1.7
mmol) in ethanol (10 ml) and sodium hydroxide (0.2 g, 5
mmol) in 2 ml water alkyl halide ( 8.5 mmol) was added.
The solution was stirred at room temperature for 30 min,
then heated under reflux over night, cooled to room
temperature and 50 ml cold water added. The solid
precipitate was then collected by filtration, washed with
water, purified on a silica gel column with dichloromethane
and methanol (9/1) as eluent.
(Alkylating agent: sec-bromobutane), 0.30 g Yield (50
%); mp. 212-214 ºC. H NMR (DMSO-d6): ꢀ 12.51 (s, 1H,
1
N-H), 7.49 (d, J = 9.6 Hz, 1H, H-5), 7.30 (d, J = 13.5 Hz,
1H, H-8), 3.03, 2.50 (each bs, each 4H, piperazine), 2.16 (s,
3H, N-CH3), 3.84-3.95 (m, 1H, CH3CH2CH(CH3)-), 1.66-
1.71 (m, 2H, CH3CH2CH(CH3)-), 1.37 (d, J = 9.0 Hz, 3H,
CH3CH2CH(CH3)-), 0.97 (t, J = 7.7 Hz, 3H, CH3CH2CH
(CH3)-). 13C (DMSO-d6): ꢀ 161.30 (C=O), 157.97 (C=N),
112.67, 115.00, 117.32, 139.13, 145.40, 155.65 (Ar), 54.97,
50.53 (piperazine), 46.16 (N-CH3), 42.15 (CH3CH2CH
(CH3)-), 29.23 (CH3CH2CH(CH3)-), 20.92 (CH3CH2CH
(CH3)-), 11.69 (CH3CH2CH(CH3)-). IR (KBr): 3400, 1672,
1580 cm-1; MS m/z: 350 (M+). Anal. Calcd. for
C17H23FN4OS: C, 58.26; H, 6.62; N, 15.99; S, 9.15. Found:
C, 58.28; H, 6.60; N, 16.05; S, 9.00 %.
The following compounds were prepared following the
previous procedure.
7-Fluoro-6-(4-methyl-1-piperazinyl)-2-ethylthio-4(3H)-
quinazolinone 5a
(Alkylating agent: n-iodoethane); Yield 0.25 g (45%);
mp. 228-230 ºC. 1H NMR (DMSO-d6): ꢀ 12.46 (s, 1H, N-H),
7.48 (d, J = 9.6 Hz, 1H, H-5), 7.20 (d, J = 13.8 Hz, 1H, H-8),
3.03, 2.50 (each bs, each 4H, piperazine), 2.23 (s, 3H, N-
CH3), 3.12 (q, J = 6.00 Hz, 2H, CH3CH2-), 1.30 (t, J = 6.00
Hz, 3H, CH3CH2-). 13C (DMSO-d6): ꢀ 161.09 (C=O), 157.27
(C=N), 112.67, 115.00, 117.32, 139.13, 145.40, 155.65 (Ar),
55.04, 50.66 (piperazine), 46.18 (N-CH3), 24.46 (CH3CH2-),
15.13 (CH3CH2-). IR (KBr): 3420, 1678, 1537 cm-1; MS m/z:
322 (M+). Anal. Calcd. for C15H19FN4OS: C, 55.88; H, 5.94;
N, 17.38;; S, 9.95. Found: C, 55.95; H, 5.87; N, 17.31;; S,
9.86 %.
7-Fluoro-6-(4-methyl-1-piperazinyl)-2-benzylthio-4(3H)-
quinazolinone 5e
(Alkylating agent: benzylchloride):, Yield 0.22 g (33%);
mp. 240-246 ºC (dec.). 1H NMR (DMSO-d6): ꢀ 12.60 (s, 1H,
N-H), 6.91-7.46 (m, 7H, Ar), 2.96, 2.50 (each bs, each 4H,
piperazine), 2.22 (s, 3H, N-CH3), 4.29 (s, 2H, C6H5CH2-).
13C (DMSO-d6): ꢀ 173.75 (C=O), 169.26 (C=N), 110.13,
115.48, 118.24, 126.88, 128.83, 129.34, 133.72, 136.18,
140.42, 148.68, 156.82, 160.11 (Ar), 55.24, 51.15
(piperazine), 46.23 (N-CH3), 23.75 (C6H5CH2-). IR (KBr):
3423, 1661, 1579 cm-1; MS m/z: 384 (M+). Anal. Calcd. for
C20H21FN4OS: C, 62.48; H, 5.51; N, 14.57; S, 8.34. Found:
C, 62.44; H, 5.43; N, 14.63; S, 8.40 %.
7-Fluoro-6-(4-methyl-1-piperazinyl)-2-iso-propylthio-4(3H)-
quinazolinone 5b
(Alkylating agent: iso-iodopropane), Yield 0.23 g (40%);
mp. 238-240 ºC. 1H NMR (DMSO-d6): ꢀ 12.50 (s, 1H, N-H),
7.51 (d, J = 9.3 Hz, 1H, H-5), 7.29 (d, J = 13.5 Hz, 1H, H-8),
3.08, 2.60 (each bs, each 4H, piperazine), 2.31 (s, 3H, N-
CH3), 3.94-4.03 (m, 1H, (CH3)2CH-), 1.38 (d, J = 6.00 Hz,
6H, (CH3)2CH-). 13C (DMSO-d6): ꢀ 160.94 (C=O), 155.10
(C=N), 112.85, 115.06, 117.33, 139.64, 157.91, 144.77 (Ar),
54.72, 50.21 (piperazine), 45.78 (N-CH3), 36.07 ((CH3)2CH-
), 23.17 ((CH3)2CH-). IR (KBr): 3418, 1648, 1582 cm-1; MS
m/z: 336 (M+). Anal. Calcd. for C16H21FN4OS: C, 57.12; H,
6.29; N, 16.65; S, 9.53. Found: C, 57.22; H, 6.33; N, 16.74;
S, 9.48 %.
7-Fluoro-6-(4-methyl-1-piperazinyl)-2-allylthio-4(3H)-
quinazolinone 5f
To a mixture of 7-fluoro-2-mercapto-6-(4-methyl-1-
piperazinyl)-4(3H)-quinazolinone (4) (0.5 g, 1.7 mmol) and
triethylamine (0.5 mL, 3.6 mmol) in ethanol (10 mL), allyl
chloride (0.65 g, 8.5 mmol) was added. The reaction mixture
was heated under reflux for 4-6 hr and then concentrated
under reduced pressure. The solid obtained was filtered and
then purified on a silica gel column with dichloromethane
and methanol (9/1) as eluent to give compound 5f, Yield
0.18 g (31%); mp. 222-224 ºC. 1H NMR (DMSO-d6): ꢀ
12.56 (s, 1H, N-H), 7.50 (d, J = 9.6 Hz, 1H, H-5), 7.31 (d, J
= 13.5 Hz, 1H, H-8), 3.23, 2.53 (each bs, each 4H, pipera-
zine), 2.23 (s, 3H, N-CH3), 5.88-6.02 (m, 1H, CH2=CHCH2-),
5.35 (dd, J = 1.3, 16.9 Hz, 1H, CH2=CHCH2-), 5.14 (dd, J =
1.0, 9.9 Hz, 1H, CH2=CHCH2-), 3.87 (d, J = 6.9 Hz, 2H,
CH2=CHCH2-). 13C (DMSO-d6): ꢀ 161.11 (C=O), 157.78
7-Fluoro-6-(4-methyl-1-piperazinyl)-2-butylthio-4(3H)-
quinazolinone 5c
(Alkylating agent: n-bromobutane), Yield 0.28 g (47%);
mp. 162-164ºC. 1H NMR (DMSO-d6): ꢀ 12.50 (s, 1H, N-H),
7.49 (d, J = 9.3 Hz, 1H, H-5), 7.25 (d, J = 13.5Hz, 1H, H-8),