Mar-Apr 2008
Regioselective Synthesis of N(3)- and O-acylmethyl Derivatives
609
mmol) in acetonitrile (2 ml) was slowly added dropwise. The
reaction mixture was refluxed for 18 hours and filtered of. The
solvent was evaporated and the crude material was purified by
column chromatography using silica gel Kieselgel 60 (0.063-0.2
mm) with eluent chloroform-ethyl acetate (25:1); Rf = 0.78 (2a),
Rf = 0.58 (3a). Compound 2a, yield 0.19 g (18%), mp 99-100
was stirred at reflux for 14 hours and filtered. Toluene was
evaporated under reduced pressure. The remainder was
crystallized from ethanol to give 0.93 g (70%) of 3b as a white
solid, mp 176-178 C°: ir 1673, 1698 (C=O) cm-1; 1H nmr
(CDCl3): δ 2.69 (s, 3H, SCH3), 5.68 (s, 2H, NCH2), 7.40-7.46
(m, 1H, Ar-H), 7.55-7.78 (m, 5H, Ar-H), 8.07-8.11 (m, 2H, Ar-
H), 8.24-8.27 (m, 1H, Ar-H) ppm; 13C nmr: δ 15.4, 50.0, 119.3,
126.1, 126.6, 127.4, 128.4, 129.2, 134.3, 134.8, 135.0, 147.9,
162.0, 191.3 ppm. Anal. Calcd for C17H14N2O2S (310.37): C,
65.79; H, 4.55; N, 9.03. Found: C, 65.60; H, 4.75; N, 8.77.
Ethyl (2-Methylthio-4-oxo-3-quinazolinyl)acetate (3c). A
mixture of quinazolinone 1 (0.83 g, 4.3 mmol), potassium
carbonate 0.42 g, 3 mmol) and toluene (20 ml) was stirred for 5
min. at reflux and then a solution of ethyl bromoacetate (0.835
g, 0.55 ml, 5 mmol) in toluene (2 ml) was slowly added
dropwise. The reaction mixture was refluxed for 16 hours and
filtered. The solvent was removed in vacuum. The remainder
was stirred with 1% sodium hydroxide solution (ca 20 ml) at
room temperature for 0.5 hour, then the pH was adjusted to 7 by
dropwise addition of acetic acid. The precipitate was collected
by filtration and crystallized from ethanol to give colorless
crystals of 3c, yield 0.86 g (72%), mp 108-109 °C (ref. [19] mp
107-109 °C): (ir 1685, 1728 (C=O) cm-1; 1H nmr (CDCl3): δ 1.33
(t, J = 7.2 Hz, 3H, CH3), 2.71 (s, 3H, SCH3), 4.29 (q, J = 7.2 Hz,
2H, CH2), 4.95 (s, 2H, OCH2), 7.42-7.45, 7.60-7.63, 7.72-7.75,
8.23-8.26 (4m, 4x1H, quinazoline) ppm; 13C nmr: δ 14.4, 15.5,
45.1, 62.3, 119.2, 126.1, 126.5, 134.9, 147.8, 153.5, 161.8, 167.3
ppm. Anal. Calcd for C13H14N2O2S (278.33): C, 56.10; H, 5.07;
N, 10.06. Found: C, 56.14; H, 4.99; N, 10.14.
1
°C: ir 1744 (C=O) cm-1; H nmr (CDCl3): δ 2.30 (s, 3H, CH3),
2.63 (s, 3H, SCH3), 5.13 (s, 2H, OCH2), 7.44-7.50 (m, 1H,
quinazoline), 7.79-7.80 (m, 2H, quinazoline), 8.14-8.17 (m, 1H,
quinazoline) ppm; 13C nmr: δ 14.4, 26.7, 70.7, 113.9, 123.9,
125.9, 126.6, 134.5, 152.3, 165.0, 167.2, 202.7 ppm. Anal. Calcd
for C12H12N2O2S (248.30): C, 58.05; H, 4.87; N, 11.28. Found:
C, 58.24; H, 5.01; N, 11.23.
2-(2-Methylthio-4-quinazolinyloxy)-1-phenylethanone (2b).
A mixture of quinazolinone 1 (0.83 g, 4.3 mmol), potassium
carbonate 0.42 g, 3 mmol) and dimethylformamide (15 ml) was
stirred for 10 min. at room temperature and then ω-
bromoacetophenone (0.995 g, 5 mmol) was added portion wise
over an hour. The reaction mixture was stirred at room
temperature for 16 hours and filtered of. Water was added to the
filtrate. The precipitate formed was collected by filtration and
recrystallized from 2-propanol to give 2b as a white solid, 0.91 g
1
(68%), mp 133-135 C°: ir 1698 (C=O) cm-1; H nmr (CDCl3): δ
2.54 (s, 3H, SCH3), 5.86 (s, 2H, OCH2), 7.50-7.59 (m, 3H, Ar-
H), 7.65-7.68 (m, 1H, Ar-H), 7.80-7.82 (m, 2H, Ar-H), 8.03-
8.06 (m, 2H, Ar-H), 8.24-8.26 (m, 1H, Ar-H) ppm; 13C nmr: δ
14.4, 68.4, 114.1, 124.2, 125.9, 126.5, 128.1, 129.2, 134.2,
134.4, 134.8, 152.4, 165.2, 167.2, 192.8 ppm. Anal. Calcd for
C17H14N2O2S (310.37): C, 65.79; H, 4.55; N, 9.03. Found: C,
66.04; H, 4.63; N, 8.89.
Ethyl (2-Methylthio-4-quinazolinyloxy))acetate (2c).
Compound 2c was prepared analogously 2b using ethyl bromo
acetate (5 mmol, 0.835 g, 0.57 ml). The reaction mixture was
stirred at room temperature for 2 hours and isolated as above
to give 2c as a white solid, 0.96 g (80%), mp 75-76 °C: ir 1750
REFERENCES
[1] Michael, J. P. Natural Prod. Reports 2007, 24, 223.
[2] Mashe, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
[3] Sinha, S.; Srivastava, M. Progress. Drug Res. 1994, 43, 143.
[4] Horton, D. A.; Boume, G. T.; Smythe, M. C. Chem. Rev.,
2003, 103, 893.
1
(C=O) cm-1; H nmr (CDCl3): δ 1.33 (t, J = 7.2 Hz, 3H, CH3),
2.64 (s, 3H, SCH3), 4.30 (q, J = 7.2 Hz, 2H, CH2), 5.12 (s, 2H,
OCH2), 7.46-7.48 (m, 1H, quinazoline), 7.80-7.82 (m, 2H,
quinazoline), 8.16-8.19 (m, 1H, quinazoline) ppm; 13C nmr: δ
14.4, 14.5, 61.7, 63.5, 113.9, 124.1, 125.9, 126.5, 134.4, 152.4,
165.1, 167.1, 168.2 ppm. Anal. Calcd for C13H14N2O2S
(278.33): C, 56.10; H, 5.07; N, 10.06. Found: C, 56.07; H,
4.95; N, 10.34.
[5] Baker, B. R.; Querry, M. V.; Kadish, A. F.; Williams, J. H. J.
Org. Chem. 1952, 17, 35.
[6] Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2001, 3, 953.
[7] Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-
S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833.
2-Methylthio-3-(2-oxopropyl)-4(3H)-quinazolinone (3a). A
mixture of quinazolinone 1 (0.83 g, 4.3 mmol), potassium
carbonate 0.42 g, 3 mmol) and toluene (20 ml) was stirred for 5
min. at reflux and then a solution of chloroacetone (0.463 g, 0.42
ml, 5 mmol) in toluene (2 ml) was slowly added dropwise. The
reaction mixture was refluxed for 18 hours. The solid was
collected by filtration and recrystallized from 2-propanol to give
3a, yield 0.79 g (74%), mp 132-133 °C: ir 1685, 1728 (C=O)
[8] Takaya, Y.; Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, H.-S.;
Kim, Y.; Wataya, Y.; Miura, M.; Takeshita, M.; Oshima, Y. J. Med.
Chem. 1999, 42, 3163.
[9] Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.
Tetrahedron Lett. 1999, 40, 2175.
[10] Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.;
Carson, D. A.; Cottan, H. B. J. Med. Chem. 1999, 42, 3860.
[11] Goto; S.; Tsuboi, H.; Kanoda, M.; Mukai, K.; Kagara, K.
Org. Procc. Res.& Develop. 2003, 7, 700.
1
cm-1; H nmr (CDCl3): δ 2.33 (s, 3H, CH3), 2.69 (s, 3H, SCH3),
5.00 (s, 2H, NCH2), 7.39-7.45, 7.60-7.64, 7.71-7.75, 8.21-8.24
(4m, 4x1H, quinazoline) ppm; 13C nmr: δ 15.4, 27.5, 52.9,
119.2, 126.1, 126.6, 127.4, 134.9, 147.9, 156.5, 161.7, 200.2
ppm. Anal. Calcd for C12H12N2O2S (248.30): C, 58.23; H, 4.83;
N, 11.29. Found: C, 58.05; H, 4.87; N, 11.28.
[12] Walter, H.; Zeun, R. Chimia 2003, 57, 692.
[13] Lamberth, C. Heterocycles 2006, 68, 561.
[14] Lempert, K.; Doleschall, G. Acta Chim. Acad. Sci. Hung.,
1963, 37, 457; Chem. Abstr. 1963, 59, 12809e.
[15] Kienzle, F.; Kaiser, A.; Minder, R. E. Helv. Chim. Acta 1983,
66, 148.
2-Methylthio-3-(2-oxo-2-phenylethyl)-4(3H)-quinazolinone
(3b). A mixture of quinazolinone 1 (0.83 g, 4.3 mmol),
potassium carbonate 0.42 g, 3 mmol) and toluene (20 ml) was
stirred for 5 min. at reflux and then ω-bromoacetophenone
(0.995 g, 5 mmol) was added portion wise. The reaction mixture
[16] Chan, Ch. H.; Shish, F. J.; Liu, K., Ch.; Chern, J. W.
Heterocycles 1987, 26, 3193.
[17] Sinha, S. K. P.; Kumar, P. Indian J. Chem. Sec. B. 1989, 28B
(3), 274; Chem. Abstr. 1989, 111, 174058a.