LETTER
A Facile and Versatile Route to 2-Substituted-4(3H)-Quinazolinones
1709
(17) (a) Ried, W.; Stephan, W. Chem. Ber. 1963, 96, 1218.
(b) Ried, W.; Stephan, W. Chem. Ber. 1962, 95, 3042.
(c) Ried, W.; Sinharay, A. Chem. Ber. 1963, 96, 3306.
(18) Hennequin, L. F.; Boyle, F. T.; Wardleworth, J. M.;
Marsham, P. R.; Kimbell, R.; Jackman, A. L. J. Med. Chem.
1996, 39, 695.
(19) Pattenden, G.; Thom, S. M. J. Chem. Soc., Perkin Trans 1
1993, 1629.
(20) Schaefer, F. C.; Peters, G. A. J. Org. Chem. 1960, 26, 412.
(21) Typical experimental procedure for the preparation of
2,2-Dimethyl-propionimidic Acid Methyl Ester (5f):
Hydrogen chloride was bubbled through a solution of 2,2-
dimethylpropanenitrile (48 mL, 0.434 mol) in anhyd MeOH
(19 mL, 0.486 mol) and hexane (160 mL) in a 2-necked flask
for 4 h at 0–5 °C. The mixture was allowed to stir for 30 min
until a white precipitate formed. Further precipitation
occurred after storage at –10 °C for three days. The product
was filtered and dried to give the 2,2-dimethyl-
verted to the corresponding 4-chloroquinazolines in good
yield. Product isolation in the above transformations was
facilitated by the development of work up procedures that
did not include purification by column chromatography.
We believe that such a versatile and experimentally sim-
ple route to 4(3H)-quinazolinones will prove a useful ad-
dition to the methods currently employed. The 2-
substituted-4-chloroquinazolines prepared in this study
are currently being used in the preparation of a series of
our Quinazolinap ligands and their synthesis, resolution
and application in asymmetric catalysis will form the ba-
sis of future publications from these laboratories.24
Acknowledgement
D. J. C. thanks Enterprise Ireland for the award of a Research Scho-
larship (BR/99/238) and Schering Plough (Avondale) Company for
their sponsorship of his graduate programme.
propionimidic acid methyl ester (55.6 g, 85%) as a cream-
coloured solid, mp 152–155 °C; FTIR (KBr): 3156, 2980,
2176, 1706, 1624, 1495 cm–1; 1H NMR (300 MHz; CDCl3)
= 12.1 and 11.8 (2 H, br. s), 4.35 (3 H, s), 1.42 (9 H, s); 13
NMR (75 MHz; CDCl3) = 185.83, 61.63, 38.96, 27.54.
C
References and Notes
(22) Typical experimental procedure for the preparation of
2-tert-Butyl-4(3H)-quinazolinone(3f): Anthranilic acid
(5.00 g, 36.46 mmol)was dissolved in anhyd MeOH (40 mL)
under N2 on a vacuum line. 2,2-Dimethylpropionimidic acid
methyl ester (5.70 g, 37.86 mmol) was dissolved in anhyd
MeOH (40 mL) in a separate schlenk tube under an
(1) (a) Xia, Y.; Yang, Z. Y.; Hour, M. J.; Kuo, S. C.; Xia, P.;
Bastow, K. F.; Nakanishi, Y.; Nampoothiri, P.; Hackl, T.;
Hamel, E.; Lee, K. H. Bioorg. Med. Chem. Lett. 2001, 11,
1193. (b) Nordisk Droge- and Kemi-Kalieforretning AIS;
Neth. Appl. Patent 295 501, 1965 (c) Chem. Abstr. 1965,
63, 18113. (d) Hess, H. J.; Cronin, T. H.; Scriabine, A. J.
Med. Chem. 1967, 11, 130.
(2) Reviews: (a) Armarego, W. L. F. In Fused Pyrimidines, Part
1:Quinazolines; Brown, D. J., Ed.; Interscience: New York,
1967. (b) Undheim, K.; Benneche, T. In Comprehensive
Heterocyclic Chemistry II, Vol. 6; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1998,
Chap. 2.
(3) (a) Bogert, M. T.; Hand, W. F. J. Am. Chem. Soc. 1902, 24,
1031. (b) Bogert, M. T.; Hand, W. F. J. Am. Chem. Soc.
1903, 25, 935. (c) Taylor, E. C.; Knopf, R. J.; Borror, A. L.
J. Am. Chem. Soc. 1960, 82, 3152.
(4) Segarra, V.; Crespo, M. I.; Pujol, F.; Belata, J.; Domenech,
T.; Miralpeix, M.; Palacios, J. M.; Castro, A.; Martinez, A.
Bioorg. Med. Chem. Lett. 1998, 8, 505.
(5) Kotsuki, H.; Sakai, H.; Morimoto, H.; Suenaga, H. Synlett
1999, 1993.
(6) Deetz, J. M.; Malerich, J. P.; Beatty, A. M.; Smith, B. D.
Tetrahedron Lett. 2001, 42, 1851.
(7) Akazome, M.; Yamamoto, J.; Kondo, T.; Watanabe, Y. J.
Organomet. Chem. 1995, 494, 229.
(8) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773.
(9) Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y.; Yashima,
E.; Okamoto, Y. J. Org. Chem. 1996, 61, 7316.
(10) (a) Von Niementowski, S. J. Prakt. Chem. 1895, 51, 564.
(b) Endicott, M. M.; Wick, E.; Mercury, M. L.; Sherrill, M.
J. Am. Chem. Soc. 1946, 68, 1299. (c) Gotthelf, P.; Bogart,
M. T. J. Am. Chem. Soc. 1901, 68, 1299.
(11) McCarthy, M.; Guiry, P. J. Tetrahedron 1999, 55, 3601.
(12) McCarthy, M.; Goddard, R.; Guiry, P. J. Tetrahedron:
Asymmetry 1999, 10, 2797.
atmosphere of nitrogen to give a cloudy white suspension.
Na metal (1.04 g, 0.045 mol) was added carefully in several
portions to this suspension, which was pre-cooled over an
ice bath. The anthranilic acid solution was transferred via
cannula to the free based imidate in MeOH and stirred for 30
min. The reaction mixture was heated at 80 °C for 6 h and
the resulting dark brown solution was cooled to r.t. Addition
of water (50 mL) to the solution gave a light cream-coloured
precipitate which was filtered, washed with cold MeOH
(5 mL), then H2O (5 mL) and dried under vacuum to afford
2-tert-butyl-4(3H)-quinazolinone (4.13 g, 56%) as a cream-
coloured solid, mp 184–186 °C; FTIR (KBr): 3677, 3175,
2924, 1685, 1460 cm–1; 1H NMR (300 MHz; CDCl3)
= 10.98 (1 H, br. s, NH), 8.29 (1 H, ddd, J = 8.5, 2.3, 0.9
Hz), 7.73 (2 H, m), 7.45 (1 H, ddd, J = 8.5, 7.6, 1.7 Hz), 1.49
(9 H, s, C(CH3)3); 13C NMR (75 MHz; CDCl3) 164.2, 162.5,
149.5, 134.7, 127.9, 126.5, 126.3, 120.8, 37.7, 28.5; MS
(EI): m/z (%) = 202 (M+, 30), 187 (100), 160 (46), 119 (29),
90 (41).
(23) Typical experimental procedure for the preparation of
2-tert-Butyl-4-chloroquinazoline(2f): A solution of 2-tert-
butyl-4(3H)-quinazolinone (8.00 g, 39.55 mmol), N,N-
diethylaniline (8.85 mL, 59.33 mmol)and anhyd benzene
(120 mL) were refluxed for 5 min. Phosphorous oxychloride
(5.00 g, 32.96 mmol)was added by syringe and the resultant
mixture was refluxed for 3 h and anhyd conditions were
maintained by use of a CaCl2 drying tube attached to the
condenser. The solution was cooled to r.t. and was filtered.
The insoluble precipitate was washed with anhyd benzene
(15 mL). The combined filtrate was rapidly washed
sequentially with ice H2O (50 mL), ice-cooled 20% NaOH
(2 50 mL), ice H2O (50 mL) and sat. NaCl (50 mL). The
organic layer was immediately washed with a HCl solution
(1 M, 50 mL), H2O (50 mL) and dried over Na2SO4. The
solvent was removed in vacuo at 30 °C to yield 2-tert-butyl-
4-chloroquinazoline (7.15 g, 82%) as a light pink-coloured
solid, mp 112–116 °C; FTIR (KBr): = 2953, 2611, 1833,
1803, 1710, 1557 cm–1; 1H NMR (300 MHz; CDCl3)
(13) McCarthy, M.; Hooper, M. W.; Guiry, P. J. Chem. Commun.
2000, 1333.
(14) Lacey, P. M.; McDonnell, C. M.; Guiry, P. J. Tetrahedron
Lett. 2000, 41, 2475.
(15) Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tetrahedron 1994,
50, 4493.
(16) Hand, E. S.; Baker, D. C. Can. J. Chem. 1984, 62, 2570.
Synlett 2001, No. 11, 1707–1710 ISSN 0936-5214 © Thieme Stuttgart · New York