George T. Lee et al.
FULL PAPERS
1H NMR (300 MHz, CDCl3): d¼8.28–8.31(2H, d, J¼
0.03 Hz), 7.57–7.60 (2H, d, J¼0.03 Hz), 2.50 (3H, s), 2.45
(3H, s); 13C NMR (300 MHz, CDCl3): d¼153.40, 145.51,
141.62, 130.42, 129.88, 128.63, 118.19, 11.42, 7.48; MS (ESI):
m/z¼224 (Mþ); anal. calcd. for C11H11Cl2NO2: C 50.79, H
4.26, N 5.38, Cl 27.26; found: C 51.06, H 3.75, N 5.32, Cl 27.59.
(3H, s); 13C NMR (300 MHz, CDCl3): d¼160.45, 146.97,
132.28, 130.67, 129.10, 127.59, 126.57, 37.69, 10.78; MS (ESI):
m/z¼208 (MHþ); anal. calcd. for C11H10ClNO: C 63.62, H
4.85, N 6.75, Cl 17.07; found: C 63.39, H 4.63, N 6.39, Cl 17.17.
4-Chloromethyl-5-methyl-2-(4-fluorophenyl)-oxazole
(4c): Yield: 83%; white solid; mp 77–788C; 1H NMR
(300 MHz, CDCl3): d¼7.96–8.01 (2H, m), 7.09–7.15 (2H,
m), 4.54 (2H, s), 2.41 (3H, s); 13C NMR (300 MHz, CDCl3):
d¼166.02, 162.69, 159.61, 146.98, 133.30, 128.72, 128.61,
123.98, 123.93, 116.42, 116.13, 37.60, 10.71; MS (ESI): m/z¼
226 (MHþ); anal. calcd. for C11H9ClFNO: C 58.55, H 4.02, N
6.21, Cl 15.71; found: C 58.66, H 3.94, N 6.24, Cl 15.66.
4-Chloromethyl-5-methyl-2-(4-chlorophenyl)-oxazole
(5c): Yield: 90%; white solid; mp 97.5–98.58C; 1H NMR
(300 MHz, CDCl3): d¼7.90–7.95 (2H, m), 7.27–7.42 (2H,
m), 4.54 (2H, s), 2.41 (3H, s); 13C NMR (300 MHz, CDCl3):
d¼159.50, 147.22, 136.72, 133.49, 129.81, 129.42, 129.10,
128.72, 128.10, 127.83, 126.06, 37.54, 10.77; MS (ESI): m/z¼
242 (MHþ); anal. calcd. for C11H9Cl2NO: C 54.57, H 3.75, N
5.79, Cl 29.29; found: C 54.43, H 3.60, N 5.56, Cl 29.28.
4,5-Dimethyl-2-(4-trifluoromethylphenyl)-oxazole
3-Oxide (3)
Into a suspension of 6a (30 g, 0.102 mol) in 270 mL of water and
300 mL of methylene chloride, concentrated ammonium hy-
droxide (30 mL) was slowly added and the mixture stirred at
228C for 30 min. The bottom organic extract was dried over an-
hydrous magnesium sulfate, filtered, and concentrated under
vacuum to give 4d as a white solid; yield: 25.5 g (97%); mp
147–147.58C; 1H NMR (300 MHz, CDCl3): d¼8.56–8.59
(2H, d, J¼0.03 Hz), 7.72–7.7.75 (2H, d, J¼0.03 Hz), 2.39
(3H, s), 2.2.22 (3H, s).
4-Chloromethyl-5-methyl-2-(4-trifluoromethylphenyl)-
oxazole (4a)
References and Notes
[1] a) A. T. Bach, P. K. Kapa, G. T. Lee, E. M. Loeser, M. L.
Sabio, J. L. Stanton, T. R. Vedananda, Patent WO 03/
043985 A1, 2003; Chem. Abstr. 2003, 139, 6767; b) M.
Boehringer, D. Hunziker, H. Kuehne, B. M. Loeffler, R.
Sarabu, H. P. Wessel, Patent WO 03/037327 A1, 2003;
Chem. Abstr. 2003, 138, 368754; c) Y. Momose, T. Maeka-
wa, T. Yamano, M. Kawada, H. Odaka, H. Ikeda, T. Soh-
da, J. Med. Chem. 2002, 45, 1518–1534 and references cit-
ed therein.
[2] M. S. Malamas, J. Sredy, I. Gunawan, B. Mihan, D. R. Sa-
wicki, L. Seestaller, D. Sullivan, B. R. Flam, J. Med. Chem.
2000, 43, 995–1010 and references cited therein.
[3] Our work was started with the study of 4-trifluoromethyl-
benzaldehyde as the starting material mentioned in the
above reference. The importance of the effect of substitu-
ents on the aromatic ring on the regioselectivity of deoxy-
genation-chlorination of free N-oxides was not addressed
by us. However, the corresponding HCl salts are highly se-
lective.
A suspension of 4,5-dimethyl-2-(4-trifluoromethylphenyl)-ox-
azole 3-oxide hydrochloride (3d, 500 g, 1.702 mol) in 4.06 L of
acetonitrile was stirred at 228C for 30 min and cooled to 108C.
Phosphorus oxychloride (491 g, 3.17 mol) was added at 15–
188C over 15 min. The reaction mixture was warmed up slowly
to 288C by its own exotherm over 1 h and stirred at 28 ! 228C
for 16 h. TLC analysis (5% CH3OH/CH2Cl2) of the reaction
mixture showed no starting material. Water (6.0 L) was slowly
added into the mixture at 10!258C over 1 h. The resulting
white suspension was stirred at 22–288C for 16 h. The contents
were filtered at 228C, and the filter cake was washed with 4Â
500 mL water. The solid was dried under vacuum at 608C over-
night to give 4a as a white solid; yield: 400 g (85%); mp 97–
1
988C; H NMR (300 MHz, CDCl3): d¼8.09–8.12 (2H, d, J¼
0.03 Hz), 7.68–7.71 (2H, d, J¼0.03 Hz), 4.56 (2H, s), 2.45
(3H, s); 13C NMR (300 MHz, CDCl3): d¼159.01, 147.88,
133.88, 132.44, 130.68, 126.77, 126.17, 126.12, 126.07, 37.37,
10.80; MS (ESI). m/z¼276 (MHþ); anal. calcd. for C12H9ClF3
NO: C 52.29, H 3.29, N 5.08, Cl 12.86; found: C 52.13, H 3.29,
N 4.97, Cl 12.85.
[4] P. M. Weintraub, J. Med. Chem. 1972, 15, 419–420 and ref-
erences cited therein.
[5] To our knowledge, no one has addressed the regioselectiv-
ity issue in this type of deoxygenation-chlorinations using
oxazole N-oxides.
Compounds 4b, 4c, and 4d were prepared following the pro-
cedure described for 4a, and their physical and spectroscopic
data are as follows.
4-Chloromethyl-5-methyl-2-phenyloxazole (4b): Yield:
86%; white solid; mp 84–858C; 1H NMR (300 MHz, CDCl3):
d¼7.99–8.02 (2H, m), 7.42–7.45(3H, m), 4.55 (2H, s), 2.42
1464
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1461–1464