3-Chloro-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methoxy-2-
methylpropanamide (8). 3-(4-Cyano-3-(trifluoromethyl)phenyl-
50, 5696–5704; A. B. McElroy and S. Warren, Tetrahedron, 1985, 26,
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2 H. Tucker, J. W. Crook and G. J. Chesterson, J. Med. Chem., 1988, 31,
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5 C. G. Swain, A. D. Ketley and R. F. W. Bader, J. Am. Chem. Soc., 1959,
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6 P. Ballinger and F. A. Long, J. Am. Chem. Soc., 1960, 82, 795–
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7 M. Jarman and W. C. J. Ross, Carb. Res., 1969, 9, 139–147; J. Kuszmann
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amino)-2-methoxy-2-methyl-3-oxopropyl
methanesulfonate
(500 mg, 1.31 mmol) and lithium chloride (557 mg, 13.15 mmol)
were suspended in DMF (10 ml)and sealed in a microwave
tube. The reaction was heated to 150 ◦C for 60 min in the
microwave reactor and cooled to room temperature. The reaction
mixture was diluted with dichloromethane (200 ml), and washed
sequentially with water (400 ml) and saturated brine (400 ml).
The organic layer was dried over MgSO4, filtered and evaporated
to afford crude product. The crude product was purified by
flash silica chromatography, elution gradient 0 to 2% MeOH
in dichloromethane. Pure fractions were evaporated to dryness
to afford 3-chloro-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-
methoxy-2-methylpropanamide (150 mg, 35.6%) as a cream
solid. Elemental Analysis Found: C, 48.5; H, 3.7; N, 8.7
(C13H11N2O2ClF3 requires: C, 48.7; H, 3.8; N, 8.7%). HPLC,
MS detection: m/z (ESI-) (M - H)- = 319.04666; HPLC tR
=
1
2.57 min. H NMR (300.132 MHz, CDCl3) d 1.45 (3H, s), 3.39
(3H, s), 3.66 (1H, d, J = 12.2 Hz), 3.88 (1H, d, J = 12.2 Hz), 7.73
(1H, d, J = 8.5 Hz), 7.90 (1H, dd, J = 8.5, 2.1 Hz), 8.00 (1H, d,
J = 2.1 Hz), 8.88 (1H, s) ppm.
9 B. Yagen, O. Hernandez, J. Bend and R. H. Cox, Bioorg. Chem., 1981,
10, 299–310.
4-(3-Methoxy-3-methyl-2-oxoazetidin-1-yl)-2-(trifluoromethyl)-
benzonitrile (9). 3-chloro-N-(4-cyano-3-(trifluoromethyl)phe-
nyl)-2-methoxy-2-methylpropanamide (80 mg, 0.25 mmol) was
added to sodium carbonate buffer (pH 10) (12.5 ml) and DMSO
(12.5 ml) at 30 ◦C. The resulting solution was stirred at 30 ◦C
for 24 hours. The reaction mixture was concentrated and filtered
to afford a DMSO solution of the product. The crude solution
was purified by preparative HPLC (Waters XBridge Prep C18
OBD column, 5 m silica, 19 mm diameter, 100 mm length), using
decreasingly polar mixtures of water (containing 1% NH3) and
MeCN as eluants. Fractions containing the desired compound
were evaporated to dryness to afford 4-(3-methoxy-3-methyl-
2-oxoazetidin-1-yl)-2-(trifluoromethyl)benzonitrile (26.0 mg,
36.6%) as a white solid. Elemental Analysis Found: C, 54.7; H,
3.9; N, 9.53 (C13H11N2O2F3 requires: C, 54.9; H, 3.9; N, 9.8%).
HPLC, MS detection: m/z (ESI+) (M∑)+ = 284.0776; HPLC tR =
10 R. P. Hanzlik and M. Leinwetter, J. Org. Chem., 1978, 43, 438–440;
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1
2.31 min. H NMR (300.132 MHz, DMSO) d 1.53 (3H, s), 3.35
(3H,s), 3.80 (1H, d, J = 7.1 Hz), 4.11 (1H, d, J = 7.1 Hz), 7.77
(1H, dd, J = 8.6, 1.9 Hz), 7.87 (1H, d, J = 2.1 Hz), 8.19 (1H, d,
J = 8.5 Hz) ppm.
Acknowledgements
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21 K. N. Dalby and W. P. Jencks, J. Chem. Soc. Perkin. Trans. 2, 1997,
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The authors would like to thank Neil Hales for sharing his
invaluable expertise and also Trevor Johnson, Abid Suleman and
Madeleine Vickers for additional experiments that informed this
work.
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