1880
M. L. Micklatcher, M. Cushman
SHORT PAPER
18 h at r.t. At this point, 4-bromo-2-(trifluoromethyl)phenol (6)
3-Trifluoromethylsalicylic Acid (9)
could be isolated as a slightly yellow solid by the usual workup.
This compound was prepared in 85% yield according to the proce-
dure described for 3-fluorosalicylic acid (4). An analytical sample
was prepared by flash column chromatography on silica gel using
0.5% HOAc in CHCl3 as the eluent. The column-purified product
was further purified by twice recrystallizing from benzene, mp 160–
162°C (Lit.8 mp 156–158 °C).
4-Bromo-2-(trifluoromethyl)phenol (6)
Mp 82–84 °C.
IR (KBr): ν = 3356, 1613, 1496, 1430, 1383, 1314, 1281, 1253,
1229, 1172, 1129, 1050, 892, 823, 768 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.64 (d, J = 2.4 Hz, 1 H), 7.53 (dd,
J = 8.7, 2.4 Hz, 1 H), 6.87 (d, J = 8.8 Hz, 1 H), 5.41 (q, J = 2.0 Hz,
1 H).
19F NMR (282 MHz, C6D6, rel. to TFA ext. std): δ = –12.67 (s).
CI-MS: m/z = 240 (M+), 242 (M + 2+).9
IR (KBr): ν = 3038, 2855, 2574, 1664, 1619, 1438, 1328, 1293,
1253, 1172, 1131, 1099, 1073, 898, 842, 766, 681 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 8.17 (d, J = 7.9 Hz, 1 H), 7.88
(d, J = 8.8 Hz, 1 H), 7.13 (t, J = 7.9 Hz, 1 H), 3.40–2.50 (br s, 2 H).
19F NMR (282 MHz, acetone-d6, TFA ext. std): δ = 8.8.
CI-MS: m/z = 207 (MH+).
Anal. Calcd for: C7H4BrF3O: C, 34.89; H, 1.67; Br, 33.15. Found C,
35.17; H, 1.45; Br, 33.03.
Anal. Calcd for C8H5F3O3: C, 46.62; H, 2.45. Found: C, 46.69; H,
2.24.
Alternatively, the crude bromination product could be taken to the
salicylaldehyde by addition of CF3CO2H (5 mL) and HMT (3.46 g,
24.7 mmol). After addition of the reagents, the bomb was sealed
tightly and placed into an oven preheated to 90 °C. After 18 h of
heating, the bomb was cooled to r.t., and H2O (15 mL) and 50%
H2SO4 (7 mL) were added. The solution was stirred for an addition-
al 2 h. Additional H2O (50 mL) was added and the resulting precip-
itate was collected by vacuum filtration on a Büchner funnel. The
precipitate was recrystallized from 20% aq EtOH yielding the prod-
uct as slightly yellow crystals (1.82 g, 55% over 2 steps). An ana-
lytical sample was prepared by sublimation under reduced pressure;
mp 86–87 °C.
Acknowledgement
MLM gratefully acknowledges the Purdue Research Foundation for
a predoctoral fellowship. MLM also wishes to thank Dr. Jeffrey
Ruell for helpful discussions. This investigation was made possible
by Grant RO1-Al-43637, awarded by the National Institute of
Health, DHHS.
References
5- Bromo-3-(trifluoromethyl)salicylaldehyde (7)
(1) Cushman, M.; Casimiro-Garcia, A.; Hejchman, E.; Ruell, J.
A.; Huang, M.; Schaeffer, C. A.; Williamson, K.; Rice, W. G.;
Buckheit, R. W. Jr. J. Med. Chem. 1998, 41, 2076.
Cushman, M.; Golebiewski, W. M.; Graham, L.; Turpin, J.;
Rice, W. G.; Fliakas-Woltz, V.; Buckheit, R. W. Jr. J. Med.
Chem. 1996, 39, 3217.
(2) Ferguson, L. N.; Reid, J. C.; Calvin, M. J. Am. Chem. Soc.
1946, 68, 2502.
(3) Aldred, R.; Johnston, R.; Levin, D.; Nailan, J. J. Chem. Soc.
Perkin Trans. I 1994, 1823.
IR (KBr): ν = 3082, 2890, 1654, 1618, 1458, 1438, 1327, 1293,
1283, 1215, 1167, 1132, 931, 891, 766, 710, 680 cm–1.
1H NMR (300 MHz, CDCl3): δ = 11.62 (s, 1 H), 9.90 (s, 1 H), 7.92
(d, J = 2.2 Hz, 1 H), 7.88 (d, J = 2.2 Hz, 1 H).
19F NMR (282 MHz, CDCl3, rel. to TFA ext. std): δ = –11.7 (s).
CI-MS: m/z (%) = 269 (MH+), 271 (M + 2+).
Anal. Calcd for C8H4BrF3O2: C, 35.72; H, 1.50; Br, 29.70. Found:
C, 35.62, H 1.24, Br, 29.78.
(4) Ferguson, L. N.; Holmes, R. R.; Calvin, M. J. Am. Chem. Soc.
1950, 72, 5315.
(5) Weidner-Wells, M. A.; Fraga-Spano, S. A. Syn. Comm. 1996,
26, 2775.
(6) For a review, see: Tashiro, M. Synthesis 1979, 921.
(7) Duff, J. C. J. Chem. Soc. 1941, 547.
(8) Abubaker, A. B.; Booth, B. L.; Suliman, N. N. E.; Tipping, A.
E. J. Fluorine Chem. 1992, 56, 359.
5-Bromo-3-(trifluoromethyl)salicylic Acid (8)
This compound was prepared according to the procedure described
for 5-bromo-3-fluorosalicylic acid (3) in 87% yield. An analytical
sample was prepared by sublimation; mp 185–188 °C.
IR (KBr): ν = 3190, 3082, 2884, 1676, 1608, 1437, 1325, 1284,
1233, 1143, 1119, 903, 879, 803, 680 cm–1.
1H NMR (300 MHz, CDCl3): δ = 11.41 (s, 1 H), 8.19 (d, J = 2.5 Hz,
1 H), 7.89 (d, J = 2.3 Hz, 1 H).
19F NMR (282 MHz, acetone-d6, rel. to TFA ext. std): δ = –12.2 (s).
FAB-MS: m/z = 283 (M+), 285 (M + 2+).
(9) These ions are the result of direct EI due to the volatility of the
molecule.
Article Identifier:
1437-210X,E;1999,0,11,1878,1880,ftx,en;M00599SS.pdf
Anal. Calcd for C8H4BrF3O3: C, 33.71; H, 1.41; Br, 28.04. Found:
C, 33.94; H, 1.34; Br, 27.96.
Synthesis 1999, No. 11, 1878–1880 ISSN 0039-7881 © Thieme Stuttgart · New York