K. Umezu et al. / Journal of Fluorine Chemistry 121 (2003) 97–99
99
Table 3
NMR (DMSO-d6 þ CDCl3) d: 6.79 (d, J ¼ 10:3 Hz, 1H),
7.92 (d, J ¼ 8:8 Hz, 1H), 9.46 (brs, 2H). IR (KBr) (cmꢀ1):
3630–3280, 1669, 1616, 1590, 1491, 1475, 1449, 1377, 1276,
1248, 1212, 1166, 849, 703, 611.
Examples of ortho-hydroxylations
Substrate
Product ratio of 2:3
Solid NaOH in DMIa Aqueous NaOHb
1a
1b
1c
1d
1e
1f
99:1 (95)c
99.8:0.2 (95)c
93:7 (88)c
92:8 (87)c
97:3 (87)c
72:28
20:80
25:75
3:97
9:91
–
3.4. 3,5-Dichloro-4-fluoro-2-hydroxybenzoic acid (2d)
It was obtained from 3,5-dichloro-2,4-difluorobenzoic
acid (1d) (10.0 mmol) in 86.7% yield, mp 119.4–120.9 8C.
1
2:98
–
The 60 MHz H NMR (DMSO-d6 þ CDCl3) d: 7.39 (brs,
2H), 7.89 (d, J ¼ 8:2 Hz, 1H). IR (KBr) (cmꢀ1): 3451, 3428,
1674, 1641, 1607, 1543, 1474, 1458, 1432, 1307, 1292, 1241,
1057, 1432, 1307, 1292, 1241, 1057, 810, 720, 659.
1g
1h
67:33
Complex mixture
–
a Product ratios after completion of the reaction.
b Product ratios after 7 h under reflux condition (a large amount of
the starting materials (ꢁ80%) were remained). Though the reactions in
aqueous NaOH were generally slow under reflux conditions, we did not
further investigate due to our research interest for the preparation of
salicylic acid derivatives.
c Yields in parenthesis are referred to isolated yields of 2 (see
experimental).
3.5. 4,6-Difluoro-2-hydroxybenzoic acid (2e)
One fluorine out of three was selectively replaced to
hydroxide from a mixture of 2,4,6-trifluorobenzoic acid
(1e) (10.0 mmol), 99% NaOH (40.0 mmol) in NMP in
1
86.7% yield, mp 180.8–183.4 8C. The 60 MHz H NMR
(DMSO-d6 þ CDCl3) d: 6.27–6.80 (m, 2H), 7.20 (brs, 2H).
IR (KBr) (cmꢀ1): 3421, 3274, 3106, 3005, 2964, 2929, 1667,
1632, 1598, 1561, 1509, 1465, 1436, 1365, 1325, 1253,
1178, 1137, 1065, 854, 830, 787, 612.
solution (2.50 l) with stirring at room temperature. The gen-
erated precipitates were collected, washed with water, and
dried to give (2a) (29.7 g, 95.1%), and the purity was deter-
minedas99.2%byHPLC.Recrystallizationfromamixtureof
2-propanol and water (1:3) gave a pure 2a having mp 185.1–
185.3 8C ([2] mp 185 8C).
1
4. Conclusion
The 300 MHz H NMR (CDCl3) d: 6.67 (ddd, J ¼ 10:2,
9.0, 2.4 Hz, 1H), 6.70 (dd, J ¼ 10:2, 2.4 Hz, 1H), 7.93 (dd,
J ¼ 9:0, 6.6 Hz, 1H), 10.67 (brs, 1H).
Regio-selective ortho-substitution of multi-fluorobenzoic
acid derivatives was demonstrated by sodium hydroxide
under substantially anhydrous conditions to afford the cor-
responding salicylic acid derivatives in good yields. This
process which is operationally simple, chromatographic-
free preparation, and gives excellent yields of fluorosalicylic
acid derivatives, is suitable for large scale synthesis.
IR (KBr) (cmꢀ1): 3261, 3006, 1671, 1624, 1598, 1509,
1441, 1327, 1251, 1208, 1170, 1153, 1134, 887, 852, 795,
772, 669, 613.
LC mass spectrum m/z: 156 (Mþ), 138, 110.
3.2. 3,4-Difluoro-2-hydroxybenzoic acid (2b)
A mixture of 2,3,4-trifluorobenzoic acid (1b) (1.76 g,
10.0 mmol), 99% sodium hydroxide (1.62 g, 40.0 mmol),
and DMI (20.0 ml) was stirred at 150 8C for 2 h. After a part
of DMI was removed in vacuo, water (500 ml) and 10% HCl
were added up to pH 1. The generated precipitate was
collected by filtration, washed with water, dried to give
2b (1.66 g, 95.1%) having mp 176.8–178.2 8C. The 60 MHz
1H NMR (DMSO-d6 þ CDCl3: d: 6.63–7.20 (m, 1H), 7.47–
7.90 (m, 1H), 8.33 (brs, 2H). IR (KBr) (cmꢀ1): 3431, 3211,
3104, 3079, 3022, 2942, 2864, 2677, 2546, 2343, 1658,
1573, 1540, 1512, 1470, 1445, 1384, 1316, 1277, 1214,
1200, 1149, 1054, 909, 831, 785, 716, 689, 609.
Acknowledgements
The authors are indebted to Prof. T. Sonoda, Kyushu
University, for valuable discussions.
References
[1] O. Baine, G.F. Adamson, J.W. Barton, J.L. Fitch, D.R. Swayampati, H.
Jeskey, J. Org. Chem. 19 (1954) 510–514.
[2] F. Zuber, E. Sorkin, H. Erlenmeyer, Helv. Chim. Acta 33 (1950)
1269–1271.
[3] A. Ostaszynski, Z. Olsenko-Piontek, T. Urbanski, Bull. Acad. Pol.
Sci., Ser. Sci. Chim. 8 (1960) 591–597;
3.3. 5-Chloro-4-fluoro-2-hydroxybenzoic acid (2c)
A. Ostaszynski, Z. Olsenko-Piontek, T. Urbanski, Chem. Abstr. 60
(1964) 1638f.
In the same manner, a mixture of 5-chloro-2,4-difluoro-
benzoic acid (1c) (1.93 g, 10.0 mmol), 99% NaOH (1.62 g,
40.0 mmol), and NMP (20.0 ml) was stirred at 130 8C for 3 h.
5-Chloro-4-fluoro-2-hydroxybenzoic acid (2c) was given in
[4] G.M. Shutske, J. Org. Chem. 49 (1984) 180–183.
[5] J.H. Clark, D. Wails, T.W. Bastock, Aromatic Fluorination, CRC
Press, Boca Raton, 1996, pp. 19–56;
H. Kageyama, H. Suzuki, Y. Kimura, J. Fluorine Chem. 101 (2000)
85–89, and references cited therein.
1
87.6% yield (1.67 g), mp 200.0–201.2 8C. The 60 MHz H