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J. Li et al.
LETTER
Table 2 NMR Data on the Assignment of Regiochemistry
Entrya
1
Structure assignment
nJC1,F (Hz)
3J = 1.8
d
C1 (ppm)
nJH,H and nJH,F (Hz)
dH (ppm)
2-OH, 3-F (4a)
111.0
3JH4,H5 = 9.16,
3JH4,F = 9.16
H4 = 7.05, t
2-F, 3-OH (4a¢)
3-OH, 4-F (4b)
2J = 18.2
4J = 2.2
108.9
116.8
N/Ab
N/Ab
2
4JH2,H6 = 2.14,
4JH2,F = 7.63
H2 = 7.15, dd
3-F, 4-OH (4b¢)
3-F, 4-OH (4d)
2-OH, 3-F (4e)
3J = 8.6
3J = 4.8
3J = 1.9
111.6
125.6
128.9
4JH2,H6 = 2.29,
3JH2,F = 9.96
H2 = 7.23, dd
H6 = 7.66, dd
H5 = 6.77, td
4
5
3JH5,H6 = 12.36,
4JH6,H2 = 1.98
3JH4,H5 = 7.93,
3JH5,H6 = 7.93,
4JH5,F = 4.88
2-F, 3-OH (4e¢)
2-OH, 4-F (4g)
2J = 19.2
4J = 3.8
127.3
104.8
N/Ab
N/Ab
7
8
3JH5,H6 = 8.39,
3JH5,F = 8.39,
4JH5,H3 = 2.59
H5 = 6.58, td
2-F, 4-OH (4g¢)
2-F, 4-OH (4h)
2J = 21.1
2J = 13.8
99.3
3JH5,H6 = 7.32,
4JH5,H3 = 1.53
H5 = 6.54, dd
N/Ab
121.9
N/Ab
a Corresponding to Table 1.
b The peak of interest was overlapped with other aromatic protons so the H–H coupling constants were unable to be measured.
(2) (a) Fukuhara, T.; Yoneda, N.; Takamura, K.; Suzuki, A.
J. Fluorine Chem. 1991, 51, 299. (b) Sasaki, K.; Oishi, M.;
Imaki, N. J. Fluorine Chem. 1996, 76, 59. (c)Umemoto,T.;
Kawada, K.; Tomita, K. Tetrahedron Lett. 1986, 27, 4465.
(d) Lerman, O.; Tor, Y.; Rozen, S. J. Org. Chem. 1981, 46,
4629. (e) Chambers, R. D.; Hutchinson, J.; Sparrowhawk,
M. E.; Sandford, G.; Moilliet, J. S.; Thomson, J. J. Fluorine
Chem. 2000, 102, 169. (f) Pews, R. G.; Gall, J. A. J.
Fluorine Chem. 1990, 50, 377; and references cited therein.
(g) Umezu, K.; Tabuchi, F.; Kimura, Y. J. Fluorine Chem.
2003, 121, 97. (h) Maleczka, R. E. Jr.; Shi, F.; Holmes, D.;
Smith, M. R. J. Am. Chem. Soc. 2003, 125, 7792.
(i) Fujimoto, K.; Tokuda, Y.; Maekawa, H.; Matsubara, Y.;
Mizuno, T.; Nishiguchi, I. Tetrahedron 1996, 52, 3889.
(3) (a) Levin, J. L.; Du, M. T. Synth. Commun. 2002, 32, 1401;
and references cited therein. (b) Rogers, J. F.; Green, D. M.
Tetrahedron Lett. 2002, 43, 3585.
played an important role on the reactivity of difluoroben-
zene derivatives, the polar solvent DMSO dramatically
promoted the reaction.
References and Notes
(1) (a) Salvati, M. E.; Finlay, H.; Chen, B.-C.; Harikrishnan,
L. S.; Jiang, J.; Johnson, J. A.; Kamau, M. G.; Lawrence,
M. R.; Li, J.; Lloyd, J.; Miller, M. M.; Pi, Z.; Qiao, J. X.;
Rampulla, R.; Wang, T. C.; Wang, Y.; Yang, W.; Roberge,
J. Y. WO 2007/062308, 2007. (b) Mano, T.; Okumura, Y.;
Sakakibara, M.; Okumura, T.; Tamura, T.; Miyamoto, K.;
Stevens, R. W. J. Med. Chem. 2004, 47, 720. (c) Yang, C.;
Edsall, R.; Harris, H. A.; Zhang, X.; Manas, E. S.;
Mewshaw, R. E. Bioorg. Med. Chem. 2004, 12, 2553.
(d) Hebel, D.; Kirk, K. L.; Cohen, L. A.; Labroo, V. M.
Tetrahedron Lett. 1990, 31, 619. (e)Pommery, N.; Taverne,
T.; Telliez, A.; Goossens, L.; Charlier, C.; Pommery, J.;
Goossens, J.-F.; Houssin, R.; Durant, F.; Henichart, J.-P.
J. Med. Chem. 2004, 47, 6195. (f) Gust, R.; Keilitz, R.;
Schmidt, K. J. Med. Chem. 2002, 45, 2325. (g) Van Zandt,
M. C.; Sibley, E. O.; McCann, E. E.; Combs, K. J.; Flam, B.;
Sawicki, D. R.; Sabetta, A.; Carrington, A.; Sredy, J.;
Howard, E.; Mitschler, A.; Podjarny, A. D. Bioorg. Med.
Chem. 2004, 12, 5661. (h) Morice, C.; Domostoj, M.;
Briner, K.; Mann, A.; Suffert, J.; Wermuth, C.-G.
Tetrahedron Lett. 2001, 42, 6499. (i) Micklatcher, M. L.;
Cushman, M. Synthesis 1999, 1878. (j) Li, J.; Qiao, J. X.;
Smith, D.; Chen, B.-C.; Salvati, M. E.; Roberge, J. Y.;
Balasubramanian, B. N. Tetrahedron Lett. 2007, 48, 7516.
(k) Sanz, R.; Castroviejo, M. P.; Fernandez, Y.; Fananas,
F. J. J. Org. Chem. 2005, 70, 6548.
(4) Feldman, D.; Segal-Lew, D.; Rabinovitz, M. J. J. Org.
Chem. 1991, 56, 7350.
(5) Typical Procedure
To a N2-flushed four-necked round-bottom flask (2 L)
equipped with a mechanical stirrer, a condenser, a tem-
perature controller, and a N2 inlet, was added potassium
trimethylsilanolate (225.0 g, 1.75 mole), 1-bromo-3,5-
difluorobenzene (1i, 96.5 g, 0.5 mole), and diglyme (300
mL) under N2. The reaction mixture was heated to 120 °C
for 5 h. After cooling to r.t., a solution of 1 N HCl (600 mL)
was added slowly. The mixture was then extracted with
TBME (1 L). The organic extract was washed with H2O (3 ×
500 mL), brine (500 mL), dried over MgSO4, filtered, and
concentrated in vacuo to give the crude product as a reddish
liquid. The crude material was then distillated to give the
pure product 3-bromo-5-fluorophenol (4i) as a slightly
Synlett 2009, No. 4, 633–637 © Thieme Stuttgart · New York