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Synlett 2009(4): 633-637  
DOI: 10.1055/s-0028-1087564
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Preparation of Monofluorophenols via the Reaction of Difluorobenzene Derivatives with Potassium Trimethylsilanoate

Jianqing Li*a, Daniel Smitha, Jennifer X. Qiaob, Stella Huanga, Subramaniam Krishnananthana, Henry S. Wonga, Mark E. Salvatib, Balu N. Balasubramanianc, Bang-Chi Chenc
a Bristol-Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
Fax: +1(203)6777702; e-Mail: Jianqing.Li@bms.com;
b Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA
c Bristol-Myers Squibb Company, Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA
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Publication History

Received 11 June 2008
Publication Date:
16 February 2009 (online)

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Abstract

An efficient synthesis of monofluorophenols via the ­reaction of difluorobenzene derivatives with potassium trimethyl­silanoate in moderate to excellent yields is described. High regio­selectivity was observed in some cases.

Key words

fluorophenols - synthesis - regioselective - aromatic - substitution

    References and Notes

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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 yellow liquid (88.0 g, 92% yield); bp 52-55 ˚C/1.33˙10-4 bar. ¹H NMR (300 MHz, CDCl3): δ = 5.634 (s, 1 H), 6.66-6.72 (m, 1 H), 6.78-6.82 (m, 1 H), 7.11-7.23 (m, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 98.0 (d, J = 23.0 Hz, 1 C), 108.0 (d, J = 21.8 Hz, 2 C), 111.4 (d, J = 2.9 Hz, 2 C), 128.9 (d, J = 9.5 Hz, 2 C), 153.8 (d, J = 2.7 Hz, 1 C), 159.4 (d, J = 245.6 Hz, 1 C). ESI-HRMS: m/z calcd for C6H4BrFO
[M + 1]+: 190.9430; found: 190.9508.