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

Jianqing Li; Daniel Smith; Jennifer X. Qiao; Stella Huang; Subramaniam Krishnananthan; Henry S. Wong; Mark E. Salvati; Balu N. Balasubramanian; Bang-Chi Chen

doi:10.1055/s-0028-1087564

LETTER

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

Jianqing Li*^a, Daniel Smith^a, Jennifer X. Qiao^b, Stella Huang^a, Subramaniam Krishnananthan^a, Henry S. Wong^a, Mark E. Salvati^b, Balu N. Balasubramanian^c, Bang-Chi Chen^c
^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

Abstract

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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

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References and Notes

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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.

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