Organic Process Research & Development 2010, 14, 477–480
A Synthesis of 3,5-Disubstituted Phenols
James P. Davidson,*,† Keshab Sarma,‡ Dan Fishlock,‡ Michael H. Welch,† Sunil Sukhtankar,§ Gary M. Lee,† Michael Martin,⊥
and Gary F. Cooper¶
Chemical Synthesis, Roche Palo Alto LLC, 3431 HillView AVenue, Palo Alto, California 94304, U.S.A., Chemical Synthesis,
Hoffmann-La Roche, 340 Kingsland AVenue, Nutley, New Jersey 07110, U.S.A.
Abstract:
Robust and scalable syntheses of some synthetically useful 3,5-
disubstituted phenols are presented. The process involves the
selective displacement of a halogen by nucleophilic aromatic
substitution using a preformed mixture of potassium tert-butoxide
and p-methoxybenzyl alcohol (PMB-OH), followed by deprotec-
tion of the PMB ether with acid in the presence of 1,3-dimethoxy-
benzene. These processes have been demonstrated on kilogram
scale, providing crystalline phenols in good yield and high purity.
Figure 1. 3,5-Disubstituted phenols of interest.
Scheme 1. Early approaches to 1 and 2
Introduction
Phenols with the 3,5-substitution pattern can be synthetically
challenging and are not widely available in significant quantities
from commercial sources. As part of a research effort, we had
need of a reliable synthesis of phenols of this type. Phenols 1
and 2 were identified early on as key starting materials.1 Our
medicinal chemistry colleagues were interested in further
modifications at the 3- and 5-positions and so compounds 3
and 4 were chosen as they could easily be elaborated by taking
advantage of various chemistries known for aryl halides.
Classically, phenols of this type have been prepared accord-
ing to the method of Hodgson2 by using diazonium chemistry.
Various 1,3,5 substituted benzenes are currently available
commercially, possibly from similar Sandmeyer type processes.
Phenols 1-4 have become available from catalog vendors in
the past few months indicating an increasing interest.
Although unknown to us at the outset of this work, recent
progress in the transition metal catalyzed coupling of hydroxide
has opened up the possibility of replacing halogens directly to
access a variety of phenols and avoiding biaryl ether formation.3
A recent report describing the preparation of 3 by C-H
activation has also surfaced.4 Notwithstanding, experimental
details for larger scale syntheses, and more generally, descrip-
tions of synthetic approaches readily amenable to scale-up are
quite limited. Our requirements for phenols 1-4 ranged from
hundreds of grams to >10 kg, and at the start of our effort there
were few viable options.
* Author for correspondence. E-mail: james.davidson.jd1@roche.com.
† Chemical Synthesis, Roche Palo Alto LLC.
‡ Chemical Synthesis, Hoffmann-La Roche.
§ Chemical Research and Development, Pfizer Pharmaceutical India.
⊥ Present address: 238 Mississippi St., San Francisco, CA 94107.
¶ Present address: 16 Valley Oak St. Portola Valley, CA.
Results and Discussion
Dichloro- and difluoro-benzonitrile 5 and 6 are commercially
available, and 6 had been reported5 to react selectively with
sodium methoxide to displace one halogen (Scheme 1). The
resulting methyl ether has been cleaved by either reaction with
lithium iodide in collidine under reflux (186 °C), or with boron
tribromide.6
This methoxide approach had a number of potential limita-
tions. Boron tribromide, or the rather forcing conditions of
lithium iodide in refluxing collidine were needed to remove the
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10.1021/op900322u 2010 American Chemical Society
Published on Web 02/04/2010
Vol. 14, No. 2, 2010 / Organic Process Research & Development
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