Angewandte
Chemie
DOI: 10.1002/anie.201310572
Synthetic Methods
Continuous-Flow Synthesis of Functionalized Phenols by Aerobic
Oxidation of Grignard Reagents**
Zhi He and Timothy F. Jamison*
Abstract: Phenols are important compounds in chemical
industry. An economical and green approach to phenol
preparation by the direct oxidation of aryl Grignard reagents
using compressed air in continuous gas-liquid segmented flow
systems is described. The process tolerates a broad range of
functional groups, including oxidation-sensitive functionalities
such as alkenes, amines, and thioethers. By integrating
a benzyne-mediated in-line generation of arylmagnesium
intermediates with the aerobic oxidation, a facile three-step,
one-flow process, capable of preparing 2-functionalized phe-
nols in a modular fashion, is established.
flow preparation of ortho-functionalized phenols in a modular
fashion has been realized. This method complements the
existing ones described above and highlights several of the
most advantageous aspects of synthesis under continuous-
flow conditions, including, superior gas-liquid mixing, effi-
cient heat transfer, and the use of reagents and intermediates
whose very high reactivity would otherwise be limiting or
prohibitive, in this case O2 (compressed air) and benzyne
derivatives.
Given the fact that alkyl Grignard reagents easily undergo
oxidation with molecular O2 to yield alcohols,[6] the analogous
transformation using arylmagnesium species is envisioned as
an appealing approach to access phenols. With regard to
green synthesis, this approach is particularly attractive given
the use of molecular O2 as an inexpensive and sustainable
oxidant, the absence of precious or toxic transition-metals and
ligands, the easy access of functionalized arylmagnesium
reagents,[7] as well as the step economy compared to boronic
acid/ester oxidation. However, while high yields of alcohols
(60–90%) are usually obtained from alkyl Grignard reagents
during the aerobic oxidation using pure O2, aryl substrates
remain problematic in that poor yields of phenols (10–20%)
are afforded along with a complex mixture of byproducts.[8]
A two-stage reaction sequence involving a radical chain
process is believed to take place during the oxygenation of
Grignard reagents (Scheme 1).[9] An alkyl or aryl radical is
P
henols are important structural motifs which are widely
present in agrochemicals, pharmaceutical products, and
naturally occurring compounds.[1] As such, efficient prepara-
tion of phenols is of great significance to several fields within
the chemical, biological, and materials sciences.
In laboratory or industrial fine-chemical production,
functionalized phenols are usually prepared by either tradi-
tional nucleophilic aromatic substitution[2] or oxidative meth-
ods using aryl boronic acids/esters.[3] Hydroxylation of
aromatic derivatives with transition-metal catalysis has also
emerged as an attractive alternative for the synthesis of
phenols in recent years.[4] However, applications of these
methods are constrained by harsh reaction conditions, limited
functional-group tolerance, or high costs and toxicity as
a result of the use of transition-metal catalysts and sophisti-
cated ligands. Consequently, preparation of functionalized
phenols in a mild, economical, and green manner still
constitutes a significant challenge.
In this regard, we herein report the development of
phenol synthesis by direct aerobic oxidation of aryl Grignard
regents with compressed air in continuous gas-liquid seg-
mented flow systems.[5] By way of the method we developed,
a wide range of substituted phenols can be easily obtained. In
addition, by incorporating an in-line generation of function-
alized arylmagnesium species, from benzyne intermediates,
before the aerobic oxidation process, a facile three-step one-
Scheme 1. Proposed mechanism for oxidation of Grignard reagents
with O2.
[*] Dr. Z. He, Prof. Dr. T. F. Jamison
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
first generated from the initial interaction between organo-
magnesium species and molecular O2. The carbon-centered
radical intermediate is then trapped by another O2 to form an
organoperoxide radical which in turn reacts with a second
Grignard molecule to create an organoperoxide magnesium
salt, which ultimately provides the formation of alkoxide or
phenoxide products. It is believed that, compared to alkyl
radicals, aryl radicals formed from the arylmagnesium species
are intrinsically much less reactive towards O2,[10] thereby
E-mail: tfj@mit.edu
[**] We are grateful to the Novartis-MIT Center for Continuous
Manufacturing for financial support. We thank several colleagues at
MIT (Dr. Yuan Zhang, Dr. Ping Zhang, and Dr. Jie Wu) and at
Novartis (Dr. Berthold Schenkel, Dr. Gerhard Penn, and Dr.
Benjamin Martin) for insightful discussions.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 3353 –3357
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3353