Angewandte
Chemie
DOI: 10.1002/anie.201409375
Synthetic Methods
Trifluoromethoxylation of Arenes: Synthesis of ortho-
Trifluoromethoxylated Aniline Derivatives by OCF3 Migration**
Katarzyna N. Hojczyk, Pengju Feng, Chengbo Zhan, and Ming-Yu Ngai*
Dedicated to Professor Iwao Ojima on the occasion of his 70th birthday
Abstract: Aryl trifluoromethoxylation by a two-step sequence
of O-trifluoromethylation of N-aryl-N-hydroxylamine deriva-
tives and intramolecular OCF3 migration is presented. This
protocol allows easy access to a wide range of synthetically
useful ortho-OCF3 aniline derivatives. In addition, it utilizes
bench-stable reagents, is operationally simple, shows high
functional-group tolerance, and is amenable to gram-scale as
well as one-pot synthesis. A reaction mechanism of a heterolytic
À
cleavage of the N OCF3 bond followed by recombination of
the resulting nitrenium ion and trifluoromethoxide is proposed
for the OCF3-migration reaction.
F
luorine atoms are often introduced into organic molecules
to enhance their pharmacological properties such as solubil-
ity, metabolic and oxidative stability, lipophilicity, and bio-
availability.[1] Among the fluorine-containing functional
groups, the trifluoromethoxy group (OCF3) is of current
interest because of its unique structural and electronic
properties, which can be useful in materials, agricultural,
and pharmaceutical science.[2] For example, one of the distinct
structural features of trifluoromethoxylated arenes (Ar-
OCF3) is that the OCF3 moiety is orthogonal to the aryl
plane.[1b,3] As a result, lone-pair electrons on oxygen only
weakly delocalize into the ring, which renders OCF3 an
electron-withdrawing group (c = 3.7).[4] In addition, the OCF3
group has one of the highest lipophilicity values (px = 1.04)
compared to that of the CF3 (px = 0.88), CH3 (px = 0.52), F
(px = 0.14), and OCH3 (px = À0.02) groups.[5] Compounds
with higher lipophilicity show enhancement in their in vivo
uptake and transport in biological systems. Indeed, many
OCF3-containing pharmaceuticals and agrochemicals show
enhanced effectiveness often coupled with diminished side
effects (Figure 1a,b).[2a,b,6]
Figure 1. Examples of OCF3-containing a) pharmaceuticals, b) agro-
chemicals, and c) building blocks.
remains a challenge. Only a handful of transformations have
been developed over the last few decades.[1l,2a–c,e,6g] These
include 1) chlorine–fluorine exchange on trichlorinated pre-
cursors;[7] 2) deoxyfluorination of fluoroformates;[8] 3) oxida-
tive fluorodesulfurization;[9] 4) electrophilic trifluoromethy-
lation of alcohols;[10] 5) nucleophilic trifluoromethoxyla-
tion;[11] 6) transition metal-mediated trifluoromethoxylation
of aryl borates and stannanes;[12] and 7) radical trifluoro-
methoxylation.[13] However, most of these approaches either
suffer from poor substrate scope or require use of highly toxic
and/or thermally labile reagents. As a result, many of OCF3-
containing building blocks are prohibitively expensive (Fig-
ure 1c).
Despite the intriguing properties of the OCF3 group, facile
introduction of this functional group into organic molecules
Clearly, direct trifluoromethoxylation reactions which
avoid the use of highly toxic and thermally labile reagents
are greatly desired. Therefore, we initiated a program to
develop easily handled and bench-stable trifluoromethoxyla-
tion reagents for direct introduction of the OCF3 group into
various organic molecules to facilitate studies of this func-
tional group in the context of materials, agricultural, and
pharmaceutical regimes. In the course of the trifluoro-
methoxylation reagent development, we observed a thermally
induced OCF3 migration to generate synthetically useful
ortho-trifluoromethoxylated aniline derivatives (Sche-
me 1).[14] Herein, we report the first synthesis, isolation, and
[*] K. N. Hojczyk,[+] Dr. P. Feng,[+] C. Zhan, Prof. M.-Y. Ngai
Department of Chemistry, State University of New York at Stony
Brook, Stony Brook, NY 11794-3400 (USA)
and
Institute of Chemical Biology and Drug Discovery
State University of New York at Stony Brook
Stony Brook, NY 11794-3400 (USA)
E-mail: ming-yu.ngai@stonybrook.edu
[+] These authors contributed equally to this work.
[**] We acknowledge generous start-up funds from the State University
of New York at Stony Brook in support of this work.
characterization
of
protected
N-aryl-N-(trifluoro-
methoxy)amines[15] and their application in the synthesis of
Supporting information for this article is available on the WWW
ortho-trifluoromethoxylated aniline derivatives.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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