Direct Dehydroxytrifluoromethoxylation of Alcohols

Article abstract of DOI:10.1002/anie.201711050

The first example of a direct dehydroxytrifluoromethoxylation of alcohols has been developed. This method generated an alkyl fluoroformate in situ from alcohols, followed by nucleophilic trifluoromethoxylation with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. The reaction is operationally simple and scalable, and it proceeds under mild reaction conditions to provide access to a wide range of trifluoromethyl ethers from alcohols. In addition, this method is suitable for the late-stage trifluoromethoxylation of complex small molecules.

Full text of DOI:10.1002/anie.201711050

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Accepted Article
Title: Direct Dehydroxytrifluoromethoxylation of Alcohols
Authors: Xiaohuan Jiang, Zhijie Deng, and pingping tang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711050
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10.1002/anie.201711050
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Trifluoromethoxylation
Direct Dehydroxytrifluoromethoxylation of Alcohols**
Xiaohuan Jiang, Zhijie Deng and Pingping Tang*
Dedicated to Professor Biao Yu on the occasion of his 50th birthday
Abstract:
The
first
example
of
a
direct
trifluoromethylation of alcohols with trifluoromethyl iodonium
salts.[8] The disadvantage of these methods was the use of
excess alcohols, and tertiary alcohols proved ineffectual.
dehydroxytrifluoromethoxylation of alcohols has been developed.
This method generated an alkyl fluoroformate in situ from alcohols
and
followed
nucleophilic
trifluoromethoxylation
with
Recently,
Qing
reported
a
silver-mediated
oxidative
trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation
reagent. This reaction is operationally simple, scalable and
proceeds under mild reaction conditions, and provides access to a
wide range of trifluoromethyl ethers from alcohols. In addition, this
method is suitable for the late-stage trifluoromethoxylation of
complex small molecules.
trifluoromethylation of alcohols to generate the alkyl trifluorometyl
ethers with the Ruppert-Prakash reagent (TMSCF3).[9] Various
primary, secondary, and tertiary alcohols proceeded efficiently.
However, this reaction required stoichiometric silver salts. Despite
the
development
of
these
methods,
the
direct
dehydroxytrifluoromethoxylation of alcohols was not reported to
date. Therefore, the development of a general and practical
method for direct dehydroxytrifluoromethoxylation of alcohols is
highly desirable.
F
luorinated compounds
have become significant in
agrochemical, pharmaceutical, and materials science.[1] Due to its
strong electron-withdrawing effect and high lipophilicity,
trifluoromethoxy (OCF3) group has received much attention in the
recent years.[2] However, methods for the synthesis of
trifluoromethyl ethers are limited due to the reversible
decomposition of trifluoromethoxide anion and limited
trifluoromethoxylation reagents.[3] Thus, the development of
efficient methods for the synthesis of OCF3-containing
compounds is of great importance.[4] Herein, we have
successfully used the reversible decomposition property of
trifluoromethoxide anion, which generated in situ from
trifluoromethyl arylsulfonate (TFMS) to develop the first example
of a direct dehydroxytrifluoromethoxylation of alcohols under the
mild reaction conditions (Scheme 1).
The conventional methods for the synthesis of alkyl
trifluoromethyl ethers from alcohol through electrophilic
trifluoromethylation suffer from harsh reaction conditions, poor
substrates scope.[5-8] For example, Umemoto reported a direct
Scheme 1. Direct dehydroxytrifluoromethoxylation of alcohols.
electrophilic
trifluoromethylation
of
alcohols
with
O-
(trifluoromethyl)-dibenzofuranium reagents,[6] however, this
Umemoto’s reagent is highly active which need to be generated
in situ from diazonium salts at -100 to -90 °C . Togni reported a
zinc-mediated formation of trifluoromethyl ethers from alcohols
with Togni’s reagents.[7] Toste reported a direct electrophilic
Recently, trifluoromethyl arylsulfonate (TFMS) as
a new
trifluoromethoxylation reagent was found by our group, which was
used to generate trifluoromethoxide anion (–OCF3) in situ in the
presence of fluoride ions (Scheme 1a).[10] Although the reversible
decomposition of trifluoromethoxide anion to form fluorophosgene
and fluoride (Scheme 1b),[11] we wondered if it was possible to
use this unique property to develop new reactions. Inspired by the
Sheppard’s work that alcohols react with fluorophosgene to form
the corresponding fluoroformate,[12] we reasoned that a direct
dehydroxytrifluoromethoxylation of alcohols could be achieved
[]
X. Jiang, Z. Deng, Prof. P. Tang
State Key Laboratory and Institute of Elemento-Organic
Chemistry, College of Chemistry, Nankai University
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin)
Tianjin 300071, China
E-mail: ptang@nankai.edu.cn
with
trifluoromethyl
arylsulfonate
(TFMS)
as
the
trifluoromethoxylation reagent, through alkyl fluoroformate
generated in situ from alcohols and followed nucleophilic
trifluoromethoxylation to prepare the alkyl trifluoromethyl ethers
(Scheme 1c).
[] We gratefully acknowledge the State Key Laboratory of
Elemento-organic Chemistry for generous start-up financial
support. This work was supported by the National Key
Research and Development Program of China
(2016YFA0602900) and NFSC (21402098, 21421062,
21522205).
Table 1. Optimization of the reaction conditions.a
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/anie.201711050
Angewandte Chemie International Edition
Entry
1
TFMS
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
Activator
none
Solvent
NMP
Yield(%)b
[a] 3.0 equiv of TFMS and 2.5 equiv of fluorine salts were used. [b]
Yields were determined by 19F NMR with benzotrifluoride as a
standard. [c] 0.5 equiv of quaternary ammonium salts was used.
0
2
NaF
NMP
0
3
KF
NMP
3
4
CsF
NMP
50
2
5
AgF
NMP
Initially, 4-phenyl-1-butanol (1a) was chose as the model
substrate to optimize the reaction conditions. Various fluorine
sources were evaluated in the presence of TFMS (2a) (Table 1,
entries 1-5). Less than 5% desired product 3a was found when
NaF, KF or AgF was used. To our delight, 50% yield of the
desired product 3a was observed in the presence of CsF (Table 1,
entry 4). Different trifluoromethyl arylsulfonates (TFMS, 2) were
evaluated, which revealed that substituents on the aromatic rings
influenced the reaction yields, and trifluoromethyl 4-
methylbenzenesulfonate (2a) gave the highest yield (Table 1,
entries 5-10). To improve the solubility of CsF and increase the
stability of trifluoromethoxide anion (–OCF3), different quaternary
ammonium salts were investigated (Table 1, entries 11-13). The
yield of 3a was further improved to 78% by adding 0.5 equiv of
tetramethylammonium bromide (TMABr). Further optimization of
the reaction conditions to improve the reaction yields were
achieved when different solvents were used (Table 1, entries 14-
16). After thorough optimization of the reaction conditions (see
more details in the Supporting Information), reactions with 2.5
equiv of CsF, 3.0 equiv of TFMS (2a), 0.5 equiv of TMABr in 9:1
(v:v) DMA/HMPA under N2 atmosphere at 30 °C to 100 °C were
found to give the high yields of the desired product.
6
CsF
NMP
16
46
45
13
10
7
7
CsF
NMP
8
CsF
NMP
9
CsF
NMP
10
11c
12c
13c
14c
15c
16c
CsF
NMP
2a
2a
2a
2a
2a
2a
CsF, TBABr
CsF, TMABr
CsF, TMACl
CsF, TMABr
CsF, TMABr
CsF, TMABr
NMP
NMP
78
50
86
87
88
NMP
DMA
DMA/NMP
DMA/HMPA
2
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10.1002/anie.201711050
Angewandte Chemie International Edition
Scheme 2. Substrate scope for dehydroxytrifluoromethoxylation of alcohols. [a] Condition: alcohols (1.0 equiv), CsF (2.5 equiv), TFMS (2a) (3.0
equiv), TMABr (0.5 equiv), DMA/HMPA (v/v 9:1), N2 atmosphere, 30 to 100 °C. Yields of isolated products are given unless otherwise noted. [b]
DMA was used as the solvent. [c] 60 °C was used. [d] 40 °C was used. [e] 70 °C was used. [f] TMABr (0.3 equiv) was used. [g] CsF (3.5 equiv),
TFMS (2a) (3.5 equiv), TEABr (1.0 equiv) were used. [h] CsF (5.0 equiv), TFMS (2a) (5.0 equiv) were used. [i] Yield was determined by 19
F
NMR with benzotrifluoride as a standard. TMABr = tetramethylammonium bromide, TEABr = tetraethylammonium bromide.
Having established optimized reaction conditions, we then
explored the scope of trifluoromethoxylation with structurally
diverse alcohols. As displayed in Scheme 2, a wide range of
primary and secondary alcohols including alkyl (1a to 1g, 1x),
propargyl (1h), allyl (1i), and benzyl alcohols (1j to 1w), were
successfully converted into the desired trifluoromethoxylation
products with yields ranging from 43% to 87% (3a to 3x).
Substrates bearing electron-donating and electron-withdrawing
substituents on aryl rings proceeded well. A good range of
functional groups including ester, ether, ketone, nitrile, nitro,
amide, chloride, bromide, and iodide were well tolerated under
the mild reaction conditions. Moreover, the trifluoromethoxylation
of cyclohepatanol (1y) proceeded smoothly to give the desired
product 3y in 54% yield. However, less than 5% yield of desired
trifluoromethoxylation products were observed with cyclohexanol,
and fluoroformate intermediate was found. For the substrate 1z
including primary and secondary hydroxyl groups, 43% yield of 3z
was isolated with dehydroxytrifluoromethoxylation of primary
alcohol, along with 31% yield of trifluoromethoxylation of both
hydroxyl groups. It is worth mentioning that highly chemoselective
dehydroxytrifluoromethoxylation of primary alcohol in the
presence of tertiary aclohols was observed. For example, the
primary alcohol in substrate 1aa was selective converted to
trifluoromethoxy group while the tertiary alcohol remained intact.
The yield of fluorination byproducts was less than 5% in all cases.
These results encouraged the application of this method to more
complex small molecules, which gave the corresponding
trifluoromethoxylation products (3bb, 3cc) in moderate yields. For
example, pleuromutilin (1cc), which is an antibacterial drug,[13]
were selectively converted the primary hydroxyl group to the
trifluoromethoxylation product (3cc) in 30% isolated yield.
Futhermore, due to the toxicity of HMPA, we also evaluated the
reaction using DMA as the solvent, and slightly lower isolated
yields were observed with selected substrates (1a, 1b, 1s, 1w
and 1x). In addition, we prepared compound 3m in gram scale
under the standard reaction conditions in 80% isolated yield,
which demonstrates the scalability and practicality of this method.
The limitation of this method was that no desired products were
observed with tertiary alcohols, and the major byproducts were an
alkene; Substrates with free carboxylic acids and amines proved
ineffectual under the standard conditions.
atom of OCF3 group in the product came from
trifluoromethoxylation reagent (TFMS) (Scheme 3b). Furthermore,
the substrate 1x’ with 99% ee was used and the product 3x’ with
20% ee was found (Scheme 3c), which suggested that the SN1-
type nucleophilic trifluoromethoxylation of alcohols might be
involved in the reaction.
Scheme 3. Mechanism studies.
In conclusion, we have developed the first example of direct
dehydroxytrifluoromethoxylation of alcohols with trifluoromethyl
arylsulfonate (TFMS) as the trifluoromethoxylation reagent under
mild reaction conditions. This method enables the transformation
of various primary and secondary alcohols to the corresponding
trifluoromethoxylation products and tolerates a wide range of
functional groups. Additionally, preliminary mechanistic studies
indicated that the reaction might proceed through an alkyl
fluoroformate intermediate and followed SN1-type nucleophilic
trifluoromethoxylation. Owing to the efficient and practical of this
reaction, we anticipate that this method will find a broad
application to prepare alkyl trifluoromethyl ethers in the
pharmaceutical and agrochemical fields.
To gain more insight into the reaction mechanism, we
performed some preliminary studies (Scheme 3). Monitoring of
the reaction by 19F NMR spectroscopy indicated that butyl
fluoroformate 5 was generated from butanol in situ at 30 °C for 3
h, and 68% yield of desired product 6 was formed when
temperature was increase to 100 °C (Scheme 3a). The NMR
spectrum of isolated butyl fluoroformate 5 was in accord with the
reported data.[14] These observations provides solid evidence that
alkyl fluoroformate was generated in situ from alcohols in the
reactions. In addition, no 18O incorporation in the product 3t was
observed when [18O]1t was used as the substrates. In the
presence of [18O]2a, the corresponding product [18O]3t was
generated with 33% 18O incorporation. We reasoned that the
equilibration of oxygen isotope occurred in the trifluoromethyl
arylsulfonate (TFMS) during the reaction (see more details in the
Supporting Information). Together, these results indicated that O
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: trifluoromethoxylation · trifluoromethyl arylsulfonate ·
alcohols · nucleophilic reaction · synthetic methods
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10.1002/anie.201711050
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4
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Angewandte Chemie International Edition
Entry for the Table of Contents
Trifluoromethoxylation
Xiaohuan Jiang, Zhijie Deng and
Pingping Tang* __________ Page –
Page
Direct Dehydroxytrifluoromethoxylation
of Alcohols
A direct dehydroxytrifluoromethoxylation of alcohols with trifluoromethyl
arylsulfonate (TFMS) as the trifluoromethoxylation reagent has been reported for
the first time. The reaction is operationally simple and amenable to gram-scale
synthesis. Preliminary mechanistic studies suggest that the reaction may proceed
through an alkyl fluoroformate intermediate and followed nucleophilic
trifluoromethoxylation.
5
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