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Efficient Difluoromethylation of Alcohols Using TMSCF2Br as
a Unique and Practical Difluorocarbene Reagent under Mild
Conditions
Abstract: A general method for the efficient difluoromethyla-
tion of alcohols using commercially available TMSCF2Br
(TMS = trimethylsilyl) as a unique and practical difluorocar-
bene source is developed. This method allows primary,
secondary, and even tertiary alkyl difluoromethyl ethers to be
synthesized under weakly basic or acidic conditions. The
reaction mainly proceeds through the direct interaction
between a neutral alcohol and difluorocarbene, which is
different from the difluoromethylation of phenols. Moreover,
alcohols containing other moieties that are also reactive toward
difluorocarbene can be transformed divergently by using
TMSCF2Br. This research not only solves the synthetic
problem of difluorocarbene-mediated difluoromethylation of
alcohols, it also provides new insights into the different reaction
mechanisms of alcohol difluoromethylation and phenol
difluoromethylation with difluorocarbene species.
To access difluoromethyl ethers,[8–11] the difluoromethyla-
tion of alcohols and phenols with difluorocarbene (:CF2) is
a facile approach owing to the ready availability of many
reagents.[10,11] However, current syntheses of difluoromethyl
ethers with :CF2 reagents mainly focus on the difluorome-
thylation of phenols under basic conditions;[10] the difluoro-
methylation of alcohols under similar reaction conditions is
usually less productive as a result of the competitive reactions
caused by the base. To date, only several reagents, including
HCF2Cl,[12] BrCF2P(O)(OEt)2,[13] and TMSCF2Br,[14] have
been reported for difluoromethylation of alcohols under
basic conditions with limited functional group compatibility
(Scheme 1a, basic). Although some methods that can avoid
a-Fluoroethers, as a valuable class of organofluorine
compounds, have found wide application in pharmaceuticals,
agrochemicals, and functional materials, owing to the impres-
sive conformational changes and maximal shifts in electron
distribution brought by fluorine.[1,2] Moreover, the a-fluorine
À
substitution of alkyl ethers shortens and strengthens the C O
bond[3] and thus improves the in vivo oxidative stability of the
ether moiety of a drug.[4] Among various a-fluoroethers,
difluoromethyl ethers are of particular interest as the
difluoromethyl group is capable of acting as a lipophilic
hydrogen-bond donor.[5] In the past decades, difluoromethyl
ethers have been applied in developing enzyme inhibitors/
activators, anti-HIV agents, antimicrobial agents, and anes-
thetic drugs.[2b,c,6,7] For instances, Desflurane, a widely used
anesthetic drug,[7a] and Roflumilast, a newly approved respi-
ratory system drug for treatment of chronic obstructive
pulmonary disease (COPD) exacerbations,[7b] are both
difluoromethyl ethers.
Scheme 1. Difluoromethylation of alcohols with various difluorocar-
bene reagents. HFPO=hexafluoropropylene oxide, TMS=trimethyl-
silyl.
strongly basic conditions by the use of special :CF2 reagents,
such as CF2N2,[15] HFPO,[16] and CF3ZnBr·2CH3CN,[17] have
been exploited for alcohol difluoromethylation, these meth-
ods usually require excess amounts of alcohols and suffer
from narrow substrate scope (Scheme 1a, neutral). Recently,
a modification of Chenꢀs method has led to an effective
difluoromethylation of primary and secondary alcohols with
FSO2CF2CO2H (Scheme 1a, acidic);[18] however, the reaction
with tertiary alcohols is still unmet. Furthermore, the elution
of SO2, an air pollutant,[19] as a byproduct may prohibit this
method from wide application. In general, efficient difluoro-
methylation of structurally diverse alcohols with :CF2 still
remains a challenge, which is strikingly different from the
difluoromethylation of phenols.[10] Therefore, it is not only of
great demand, but also of immense fundamental interest to
seek a mild and general approach for the difluoromethylation
of alcohols with readily available :CF2 reagents.
[*] Q. Xie, Dr. C. Ni, R. Zhang, Dr. L. Li, J. Rong, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai, 200032 (China)
E-mail: nichuanfa@sioc.ac.cn
R. Zhang, Prof. Dr. J. Hu
School of Physical Science and Technology
ShanghaiTech University
100 Haike Road, Shanghai 201210 (China)
Previously, we developed TMSCF2Br as a versatile :CF2
reagent for difluoromethylation/difluoromethylenation of
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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