Angewandte
Communications
Chemie
Synthetic Methods
PhSO2SCF2H: A Shelf-Stable, Easily Scalable Reagent for Radical
Difluoromethylthiolation
Dianhu Zhu+, Xinxin Shao+, Xin Hong, Long Lu,* and Qilong Shen*
Abstract: A new shelf-stable and easily scalable difluoro-
methylthiolating reagent S-(difluoromethyl) benzenesulfono-
thioate (PhSO2SCF2H) was developed. PhSO2SCF2H is
a powerful reagent for radical difluoromethylthiolation of
aryl and alkyl boronic acids, decarboxylative difluorome-
thylthiolation of aliphatic acids, and a phenylsulfonyl-difluoro-
methylthio difunctionalization of alkenes under mild reaction
conditions.
thiol is not an easy task. Several complementary methods
involving reaction of thiolate with either an electrophilic
difluoromethylated reagent,[6] nucleophilic difluoromethyla-
tion of disulfides,[7] or a reagent which can easily generate
a difluoromethyl radical have also been reported.[8] Yet, these
methods suffer from problems similar to those of the classic
methods. Very recently, a straightforward approach for the
construction of difluoromethylthio group by a copper-medi-
ated difluoromethylation of organothiocyanates was reported
by Goossen and co-workers.[9] Nevertheless, the scope of
these reactions is limited to substrates which can form RSCN.
Compared to these indirect approaches, direct introduc-
tion of the difluoromethylthio group using a difluoromethyl-
thiolating reagent represents a conceptually straightforward
approach which could overcome the shortcomings mentioned
above.[10] In this respect, in the last two years, several
nucleophilic and electrophilic difluoromethylthiolating
reagents (1–4, Figure 1) have been developed by the groups
of Shibata,[11] Billard,[12] as well as ourselves.[13] These reagents
were able to difluoromethylthiolate a variety of substrates
under mild reaction conditions. Yet, the widespread use of
these reagents was hampered by either the inefficiency in
their scale-up synthesis, lack of atom economy, or step
efficiency in delivering the difluoromethylthio group. For
example, preparation of 1 and 2 requires a stoichiometric
amount of (SIPr)Ag(CF2H),[14] which is expensive for large-
scale synthesis, while a desulfonylation step is required when
4 is used.
Because of the well-known “fluorine effect” of the fluo-
roalkyl groups on the chemical, physical, and biological
properties of molecules which may have wide applications in
the fields from materials to life sciences, development of
general methods for the introduction of fluoroalkyl groups
has been the focus of intense recent research efforts.[1] In
particular, in the recent years, the difluoromethylthio group
(SCF2H) has attracted special interest from pharmaceutical
and agrochemical industry because of its advantageous
properties:[2] 1) the difluoromethylthio group (Hansch lip-
ophilicity parameter p = 0.68) is much less lipophilic than its
analogous trifluoromethylthio group (SCF3; Hansch lipophi-
licity parameter p = 1.44), thus providing medicinal chemists
the flexibility in adjusting the lipophilicity of the drug
molecule;[3] 2) the difluoromethylthio group contains
a slightly acidic proton which can act as a hydrogen-bond
donor, and consequently, increase the binding selectivity of
the drug molecule with either target enzymes or proteins;[4]
3) difluoromethylsulfide can be selectively transformed into
either sulfoxide or sulfone to expand the diversity of the
functional groups on a drug and may change the bioavaila-
bility and bioactivity of the molecule.[4]
The most widely studied methods for the preparation of
difluoromethylthiolated compounds involves the nucleophilic
attack of the in situ formed difluoromethyl carbene inter-
mediate by an appropriate thiolate.[2a,5] However, these
methods were typically conducted under strong basic con-
ditions, which might be problematic for molecules with
multiple functional groups. In addition, a pre-formation of
thiol is required and preparation of structurally complicated
Figure 1. Difluoromethylthiolating reagents.
[*] Dr. D.-H. Zhu,[+] Dr. X.-X. Shao,[+] X. Hong, Prof. Dr. L. Lu,
Prof. Dr. Q. Shen
Meanwhile, radical fluoroalkylation has emerged in
recent years as a useful strategy for the introduction of
a fluoroalkyl group into small molecules.[15] In this context, we
envisioned that, if an easily scalable and widely applicable
radical difluoromethylthiolating reagent could be developed,
a promising and complementary new difluoromethylthiolat-
ing strategy that could considerably expand the arsenal of the
difluoromethylthiolating reactions, would be created. Herein,
we report the design and synthesis of S-(difluoromethyl)ben-
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: lulong@sioc.ac.cn
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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