Dehydroxylative Trifluoromethylthiolation, Trifluoromethylation, and Difluoromethylation of Alcohols

Article abstract of DOI:10.1002/cjoc.201900364

CF₃S, CF₃ and HCF₂ groups have been identified as valuable functionalities for drug development. Despite significant accomplishments in the trifluoromethylthiolation, trifluoromethylation and difluoromethylation reactions, directly converting common functional groups into CF₃S, CF₃ or HCF₂ groups is still highly desirable. Described here is the dehydroxylative trifluoromethylthiolation, trifluoromethylation and difluoromethylation of alcohols promoted by a R₃P/ICH₂CH₂I system. All of these dehydroxylative reactions were achieved under mild conditions via the activation of the hydroxyl group by the R₃P/ICH₂CH₂I system. A wide substrate scope and good functional group tolerance were observed.

Full text of DOI:10.1002/cjoc.201900364

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Dehydroxylative trifluoromethylthiolation, trifluoromethylation, and
difluoromethylation of alcohols
Authors: Wei Zhang, Jin-Hong Lin, Wenfeng Wu,* Yu-Cai Cao, and Ji-Chang Xiao*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.201900364.
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Dehydroxylative trifluoromethylthiolation, trifluoromethylation, and
difluoromethylation of alcohols
Wei Zhang,a Jin-Hong Lin,a Wenfeng Wu,b* Yu-Cai Cao,c and Ji-Chang Xiaoa*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032 (P.R. China)
bCollege of Chemistry and Materials Engineering, Guiyang University, 103 Jianlongdong Road, Nanming District, Guiyang, Guizhou 550005 (P.R. China)
cState key Laboratory of polyolefins and Catalysis, Shanghai Key Laboratory of Catalysis Technology for Polyolefins, Shanghai Research Institute of
Chemical Industry Co. Ltd.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
CF3S, CF3 and HCF2 groups have been identified as valuable functionalities for drug development. Despite significant accomplishments in the
trifluoromethylthiolation, trifluoromethylation and difluoromethylation reactions, directly converting common functional groups into CF3S, CF3 or HCF2
groups are still highly desirable. Described here is the dehydroxylative trifluoromethylthiolation, trifluoromethylation and difluoromethylation of alcohols
promoted by a R3P/ICH2CH2I system. All of these dehydroxylative reactions were achieved under mild conditions via the activation of the hydroxyl group
by the R3P/ICH2CH2I system. A wide substrate scope and good functional group tolerance were observed.
a limited substrate scope (limited to allylic and benzylic alcohols),7
a long reaction time (10 h),8 or a tedious process for the synthesis
of the CF3S-reagent.9a, 9c Trifluoromethylation usually requires a
Due to its unique electronic properties such as strong
multi-step procedure involving the conversion of the OH group
into a good leaving group.10 Recently, Altman and co-workers
disclosed that one-step trifluoromethylation could be enabled by
the in situ activation of the hydroxyl group.11 Direct
dehydroxylative difluoromethylation of alcohols is an issue that
remains to be addressed. In these dehydroxylative reactions, the
activation of the OH group is a key step. However, a general
reagent system for the OH activation to achieve all of the
dehydroxylative trifluoromethylthiolation, trifluoromethylation,
and difluoromethylation reactions has never been developed.
We have previously shown that the R3P/XCH2CH2X/I- (X= Cl or
Br) or R3P/ICH2CH2I system could effectively activate the carbonyl
or hydroxyl group for nucleophilic reactions.12 In continuation of
electronegativity (4.0 in Pauling scale) and small atomic radius (rv
= 0.71 Å), fluorine has been considered as a magic element in
medicinal chemistry, agrochemistry, and material science.1 It is
well known that the incorporation of a fluorine atom or a
fluorinated group into an organic molecule can result in profound
changes of the physicochemical properties. A survey in 2006
showed that approximately 20% of all drugs contain at least one
fluorine atom (over 150 fluorinated drugs),2 and the percentage
have increased to 30% until now.3 Many fluorinated groups,
including CF3S, CF3 and HCF2 have been recognized as valuable
functionalities for drug development.
A large number of
pharmaceuticals containing one of these fluorinated groups have
emerged, such as Cefazaflur, Efavirenz, Eflornithine and Deracoxib.
Therefore, intensive research efforts have been devoted to the
development of efficient methods for trifluoromethylthiolation,4
our
research
interests
in
fluoroalkylation13
and
fluoroalkylthiolation14 conversions, we have now investigated the
R3P/ICH2CH2I-promoted dehydroxylative trifluoromethylthiolation,
trifluoromethylation, and difluoromethylation of alcohols.
R3P/ICH2CH2I was found to be a general activation system for all of
these reactions.
5
trifluoromethylation,4d,
and difluoromethylation6 reactions.
Despite many accomplishments in these transformations, general
protocols for directly converting common functional groups into
CF3S, CF3 or HCF2 groups are still highly desirable.
After screening the reaction conditions (See Supporting
Hydroxyl moiety is a common functional group and alcohols
are important structural motifs in various bioactive molecules,
materials, and synthetic intermediates. Given the ubiquity of
alcohols, direct dehydroxylative trifluoromethylthiolation,
trifluoromethylation and difluoromethylation of alcohols are
apparently attractive protocols for the installation of CF3S, CF3 and
HCF2 groups, respectively. However, due to the poor leaving ability
of the hydroxyl group, these reactions are challenging and have
been less developed. Rueping,7 Qing,8 and other groups9 have
reported the dehydroxylative trifluoromethylthiolation via the OH
activation. These methods are quite effective, but they suffer from
Information,
Table
S1),
it
was
found
that
the
trifluoromethylthiolation of benzylic alcohols with AgSCF3
promoted by Ph3P/ICH2CH2I proceeded rapidly (15 min). As shown
in Table 1, a wide substrate scope was observed, and various
functional groups could be tolerated, including ether, sulfonyl
amide, ester, nitro, cyano, and heteroaryl groups. A moderate
yield was obtained for the conversion of a secondary benzyl
alcohol (2l). Besides benzylic alcohols, propargylic alcohols and
primary allylic alcohols (2m-2n) also showed high reactivity.
Interestingly, the conversion of secondary allylic alcohol
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First author et al.
Report
17
PhCH(OH)CH=CH2 afforded the terminal substitution product, 2n
(PhCH=CHCH2SCF3), in 23% yield, and internal substitution
product PhCH(SCF3)CH=CH2 was almost not detected, probably
because of a resonance effect and a steric effect. In the case of
alkyl alcohols, the use of Ph3P led to a low yield, and the yield was
increased significantly by using Ph2PCH=CH2 instead of Ph3P (See
Supporting Information, Table S2). Primary alkyl alcohols could be
converted smoothly into the desired products (2o-2t), whereas
secondary alcohols showed a lower reactivity and thus a higher
reaction temperature was necessary (2u).
reactive towards Cu-promoted trifluoromethylation,15,
aryl
bromides remained intact under these conditions (4h). In the case
of aryl iodides, undesired trifluoromethylation of C-I bond was
observed, and thus a low yield of the desired product was
obtained (4i). Lower yields were obtained when the aromatic
rings contained
a strong electron-withdrawing group (4k).
Although benzylic alcohols were found to be quite reactive, no
expected product was detected for the conversions of alkyl
alcohols.
Table 1 Trifluoromethylthiolation of alcohols
R
ICH CH nBu4NI
2I,
3P,
2
+
ROH
RSCF3
AgSCF3
DMF/CH3CN, 80 o 15 min
C,
1
2
=
For
alcohols, R P Ph3P
benzylic
3
Me
N
Me
O
O
SCF3
tBu
SCF3
SCF3
SCF3
SCF3
MeSO2
MeO
N
N
2a
,
2b
2f
2c
71%
,
Me
79%
73%
71%
,
F
2d
87%
,
CN
SCF3
NO2
CF3S
SCF3
SCF3
MeO2C
N
N
2e
2g
2h
2i
78%
,
81%
67%
81%
,
,
,
,
Table 2. Dehydroxylative trifluoromethylation of alcohols
SCF3
SCF3
SCF3
S
SCF3
N
SCF3
S
Cu, Ph3
DMF, 80 o 7 h
I
P,
I(CH2)2
+
2j
2k 77%
2l
2m
2n
R-OH
R-CF3
81%
63%
73%
23%a
FSO2CF2CO2Me
,
,
,
,
, 70%,
C,
1
4
3
=
For alkyl alcohols, R3P Ph2PCH=CH2
Me
CF3
CF3
SCF3
Me
SCF3
CF3
CF3
Me
TsO(CH2 9SCF3
)
Ph
tBu
Me
Me
Ph
4b
Me
4d
,39%
2o
2p
2q
81%
,
83%
75%
66%
,
,
4a
4c
68%
,
65%
CF3
70%
,
,
O
CF3
SCF3
Me
SCF3
MeO
MeO
SCF3
(CH2)10
Me
SCF3
CF3
CF3
N
Br
MeO2C
4f
,
4g
4h
,
64%
60%
71%
O
,
O
86%
43%b
2u
,
,
4e
4i
2r
2s
,
2t
61%
35%
68%
,
,
CF3
CN
S
CF3
Isolated yields. Reaction conditions for benzylic alcohols: alcohol 1 (0.5
mmol), CH3CN-solvated AgSCF3 (1 M, 1.5 mL), Ph3P (1.4 equiv), ICH2CH2I
(1.4 equiv), and nBu4NI (1.5 equiv) in DMF (3 mL) at 80 oC for 15 min under
a N2 atmosphere; For alkyl alcohols: alcohol 1 (0.5 mmol), CH3CN-solvated
AgSCF3 (1 M, 1 mL), Ph2PCH=CH2 (2.6 equiv), ICH2CH2I (1.2 equiv), and
nBu4NI (1.0 equiv) in DMF (3 mL) at 80 oC for 15 min under a N2
atmosphere. aFor the conversions of allylic alcohols PhCH=CHCH2OH and
PhCH(OH)CH=CH2, product 2n was isolated in 70% and 23% yields,
respectively; bIn the case of product 2u, 1.75 mL of AgSCF3 solution and
3.0 mmol of nBu4NI were used, and the reaction was performed at 100 oC.
NO2
CF3
CF3
4k
,
36%
I
CF3
4m 41%
,
4l 55%
,
,
4j
45%
,
Isolated yields. Reaction conditions: alcohol 1 (0.5 mmol), FSO2CF2CO2Me
(5.0 equiv), Cu (1.0 equiv), Ph3P (1.2 equiv), ICH2CH2I (1.2 equiv) in DMF (5
mL) at 80 oC for 7 h under a N2 atmosphere.
The
successful
trifluoromethylation
trifluoromethylthiolation
us to examine
and
the
prompted
difluoromethylation of alcohols (See Supporting Information,
Tables S4-S5 for the optimization of the reaction conditions).
Although the in situ preparation of [CuCF2H] complex is necessary,
the difluoromethylation process under the optimal reaction
conditions could be extended to a variety of alcohols (Table 3). In
contrast to trifluoromethylation, difluoromethylation could be
applied well to alkyl alcohols. Secondary benzylic alcohols showed
a low reactivity(6l). Secondary alkyl alcohols could not undergo
difluoromethylation under these conditions (6s), and 54% of the
substrate remained as determined by 1H NMR spectroscopy.
Chen’s reagent, FSO2CF2CO2Me, was developed in 198915 and
has become one of the most widely used trifluoromethylation
reagents.16 CuI is usually required to promote the
trifluoromethylation with this reagent by forming
intermediate, [CuCF3]. Interestingly, brief survey of the
conditions for the Ph3P/ICH2CH2I-initiated dehydroxylative
trifluoromethylation revealed that Cu (zero valent copper) instead
of CuI could also give a good yield (See Supporting Information,
Table S3). After the optimal conditions were established, the
substrate scope was investigated (Table 2). Good functional group
tolerance was observed. Although aryl halides have proved to be
a key
a
Table 3. Dehydroxylative difluoromethylation of alcohols.
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
I-
R'
I
Ph
3P,
ICH CH I
[Cu],
2
2
+
R
H
R
CF2H
6
OH
1
TMSCF2
P
R'
R'
CsF, DMF,
8-12 h
Temp.,
5
O
o
=
=
rt
For
alcohols,
CuSCN, Temp. 40 C to
H
R
benzylic
[Cu]
Me
A
CF2H
CF2H
CF2H
CF2H
tBu
CF2
H
Me
Me
OR
H
Me
Me
I
Me
R'
ICH CH I
2 2
3P,
[MRF]
R-RF
N
I
Ph
MeS
ROH
N
=
or
Cu
M
DMF
Ag
6a
6b
6c
49%
,
Me
52%
40%
,
,
H
=
RF CF
3S,
CF3 HCF2
B
6d
C
43%
,
or
CF2H
CF2H
R-I
CF2H
MeO2C
Br
6e
6f 55%
6g 55%
6h
51%
,
40%
,
,
,
In summary, we have described the dehydroxylative
trifluoromethylthiolation, trifluoromethylation and
CF2H
Me
S
O
CF2H
difluoromethylation of alcohols promoted by the R3P/ICH2CH2I
system. This is the first general protocol for the installation of CF3S,
CF3 and HCF2 groups from easily available alcohols. Due to the
ubiquity of alcohols, this dehydroxylation protocol may find
applications in the synthesis of biologically active
fluorine-containing molecules.
CF2H
CF2H
I
Ph
6i 41%
6
j,
6k
6l
31%
,
56%
38%
,
,
CuI, Temp. 40 oC
=
=
For alkyl alcohols,
[Cu]
CF2H
nC14
H
29CF2H
CF2H
CF2H
Cl(CH2)8
Ph
Br
6m
6n 55%
,
6o
6p 53%
,
60%
50%
,
,
CF2H
Ph
CF2H
S
CH2=CH(CH2 9CF2H
)
Me
a
Supporting Information
6q
6r 57%
,
38%
,
6s
,
(0%)
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Isolated yields. Reaction conditions for benzylic alcohols: CuSCN (2.0
mmol), 5 (1.5 mmol), and CsF (2.5 mmol) in DMF (2 mL) at 40 oC for 1h.
Into the mixture was added a solution of alcohol 1 (0.5 mmol), Ph3P (1.2
equiv.), and ICH2CH2I (1.2 equiv) in DMF (3 mL). The resulting mixture was
stirred at room temperature for 8-12 h under a N2 atmosphere. For alkyl
alcohols: CuI (1.0 mmol), CsF (2.5 mmol) and 5 (2.5 mmol) in DMF (2 mL)
Acknowledgement
The authors thank the National Natural Science Foundation
(21421002, 21672242, 21971252), Key Research Program of
Frontier Sciences (CAS) (QYZDJSSW-SLH049), Youth Innovation
Promotion Association CAS (2019256) and Shanghai Research
Institute of Chemical Industry Co., LTD. (SKL-LCTP-201802) for
financial support.
o
at 40 C for 1h. Into the mixture was added the solution of alcohol 1 (0.5
mmol), Ph3P (1.2 equiv.) and ICH2CH2I (1.2 equiv) in DMF (3 mL). The
mixture was stirred at 40 oC for 8-12 h under a N2 atmosphere. aThe 19F
NMR analysis revealed that 6s was not produced.
Based on the above results and combined with our previous
reports,12 we propose the plausible reaction mechanism, as
shown in Scheme 1. We have previously shown that a strong
halogen bonding between R’3P and ICH2CH2I would drive the
formation of iodophosphonium salt (R’3P+I I-), which could
activate the alcohols by coordination to form complex A. The
iodophosphonium salt may also react with the solvent DMF to
generate a Vilsmeier-Haack-type intermediate B, by which the
alcohols could be activated via the formation of intermediate C.12b,
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This article is protected by copyright. All rights reserved.

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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
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Dehydroxylative
trifluoromethylthiolation,
R-
R-
CF S
or
SCF3
or
R-
CF3
or
trifluoromethylation, and difluoromethylation
of alcohols
[
]
]
3
R'
2I
ICH CH
3P,
2
+
R
OH
CF
or3
[
]
H
CF2
HCF
[
2
Dehydroxylative trifluoromethylthiolation, trifluoromethylation and difluoromethylation of
alcohols were achieved under mild conditions via the activation of the hydroxyl group by a
R3P/ICH2CH2I system.
Wei Zhang, Jin-Hong Lin, Wenfeng Wu,* Yu-Cai
Cao, and Ji-Chang Xiao*
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.