Silver-mediated oxidative aliphatic C-H trifluoromethylthiolation

Article abstract of DOI:10.1002/anie.201411807

The first example of a practical and direct trifluoromethylthiolation reaction of unactivated aliphatic C-H bonds employs a silver-based reagent. The reaction is operationally simple, scalable, and proceeds under aqueous conditions in air. Furthermore, its broad scope and good functional-group compatibility were demonstrated by applying this method to the selective trifluoromethylthiolation of natural products and natural-product derivatives.

Full text of DOI:10.1002/anie.201411807

Angewandte
Chemie
DOI: 10.1002/anie.201411807
Trifluoromethylthiolation
À
Silver-Mediated Oxidative Aliphatic C H Trifluoromethylthiolation**
Shuo Guo, Xiaofei Zhang, and Pingping Tang*
Dedicated to Professor Li-Xin Dai on the occasion of his 90th birthday
Abstract: The first example of a practical and direct trifluoro-
Methods to indirectly access this important class of
compounds include halogen–fluorine exchange reactions
and the trifluoromethylation of sulfur-containing com-
pounds.[4] However, both of these methods require the
preparation of complex precursors. The trifluoromethylthio-
À
methylthiolation reaction of unactivated aliphatic C H bonds
employs a silver-based reagent. The reaction is operationally
simple, scalable, and proceeds under aqueous conditions in air.
Furthermore, its broad scope and good functional-group
compatibility were demonstrated by applying this method to
the selective trifluoromethylthiolation of natural products and
natural-product derivatives.
À
lation of substrates by the direct formation of the C SCF3
bond is a more efficient approach.[5] For example, trifluoro-
methylthiolation reactions of aryl Grignard reagents,[6] aryl
halides,[7–10] boronic acids,[11–15] diazo compounds,[16–19]
alkenes,[20] and terminal alkynes[21–22] with different trifluoro-
methylthiolation reagents have been developed. Moreover,
T
he growing importance of fluorinated organic compounds
as pharmaceuticals, agrochemicals, and materials has driven
the development of new methods for the introduction of
fluorine into small molecules.[1] The incorporation of the
trifluoromethylthio group (SCF3) into new drugs and agro-
chemicals has attracted much attention owing to its strongly
electron-withdrawing nature and high lipophilicity.[2] Conse-
quently, the development of new trifluoromethylthiolation
methods is of great interest to synthetic organic chemists.[3]
the introduction of a trifluoromethylthio group has been
2
À
achieved through C(sp ) H bond functionalization and the
3
[23]
À
activation of C(sp ) H bonds adjacent to a carbonyl group.
À
For instance, the trifluoromethylthiolation of aryl C H bonds
in the presence of a directing group was studied by the groups
of Daugulis,[23c] Shen,[23i] and Huang.[23k] Although progress
has recently been made in the trifluoromethylthiolation of
2
À
À
However, the selective trifluoromethylthiolation of unacti-
C(sp) H and C(sp ) H bonds, methods for the transforma-
3
3
3
À
À
À
vated C(sp ) H bonds remains a significant challenge.
tion of unactivated C(sp ) H bonds into C(sp ) SCF3 bonds
have hardly been reported. Traditional methods for the
Herein, we present the first example of a silver-mediated
À
oxidative aliphatic C H trifluoromethylthiolation. The devel-
synthesis of alkyl trifluoromethylthioethers through the
3
À
oped method is operationally simple and scalable; the desired
transformation proceeds under aqueous conditions in air and
can be applied for the late-stage trifluoromethylthiolation of
complex small molecules (Scheme 1).
functionalization of unactivated C(sp ) H bonds with danger-
ous reagents, such as trifluoromethylthiol chloride, suffer
from poor selectivity.[24] Recently, Qing and co-workers
reported the copper-catalyzed trifluoromethylthiolation of
3
[25]
À
benzylic C(sp ) H bonds. Although the reaction provides
a straightforward method for the formation of benzyl
trifluoromethyl sulfides, a large excess of the methyl arene
was required. To date, no examples of transition-metal-
catalyzed/mediated trifluoromethylthiolation reactions of
3
À
unactivated C(sp ) H bonds have been reported. Therefore,
the development of general and practical methods for the
trifluoromethylthiolation of unactivated aliphatic C(sp ) H
bonds is highly desirable.
Scheme 1. Silver-mediated trifluoromethylthiolation of aliphatic
3
À
3
À
C(sp ) H bonds.
3
À
Herein, we report a practical and direct C(sp ) H
trifluoromethylthiolation method employing AgSCF3 and
Na2S2O8 under mild conditions. AgSCF3 was chosen as the
trifluoromethylthiolation reagent owing to its ease of prep-
aration and favorable stability.[26] We began our study by
examining the reaction between 4-methyl-2-pentyl benzoate
(1e) and AgSCF3 as a model system to optimize the reaction
conditions. After extensive screening, we found that when 1e
was subjected to AgSCF3 and Na2S2O8 in a mixture of
acetonitrile, H2O, and DCE (6:2:1, v/v/v) at 358C for ten
hours in air, the trifluoromethylthiolated product 2e could be
isolated in 76%. As briefly illustrated in Table 1, various
oxidants were evaluated, and Na2S2O8 was found to give the
highest yield (entries 7–9; see the Supporting Information for
[*] S. Guo, X. Zhang, Prof. Dr. P. Tang
State Key Laboratory and Institute of Elemento-Organic Chemistry
Collaborative Innovation Center of Chemical Science and Engi-
neering (Tianjin), Nankai University
Tianjin 300071 (China)
E-mail: ptang@nankai.edu.cn
[**] We gratefully acknowledge the State Key Laboratory of Elemento-
Organic Chemistry for generous start-up financial support. This
work was supported by the “1000 Youth Talents Plan”, the NSFC
(21402098, 21421062), and the Natural Science Foundation of
Tianjin (13JCYBJC36500). Prof. Jennifer M. Murphy is greatly
acknowledged for helpful comments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411807.
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Table 1: Optimization of the reaction conditions.
as the third solvent in the reaction mixture, and DCE was
found to further improve the yield (entry 7). The reaction
gave the highest yield when conducted at 358C whereas
a yield of 68% was achieved for the reaction at 508C owing to
the formation of larger amounts of side products. Further-
more, in the absence of Na2S2O8, trifluoromethylthiolation
products were not observed (entry 10). The amounts of
AgSCF3 and Na2S2O8 were crucial for the reaction to proceed
efficiently. After thorough optimization of the reaction
conditions, reactions with 2.5 equivalents of AgSCF3 and
4.0 equivalents of Na2S2O8 were found to give the high yields
of the desired product.
Entry
Conditions[a]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
Na2S2O8, MeCN
Na2S2O8, H2O
Na2S2O8, DCE
Na2S2O8, DMSO
Na2S2O8, MeCN/H2O (3:1, v/v)
Na2S2O8, DCE/H2O (3:1, v/v)
Na2S2O8, MeCN/H2O/DCE (6:2:1, v/v/v)
(NH4)2S2O8, MeCN/H2O/DCE (6:2:1, v/v/v)
K2S2O8, MeCN/H2O/DCE (6:2:1, v/v/v)
MeCN/H2O/DCE (6:2:1, v/v/v)
22
0
0
22
74
0
89
61
0
With the optimized reaction conditions in hand, a variety
3
À
of simple molecules with multiple unactivated C(sp ) H
bonds were successfully converted into the corresponding
trifluoromethylthiolated products with yields ranging from
32% to 94% (Scheme 2). A wide range of functional groups,
such as ketones, ethers, esters, amides, aromatic nitriles,
chlorides, fluorides, and bromides, were tolerated under the
standard reaction conditions. Trifluoromethylthiolation was
observed to occur selectively at methine or methylene
positions that are remote from electron-withdrawing groups.
For instance, the trifluoromethylthiolation of butyl benzoate
(1a) led to the formation of a mixture of regioisomers in
a combined yield of 80% (as determined by NMR spectros-
copy); the major isomer, 2a, was isolated in 32% yield. For
substrates 2b–2z, the regioisomeric products were formed in
0
[a] All reactions were run at 358C with AgSCF3 (2.5 equiv) and the
indicated oxidant (4.0 equiv). [b] Yields were determined by 19F NMR
spectroscopy with 1-fluoro-3-nitrobenzene as the internal standard.
details). The addition of water also increased the reaction
yield by improving the solubility of Na2S2O8 (entry 5). To
prevent the oxidative decomposition of the starting materials
and products, we reasoned that a biphasic system could
physically separate the starting materials and products from
the oxidant.[5d] Therefore, nonpolar solvents were investigated
Scheme 2. Scope of the silver-mediated trifluoromethylthiolation. Yields of isolated products are given unless otherwise noted. The ratios of the
shown products to other regioisomers were determined by 19F NMR spectroscopy and are given in parentheses. [a] Yield determined by 19F NMR
spectroscopy with 1-fluoro-3-nitrobenzene as the internal standard. [b] Substrate (5.0 equiv). [c] 1:0.9 d.r. Bz=benzoyl, Phth=phthalimido.
2
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less than 10% yield according to 19F NMR spectroscopy. In
addition, a substrate with a heteroaromatic substituent (1o)
afforded the corresponding trifluoromethylthiolated product
in good yield. This method could also be applied to the
trifluoromethylthiolation of an amino acid derivative and
provided the corresponding product with high selectivity and
in good yield (2s). An excess of starting material was
employed for some substrates (1v–1x) as the polytrifluoro-
methylthiolation products were observed with one equivalent
of substrate; the trifluoromethylthiolation yields for these
substrates are based on the amount of AgSCF3 that was
employed in these reactions. Moreover, the two diastereo-
mers of 2y were formed in a 1:0.9 ratio when cis-4-methyl-1-
cyclohexanol benzoate (1y) was subjected to the standard
reaction conditions, which is consistent with a reaction
mechanism that involves either radical species or a carbocat-
ion. Furthermore, the reaction of 1l could be carried out on
gram scale under the standard reaction conditions and
enabled the isolation of 2l in 90% yield, which demonstrates
both the scalability and practicality of this method.
Encouraged by our success with simple alkanes, more
complex substrates were then investigated. To our delight, the
trifluoromethylthiolation of the natural product sclareolide
(1aa) proceeded under the standard reaction conditions to
yield the corresponding product in 42% yield (yield of the
major isomer, ca. 50% recovered starting material; Sche-
me 3a). The trifluoromethylthiolation did not occur at either
of the two methine positions because of steric hindrance
and the deactivation of these positions; instead, selective
trifluoromethylthiolation was observed at the C2 methylene
position, which is less sterically hindered.[27] Furthermore,
other molecules derived from complex natural products were
successfully trifluoromethylthiolated with our method. For
instance, the transformation of a derivative of 5a-androstane-
3b,17b-diol gave the trifluoromethylthiolated product 2bb in
53% yield (Scheme 3b). A derivative (1cc) of the anticancer
drug taxol provided the corresponding trifluoromethylthio-
lated product 2cc in 36% yield (ca. 50% recovered starting
material; Scheme 3c). Trifluoromethylthiolation occurred
selectively at the methine position on the side chain owing
to steric hindrance and the deactivation of the available
À
tertiary C H bonds on the rings of these substrates (1bb,
1cc).
To gain mechanistic insights into the trifluoromethyl-
thiolation process, some preliminary studies were conducted.
The trifluoromethylthiolated product was formed in less than
5% yield when a radical inhibitor, namely 2,6-di-tert-butyl-4-
methylphenol (BHT) or 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO; 1 equiv each), was added. Whereas similar yields
were achieved when the reaction was performed in air or
under inert atmosphere in a 2 mL sealed vial, the yield
decreased under O2 atmosphere, which is consistent with
a free radical mechanism. Furthermore, trifluoromethylthio-
lated products were not observed when CsSCF3 or
nBu4NSCF3 were used as the trifluoromethylthiolation
reagents in the presence of silver salts (see the Supporting
Information for details), which indicates that the reaction may
not proceed through a carbocationic intermediate. Finally,
cyclized product 3 was observed when ketone 1n was used as
the substrate under the standard reaction conditions, whereas
cyclized products were not observed with esters 1b and 1d.
Cyclopropane 4 was designed as a radical probe, and the ring-
opening product 5 was indeed formed under the reaction
conditions (Scheme 4a), which provides solid evidence for the
intermediacy of carbon-centered radicals in the reaction. All
of these observations support the hypothesis that a radial-
chain mechanism or single-electron transfer (SET) may be
involved in this transformation. Furthermore, monitoring of
the reaction by 19F NMR spectroscopy showed that CF3SSCF3
3
À
Scheme 3. Silver-mediated C(sp ) H trifluoromethylthiolation reac-
tions of natural products and natural-product derivatives. Reaction
conditions: a) AgSCF3 (2.5 equiv), Na2S2O8 (4.0 equiv), MeCN/H2O/
DCE, 358C.
Scheme 4. a) Mechanistic studies. b) Proposed mechanism.
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was generated in the reaction.[20b,28] When CF3SSCF3 was used
as the trifluoromethylthiolation reagent, the trifluorome-
thylthiolation product was formed in 38% yield in the
presence of silver salts whereas no product was formed in
the absence of silver salts (see the Supporting Information for
details). To gain further insights into the reaction mechanism,
the intermolecular kinetic isotope effect (KIE) was deter-
mined. A significant KIE (kH/kD = 3.8) was observed in
competition experiments using an excess amount of a 1:1
mixture of cyclohexane and [D12]cyclohexane under the
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À
standard reaction conditions, which suggests that C H bond
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transformation.[29]
On the basis of these observations, a plausible mechanism
is proposed (Scheme 4b). It is known[30] that peroxydisulfate
anions disproportionate into sulfate dianions and sulfate
radical anions in the presence of silver(I) salts. We hypothe-
sized that carbon radical II is formed by oxidation with
a sulfate radical anion. AgIISCF3 or CF3SSCF3, which may be
formed from AgIISCF3 through single electron transfer,[20b]
can then readily react with the generated carbon radical II to
provide the desired trifluoromethylthiolated product III.[31]
In conclusion, we have reported the first silver-mediated
À
trifluoromethylthiolation of unactivated aliphatic C H
bonds, which proceeds under mild conditions. The new
method enables the functionalization of a variety of sub-
strates, including natural products and amino acid derivatives.
Furthermore, the reaction tolerates a wide range of functional
groups and can be run on gram scale. Owing to its operational
simplicity, this method could find wide applications in the
synthesis of pharmaceutical and agrochemical compounds.
Received: December 8, 2014
Revised: February 2, 2015
Published online: && &&, &&&&
À
Keywords: C H activation · fluorine · radicals ·
synthetic methods · trifluoromethylthiolation
.
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1299.
À
C H functionalization methods; for selected examples, see:
a) M. S. Chen, M. C. White, Science 2010, 327, 566; b) W. Liu,
J. T. Groves, J. Am. Chem. Soc. 2010, 132, 12847; c) W. Liu, X.
Huang, M. J. Cheng, R. J. Nielsen, W. A. Goddard, J. T. Groves,
Science 2012, 337, 1322; d) C. W. Kee, K. M. Chan, M. W. Wong,
C. H. Tan, Asian J. Org. Chem. 2014, 3, 536; e) S. Bloom, J. L.
Knippel, T. Lectka, Chem. Sci. 2014, 5, 1175; f) J. B. Xia, Y. Ma,
C. Chen, Org. Chem. Front. 2014, 1, 468; g) S. D. Halperin, H.
Fan, S. Chang, R. E. Martin, R. Britton, Angew. Chem. Int. Ed.
2014, 53, 4690; Angew. Chem. 2014, 126, 4778; h) V. A. Schmidt,
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Trifluoromethylthiolation
S. Guo, X. Zhang,
P. Tang*
&&&& — &&&&
À
Silver-Mediated Oxidative Aliphatic C H
Trifluoromethylthiolation
The silver-mediated trifluoromethylthio-
sis, and can be employed for the late-
stage trifluoromethylthiolation of com-
plex small molecules.
À
lation of unactivated aliphatic C H bonds
is reported. The reaction is operationally
simple, amenable to gram-scale synthe-
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!