Direct trifluoromethylthiolation of unactivated C(sp3)-H using silver(I) trifluoromethanethiolate and potassium persulfate

Article abstract of DOI:10.1002/anie.201411953

A practical and efficient method for the direct trifluoromethylthiolation of unactivated C(sp³)-H bonds by AgSCF₃/K₂S₂O₈ under mild conditions is described. The reaction has a good functional-group tolerance and good selectivity. Initial mechanistic investigations indicate that the reaction may involve a radical process in which K₂S₂O₈ plays key roles in both the activation of the C(sp³)-H bond and the oxidation of AgSCF₃.

Full text of DOI:10.1002/anie.201411953

Angewandte
Chemie
DOI: 10.1002/anie.201411953
À
C H Activation
3
À
Direct Trifluoromethylthiolation of Unactivated C(sp ) H Using
Silver(I) Trifluoromethanethiolate and Potassium Persulfate**
Hao Wu, Zhiwei Xiao, Junhui Wu, Yong Guo, Ji-Chang Xiao, Chao Liu,* and Qing-Yun Chen*
Abstract: A practical and efficient method for the direct
methylthioethers, they generally require prefunctionalized
starting materials. From a preparative and atom-economical
3
À
trifluoromethylthiolation of unactivated C(sp ) H bonds by
AgSCF3/K2S2O8 under mild conditions is described. The
reaction has a good functional-group tolerance and good
selectivity. Initial mechanistic investigations indicate that the
point of view, the direct trifluoromethylthiolation of an
3
À
unactivated C(sp ) H bond constitutes the most straightfor-
ward approach to alkyltrifluoromethylthioethers. However,
only few synthetic methods have been reported thus far
reaction may involve a radical process in which K2S2O8 plays
3
À
key roles in both the activation of the C(sp ) H bond and the
oxidation of AgSCF3.
A
trifluoromethylthio group (CF3S) can significantly influ-
ence the chemical, physical, and biological properties of
a parent substrate because of its strong electronegativity and
high lipophilicity.[1] Considerable efforts have thus been
devoted to the development of methods to introduce this
group into organic molecules. Two major strategies for the
chemical introduction of trifluoromethylthio groups were
À
À
developed: the direct formation of C S bonds (R SCF3) and
À
the trifluoromethylation of thiols and their derivatives (RS
CF3).[2] In recent years, several elegant methods have been
reported for the electrophilic,[3] nucleophilic,[4] and oxidative
direct trifluoromethylthiolation.[5] These methods enable the
fast and efficient synthesis of various CF3S-containing com-
pounds.
Scheme 1. Previous reports on the direct trifluoromethylthiolation of
3
À
unactivated C(sp ) H bonds.
In comparison to the recent progress made in the
2
À
À
formation of C(sp ) SCF3 or C(sp) SCF3 bonds, only few
3
À
methods have been developed for the formation of C(sp )
(Scheme 1). Harris first reported in 1966 the free-radical
chain reaction of alkanes with the highly toxic gas trifluoro-
methanesulfenyl chloride (CF3SCl).[8] Although various tri-
fluoromethylthiolated isomers were successfully obtained, the
reaction showed a narrow substrate scope and poor selectiv-
ity. In 1986, Mokrosz reported the direct trifluoromethyl-
thiolation of the allylic H atom in alkylidenemalononitrile
dimers by reaction with CF3SCl.[9] In 2009, Billard and co-
workers reported a method for the direct trifluromethylth-
iolation of allylic H atoms of hindered olefins with the
electrophilic reagent CF3SNMePh.[10] Very recently, Qing
and co-workers disclosed the Cu-mediated direct trifluoro-
SCF3 bonds. Besides the classical halogen–fluorine exchange
of polyhalogenomethyl thioethers or the trifluoromethylation
of sulfur-containing compounds,[2] alkyltrifluoromethyl thio-
ethers are mainly accessed by employing electrophilic[3a,l,6] or
nucleophilic[7] trifluoromethylthiolation reagents. Although
these methods efficiently lead to the desired alkyltrifluoro-
[*] H. Wu, Z. Xiao, Prof. Dr. Y. Guo, Prof. Dr. J.-C. Xiao, Prof. Dr. C. Liu,
Prof. Dr. Q.-Y. Chen
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, 200032, Shanghai (China)
E-mail: chaoliu@sioc.ac.cn
[5e]
À
methylthiolation of a benzylic C H bond.
development of reagent systems that can efficiently trifluoro-
Thus, the
3
À
methylthiolate the unactivated C(sp ) H bond under mild
chenqy@sioc.ac.cn
conditions is highly desirable.
3
J. Wu
À
On the other hand, unactivated C(sp ) H bonds, espe-
cially those that are not adjacent to an sp2-hybridized C atom
or a functional group that favors the formation of radicals or
anions, exhibit the least reactivity, as they are less acidic and
have no empty low-energy or filled high-energy orbitals that
easily interact with orbitals of a metal center. Their selective
functionalization under mild conditions represents a signifi-
School of Chemical and Environmental Engineering
Shanghai Institute of Technology
100 Haiquan Road, Shanghai 201418 (China)
[**] The authors gratefully acknowledge the financial support from the
National Basic Research Program of China (2012CB821600) and the
National Natural Science Foundation of China (21032006,
21302207, 21421002).
cant challenge and goal in modern synthetic chemistry.[11]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411953.
3
À
Recently, the direct fluorination of unactivated C(sp ) H
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Table 1: Optimization of reaction conditions for trifluoromethylthiola-
bonds has received great interest and impressive progress has
tion of cyclooctane.[a]
3
been made.[12] Various C(sp ) F bond-containing compounds
À
were efficiently and readily produced, typically through
a radical pathway involving the generation and trapping of
alkyl radicals with fluorine-transfer reagents. These important
3
À
advances inspired us to investigate the formation of C(sp )
3
Entry
Oxidant
Solvent
T [8C]
Yield [%][b]
À
SCF3 bonds through radical C(sp ) H activation and func-
tionalization.
1[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[g]
17
18
19[h]
20[i]
21[j]
K2S2O8
K2S2O8
NaIO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
60
60
60
60
60
60
60
60
60
60
60
60
60
40
50
50
70
80
60
60
60
82
82
0
<5
0
74
48
trace
8
10
0
0
<5
0
80
0
81
79
0
In order to test our hypothesis, we chose cyclooctane 1 as
the model substrate for the direct trifluoromethylthiolation of
3
À
PhI(OAc)2
Pb(OAc)4
C(sp ) H bonds. As radical initiator we used N-hydroxyph-
thalimide (NHPI), a precursor of the phthalimido-N-oxyl
[d]
K2S2O8
K2S2O8
(PINO) radical and a well-known organocatalyst for the
[e]
3
effective C(sp ) H activation by hydrogen abstraction.[13] For
À
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
[14]
a CF3S-transfer reagent system, we used AgSCF3 as the
DMSO
convenient CF3S resource and K2S2O8 as the oxidant.[5 g]
When a mixture of 1 (1 equiv), NHPI (0.1 equiv), AgSCF3
(1.5 equiv), and K2S2O8 (2 equiv) in CH3CN was stirred at
608C under Ar atmosphere for 12 h, the desired mono-
trifluoromethylthiolated product 2 was formed in 43% yield
along with some poly-trifluoromethylthiolated products,
which were identified by their characteristic signals in
19F NMR spectroscopy and GC-MS mass spectrometry.
Encouraged by this preliminary result, we optimized the
reaction conditions (Table 1). When AgSCF3 was used as the
limiting reagent with 10 equiv of 1 under similar conditions,
the desired mono-trifluoromethylthiolated product 2 was
obtained in 82% yield without the formation of any poly-
trifluoromethylthiolated products (Table 1, entry 1). Later,
we found that only a little excess of substrate (2 equiv) was
required for the selective formation of the mono-trifluoro-
methylthiolated product, thus demonstrating the high effi-
ciency of the reaction (Table 1, entry 2). The oxidant K2S2O8
played an important role in the reaction, as no desired
product was obtained in its absence or in the presence of other
oxidants, such as NaIO4, PhI(OAc)2, Pb(OAc)4 (Table 1,
entries 3–5). A survey of the oxidant-to-substrate ratio
showed that 2 equiv of K2S2O8 gave the best yield (Table 1,
entries 6 and 7). Among several common solvents that we
screened, CH3CN stood out as the best one and water was
harmful for the reaction (Table 1, entries 8–13). A reaction
temperature higher than 508C was required for an effective
transformation, as no obvious conversion of AgSCF3 was
observed at lower temperatures (Table 1, entries 14–18).
Interestingly, when the reaction was conducted at 508C,
a longer reaction time (12 h) was required, as no reaction
occurred within 4 h (Table 1, entry 16). Finally, the presence
of the free silver cation was crucial for the reaction, because
both the replacement of AgSCF3 with CuSCF3 and the
addition of KCl (KCl/AgSCF3 = 1:1) to the reaction mixture
prevented the formation of the desired trifluoromethylthio-
lated product (Table 1, entries 19 and 20). To our surprise, the
reaction proceeded smoothly in the absence of NHPI, which
we originally considered as the key alkyl radical initiator
(Table 1, entry 21). Based on these test reactions, the
combination of AgSCF3, K2S2O8, and CH3CN at 608C was
established as the optimal conditions for the simple, mild, and
acetone
ClCH2CH2Cl
MeOH
CH3CN/H2O[f]
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0
82
[a] Reaction conditions: cyclooctane (2.0 equiv), AgSCF3 (0.2 mmol,
1.0 equiv), oxidant (2.0 equiv) and NHPI (0.1 equiv) in solvent (2 mL)
under Ar atmosphere for 12 h. [b] Yields were determined by 19F NMR
spectroscopy with trifluorotoluene as an internal standard. [c] Cyclo-
octane (10 equiv) was used. [d] K2S2O8 (3.0 equiv) was used. [e] K2S2O8
(1.0 equiv) was used. [f] The reaction was conducted in CH3CN/H2O
(1:0.1 v/v). [g] Reaction time: 4 h. [h] CuSCF3 (1.0 equiv) was used
instead of AgSCF3. [i] KCl (1.0 equiv) was added to the reaction. [j] No
NHPI was used. The entry in bold marks optimized reaction conditions.
Various unactivated saturated hydrocarbons were then
subjected to the optimized reaction conditions. All examined
substrates were effectively transformed to the desired prod-
ucts in good yields (Scheme 2, 2–13). The reaction also
À
showed good site selectivity with preference for tertiary C H
bonds over secondary ones (11–13). The substrate scope of
the reaction was investigated next. A variety of functional
groups, such as ketones, esters, bromides, chlorides, alcohols,
cyanates, and phthalimides, were well tolerated under the
reaction conditions (14–34). Similarly, the direct C(sp ) H
3
À
trifluoromethylthiolation occurred predominantly at tertiary
À
C H bonds. Cyclopentanone and cyclohexanone were not
suitable substrates for the reaction, as only trace amounts of
the desired products were observed, however, the reaction of
cycloheptanone and cyclooctanone successfully resulted in
the desired products (14–17). Various acyclic ketones under-
went the trifluoromethylthiolation to give the desired prod-
ucts in acceptable yields (18–25). Notably, although the
a position of the carbonyl group is generally the most reactive
site in ketones, a-CF3S products were not the major products
and were commonly formed in negligible yields, which might
efficient direct trifluoromethylthiolation of unactivated
be ascribed to the strong polar effect exerted by the carbonyl
3
3
À
À
C(sp ) H bonds.
group in the C(sp ) H bond cleavage step in this reac-
2
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À
Scheme 2. Scope of the direct trifluoromethylthiolation of various unactivated C(sp ) H bonds. Reaction conditions: substrate (2.0 equiv), AgSCF3
(0.2 mmol, 1.0 equiv), oxidant (2.0 equiv) in acetonitrile (2 mL) under Ar atmosphere for 12 h. Yields were determined by 19F NMR spectroscopy
with trifluorotoluene as internal standard. The ratio of isomers was determined by 19F NMR spectroscopy or GC-MS. Yields of isolated products
are given in parentheses. [a] 5.0 mmol scale. [b] 1.0 mmol scale. 28=secondary carbon center, 38=tertiary carbon center.
tion.[13b,15] It should be mentioned that primary and secondary
aliphatic alcohols could not be transformed in the reaction
and no desired trifluoromethylthiolated products were
observed, which might be due to the thermodynamically
À
weaker C H bond adjacent to the OH group. Indeed, when
1-adamantanol was used as the substrate, the trifluorome-
thylthiolation reaction proceeded smoothly to produce the
desired trifluoromethylthiolated product in good yield (32).
However, the reaction was not compatible with alkene and
alkyne groups and a complicated reaction mixture was
formed.
product 36 was isolated as the major product in 48% yield
with minor amounts of product 37 (SCF3 at C3). The structure
of 36 was unambiguously determined by various analytical
techniques, including X-ray single-crystal analysis (see the
Supporting Information for details).
The possible scalability of the direct trifluoromethyl-
3
À
thiolation of unactivated C(sp ) H bonds was demonstrated
by the reaction of cyclooctane on a 5 mmol scale. The reaction
proceeded smoothly and led to the isolated product in 60%
yield (Scheme 2, 2). Furthermore, to show the potential of the
reaction in late-stage synthetic planning, (+)-sclareolide (35),
Some preliminary mechanistic studies on the direct
3
À
trifluoromethylthiolation of C(sp ) H bonds were conducted
in order to gain some insights into the reaction pathway. First,
kinetic isotope effects (KIE) were measured by using cyclo-
octane and [D16]cyclooctane (1:1) as the substrates under the
standard reaction conditions [Eq. (2)], affording an intermo-
lecular competitive KIE of 3.3. This large KIE suggested that
a terpenoid natural product with antifungal and cytotoxic
3
À
properties, was subjected to the direct C(sp ) H trifluorome-
thylthiolation [Eq. (1)]. Although 35 contains 26 aliphatic
C(sp ) H bonds, the C2-equatorial trifluoromethylthiolated
3
À
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Communications
AgSCF3 by K2S2O8 affords the AgIISCF3 species,[18] a CF3S
radical, or CF3SSCF3. The produced alkyl radical abstracts the
CF3S ligand of Ag(II)SCF3 or couples with a CF3S radical or
CF3SSCF3 to afford the corresponding trifluoromethylthio-
lated product.
À
the cleavage of the C H bond is the rate-limiting step.
Second, an electron-transfer scavenger (1,4-dinitrobenzene),
a radical inhibitor (hydroquinone), or a radical scavenger
(2,2,6,6-tetramethyl-1-piperidinyloxy, TEMPO) were added
to the reaction of cyclooctane [Eq. (3)]. The addition of 1,4-
In conclusion, a direct trifluoromethylthiolation of unac-
3
À
tivated C(sp ) H bond proceeds with AgSCF3 and K2S2O8.
The reaction is mild, efficient, and practical and produced
3
À
C(sp ) SCF3 bonds with good functional-group tolerance and
selectivity. Preliminary investigations show a radical reaction
pathway with K2S2O8 not only as an oxidant, but also as
a good H atom abstractor. Further studies on the exploration
of K2S2O8 as an efficient radical initiator for other radical
reactions are in progress.
Received: December 12, 2014
Revised: January 22, 2015
Published online: && &&, &&&&
À
Keywords: C H activation · fluorine · radical reactions ·
synthetic methods · trifluoromethylthiolation
dinitrobenzene resulted in a sharp decrease in the yield, while
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the strongly oxidizing reaction conditions.[16] Moreover, the
addition of benzoquinone to the reaction system resulted in
the formation of product 38 [Eq. (4)].[7m] All these exper-
.
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3
À
tion of C(sp ) H bonds might proceed through a radical
3
À
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Scheme 2) and the main side product in most cases is
CF3SSCF3 (19F NMR signal at À46.65 ppm), thus demonstrat-
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Based on these preliminary results and previous reports
3
[11–13]
À
on the C(sp ) H activation,
we propose a radical mech-
3
À
anism for the direct trifluoromethylthiolation of C(sp ) H
bonds (Scheme 3). K2S2O8 decomposes into a sulfate radical
anion with the help of the silver cation present in the reaction
system, which (as PINO) abstracts the hydrogen atom from
3
À
a C(sp ) H bond in the substrate to generate the correspond-
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Scheme 3. Proposed mechanism for the direct trifluoromethylthiolation
3
À
of unactivated C(sp ) H bond.
4
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3
À
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[14] Silver(I) trifluoromethanethiolate was prepared according to
Ref. [4a]. Its exact molecular formula is 3AgSCF3·CH3CN, and it
was unambiguously characterized by X-ray crystal and elemen-
tal analysis. For simplicity, we used AgSCF3 instead of
3AgSCF3·CH3CN in the text. For details, see the Supporting
Information.
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
À
C H Activation
H. Wu, Z. Xiao, J. Wu, Y. Guo, J.-C. Xiao,
C. Liu,* Q.-Y. Chen*
&&&& — &&&&
Direct and mild: A variety of alkyl-
trifluoromethylthioethers were efficiently
synthesized by direct trifluoro-
methylthiolation of unactivated C(sp ) H
bonds under mild reaction conditions.
The reagent system comprises AgSCF3
and K2S2O8, the latter of which both
3
À
Direct Trifluoromethylthiolation of
activates the C(sp ) H bond and oxidizes
3
À
Unactivated C(sp ) H Using Silver(I)
AgSCF3. The reaction has a broad sub-
strate scope with good functional-group
tolerance and good selectivity.
3
À
Trifluoromethanethiolate and Potassium
Persulfate
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!