Electrophilic trifluoromethylthiolation of allylsilanes with trifluoromethanesulfanamide

Article abstract of DOI:10.1021/ol400032g

A CH₃COCl-promoted allylic trifluoromethylthiolation of allylsilanes with trifluoromethanesulfanamide has been described. The method allows for an efficient synthesis of a wide range of allylic trifluoromethylthiolated compounds under mild conditions.

Full text of DOI:10.1021/ol400032g

ORGANIC
LETTERS
2013
Vol. 15, No. 4
894–897
Electrophilic Trifluoromethylthiolation of
Allylsilanes with Trifluoromethanesulfanamide
Jianbo Liu,† Lingling Chu,† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China, and College of
Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North
Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
Received January 5, 2013
ABSTRACT
A CH3COCl-promoted allylic trifluoromethylthiolation of allylsilanes with trifluoromethanesulfanamide has been described. The method allows for
an efficient synthesis of a wide range of allylic trifluoromethylthiolated compounds under mild conditions.
The trifluoromethylthio moiety (CF3SÀ) is one of the
key structural units found in pharmaceuticals and agro-
chemicals mainly due to its strong electron-withdrawing
effect and extremely high lipophilicity.1 Consequently,
extensive efforts have been devoted to the incorporation
the CF3S group into a series of pharmaceutically and
agrochemically related agents. Earlier studies in this area
primarily focused on indirect methods, including nucleo-
philic fluorination of perchloroalkyl sulfides2 and trifluoro-
methylation of sulfur-containing precursors,3 while more
attention has been recently turned toward the direct and
attractive trifluoromethylthiolation.4À11 For example, signif-
icant progress has been made in the construction of CÀSCF3
bonds using CF3SM or CF3SNMe4 as a nucleophilic CF3S
source, including nucleophilic substitution5 of aryl halides
or diazonium salts and trifluoromethylthiolations of aryl
(4) For radical trifluoromethylthiolation, see: (a) Harris, J. F.;
Stacey, F. W. J. Am. Chem. Soc. 1961, 83, 840. (b) Harris, J. F. J. Am.
Chem. Soc. 1962, 84, 3148. (c) Sheppard, W.; Andreades, S.; Harris, J. F.
J. Org. Chem. 1964, 29, 898. (d) Harris, J. F. J. Org. Chem. 1966, 31, 931.
(j) Munavalli, S.; Rohrbaugh, D. K.; Rossman, D. I.; Wagner, W. G.;
Durst, H. D. Phosphorus Sulfur Silicon Relat. Elem. 2002, 177, 1021.
(5) (a) Adams, D. J.; Clark, J. H. J. Org. Chem. 2000, 65, 1456.
(b) Adams, D. J.; Goddard, A.; Clark, J. H.; Macquarrie, D. J. Chem.
Commun. 2000, 987. (c) Tyrra, W.; Naumann, D.; Hoge, B.; Yagupolskii,
Y. L. J. Fluorine Chem. 2003, 119, 101.
(6) (a) Chen, Q.-Y.; Duan, J.-X. J. Chem. Soc., Chem. Commun. 1993,
918. (b) Teverovskiy, G.; Surry, D. S.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2011, 50, 7312. (c) Zhang, C.-P.; Vicic, D. A. J. Am. Chem. Soc.
2011, 134, 183. (d) Weng, Z.; He, W.; Chen, C.; Lee, R.; Tan, D.; Lai, Z.;
Kong, D.; Yuan, Y.; Huang, K.-W. Angew. Chem., Int. Ed. 2013, 52,
1548.
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
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E. J. J. Med. Chem. 1973, 16, 1207. (c) Leroux, F.; Jeschke, P.; Schlosser,
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r
10.1021/ol400032g
Published on Web 02/04/2013
2013 American Chemical Society

halides,6 aryl boronic acids,7 and terminal alkynes8 in the
presence or absence of transition metal catalysts. These
methods allowed efficient access to a wide range of
CF3S-containing compounds under relatively mild reac-
tion conditions. However, the utility of electrophilic tri-
fluoromethylthiolating reagents to construct CÀSCF3
bonds, which would broaden the scope of direct trifluo-
romethylthiolation reactions, remains less extensively ex-
plored. Until now, only several examples of the direct
electrophilic trifluoromethylthiolation reactions have been
reported.9À11 Steppard9a and Bogdanowicz-Szwed9b re-
spectively reported the electrophilic reactions of arylmag-
nesium halides and enamines with CF3SCl as the elec-
trophile. Remarkably, Daugulis and co-workers described
the first example of a copper-promoted direct trifluoro-
methylthiolation of aryl CÀH bonds using CF3SSCF3 as
the electrophilic trifluoromethylthiolating reagent.9c Never-
theless, these electrophilic protocols have significant limita-
tions including the modest substrate scope/generality
and the use of gaseous and/or highly hazardous reagents.
Recently, Billard and Langlois reported that trifluoro-
methanesulfanamides (2)10 could be used as a new and
easy-to-handle electrophilic CF3S source, enabling the
direct trifluoromethylthiolation of a series of nucleophiles,
such as alkenes, alkynes,10b electron-rich arenes,10c and
organometallic reagents10d in the presence of acidic initia-
tors. Most recently, our group also accomplished an acid-
promoted trifluoromethylthiolationÀcyclization cascade
with trifluoromethanesulfanamide 2a.11 In our continuing
efforts to develop new and efficient trifluoromethylation
and trifluoromethylthiolation reactions, herein we de-
scribe a Lewis acid promoted electrophilic trifluoro-
methylthiolation of allylsilanes to afford a range of
allylic trifluoromethylthiolated products under mild con-
ditions (Scheme 1a).
which would be an efficient method to access allylic
SCF3 compounds, has hardly been demonstrated. A single
example of this type of reaction was disclosed by Billard
and co-workers, in which allylic SCF3 products were
obtained when hindered olefins were employed in the
electrophilic trifluoromethylthiolation of alkenes with tri-
fluoromethanesulfanamides (Scheme 1b, 1c).10b The scope
of the reaction was considerably limited, and the reaction
efficiency was low. Inspired by the work of Sodeoka’s and
Gouverneur’s groups,14 we surmised that the utility of
allylsilanes as the substrates, in which the pendant tri-
methylsilyl group could enhance the nucleophilicity of
olefins and control the regioselectivity via the β-silyl effect,
would facilitate the selective formation of allylic SCF3
products in the electrophilic trifluoromethylthiolation re-
actions (Scheme 1a).
Scheme 1. Electrophilic Trifluoromethylthiolation Reactions
with Trifluoromethanesulfanamides
Compounds carrying a fluoroalkyl group at their allylic
positions are versatile building blocks for the synthesis of a
variety of fluoroalkyl-containing compounds.12 Currently,
strategies for the preparation of allylic CF3 compounds
have been developed.13 For example, Buchwald’s,13a
Liu’s,13b Wang’s,13c and our group13d successively re-
ported the Cu-catalyzed allylic trifluoromethylation of
olefins, providing a series of trifluoromethylated allylic
compounds. To further expand the substrate scopeof these
reactions, Sodeoka14a and Gouverneur14b subsequently
developed the Cu-catalyzed trifluoromethylation of allyl-
silanes using Togni’s reagent.14 However, a similar trans-
formation employed in the trifluoromethylthiolation,
Considering the fact that an acidic initiator is required
for the transfer of the SCF3 group from the electrophilic
trifluoromethanesulfanamides,10,11 we initially examined
various Bronsted acids and Lewis acids for the electro-
philic trifluoromethylthiolation of allylsilanes (Table 1).
(2-Phenylallyl)trimethylsilane 1a was chosen as a model
substrate, and the reaction was conducted with trifluoro-
methanesulfanamide 2a as a source of the electrophilic
CF3S reagent at room temperature in dichloromethane
(Table 1, entries 1À5). However, BF3 OEt2 and TsOH
3
3
H2O, the most common Lewis acid and Bronsted acid
employed for the electrophilic trifluoromethylthioltion
reactions,10b,c,11 gave the desired product 3 in 26% and
13% yield, respectively (entries 1 and 2). Both a weak acid
(CH3COOH) and strong acid (CF3COOH) were found to
be ineffective in the current reaction, leaving reagent 2a
essentially untouched (entries 3 and 4). The biggest pro-
blem is that most of the allylsilane substrate underwent
desilylation under the acidic reaction conditions to give the
desilylated byproduct 4a and/or its dimers (entries 1À4).
To overcome this problem, we surmised that a proper
acidic initiator, which would preferentially activate
(12) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, 2004. (b) Uneyama, K. Organofluorine Chemistry; Blackwell
Publishing: Oxford, 2006. (c) Kirk, K. L. Org. Process Res. Dev. 2008, 12,
305.
(13) (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011,
50, 9120. (b) Xu, J.; Fu, Y.; Luo, D. F.; Jiang, Y. Y.; Xiao, B.; Liu, Z. J.;
Gong, T. J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 15300. (c) Wang, X.;
Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem.
Soc. 2011, 133, 16410. (d) Chu, L.; Qing, F.-L. Org. Lett. 2012, 14, 2106.
(14) (a) Shimizu, R.; Egami, H.; Hamashima, Y.; Sodeoka, M.
ꢀ
Angew. Chem., Int. Ed. 2012, 51, 4577. (b) Mizuta, S.; Galicia-Lopez,
O.; Engle, K. M.; Verhoog, S.; Wheelhouse, K.; Rassias, G.; Gouverneur,
V. Chem.;Eur. J. 2012, 18, 8583.
Org. Lett., Vol. 15, No. 4, 2013
895

trifluoromethanesulfanamide rather than allylsilane, should
be employed.
Table 2. CH3COCl-Promoted Trifluoromethylthiolation of
Allylsilanesa
Table 1. Optimization of the Reaction Conditionsa
Lewis acid
(equiv)
solvent
[0.05M]
yield of
3a (%)b
entry
1
BF3 Et2O (5.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
DMSO
DMF
26
3
2c
3
TsOH H2O (2.4)
13
3
CH3CO2H (2.4)
CF3CO2H (2.4)
CH3COCl (2.4)
CH3COCl (2.4)
CH3COCl (2.4)
CH3COCl (2.4)
CH3COCl (2.4)
CH3COCl (2.4)
CH3COCl (2.4)
CH3COCl (2.4)
none
trace
37
4
5
6
29
7
25
8
23
9
78
10
11d
12d,e
DMAC
DMAC
DMAC
84
86
92 (75)f
a Reaction conditions: 1a (0.1 mmol), acid, 2a (0.1 mmol, 1.0 equiv),
solvent (2 mL), room temperature, 10 h. b Yield was determined by 19
F
NMR analysis using PhCF3 as an internal standard. c Reaction was
conducted at 50 °C. d 2a (0.12 mmol, 1.2 equiv). e DMAC (1 mL).
f Isolated yield.
After surveying some other Lewis acids, we found that
the trifluoromethylthiolation proceeded in the presence of
CH3COCl, affording the desired product in 37% yield as
well as certain amounts of byproducts 4a and 5a (entry 5).
Interestingly, the use of CH3COCl as an acidic initiator in
the trifluoromethylthiolation has not been reported. Based
on previous studies,10,11 we conjectured that the in situ
generated acetylated form of reagent 2a was the reactive
intermediate in this reaction. Consistent with the hypothesis
proposed by Langlois and Billar that the acid-promoted
trifluoromethylthiolation reactions with trifluoromethane-
sulfanamides might proceed via an SN1 pathway,10c we
expected that the acetylated species would be more reactive
to transfer the CF3S group than its related protonated
species due to the better leaving group ability of the
acetanilide moiety than the aniline group. More impor-
tantly, the observation of a large amount of acetanilide
implied that the reaction between CH3COCl and trifluor-
omethanesulfanamide 2a occurs faster than the one between
CH3COCl and allylsilane 1a, providing a promising model
for retarding the undesired desilylation of allylsilanes.
To improve the reaction efficiency further, various
solvents were screened (entries 5À10). Gratifyingly, the
use of N,N-dimethylformamide (DMF) and its analogue
N,N-dimethylacetamide (DMAC) as a solvent could re-
duce the amount of the desilylated byproduct 4a to less
than 10% (determined by GC-MS) (entries 9 and 10).
Particularly, DMAC significantly improved the yield of
the trifluoromethylthiolation reaction to 84% (entry 10).
a Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), CH3COCl
(2.4 mmol), DMAC (10 mL), rt, 10 h, isolated yields. b On a 10 mmol
scale, isolated yield is given in parentheses. c At the end of reaction,
CH3COOH (0.4 equiv) and TBAF (1.0 M in THF, 4.0 equiv) were added
and the resulting mixture was stirred for another 10 h at room tempera-
ture; please see Supporting Information for details. d Under the standard
conditions, the 19F NMR yield is given in parentheses. e 1n used as
a mixture of isomer, Z/E = 1.8:1. f 1o used as a mixture of isomer,
Z/E = 1.7:1.
896
Org. Lett., Vol. 15, No. 4, 2013

A slightly higher yield was observed when reagent 2a was
used in excess (entry 11). Further investigation of the sub-
strate concentration showed that the highest yield could be
obtained by increasing the reaction concentration to 0.1 M
(entry 12).15
substituents at both the 2- and 3-position are acceptable
substrates, generating the branched allylic SCF3 com-
pounds in 44À56% yields (entries 14À17). However, the
yields of these transformations were generally lower than
those of the 2-monosubstituted allylsilanes, probably due
to the steric hindrance effects (Table 2). In addition, the
reactionof1aon a10mmol scale alsoproceededefficiently,
indicating the good scalability and reliability of the transfor-
mation (entry 1). Notably, manipulation of the trifluoro-
methylthiolation reactions is very simple, and all reactions
are carried out at room temperature on unprotected systems
without the need for solvent purification (Table 2).
In conclusion, a mild and convenient method for the
efficient allylic trifluoromethylthiolation of allylsilanes
based on a combination of trifluoromethanesulfanamide
and CH3COCl has been developed. The utility of CH3COCl
as an acidic initiator was observed to play a pivotal role in
the success of this trifluoromethylthiolation. Due to the
potential utility of the resulting allylic SCF3 compounds, the
mild conditions employed, and the simple manipulation, we
expect this method to be widely applied in the pharmaceu-
tical and agrochemical fields.
With the optimized conditions in hand, we next investi-
gated the substrate scope of allylsilanes (Table 2). A series
of 2-substituted allylsilanes were found to undergo the
desired trifluoromethylthiolation smoothly under the
standard reaction conditions, affording the corresponding
allylic SCF3 products in 40À89% yields (Table 2, entries
1À11). Several functional groups, including chloro, het-
eroaromatic rings, trimethylsilyl, and alkynyl groups, are
easily tolerated under the acidic conditions (entries 6, 8,
10À11). The position and electronic nature of the substi-
tuents on the aromatic rings have no significant influence on
the reaction efficiency, and the substrates bearing electron-
donating or -withdrawing substituents on the ortho-, meta-,
or para-positions could be trifluoromethylthiolated in mod-
erate to good yields (entries 1À8). Additionally, 2-naphtyl,
2-pyridyl, 2-phenylalkynyl, 2-styryl, and even 2-cyclohexyl
substituted allylsilanes were compatible with this protocol,
and all reactions occurred smoothly to give the desired
products (3iÀ3m) in moderate yields, albeit with slightly
lower yields of products 3k, 3l, and 3m (entries 9À13).
Next, more substituted allylsilanes were examined to
evaluate the electrophilic trifluoromethylthiolation reac-
tion further. Both acyclic and cyclic allylsilanes bearing
Acknowledgment. The National Natural Science Foun-
dation of China (21072028, 21272036) and National Basic
Research Program of China (2012CB21600) are gratefully
acknowledged for funding this work.
Supporting Information Available. Detailed experimen-
tal procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) To further illustrate the important role of the pendant trimethyl-
silyl group, the reaction of R-methylstyrene 4a with trifluoromethane-
sulfanamide 2a was conducted under the optimal reaction conditions,
while the desired product 3a and byproduct 5a were obtained in 9% and
8% yield (determined by 19F NMR analysis using PhCF3 as an internal
standard), respectively.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
897