An efficient and practical approach to trifluoromethylthiolation of α-haloketones/α-haloarylmethanes

Article abstract of DOI:10.1039/c5ob00858a

An efficient and practical approach to trifluoromethylthiolation of α-haloketones/α-haloarylmethanes was developed. The transformation employs only AgSCF₃ and KI in situ generated active nucleophilic trifluoromethylthio species and cleanly occurs in up to quantitative yield at room temperature, thereby providing an unprecedentedly easy entry to various α-SCF₃-substituted ketones/arylmethanes.

Full text of DOI:10.1039/c5ob00858a

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DOI: 10.1039/C5OB00858A
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An Efficient and Practical Approach to Trifluoromethylthiolation
of α-Haloketones/α-Haloarylmethanes
Min Jiang,a Fangxia Zhu, a Haoyue Xiang, b Xing Xu, a Lianfu Deng, a* and Chunhao Yang b*
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient and practical approach to trifluoromethylthiolation of α‐haloketones/α‐haloarylmethanes was developed. The
transformation employs only AgSCF3 and KI in situ generated active nucleophilic trifluoromethylthio species and cleanly
occurs in up to quantitative yield at room temperature, thereby providing an unprecedentedly easy entry to various α‐
SCF3‐substituted ketones/arylmethanes.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Carbonyl compounds, which are found in many natural
Introduction
products and pharmaceuticals with
a wide range of
physiological and biological activities, constitute a large family
of interesting building blocks.7a Therefore, fluorine‐containing
carbonyl compounds could be of great interest for further
applications not only in organofluorine chemistry but also in
medicinal chemistry.8 Various efficient methods for synthesis
of α‐CF3‐substituted carbonyl compounds have been
reported,9 such as trifluoromethylation of α‐haloketones.9d
Nevertheless, approaches to α‐SCF3‐substituted carbonyl
compounds have been considerably less studied up to now
(Scheme 1). Initially, the extremely toxic and corrosive
trifluoromethylsulfenyl chloride was used as an electrophilic
The SCF3 group is frequently introduced in many
pharmaceutical and agrochemical products, because of its
desirable electronegativity and lipophilicity properties.1 Over
the past few decades, numerous methods for the indirect
insertion of the SCF3 group into organic compounds have been
reported, including halogen‐fluorine exchange reactions of
trihalogenomethyl thioethers,2 trifluoromethylations of sulfur‐
containing compounds,3 whereas often under harsh conditions
or need additional steps for preparation of the precursors.
Apart from earlier indirect strategies, a more elegant way is
the direct trifluoromethylthiolation of diverse substrate
scaffolds by the formation of C‐SCF3 bond, and kinds of
efficient methods have emerged to propose such reactions.1a,
1b, 4 Notably, in most of these elegant strategies, a great effort
has been focused on the formation of C(sp)‐SCF3 or C(sp2)‐
5
5a, 5e, 6
SCF3 bonds
to give alkynyl‐SCF3 and aryl‐SCF3 molecules
respectively, but processes that facilitate the construction of
7
C(sp3)‐SCF3 bonds5a, from alkyl substrates are much less
explored. Actually, the molecules containing C(sp3)‐SCF3 bonds
are useful and versatile class of synthetic synthons for
constructing numerous trifluoromethylthiolated derivatives.
Thus the development of facile and straightforward methods
for construction of C(sp3)‐SCF3 bonds is of interest to the fields
of organofluorine chemistry and medicinal chemistry.
a.Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of
Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong
University School of Medicine, Shanghai, 20025, P.R. China. E‐mail:
lfdeng@msn.com.
b.State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555Zuchongzhi Road, Shanghai, 201203,P.R. China.
Fax: 86‐21‐50806770; Tel: 86‐21‐50806770; E‐mail: chyang@simm.ac.cn.
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. Methods for Synthesis of α‐SCF3/CF3‐substituted Ketones
trifluomethylthiolating reagent for synthesis of α‐SCF3‐
substituted ketones.10 However, until very recently, impressive
progress has been made in construction of α‐SCF3‐substituted
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ketones. Recently, the Shen’s, the Shibata’s and billard’s group too small to stabilize large diffuse anions. The reactivity decreased
independently designed novel electrophilic SCF3 sources that in the order as KI>KBr>KCl>KF due to theDsOtaI:b1i0li.t1i0e3sV9io/eCwf5AtOhrtBiec0lea0Oc8nt5il8ivnAee
could be used to trifluoromethylthiolation of β‐ketoesters to anions.17 Based on this pioneering work, we herein present a
afford the corresponding α‐SCF3‐substituted carbonyl convenient and efficient method for nucleophilic
,
11
compounds,7a
transformation as well by using Munavalli’s reagent.12 As an
alternative, Li and Zard described nucleophilic
and the Rueping’s group realized this
trifluoromethylthiolation
of
α‐haloketones/α‐
haloarylmethanes via in situ generation of active
trifluoromethylthiolate anion from AgSCF3 and KI. In contrast
to most of other methods reported, this protocol proceeded
under mild conditions in an extremely short reaction time and
was insensitive to air and moisture with almost quantitative
yields.
trifluoromethylthiolation of α‐bromoketones with O‐
octadecyl‐S‐trifluorothiolcarbonate at the same time.13 Most
recently, Weng’s group reported another route to nucleophilic
trifluoromethylthiolation of α‐bromoketones with elemental
sulfur and CF3SiMe3 by the catalysis of copper.14a Although
preparation of electrophilic‐type trifluoromethylthiolation
reagent in advance is not required in this method, whereas a
large excess of elemental sulfur are used. Furthermore, the
reaction time is relatively long, and low yields are obtained
when the substrates with electron‐withdrawing substituents
on the aromatic ring are employed. Afterwards an improved
protocol was published by the same group using (bpy)Cu(SCF3)
as the trifluoromethylthiolation reagent and it still need long
time(16 h) under N2 atmosphere.14b Considering the above,
the development of concise and novel strategies for the
synthesis of α‐SCF3‐substituted ketones would be an
alternative approach. With the advances in the field of direct
C(sp3)‐SCF3 bonds formation to afford aliphatic‐SCF3 molecules,
a few of efficient synthetic protocols have also been reported
to prepare another useful and versatile class of building blocks,
benzyl trifluoromethyl sulphides.15
Results and discussion
Our initial investigation commenced with the treatment of
2‐bromoacetophenone (1a) as the substrate and AgSCF3 as the
trifluoromethylthiolation reagent in acetone at room
temperature (Table 1). First, no desired compound was
observed without any additive (entry 1). It seemed that AgSCF3
was not active enough for this transformation. Then KI was
Table 2. Scope of the Reaction Using Different α‐Haloketones a, b
Table 1. Optimization of the Reaction Conditionsa
Entry
AgSCF3
(equiv.)
2.0
KI
(equiv.)
-
Solvent
Yield (%) b
1
2
3
4
5
6
7
8
Acetone
Acetone
MeCN
NR c
99
2.0
2.0
2.0
2.0
99
2.0
2.0
Acetone/H2O
EtOH
75
2.0
2.0
NR
NR
60
2.0
2.0
H2O
1.0
1.0
Acetone
Acetone
2.0
2.0
56 d
a Reaction conditions: 1 (50 mg), AgSCF3( 2.0 equiv), KI (2.0 equiv), acetone
(2 mL). b Isolated yield. c NR = no reaction. d Using NaI to replace KI.
Recently, our group become interested in the development
of efficient approaches to diverse fluorine‐containing
molecules from the view of their potential application in
medicinal chemistry,16 and we reasoned that both of SCF3‐
containing carbonyl and benzyl compounds could be
a Unless otherwise specified, all reactions were performed under optimized
c
conditions, using corresponding bromides as substrates. b Isolated yield.
d
Corresponding organoiodine compound was used as the substrate.
Corresponding chloride was used as the substrate under the optimized
conditions. e KI and chloride were refluxed for 10 min, then AgSCF3 was added
for another 30 min at 30 ℃. f MeCN was used as the reaction solvent.
synthesized
through
trifluoromethylthiolation
of
corresponding halide substrates via C(sp3)‐SCF3 bonds
generation. In 2000, Clark et al. reported the AgSCF3‐KI system,
which could be used to trifluoromethylthiolation of very
electron‐deficient aryl halides.17 In this paper Clark explained
the mechanism. It seemed that not unstable CF3S‐ but active
[Ag(SCF3)I]‐ anion was the key intermediate in the reaction.
Inorganic halide source plays an important role in the system.
Sodium halides were ineffective that the sodium cation is maybe
added and we found that the reaction occurred smoothly,
giving
the
corresponding
products
1‐phenyl‐2‐
((trifluoromethyl)thio)ethan‐one 2a in a quantitative yield
(entry 2). Afterward, we performed a solvent screening. We
found that MeCN could give a quantitative yield as well, but
the use of other solvent, e.g., Acetone/H2O, EtOH or H2O
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(entries 3−6), was found to be detrimental. When halving the
dosage of AgSCF3 and KI, the yield decreased to 60% (entry 7).
Additionally, the yield would also decrease when KI was
replaced by NaI (entry 8).
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DOI: 10.1039/C5OB00858A
SCF3
SCF3
SCF3
SCF3
SCF3
NO2
CN
4b 96%
NC
F
4a, 39%
4d 90%
4d 96%d
4c 97%
SCF3
SCF3
SCF3
Under the optimized reaction conditions (2 equiv. AgSCF3
and 2 equiv. KI in acetone at room temperature), various α‐
haloketones analogues were tested as the substrates for the
direct C−S bond formation. As shown in Table 2, different
electron‐donating or withdrawing substituents at different
positions of the aromatic ring were all well tolerated and the
desired products were obtained in excellent yields. Both the
unfunctionalized aromatic substrates and those bearing Me or
MeO group underwent quantitative trifluoromethylthiolation
to afford products 2a‐e. We were pleased to find that the
hydroxyl‐substituted compound 1f was a suitable reactant as
well under the standard conditions, leading to the desired
product 2f in 60% yield. Remarkably, not only α‐bromo but
also α‐iodo and α‐chloro derivatives could be
4e 94%
NO2
NO2
4f >99%
4f 91%e
4g 55%
4h NR
a Reaction conditions: 3 (50 mg), AgSCF3( 2.0 equiv), KI (2.0 equiv), acetone (2
mL) . Isolated yield. NR = no reaction. 1 gram of 3d was used.
Corresponding chloride was used as the substrate.
b
c
d
e
With the excellent results in hand, this method can also be
applied in the synthesis of benzyl trifluoromethyl sulfide
derivatives, and the results are shown in Table 3. The reaction
of substrate without electron‐withdrawing group (benzyl
bromide, 3a) furnished the benzyl trifluoromethyl sulphides 4a
in a low yield (39%). Facile transformations of bromides
containing electron‐withdrawing groups on the aromatic ring
gave the corresponding trifluoromethylthiolated products in
excellent yields (4b‐f). To our delight, we found 4‐nitrobenzyl
chloride could give a good yield of 91% when using the
trifluoromethythiolated smoothly (2a, 2g).
However, the α‐chloro substrate gave lower yield (39%)
under the same reaction conditions. Consequently, we treated
2‐chloro‐1‐(4‐fluorophenyl)ethanone with KI under reflux at
first to activate the substrate, and then AgSCF3 was added, and
a quantitative yield of this corresponding product 2g was
obtained. Furthermore, halo‐substituted aryl substrates also
provided the desired products 2g‐i in excellent yields, which
offer opportunities for subsequent chemical transformations.
Notably, α‐bromoketone possessing electron‐withdrawing
groups, such as methylsulfonyl, nitrile or nitro group, could
quantificationally provide the desired products 2j‐l. However,
less of 20% yield of products 2i and 2k‐l were observed under
conditions
fluorophenyl)ethanone.
as
the
same
Furthermore,
as
2‐chloro‐1‐(4‐
fluoro‐substituted
product 4g was prepared in the yield of 55%. Substrates
bearing electron‐donating groups, such as 3‐methylbenzyl
bromide can’t afford the desired product 4h. From the above
results, a rule can be drawn out that the higher activity the
halo group has, the higher the yield is.
To prove the practicality and usefulness of the present
reaction for large‐scale synthesis, we prepared 4d on a gram
scale in 96% yield (Table 3).
This transformation is also suitable for medicinal chemistry.
Estrone is a natural active oestrogen receptor ligand.18 The
utility of the reaction is further illustrated by the synthesis of
SCF3‐containing analogue of estrone 5c, which is of great
interest in medicinal chemistry.
the reaction conditions reported by Weng’s group (20% for 2i
,
13% for 2k and 17% for 2l respectively, determined by 19F NMR
spectroscopy), but resulting in the addition of CF3 to the
carbonyl groups to afford the trifluoromethylated alcohols as
side product.14 Additionally, we found that the scope of this
reaction could be further extended to the use of secondary
bromides, giving the corresponding product 2m in quantitative
yield. While moderate yield for α‐phenyl substituted bromide
substrate 1n is possibly due to the steric hindrance of phenyl
group at the α‐position. Moreover, this method could be
applied to synthesis of trifluoromethylthiolatedheterocyclic
carbonyl compounds 2o‐r, including benzofuran, indole, furan
and thiophene rings. Amazingly, the trifluoromethylthiolation
of aliphatic α‐bromoketones and an aliphatic α‐bromoester
was possible and proceeded in excellent yield (2s, 2t and 2u),
thus enhancing the scope and the utility of our reaction. The
product 2t was obtained in lower yield than 2u perhaps
because of its low boiling point.
Scheme 2. Synthetic Utility of the Reaction
Table 3. Scope of the Reaction Using Different Benzyl Halides a, b, c
Experimental
General Procedure for the Synthesis of Compounds 2a‐2s
To a reaction tube were added AgSCF3 (2.0 equiv), KI (2.0
equiv),
1 (50 mg) and acetone (2 mL). The mixture was stirred
at room temperature for 10 min. The solvent was removed
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Conclusions
In conclusion, we have successfully employed AgSCF3 for
nucleophilic trifluoromethylthiolation of α‐haloketones, electron‐
deficient benzyl halides and active aliphatic bromides in the
presence of KI. This transformation utilized AgSCF3 and KI to in situ
generate active nucleophilic trifluoromethylthio species and are not
sensitive to moisture and air. The reaction provides an efficient and
convenient access to α‐trifluoromethylthiolated carbonyl molecules
and electron‐deficient benzyl trifluoromethyl sulphides in excellent
yields under very mild conditions in a short reaction time.
Additionally, the desired α‐trifluoromethylthiolated products are
very important synthons for the preparation of various SCF3‐
containing derivatives. The application of the present method for
further challenging and complex substrates is in progress in our lab
and will be reported in due course.
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This study was supported by Shanghai Municipal Health
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20144Y0055), the Shanghai Committee of Science and
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