Practical and regioselective halo-trifluoromethylthiolation of sulfur ylides

Article abstract of DOI:10.1039/d0cc03171b

A H2O mediated practical and highly regioselective chloro- and bromo-trifluoromethylthiolation of sulfur ylides is reported using a difunctionalization strategy. In the reaction sequence, sulfur ylides presumably react with an electrophilic trifluoromethylthiolating reagent to generate an α-SCF3 substituted sulfonium salt intermediate, which then undergoes a substitution with nucleophilic halogens. This journal is

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Practical and regioselective halo-trifluoromethylthiolation of
sulfur ylides
Received 00th January 20xx,
Accepted 00th January 20xx
Hongmei Qin, Yimin Jia, Na Wang, Zhong-Xing Jiang, and Zhigang Yang*
DOI: 10.1039/x0xx00000x
A H2O mediated practical and highly regioselective chloro- and
bromo-trifluoromethylthiolation of sulfur ylides are reported by a
difunctionalization strategy. In the reaction sequence, sulfur ylides
presumably reacts with electrophilic trifluoromethylthiolating
(a) Previous work: 1,2-difunctionalization of alkenes or alkynes
Nu
[Cu], [Se], [HA]
R4
R4
R3
[SCF3]
[Nu]
+
+
R3
or CF3SO2Cl
SCF3
(Nu = H, Ar, alkyl, NHR, OR, SR, SeR, Cl)
reagent to generate
a α-SCF3 substituted sulfonium salt
(b) Previous work: 1,1-difunctionalization of diazocarbonyl compounds
intermediate, and then substitution with nucleophilic halogens.
O
O
R6
[Cu], [Rh], [Zn]
Nu
SCF3
R6
As the most abundant and electronegative halogen element,
fluorine is prevalent in pharmaceuticals, functional materials,
and agrochemicals.1 Therefore, the incorporation of fluorine-
containing groups into organic molecules has attracted much
interest in the last few years. Among fluoroalkyl groups, the
trifluoromethylthio (SCF3) group is of special attention owing
to its high Hansch lipophilicity parameter (π =1.44) and strong
electron-withdrawing ability, which could improve the physico-
chemical and biophysical properties of lead compounds.2 As a
result, a wide variety of approaches for the introduction of
SCF3 group into small molecules have been reported with
recent efforts focusing on the use of nucleophilic or
electrophilic sources of SCF3.3 In particular, the synthesis of
structurally complex SCF3 frameworks by difunctionalization
strategy, which could readily access alkenes, alkynes or diazo
compounds with electrophiles and nucleophiles, is an efficient
multicomponent method and has attracted growing interest.
For instance, a variety of transition metal or organocatalyst-
promoted 1,2-difunctionalized trifluoromethylthiolation of
alkenes, such as hydro-,4 aryl-,5 alkyl-,6 amino-,7 oxy-,6b,7a-d,8
thio-,9 seleno,10 and chloro-containing8a,11 trifluoromethyl-
thiolation, have been successively demonstrated (Scheme 1a).
Recently, the 1,2-difunctionalization of alkynes involving
trifluoromethylthiolation have also been explored.8a,11a,12 In
addition, copper-mediated hydro-trifluoromethylthiolation13
of diazocarbonyl compounds were independently developed
by Hu,13a Wang,13b and Rueping group,13c represent seminal
R5
[SCF3]
+
R5
[Nu]
N2
(Nu = H, OR, allyl, Ar)
(c) This work:
regioselective halo-trifluoromethylthiolation of sulfur ylides
O
O
R2
S
O
H2O
H2O, LiCl
Cl/Br
Cl/Br
4
S
R
R
2
R1
R
[SCF ] SOX
[SCF3], SOX2
,
3
SCF3
Y
SCF3
R = Ar, alkyl, alkoxy
Y = Br/BF4
Scheme 1 Trifluoromethylthiolation based on difunctionalization strategy.
advances in this area and have stimulated a few 1,1-
difunctionalization
involving
trifluoromethylthiolation,
including oxy-,14 allyl-15 and aryl-16 trifluoromethylthiolation
(Scheme 1b).
Sulfur ylides, which are typical carbanion bearing a vicinal
sulfur cation, and could be widely used in organic synthesis,
such as epoxidation, aziridination, cyclopropanation,
olefination, rearrangement, cycloaddition and cross-coupling
reactions.17,18 Although sulfur ylides have some similar
chemical properties to diazo compounds, they are more stable
and less hazardous than the latter and may afford a safer
carbene precursor. Furthermore, organic halides are versatile
intermediates and building blocks, and are widely applied in
the synthesis of agrochemicals, pharmaceuticals and natural
products. In this work, we demonstrate a novel, one-pot,
transition-metal-free method for the regioselective halo-
trifluoromethylthiolation of sulfur ylides through 1,1-
difunctionalization strategy (Scheme 1c).
Hubei Province Engineering and Technology Research Center for Fluorinated
Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University, 185
Donghu Road, Wuhan 430071, China. E-mail: zgyang@whu.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental procedures,
structural characterization and spectral data of new compounds. See
DOI: 10.1039/x0xx00000x
We initiated our study of this transformation by utilizing
easily available sulfonium salt 3a as the starting material,
which could generate a sulfur ylide in situ under alkaline
condition. However, the desired 1,1-difunctionalized halo-
Chem. Commun., 2020, 00, 1-4 | 1
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Table 1 Investigation of the reaction conditionsa
and >99%, respectively (entries 12-13). When theVrieewaAcrttiicolenOwnlianes
carried out in NMP and an excess of the Lewis acid LiCl was
DOI: 10.1039/D0CC03171B
2a
(1.0 equiv)
added, intended to accelerate the ring opening process,
further improved the reaction result, and provided ring
opening product 5a in 85% yield (entry 14). Meanwhile, other
Lewis acid additives, such as NaCl, KCl, CaCl2, MgCl2, BaCl2,
AlCl3 and ZnCl2, were also investigated, but no superior result
was observed (see Table S5 in Supporting Information).
[Cl]
(1.0 equiv)
O
O
O
H2O (2.0 equiv)
Cl
Cl
4
S
S
+
Ph
Ph
Ph
DIPEA (1.0 equiv)
solvent, rt, Ar, 12 h
Br
SCF3
SCF3
3a
4a
5a
Entry
3a or 1
Solvent
[Cl]
Yieldb (%)
4a
5a
trace
40
20
37
26
ND
47
24
43
11
-
With the optimized reaction conditions in hand (Table 1,
entry 13), we explored the substrate scope of the
1c
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3a
3a
DMF
DMF
DMF
DMF
DMF
DMF
NMP
PhMe
THF
MeOH
DMF
DMF
DMF
NMP
SOCl2
SOCl2
trace
60
28
56
37
ND
50
15
44
11
disubstituted halo-trifluoromethylthiolation (Table 2).
A
TMSCl
(COCl)2
Conc HCl (37%)
Bu4NCl
SOCl2
variety of sulfonium salts were feasible in the disubstituted
halo-trifluoromethylthiolation, leading to the expected
products 4a-v in excellent yields. In general, an electron-
withdrawing group (R’ = Cl, Br, NO2, CF3) or electron-rich group
(R’ = Me, OMe) on the para position of the phenyl ring did not
affect the reaction much, the desired products 4a-g were
formed in 91-97% yields. The sulfonium salts bearing a chloro
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
10
11
12
13
14d
3a
1aa
1ab
1ac
3a
54
95
>99
15
-
-
85
Table 2 Substrate scope for the disubstituted halo-trifluoromethylthiolation of sulfur
ylidesa
O
H2O (2.0 equiv)
SOCl
2 (1.0 equiv)
O
Ph
S
O
O
O
Me
S
O
Me
S
O
Ph
Cl/Br
SCF3
SCF3
N
+
R
Ph
O
R
S
DIPEA (1.0 equiv)
DMF, rt, Ar, 12 h
N
SCF3
Ph
Me
Ph
Tol
Ph
Ph
BF4
O
Br
1aa
MeOSO3
1ab
BF4
1ac
1
2a
4a
4
O
2a
O
, R' = H, 97%
a Reaction conditions: 1a (0.1 mmol), 2a (1.0 equiv), Cl source (1.0 equiv),
4b
, R' = Me, 96%
Cl
R'
Cl
b
4c
, R' = OMe, 95%
H2O (2.0 equiv) and DIPEA (1.0 equiv) in solvent (1.0 mL) at rt for 12 h.
SCF3
SCF3
Yields determined by 19F NMR spectroscopy using PhCF3 as an internal
standard. c Without H2O. d LiCl (10.0 equiv) was added and SOCl2 (2.0 equiv)
was used. Tol = p-tolyl, DIPEA = iPr2NEt, ND = not detected.
4d
, R' = Cl, 91%
, R' = Br, 96%
, R' = NO2, 93%
R'
4e
4f
4g
4h
, R' = Cl, 93%
, R' = NO2, 94%
4i
, R' = CF3, 95%
O
O
O
trifluoromethylthiolation did not proceed when the reaction
was performed with Munavalli’s SCF3 reagent 2a (1.0 equiv),
thionyl chloride (1.0 equiv) and DIPEA (1.0 equiv) in DMF at
room temperature under an argon atmosphere for 12 h (Table
1, entry 1). Gratifyingly, the addition of 2.0 equivalents of H2O,
the desired disubstituted product 4a was observed in 60%
yield with the formation of 5a (40% yield), which was
generated from ring opening of the cyclic thioether moiety
(Table 1, entry 2). The other additives, including MeOH, EtOH,
tBuOH, and AcOH were used instead of water, the expected
reaction could also occurred, but no superior result was
observed (see Table S3 in Supporting Information). It indicated
that the difunctionalization process might be accelerated in
the presence of excessive acidic additive. Inspired by the
preliminary result, we further intended to examine different
chlorine sources, such as TMSCl, (COCl)2, hydrochloric acid (37%
solution in water) and Bu4NCl, and the lower yields were
obtained (entries 3-6). Subsequently, several other solvents
such as NMP, PhMe, THF, MeOH were screened (entries 7-10),
but the yield and regioselectivity did not improve. It is
noteworthy that the steric bulk of thioether moiety had a
significant effect on the yield of 4a. When the less hindered
sulfonium salt 1aa was employed, the yield of 4a was
decreased slightly (entry 11). In contrast, bulky sulfonium salts
1ab and 1ac significantly increased the yield of 4a to 95%
Cl
Cl
Cl
O
Cl
Cl
SCF3
SCF3
SCF3
F
O
4j
4k
4l
, 93%
, 94%
, 95%
O
O
O
Cl
Cl
Cl
SCF3
SCF3
SCF3
O
F
4m
4n
, 82%
4o
, 96%
, 97%
O
O
O
Cl
Cl
Cl
SCF3
S
SCF3
SCF3
O
4p
4q
4r
, 81%
, 90%
, 93%
O
O
Cl
Cl
O
O
Ph
O
O
O
SCF3
, 91%
SCF3
4s
4t
, 68%
(from polyethylene glycol)
O
O
Br
Cl
O
SCF3
SCF3
c
b
4v
, 91%
4u
, 76%, d. r. = 1:1
(from L-menthol)
a
Reaction conditions: 1 (0.5 mmol), 2a (1.0 equiv), SOCl2 (1.0 equiv), H2O (2.0
equiv) and DIPEA (1.0 equiv) in DMF (5.0 mL) at rt for 12 h. Yields are for the
isolated products 4. Diastereoselectivity was determined by 1H NMR and 19F
b
NMR analysis of the crude product. c SOBr2 (1.0 equiv) was used instead of SOCl2.
2 | Chem. Commun., 2020, 00, 1-4
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(a) Gram-scale experiment
or nitro substituents the on meta position of the aromatic ring,
tolerated this trifluoromethylthiolation and were converted
into the corresponding products 4h-i with 93% and 94% yield,
respectively. Also, sterically hindered 2-fluoro substrate 1j
underwent smooth reaction to give 4j in 93% yield. For the
substrates that the aromatic ring having two groups, the
reaction proceeded very well to give the desired products 4k-
m with satisfactory yields (94-97%). Other types of sulfonium
salts such as heteroaryl and fused ring derivatives were
examined under similar conditions. They gave the resulting
products 4n-q in 82-96% yields. Significantly, success of this
transformation was further extended to aliphatic ketone and
ester sulfonium salts (4r-s, 81-91% yields). Particularly, the
synthetic utility of the current process was investigated
through the functionalization of sulfonium salts 1t-u bearing
polyethylene glycol (PEG) and L-menthol moieties. The
expected chloro-trifluoromethylthiolated products 4t-u could
be achieved in an acceptable isolated yield. It is noteworthy
that the bromo-trifluoromethylthiolation also performed well
under the same reaction conditions by employing SOBr2 as the
halogen source (4v, 91% yield).
View Article Online
O
DOI: 10.1039/D0CC03171B
H2O (2.0 equiv)
O
Ph
S
O
SOCl
2 (1.0 equiv)
Cl
SCF3
+
N
Ph
Ph
Ph
DIPEA (1.0 equiv)
DMF, rt, Ar, 12 h
BF4
, 4 mmol, 1.57 g
SCF3
O
1ac
2a
4a
, 1.0 g, 98%
(b) Synthetic transformations of products
O
S
NaOH
MeOH/H2O
SCF3
O
Me
Me
6
, 99%
Cl
rt, 24 h
S
4
OH
SCF3
Me
Cl
S
NaBH4
5b
4
EtOH, 0 o
1 h
C
SCF3
, 82%
7
Scheme 2 Gram-scale experiment and further transformations.
the results are depicted in Table 3. Various sulfonium salts
with different substituents such as hydrogen, methyl, methoxy,
fluoro, chloro, bromo, or trifluoromethyl at the aryl ring
worked efficiently to produce the corresponding products in
good yields (5a-n, 61-91%). Naphthyl and heteroaryl
derivatives 5o-r were also obtained in high yields. Remarkably,
the substrate derived from aliphatic ketone or ester was
completely compatible with the current reaction system (5s-t,
92-93% yields). When Me3SiBr was used instead of SOCl2, the
resulting brominated product 5u was formed in 69% yield.
Similarly, dimethyl sulfide derived sulfonium salt 1aa was
employed as a substrate, furnishing the corresponding product
5v with a methylthio moiety.
To further demonstrate the scalability of the present chloro-
trifluoromethylthiolation, a gram-scale reaction of 1ac was
conducted. The reaction occurred smoothly under the
standard conditions, leading to the formation of 4a in 98%
yield (Scheme 2a). Subsequently, treatment of 5b with sodium
hydroxide in a mixture solvent of MeOH and H2O, a
disubstituted sulfur ylide 6 was observed in 99% yield. The
carbonyl group of 5b readily underwent reduction by NaBH4 to
generate the only cis- configured alcohol 7 (Scheme 2b).
Subsequently, the scope of the halo-trifluoromethylthio-
lation involving ring opening of cyclic thioether was evaluated
with the above mentioned conditions (Table 1, entry 14), and
Table 3 Substrate scope for the halo-trifluoromethylthiolation of sulfur ylides involving
ring opening of cyclic thioethera
H2O (2.0 equiv)
LiCl (10.0 equiv)
O
O
O
SOCl2 (2.0 equiv)
S
S
Cl/Br
4
SCF3
N
+
R
R
DIPEA (1.0 equiv)
NMP, rt, Ar, 12 h
Br
SCF3
O
3
2a
5
O
O
O
5a
, R' = H, 82%
5b
, R' = Me, 79%
Cl
4
Cl
4
S
R'
S
5c
, R' = OMe, 78%
SCF3
SCF3
5d
5e
5f
, R' = Cl, 68%
, R' = Br, 75%
, R' = CF3, 61%
R'
5g
5h
, R' = Me, 86%
, R' = Cl, 58%
O
5i
5j
, R' = Me, 91%
, R' = Cl, 71%
Cl
4
Cl
4
S
O
S
On the basis of above experimental results, a potential
mechanistic course for the difunctionalization of sulfur ylides
was presented (Scheme 3). First, upon a deprotonation with
iPr2NEt, the sulfonium salt substrate would be converted to
the corresponding sulfur ylide in situ, which reacts with an
electrophilic SCF3 reagent 2a and SOCl2, delivering the α-SCF3
substituted sulfonium vinyl chlorosulfite intermediate A. Then,
the vinyl chlorosulfite unit was hydrolyzed by water to produce
the carbonyl sulfonium intermediate B, which forms
corresponding disubstituted product 4a through a nucleophilic
substitution reaction with chloride anion for the aryl sulfonium
(where R1 =R2 = phenyl). For the alkyl sulfonium [where R1, R2=
-(CH2)4- ], with an excessive amount of lithium chloride, the
SCF3
SCF3
5k
, R' = F, 64%
R'
O
O
5l
, 88%
O
O
Cl
4
Cl
Cl
4
Cl
Cl
S
S
S
R'
4
SCF3
SCF3
SCF3
O
F
5m
5o
5p
, 61%
5n
, 80%
, R' = 1-naphthyl, 96%
, R' = 2-naphthyl, 79%
O
O
O
Cl
4
Cl
Cl
4
S
S
S
4
SCF3
SCF3
SCF3
, 93%
O
5q
S
5r
5s
5v
, 80%
, 91%
O
O
O
Cl
4
Br
S
S
S
Ph
O
4
metal enolate intermediate
C could be obtained after
SCF3
SCF3
SCF3
b
c
hydrolysis of intermediate A. Subsequently, the attack of
chloride ion on the thienyl ring of intermediate C results in the
ring opening of five-membered episulfide and the formation of
chloroalkylthio product 5a.
5t
5u
, 69%
, 92%
, 80%
a
Reaction conditions: 3 (0.5 mmol), 2a (1.0 equiv), SOCl2 (2.0 equiv), H2O (2.0
equiv), LiCl (10.0 equiv) and DIPEA (1.0 equiv) in DMF (5.0 mL) at rt for 12 h.
Yields are for the isolated products 5. b Me3SiBr (2.5 equiv) was used instead of
SOCl2. c 1aa was employed as the substrate.
In summary, we have developed a novel and regioselective
This journal is © The Royal Society of Chemistry 20xx
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O
Liang, J. Ji, J. Luo and X. Zhao, J. Am. Chem. SocVi.e,w2A0rt1ic8le,O1n4lin0e,
4782-4786.
S
R2
S
7
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2017, 19, 3434-3437.
O
R2
S
O
R2
S
Cl
O
DIPEA
-HY
2a
SOCl2
R1
Ph
R1
Ph
R1
Ph
Y
SCF3
Cl
Y = Br/BF4
A
O
O
Ph
O
R1, R2 = Ph
Cl
S
Ph
Ph
Ph
Ph
SCF3
SCF3
Cl
H2O
B
4a
8
9
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Zhao, Org. Lett., 2017, 19, 4940-4943.
LiLn
hydrolysis
O
LiCl
R1, R2 = -(CH2)4-
H2O
Cl
4
S
S
Ph
Cl
SCF3
SCF3
C
5a
Scheme 3 Plausible mechanism
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1,1-difunctionalized chloro- and bromo-trifluoromethylthio-
lation of sulfur ylides with nucleophilic halide reagent (SOX2)
and electrophilic SCF3 reagent, a protocol that previously
posed a formidable challenge. This transformation provides a
straight-forward and efficient strategy for the divergent
preparation of various α-SCF3 halogens and α-SCF3
haloalkylthioethers in
a one-pot operation from readily
available starting materials, and is easy to scale up as well as
well-suited for the late-stage modification of bioactive
molecules.
This work was supported by The National Key Research and
Development Program of China (grant No. 2016YFC1304704
and 2018YFA0704000), and The Key Research Program of
Frontier Sciences, CAS (QYZDY-SSW-SLH018).
Conflicts of interest
There are no conflicts to declare.
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Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/D0CC03171B
Practical and regioselective halo-trifluoromethylthiolation
of sulfur ylides
Hongmei Qin, Yimin Jia, Na Wang, Zhong-Xing Jiang and Zhigang Yang*
Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, School
of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
Graphical Abstract
A regioselective trifluoromethylthiolation based on 1,1-difunctionalization of sulfur ylides has been
developed for the preparation of Cl/Br-containing trifluoromethylthiolated derivatives.
O
O
R2
S
O
H2O
SCF SOX
H2O, LiCl
Cl/Br
SCF3
Cl/Br
4
S
R
R
R1
R
SCF SOX
[
3],
[
3],
2
2
Y
SCF3
R1, R2 = -(CH2)4-
44 examples
transition-metal free
high regioselectivity
important and diverse
1