Carbosulfenylation of Alkenes with Organozinc Reagents and Dimethyl(methylthio)sulfonium Trifluoromethanesulfonate

Article abstract of DOI:10.1021/acs.orglett.0c03810

The electrophilic alkylthiolation of alkenes, initiated by dimethyl(methylthio)sulfonium salts and the subsequent addition of various heteronucleophilies has been well-established. Regarding the use of carbon nucleophiles, however, only carefully designed sp-type carbon sources have been successfully applied. We herein present our findings on the methylthiolation of alkenes with dimethyl(methylthio)sulfonium trifluoromethanesulfonate, followed by carbon-carbon bond formation in the presence of organozinc reagents, thus achieving a catalyst-free protocol toward to the carbosulfenylation of alkenes.

Full text of DOI:10.1021/acs.orglett.0c03810

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Letter
Carbosulfenylation of Alkenes with Organozinc Reagents and
Dimethyl(methylthio)sulfonium Trifluoromethanesulfonate
Meizhong Tang, Shuxiong Han, Shenglan Huang, Shenlin Huang, and Lan-Gui Xie*
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ABSTRACT: The electrophilic alkylthiolation of alkenes, initiated by dimethyl(methylthio)sulfonium salts and the subsequent
addition of various heteronucleophilies has been well-established. Regarding the use of carbon nucleophiles, however, only carefully
designed sp-type carbon sources have been successfully applied. We herein present our findings on the methylthiolation of alkenes
with dimethyl(methylthio)sulfonium trifluoromethanesulfonate, followed by carbon−carbon bond formation in the presence of
organozinc reagents, thus achieving a catalyst-free protocol toward to the carbosulfenylation of alkenes.
Scheme 1. State of the Art and Proposed Strategy
imethyl(methylthio)sulfonium trifluoromethanesulfonate
D(DMTSM) and dimethyl(methylthio)sulfonium tetra-
fluoroborate (DMTSF)1 are readily available, crystallizable,
and easily handled electrophilic thiolating reagents. Their
applications in the direct alkylthiolation of various nucleo-
philes,2 initiation of dithioacetals to undergo the formation of
thionium ion induced carbon−carbon bonds,3 and macro-
cyclization4 have been studied. Thioglycosides5 and peptides6
have also been found to undertake important conversions with
DMTSM or DMTSF as the activator. Pioneered by the group
of Trost, the electrophilic thiolation of alkenes and subsequent
nucleophilic addition represents the most attractive application
of these two dimethyl(methylthio)sulfonium salts in synthetic
chemistry, because alkenes are commonly found in synthetic
intermediates and industrial feedstocks. A vast scope of
heteronucleophiles has been explored in this context, leading
to the development of azasulfenylation,7 oxy(oxo)-
sulfenylation,8 fluorosulfenylation,9 and other sulfenofunction-
alizations10 of various alkenes (see Scheme 1A). Conceptually,
in the presence of 1, alkenes would deliver an equilibrium of
active episulfonium ion I and sluggish thiosulfonium ion II. By
submitting to the reported heteronucleophiles, intermediate
thiosulfonium ion II can be persuaded to the conversion of its
episulfonium analogue I prior to the formation of carbon-
hetero bonds. Whereas, a typical nucleophilic carbon reagent
with stronger basicity could result in fast decomposition of
sulfonium salt II, thus excises anticipated carbon−carbon bond
formation.11 As a consequence, most of the typical carbon
nucleophiles have proved problematic to undergo the
carbosulfenylation of alkenes initiated by DMTSF or
DMTSM. Two successful examplescyanosulfenylization
and alkynylsulfenylization (Scheme 1B)have been reported
Received: November 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03810
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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by Trost group,8a,11a both by employing sp carbon
nucleophilescyanide and alkynylalaneate (prepared by the
reaction of alkynyl lithium with triethylaluminum). The key to
the success was interpreted as that these carbon nucleophiles
were of low basicity, which allowed the conversion of
intermediate II to I. Recent studies involving episulfonium
ion intermediates12 have introduced asymmetrical sulfeno-
functionalization of alkenes,13 leading to the prosperity of
imaginative protocols. However, a directly carbosulfenylation
of alkenes with different types of carbon sources, initiated by
dimethyl(methylthio)sulfonium salt, would still find academic
significance and synthetic utility.
Organozinc reagents have been wildly used as general
nucleophilic partners in reactions of carbon−carbon bond
formation and are readily available in laboratory synthesis.14
They have been found to possess lower basicity and excellent
functional group tolerability, because of the relatively covalent
carbon−zinc bond, in comparison with main group carbon−
metal bonds such as carbon−lithium and carbon−magnesi-
um.15 Although they generally were sluggish to undergo
uncatalyzed reactions, they have been reported to react with a
few reactive electrophiles, such as halogens, halonium ions, and
phosphine chlorides.16 Furthermore, magnesium salts have
been demonstrated to promote the reactions of organozinc
reagents and electrophilic carbon partners in a catalyst-free
fashion.17 We envision that magnesium salts would possibly be
able to drive the equilibrium previously discussed to the
episulfonium ion I by a strong coordination with dimethylth-
ioether, thereby facilitating the successive carbon−carbon
bond formation upon the addition of an organozinc reagent to
the active intermediate I (Scheme 1C). Herein, we report the
reaction that enables the access to sulfenyl carbon−carbon
bond formation of various alkenes, by the addition of
organozinc reagents in the presence of magnesium salt, with
DMTSM as the activator.
We chose the sulfenyl arylation of 2-vinylnaphthalene 2a as a
model reaction and selected DMTSM (1) for the step of
sulfonium ion generation. Quantitative conversion of alkene
was observed by thin-layer chromatography (TLC), 3 h after
mixing 2a and slightly excess DMTSM in dichloromethane
(DCM, 0.05 M) at ambient temperature. Successive addition
of 1.5 equiv PhZnCl·MgCl2 (3a) in THF (0.45 M, prepared
from stoichiometric phenyl magnesium chloride and zinc
chloride) to the reaction mixture afforded the sulfenyl arylated
product 4aa in very promising isolated yield (80%) after flash
column chromatography (Table 1, entry 1). Satisfactory yield
(89%) of 4aa was obtained by increasing the chemical amount
of organozinc and magnesium salt complex to 2.0 equiv.
Further excess of 3a (Table 1, entry 3) or slightly concentrated
sulfonium ion intermediate (Table 1, entry 4) provided
relatively lower yields. A diminished yield (48%) of target
compound 4aa was obtained when 1.0 equiv of LiCl was
employed as an additive (Table 1, entry 5). Whereas, only a
trace amount of 4aa could be detected when phenyl zinc
chloride prepared from phenyl lithium and zinc dichloride was
applied (Table 1, entry 6), which was believed to be consistent
with our suspect, that the magnesium salt could drive the
equilibrium previously discussed to the formation of active
intermediate I via the complexation with dimethylthioether,
thus facilitating the formation of anticipated product 4aa.
Replacing DCM with dichloroethane (DCE) or polar solvents,
including tetrahydrofuran (THF), acetonitrile (MeCN),
CH3NO2, and N-methyl-2-pyrrolidone (NMP), leading to
a
Table 1. Optimization of the Conditions
b
entry
solvent
CH2Cl2
concentration (M)
X
yield (%)
1
2
3
4
0.05
0.05
0.05
0.1
1.5
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
71
89
50
80
48
trace
65
41
26
trace
26
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
THF
CH3CN
CH3NO2
NMP
c
5
d
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
6
7
8
9
10
11
e
12
CH2Cl2
CH2Cl2
CH2Cl2
trace
trace
trace
f
13
g
14
a
Standard conditions: alkene 2a 0.27 mmol, DMTSM 1 0.3 mmol,
solvent 5 mL, PhZnCl 3a 0.54 mmol (1.2 mL, 0.45 M in THF).
Isolated yields are given. 1.0 equiv of LiCl was added with 3a.
PhZnCl was prepared from PhLi and ZnCl2; 5 mol % Pd(PPh3)2Cl2
was added immediately after the addition of phenyl zinc chloride
solution. 5 mol % CuI was added immediately after the addition of
phenyl zinc chloride solution. 5 mol % Ni(acac)2 was added
immediately after the addition of phenyl zinc chloride solution.
b
c
d
e
f
g
lower yields (Table 1, entries 7−11). Note that attempts to
employ Pd(PPh3)2Cl2, CuI, and Ni(acac)2 as transition-metal
catalysts for the stage of carbon−carbon bond formation led to
the absence of anticipated product (Table 1, entries 12−14).
With optimized conditions in hand, we then examined the
scope of alkenes for this protocol of aryl sulfenylation reaction.
As shown in Scheme 2, a broad range of styrenes was able to
deliver desired sulfide products. Both substituted naphthalene
and phenyl rings were applicable to the reaction conditions
(4aa−4ea). Styrenes with ortho-, meta-, para-alkyl or aryl
groups were all good substrates for this protocol (4fa−4ja).
Note that the tolerance of chloride, bromide, and iodide, as
well as pinocol boronate ester, on the rings of styrenes
indicated the compatibility with the well-developed transition-
metal-catalyzed cross-coupling reactions of this methodology
(4ka−4na), establishing its synthetic potential in the
construction of thio-derived building blocks. Fluorine-contain-
ing styrenes were also amenable, affording the corresponding
sulfenoarylated products in good yields (4oa−4qa). Interest-
ingly, small-ring-containing styrenes were viable partners to
this transformation with moderate to good yields of the
corresponding products obtained (4sa−4ua). Substituted
carbon−carbon multiple bonds were able to be delivered to
the target products under the standard conditions (4va and
4wa). Disubstituted styrene (indene) also smoothly underwent
aryl sulfenylation under these conditions, delivering a
moderate yield of product 4xa. A trans conformation of 4xa
was evidenced by the X-ray diffraction analysis of its
corresponding sulfone derivative (see the Supporting In-
formation for details). Ferrocene-derived sulfide compound
4ya was obtained when vinyl ferrocene was applied to this
method. The possibility of applying estrone-derived styrene,
furnishing the corresponding methylthio compound 4za in
70% yield, further highlighted the generality of this protocol by
B
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a
a
Scheme 2. Scope with Respect to Alkenes
Scheme 3. Scope with Respect to Arylzinc Reagents
a
Standard conditions: alkene 2, 0.27 mmol; DMTSM 1, 0.3 mmol;
CH2Cl2, 5 mL; PhZnCl 3a, 0.54 mmol (1.2 mL, 0.45 M in THF).
Isolated yields are given. Bpin = pinacol boronate.
tolerating a relatively more polar CO double bond. Arylated
sulfide product was not found when α-methylstyrene was
applied in this protocol, indicating that the carbon−carbon
bond formation might be sensitive to steric hindrance. In
addition, allylbenzene, cyclohexene, and cyclododecene were
proved unsuccessful to undergo this conversion under the
standard conditions. Note that this approach of carbosulfeny-
lation showed excellent selectivity, with the formal Markovni-
kov addition being predominant.
a
Standard conditions: alkene 2a, 0.27 mmol; DMTSM 1, 0.3 mmol;
CH2Cl2, 5 mL; and RZnCl 3, 0.54 mmol (1.2 mL, 0.45 M in THF).
Isolated yields are given.
Scheme 3 depicts the scope of the sulfenyl arylation reaction,
with respect to the scope of arylzinc reagents. Both
naphthalene and toluene ring-derived zinc compounds were
amenable, providing sulfide products in good yields (4ab and
4ac). Very bulky units also were able to be delivered into the
anticipated product (4ad). Electron-rich aryl zinc reagents,
methoxyl- and N,N-dimethylamino-phenyl zinc chlorides, all
furnished the target thioethers in reasonable yields (4ae−4ah).
Protected phenol and diphenol derived products were ready to
be synthesized under the standard conditions (4ai and 4aj).
Potential Hiyama cross-coupling thio-containing partner 4ak
could be prepared by using trimethylsilane (TMS)-substituted
arylzinc chloride. Chloride and bromide functionalities were
also able to be delivered from the aryl zinc nucleophiles (4al−
4an). Fluorine-containing arylzinc reagents were suitable
reaction partners for this protocol (4ao−4aq). Ethylene-
glycol-protected aldehyde-derived aryl zinc was also applicable
and provided the corresponding sulfide product in syntheti-
cally useful yield (4ar). Excellent yield (90%) of carbosulfeny-
lated product (4as) was obtained when furan-derived organo-
zinc was subjected to the standard conditions. As it is well-
known that functionalized organozinc reagents can be readily
prepared by Mg/I exchange and the following metathesis
reaction with zinc dichloride,18 we then prepared arylzinc
chlorides derived from norbornene, α-D-glucofuranose and
cholesterol derivatives using the Knochel procedure, and we
were delighted to find that they all reacted with the sulfonium
ion intermediate smoothly, furnishing the anticipated struc-
tures in satisfactory yields (4at−4av). However, attempts to
apply electron-deficient hetero arylzincs, pyrazin-2-ylzinc
chloride, and pyridin-2-ylzinc chloride to this method led to
no anticipated products detected.
Encouraged by the excellent reactivity of the sulfonium ion
intermediate toward arylzinc reagents, we then tried to apply
several other types of organozinc reagents in this sequence (see
Scheme 3, 4aw−4az′). Another typical sp2 carbon nucleophile,
vinyl zinc chloride, behaved similar to its phenyl analogues,
affording arylvinyl thioether product 4aw in 60% yield.
Relatively stable acetylenyl zinc chloride was also proven
compatible with our standard conditions (4ax). The allylzinc
reagent underwent this transformation smoothly, delivering the
target product 4ay in good yield. Relatively lower yields of
anticipated products were detected when alkyl zinc nucleo-
philes, benzyl zinc chloride and ethyl zinc chloride, were
subjected to the standard conditions (4az and 4az′).
Competitive product S4az (see the Supporting Information),
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which arose from the dimethylthiolation of 2-vinylnaphthalene,
could be isolated from these two reactions.
Moreover, performing the reaction in gram scale facilitated
the synthesis of target compound 4aa in 84% yield (Scheme
4A). The synthetic utility of our sulfide product was then
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03810.
■
sı
Experimental details, characterization data, and spectra
(PDF)
a
Scheme 4. Synthetic Applications
Accession Codes
CCDC 2033474 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Lan-Gui Xie − School of Chemistry and Materials Science,
Jiangsu Collaborative Innovation Center of Biomedical
Functional Materials, Nanjing Normal University, Nanjing
210023, People’s Republic of China; orcid.org/0000-
0001-9577-9704; Email: xielg@njnu.edu.cn
a
Authors
(A) Compound 4aa can be prepared in gram scale (transformations
of compound 4aa are shown); (B) palladium-catalyzed cross-coupling
of 4la with 4-tolylboronic acid.
Meizhong Tang − School of Chemistry and Materials Science,
Jiangsu Collaborative Innovation Center of Biomedical
Functional Materials, Nanjing Normal University, Nanjing
210023, People’s Republic of China
Shuxiong Han − School of Chemistry and Materials Science,
Jiangsu Collaborative Innovation Center of Biomedical
Functional Materials, Nanjing Normal University, Nanjing
210023, People’s Republic of China
Shenglan Huang − School of Chemistry and Materials Science,
Jiangsu Collaborative Innovation Center of Biomedical
Functional Materials, Nanjing Normal University, Nanjing
210023, People’s Republic of China
Shenlin Huang − Jiangsu Co-Innovation Center of Efficient
Processing and Utilization of Forest Resources, College of
Chemical Engineering, Nanjing Forestry University, Nanjing
210037, People’s Republic of China; orcid.org/0000-
0001-7322-6981
outlined by the transformations of product 4aa. Treated with
(diacetoxyiodo)benzene and ammonium carbonate in meth-
anol, 4aa was converted to the corresponding sulfoximine 5 in
excellent yield.19 N-cyano sulfilimine 6 could be readily
prepared by an imination procedure with cyanogen amine in
the presence of PhI(OAc)2.20 Subjecting 4aa to the mixture of
Raney-Ni in ethanol led to the removal of sulfide residue,
providing 1,1-diarylethane product 7 in excellent yield. The
methylthio derivative could be readily oxidized by stoichio-
metric meta-chloroperoxybenzoic acid (m-CPBA), delivering
the corresponding methylsulfoxyl analogues, in which the
methylsulfoxyl group is easily removed by elevating the
temperature of its solution in DMF, with 1,1-diarylethylene 8
as the product. Furthermore, a palladium-catalyzed cross-
coupling of our sulfide product 4la with tolylboronic acid was
conducted,21 leading to the synthesis of biaryl sulfide
compound 9 in 83% yield (Scheme 4, B). These nice
derivations of sulfide product illustrated the versatility and
possible power in laboratory syntheses of the protocol
presented herein.
In summary, a reaction of catalyst-free sulfenyl carbon−
carbon bond formation on alkenes has been developed, by
employing DMTSM as the initiator at the activation stage.
Benefiting from the strategic application of readily available
organozinc reagents as the nucleophilic carbon sources, this
process shows excellent practicality and generality by tolerating
the large scope of functional groups within both alkene and
organozinc partners. We believe that this simple and modular
methodology should find many adoptions in synthetic
chemistry.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03810
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Jiangsu Specially Appointed Professor
Plan, National Natural Science Foundation of China (No.
21901123) and Natural Science Foundation of Jiangsu
Province (No. BK20190694).
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