Cu(II)-mediated methylthiolation of aryl C-H bonds with DMSO

Article abstract of DOI:10.1021/ol100449c

(Figure Presented) An unprecedented Cu(II)-mediated methylthiolation of aryl C-H bonds under oxidative conditions that employs the widely available DMSO as the methylthiolation reagent is described. Various functional groups in the substrates were tolerat

Full text of DOI:10.1021/ol100449c

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1644-1647
Cu(II)-Mediated Methylthiolation of Aryl
C-H Bonds with DMSO
Lingling Chu,† Xuyi Yue,† 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 February 23, 2010
ABSTRACT
An unprecedented Cu(II)-mediated methylthiolation of aryl C-H bonds under oxidative conditions that employs the widely available DMSO as
the methylthiolation reagent is described. Various functional groups in the substrates were tolerated, and ethylthiolation was also successfully
achieved directly from diethyl sulfoxide under the same reaction conditions.
Aryl sulfides are indispensable in many fields of biology and
material sciences, especially in the pharmaceutical area.1
Among them, aryl methyl thioethers are important com-
pounds with biological activities or skeletons that lead to
biologically active compounds.2 The classic method for
preparing aryl methyl thioethers directly from aromatics
usually consists of directed or heteroatom-facilitated lithiation
and subsequent electrophilic substitution with dimethyl
disulfide (Scheme 1).3 A multistep transformation has also
been reported, that is, chlorosulfonylation of electron-rich
aromatics using chlorosulfonic acid followed by reduction
with zinc powder and 30% HCl and then S-methylation with
MeI (Scheme 1).2c These methods have become common
and reliable methods in application, although the limitation
of their harsh or multistep reaction conditions could be
inevitable.2c,3 Although carbon-sulfur bond formation via
the cross-coupling reaction of thiols and aryl halides or vinyl
halides catalyzed by the transition metals has recently gained
significant developments,4 no example for preparation of aryl
methyl thioethers in this fashion has appeared so far.
Recently, the development of selective functionalization of
C-H bonds catalyzed by transition metals combining with
directing groups has witnessed tremendous progress.5 Among
the transition metals, copper is particularly attractive for C-H
bond activation because of its low cost and low toxicity.6
Scheme 1. Traditional Methods versus Our Method
However, the formation of a C-S bond through transition-
metal-mediated C-H functionalization has been less fruitful.7
To our knowledge, only Yu reported Cu(OAc)2-catalyzed
thioetherification of the C-H bond of 2-phenylpyridine with
PhSH and MeSSMe using O2 as the oxidant.7a Doi and Batey
independently described the palladium-catalyzed synthesis of
2-substituted benzothiazoles from thiobenzanilides via C-H
functionalization/intramolecular C-S bond formation,7b-d and
Dong disclosed a Pd-catalyzed C-H bond activation/
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
10.1021/ol100449c  2010 American Chemical Society
Published on Web 03/11/2010

coupling with ArSO2Cl to produce sulfones.7e Described
herein is the unprecedented Cu(II)-mediated methylthiolation
of aryl C-H bonds under oxidative condition that employs
the widely available DMSO as the methylthiolation reagent.
Scheme 2. Methylthiolation of Aryl C-H Bond Found
Accidentally
This new reaction was accidentally found during the course
of our recent investigation on Cu(II)-mediated trifluorom-
ethylation of an aryl C-H bond in the presence of an oxidant.
Upon treatment of 2-phenylpyridine 1 with CuF2 (1 equiv),
K2S2O8 (2 equiv), and CF3SiMe3 (2 equiv) in DMSO at 125
°C for 72 h, it was surprisingly found that only the
methylthiolation of aryl C-H bond product 1a was formed
in 14% yield determined by GC (Scheme 2). This result
showed that DMSO was used as methylthiolation agent in
the C-S bond formation which is rare and attractive.8
Intrigued by this experimental observation, we decided to
optimize the conditions of methylthiolation. A screening of
the catalysts showed copper salts profoundly affected the
reaction outcomes. CuF2 was infinitely superior to other
copper salts (Cu(OTf)2, Cu(OAc)2, CuCl2, and CuBr2) as no
product was observed with the latter four catalysts (Table 1,
entries 1-5). Considering the organic sulfur compound may
bind to Cu(II) salt which leads to catalyst deactivation,9 an
excess amount of Cu(II) is most likely required. Thus, we
increased the amount of CuF2 from 1 equiv to 4 equiv and
were delighted to find that 1 was almost totally consumed
(entries 5-8). Under the reaction conditions of entry 8, the
GC-MS analysis of the reaction mixture showed that the
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Org. Lett., Vol. 12, No. 7, 2010
1645

Table 1. Optimization Studies for Cu-Mediated C-H
Table 2. Cu(II)-Mediated C-H Methylthiolation of Aryl C-H
Bonds
Methylthiolationa
Cu(II)
(equiv)
oxidant
(2 equiv)
convnb
(%)
yield of 1ab
entry
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cu(OTf)2 (1)
Cu(OAc)2 (1)
CuCl2 (1)
CuBr2 (1)
CuF2 (1)
CuF2 (2)
CuF2 (3)
CuF2 (4)
CuF2 (4)
CuF2 (4)
CuF2 (4)
CuF2 (4)
CuF2 (4)
CuF2 (4)
No
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
no
O2
CAN
BPO
OXONE
BQ
13
18
25
17
48
59
82
95
29
22
29
38
31
21
11
none
trace
none
none
14
27
59
83
26
12c
21
17
25
trace
K2S2O8
none
a All of the reactions were carried out with 0.4 mmol of 1 in 0.8 mL of
DMSO. b Determined by GC analysis. c The reaction was carried out under
oxygen atmosphere.
desired product 1a was formed in 83% yield along with the
dimethylthiolated product 1a′ (7%), sulfoxide product 1a′′
(3%), dimethyl sulfone ((CH3)2SO2 5%), and dimethyl sulfate
((CH3O)2SO2 10%). Compound 1a′′ and dimethyl sulfone
were produced from the oxidation of 1a and DMSO with
K2S2O8, respectively. Oxidants also highly affected this
reaction. Switching the oxidant from K2S2O8 to no oxidant
or other oxidants, such as oxygen, ammonium cerium(IV)
nitrate (CAN), benzoyl peroxide (BPO), p-benzoquinone
(BQ), and potassium monopersulfate compound (OXONE),
resulted in the incomplete conversion of 1 and a decreased
amount of 1a (entries 9-14). These results further indicated
that the S atom in 1a was transferred from DMSO10 instead
of K2S2O8. No reaction was observed in the absence of
Scheme 3. Proposed Mechanism for the Methylthiolation
a Reaction conditions: substrate (0.4 mmol), K2S2O8 (0.8 mmol), CuF2
(1.6 mmol), DMSO (11.2 mmol), 125 °C for 72 h. b Determined by GC.
c Isolated yield based on conversion. The yield of corresponding dimeth-
ylthiolated product is shown in parentheses and determined by GC-MS of
the reaction mixture. d 4-p-Tolylpyridine (0.4 mmol), K2S2O8 (0.8 mmol),
CuF2 (1.6 mmol), diethyl sulfoxide (11.2 mmol), 125 °C for 72 h.
1646
Org. Lett., Vol. 12, No. 7, 2010

copper salt, indicating that the mediation of Cu(II) is
necessary (entry 15).
sion when the phenyl group bore electron-donating groups
(Table 2, entries 1-11). It should be noted that the
chemoselectivity of 2-(3-(trifluoromethyl)phenyl)pyridine
was different from that of 2-(benzo[d][1,3]dioxol-5-yl)py-
ridine, and we ascribed the chemoselectivity of the former
mainly to steric factors and the latter to electronic effects
(entries 9 and 10). Functional groups such as MeO, F, and
CO2Et were tolerated (entries 3, 4, and 7). The reactions of
2-o-tolylpyridine, 2-phenylquinoline, and benzo[h]quinoline
were very sluggish, and only moderate portion of starting
materials were consumed (entries 8, 12, and 13). We surmise
that the low reactivity is due to the restricted conformation
of these compounds.13 Other directing groups such as
pyrimidine were also effective for aryl C-H methylthiolation
under the optimized conditions, while the yields were lower
than the pyridine counterpart 1 (entry 14). Furthermore, the
ethylthiolation is also successfully achieved directly from
diethyl sulfoxide under the same reaction conditions (entry
15). It was noteworthy that the corresponding dimethylthi-
olated products were also detected by GC-MS of the
reaction mixtures, but the yields were very low for most of
the substrates.
We also conducted a preliminary mechanistic investigation
to gain insight into this novel reaction. It is reasonable to
assume that sulfonium intermediate B would be formed in
this reaction and then one methyl transferred in the presence
of a nucleophile (Scheme 3).8,11 No reaction was observed
in the absence of copper salt, and biphenyl was an ineffective
substrate, suggesting that copper is involved in the reaction
and the coordination of Cu(II) to the N atom of the pyridine
in the substrate promoted the formation of the sulfonium B
with high ortho-selectivity. Two potential pathways led to
intermediate B from the copper complex A. Route A
involved an intramolecular eletrophilic aromatic substitution
and then cleavage of the S-O bond in the assistance of
Cu(II). In route B, a metalacycle could be formed from A
via SEAr and then rearranged to give the intermediated B.12
A subsequent methyl-transfer process promoted by a nu-
cleophile would deliver the methylthiolated product 1a.11
Since a small amount (10% by GC-MS) of dimethyl sulfate
(CH3O)2SO2) was detected (Table 1, entry 8), it is very likely
that one methyl group of sulfonium B was captured by the
sulfate ion generated by the decomposition of K2S2O8.
However, the reaction did not give an appreciable amount
of dimethyl sulfate (it should be 41.5% by GC-MS), and
we surmised that sulfuric acid monomethyl ester and its
corresponding potassium methyl sulfate were also generated
and could not be detected by GC-MS.
In conclusion, this communication highlights the direct
use of DMSO as the reagent for Cu(II)-mediated C-H bond
methylthiolation and the tolerance of various functional
groups in substrates. Compared to the traditional methods
for preparing aryl methyl thioethers, our method is more
direct and convenient.
With a set of optimized conditions in hand, we promptly
examined the scope of the arylpyridine motif in the C-H
methylthiolation process. We found that the 2-phenylpyridine
derivatives bearing either electron-donating or electron-
withdrawing functional groups on the phenyl ring reacted
smoothly to afford the desired monomethylthiolated products
in 54-72% yield, while the reaction afforded higher conver-
Acknowledgment. The National Natural Science Founda-
tion of China is greatly acknowledged for funding this work.
Supporting Information Available: Detailed experimen-
tal procedures and characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) No any MeSSMe or MeSH was detected by LC-MS in our used
DMSO.
OL100449C
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Chem. Soc. 2008, 130, 5858.
Org. Lett., Vol. 12, No. 7, 2010
1647