Investigation of the scope and mechanism of copper catalyzed regioselective methylthiolation of aryl halides Dedicated to Professor Dr. Irina Beletskaya

Article abstract of DOI:10.1016/j.tet.2013.07.039

Methylthiolation of structurally diverse aryl halides was accomplished under fluoride free conditions using catalytic amounts of CuI, and DMSO as the methylthiolation source. Optimization studies unveiled several varieties of promoters among which Zn(OAc)₂ was found ideal. The analogous reaction with DMSO-d₆ afforded corresponding deuterated aryl methyl thioether with 99% purity. Mechanistic studies revealed CuSMe as the active methylthiolation agent.

Full text of DOI:10.1016/j.tet.2013.07.039

Tetrahedron 69 (2013) 8276e8283
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Investigation of the scope and mechanism of copper catalyzed
regioselective methylthiolation of aryl halides
*
P.J. Amal Joseph, S. Priyadarshini, M. Lakshmi Kantam , B. Sreedhar
Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Methylthiolation of structurally diverse aryl halides was accomplished under fluoride free conditions
using catalytic amounts of CuI, and DMSO as the methylthiolation source. Optimization studies unveiled
several varieties of promoters among which Zn(OAc)2 was found ideal. The analogous reaction with
DMSO-d6 afforded corresponding deuterated aryl methyl thioether with 99% purity. Mechanistic studies
revealed CuSMe as the active methylthiolation agent.
Received 9 March 2013
Received in revised form 30 June 2013
Accepted 4 July 2013
Available online 17 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated to Professor Dr. Irina Beletskaya
Keywords:
Methylthiolation
Aryl halides
Aryl sulfides
CuSMe
Catalysis
1. Introduction
methanethiol or toxic dimethyl disulfide; however, their utility is
confined to heteroarene substrates. An important advancement in
Aryl methyl thioethers are ubiquitous structural constituents
that are present in pharmaceuticals and various biologically active
compounds.1 In addition, they are versatile intermediates that can
be converted into sulfoxides,2 thiols and arenes,3 and also finds
application in CeC coupling reactions.4 Straightforward methods
for the synthesis of aryl methyl thioethers include reduction of
sulfoxides,5 reaction of aryl thiols with iodomethane6 and aryl
halides with dimethyl disulfide.7 Multistep processes, such as
lithiation of aryl halide or heteroatom-assisted lithiation of aro-
matic CeH bonds and subsequent electrophilic substitution with
dimethyl disulfide were utilized for their synthesis.8 A direct ortho-
methylthiolation of 2-phenylpyridine with dimethyl disulfide
promoted by copper(II) acetate under air atmosphere has also been
realized.9 Notably, Jiang et al. has reported an important catalytic
process involving the coupling of aryl halide with sulfur in presence
of copper(I)iodide followed by subsequent reduction and reaction
with iodomethane.10
this field is the report by Cheng et al. of CuI catalyzed methyl-
thiolation of aryl iodides and aryl bromides with DMSO using ZnF2
at 150 ꢀC.12 The procedure has the merit of starting from available
or easy to prepare aryl halides. Importantly, their study demon-
strated that the presence of fluoride as a promoter was essential for
the process. Therefore, to ascertain the mechanistic aspects of
methylthiolation and to evaluate the scope of the reaction under
fluoride free conditions; herein, we report a convenient process for
methylthiolation of aryl halides involving CuI and Zn(OAc)2 using
DMSO as the methylthiolation source under comparatively mild
conditions.
2. Results and discussion
The preliminary studies for the methylthiolation of aryl halides
were aimed to find the best promoter. For this, several reactions
were carried out on a 0.5 mmol scale with different promoters
using 4-iodoanisole as the model substrate and 10 mol % of CuI
catalyst in 1.6 mL of DMSO. Selected results of the optimization
studies are tabulated in Table 1, which clearly demonstrate that
fluorides are not essential for accomplishing methylthiolation.
Moreover, these studies prove that acetates, amines and ammo-
nium salts are comparatively better promoters than fluorides.13
Among the promoters screened, good results were obtained with
Recently, DMSO was used as a methylthiolation source for ortho-
methylthiolation of the 2-arylpyridine and CeH thiolation of het-
eroarenes.11 These protocols evade the direct usage of gaseous
* Corresponding author. Tel.: þ91 40 27193510; fax: þ91 40 27160921; e-mail
addresses: mlakshmi@iict.res.in, lkmannepalli@gmail.com (M.L. Kantam).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.039

P.J.A. Joseph et al. / Tetrahedron 69 (2013) 8276e8283
8277
Table 1
Optimization of reaction parameters for methylthiolation of 4-iodoanisolea
Scheme 2. Methylthiolation versus hydroxylation.
Entry
Catalyst
Promoter (equiv)
Yielde/%
result was obtained by employing 10 mol % CuI, 1.5 equiv
Zn(OAc)2 and 1.6 mL DMSO at 135 ꢀC for 24 h (Table 1, entry 28). In
addition, we have also studied the effect of ligands and secondary
additives in altering the reaction outcome. Contrarily, the ligand did
not show any effect on the reactions using Zn(OAc)2 and Cu(OAc)2
as promoters. Nevertheless, some of the interesting combinations
evaluated during the optimization studies are presented in Table S1
(see Supplementary data).
With the above optimized reaction conditions in hand (i.e., Table
1, entry 28), various structurally diverse aryl iodides were tested for
methylthiolation. Electron-rich aryl iodides like 4-iodotoluene, 1-
(tert-butyl)-4-iodobenzene, 1-(benzyloxy)-3-iodobenzene and 4-
iodo-1,10-biphenyl (Table 2, entries 2e4 and 6) underwent the re-
action smoothly to afford the corresponding products in excellent
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
d
NH4F (4)
NH5F2 (4)
4
56
35
80
52
32
10
8
25
Et3N$3HF (4)
Pyrrolidine (4)
Piperidine (4)
Morpholine (4)
N-Methylpyrrolidine (4)
2-Methylpiperidine (4)
ZnF2 (2)
AgF (2)
Cu2O (2)
CuI (2)
Cu(OSO2CF3)(2)
Cu(acac)2(2)
CuOAc (2)
Cu(OAc)2 (1.5)
Zn(OAc)2 (2)
Ni(OAc)2 (2)
Mn(OAc)2 (2)
Zn(OAc)2 (2)
K(OAc) (2)
Ni(OCOCF3)(2)
Zn(OAc)2 (2)
Zn(OAc)2 (2)
Zn(OAc)2 (2)
Zn(OAc)2 (2)
Zn(OAc)2 (1)
Zn(OAc)2 (1.5)
Zn(OAc)2 (2)
Zn(OAc)2 (2)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
27
0
d
0
0
d
d
27b
93
d
d
95
85
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
Cu2O
Cu powder
CuBr2
CuI
CuI
d
48b
74b
95b
5b
Table 2
Copper catalyzed methylthiolation of aryl halides
46b
93b
90b
93b
83b
80b
94b
14b,d
48c,d
Entry
ArX
ArSMe
Yieldf/%
94,a 95b
d
a
Unless otherwise stated, the reactions were performed on a 0.5 mmol scale with
4-iodoanisole (0.5 mmol), catalyst (10 mol %) and promoter (1e4 equiv) in 1.6 mL of
DMSO at 130 ꢀC for 24 h.
2
3
82,a 84b
94,a 93b
b
Temperature¼135 ꢀC.
c
Temperature¼140 ꢀC.
d
Reaction performed in the absence of catalyst.
e
Isolated yield.
pyrrolidine, Cu(OAc)2, Cu(OAc) and Zn(OAc)2. However, pyrrolidine,
Cu(OAc)2 and Cu(OAc) cannot be employed as promoters for
methylthiolation of electron-deficient aryl halides like 4-
iodonitrobenzene, since pyrrolidine exclusively undergoes N-ary-
lation with 4-iodonitrobenzene instead of methylthiolation
(Scheme 1), whereas significant amounts of 4-nitrophenol were
formed when Cu(OAc)2 and Cu(OAc) were used as promoters
(Scheme 2). Thereafter, Zn(OAc)2 was selected as the promoter and
further screening studies were carried out to find the best catalyst.
Notably, comparable results were obtained for most of the copper
salts, although CuI, CuBr and copper powder showed slightly su-
perior yields. Thus as illustrated in Table 1, the most promising
4
5
75a
78a
6
87a
78a
79a,c
78a
80a
7
8
9
10
11
96a
Scheme 1. N-Arylation versus methylthiolation.
(continued on next page)

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P.J.A. Joseph et al. / Tetrahedron 69 (2013) 8276e8283
Table 2 (continued )
heterocycles like bromo-quinolines, pyridines and pyrimidines
(Table 2, entries 20e23). It is significant to note that aryl halides
with sensitive functional groups like CN, COOEt, NMe2, SMe, OMe,
OCH2Ph, OH, CHO, COPh, acetal, CF3 and NO2 tolerated the reaction
conditions to furnish the respective products in good yields. In
contrast, free amino groups did not survive under this protocol as
the reaction of 3-iodoaniline failed to yield the desired product. On
the other hand, the methylthiolation of iodoanilines was accom-
plished in good yields using pyrrolidine as promoter instead of
Zn(OAc)2 (Scheme 3). However, the protocol failed for aryl triflates,
aryl mesylates and both electron-rich and electron-deficient aryl
chlorides.
Entry
ArX
ArSMe
Yieldf/%
84,d 90e
12
13
74d
14
96,d 96e
15
16
78d
83,d 53e
17
18
70d
84d
19
20
21
78d
83d
85d
Scheme 3. Chemoselective methylthiolation of iodoaniline promoted by pyrrolidine.
To explore the mechanism of the methylthiolation reaction,
various studies were carried out using GCeMS and NMR. The va-
pour phase analysis (using GCeMS Headspace) of the reaction
performed under standard conditions using 4-iodoanisole revealed
the presence of significant amount of MeSMe along with compar-
atively smaller amounts of MeSSMe, MeSSSMe, MeSCH2SMe and
MeSCH2CH2OH.14 In a similar way, the corresponding reaction with
DMSO-d6 provided the respective deuterated intermediates and
products. It is noted that for this reaction, no kinetic isotope effect
was observed. To verify whether MeSMe and MeSSMe are the
precursors for methylthiolation of aryl halides, three sets of re-
actions were performed, one with added MeSMe (4 equiv), another
with added MeSSMe (4 equiv) and another blank under standard
conditions using 4-iodoanisole and DMSO-d6 at 135 ꢀC. It is to be
noted that if MeSMe or MeSSMe are the active methylthiolation
agents, good yields and low deuterium incorporation in product
should be obtained. Notably, the yields and the amount of deute-
rium incorporated in the products were of the order, blank (94, 99%
D)>MeSMe (90, 95% D)>MeSSMe (35, 22% D) (Scheme 4 and
Fig. 1).15 Additionally, to check any involvement of the above
mentioned intermediates in their copper coordinated forms, two
more experiments were performed using stoichiometric amounts
of preformed CuI(SMe2)0.75 and CuI[(SMe)2], respectively, in ab-
sence of both catalyst and additive using 4-iodoanisole and DMSO-
d6.16 However, the reaction failed in the former case, whereas poor
yield of product was obtained with the latter. All these results
clearly show that MeSMe, MeSSMe and the aforementioned copper
coordinated species are less likely to be the active methylthiolation
agents in the reaction performed under the standard conditions.
Interestingly, when CuI is heated with Zn(OAc)2 in DMSO at
135 ꢀC for 12 h, a yellow precipitate (intermediate 1) was obtained,
which was practically insoluble in all solvents except in mineral
acids where it decomposes, liberating gas having a sulfurous odour.
This intermediate was characterized using powder XRD, TGAeMS,
22
80d
74d
23
a
Reaction performed with aryl halides (0.5 mmol), CuI (10 mol %) and Zn(OAc)2
(1.5 equiv) in 1.6 mL DMSO at 135 ꢀC for 24 h.
b
Reaction performed with Cu(OAc)2 (1.5 equiv) instead of Zn(OAc)2 and CuI at
130 ꢀC.
c
Reaction performed at 130 ꢀC for 36 h.
Reaction performed with CuI (25 mol %) and Zn(OAc)2 (2 equiv) for 36 h.
Reaction performed with Cu(OAc)2 (2 equiv) instead of Zn(OAc)2 at 135 ꢀC for
d
e
36 h.
f
Isolated yield.
yields. On the other hand the reactions of electron-deficient sub-
strates like 4-iodobenzonitrile, 1-iodo-4-(trifluoromethyl)benzene
and 4-iodonitrobenzene, were rather sluggish at 130 ꢀC. However,
excellent yields were obtained with these substrates albeit at
135 ꢀC (Table 2, entries 9e11). Thereafter, the utility of this protocol
was explored for commercially more attractive aryl bromides as
substrates. Unlike electron-rich aryl iodides, the reactions of their
corresponding bromo-counterparts were rather sluggish at 130 ꢀC.
Notably, several electron-rich and electron-deficient aryl bromides
reacted smoothly at a slightly higher temperature (135 ꢀC) in
presence of 25 mol % CuI catalyst to afford the corresponding
methylthiolation products in good yields (Table 2, entries 12e19). It
is noteworthy that the reaction of 4-bromoiodobenzene proceeded
chemoselectively to afford 4-bromothioanisole in good yields
(Table 2, entry 8). The reaction of sterically hindered 2-iodo-1,3-
dimethoxybenzene also furnished a good yield of product (Table
2, entry 5). The reaction scope was expanded successfully to

P.J.A. Joseph et al. / Tetrahedron 69 (2013) 8276e8283
8279
Fig. 2. XRD pattern: (a) intermediate 1 (identical for intermediate 4 and CuSMe), (b)
intermediate 3 and (c) intermediate 3 isolated after 24 h.
Scheme 4. Isotopic substitution studies for methylthiolation.
Fig. 3. TGA and MS spectra of intermediate 1 (CuSMe).
Fig. 1. 1H NMR spectra of (4-methoxyphenyl)(methyl)-sulfane. Reactions performed
with (a) DMSO-d6; (b) DMSO-d6 and MeSMe; (c) DMSO-d6 and MeSSMe; (d) DMSO-d6
and intermediate 2.
All these characterization data strongly emphasize the in-
termediate 1 to be CuSMe containing trace amounts of polymeric
residue. In a similar way, we have isolated and characterized the
intermediates obtained in the reaction of Cu(OAc)2, Cu(OAc) and
XPS, IR and elemental analysis (see Supplementary data). The XRD
pattern of this compound was identical to that of polymeric
{Cu(CH3Sꢁ)}x reported by Bumgartner et al. (Fig. 2).17 ICP OES and
CHNS analysis of this compound revealed the presence of 54.20% of
copper, 11.05% of carbon, 25.88% of sulfur and 2.52% of hydrogen,
respectively. The remaining content of the sample was assumed to
be oxygen originating from the polymeric residue. TGAeMS anal-
ysis of this compound revealed w25% weight loss between 230 and
320 ꢀC, which can be attributed due to the formation of Cu2S by the
decomposition of CuSMe (Fig. 3), and is in consonance with the m/z
values of 15, 47 and 48 obtained in the mass spectrum corre-
sponding to CH3þ; CH3þ, CH3Sþ and CH3SHþ ion fragments, re-
spectively (Fig. 3). In agreement with the above results, the IR
spectrum of this compound also showed characteristic absorption
peaks at 2958, 2913, 1411, 1299, 934, 682 cmꢁ1 corresponding to
na(CeH), ns(CeH), da(CH3), ds(CH3), r(CH3) and n(SeC), respectively
(see ESD).16c Notably, the binding energy peaks at 933.0 and
952.9 eV found in the XPS spectra correspond to the Cu 2p3/2 and Cu
2p1/2 lines, exemplifying the þ1 oxidation state of copper (Fig. 4).
Fig. 4. XPS spectra of intermediate 1 (CuSMe).

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P.J.A. Joseph et al. / Tetrahedron 69 (2013) 8276e8283
pyrrolidine (namely, intermediate 2, intermediate
3 and in-
termediate 4, respectively) with DMSO at 135 ꢀC for 12 h. Re-
markably, these intermediates resembled the intermediate 1;
however, the presence of small amounts of Cu2O was also con-
firmed in intermediate 2 and intermediate 3 by XRD analysis. The
amount of the Cu2O formed was found to increase with increase in
reaction time and temperature as demonstrated by XRD studies
(Fig. 2). The diffraction peaks at 2q
values of 29.60ꢀ, 36.52ꢀ, 42.44ꢀ,
61.54ꢀ correspond to (110), (111), (200) and (220) crystal planes of
crystalline Cu2O, respectively (JCPDS file no. 05-0667). When
methylthiolation of 4-iodoanisole was carried out with in-
termediate 2 in the absence of catalyst and promoter in DMSO-d6 at
130 ꢀC, excellent yield was obtained for the corresponding meth-
ylthiolation product (97, 17% D, Scheme 4). Remarkably, only very
small amount of deuterium was incorporated into the methyl thi-
oether moiety, specifying the presence of SMe group in the
intermediate.18
Scheme 6. Effect of added base on methylthiolation.
A plausible mechanism for methylthiolation is illustrated in
Scheme 5. Initially, DMSO will be O-activated by Zn(OAc)2 (or any
Lewis Acid), and an a-H of DMSO is abstracted by acetate anion to
form I and acetic acid within the reaction sphere.19e21 This hy-
pothesis is supported by the fact that the methylthiolation of 4-
iodoanisole failed under the standard conditions in presence of
added base (e.g., K2CO3 or K3PO4); see Scheme 6. In addition, the
Scheme 7. Chemoselective phenylthiolation of 4-iodoanisole with methyl phenyl
sulfoxide.
Subsequently, MeSH and HCHO are formed by the isomerization
of II a, followed by the decomposition of II b as depicted in Scheme
5.24e31 It is to be noted that the MeSCH2SMe peak detected in
GCeMS analysis of the reaction mixture (Fig. 5) can be attributed to
the reaction of MeSH with HCHO, which is an indirect evidence
for the formation of the same. Thus, CuSMe is formed by the re-
action of CuI with MeSH,32a and finally aryl halides will react
with CuSMe forming the methylthiolation product.32,33 In addition,
the formation of phenol in the reaction of activated aryl halides
(e.g., 4-iodonitrobenzene) with Cu(OAc)2 or Cu(OAc) can be
accounted considering the mechanistic pathway mentioned in
Scheme 8.32c,d,34 The formation of Cu2O and the intermediate
(methylthio)methyl acetate was confirmed by XRD and GCeMS
analysis, respectively (Figs. 2 and 6).24 In a similar manner, the role
of pyrrolidine as a promoter can be explained considering the hy-
drogen bonding between oxygen of DMSO and N-hydrogen of
pyrrolidine. The hydrogen bonding increases the acidity of methyl
protons of DMSO,35 thus promoting the proton abstraction step by
base (Scheme 9). Accordingly, the reaction will be more efficient for
strong and sterically less hindered bases like pyrrolidine, which is
in consistent with the data presented in Table 1 (entries 4e8).13,36
In an analogous way, we have probed SNAr mechanistic aspect of
methylthiolation, the results of which are tabulated in Table S2 (see
same reaction using diphenyl sulfoxide (which does not have a-H),
failed, whereas with methyl phenyl sulfoxide proceeded chemo-
selectively to furnish the respective phenylthiolation product ex-
clusively in good yield (Scheme 7).22 In succession, formation of II
a occurs through the reaction of acetic acid with I thereby regen-
erating Zn(OAc)2; concentration of the latter was in turn found to
be rather unchanged throughout the course of the reaction as
inferred from NMR analysis (see Supplementary data).23
Fig. 5. EIMS spectra of bis(methylthio)methane (left) and deuterated bis(methylthio)
Scheme 5. Proposed mechanism for methylthiolation.
methane (right).

P.J.A. Joseph et al. / Tetrahedron 69 (2013) 8276e8283
8281
acetal, OCH2Ph, COPh, NO2 etc. were tolerated to afford the re-
spective aryl methyl thioethers in excellent yields. Extensive opti-
mization studies unveiled different promoters that include amines,
ammonium salts and metal acetates besides metal fluorides. Iso-
topic studies showed that the protocol can be successfully
employed for the synthesis of deuterated aryl methyl thioethers in
high purity. The mechanistic studies revealed that irrespective of
the nature of promoters, the active catalyst in this process was
found to be CuSMe, which was isolated and characterized by
employing various techniques.
Scheme 8. Proposed mechanism for hydroxylation.
4. Experimental section
4.1. General remarks
All the chemicals were purchased from either SigmaeAldrich
or Alfa Aesar Company and are used as received. The Thin Layer
Chromatography (TLC) was performed on Merck silica gel 60 F254
plates using diethyl ether and hexane as eluting agents. Purifica-
tion of products was carried out by column chromatography using
silica gel (200e400 mesh) and a mixture of ethyl acetate and
hexane (or diethyl ether and n-pentane) as eluting agent. All
products were characterized by 1H and 13C NMR, and mass spec-
trometry. The NMR spectra of samples were acquired on a Bruker
Avance 300 MHz or Varian Unity Inova 500 MHz spectrometer
using TMS as an internal standard in CDCl3 or DMSO-d6 as solvent.
EIMS and ESI MS spectra were acquired on a Shimadzu QP
2010þGCeMS and Thermo LCQ fleet ion trap mass spectrometer
(ESI MS), respectively. High resolution mass spectra were acquired
using Exactive Orbitrap LCeMS, Thermo Scientific. Elemental
analysis was carried out on an Elementar Vario-EL CHNS analyzer.
Static Headspace GCeMS analysis was performed using 6890 NGC
with 5973 inert MSD, Agilent Technologies. Infrared (IR) absorp-
tion data were acquired on a Thermo Nicolet Nexus 670 FT-IR
spectrometer with DTGS KBr detector. XPS spectra were recor-
Fig. 6. EIMS spectra of (methylthio)methyl acetate (left) and deuterated (methylthio)
methyl acetate (right).
ded on a Kratos AXIS 165 equipped with Mg K
a radiation
(1253.6 eV) at 75 W apparatus using Mg K anode and a hemi
a
spherical analyzer. The C 1s line at 284.6 eV was used as an in-
ternal standard for the correction of binding energies. The X-ray
diffraction (XRD) patterns of intermediates were obtained on
a Rigaku Miniflex X-ray diffractometer using Ni filtered Cu K
a
¼0.15406 nm), at a scan rate of 2ꢀ minꢁ1, with the
Scheme 9. Proposed mechanism for formation of CuSMe using pyrrolidine.
radiation (
l
beam voltage and beam current of 30 kV and 15 mA, respectively.
ICP OES analysis was performed on a Thermo Intrepid XSP DUO
instrument. TGAeMS was performed using 851e Mettler Toledo.
Scanning electron micrograph (SEM EDAX) was acquired on an
SEM Hitachi S520.
Supplementary data). It is important to note that for an SNAr re-
action to proceed, the intermediacy of a thiolate anion is essen-
tial.37 In a standard reaction, MeSSMe and MeSH are two plausible
precursors for the thiolate anion.38 However, the concentration of
these intermediates formed in a standard reaction is low thereby
ruling out the likely involvement of SNAr mechanism in the major
mechanistic pathway of methylthiolation.25 Notably, a reaction
performed with Zn(OAc)2 and 4-iodoanisole in DMSO at 140 ꢀC
furnished the methylthiolation product in moderate yield (Table 1,
entry 30), whereas the analogous reaction of 4-bromoanisole and
4-chloronitrobenzene failed at 140 ꢀC.39,40 These results suggest a
U-bond metathesis type mechanism for the reaction mentioned in
Table 1, entry 30.32,34
4.2. General procedure for methylthiolation of aryl iodides
and aryl bromides listed in Table 2
An oven dried pressure tube was charged with aryl halide
(0.5 mmol), CuI (10e25 mol %), anhydrous Zn(OAc)2 (1.5e2 equiv)
and anhydrous DMSO (1.6 mL). The tube was sealed with a Teflon
screw cap and stirred at 135 ꢀC for 24e36 h. The reaction mixture
was then cooled to room temperature and stirred in 10 mL of
diethyl ether for 5 min. It is filtered through a sintered funnel and
the filtrate is washed with excess ice cold water and further
extracted with diethyl ether (3ꢂ10 mL). The combined organic
extracts were dried over anhydrous Na2SO4, filtered and concen-
trated under reduced pressure to give the crude product, which was
purified by column chromatography using 200e400 mesh silica gel
and a mixture of diethyl ether and hexane (or pentane, for Table 2,
entries 2, 8, 10, 14, 16 and 24) as eluents to afford the desired
products in good yields.
3. Conclusions
In conclusion, a convenient and efficient protocol for the
regioselective methylthiolation of various structurally diverse aryl
halides, such as aryl iodides, aryl bromides and heterocyclic aryl
bromides is demonstrated under fluoride free conditions. Several
sensitive functional groups like NH2, NMe2, OH, CHO, CN, COOEt,

8282
P.J.A. Joseph et al. / Tetrahedron 69 (2013) 8276e8283
9. Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
6790e6791.
10. Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org. Lett. 2009, 11,
5250e5253.
11. (a) Chu, L.; Yue, X.; Qing, F.-L. Org. Lett. 2010, 12, 1644e1647; (b) Dai, C.; Xu, Z.;
Huang, F.; Yu, Z.; Gao, Y.-F. J. Org. Chem. 2012, 77, 4414e4419.
12. Luo, F.; Pan, C.; Li, L.; Chen, F.; Cheng, J. Chem. Commun. 2011, 5304e5306.
13. Poor yields were obtained when promoters like eurotropine, Et2NH, DBU,
DABCO, Et3N, DIPEA, cis-2,6-dimethylpiperidine, N-methylmorpholine-N-oxide,
TEMPO, cyclohexanone, pyridine, AgF2, TBAF, CsF and KF were used, whereas
reaction failed with acetic acid, trimesic acid, triflic anhydride, glycol, iodine,
selectfluorÔ and NH4Cl.
4.2.1. (3-(Benzyloxy)phenyl)(methyl)sulfane(Table 2, entry 4). Rf¼0.72
(1:9 ethyl acetate/hexane); Colourless liquid; IR (KBr):
¼2921, 1585,
1475, 1428, 1379, 1283, 1229, 1165, 1100, 1078, 1024, 855, 768, 738,
692 cmꢁ1 1H NMR (300 MHz, CDCl3):
¼7.54e7.28 (m, 5H),
7.24e7.15 (m,1H), 6.96e6.81 (m, 2H), 6.79e6.70 (m,1H), 5.03 (s, 2H),
2.44 (s, 3H). 13C NMR (75 MHz, CDCl3):
129.58, 128.53, 127.95, 127.44, 118.95, 112.94, 111.25, 69.93, 15.57.
EIMS: m/z 230 [M]þ. Anal. Calcd for C14H14OS: C, 73.01; H, 6.13; S,
13.92. Found: C, 73.09; H, 6.17; S, 13.87.
n
;
d
d
¼159.04, 139.84, 136.74,
14. These intermediates are formed in absence of 4-iodoanisole as well as in ab-
sence of CuI or both.
4.2.2. 4-(4-(Methylthio)phenyl)pyrimidine (Table 2, entry 23). Rf¼0.27
15. Low amount of deuterium incorporation in methylthiolation product for the
reaction employing MeSSMe and DMSO-d6 (Scheme 4) is assumed due to the
thiolateedimethyl disulfide interchange reaction (see Scheme S1 and S2 in
Supplementary data for details). Similarly, the low yield obtained in this re-
action is probably due to saturation of the coordination site of Zn (in Zn(OAc)2)
by excess MeSSMe. For thiolateedimethyl disulfide interchange reaction, see
reference: (a) Bach, R. D.; Dmitrenko, O.; Thorpe, C. J. Org. Chem. 2008, 73,
12e21; (b) Singh, R.; Whitesides, G. M. In Supplement S: the Chemistry of Sul-
phur-containing Functional Groups; Patai, S., Rappoport, Z., Eds.; John Wiley &
Sons: Chichester, UK, 1993; pp 633e658.
16. For the preparation of CuI(SMe2)0.75 and CuI[(SMe)2]; see: (a) House, H. O.; Chu,
C.-Y.; Wilkins, J. M.; Umen, M. J. J. Org. Chem. 1975, 40, 1460e1469; (b) Boorman,
P. M.; Kerr, K. A.; Kydd, R. A.; Moynihan, K. J.; Valentine, K. A. J. Chem. Soc.,
Dalton Trans. 1982, 1401e1405; (c) Miller, B. P.; Li, Z.; Walker, J.; Burkholder, L.;
Tysoe, W. T. Langmuir 2010, 26, 16375e16380.
(3:7 ethyl acetate/hexane); Colourless solid; mp 124 ꢀC; IR (KBr):
n
¼2917, 1576, 1532, 1490, 1460,1388,1313, 1260,1172, 1091, 818, 769,
654, 467 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
¼9.24 (s, 1H), 8.74 (d,
J¼5.3 Hz, 1H), 8.03 (d, J¼8.3 Hz, 2H), 7.71e7.65 (m, 1H), 7.35 (d,
J¼8.3 Hz, 2H), 2.54 (s, 3H). 13C NMR (75 MHz, CDCl3):
¼163.15,
d
159.03, 157.32, 143.05, 132.69, 127.29, 125.96, 116.32, 15.05. ESI MS:
m/z 203 [MþH]þ. HRMS (ESI): m/z calcd for C11H11N2S (MþH):
203.06375; found 203.06364.
Acknowledgements
P.J.A.J. thank UGC, India for the award of fellowship. S.P. thanks
CSIR New Delhi for the award of fellowship. We are grateful to Dr.
U.V.R. Vijaya Sarathi of NCMS division, CSIR-IICT for performing
GCeMS Headspace analysis.
17. Baumgartner, M.; Schmalle, H.; Baerlocher, C. J. Solid State Chem. 1993, 107,
63e75.
18. The intermediate 2 (same case with intermediates 1, 3 & 4) remains initially as
a precipitate in the reaction medium. This precipitate slowly disappears with
the progress of reaction (if taken stoichiometrically), indicating the formation
of
a soluble copper salt (likely CuI). In addition, methylthiolation of 4-
iodoanisole proceeded in toluene as well as in DMF with these intermediates
in the absence of catalyst, additive and DMSO, albeit in poor yield.
19. Calligaris, M.; Carugo, O. Coord. Chem. Rev. 1996, 153, 83e154.
20. The reactions of O-activated DMSO are well known, such as in Moffatt oxida-
tion and Swern oxidation. The final fate of DMSO in these reactions is reduction
to MeSMe.
Supplementary data
Characterization data, 1H and 13C NMR spectra of all the com-
pounds; GCeMS Headspace analysis, TGA, XPS, XRD, HRMS and FT-
IR spectra are provided in the Supplementary data. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2013.07.039.
21. Zn2þ and Cu2þ are good Lewis acids. Zn(OAc)2 is highly soluble in DMSO,
whereas ZnF2 is only slightly soluble in DMSO. The order of solubilities of ac-
etates in DMSO is Zn(OAc)2>Cu(OAc)2wMn(OAc)2>Ni(OAc)2>K(OAc). How-
ever; when compared to acetates, fluorides are more basic and nucleophilic.
22. The GCeMS and NMR analysis of the reaction mixture disclosed the formation
of PhSPh, PhSSPh and PhSMe, and also the absence of methylthiolation
product.
References and notes
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stereochemistry.
32.
A s-bond metathesis type mechanism involving CuSMe and aryl halides is
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39. Zn(OAc)2 used was of 99.99 % purity.
40. Activated substrate like 4-chloronitrobenzene readily undergoes SNAr reactions
with a nucleophile at high temperature. However, here the result is quite dif-
ferent, which clearly rule out an uncatalyzed SNAr mechanistic pathway in-
volving thiolate anion.
33. The addition of a free radical inhibitor (for e.g., TEMPO) did not show any affect
on the reaction outcome, thereby ruling out the possibility of a free radical
mechanism.
34. The mechanism of ipso-hydroxylation is yet not well studied. However, for the
mechanism of CeO coupling; see references: (a) Tye, J. W.; Weng, Z.; Giri, R.;