A mild and highly convenient chemoselective alkylation of thiols using Cs2CO3-TBAI

Article abstract of DOI:10.1016/j.tetlet.2005.10.062

A mild and improved method for the synthesis of thioethers has been developed. In the presence of cesium carbonate, tetrabutylammonium iodide, and DMF, various alkyl and aryl thiols underwent S-alkylation to afford structurally diverse sulfides in high yield. Unprotected mercaptoalcohols and thioamines reacted chemoselectively at the sulfur moiety exclusively. An example of a one-pot, solid-phase synthesis of a thioether is also described.

Full text of DOI:10.1016/j.tetlet.2005.10.062

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8931–8935
A mild and highly convenient chemoselective alkylation of
thiols using Cs2CO3–TBAI
a
a
Ralph Nicholas Salvatore,a,b, Robert A. Smith, Adam K. Nischwitz and
*
Terrence Gavinb
aDepartment of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA 02125-3393, USA
bDepartment of Chemistry, Iona College, 715 North Avenue, New Rochelle, NY 10801-1890, USA
Received 28 June 2005; revised 15 October 2005; accepted 17 October 2005
Available online 4 November 2005
Abstract—A mild and improved method for the synthesis of thioethers has been developed. In the presence of cesium carbonate,
tetrabutylammonium iodide, and DMF, various alkyl and aryl thiols underwent S-alkylation to afford structurally diverse sulfides
in high yield. Unprotected mercaptoalcohols and thioamines reacted chemoselectively at the sulfur moiety exclusively. An example
of a one-pot, solid-phase synthesis of a thioether is also described.
Ó 2005 Elsevier Ltd. All rights reserved.
Thioethers have emerged as preeminent classes of organ-
ic compounds, which hold useful applications as key
reagents in organic synthesis, bio-organic, medicinal,
and heterocyclic chemistry.1 Numerous synthetic meth-
ods exist for the preparation of sulfides,2–7 however,
the classical method of choice is the condensation of a
metal alkyl or aryl thiolate with an alkyl halide in the
presence of a strong base.8 The synthetic scope of this
aforementioned reaction condition is often hampered
by prolonged reaction times, high temperatures, the
use of cumbersome bases and result in low product
yields. In addition, these procedures are often not appli-
cable to the synthesis of sulfides, which contain epimeri-
zable stereocenters. Moreover, side products including
sulfonium salts and disulfides may accompany the corre-
sponding thioether products. During the course of our
synthetic studies toward sulfur heterocycles9 and bioac-
tive compounds such as nelfinavir,10 a potent HIV
protease inhibitor containing the sulfide moiety, the
need for a mild approach for the construction of the
C–S bond that circumvent the common impediments is
clearly warranted.
dures for the formation of a plethora of functional
groups.11 Recently, we disclosed a mild and efficient syn-
thesis of unsymmetrical organoselenides using cesium
bases.12 Building on these successful results, we now
report herein the facile synthesis of thioether 3 by the
chemoselective alkylation of in situgenerated thiolate
anion 2 easily prepared from thiol 1 using cesium car-
bonate (Cs2CO3), tetrabutylammonium iodide (TBAI),
and anhydrous DMF in the presence of various alkyl
halides (Scheme 1).
Initially, the choice of base was examined (Table 1,
entries 1–8). As a representative procedure employed,
1-dodecanethiol (1 mmol) (4) was stirred under nitrogen
atmosphere at room temperature for 1 h in the presence
of a base (1 mmol), TBAI (1 mmol),13 and DMF. The
reaction mixture was subsequently cooled to 0 °C,
methyl iodide (1.1 mmol) was added, and the reaction
mixture was allowed to slowly warm to room tempera-
ture. Of the bases examined, cesium carbonate was far
superior to deliver the odorless dodecyl methyl sulfide
(Dod-S-Me) (5)14 exclusively, in quantitative yield after
Over the past several years, we have reported numerous
chemoselective cesium base-promoted alkylation proce-
Cs
Cs2CO3
R'X
0 oC-rt
R-SH
R-S-R'
R-S
TBAI, DMF,
rt, 1 h
1
2
3
Keywords: Thioethers; Thiols; Alkyl halides; Cesium carbonate; Tetra-
butylammonium iodide.
(R = alkyl, aryl, or alkyl aryl; R' = alkyl)
*
Corresponding author. Tel.: +1 617 2876117; fax: +1 617 2876030;
e-mail: ralph.salvatore@umb.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.062

8932
R. N. Salvatore et al. / Tetrahedron Letters 46 (2005) 8931–8935
Table 1. Synthesis of Dod-S-Me (5) using various bases
Table 3. Alkylation of alkyl thiols and aryl alkyl thiols using various
halides
Base, MeI
TBAI, DMF, 0 oC-rt, 1 h
C12H25SH
C
12H25SMe
Cs2CO3, R'X
4
5
RSR'
RSH
1
TBAI, DMF, 0 oC-rt
3
Entry
Base (1 equiv)
Yield (5) (%)
Entry Thiol (1)
Halide (R0X) Time Yield of
1
2
3
4
5
6
7
8
Li2CO3
Na2CO3
K2CO3
Rb2CO3
Cs2CO3
BaCO3
(NH4)2CO3
Ag2CO3
79
69
82
79
Quant
72
73
(h)
3 (%)a
1
2
(6)
n-BuBr (7)
2
1
93
SH
Br
SH
(9)
Quant
(8)
Ph
3
4
5
6
C11H23SH (10)
(12)
MeI (11)
n-PrI (13)
Br
1
2
Quant
Quant
81
65
Ph
SH
12
1
(14)
(16)
Table 2. Synthesis of Dod-S-Me (5) using various solvents
SH
18
Quant
(15)
I
Cs2CO3, MeI
C12H25SH
C
12H25SMe
TBAI, Solvent,
0 oC-rt, 1 h
a Yields refer to isolated pare products characterized by IR, MS, 1H
and 13C NMR spectroscopic data, and elemental analysis.
4
5
Entry
Solvent
Yield (5) (%)
1
2
3
4
5
6
DMF
Quant
83
83
74
68
ation of thiophenol (17) with crotyl bromide (29) gave
rise to the SN2 product, where the SN20 product was
not detected (entry 9).
DMAC
DMSO
NMP
CH3CN
HMPA
69
After substantiating the generality of the approach, we
then directed our efforts toward the alkylation of aryl
bis-thiols. Dithiols are commonly used as precursors
toward organo-polysulfides, spirans, macrocycles and
serve as efficacious analogs in asenical therapy.16 In
addition, the coordination chemistry of dithiolate li-
gands has also been extensively studied. Keeping this
in mind, we extended the above preliminary results using
various alkyl bromides (2.2 equiv) in the presence of
1 equiv of an arene dithiol (Table 5). As shown in entry
1, benzene-1,2-dithiol (29), underwent S-alkylation
using ethyl bromide (30) as the halide of choice to afford
the corresponding dialkylated 1,2-benzenedithiol com-
pound 31 in excellent yield (90%) after 2 h. Subse-
quently, we developed a slightly modified procedure
for a one-pot, sequential S-alkylation, using two differ-
ent alkyl halides that resulted in the synthesis of func-
tionalized 1,2-benzenedithiol derivatives. For example,
dithiol 29, reacted with 1.1 equiv of EtBr to give the
mono-S-alkylated product with complete consumption
of the starting dithiol (TLC) after 2 h. After stirring
for this time period, additional Cs2CO3 was added
(1 equiv) and allowed to react for another hour. At this
point, a different activated halide, benzyl bromide (21)
was added to generate the unsymmetrical functional-
ized-1,2-benzenedithiol adduct 32 in high yield (entry
2). Following the aforementioned protocol, 4,40-thiobis-
benzenethiol (33) underwent mono-S-methylation
quickly giving rise to 34 (entry 3). However, when MeI
(2.2 equiv) was employed, the symmetrical dimethyl
dithioether 35 product was produced as an
off-white solid in quantitative yield (entry 4).
1 h (entry 5). In addition, the simultaneous formation of
disulfide products stemming from aerial oxidation and
overalkylation was completely mitigated. We attribute
the high yield and excellent chemoselectivity as further
evidence of the ꢀcesium effectꢁ.15
Next, various solvents were then subjected to our S-
alkylation procedures to evaluate the scope and limita-
tions of the reaction. We found that anhydrous DMF
was the solvent of choice, whereas other polar aprotic
solvents were less suitable (Table 2, entries 2–6). With
the optimized conditions in hand, numerous halides
and structurally diverse thiols were examined and found
to be generally applicable to the developed techniques.
As demonstrated in Table 3, various primary aliphatic
bromides and alkyl thiols reacted quickly providing
the unsymmetrical thioethers 3 within 2 h in remarkable
yields (entries 1–5). In turn, a sterically more demanding
secondary halide such as 2-iodopropane (16) offered
similar results, however, longer reaction times were
required for the desired transformation (entry 6). As
expected, tertiary halides were resistant to alkylations
under these conditions.
In addition, our method was highly useful for the prepa-
ration of numerous alkyl aryl thioethers in excellent
yields. For example, thiophenol (17) reacts with 1-bromo-
dodecane (18) producing the requisite thioether in
quantitative yield using our mild Cs2CO3–TBAI method
(Table 4, entry 1). Substituted aromatic thiols bearing
an electron-withdrawing or electron-donating group
also reacted efficiently with a wide array of halides in
outstanding yields (entries 2–8). Furthermore, alkyl-
The chemoselective S-alkylation in the presence of
unprotected reactive functional groups such as mercap-
toalcohols and thioamines also proved successful.
As demonstrated in Scheme 2, 2-mercaptoethanol (36)

R. N. Salvatore et al. / Tetrahedron Letters 46 (2005) 8931–8935
8933
Table 4. Cs2CO3-promoted S-alkylation of aromatic thiols with
halides
symmetrical nitrogen–sulfur–nitrogen (NSN) ligand
precursor 40 cleanly in moderate yield. Notably, in both
examples, protection of the alcohol or the primary
amine proved unnecessary, confirming the high che-
moselectivity of this protocol.
SH
S
Cs2CO3, R'X
R'
TBAI, DMF, 0 oC-rt
R
R
Entry Thiol (ArSH)
Halide (R0X)
Time Yield
(h)
(%)a
At this stage, it was gratifying to note that the chemose-
lective S-alkylation of biologically important molecules
such as ribosides and amino acid derivatives followed
a similar course. As represented in Scheme 3, the cou-
pling of the commercially available 6-mercaptopurine
riboside (41) using benzyl chloride (27) yielded the S-
benzylated-6-purinethiol riboside (42) in 62% yield.
Again, O-alkylation of the primary or secondary alco-
hols was not detected. Recently, an improved method
using NaOMe in MeOH at reflux temperature for the
synthesis of various S-alkylated cysteine derivatives,
which are important pharmacophores in anti-leukemia
drug discovery research.17 In this study, various N-ace-
tyl cysteine analogs underwent efficient S-alkylation un-
der the strongly basic conditions and no racemization
was reported. However, cysteine methyl ester itself was
found to epimerize. Owing to our mild conditions, we
decided to investigate S-alkylation of this substrate as
a direct comparison. Under the disclosed conditions,
L-cysteine methyl esterÆHCl (43) underwent coupling
exclusively at the sulfur moiety to afford S-benzyl cys-
teine methyl ester (44) in moderate yield with accompa-
niment of starting material 43. After purification, a
direct comparison of the optical rotations of the synthe-
sized product with the authentic sample revealed no
racemization or ester hydrolysis had occurred during
the alkylation making our protocol highly attractive.
SH
1
2
C12H25Br (18)
1
Quant
(17)
SH
(19)
11
1
93
H3C
CF3
SH
3
4
BnBr (21)
1
1
85
99
(20)
21
F3C
SH
(22)
t
5
6
7
8
9
1.5
1
97
93
80
88
75
(23) Br
CO2 Bu (24)
MeO
23
SH
Cl
(25)
23
7
2
BnCl (27)
2
)
Br
SH
(26
17
3
(28)
CH2Br
a Yields refer to isolated pure products characterized by IR, MS, 1H
and 13C NMR spectroscopic data, and elemental analysis.
reacted quickly with BnCl (27) giving rise to the
S-benzyl thioether 37. It is important to highlight, that
no ether formation was observed. Furthermore, 2-thio-
ethylamine hydrochloride (38) underwent efficient cou-
pling with 2-bromoethylamineÆHBr (39) generating the
Having fully established the scope and limitations of this
methodology in solution, we next directed our attention
toward a solid-phase synthesis, since this technique is
becoming a standard tool in combinatorial chemistry
and the drug discovery process.18 As illustrated in
Table 5. Alkylation of bis-thiols
Cs2CO3, R'X
TBAI, DMF, 0 oC-rt
ArSH
ArSR'
Entry
1
Dithiol (ArSH)
Conditions
Product (ArSR0)
Time (h)
2
Yield (%)e
90
SH
SEt
(31)
SEt
(30)a
Br
(29)
SH
SEt
(32)
SBn
2
3
4
29
30 then 21b
4.5
1
90
HS
S
SH
11c
11d
85
HS
S
SMe
(34)
(33)
MeS
S
SMe
33
1.5
Quant
(35)
a
2.2 equiv Cs2CO3, 2.2 equiv TBAI, 2.2 equiv EtBr, 0 °C to rt.
b 1 equiv Cs2CO3, 1 equiv TBAI, 1.1 equiv EtBr, Stir 2 h, then add 1 equiv Cs2CO3, 1 equiv TBAI, 1.1 equiv BnBr, Stir 2.5 h, 0 °C to rt.
c 1 equiv Cs2CO3, 1 equiv TBAI, 1.1 equiv MeI, 0 °C to rt.
d 2.2 equiv Cs2CO3, 2.2 equiv TBAI, 2.2 equiv MeI, 0 °C to rt.
e Yields refer to isolated pure products characterized by IR, 1H and 13C NMR spectroscopic data, and elemental analysis.

8934
R. N. Salvatore et al. / Tetrahedron Letters 46 (2005) 8931–8935
Cs2CO3, 27
SBn
SH
HO
HO
TBAI, DMF,
45 min., 0 oC-rt
36
37 (73%)
Br
HBr H N
(39)
Cs2CO3,
2
S
SH
H2N
NH2
HCl H2N
38
TBAI, DMF, 12 h, 0 oC-rt
40 (60%)
Scheme 2.
were circumvented. Exclusive chemoselective S-alkyl-
ation using unprotected mercaptoalcohols and amino-
thiols is a particularly noteworthy feature of this
approach. Finally, the successfully preparation of a sul-
fide on solid support in moderate yield and purity is also
disclosed. Application of this methodology toward the
synthesis of sulfur heterocycles is currently underway.
SBn
N
SH
N
N
N
N
N
Cs2CO3, 27
N
TBAI, DMF,
2.5 h, 0 oC-rt
N
O
O
HO
HO
OH
OH
OH
OH
41
42 (62%)
SBn
SH
Acknowledgments
Cs2CO3, 27
TBAI, DMF,
2 h, 0 oC-rt
H2N
CO2Me
H2N
CO2Me
HCl
Financial support from the NSF-KY EPSCoR grant
#596208 and the NSF Department of Undergraduate
Education through grant #012793 is gratefully acknow-
ledged. In addition, the authors wish to acknowledge
support from the Research Corporation, the University
of Massachusetts Boston, IONA College and Western
Kentucky University. Also, we wish to thank Chemetall
for their generous supply of cesium bases.
43
44 (60%)
Scheme 3.
Supplementary data
Scheme 4.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.10.062.
Scheme 4, using Merrifieldꢁs resin (45) as the solid sup-
port, 1-dodecanethiol (11) was efficiently tethered to
the resin by stirring overnight for 12 h at 60 °C. This
temperature was found to be optimal from our previous
experiments reported for the incorporation of selenides
on solid support.11 After stirring for the time period
mentioned, MeI (11) was injected into the milky white
suspension containing the resin-bound sulfide linkage
and allowed to react for an additional 12 h to generate
methyl dodecyl sulfonium salt (46) in high yield. Subse-
quent detachment of sulfide 5 from the resin was
smoothly accomplished using LAH at room tempera-
ture to afford the requisite crude Dod-S-Me (5) in good
yield and high purity. This product proved to be identi-
cal with that prepared via solution phase synthesis (Ta-
ble 1, entry 5). Further examples and applications of this
solid-phase technique will be reported in due course.
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