Regioselective Mono- and Bis-Sulfenylation of Active Methylene Compounds

Article abstract of DOI:10.1002/ejoc.201501148

Selective mono- and bis-sulfenylation of active methylene groups with a variety of disulfides at an ambient temperature is reported. Sulfenylation is promoted by iodine as a catalyst and sulfenyl iodides as intermediates, under metal-free conditions. The

Full text of DOI:10.1002/ejoc.201501148

DOI: 10.1002/ejoc.201501148
Full Paper
Selective Sulfenylation
Regioselective Mono- and Bis-Sulfenylation of Active Methylene
Compounds
Namita Devi,[a] Rajjakfur Rahaman,[a] Kuladip Sarma,[a] and Pranjit Barman*[a]
Abstract: Selective mono- and bis-sulfenylation of active free conditions. The method is greener in terms of solvent selec-
methylene groups with a variety of disulfides at an ambient tion and the use of less hazardous DMSO as an oxidant. The
temperature is reported. Sulfenylation is promoted by iodine as procedure is highly efficient with readily available starting ma-
a catalyst and sulfenyl iodides as intermediates, under metal- terials, giving good to excellent yields.
Introduction
of mono- and bis-sulfenyl products from active methylene com-
pounds. However, the reactions were often temperature-sensi-
tive, which led to side reactions and poor yields. Moreover, the
claimed[20b] sulfenylation with sulfenamides has also been con-
tradicted.[23] The method of sulfenylation reported by Fujisawa
and co-worker[22a] was a simple one in which a deprotonated
anion attacks a disulfide. Nevertheless, the method was limited
due to the formation of thiols as major byproducts. However,
bis-sulfenylation was possible only for malononitrile and not
applicable to other cases.
C–S bond formation has received considerable interest over the
past few decades, due to the presence of these bonds in com-
pounds of pharmacological and therapeutic value.[1] Diaryl thio-
ethers display a large spectrum of biological activities. Sulfur-
substituted heterocycles such as indole, imidazole, thiazole,
purine and deazapurine[2] have potential applications in the
fields of HIV,[3] breast cancer,[4] diabetes, tubulin polymeriza-
tion,[5] inflammatory effects, tumors[6] and vascular and respira-
tory diseases.[7] Sulfur functionalities are important intermedi-
ates in many synthetically important reactions. α-Sulfenylated
carbonyl compounds promote numerous organic transforma-
tions.[8] The antitumor activity of Myleran is due to the presence
of a sulfonate group. Therefore, the introduction of a sulfonate
and a thiosulfonate group in the active methylene moiety is
highly desirable.[9] All these applications make sulfenylation an
interesting topic in synthetic chemistry that continues to draw
the attention of researchers.[10]
Most sulfur-transfer agents – such as sulfenamides, N-(phen-
ylthio)succinimide, sulfenyl halides,[11] sulfonyl hydrazides[12]
and N-phenylthiocaprolactam[13] – are electrophilic in nature.
At present, disulfides have become alternate sulfenylating
agents to thiols[14] in metal-catalysed[15] and metal-free[7a,16] re-
actions. This is because of their stability, cost efficiency, easy
preparation and commercial availability.[17] Metal-mediated and
metal-free sulfenylation of indole[18] and imidazole[19] deriva-
tives with different sulfenylating agents has often been re-
ported, but only a few works to date have discussed the sulf-
enylation of active methylene compounds such as acetyl-
acetone, ethyl acetoacetate and malononitrile. Traditionally,
sulfenamides,[20] thiosulfonates,[9] sulfuryl chloride[21] and di-
sulfides[22] have been used as thio sources for the preparation
A few reports of particular interest on mono-sulfenylation
deal with the sulfenylation and dehydrosulfenylation of
amides,[24] the sulfenylation of esters and ketones,[25] rhodium-
catalysed thiolation of 1-nitroalkanes[26] and the synthesis of
thioethers by use of carbon tetrachloride as a mild oxidant.[27]
The asymmetric sulfenylation of ꢀ-keto esters[28] would be ex-
pected to provide versatile building templates and synthons for
biologically active molecules,[29] which is also in the purview
of mono-sulfenylation. Tan et al. reported carbon-tetrabromide-
mediated sulfenylation of active methylenes, via sulfenyl bro-
mides as intermediates.[30] Sulfenylation with sulfenyl halides
has been reported in the cases of indole and imidazole,[16b,18j,31]
and a few reactions of importance with active methylene com-
pounds[32] have been carried out. Recently, Chennapuram et al.
have established I2/DMSO/PTSA-promoted oxidative cross-cou-
pling of imidazopyridines and methyl ketones.[33] During our
research into active methylene compounds and tetrabutylam-
monium tribromide (TBATB) we found that mono-sulfenyl deriv-
atives were synthesized within short reaction times with high
yields. However, the same could not be achieved in the synthe-
sis of disulfenylated products.[34]
In this work we focus on an improved regioselective method
for the synthesis of mono and bis derivatives by use of sulfenyl
iodides, with variable reaction conditions. These reactions are in
compliance with green chemistry principles in terms of solvent
selection, a less hazardous oxidant (DMSO) and use of iodine
as a catalyst. The use of I2 as a catalyst is an attractive alterna-
tive to corrosive and hazardous chlorine, sulfuryl chloride etc.
The use of disulfides instead of thiols offers atom economy and
[a] Department of Chemistry, National Institute of Technology
Silchar,
Silchar 788010, India
E-mail: barmanpranjit@yahoo.co.in
http://www.nits.ac.in/departments/chem/chem.php
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501148.
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limits the wastage associated with thiols. The reactions were
The solvent screening showed that use of nonpolar solvents
conducted at ambient temperature, leading to high yields. In- such as THF and cyclohexane gives mono derivative 3aa,
terestingly, the oxidation of the disulfides to sulfoxides or sulf-
ones was restricted.
whereas use of toluene gives 4aa selectively with lower yields.
Use of polar solvents was effective for the reaction, and in this
study dimethyl carbonate (DMC, Entries 8 and 21) was found to
be the optimal solvent. The reactions were carried out at ambi-
ent temperature. After the optimization process, a mixture of
1a (0.5 equiv.), 2a (1.2 equiv.), DMSO (3.0 equiv.), Et3N
(1.2 equiv.), and I2 (0.06 equiv., 5 mol-%) was allowed to react
for 2.5 h, to give the mono derivative, C–S coupling product
3aa, in almost 88 % yield (≈ 95 % purity). The identity of
product 3aa was confirmed by its spectral and analytical char-
acterization (Figure S3aa in the Supporting Information). Here,
iodine is used as a catalyst for the complete utilization of –SR
groups from disulfide, and so an improved yield relative to oth-
ers was obtained. Increasing the amounts of oxidant, base and
disulfide gives the bisulfenylated product as the major compo-
nent in the presence of Br2 or I2 as catalyst. However, with the
higher concentration of disulfide and base (Entry 3), Br2 gives
both mono- and bis-sulfenylated products, but in the presence
of I2, under optimized reaction conditions, only mono-sulfenyla-
tion occurs. Thus, the regioselectivity of the product is depend-
ent on the amounts of disulfide, base and oxidant. Moreover,
Results and Discussion
Our initial studies were focused on the synthesis of the mono
derivatives 3 in a regioselective manner. However, it was found
that at different concentrations of base, oxidant and disulfide,
3 and 4 are both obtained as exclusive products, selectively
with high yields (Scheme 1).
Scheme 1. Mono- and bis-sulfenylation.
A model reaction between bis(p-nitrophenyl) disulfide (1a)
and acetylacetone (2a) in the presence of iodine was first exam-
ined under various conditions (Table 1).
Table 1. Optimization of coupling between bis(p-nitrophenyl) disulfide (1a) and acetylacetone (2a) under different conditions.
Entry
1a/2a/oxidant/base
Oxidant
Base
Solvent[c]
Catalyst
Yield [%][d] 3aa
Yield [%][d] 4aa
1
2
3
4
5
6
7
0.5:1.2:3.0:1.2
0.5:1.2:3.0:1.0
1.0:1.2:2.0:2.0
0.5:1.2:3.0:2.0
0.5:1.2:1.0:1.2
0.5:1.2:3.0:1.2
0.5:1.2:3.0:1.2
0.5:1.2:3.0:1.2
0.5:1.2:3.0:1.2
0.5:1.2:3.0:1.2
0.5:1.2:3.0:1.2
1.0:1.2:3.0:2.5
0.5:1.2:3.0:1.2
0.5:1.2:6.0:1.2
0.5:1.2:3.0:1.0
0.5:1.2:6.0:1.0
0.5:1.2:3.0:1.0
0.5:1.2:3.0:1.0
0.5:1.2:3.0:1.2
0.5:1.2:3.0:1.2
1.0:1.2:6.0:2.5
1.0:1.2:6.0:1.2
0.5:1.2:3.0:1.0
0.5:1.2:3.0:1.0
H2O2
H2O2
H2O2
KOtBu
EtONa
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
–
KtOBu
EtONa
Et3N
Et3N
Et3N
KOH
Et3N
Et3N
KOH
Et3N
Et3N
Et3N
Et3N
Et3N
KOH
ethanol
ethanol
DMC
DMF
DCM
DCM
dioxane
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMF
I2
n-TBAB
Br2
I2
I2
I2
I2
I2
I2
I2
40
38
10
15
48
63
59
88
49
55
42
–
48
10
23
30
10
20
–
–
–
50
62
25
12
15
–
–
–
–
68
24
65
–
45
15
–
45
–
90
64
–
H2O2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
(NH4)2S2O8
(NH4)2S2O8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
8[a]
9
10
11
12
13
14
15
16
17
18
19
20
21[b]
22
23
24
I2
I2
I2
I2
I2
Br2
NCS
I2
I2
I2
I2
I2
I2
I2
toluene
THF
DMC
DMC
cyclohexane
DMC
38
–
–
24
10
–
[a] Disulfide (0.5 equiv.), I2 (0.06 equiv., 5 mol-%), DMSO (3 equiv.), acetylacetone (1.2 equiv.), Et3N (1.2 equiv.), DMC (2–5 mL). [b] Disulfide (1.0 equiv.), I2
(0.06 equiv., 5 mol-%), DMSO (6 equiv.), acetylacetone (1.2 equiv.), Et3N (2.5 equiv.), DMC (10 mL). [c] DMC: dimethyl carbonate, DCM: dichloromethane, DMF:
dimethylformamide. [d] Isolated yields.
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when Br2 was used in place of I2 under optimized reaction con- Entry 8). The obtained results (Table 2) revealed that the mono-
ditions (Entry 8), the procedure lost its regioselective nature, sulfenylation reaction has tolerance to changes of functional
affording a mixture of products.
groups both of active methylene compounds and of disulfides.
When iodine-containing catalysts such as I2O5 and TBAI were
screened, no products were formed. The absence of iodine in
the reaction under basic conditions resulted in a 20–25 % yield
of 3aa with p-nitrothiophenol as major byproduct, but in the
absence of both base and catalytic iodine no product was
formed. The reaction in the presence of various oxidants and
bases was further examined. The solvents DMSO and Et3N were
found to be more efficient than the others. If strong oxidants
are used, a disulfide will be converted into a benzenesulfono-
thioate, thus lowering the formation of the desired product. The
use of NaOEt and KOtBu (Entries 1 and 2) resulted in only 30–
55 % conversion of the disulfide into 3aa and the unreacted
disulfide precipitated when the solution was kept for 24 h.
When KOH (Entry 24) was used, o-nitrobenzenethiol became
the major product, together with a small amount of 3aa. How-
ever, the reaction was feasible even in the absence of any base
(Entry 9, 49 %), giving 3aa but with a comparatively longer re-
action time (≈ 48 h).
Table 2. Substrate scope of disulfides 1 and active methylenes 2.[a]
Entry Disulfide
2
EWG1
EWG2
Product
Yield
[%][b]
1
3
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1f
2a
2b
2c
2d
2e
2a
2b
2c
2d
2a
2b
2c
2e
2a
2b
2c
2d
2a
2d
2a
MeCO
MeCO
EtOCO
CN
MeCO
MeCO
MeCO
EtOCO
CN
MeCO
MeCO
EtOCO
MeCO
MeCO
MeCO
EtOCO
CN
MeCO
EtOCO
EtOCO
CN
MeOCO
MeCO
EtOCO
EtOCO
CN
MeCO
EtOCO
EtOCO
MeOCO
MeCO
EtOCO
EtOCO
CN
3aa
3ab
3ac
3ad
3ae
3ba
3bb
3bc
3bd
3ca
3cb
3cc
3ce
3da
3db
3dc
3dd
3ea
3ed
3fa
88
91
81
74
83
92
96
87
83
79
82
68
70
65
71
65
64
48
46
58
9
10
11
12
13
14
15
16
17
18
19
20
The reaction showed a significant effect of Et3N and DMSO,
depending on their molar proportions. It was observed that
when Et3N and DMSO were used individually (at twice the
amounts listed in Entry 8), instead of giving mono derivative
3aa, the reaction produced the bis-sulfenylated product 4aa in
68 % or 64 % yield (Entries 12 and 22, respectively). Optimiza-
tion showed that use of a mixture of 1a (1.0 equiv.), 2a
(1.2 equiv.), DMSO (6 equiv.), Et3N (2.5 equiv.) and I2 (0.06 equiv.,
5 mol-%) improved the yield of 4aa to almost 90 % within 4 h.
The product was characterized spectroscopically. When only a
catalytic amount of Et3N (5 mol-%) was used the yield of mono
derivative (52 %) was lowered significantly, and so a stoichio-
metric quantity of Et3N was used. There was always a small
amount of 2a left unreacted. For completion of the reaction,
acetylacetone was added in slight excess to the disulfide. The
presence of a phenylthio group (adjacent to a diketone) enhan-
ces the reactivity of the remaining methylenic proton,[35] which
results in the substitution of the proton by another phenylthio
group. In this reaction scenario, steric effects are also an impor-
tant factor that needs to be considered. The reactivity or ther-
modynamic acidity of that proton during the synthesis of com-
pound 4 dominates over the steric effect, but the reaction time
is increased. The formation of the mono derivative is confirmed
by the presence of a –CH peak, observed at around 4 ppm (or
at δ = 14 ppm in the case of an enol derivative), which is absent
in the case of the bis-sulfenylated product.
MeCO
CN
MeCO
MeCO
CN
MeCO
[a] Disulfide (0.5 equiv.), I2 (0.06 equiv., 5 mol-%), DMSO (3 equiv.), active
methylene compounds (1.2 equiv.), base (1.2 equiv.), DMC (2–5 mL). [b] Iso-
lated yields.
Then, reactions between various active methylene com-
pounds and other disulfides were also carried out. Under identi-
cal conditions, reactions of bis(2,4-dinitrophenyl) disulfide (1b),
bis(o-nitrophenyl) disulfide (1c), 1,2-diphenyldisulfide (1d), di-
ethyl disulfide (1e), and bis(p-methoxyphenyl) disulfide (1f)
were performed. All the reactions proceeded smoothly, giving
the desired products 3aa–3fa. The order of substituent effect
in relation to yields is: electron-withdrawing groups > unsubsti-
tuted disulfides > electron-donating groups > aliphatic di-
sulfides (1b > 1a > 1c > 1d > 1f > 1e). In the case of diphenyl
disulfide, a minimal amount of thiophenol was produced along
with the desired mono- and bis-sulfenylated products.
After the efficient synthesis of mono derivatives 3aa–3fa, we
carried out reactions between acetylacetone (2a) and different
disulfides 1a–1d with the goal of bis-sulfenylation. Under opti-
mized conditions (Table 1, Entry 21), the bis-sulfenylated deriva-
tives 4aa–4ca (11 examples) were prepared efficiently (Table 3).
To determine a plausible mechanism, exploration of the cata-
lytic cycle was essential, and this was attempted by using HI
and DMSO. When HI and DMSO were used directly, the reaction
produced a higher yield of mono-sulfenylated derivative
(Table 4, Entry 1). On treatment with KI in the absence either
of HCl (Table 4, Entry 2) or of DMSO (Table 4, Entry 3), no con-
version into sulfenylated product was observed. However, with
Monitoring of temperature effects showed that at room tem-
perature no conversion occurred. When the temperature was
maintained at 40–50 °C, high yields of products were obtained.
With increasing temperature above 60 °C the reaction gave mix-
tures of products 3aa and 4aa with very low yields. This may be
due to the low reactivity of acetylacetone at high temperature.
Therefore, the optimized reaction temperature was set at 40–
50 °C for all the reactions.
The substrate scope was then examined, under the set of a suitable HCl concentration and DMSO, generation of HI was
optimized conditions (as above) for mono derivatives (Table 1, followed by the successful synthesis of sulfenyl derivatives.
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Table 3. Substrate scope of bis-sulfenylated derivatives 4.[a]
2
Entry Disulfide
2
EWG1
EWG
Product
Yield
[%][b]
1
4
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1c
1c
1d
1e
1f
2a
2b
2d
2e
2a
2a
1b
2d
2a
2d
1a
MeCO
MeCO
CN
MeCO
MeCO
MeCO
MeCO
CN
MeCO
EtOCO
CN
MeOCO
MeCO
MeCO
EtOCO
CN
4aa
4ab
4ad
4ae
4ba
4ca
4cb
4cd
4da
4ed
4fa
90
92
94
86
93
82
84
88
68
51
46
Scheme 2. Plausible reaction pathway.
9
10
11
MeCO
CN
MeCO
MeCO
CN
MeCO
ing Information). Trapping of the sulfenyl iodide (RSI) by olefin
is not possible, because sulfenyl iodides are not stable at room
temperature. The instability is probably due to the very easy
disproportionation reaction of the RSI to the more stable di-
sulfide (2RSI → RSSR + I2).[36]
[a] Disulfide (1.0 equiv.), I2 (0.06 equiv., 5 mol-%), DMSO (6 equiv.), active
methylene compounds (1.2 equiv.), base (2.5 equiv.), DMC (10 mL). [b] Iso-
lated yields.
It can be clarified that the reaction is tolerant to a wide range
of substituents, such as various disulfides and active methylene
compounds. The only limitation is that diethyl malonate (DEM)
cannot be transformed into bis-sulfenyl derivatives. This may be
Thus, the prominent reactivity of HI and DMSO for the C–S cou-
pling is optimized.
Table 4. Reaction between bis(p-nitrophenyl) disulfide and acetylacetone.[a]
related to the acidity constant, which is lower in DEM (≈ 10–14
)
than in other active methylene compounds. The steric effect
due to the presence of two bulkier –COOEt groups in DEM may
be another reason for the lower reactivity towards bis-sulfenyla-
tion. However, mono derivatives are successfully prepared, and
this is a limitation of other methods.[29]
Entry
Catalyst
Oxidant
Acid
Yield [%][b]
1
2
3
4
–
DMSO
DMSO
–
HI
–
HCl
HCl
75
0
0
KI
KI
KI
Conclusions
DMSO
70
We have shown an improved procedure to sulfenylate active
methylene compounds in a straightforward and regioselective
manner, with high yields and short reaction times. In compari-
son with reported procedures, the present work is more regio-
selective with regard either to mono or to bis derivatives. The
reaction has wide substrate scope and is "greener" in terms of
substrate, solvent, oxidant and base. Under mild reaction condi-
tions, the method regioselectively gives a wide range of pro-
ducts with minimal quantities of byproducts.
[a] Reaction conditions: KI (10 mol-%), HCl (10 mol-%), DMSO (3 equiv.). [b]
Isolated yields after column separation.
From the above experimental observations, the promotion
of the reaction through intermediary reaction steps through
the following plausible mechanism can be assumed. Scheme 2
shows two catalytic cycles. In the first cycle, the active methyl-
ene group (in the presence of Et3N) easily losses active H and
binds to the sulfenyl iodide to form a product 3 and the catalyst
I2 is regenerated. However, if the amounts of the intermediate
(RSI), Et3N and DMSO are sufficiently large, the reaction select-
ively affords a product 4 at high yield. Quenching of acid by
base does not occur because the addition of base promotes
the reaction by abstracting the active proton, whereas its ab-
sence leads to a very slow process with lower levels of conver-
sion. The formation of RSI species from iodine and disulfides at
40 °C has already been reported.[16b]
Experimental Section
Experimental Procedures: All reagents were purchased from com-
mercial suppliers and used without further purification. The sol-
vents and reagents were dried wherever necessary and the reac-
tions were carried out with predried glassware. DMSO was distilled
from CaH2. Yields corresponding to isolated compounds were al-
most quantitative. For TLC, silica gel-GF was used, with monitoring
with a UV fluorescence analysis cabinet (Ikon instruments) to visual-
ize developed chromatograms. Separations were carried out on
Merck silica mesh (60–120 mm). FT-NMR spectra were recorded with
Bruker 500 MHz, 400 MHz and 300 MHz instruments. Chemical shifts
are reported in δ (ppm) with reference to the residual peak of CDCl3
for both 1H and 13C NMR; multiplicity is denoted as s = singlet, d =
In order to confirm that the hypothetical reaction pathway
(Scheme 2) proceeds through the RSI intermediate, we per-
formed a reaction between diphenyl disulfide and styrene to
trap the intermediate RSI. Under optimized conditions, the reac-
tion afforded [1-phenyl-2-(phenylthio)ethylthio]benzene (5a) in-
stead of any trapped product. The formation of the disubsti-
tuted thioether 5a was confirmed by 1H NMR (see the Support- doublet, t = triplet, dd = doublet of doublets, dt = doublet of trip-
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lets, and m = multiplet. The elemental analyses were performed
with a Flash 2000 Thermo Scientific instrument. The preparation
and characterization of all the reported mono- and bis-sulfenylated
derivatives are available as Supporting Information.
Acknowledgments
The authors are thankful to Sophisticated Analytical Instrument
Facility (SAIF), Indian Institute of Technology (IIT) Madras and
IIT Indore for spectral analysis.
Keywords: Regioselectivity · Green chemistry · Sulfenylation
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Received: September 4, 2015
Published Online: November 18, 2015
Eur. J. Org. Chem. 2016, 384–388
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