Amino acid and water-driven tunable green protocol to access S-S/C-S bonds via aerobic oxidative coupling and hydrothiolation

Article abstract of DOI:10.1039/c4ra02909g

A green methodology utilizing a natural supplement such as l-arginine in conjunction with water and oxygen led to oxidative coupling of thiols into disulfides (S-S bond) whereas thiol-yne coupling to access vinyl sulfides (C-S bond) was facilitated in a nitrogen atmosphere. The tunable protocol offers several advantages such as low catalyst loading, high yields, clean reaction, no over-oxidation of the S-S bond besides being metal/base/waste-free. The synthesis of ubiquitous cystine and glutathione disulfide in the same catalytic system is an added advantage and the catalytic system has been recycled up to seven times. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra02909g

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Graphical Abstract
O
NH2
OH
O
O
S
HO
S
HS
OH
NH2
L -Cystine
NH2
R
S
O2
L-Arginine
H O
L -Cysteine
O2
S
X
X
R
X
SH
+
Diphenyl disulfide
X = N, -CH
2
R
N2
O
H
R2
S
n
R1
n = 0-1
WhereR , R = H, OMe, Cl etc
1
2
R1
R2
n=o, Vinyl sulfide
SH
n=1, Phenyl-sulfanyl-propenone
Arginine in conjunction with water has been employed as an effective and recyclable
organocatalyst for oxidative coupling of thiophenols and hydrothiolation of alkynes.

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Amino Acid and Water-Driven Tunable Green Protocol to
Access S-S/C-S Bonds via Aerobic Oxidative Coupling and
Hydrothiolation
1
2
3
4
Amit Shard,a,b Rajesh Kumar,a Saima,a,c Nidhi Sharmaa and Arun K. Sinha*a, b, c
5
Abstract
6
7
A green methodology utilizing natural auxiliary like LꢀArginine in conjunction with
water and oxygen led to oxidative coupling of thiols into disulfides (SꢀS bond) whereas
thiolꢀyne coupling (TYC) to access vinyl sulfides (CꢀS bond) was facilitated in nitrogen
atmosphere. The tunable protocol offers several advantages like low catalyst
loading, high yields, clean reaction, no overꢀoxidation of SꢀS bond besides being
metal/base/wasteꢀfree. The synthesis of ubiquitous cystine and GSSG in the same
catalytic system is an added advantage and the catalytic system has been recycled up to
seven times.
8
9
10
11
12
13
14
Keywords: Amino acids / Oxidative coupling / Vinyl sulfides / Wasteꢀfree
15 Introduction
16
17
18
19
20
21
22
Nature1 has nurtured the mankind with an infinite repository of diverse1a type of
biochemicals and carries out innumerable biochemical processes utilizing the native
solvent of cell i.e. water.1b Additionally water in conjunction with air leads to the
complexity of the biochemical world. The use of water as a new paradigm to innovate
ecoꢀsustainable chemical reactions are also gaining momentum because either its
release1c as a byꢀproduct or its use as a solvent,1dꢀe will clearly have the least impact on
the environment. Nevertheless, conducting reactions in water is still challenging because

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23
most of the organic reactants are insoluble in water. Further, water may deteriorate the
catalytic activity besides disruption of polar interaction among catalyst and substrate
molecules. Therefore, the development of waterꢀcompatible organocatalyst and their
application to chemical reactions using water as the reaction medium is of considerable
interest. Furthermore, it is also highly desirable to develop environmentally benign
chemical1f processes that use oxygen from air in aqueous medium without requirement of
any metal oxidant.
24
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Besides water, Lꢀamino acids also dominate the natural world2 and display a central
theme in biological systems.3 Recently, they are efficiently employed as organocatalysts
in triggering a variety of chemical reactions4 like synthesis5 of Pfizer’s antiꢀglaucoma
drug latanoprost5a and anticancer drug carboplatin.5b Interestingly, under physiological
conditions, sulphur containing amino acids like cysteine and glutathione, undergo
oxidative coupling to form ubiquitous cystine and GSSG having disulphide (SꢀS) bond
of high practical value.6 Likewise, an alicyclic disulfide known as lipoic acid6a also acts
as an essential cofactor of mitochondrial enzymatic complexes which highlights the
importance of SꢀS bond. Some of the medicinally significant examples of disulphide
bond6bꢀc are shown below (Fig. 1).
O
CH3
O
N
O
S
S
S
N
OH
HO
S
H
O
OH
Gliotoxin
Bruguiesulfurol
(antitubercular agent)
(PTP1B inhibitor)
40
41
Fig. 1 Medicinally significant disulphides.

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The disulfide bond has widespread occurrence in flora and fauna.7 It also plays
substantial roles in design of rechargeable lithium batteries, in a number of chemical
reactions8 and catalysis.9 Further, many of the next generation10 pharmaceuticals
incorporating disulfide bonds have already hit the market. In this context, a large number
of oxidative coupling protocols11ꢀ13 mediated by gold nanoparticles11a or rhenium13b metal
as an effective catalyst have emerged for the synthesis of disulphides. However, most of
the approaches suffer from inadequacies such as low selectivity due to over oxidation13a
of final product into sulphoxides/sulphones, expensive nature of catalyst with poor
recovery and finally laborious work up procedures. Recently, environmentally benign
approaches to synthesize heterocyclic disulfides13g have also been surfaced using a
cocktail of enzymes, buffer and methanol. Besides this supported iron oxide
nanoparticles13h are also used to synthesize disulfides but these methods not truly fall
under the periphery of green reactions due to use of organic solvent and expensive nature
of reagents. So there is a strong need to develop such a catalytic system for the
chemoselective oxidation of thiols to disulfides which comprises all, that is, green
catalyst, solvent, and reagent besides recyclability of catalytic system and wasteꢀfree
greenꢀapproach in comparison to relentless conventional protocols13bꢀf (which utilize
metal oxidant/base/organic solvent).
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Apart from making disulfide (SꢀS) bond, thiols are also known to participate in
hydrothiolation,14 with alkynes via thiolꢀyne click14a (TYC) reactions to generate vinyl
sulphide (CꢀS bond) having miscellaneous medicinal and physicochemical
applications.14b Some of the medicinally significant examples of vinyl sulfides14c are
shown below (Fig. 2).

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R1
O S
OH
O
H
O
S
R1
R2
O
R1 = Benzyl
R1 = NH2, R2 = COOH
Precursor of Griseoviridin
Benzylthiocrellidone
65
66
Fig. 2 Important drug intermediates with CꢀS bond.
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In this article, we disclose for the first time, a waste free and atom economical protocol
for direct oxidative coupling of thiols to disulfides utilizing quasi natural rudiments14d
(amino acid/water/air) precluding any oxidant, base or metal. Among the various tested
amino acids, arginine (Arg) provided chemoselective access to disulfides including
ubiquitous cystine and GSSG in ample yield with recyclability of catalytic system up to
seven cycles. Additionally, the zwitterionic character of Arg also worked as a driving
force towards rapid hydrothiolation of alkynes i.e. thiolꢀyne coupling (TYC) thus leading
to an environmentally benign synthesis of vinyl sulfides (CꢀS bond). Interestingly, our
tunable catalytic system also clearly demonstrated that CꢀS bond formation is faster than
SꢀS bond in nitrogen atmosphere (Fig. 3).

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Advantages
Metal and base-free,
recyclable upto seven times
Quasi natural rudiments used
S
Arg. (as an organocatalyst)
R
H O (as a solvent)
R
2
S
O (as an oxidant)
2
Disulfides
S
SH
R
R
Vinyl sulfide
R = aromatic,
aliphatic, heter
ocyclic, acyclic
O
O
S
Arg, H O
2
N
2
Sulfanyl-propenone
77
78
79
Fig. 3 Arginine/H2O catalysed oxidation of thiols and hydrothiolation of alkynes.
80 Results and Discussion
81
82
83
84
85
86
87
88
89
90
In continuation of our interest in the development15 of greener approaches,15aꢀc our group
has recently reported ambiphillicity (cationic and anionic character) of [hmim]Br (1ꢀ
hexyl 3ꢀmethyl imidazolium bromide), a neutral ionic liquid (I.L.),15d was found
imperative for oxidative coupling of thiophenol into disulfides (SꢀS bond). Enthused by
this, we now attempted to perform oxidative coupling of thiols to disulfides in histidine, a
versatile amino acid16 with imidazolium ring analogous to the heterocyclic core of
[hmim]Br, having
zwitterionic character16a in water (Fig. 4) and is more
environmentally benign, safe and abundant in comparison to I.L.

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COO-
NH3+
+
Br-
H3C N
N
N
N
H
C6H13
Histidine
[hmim]Br
91
92
93
Fig. 4 Diagram showing analogy between zwitterionic histidine and ambiphillic
[hmim]Br.
94
95
Initially, 4ꢀchloro thiophenol (0.25 mmol), water (0.6 mL) and Lꢀhistidine (50 mol%)
were taken in a round bottom flask and stirred at room temperature for 12 h. To our
delight the desired 4,4'ꢀdichloro diphenyl disulfide (1b) was formed in 64% yield (on
GCꢀMS basis). It is worth mentioning that our green oxidative coupling process
comprised of histidineꢀwaterꢀair might be corroborating with biochemical process where
intracellular16b disulfide bond forms in presence of amino acids like cysteine. However,
well known amino acid Lꢀproline (Table 1, entry 2) provided 1b in poor yield (37%).
Thereafter, a series of neutral, acidic and basic amino acids were screened (Table 1), out
of which Arg, a basic amino acid with pka = 2.488 provided 1b in good yield (70%, 12 h)
in air (Table 1, entry 10) whereas reaction using O2 balloon provided 1b in same yield in
shorter reaction time of 5 h (Table 1, entry 15).
96
97
98
99
100
101
102
103
104
105
106
107
108

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Table 1 Screening of different amino acids for the formation of disulphide.a
SH
H O (0.6mL)
LꢀAmino Acid,
Air,
2
2
Cl
S S
Cl
rt, 12 hr
Cl
1a
1b
Yieldb(%)
Amino acid
Yieldb(%)
Entry
Entry
Amino acid
1
2
3
4
Histidine
64
37
33
11
12
13
14
Glycine
42
15
Proline
Serine
Aspartic acid
Glutamic Acid
Cysteine
14
traces
Phenylalanine
Glutamine
23
Argininec
Arginined
Argininee
70
5
6
15
33
61
60
traces
Valine
16
17
7
8
Leucine
nd
Alanine
Isoleucine
18
19g
Argininef
ꢀ
25
42
70
nd
nd
9
Arginine
10
110
111
112
113
114
a The reaction conditions involved usage of 0.25 mmol of 1a, atmospheric O2, 50 mol% of LꢀAmino acid,
b c
0.6 mL of HPLC grade water. Yields on the basis of GCꢀMS. In O2 atmosphere the reaction got
completed in 5 hr . d N2 atmosphere. e Ethanol was used as solvent. f Chloroform was used as solvent. g No
Arg used.
115
116
117
118
119
As expected, 1b was obtained in traces in nitrogen atmosphere (Table 1, entry 16)
whereas replacement of water with ethanol or chloroform did not form 1b (entry 17ꢀ18).
This is possibly because of lack of formation of hydrogen bonding and inefficient
generation of zwitterion in organic solvents. Following the above lead, amount of
Arginine and effect of temperature for the synthesis of 1b was optimized (Table 2).
120
121
122
123
124
125
126

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Table 2 Optimization of the reaction conditions for formation of 1b under O2
atmosphere.
SH
H O (0.6mL)
2
LꢀArg,
2
Cl
S
S
Cl
O2
Cl
1a
1b
% Yield
Amount of Organocatalyst Temp in oC
(L-Arginine)
S.No
Time
(on GC basis)
R.T.
5 hr
1.
2.
92
50 mol%
91
92
93
5 hr
5 hr
5 hr
8 hr
100 mol%
R.T.
R.T.
R.T.
R.T.
3.
4.
30 mol%
20 mol%
5.
70
10 mol%
20 mol%
20 mol%
20 mol%
20 mol%
6.
7.
8.
9.
50
15 min
90 min
20 min
15 min
98
90
40
70
80
92
80
130
131
132
133
134
135
136
137
138
139
140
141
Hence a decreased catalyst load of 20 mol% in presence of O2 was found to be efficient
for promoting the synthesis of 1b in 15 min at 50oC (Table 2, entry 6). Further impact of
the contemporary tools viz. microwave and ultrasonicator were evaluated (See S.I).
Unfortunately, reaction conducted in microwave12g (50°C, 80W) had no profound effect
in efficient construction of 1b in shorter reaction time (up to 45 min) as it led to several
side products. Interestingly, reaction conducted in ultrasonicator12f provided the desired
1b in 98% yield in 10 min (See S.I). However, owing to the malodorous smell17 of thiols,
the oxidative coupling was conducted under conventional conditions in well ventilated
hood.
Finally, optimized conditions using 20 mol% of Arg in 0.6 ml of water, 0.25 mmol of 1a
and 1/2O2 resulted 1b in 96% yield (isolated) at 50oC in 15 min (Table 3, 1b). The

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143
substrate scope was explored using electronically versatile thiols which provided diverse
types of disulfides (Table 3, 1bꢀ11b) in moderate to excellent yields (up to 96%)
a
144
Table 3 Substrate scope of oxidative coupling of thiols in waterꢀArgꢀOxygen.
SH
Water/1/2O2
50oC
R
S
S
Arg (20 mol%)
+
(1b-12b)b
R
R
Cl
Cl
S
S
Cl
S S
S
S
(1b, 96%, 15 min)
(2b, 91%, 35 min)
(3b, 88%, 110 min)
OMe
Cl
S S
MeO
S S
S
S
(5b, 93%, 55 min)
6b
(
, 84%, 75 min)
(4b, 70%, 35 min)
S
S
Br
S
S
Br
S
S
(9b, 91%, 25 min)
(8b, 80%, 70 min)
(7b, 60%, 120 min)
S
S
S
S
N
N
(11b, 65%, 85 min)
(12b, 70%, 95 min)
S
S
N
N
S
10b
(
, 81%, 55 min)
S
N
S
N
N
S
N
S
S
N
S
S
N
14b
(
, 61%, 90 min)
(15b, 51%, 90 min)
13b
(
, 65%, 90 min)
NH2 H2N
HO
S
S
OH
S
S
16b, ndc
17b, nd
145
146
a Reaction conditions involved usage of 0.25 mmol of thiol, 20 mol % of LꢀArg, 0.6 mL of HPLC grade
water, O2. b Isolated Yields. c nd = not detected.
147
148
149
150
151
152
153
154
155
and their NMR well matched with those of the reported values.11,15d After the synthesis of
aromatic and alicyclic disulfides (Table 3, 1bꢀ11b) the synthesis of heterocyclic disulfide
(12bꢀ15b) was inspired by previous report by AbdelꢀMohsen13g et al. which utilizes
laccases/buffer/methanol for oxidative coupling of thiophenols into a series of
heterocyclic disulfides. The heterocyclic compounds have numerous added benefits over
carbocyclic ones. To our delight our catalytic system provided heterocyclic disulfides in
up to 70% yield. Unfortunately, 16b or 17b (Table 3) could not be obtained possibly due

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to feeble zwitterionic interaction of Arg with thiol as well as electron rich hydroxy or
amine groups. Thereafter, we looked forward towards establishing the mechanism for the
synthesis of disulfides using ArgꢀO2ꢀH2O catalytic system.
159 Mechanism
160
161
162
163
164
165
166
167
168
It is known that in aqueous medium Arg interacts with water through cationꢀπ
interactions18 which in turn interact with aromatic charged residues of thiophenol. The
guanidinium group of Arg is the most polar of all the common amino acid side chains and
plays a vital role in the binding of negatively charged substrates.18b The water provides an
enhanced πꢀstacking as a result of the hydrophobic effect.18c The amino acid side chain of
zwitterionic19 Arg consists of a 3ꢀcarbon aliphatic straight chain in which the distal end is
capped by a +vely charged complex guanidinium19a group. The delocalized positive
charge on guanidinium group enables the formation of multiple hydrogen bonds with
water (Fig. 5).
+
NH
O
NH2
O
Zwitterionic form
-
H2O
( )
( )
3
H2N
N
OH
H2N
O2
N
H
O
3
H
NH2
NH2
Arginine (Arg)
SH
4
Cl
1a
Cl
S
S
H2N
NH ( )
2
3
-2H2O
-Arg.
NH2
+NH2
O
1b
Cl
-
O
H
+δ
H
O
Cl
O
S
−δ
S
Cl
complex (C)
169
170
171
Fig. 5 The plausible mechanism of the formation of diphenyl disulfide via oxidative
coupling of thiophenol.

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174
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177
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183
184
185
186
Thereafter, in the aqueous charged19b pool, hydrogen atom of one molecule of
thiophenol starts interacting with the –vely charged carboxyl terminal of the arginine
whereas sulphur atom of another molecule of thiophenol interacts with the +vely charged
guanidinium group. This complex interplay of subtle nonꢀcovalent interactions led to
efficient union of two molecules of 4ꢀchlorothiophenol and was studied using UV
spectrophotometer (Fig. 6 ). The study revealed that λmax of 4ꢀchlorothiophenol (1a) and
Arg appeared at 246.5 nm and 207.5 nm respectively. However, when the substrates were
stirred, the spectral analysis clearly indicated that 1a and an aqueous solution of
zwitterionic Arg led to immediate initiation of complexation evident by bathochromic
shift from λmax 246.5 nm to 274.6 nm. It was observed that complexation between
iminiumꢀion of arginine and the heteroatom (S) of thiophenol exponentially increased up
to 9 min leading to a hyperchromic shift which probably is an indicative of increase in
concentration of complex “C” (Fig. 5). Diminution in the absorbance (hypochromic shift)
of C appeared after 12 min with initiation of formation of 1b which finally completed in
110 min at room temperature (see S.I. for details).

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thiophenol
peak at 0 min
disulfide
arginine
187
188
Fig. 6 Absorption profiles of thiophenol, arginine, complexation and 4, 4' diphenyl
189
190
disulfide at 0 min and at the completion of reaction (after 110 min).
191
192
193
194
195
196
197
198
199
Recyclability of the catalytic system is an important factor in context of green chemistry
as it has both economical as well as ecological benefits. In this experiment, 0.25 mmol of
1a, 20 mol % of Arg, O2 and 0.6 mL of water were heated at 50oC, the resulting product
1b was formed in 20 min. The aqueous solution containing Arg and 1b was extracted
using ethyl acetate. The ethyl acetate layer was vacuum evaporated to obtain 1b, whereas
the same aqueous solution containing Arg was used repeatedly for carrying out the
oxidative coupling for a number of times. Profitably, the product could be easily
recovered from the aqueous medium merely by extracting with ethyl acetate. The
remaining aqueous solution of Arg was reused up to seven consecutive cycles (98ꢀ91%)

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201
202
(Fig. 7). Thereafter, there was considerable fall in the yield of disulfide. Interestingly,
addition of 5 mol% of Arg in the above catalytic cycle further increased the yield of 1b
up to 96% (up to ten cycles) due to rejuvenation of the organocatalytic system
Cl
S
S
SH
Cl
Cl
Ist Run
GC-MS Yield (%)
98 %
98%
2nd Run
H2O/Arginine/O2
50oC
3rd Run
97%
96%
91%
th
4 Run
th
up to 7 Run
203
204
205
Fig. 7 Recyclability studies using the same catalytic water/Arg/Oxygen system up to
seven cycles.
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207
208
209
210
211
212
213
214
215
216
217
It is well known that oxidized glutathione (GSSG) with cisplatin is a wellꢀtolerated
therapeutic adjuvant called NOVꢀ002 in standard anticancer therapy.20a Likewise cystine
is also a physiological disulfide of clinical importance. Recent biocatalytic protocol
highlights laccases13g catalyzed disulfides but does not disclose the generality towards
synthesis of physiological disulfides i.e. cystine and GSSG. Thus in parlance of their
medicinal significance and to test the generosity of our protocol, we attempted to
synthesize physiological disulfides i.e. cystine and GSSG under similar conditions
documented in Table 3. It is prudent to state that oxidations of cysteine and related
compounds have been extensively studied, utilizing metal pthalocyanines20b and
expensive noble metals,13a however, their synthesis utilizing perfectly benign conditions
sill remains a significant challenge.21 Interestingly, the developed organocatalytic system
of “ArgꢀWaterꢀOxygen” successfully led to the formation of dimmers (18b and 19b) of

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aminothiols viz. Lꢀcysteine and Lꢀglutathione in appreciable yields of 71% and 76%
respectively at 50oC in longer reaction times of 4 h (Fig. 8).
O
O
NH2
S
OH
Arginine, O
H2O
2
HS
OH
HO
S
NH2
NH2
O
L -Cysteine
18b, 71% ( isolated), L -Cystine
O
O
O
H
H
N
S
HS
N
O
O
O
HO
OH
O
H
Arginine, O
2
N
O
NH2
HO
N
OH
H2O
H
O
S
NH2
O
O
H
N
L- Glutathione (GSH)
HO
N
OH
H
O
NH2
19b, 76% ( isolated) ,Glutathione disulfide
(GSSG)
220
221
222
Fig. 8 Synthesis of Cystine (18b) and GSSG (19b) using natural rudiments like arginineꢀ
waterꢀoxygen.
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224
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226
227
228
229
230
231
Like SꢀS bonds, CꢀS22 bonds are another critical22aꢀf and ubiquitous22g constituents of
many pharmaceuticals22hꢀi and natural products22j e.g allicin, anthelmintic drug
levamisole, and antibiotics like penicillins etc. To construct the CꢀS bonds, popular
‘click’ꢀprocedures like thiolꢀyne coupling (TYC) or hydrothiolation has become an
outstanding tool for the functionalization23 of molecules. The TYC unarguably yields
useful synthetic intermediates having applications in organic24a transformations ranging
from Diels−Alder, thio−Claisen, acting as Michael acceptors and as versatile synthons in
olefin metathesis. Certain reports reveal the synthesis of vinyl sulfides using strong
base24b and ammonia.24c

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Non green protocols
Drawbacks
No recyclability
Toxic waste generation
Expensive catalysts
25d
Radical initiator/ UV light
25e
Indium bromide, AIBN
25f
or
Prevalent
Protocols
SH
R
or
or
1
Rh/Ir/Th/U/Cs CO
2
3
S
25g
Au catalysed reaction
+
R
2
R
1
H
R
2
Vinyl sulfides
Our Protocol
Recyclable catalystic system
No waste generation
Inexpensive organocatalyst
Quasi natural rudiments
are utilized like N , Arg and H O
2
2
Merits
Benign protocol
232
233
Fig. 9 Comparison of prevalent protocols with our method for TYC.
234
235
236
237
238
239
240
241
242
243
244
There are also numerous reported methods25 for hydrothiolation of terminal alkynes to
form vinyl sulfides using various transition metals like Wilkinson’s catalyst, lanthanides,
late transition metal catalysts and various free radical initiators (Fig. 9). However, a
method employing mild, environmentally compatible, efficient25c and in particular
selective route towards synthesis of Cꢀ S bond is yet awaited. Therefore, in light of their
expected utility,26 hydrothiolation between alkyne and thiophenol in Arg/water to
generate vinyl sulfides was carried out in nitrogenous atmosphere (replacing the oxygen
atmosphere to ward off the formation of SꢀS bond). However, GC analysis of the crude
product confirms the formation of vinyl sulphide (20b) in 20% yield only along with
unwanted SꢀS bond (30ꢀ35%) and unreacted thiol. Interestingly, the sequence of addition
of reactants was found very crucial, hence addition of thiophenol to a well stirred
245
246
247

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249
Table 4 Substrate scope of alkenylative crossꢀcoupling of alkynes and thiophenols to
form vinyl sulfides.a
L- Arginine, 50oC,
SH
S
N2 balloon, H2O
R2
Alkyne
R1
R1
+
(45 min-2 h)
Vinyl sulfide
Thiol
Yieldb
81
S.No
1.
Thiol
Alkyne
Alkenyl sulfide (Z/E)
S
CH3
CH3
R1= 4 ꢀOCH3
R1= H
H3C
20b (87:13) c
OMe
S
2.
3
71
H3C
21b (7:93)
S
R1= H
75
85
22b (60:40)
S
4
R1= OCH3
R1= 4 ꢀCH3
F
F
OMe
CH3
23b (100:0)
O
O
5
S
80
24b (85:15)
250
251
a Reaction conditions involved usage of 50 mg of thiol, alkyne (1.1 equiv), N2, 20 mol % of LꢀArg, 0.6 mL
252
of HPLC grade water. b Yields of isolated product. cE:Z ratio on NMR basis. (See S.I for details)
253
254
255
256
257
258
259
mixture of phenylacetylene and water/Arg in N2 atmosphere efficiently provided vinyl
sulphide (CꢀS bond) 20b (Table 4) in 45 min in 81% yield as E:Z isomeric mixture.23e
The catalytic system has been successfully extended for antiꢀMarkovnikov products (21bꢀ
24b)23e with variable appendages attached to the aromatic ring of thiophenol and alkyne
in varying yields up to 85%. The catalytic system also led to the synthesis of 1ꢀPhenylꢀ3ꢀ
pꢀtolylsulfanylꢀpropenone (24b) a unique and significant26c scaffold with α,βꢀunsaturated
26eꢀf
carbonyl moiety (O=CꢀC=CꢀS)
which might find applications in biomedical,

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261
262
263
264
265
materials chemistry and bioconjugation realms.26g The plausible mechanism for the
formation of E/Z vinyl sulfides is presented in Fig 10. Here it is presumed that
zwitterionic Arg in water interacts with the thiophenol by carboxylate terminal and the
negatively charged sulfur atom interacts with the terminal alkyne resulting in formation
of vinyl sulfide. The exact mechanism of the formation of E/Z vinyl sulfides is currently
under investigation.
266
267
268
Fig 10. Plausible mechanism for the formation of Vinyl sulfides.
269 Conclusions
270
271
272
273
274
275
276
277
278
In conclusion, we have developed an ecologically compatible tunable catalytic system
comprised of water and subꢀstoichiometric amounts of organocatalyst arginine which is
competent enough in promoting the chemoselective disulfide (SꢀS bond) synthesis via
oxidative coupling of thiol in the presence of oxygen as well as carrying out
hydrothiolation of alkynes/thiol to their alkenyl sulfides (CꢀS bond) under nitrogen
atmosphere without requirements of any metallic salts and basic medium. Moreover,
aerobic oxidative coupling of Lꢀcysteine and Lꢀglutathione into dimeric cystine and
GSSG render our green oxidative process highly practical and appealing for its
application in industrial process. Further, synthesis of vinyl sulfides (E:Z isomeric

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280
281
282
283
284
mixture) having α, βꢀunsaturated carbonyl moiety (O=CꢀC=CꢀS) emphatically
demonstrates the synthetic viability of the above catalytic system. Since the quest for
such type of novel tunable catalytic systems is high, therefore, the method would find
applications for the construction of aromatic (hetero)/alicyclic/aliphatic disulfides as well
as vinyl sulfides by concurrently maintaining the criteria of catalysis, greenness,
recyclability and selectivity.
285 Experimental Section
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
General procedure for the synthesis of disulfide: Initially 0.25 mmol of thiophenol (1a)
was added to HPLC grade water (0.6 mL) containing arginine (20 mol%), and heated for
15 min at 50oC in presence of O2. After complete consumption of starting material
(analysed by TLC), the reaction mixture was extracted with ethyl acetate (2x10 mL). The
combined organic layers were dried over Na2SO4, filtered and vacuum evaporated. The
GCꢀMS analysis confirmed the formation of disulfide (1b) in 98% yield (isolated 96%).
The residue was purified using column chromatography (silica gel 60ꢀ120) with
ethylacetate/hexane (0.5:9.5) as eluents to give the corresponding disulphide. The 1H and
13CNMR of disulfide (1b) well matched with the reported values.
General procedure for the synthesis of vinyl sulfides: 20 mol% of Arg was stirred for 5
minutes under nitrogen in HPLC grade water (0.6 mL) followed by addition of phenyl
acetylene (1.1 equiv). Next, substituted thiophenol (0.25 mmol) was added to the above
reaction mixture and stirred at 50oC under N2 atmosphere for 2 h till complete
consumption of starting material (analysed by TLC). The crude reaction mixture was
extracted with ethylacetate (2x10 mL) and the combined organic layers were dried over

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303
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Na2SO4, filtered and vacuum evaporated. The residue was purified using column
chromatography (silica gel 60ꢀ120) with ethylacetate/hexane (1:9) as eluents to give the
corresponding vinyl sulfide (E:Z isomeric mixture).
Supplementary Information (Detailed UV based mechanistic studies and NMR spectral
values of compounds are provided.)
306
Notes and references
307
308
309
310
311
312
a NPP Division, C.S.I.R.ꢀInstitute of Himalayan Bioresource Technology, Palampurꢀ
176061 (H.P.), India.
b Academy of Scientific and Innovative Research (AcSIR), New Delhi.
c Medicinal and Process Chemistry Division, C.S.I.R.ꢀCentral Drug Research Institute
(Council of Scientific and Industrial Research), Lucknowꢀ 226031 (U.P.), India. Fax:
(+) 91ꢀ522ꢀ2771941. *Eꢀmail: aksinha08@rediffmail.com
313
314
Acknowledgments
A.S and R.K thanks to C.S.I.R. for award of S.R.F. The authors gratefully acknowledge
315
316
317
Directors of C.S.I.R.ꢀI.H.B.T., Palampur and C.S.I.R.ꢀC.D.R.I., Lucknow for their kind
cooperation and encouragement. Some part of work carried out at IHBT, Palampur.
C.D.R.I. /I.H. B.T. Communication No. 8722/3418.
318
319
320

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Organic Chemistry 1981, 1972-1999, 934; (g) A. Massi and D. Nanni, Org. Biomol.
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480
Graphical Abstract
481
O
NH2
OH
O
O
S
HO
S
HS
OH
NH2
L -Cystine
NH2
R
S
O2
L-Arginine
H O
L -Cysteine
O2
S
X
X
R
X
SH
+
Diphenyl disulfide
X = N, -CH
2
R
N2
O
H
R2
S
n
R1
n = 0-1
WhereR , R = H, OMe, Cl etc
1
2
R1
R2
n=o, Vinyl sulfide
SH
n=1, Phenyl-sulfanyl-propenone
482
483
Arginine in conjunction with water has been employed as an effective and recyclable
organocatalyst for oxidative coupling of thiophenols and hydrothiolation of alkynes.
484
485
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487
488
489
490
491
492
493
494
495