Aerobic oxidation of thiols to disulfides under ball-milling in the absence of any catalyst, solvent, or base

Article abstract of DOI:10.1039/c3ra41996g

An efficient aerobic chemoselective oxidation of thiols to disulfides has been achieved under ball-milling over neutral aluminium oxide (grinding auxiliary) in the absence of any catalyst, co-oxidant, solvent, or base. A wide variety of functionalized diaryl, diheteroaryl and dialkyl disulfides have been obtained in high yields. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra41996g

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Aerobic oxidation of thiols to disulfides under ball-
milling in the absence of any catalyst, solvent, or base3
Cite this: RSC Advances, 2013, 3, 10680
Tanmay Chatterjee and Brindaban C. Ranu*
Received 23rd April 2013,
Accepted 13th May 2013
DOI: 10.1039/c3ra41996g
www.rsc.org/advances
An efficient aerobic chemoselective oxidation of thiols to
disulfides has been achieved under ball-milling over neutral
aluminium oxide (grinding auxiliary) in the absence of any
catalyst, co-oxidant, solvent, or base. A wide variety of functio-
nalized diaryl, diheteroaryl and dialkyl disulfides have been
obtained in high yields.
ported diamond nanoparticles.11g A few metal-free procedures
have also been developed using ascorbic acid in water,12a graphite
oxide,12b diethyl amine,12c and N-phenyltriazolinedione12d and
others.12e,f
Recently, ball-milling (intense mechanical grinding) has
received considerable interest as a green tool effecting a chemical
reaction.13
A variety of reactions such as Sonogashira,13a Michael,13b
aldol,13c and others13d–l have been performed efficiently by this
technique. We have recently developed an efficient way of
transesterification without any solvent and catalyst14a and a one-
pot Cu-catalysed click reaction for the synthesis of triazoles
without any solvent14b under ball-milling, and now we report an
aerobic oxidation of thiols to disulfides under ball-milling without
using any metal-catalyst, base, or solvent (Scheme 1).
1. Introduction
Organo-disulfides are of considerable interest because of their
important applications in pharmaceutical, chemical and rubber
industries.1 The disulfides are essential components of biologically
active compounds responsible for peptide and protein stabiliza-
tion2 and DNA cleavage.3 They are also used in drug delivery
systems.4 Disulfides are considered as useful synthons for many
organic reactions such as sulfenylation of anions,5 protection of
thiols,6 and oxidation of certain functional groups.7 They are also
employed as vulcanizing agents8 and for the design of recharge-
able lithium batteries.9 Thus, the development of a convenient
and efficient method for the synthesis of these useful compounds
is of prime interest.
2. Results and discussion
To standardize the reaction conditions, a series of experiments
were performed with variation of the grinding auxiliary and
reaction time for a representative reaction of thiophenol. The
results are reported in Table 1.
A variety of procedures have been developed for the synthesis
of symmetrical organo-disulfides involving oxidative coupling of
thiols using a broad range of reagents and conditions. The most
commonly used oxidative reagents are air, peroxide, heavy metal
oxides and ions, halogens and halogenating agents and some-
times combinations of these.10 However, aerobic oxidation is of
vital interest due to being eco-friendly and sustainable. Usually,
aerobic oxidation is carried out in the presence of a heavy metal
ion or a base.11 Some of the recent methods involve the use of
diaryl tellurides under photosensitized conditions,11a selenium
ionic liquids under microwave heating,11b K+/CH3CN,11c
Al(NO3)3?9H2O/SiO2–OSO3H in CH2Cl2,11d cobalt–iron magnetic
composites,11e iron metal–organic frameworks,11f and Cu sup-
Among the grinding auxiliaries used for this study, namely
silica, sodium sulphate and neutral alumina, the best yield was
obtained with neutral alumina by ball-milling for 15 min (Table 1,
entry 4). Without a grinding auxiliary the reaction did not show
any satisfactory progress (Table 1, entry 6). Under argon atmo-
sphere the reaction was virtually arrested giving only 12% yield
which might be caused by the presence of traces of air (Table 1,
entry 7). As expected, the reaction under oxygen provided similar
Department of Organic Chemistry, Indian Association for the Cultivation of Science,
Jadavpur, Kolkata 700032, India. E-mail: ocbcr@iacs.res.in; Fax: +91-33-24732805
Electronic supplementary information (ESI) available: Copies of 1H NMR and 13C
3
Scheme 1 Aerobic oxidation of thiol to disulfide.
NMR spectra of all products listed in Table 2. See DOI: 10.1039/c3ra41996g
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18) and several alkane thiols (Table 2, entries 19–22) underwent
clean dimerization in this procedure. More significantly, a highly
functionalized alkane thiol, namely a Boc-protected l-cysteine
(Table 2, entry 23), also produced the corresponding disulfide.
This oxidation reaction is also highly chemoselective as a thiol
containing a –CH2OH group underwent oxidation only at the –SH
moiety without affecting the –CH2OH group (Table 2, entries 10
and 21).16
Table 1 Standardization of reaction conditions
Entry
Grinding auxiliary
Time (min)
Yielda (%)
In general, the reactions are very clean and fast (15–30 min).
The products were obtained in high purity and excellent yields
after a simple work-up. A wide spectrum of functional groups such
as Cl, Br, OMe, OH, NH2, CH2OH, COOH, NO2, F, BOCNH and
sensitive moieties such as furanyl and pyridinyl are compatible
with this reaction. The most significant feature of this procedure is
the non-involvement of any metal catalyst, co-oxidant, or additive
unlike other literature procedures performing aerobic oxidation
using a catalyst (metal or non-metal) in combination with air or
O2. Significantly, the grinding auxiliary, Al2O3, used in this
reaction does not contain any metal impurities as shown in its
EDX (Electron Dispersive X-ray) spectrum (Fig. 1). This supports
our view that this reaction proceeds under ball milling in the
absence of any metal oxidant. The grinding auxiliary, Al2O3, is
recovered, dried and recycled. Thus, this procedure is highly cost-
effective. Several disulfides obtained by this procedure are
associated with potent biological properties such as in vitro
leishmanicidal1b (Table 2, entries 1, 5, 7 and 14) and antibacterial
activities against gram positive and gram negative strains (Table 2,
entry 8).16 Several of these compounds are also used as important
ligands (Table 2, entries 8 and 11).17
1
2
3
4
Silica
Na2SO4
30
30
30
15
10
30
15
15
15
55
55
99
99
90
50
12
99
24
Neutral Al2O3
Neutral Al2O3
Neutral Al2O3
—
Neutral Al2O3
Neutral Al2O3
—
5
6
7b
8c
9d
a
b
Yields refer to those of isolated purified products. Reaction was
c
carried out under an argon atmosphere. Reaction was carried out
under an O2 atmosphere. Reaction was carried out in ethanol with
streaming O2 gas without ball-milling.
d
results as under air (Table 1, entry 8). When the reaction was
performed by bubbling O2 through a solution of thiophenol in
ethanol in a conventional way without ball milling, the progress
was marginal leading to only 24% conversion (Table 1, entry 9).
Thus, in a typical experimental procedure, the thiol (1 mmol)
adsorbed onto neutral alumina (3 g) was subjected to ball-milling
at 600 rpm using six balls (d = 10 mm) for 15–30 min as required
to complete the reaction (monitored by TLC/NMR). The product
was isolated by washing the reaction mixture with ethanol
followed by evaporation of the solvent, and in general, products
obtained were considerably pure (.95%). However, if needed,
further purification was performed either by recrystallization from
ethanol for solid compounds or by simple column chromato-
graphy on silica gel for liquids. All the products were identified by
3. Experimental
IR spectra were recorded on a Shimadzu 8300 FTIR spectrometer.
1H-NMR and 13C-NMR spectra were run on Bruker DPX-300 and
DPX-500 instruments. HRMS data were acquired on a Microtek
Qtof Micro YA263 spectrometer. All commercial reagents were
distilled before use. Neutral alumina (SRL, India) was used for all
the reactions.
comparison of their spectroscopic data (IR, H NMR, 13C NMR,
HRMS) with those reported in the literature (see experimental
section).
1
A wide range of diversely substituted thiols underwent aerobic
oxidation by this procedure to form the corresponding disulfides.
The results are reported in Table 2. A variety of aromatic thiols
containing both electron withdrawing (COOH, NO2 etc.) and
electron releasing groups (CH3, OCH3, OH, NH2 etc.) participated
in this reaction cleanly. Sterically hindered (Table 2, entry 9) and
densely fluorinated (Table 2, entry 13) thiophenols also underwent
this reaction to form the corresponding products without any
difficulty. The reaction of heteroaryl thiols, particularly thiols
containing a furan moiety which are rarely addressed in the
literature,10–12 is very successful in this procedure. Thus,
2-mercaptopyridine (Table 2, entry 14), 5-bromo-2-mercaptopyr-
idine (Table 2, entry 15), and 2-methyl-3-mercaptofuran (Table 2,
entry 16) provided the corresponding disulfides in high yields.
These heterocyclic disulfides are of high importance as potent
therapeutic agents.1b For example, dipyridinyl disulfide is used to
produce a dendritic cell-based vaccine for HIV-1.15 The furanyl
methane thiol (Table 2, entry 17), benzyl mercaptan (Table 2, entry
General procedure for the aerobic oxidation of thiols
Representative experimental procedure for the aerobic
oxidation of thiophenol (Table 2, entry 1). Thiophenol (110
mg, 1 mmol) adsorbed on neutral Al2O3 (3 g) was ball-milled in a
25 mL stainless steel vessel at 600 rpm using 6 balls (d = 10 mm)
for 15 min (PM 100, Retsch GmbH, Germany). The solid reaction
mass was then thoroughly washed with ethanol and the solvent
was evaporated to provide diphenyldisulfide as a white solid (196
1
mg, 99%). The spectroscopic data (IR, H NMR, 13C NMR) are in
good agreement with those of the authentic compound reported
earlier.
This procedure was followed for all the reactions listed in
Table 2. All of these products except one are known compounds
and are identified by comparison of their spectroscopic data with
those previously reported. 1,2-Bis(4-(4-nitrophenoxy)butyl)disul-
fane (Table 2, entry 22), which is a new compound, was
characterized by IR, 1H NMR, 13C NMR spectroscopy and
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Table 2 Aerobic oxidation of thiols to disulfides under ball-milling
Entry
1
Thiol
Time (min)
15
Product
Yielda (%)
99
2
3
4
20
20
20
98
98
96
5
6
7
8
15
15
20
15
98
98
98
97
9
30
95
10
11
20
30
96
95
12
25
95
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Table 2 (Continued)
Entry
13
Thiol
Time (min)
25
Product
Yielda (%)
96
14
15
16
20
20
25
96
98
97
17
18
20
15
96
98
19
20
20
20
98
95
21
22
20
20
96
97
23
30
96
a
Yields correspond to those of isolated purified products.
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(d, J = 8.5 Hz, 4H); 13C NMR (125 MHz, CDCl3) d 55.3 (2C), 114.6
(4C), 128.4 (2C), 132.6 (4C), 159.9 (2C).
4-(2-(4-Hydroxyphenyl)disulfanyl)phenol18 (Table 2, entry 7).
1H NMR (500 MHz, CDCl3) d 5.44 (s, 2H), 6.76 (d, J = 8.5 Hz, 4H),
7.34 (d, J = 8.5 Hz, 4H); 13C NMR (125 MHz, CDCl3) d 116.3 (4C),
128.6 (2C), 133.0 (4C), 156.2 (2C).
2-(2-(2-Aminophenyl)disulfanyl)benzenamine12b (Table 2, entry
8). 1H NMR (500 MHz, CDCl3) d 4.22 (s, 4H), 6.59 (t, J = 7 Hz, 2H),
6.71 (d, J = 8 Hz, 2H), 7.15 (t, J = 7 Hz, 4H); 13C NMR (125 MHz,
CDCl3) d 115.3 (2C), 118.3 (2C), 118.8 (2C), 131.7 (2C), 136.9 (2C),
148.7 (2C).
1,2-Bis(2,6-dimethylphenyl)disulfane12e (Table 2, entry 9). 1H
NMR (500 MHz, CDCl3) d 2.26 (s, 12H), 7.03 (d, J = 7.5 Hz, 4H),
7.12 (t, J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 21.5 (4C),
128.1 (4C), 129.4 (4C), 134.8 (2C), 143.5 (2C).
1,2-Bis(2-(hydroxymethyl)phenyl)disulfane19 (Table 2, entry
10). 1H NMR (500 MHz, DMSO-D6) d 4.59 (s, 4H), 5.44 (br s,
2H), 7.23–7.28 (m, 4H), 7.43 (d, J = 7 Hz, 2H), 7.51 (d, J = 7.5 Hz,
2H); 13C NMR (125 MHz, DMSO-D6) d 61.4 (2C), 128.1 (2C), 128.2
(2C), 128.4 (2C), 128.9 (2C), 134.1 (2C), 141.9 (2C).
1,2-Dithiosalicylic acid20 (Table 2, entry 11). 1H NMR (500
MHz, DMSO-D6) d 7.12 (s, 2H), 7.25 (s, 2H), 7.48 (s, 2H), 7.91 (s,
2H); 13C NMR (125 MHz, DMSO-D6) d 124.6 (2C), 125.0 (2C), 129.2
(2C), 130.5 (2C), 131.3 (2C), 138.7 (2C).
Fig. 1 EDX spectrum of neutral Al2O3 (used as the grinding auxiliary) on a Cu-grid.
HRMS. The characterization data of all the products included in
Table 2 are provided below in order of their entries.
1
1,2-Bis(4-nitrophenyl)disulfane12e (Table 2, entry 12). H NMR
(300 MHz, CDCl3) d 7.61 (d, J = 7 Hz, 4H), 8.18 (d, J = 7 Hz, 4H); 13
C
1,2-Diphenyldisulfane12f (Table 2, entry 1). 1H NMR (500 MHz,
CDCl3) d 7.25 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 4H), 7.54 (d, J =
7.5 Hz, 4H); 13C NMR (125 MHz, CDCl3) d 127.3 (2C), 127.7 (4C),
129.2 (4C), 137.2 (2C).
NMR (75 MHz, CDCl3) d 124.5 (4C), 126.5 (4C), 144.1 (2C), 147.1
(2C).
1,2-Bis(perfluorophenyl)disulfane21 (Table 2, entry 13). 19F
NMR (470 MHz, CDCl3) d 2162.52 (t, J = 20 Hz, 4F), 2150.88 (t,
J = 20 Hz, 2F) 2134.42 (d, J = 21 Hz, 4F); 13C NMR (125 MHz,
CDCl3) d 110.4 (t, J = 21 Hz, 2C), 137.9 (d, J = 256 Hz, 4C), 143.4 (d, J
= 258 Hz, 2C), 147.5 (d, J = 250 Hz, 4C).
1
1,2-Bis(4-chlorophenyl)disulfane12f (Table 2, entry 2). H NMR
(500 MHz, CDCl3) d 7.32 (d, J = 8.5 Hz, 4H), 7.45 (d, J = 8.5 Hz, 4H);
13C NMR (125 MHz, CDCl3) d 129.4 (4C), 129.5 (4C), 133.0 (2C),
135.3 (2C).
1
2-(2-(Pyridin-2-yl)disulfanyl)pyridine12f (Table 2, entry 14). H
1
1,2-Bis(4-bromophenyl)disulfane12a (Table 2, entry 3). H NMR
NMR (500 MHz, CDCl3) d 7.01 (s, 2H), 7.51 (s, 4H), 8.37 (s, 2H); 13
NMR (125 MHz, CDCl3) d 119.3 (2C), 120.8 (2C), 137.0 (2C), 149.1
C
(500 MHz, CDCl3) d 7.33 (d, J = 8.5 Hz, 4H), 7.42 (d, J = 8.5 Hz, 4H);
13C NMR (125 MHz, CDCl3) d 121.7 (2C), 129.5 (4C), 132.3 (4C),
135.9 (2C).
(2C), 158.4 (2C).
5-Bromo-2-(2-(5-bromopyridin-2-yl)disulfanyl)pyridine22
(Table 2, entry 15). 1H NMR (500 MHz, CDCl3) d 7.20 (s, 2H), 7.41
(s, 2H), 8.41 (s, 2H); 13C NMR (125 MHz, CDCl3) d 118.3 (2C), 121.3
(2C), 139.8 (2C), 150.4 (2C), 157.0 (2C).
1
1,2-Bis(2-bromophenyl)disulfane12c (Table 2, entry 4). H NMR
(500 MHz, CDCl3) d 7.08 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H),
7.53–7.56 (m, 4H); 13C NMR (125 MHz, CDCl3) d 121.2 (2C), 127.0
(2C), 128.0 (2C), 128.2 (2C), 132.9 (2C), 136.2 (2C).
2-Methyl-3-(2-(2-methylfuran-3-yl)disulfanyl)furan23 (Table 2,
1,2-Di-p-tolyldisulfane12f (Table 2, entry 5). 1H NMR (500 MHz,
CDCl3) d 2.38 (s, 6H), 7.17 (d, J = 8 Hz, 4H), 7.48 (d, J = 8 Hz, 4H);
13C NMR (125 MHz, CDCl3) d 21.0 (2C), 128.5 (4C), 129.8 (4C),
133.9 (2C), 137.3(2C).
1
entry 16). H NMR (300 MHz, CDCl3) d 2.1 (s, 6H), 6.38 (d, J = 7
Hz, 2H), 7.28 (d, J = 7 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 11.5
(2C), 112.8 (2C), 114.8 (2C), 140.9 (2C), 157.1 (2C).
1,2-Bis((furan-2-yl)methyl)disulfane18 (Table 2, entry 17). 1H
NMR (300 MHz, CDCl3) d 3.7 (s, 4H), 6.24 (d, J = 3 Hz, 2H), 6.34 (d,
1,2-Bis(4-methoxyphenyl)disulfane12f (Table 2, entry 6). 1H
NMR (500 MHz, CDCl3) d 3.78 (s, 6H), 6.84 (d, J = 8.5 Hz, 4H), 7.41
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J = 3 Hz, 2H), 7.40 (s, 2H); 13C NMR (75 MHz, CDCl3) d 35.6 (2C),
108.9 (2C), 110.7 (2C), 142.4 (2C), 150.1 (2C).
Acknowledgements
We acknowledge the financial support from CSIR, New Delhi
[01(2365)/10/EMR-II] and the J. C. Bose Fellowship Grant from
DST, New Delhi (SR/S2/JCB-11/2008). TC also thanks CSIR,
New Delhi for his fellowship.
1,2-Dibenzyldisulfane12f (Table 2, entry 18). 1H NMR (500 MHz,
CDCl3) d 3.76 (s, 4H), 7.26–7.32 (m, 6H), 7.36 (t, J = 7 Hz, 4H); 13
C
NMR (125 MHz, CDCl3) d 43.3 (2C), 127.5 (2C), 128.5 (4C), 129.5
(4C), 137.4 (2C).
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22.4 (2C), 29.1 (2C), 30.9 (2C), 39.5 (2C).
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Procedure for recycling of alumina (grinding auxiliary)
After the reaction was finished, Al2O3 was thoroughly washed with
ethanol several times to ensure the total desorption of the
disulfide. Then the alumina was washed with acetone and dried in
an oven at 80 uC for 3 h to prepare it for the next reaction cycle.
4. Conclusions
In summary, we have developed a novel and efficient protocol for
the synthesis of organodisulfides by aerobic oxidation of thiols
under ball-milling in the absence of any metal, co-oxidant,
additive, or solvent. The simple operation, general applicability
to aryl, heteroaryl and alkyl thiols, compatibility with a wide variety
of functionalities, no over-oxidation of the disulfides, short
reaction time and unique chemoselectivity make this procedure
a better alternative to previous ones. Moreover, the use of no
hazardous solvent, recyclability of the grinding auxiliary and high
yields of the products deliver a cost-efficient, greener and cleaner
methodology.
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