Efficient one-pot construction of unsymmetrical disulfide bonds with TCCA

Article abstract of DOI:10.1016/j.tetlet.2016.12.007

We report herein a one-pot synthesis of unsymmetrical disulfides with trichloroisocyanuric acid (TCCA) as an oxidant. Under facile conditions, aromatic-aromatic disulfides and aromatic-aliphatic disulfides were synthesized in good to excellent yields even

Full text of DOI:10.1016/j.tetlet.2016.12.007

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Tetrahedron Letters
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Please cite this article as: Yang, F., Wang, W., Li, K., Zhao, W., Dong, X., Efficient one-pot construction of
unsymmetrical disulfide bonds with TCCA, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.12.007
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Tetrahedron Letters
Tetrahedron Letters
Efficient one-pot construction of unsymmetrical disulfide bonds with TCCA
Feng Yang, Wen Wang, Kaidi Li, Weili Zhao* and Xiaochun Dong*
School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report herein a one-pot synthesis of unsymmetrical disulfides with trichloroisocyanuric acid
(TCCA) as an oxidant. Under facile conditions, aromatic-aromatic disulfides and aromatic-
aliphatic disulfides were synthesized in good to excellent yields even without base. For the
construction of the challenging aliphatic-aliphatic disulfides, good yields of the desired products
were also obtained with slightly modified conditions. Additionally, the reactions demonstrated a
wide range of substrate scope, very short reaction time (< 5 min), and convenient procedures. .
Available online
Keywords:
Unsymmetrical disulfide
TCCA
2016 Elsevier Ltd. All rights reserved.
One-pot reaction
1. Introduction
also reported as a chlorination reagent in the preparation of
unsymmetrical disulfide derivatives. Although significant
Disulfide bonds play important roles in the protein and protein
folding and stability.1 Disulfides also exist in many bioactive
natural products and have been applied extensively in organic
transformation and medicinal chemistry.2 As a recent example,
disulfide is frequently used as a fragment of the linker of
antibody-drug conjugates (ADCs) to allow the release of toxin
inside of tumor cells by GSH which is known to be abundant in
some kinds of tumors.3 Thus the facile construction of disulfide
bond becomes increasingly important.
progress has been reported in a one-pot procedure using 1-
chlorobenzotriazole, especially with the assistance of
benzotriazole,12,13 the low temperature (78 C) was required to
prepare the active sulfenyl derivative(s) and the relative
expensive 1-chlorobenzotriazole limited the applications.
Another one-pot method reported toxic DDQ as an oxidant,
unfortunately the reaction could not be applied to amino thiols or
sterially bulky tertiary thiols.16 Herein, we developed a facile,
convenient synthesis of unsymmetrical disulfide using
trichloroisocyanuric acid (TCCA).
In contrast to symmetrical disulfides which could be readily
obtained through direct oxidation of various thiols, the direct
construction of unsymmetrical disulfide is much more
challenging. Because of the high nucleophilicity and reductivity
of sulfur, the direct construction of unsymmetrical disulfide
bonds with two different thiols is hard to manipulate and
significant amount of symmetrical byproducts are always
produced. In the previously reported approaches, an active
sulfenyl derivative was first generated and coupled with the
second thiol to construct the unsymmetrical disulfide. The
reported sulfenyl derivatives mainly include sulfenyl chlorides,4
sulfenamides,5 dithioperoxyesters6, thionitrites,7 thiolsulfonates,8
sulfenyl thiocarbonates,9 thiophosphonium salts,10 2-pyridyl
disulfides and derivatives,11 and etc. However, it usually requires
the use of environment-unfriendly reagents as well as harsh
conditions to prepare the active sulfenyl derivatives, together
with very tricky reaction procedures. Several chlorination agents
have been reported to afford the sulfenyl chlorides intermediates,
such as 1-chlorobenzotriazole,12, 13 N-chlorosuccinimide (NCS),14
trichloroisocyanuric acid (TCCA).15 1-Chlorobenzotriazole was
Trichloroisocyanuric acid is now widely used in the
purification of drinking water as sanitizing agents and in
swimming pools replacing traditional bleaching agents. It is
widely used in synthesis as a chlorination and oxidation agent.17
TCCA was used to construct symmetrical disulfide bond,15
however, to the best of our knowledge, the feasibility of TCCA
for the construction of unsymmetrical disulfide directly has never
been explored so far. We expected that TCCA, as an alternative
of NCS, may generate active sulfenyl derivative under mild
conditions and construct the unsymmetrical disulfide with high
atom economy.14
2. Results and discussion
Inspired by the work of Hunter et al. using 1-
chlorobenzotriazole as oxidant,12,13 our initial screening of model
reaction conditions were carried out using p-methyl thiophenol
(p-tolSH) and tert-butyl thiol as reaction components in
dichloromethane (DCM) and analytical HPLC was used to
monitor the reaction. Considering each TCCA could possibly
provide three active chlorine atoms, we used 1 mole of both thiol
species and 0.33 mole of TCCA. We also briefly screened the
bases based on the facts that base(s) was required12,13 in the
previous reports of disulfide formation. It turned out that thiourea
_______
 Corresponding authors. Tel: +86-21-51980123 (X. Dong); e-
mail: zhaoweili@fudan.edu.cn (W. Zhao), xcdong@fudan.edu.cn
(X. Dong)

2
Tetrahedron Letters
and sodium bicarbonate and the combination thereof led to
Then significant efforts were focused on the temperature,
solvent, base and addition sequence. The selected results are
summarized in Table 1.
better yields of the desired product and less amount of
homodimer byproduct. Most interestingly, we found that even
without base, the desired product was generated nicely.
Meanwhile, the reaction could be complete at 0 C and in few
minutes.
Low temperature (e.g. 50 C) (Table 1, entry 1) retarded the
chlorination reaction and significant amount of homodimer
disulfide was produced. Raising temperature favored chlorination
reaction and the desired unsymmetrical disulfide products were
With the promising results from the initial test, we
subsequently applied p-tolSH (1) and 2-thiol-pyridine (2) as
coupling components to construct the unsymmetric disulfide and
optimized the reaction conditions, including the order of addition,
temperature, solvent and etc. (Scheme 1).
always obtained
20 C or 0 C, even to room temperature
(Table 1, entry 24). The optimal yield was obtained at 20C.
The above results carried out without base in dichloromethane
and 20 C was selected as the standard temperature. In the next
round of screening, we investigated base effect including
triethylamine, thiourea, and sodium bicarbonate (Table 1, entries
57). To our delight, the reaction without base always afforded
the best results wherein least amount of side product formed. But
we must emphasize the reaction solution must be neutralized
once the reaction finished otherwise the fragile disulfide will
break down in acidic circumstance. Solvents were screened
mainly based on their solubility for TCCA. Though TCCA is
easily soluble in acetone and ethanol, in these two solvents no
desired product was found at all presumably because of side
reactions from their active hydrogen (Table 1, entries 9 and 10).
Though almost identical yields in DCM and acetonitrile were
found, acetonitrile was selected as the preferred solvent due to
the high solubility (Table 1, entries 2 and 8). We were also
curious about the addition sequence, thus under reversed addition
manner wherein 2 was added firstly, then 1 was added later on.
The yield of the desired product was poor and large amounts of
symmetrical disulfide produced. In a control experiment, when
the mixture of thiols was used, moderate yield of unsymmetrical
disulfide produced. Herein the experimental results suggested
that the electron rich thiol should be added into the solution of
TCCA firstly to allow fast transformation into active sulfenyl
derivatives.
Scheme 1. Model reaction for unsymmetrical disulfide synthesis.
The control reactions of p-tolSH (1) were first investigated.
When the solution of 1 was added dropwise to the solution of
TCCA in DCM under 0 C, the original colorless solution
became light yellow, cloudy yellow and then cloudy white. TLC
analysis indicated that large amount of symmetrical disulfide was
generated subsequently. When 1 was added in portions into the
solution of TCCA, successive TLC detection showed that several
intermediates were formed. Additionally, it was noticed the
reaction mixture became very acidic when the solution turned to
yellow. After addition of 2-thiol-pyridine (2), around 40% yield
of the desired product was obtained, together with 30% of the
homodimer disulfide, di-p-tolyl disulfide. In stark contrast, when
the solution of 1 in DCM was poured into the solution of TCCA,
the solution became deep cloudy yellow and pH value of the
solution turned out to be 2, concurrently the temperature
increased from 0 C to 15 C. Remarkably, TLC analysis
indicated only trace of symmetrical disulfide was generated.
Subsequent addition of 2 into the reaction mixture resulted in
76% yield of the desired product.
As for the stoichiometric ratio, since the disulfide derivatives
frequently have similar nature which requires significant effort
for the purification of the product, in the situation that high yield
and minimum amount of byproduct formed under the current
situation wherein 3: 3: 1 ratio of thiols to TCCA was used, we
fixed such a ratio for the future reactions. Because of the efficient
transformations, the reaction was carried out without the need of
further efforts for optimization.
These results suggested that immediate transformation of thiol
into sulfenyl derivatives was critical for the generation of the
desired product. Thus it is strongly preferred to add the first thiol
in one portion into a solution of TCCA and then add the 2nd thiol
species quickly.
Table 1. Screening of conditions for unsymmetrical disulfide
With a successful model reaction in place, we subsequently
focused on exploring the various types of unsymmetrical
disulfide species namely aromatic–aromatic, aromatic-aliphatic,
and aliphatic–aliphatic to investigate the scope and limitations of
our one-pot disulfide formation methodology.
synthesis
T (C)
50
20
0
Base
Solvent
DCM
R1SSR1 (%)e
27.8
R1SSR2 (%)e
38.0
Entry
1a

2a
DCM
<2
86.8


Unsymmetrical aromatic-aromatic disulfide synthesis. In
this category, we selected aromatic thiols to explore the substrate
scope and mainly focused on the functional group tolerance as
well as electronic and steric influences of the substrate reactivity.
Thus a series of aromatic thiols with substituents of either strong
electron donating amino, methoxy, methyl group, slight electron
withdrawing bromo, chloro, fluoro group placed at the para,
meta, or ortho position was used. For electron deficient species,
2-thiol-pyridine and 2-thio-benzenecarboxylic acid were selected.
Reactions were run under the optimized set of conditions
described previously with the ratio of 3:3:1 of the thiol partners
and TCCA. The first thiol species was added in one portion into
the solution of TCCA in acetonitrile at 20 C and the second
thiol species was added immediately after 10 seconds. In most
cases, the reaction completed in 5 min and generated aromatic-
aromatic disulfide in good to excellent yields. The results are
collected in Table 2. In all the cases, excellent yields of the
desired product with only trace of homodimer byproduct were
obtained (Table 2, entries 18). In general, once the electron rich
aromatic thiol was added firstly, then the yield of the desired
unsymmetrical disulfide was formed in 8193% no matter if the
3a
DCM
8.4
76.0
4a
25
DCM
12.6
78.9

5b
20
20
20
20
20
20
20
20
Et3N
DCM
10.5
72.0
6b
Thiourea
DCM
8.4
51.0
7b
NaHCO3
DCM
25.2
50.0
8a
CH3CN
EtOH
<2
88.8

9a






10a
11 c
12 d
Acetone
CH3CN
CH3CN


27
18.9
52.1
25.2
a 1 was poured into TCCA, and then 2 was added.
b 1 was poured into TCCA, and the base was added, then 2 was added.
c 2 was poured into TCCA, and then 1 was added.
d the mixture of 1 and 2 was added together.
e Isolated yield.

Tetrahedron Letters
second thiol species was either electron deficient (Table 2, entries
was added first, good yields of the desired product were obtained
(Table 3). Several aromatic thiols containing methyl, bromo,
chloro, fluoro, carboxy substituent were adopted and the partner
thiols were selected from n-butyl thiol, n-octyl thiol, steric bulky
t-butyl thiol, reductive thioglycol, carboxyl containing 3-
mercaptopropanoic acid as alkyl thiol species, as well as α-tolyl
mercaptan as arylalkyl thiol species. In all cases, good to
excellent yields of the desired unsymmetrical disulfides were
obtained with only trace amount of the homodimer disulfides. As
notable examples, 3-mercaptopropanoic acid provided excellent
yields of the unsymmetrical disulfides wherein the free carboxyl
group may be convenient for derivatization (Table 3, entries 7
and 8).
15) or rich (Table 2, entries 79). Neither does steric congestion
affect the reaction yields to a noticeable degree (Table 2, entries
4 and 5). However, for the aromatic thiols with amino
substituents, no desired unsymmetrical disulfide was detected if
it was added first as described above, presumably due to the
chlorination of the amino group instead of the sulfur group
(Table 2, entry 10).
Unsymmetrical aromatic-aliphatic disulfide synthesis. In
this category, the order of the addition between the two thiols
becomes significantly important in this approach. Pouring the
aliphatic thiol first into the solution of TCCA always resulted in
large amounts of homodimers. In contrast, when aromatic thiol
Table 2: Yields of aryl-aryl unsymmetrical disulfide
Entry
1
R1SH
R2SH
R1SSR2
Isolated yield (%)
88.8
2
3
4
5
6
93.0
83.1
86.1
87.8
88.6
7
8
9
81.0
82.3
83.5
10
0
Table 3: Yields of aryl-alkly unsymmetrical disulfide

4
Tetrahedron Letters
Entry
1
R1SH
R2SH
R1SSR2
Isolated yield (%)
86.6
2
3
74.2
79.8
4
82.0
5
6
7
85.0
78.0
93.8
8
9
97.8
65.2
Unsymmetrical aliphatic-aliphatic disulfide synthesis. It has
substitution. Thus a possible solution was to facilitate the
formation of the sufenyl chloride intermediate. Eventually,
sodium hydride was used to convert thiol to thiol anion, which
was then chlorinated by quick addition of TCCA in acetonitrile.
The desired heterodimer was formed by subsequent fast addition
of the second thiol species. Using such a modified one-pot
strategy, several aliphatic-aliphatic disulfides were synthesized
and the results were shown in Table 4 (entries 14). Although the
yields were moderate in most cases, the convenience of the “one-
pot” synthetic procedures was the key advantage. One
extraordinary example was shown in Table 4 as entry 4 wherein
heterodimer from n-octyl thiol and 3-mercaptopropanoic acid
was produced nicely which may afford a convenient method to
construct disulfide bond for antibody-drug conjugation linkage.
been a general and challenging problem in the preparation of
unsymmetrical aliphatic-aliphatic disulfide.12,13 It was known that
desired heterodimer disulfides generally could not be separated
from homodimer byproducts in view of the non-polar nature of
the thiols used. Therefore, it is crucial to maximally avoid the
generation of homodimers in the reactions. Unfortunately, based
on the routine conditions we developed earlier, direct addition of
the aliphatic thiol into TCCA always resulted in large amount of
homodimer rapidly, which was possibly inevitable through
simple optimizations of reaction conditions. Considering
aliphatic thiol is more nucleophilic than aromatic thiol, we
attributed the homodimer formation to the relatively slower rate
of chlorination of thiol group compared to the nucleophilic
Table 4. Yields for aliphatic-aliphatic disulfide
Entry
R1SH
R2SH
R1SSR2
Isolated yield (%)
67.0
50.1
1
2
3
4
55.5
85.5
Reaction mechanism. Based on our experimental studies and
literature reports12, 14, a plausible mechanism was proposed for
our novel one-pot unsymmetrical disulfide synthesis (Scheme 2).
As shown in the mechanism, two possible sulfenyl intermediates
could be generated in the reaction between R1SH and TCCA, and
both would react with R2SH upon addition. The appearance of
yellow color in the reaction initially after the addition of TCCA
is in consistent with the observations from various reports as the
evidence of the formation of arylsulfenyl chloride13. Actually, 4-
methylbenzene sulfenyl chloride is a commercially available
yellow liquid. However, the arylsulfenyl may be converted to N-
sulfenyl isocyanuric acid, because the pH of the solution dropped
to 2 corresponding to the formation of hydrogen chloride in this
step. Following the addition of the second thiol, the intermediate
would be converted to the unsymmetrical disulfides. According
to our observation, in most cases, after the addition of the first

Tetrahedron Letters
thiol, the solution just became slightly cloudy but deep yellow,
and the solution turned very acidic, which may indicate the N-
sulfenyl isocyanuric acid is the possibly dominant intermediate.
Scheme 2. Proposed reaction mechanism for unsymmetrical disulfide formation.
3. Conclusion
J = 7.4 Hz, 2H), 1.47–1.36 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13
NMR (150 MHz, CDCl3) δ: 59.75, 40.50, 38.14, 30.55, 20.99,
13.02. HRMS (ESI): calcd. for C6H14S2ONa [M+Na]+ 189.0378,
found 189.0376.
C
In summary, we communicate here a one-pot synthesis of
unsymmetrical disulfide using TCCA as an oxidant. Under facile
conditions, stoichiometric ratio of reactants provided good to
excellent yields for the preparation of aromatic-aromatic
disulfides and aromatic-aliphatic disulfides. For the construction
of aliphatic-aliphatic disulfides, with modified conditions, good
yields of the desired products were also obtained. Additionally,
this approach demonstrated a wide range of substrate scope, very
short reaction time (< 5 min), convenient procedures and is more
environment-friendly compared with reported methods.
Acknowledgments
This work was supported by NSFC (21572037), FDUROP
(Fudan’s Undergraduate Research Opportunities Program,
14111) and National University Student Innovation Program
(201510246023).
Experimental Section
Supplementary Material
Procedure for aryl-aryl and aryl-alkyl unsymmetrical disulfide
as illustrated for entry1 in Table 2.
Supplementary data associated with this article can be found,
in the online version, at
To a stirred solution of TCCA (157 mg, 0.67 mmol) in
acetonitrile (20 mL) at 20 C was poured into a solution of 4-
methyl benzenethiol (250 mg, 2.01 mmol) in acetonitrile (3 mL).
After the mixture turned deep yellow, a solution of 2-thiol
pyridine (233 mg, 2.01 mmol) in acetonitrile (3 ml) was added
quickly to the mixture. The reaction mixture was kept stirring for
5 minutes and then neutralized with ammonia water. The
solution was evaporated under reduced pressure and the crude
solid was purified directly by silica gel column chromatography
References and notes
1.
2.
3.
a) Wedemeyer, W. J.; Welker, E.; Narayan, M.; Scheraga, H. A.
Biochem. 2000, 39, 4207; b) Góngora-Benítez, M.; Tulla-Puche, J.;
Albericio, F.; Chem. Rev. 2014, 114, 901.
a) Beletskaya, I.; Moberg, C. Chem. Rev, 1999, 99, 3535. b) Vrudhula,
V. M.; MacMaster, J. F.; Zhengong, L.; Kerr, D. E.; Senter, P.D.
Bioorg. Med. Chem. Lett, 2002, 12, 3591.
Zhao, R. Y.; Wilhelm, S. D.; Audette, C.; Jones, G.; Leece, B. A.;
Lazar, A. C.; Goldmacher, V. S.; Singh, R.; Kovtun, Y.; Widdison, W.
C.; Lambert, J. M.; Chari, R. V. J. J. Med. Chem., 2011, 54, 3606.
Brown, C.; Evans, G. R. Tetrahedron Lett, 1996, 37, 9101.
Bao, M.; Shimizu, M. Tetrahedron, 2003, 59, 9655.
Leriverend, C.; Metzner, P. Synthesis. 1994, 761.
1
to afford a light yellow liquid (430 mg, 1.85 mmol, 88.8%). H
NMR (400 MHz, CDCl3) δ (ppm): 8.47 (d, J = 3.9 Hz, 1H), 7.68
(d, J = 8.1 Hz, 1H), 7.63–7.58 (m, 1H), 7.42 (d, J = 8.1 Hz, 2H),
7.14–7.07 (m, 3H), 2.31 (s, 3H). 13C NMR (150 MHz, CDCl3) δ:
159.38, 148.90, 136.99, 136.57, 132.11, 129.28, 127.48, 120.15,
119.00, 20.41.
4.
5.
6.
7.
Oae, S.; Kim, Y. H.; Fukushima, D.; Shinhama, K. J. Chem. Soc.,
Perkin Trans. 1. 1978, 913.
Procedure for alkyl-alkyl unsymmetrical disulfide as
illustrated for entry1 in Table 4.
8.
9.
Rajca, A.; Wiessler, M. Tetrahedron Lett, 1990, 31, 6075.
Brois, S.J.; Pilot, J. F.; Barnum, H. W. J. Am. Chem. Soc., 1970, 92,
843.
To a stirred solution of sodium hydride (180 mg, 4.44 mmol)
in THF (10 mL) under argon protection at 20 C was added n-
butyl thiol (400 mg, 4.44 mmol). One minute later, a solution of
TCCA (342 mg, 1.48mmol) in acetonitrile (3 mL) was added
quickly, following quick addition of 2-mercaptoethanol (346 mg,
4.44 mmol). The reaction mixture was kept stirring for 5 minutes.
The solution was evaporated under reduced pressure and the
crude solid was purified directly by silica gel column
chromatography to afford a transparent liquid (500 mg, 3.01
mmol, 67.0%). 1H NMR (400 MHz, CDCl3) δ (ppm): 3.90 (t, J =
5.6 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 2.78–2.65 (m, 2H), 1.67 (dt,
10. Masui, M.; Mituki, Y.; Sakai, K.; Ueda, C.; Ohmori, H. J. Chem. Soc.,
Chem. Commun, 1984, 843.
11. Barton, D. H. R.; Chen, C. C.; Wall, M. G. Tetrahedron, 1991, 47,
6127.
12. Hunter, R.; Caira, M.; Stellenboom, N. J. Org. Chem., 2006, 71, 8268.
13. Stellenboom, N.; Hunter, R.; Caira, M. R. Tetrahedron, 2011, 66, 3228.
14. Abe, Y.; Nakabayashi, T.; Tsurugi, J. Bull. Chem. Soc. Jpn., 1973, 46,
1898.
15. Zhong, P.; Guo, M. P. Synth. Comm., 2001, 31, 1825.
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2011, 67, 8895.
17. Tilstam, U.; Weinmann, H. Org. Proc. Res. Dev., 2002, 6, 384.
Graphical Abstract

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Efficient one-pot construction of
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unsymmetrical disulfide bonds with TCCA
Feng Yang, Wen Wang, Kaidi Li, Weili Zhao* and Xiaochun Dong*

Tetrahedron
4
Highlights




A one-pot synthesis of unsymmetrical disulfide
with TCCA as oxidant was developed.
The reaction was finished within 5 min and
wide group tolerance was allowed.
Ar-Ar and Ar-Alkyl disulfides were
synthesized in good to excellent yields.
Challenging aliphatic-aliphatic disulfides could
also be obtained in good yields.