Phenylboronic acid-catalyzed tandem construction of S-S and C-S bonds: a new method for the synthesis of benzyl disulfanylsulfone derivatives fromS-benzyl thiosulfonates

Article abstract of DOI:10.1039/d0ob00442a

A unique phenylboronic acid-catalyzed dimerization-sulfonylation ofS-benzyl thiosulfonates has been disclosed. A metal-free tandem construction of S-S and C-S bonds is an operationally simple method to access a wide range of benzyl disulfanylsulfone derivatives in high to excellent yields. Moreover, the robustness of this tandem transformation has been demonstrated by gram-scale reactions, and a plausible mechanism is also proposed.

Full text of DOI:10.1039/d0ob00442a

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COMMUNICATION
Phenylboronic Acid-Catalyzed Tandem Construction of S-S and C-S
Bonds: A New Entry for the Synthesis of Benzyl Disulfanylsulfone
Derivatives from S-Benzyl Thiosulfonates†
Received 00th January 20xx,
Accepted 00th January 20xx
Raju Jannapu Reddy,*,a Md. Waheed a and Gamidi Rama Krishna b
DOI: 10.1039/x0xx00000x
A unique phenylboronic acid-catalyzed dimerization–sulfonylation popular therapeutic drugs (Figure 1b).10 Especially the alkyl
of S-benzyl thiosulfonates have been disclosed. A metal-free sulfones can serve as potential building blocks and also been
tandem construction of S-S and C-S bonds is an operationally simple used in several promising synthetic transformations.11 With
to access a wide range of benzyl disulfanylsulfone derivatives in increasing numbers of sulfone-containing bioactive
high to excellent yields. Moreover, the robustness of this tandem compounds10a,d,e has attracted much attention to developing a
transformation has been demonstrated by gram-scale reactions, facile methodology via a metal-free sulfonylation from simple
and a plausible mechanism is also proposed.
and easily available starting materials.
Disulfanes are widely present in nature1 where the S-S
bridge plays a critical role in protein folding and mediating the
biological activity of peptides in the living systems.2
Additionally, the sulfur-sulfur structural linkage able to release
a cellular singling hydrogen sulfide virtue of their pathological
and physiological properties.3 Meanwhile, the disulfide
framework found in organic functional materials,4 food
chemistry5 and pharmaceutical chemistry6 as presented in
Figure 1a. Given the significant importance of disulfanes, the
development of a general and metal-free protocol for the
synthesis of functionalized disulfanes is always desirable.
Although numerous effective strategies have been
developed for the synthesis of both symmetrical and
unsymmetrical disulfanes,7-9 however, the construction of
unsymmetrical disulfides still a great interest. Generally, the S-
S bond formation8 involving either SN2 replacement or oxidative
cross-coupling of two different thiols. Alternatively, C-S bond
construction9 is a more straightforward approach through
disulfur (RSS) group transfer have been disclosed by Wang9a
Jiang,9c-e Xian9f and other groups. Despite these advances, the
transition-metal free methodologies are highly desirable due to
the unavoidable metal contamination could be a severe
problem in the pharmaceutical formulation process.
(a) Representative bioactive disulfanes
S
OHC
S
N
S
S
N
S
S
N
S
N
OH
S
N
NH2
O
S
Z-Ajoene
(anti-thrombotic drug)
Prosultiamine
(Vitamin B1 deficiency drug)
Disulfiram
(anti-alcoholic drug)
(b) Representative bioactive sulfones
O
N
O
O
N
O
O
S
N
S
N
S
O
O
O2N
Tinidazole
(protozoan infections)
Cl
N
H
Eletriptan
(antimigraine)
Chlormezanone
(muscle relaxant)
Figure 1. Biologically relevant organosulfur compounds.
Compared with different organosulfur substrates, the
thiosulfonates12 are generally stable crystalline solids, easy to
handle and broadly accessible versatile precursors with low
toxicity. Recently, Xu and co-workers reported electrophilic
disulfuration between S-tert-butyl p-toluenesulfono(dithio-
peroxoate) and arylboronic acids could deliver the
unsymmetrical disulfanes via persulfur transfer reaction
(Scheme 1a).9b Inspired by the works as mentioned earlier, we
envisioned that the S-benzyl thiosulfonates would be right
starting material to react with phenylboronic acid in the
presence of copper-catalysis. The anticipated benzyl phenyl
sulfide (I) would form by cleavage of weak S-S bond and the
construction new C-S bond (Scheme 1b). Instead, we overjoyed
to obtain the unprecedented benzyl disulfanylsulfone (II) via
phenylboronic acid (PBA)-catalyzed dimerization-sulfonylation
through the tandem construction of S-S and C-S bonds. We have
also realized the incorporation of sulfone moiety into disulfane
framework may increase their biological properties
significantly. Indeed, our attention turns to develop a new and
potent method toward sulfonyl derived disulfane variants.
In contrast, the sulfones are yet another class of privileged
functional scaffold due to their widespread applications in
biological, agrochemicals and materials chemistry as well as
a. Department of Chemistry, University College of Science, Osmania University,
Hyderabad
rajuchem08@yahoo.co.in
b. X-ray Crystallography, CSIR-National Chemical Laboratory, Pune 411 008, India.
Electronic Supplementary Information (ESI) available: [details of any
500
007,
India.
E-mail:
rajuchem77@osmania.ac.in;
†
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
Boronic acid (BA)-catalyzed methodologies offer a powerful
platform for rapid and efficient construction of carbon-carbon
and carbon-heteroatom bonds in organic synthesis.13 As part of
our ongoing research programme on organosulfur chemistry,14
Table 1. Optimization for the synthesis of benzyl disulfanylsulfone.a
View Article Online
DOI: 10.1039/D0OB00442A
O
Ph
O
S
O
O
S
R-B(OH)2, Base, Solvent
Temp (90 oC), Time
Ph
S
Ph
S
Ph
Ph
B(OH)2
S
herein, we disclose
a novel and extremely efficient
1aa
2aa
phenylboronic acid-catalyzed dimerization–sulfonylation of S-
benzyl thiosulfonates to access a variety of benzyl disulfanyl-
sulfones. To the best of our knowledge, the direct assemble of
two different sulfur moieties on the same carbon-atom using
thiosulfonates is remains underexplored.14c,15
B(OH)2
B(OH)2
B(OH)2
B(OH)2
I
: R = H
II
: R = Cl
: R = CN
III
N
OH
H
IV
V
VII
: R = OMe
VI
VIII
R
Entry
1
2
3
4
5
6
7
ArB(OH)2
Base (equiv)
Solvent Time
Yield b
87%
94%
97%
71%
86%
80%
NR
65%
78%
73%
72%
89%
71%
85%
10%
traces
NR
I (10 mol%)
I (20 mol%)
I (20 mol%)
II (20 mol%)
III (20 mol%)
IV (20 mol%)
V (20 mol%)
VI (20 mol%)
VII (20 mol%)
VIII (20 mol%)
I (20 mol%)
I (20 mol%)
I (20 mol%)
I (20 mol%)
I (20 mol%)
I (20 mol%)
I (20 mol%)
I (20 mol%)
I (20 mol%)
I (20 mol %)
K2CO3 (2.0 eq)
K2CO3 (2.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (0.5 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
Cs2CO3 (1.0 eq)
Na2CO3 (1.0 eq)
DABCO (1.0 eq)
DBU (1.0 eq)
K2CO3 (1.0 eq)
K2CO3 (1.0 eq)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DCM
DCE
4 h
3 h
3 h
16 h
6 h
a) Previous work
: Synthesis of disulfanes via C-S bond construction
O
O
CuSO4 (20 mol%), NaHCO3
MeOH, 60 oC, 12 h
S
Ar
S
S
+
Tol
ArB(OH)2
S
R
S
R
20
Ref. Xu et. al., Org. Lett., 2018, , 3829-3832.
8 h
b) Present work:
16 h
24 h
4 h
4 h
3 h
3 h
16 h
3 h
16 h
16 h
16 h
3 h
16 h
6 h
Tandem construction of S-S and C-S bonds
8
9
Ph
PhB(OH)2
X
Ar1
S
O
O
CuI (20 mol%), K2CO3
I
( )
10
11
12c
13d
14e
15
16
17
18
19d
20f
Ar1
Ar1,2 = aryl, heteroaryl
S
S
Ar2
Ar2
O
S
PhB(OH)2 (20 mol%)
O
K2CO3, PhCl, 90 o
C
S
Ar1
Ar1
S
Dimerization-Sulfonylation
II
( )
Scheme 1. Stratgies for the synthesis of disulfanes using thiosulfonates.
mix
53%
77%
With a motivation of our previous work on thiosulfo-
nates,14b-f we commenced our investigations by choosing S-
benzyl benzenesulfonothioate (1aa) as a model substrate. The
optimization results were summarized in Table 1 (also see
Table-S1 in the ESI for a detailed survey of reaction conditions).
Firstly, the phenylboronic acid (I)-catalyzed reaction of 1aa with
a Unless otherwise specified, all reactions performed on a 0.2 mmol scale in
solvent (1 mL) at 90 oC. b Isolated yield. c PhCl (2 mL) used. d At 50 oC. e At 110
oC. f At 80 oC.
K2CO3 (1 to 2 equiv) in chlorobenzene (PhCl) gave the desired Table 2. Substrate scope for the synthesis of benzyl dithiosulfones.a,b
O
product 2aa in high to excellent yields (entries 1-3). Notably, a
smooth conversion of 1aa with 20 mol% PBA and 1.0 equiv
K2CO3 in PhCl at 90 oC afforded 2aa in 97% yield (entry 3). Next,
a series of boronic acid derivatives (II to VIII) are also
investigated. The use of aryl-substituted boronic acids (II to V)
were unsuccessful in improving the reaction efficiency (entries
4-7). The reaction was slow with indole-5-boronic acid (entry 8),
in contrast, the aliphatic boronic acids (VII and VIII) provided
2aa in 78% and 73% yields, respectively (entries 9-10). Further,
fine-tuning the reaction condition concerning the amount of
K2CO3 (0.5 equiv); the role of concentration as well as the effect
of temperature failed to improve the reaction competency
(entries 11-14). Among various bases (Cs2CO3, Na2CO3, DABCO
and DBU) were studied (entries 15-18), the K2CO3 found to be
an optimal base for this transformation. Changing other
chlorinated solvents (DCM and DCE) further evaluated to afford
the desired product 2aa in 53% and 77% yields, respectively
(entries 19-20).
Ar
S
O
O
O
S
PhB(OH)2 (20 mol%)
K2CO3 (1 equiv), PhCl, 90 oC, 3 h
S
S
S
Ar
1a(a-l)
2a(a-l)
F
O
O
O
S
S
S
O
O
O
S
S
S
S
S
S
2ab: 98%
2ac: 91%
2aa: 96%
Cl
Br
MeO
O
O
O
O
S
S
O
O
S
S
S
S
S
S
S
2ad: 88%
2ae: 90%
2af: 94%
O2N
O
O
O
S
S
S
O
O
S
O
S
S
S
S
S
S
2ag: 87%
2ai: 86%
2ah: 89%
With optimized reaction conditions in hand, we next
proceeded to explore the generality of the reaction at different
substitutions of aryl sulfones (Table 2). A series of S-benzyl
thiosulfonates 1a(a-l) were compatible to afford the
corresponding disulfanes 2a(a-l) under the same reaction
conditions. Gratifyingly, both electron-donating and electron-
withdrawing substituents at the para position of thiosulfonates
NO2
O
O
O
S
S
O
O
S
O
S
S
S
S
S
S
2al: traces
2ak: 82%
2aj: 78%
a All reactions were performed a 0.5 mmol scale of 1a(a-l) (1.0 equiv), PBA (20
mol%), K2CO3 (1.0 equiv) in PhCl (2.5 mL) at 90 oC for 3 h. b Isolated yield.
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
1a(a-h) were well-tolerated and produced the disulfanyl provide the pseudosymmetrical dimers (2i,k/a) in satisfactory
View Article Online
DOI: 10.1039/D0OB00442A
sulfones 2aa-ah in excellent yields. On the whole, a little yields. Sterically bulky 2-chloroquinoline derived unsymmetrical
electronic effect was observed in this transformation (cf. 2af vs disulfane 2la was obtained in 72% yield with a low purity as
2ag). The 2-thiophenyl and naphthyl derived thiosulfonates compared. Disappointingly, the thiosulfonates (1ma and 1nb)
(1ai-k) gave desired products (2ai-k) in 78–86% yields. were poor substrates for this transformation to provide the
Surprisingly, the reaction with 2-nitrophenyl derived anticipated products. Interestingly, the 2-thiophenyl (1oa) and
thiosulfonate 1al proceeded sluggishly to form 2al in traces allyl derived (1pa) thiosulfonates led to form the corresponding
under the same conditions.
products (2o,p/a) with an inseparable mixture of by-products.
Encouraged by these results, the substrate scope of the
To highlight the viability of the tandem process, the
reaction was further explored and summarized in Table 3. The reactions performed in a gram-scale under the standard
tandem process works well for an array of benzyl substituted reaction conditions. As shown in Scheme 2, a 5 mmol reaction
thiosulfonates. As expected, various 4-alkyl substituted benzyl scale of S-benzyl benzenesulfonothioate 1aa and S-benzyl 4-
thiosulfonates 1(b-d)a/b were smoothly produced desired methylphenylsulfonothioate 1ab were conducted to yield the
products 2(b-d)a/b with no apparent effect on the outcome. desired products in 0.90 g (93%) of 2aa and 0.95 g (95%) of 2ab;
The para-chloro and para-bromobenzyl thiosulfonates (1e,f/a) thus the protocol could be readily scalable without any
gave desired products 2ea and 2fa in 85% and 83% yields, deviation on efficiency.
respectively. Unambiguously, the structure of 2fa was
confirmed by single-crystal X-ray data analysis (see the ESI).16
SO2Ar
O
O
S
Standard conditions
Pleasingly, the 1- and 2-naphthyl derived thiosulfonates
(1g,h/a) afforded the anticipated disulfanylsulfones (2g,h/a) in
high yields. Various 2-halobenzyl thiosulfonate derivatives
(1i,k/a) were also a suitable substrate for the transformation to
S
Ph
S
Ar
Ph
S
Ph
5 mmol scale
1aa 1.32 g
1ab 1.39 g
(
(
)
)
2aa:
2ab:
(0.90 g)
(0.95 g)
93%
95%
Scheme 2. Gram-scale reactions for the synthesis of 2aa/b.
Table 3. Substrate scope for the synthesis of benzyl
Next, the synthetic usefulness of structurally diverse
disulfanylsulfones (2aa/b) was examined (Scheme 3). The
treatment of potassium acetate (KSAc) in CH3CN at room
temperature and the expected product (4) does not form under
this condition. To our surprise, the benzyl disulfide (5) was
obtained in modest yield by simple desulfonylation process.
disulfanylsulfones.a,b
R
O
O
O
S
S
O
X
S
S
PhB(OH)2 (20 mol%)
K2CO3 (1 equiv), PhCl, 90 oC, 3 h
S
S
S
X
X
1
2
R
O
O
O
S
S
O
O
O
SO2Ar
SAc
S
S
S
S
S
KSAc (2 equiv)
CH3CN, rt, 2 h
S
S
Ph
2aa
S
Ph
S
S
: Not formed
Ph Ph
+
Ph
S
Ph
4
2ca: 88%
2ba: 90%
2bb: 92%
5
5
: 45% (from
: 39% (from
)
2aa / 2ab
2ab
)
O
O
O
Cl
S
O
S
S
O
O
Scheme 3. Synthesis of benzyl disulfane 5 via desulfonylation.
S
S
S
S
S
S
Cl
2ea: 85%
2da:87%
2cb: 89%
To understanding the reaction mechanism, a few control
experiments were conducted for dimerization–sulfonylation
reactions (Scheme 4). The reaction performed with a 1:1
mixture 1aa and 1ab under standard conditions afforded the
1:2.4 of 2aa and 2ab, thus implying the reaction possibly going
O
O
S
O
Br
S
S
S
O
S
S
Br
2ga: 84%
2fa: 83%
CCDC#1987266
1
through an intermolecular fashion (Scheme 4a; see ESI for H-
O
NMR). The standard reaction was employed with 1.5 equiv of
benzyl mercaptan afforded the unexpected benzyl disulfide (5)
in 45% yield (Scheme 4b), whereas no reaction the use of benzyl
mercaptan alone (Scheme 4c). To worth note the benzyl
mercaptan suppressed the formation of disulfanylsulfone 2ab,
it may lead to the formation benzyl disulfide only. Further, the
standard reaction was performed in the presence of radical
scavengers (Scheme 4d). With BHT the product 2ab was isolated
in 77% yield; however, the reaction with TEMPO entirely not
clear. Additionally, the reaction with NBS to produce the
disulfone (6)17 in 78% yield (Scheme 4e).
O
S
O
O
F
S
Br
O
S
O
S
S
S
S
S
S
2ha: 87%
2ia: 82%
F
Br
2ja: 79%
O
O
O
Cl
N
Cl
S
Cl
Cl
S
S
S
O
O
O
S
S
S
S
S
2la: 72%
N
Cl
2ma: NR
2kb: 81%
Cl
Cl
Cl
O
O
O
S
CN
S
S
S
O
S
O
O
S
S
S
S
S
S
2oa: impurec
2pa: impurec
2nb: NR
NC
a All reactions were performed a 0.5 mmol scale of 1a(a-l) (1.0 equiv), PBA (20
mol%), K2CO3 (1.0 equiv) in PhCl (2.5 mL) at 90 oC for 3 h. b Isolated yield. c The
obtained products were not in the pure form.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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COMMUNICATION
Journal Name
We have successfully developed metal-fVreiewe ArtticalenOdnelimne
construction of S-S and C-S bonds for tDhOeI:s1y0n.1t0h3e9s/iDs0oOfB0b0e4n4z2yAl
disulfanylsulfone derivatives using easily accessible S-benzyl
thiosulfonates as starting materials. An unprecedented
phenylboronic acid (PBA)-catalyzed protocol is easy to perform
under mild reaction conditions and the obtained products
bearing two different sulfur moieties on the same carbon-atom,
which were difficult to prepare by other methods. Remarkably,
the dimerization–sulfonylation has established by its broad
substrate scope and proved at the gram-scale reactions.
Further, mechanistic studies and applications are currently
underway in our laboratory.
SO2Ar
S
SO2Ar
Standard conditions
S
Ph
(a)
(b)
(c)
Ph
S
Ph
1aa 1ab (1:1)
+
2aa 2ab: 1:2.4
+
Ts
Standard conditions
S
Ph
Ph
S
Ph
Ph
S
PhCH2SH (1.5 equiv)
1ab
5:
45%
Standard conditions
S
Ph
Ph
SH
S
5:
Not formed
Ts
Ts
Standard conditions
S
Ph
Ph
S
(d)
(e)
Ph
Ph
S
radical scavenger
1ab
2ab
2ab
BHT
:
(77%)
(messy)
(2.0 equiv)
TEMPO :
Conflicts of interest
There are no conflicts to declare.
O
S
O
Ts
Tolyl
Standard conditions
S
S
Tolyl
NBS (2.0 equiv)
O
O
1ab
6
: 78%
Acknowledgements
Scheme 4. Control experiments for the formation of disulfanylsulfones.
We thank CSIR-EMR-II [02(0340)/18/EMR-II] and SERB-ECR
[ECR/2015/000053], New Delhi for financial assistance. RJR
thanks to UGC for faculty position under Faculty Recharge
Programme and Start-up grant (F.4-5/2006/BSR). Our special
thanks to OUDST-PURSE (SR/PURSE Phase 2/32/G) programme
for partial funding support. MW thank UGC for his Senior
Research Fellowship (SRF).
Based on literature precedents,13,18 a plausible mechanism
was proposed to rationalize the experimental outcome and the
control experiments (Scheme 5). The ionic mechanism may
initiated by the Lewis acidity of boron species of phenylboronic
acid, it may coordinate with a sulfur moiety of thiosulfonate led
to form B–S complex A.13,18c The cleavage of S-SO2 bond and
benzylic proton abstraction18a,b in the presence of K2CO3 would
generate sulfinic acid B and boron-sulfonium zwitterion C.18c
Subsequent construction of the C-S bond through the
sulfonylation of C with sulfinic acid B will allow to form
intermediary D, which prone to react with another unit of
benzyl thiosulfonate. Finally, the formation S-S bond lead to
desired product 2 and active phenylboronic acid catalyst would
be regenerated for the further catalytic process.
Notes and references
1
Selected articles: (a) B. Ren, G. Tibbelin, D. Pascale, M. Rossi,
S. Bartolucci and R. Ladenstein, Nat. Struct. Mol. Biol., 1998,
5, 602; (b) R. X. Tan, P. R. Jensen, P. G. Williams and W. Fenical,
J. Nat. Prod., 2004, 67, 1374; (c) D. H. Scharf, A. Habel, T.
Heinekamp, A. A. Brakhage and C. Hertweck, J. Am. Chem.
Soc., 2014, 136, 11674; (d) P. Chankhamjon, D. Boettger-
Schmidt, K. Scherlach, B. Urbansky, G. Lackner, D. Kalb, H.-M.
Dahse, D. Hoffmeister and C. Hertweck, Angew. Chem. Int.
Ed., 2014, 53, 13409; A leading review: (e) C.-S. Jiang, W. E. G.
Müller, H. C. Schröder and Y.-W. Guo, Chem. Rev., 2012, 112,
2179.
(a) Sulfur Chemistry, X. F. Jiang, Ed., Top. Curr. Chem.,
Springer: Berlin, 2019; (b) J. Zhao and X. Jiang, Chin. Chem.
Lett., 2018, 29, 1079; (c) M. Góngora-Benítez, J. Tulla-Puche
and F. Albericio, Chem. Rev., 2014, 114, 901; (d) T. M. Postma
and F. Albericio, Eur. J. Org. Chem. 2014, 3519; (e) K.C.
Nicolaou, M. Lu, S. Totokotsopoulos, P. Heretsch, D. GiguHre,
Y. P. Sun, D. Sarlah, T. H. Nguyen, I. C. Wolf, D. F. Smee, C. W.
Day, S. Bopp and E. A. Winzeler, J. Am. Chem. Soc., 2012, 134,
17320; (f) P. J. Hogg, Trends Biochem. Sci., 2003, 28, 210; (g)
M. Narayan, E. Welker, W. J. Wedemeyer and H. A. Scheraga,
Acc. Chem. Res., 2000, 33, 805.
SO2Ar2
O
PhB(OH)2 (20 mol%)
K2CO3 (1 equiv)
O
S
Ar1
S
1
S
Ar1
Ar1
S
2
Ar2
PhCl, 90 o
C
PhB(OH)2
(20 mol%)
2
O 3
C
K 2
SO2Ar2
Ar1
Ar2
H
OH
B
S
H
Ph
O
Ar1
S
Ar1
S
D
S
A
O
O
Ph
HO
B
S
O
H
Ar2
O
O
O 3
3
4
Selected articles: (a) M. R. Filipovic, J. Zivanovic, B. Alvarez and
R. Banerjee, Chem. Rev., 2018, 118, 1253; (b) J. Bełtowski,
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Cremers and U. Jakob, J. Biol. Chem. 2013, 288, 26489; (e) J.
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Shashikala, Y. Cui, Y. Losovyje and Y. Fu, J. Mater. Chem., A,
O
O
C
S
K 2
S
Ar2
OH
B
HO
Ar2
HO
Ph
B
B
Ar1
S
OH
C
Scheme 5. Postulated tentative mechanism catalyzed phenylboronic acid.
Conclusions
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
COMMUNICATION
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