Syntheses of thiol and selenol esters by oxidative coupling reaction of aldehydes with RYYR (Y = S, Se) under metal-free conditions

Article abstract of DOI:10.1039/c4ob01159g

Thiol and selenol esters were synthesized by a direct oxidative coupling reaction of aldehydes with disulfides or diselenides in ethyl acetate under metal-free conditions. Among the oxidants examined, tert-butyl peroxide (TBP) was shown to give the best results. For the substrates with both electron-donating and electron-withdrawing substituents, the reaction proceeded smoothly and gave moderate to good yields. Compared with the previous method, the present route is very simple, atom-economical and environmentally friendly. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01159g

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Syntheses of thiol and selenol esters by oxidative
coupling reaction of aldehydes with RYYR (Y = S,
Se) under metal-free conditions†
Cite this: Org. Biomol. Chem., 2014,
12, 6072
Received 5th June 2014,
Accepted 1st July 2014
Chunhuan He,a Xuewei Qiana and Peipei Sun*a,b
DOI: 10.1039/c4ob01159g
www.rsc.org/obc
Thiol and selenol esters were synthesized by a direct oxidative other disulfides showed poor reactivity. A hypervalent iodine
coupling reaction of aldehydes with disulfides or diselenides in reagent (DMP) was employed as the oxidant to synthesize
ethyl acetate under metal-free conditions. Among the oxidants thioesters from aldehydes and thiophenol,10 but excess explo-
examined, tert-butyl peroxide (TBP) was shown to give the best sive sodium azide had to be used as the activator. Recently, the
results. For the substrates with both electron-donating and elec- NHC or TEAB-catalyzed thioesterifications of aldehydes with
tron-withdrawing substituents, the reaction proceeded smoothly thiols were also developed, in which phenazine, Na2S2O8, or
and gave moderate to good yields. Compared with the previous electrochemical oxidation was employed.11 Our research inter-
method, the present route is very simple, atom-economical and est continuously focuses on developing efficient and environ-
environmentally friendly.
mentally benign routes for the construction of carbon–carbon
and carbon–heteroatom bonds, especially the direct oxidative
coupling reactions under the metal-free conditions.12 We now
wish to report an effective route to synthesize thiol and selenol
esters by a direct oxidative coupling reaction of aldehydes with
disulfides or diselenides using a simple oxidant.
Chalcogenoesters, especially thiol and selenol esters, are not
only biologically active building blocks playing central roles
in living cells1 but also important organic precursors used in
synthetic chemistry.2 There is growing interest in developing
effective organic transformations for the preparation of this
class of compounds in this context, but available preparative
methods are still limited. The vast majority of reported
approaches have employed acyl chlorides or aldehydes with
nucleophilic organic sulfide or organic selenide species, e.g.,
organometallic reagents.3 Metal-catalyzed transformations
have been widely studied for this purpose in recent years, by
this means metals such as Pd,4 Rh,5 Cu,6 Zn,7 In,8 etc. have
been used as catalysts. Nevertheless, the reactions under
metal-free conditions are desired particularly in the pharma-
ceutical synthesis. Several oxidative couplings from aldehydes
in the absence of a metal for the preparation of thioesters have
been reported in the last decade. Kita et al.9 reported a syn-
thesis of thioesters from aldehydes and disulfides by a radical-
mediated coupling in the presence of an azo-type initiator
under the metal-free conditions, in which disulfides were used
as the sulfur source. Unfortunately, only the reaction of penta-
fluorophenyl disulfide gave moderate to good yields, while
Initially the optimization of the reaction conditions for the
thioesterification of aldehydes was carried out using the
simple compounds diphenyl disulfide (1a) and benzaldehyde
(2a) as the substrates (Table 1). Previous reports revealed that
peroxide is an effective radical initiator (oxidant) for aldehydes
to generate the acyl radical.13 Thus 2 equiv. tert-butyl peroxide
(TBP) was first selected as the oxidant. To our delight, in ethyl
acetate (EA) at 120 °C, the reaction gave a desired oxidative
coupling product phenyl benzothioate (3aa) in 79% yield
(entry 1). For improving the yield, several Cu compounds such
as Cu(OAc)2, CuBr and CuI were tested as the catalyst. The
results showed that the presence of such compounds was not
helpful in affording the product (entries 2–4). But if the
amount of TBP is increased to 4 equiv., a yield of 90% could
be achieved in the absence of any metal catalyst (entry 5). The
oxidant was proved to have a considerable effect on the reac-
tion. Among the set of oxidants examined, TBP gave the
highest yield, while H2O2, dicumyl peroxide (DCP) and benzoyl
peroxide (BPO) gave inferior results (entries 6–8), and tert-butyl
hydroperoxide (TBHP), K2S2O8 and O2 failed to produce the
target product (entries 9–11). In the case of the solvents, ethyl
acetate was found to be superior to CH3CN and 1,2-dichloro-
ethane (DCE) (entries 12 and 13). In water, the reaction could
not take place at all (entry 14). The reaction temperature was
also investigated. The most suitable temperature was proved to
aJiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and
Materials Science, Nanjing Normal University, Nanjing 210097, China
bJiangsu Collaborative Innovation Center of Biomedical Functional Materials,
Nanjing 210023, China. E-mail: sunpeipei@njnu.edu.cn; Fax: +86-25-85891767;
Tel: +86-25-85891767
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob01159g
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Table 1 Screening of reaction conditionsa
Table 2 The reaction results of aldehydes with disulfidesa,b
Entry
Catalyst (mol%)
Oxidant (equiv.)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (4)
H2O2 (4)
DCP (4)
BPO (4)
TBHP (4)
K2S2O8 (4)
O2 (1 atm)
TBP (4)
TBP (4)
TBP (4)
TBP (4)
TBP (4)
TBP (4)
EA
EA
EA
EA
EA
EA
EA
EA
EA
EA
EA
CH3CN
DCE
H2O
EA
EA
EA
79
70
42
61
90
62
24
33
Trace
Trace
Trace
85
43
0
71
70
92
Cu(OAc)2 (10)
CuBr (10)
CuI (10)
9
10
11
12
13
14
15c
16d
17e
a Unless otherwise specified, the reaction was carried out in a sealed
tube in the presence of 1a (0.5 mmol), 2a (1.2 mmol), solvent (1 mL),
catalyst (10 mol%), and oxidant at 120 °C under an Ar atmosphere for
12 h. b Isolated yield. c Under air. d At 100 °C. e At 140 °C.
be 120 °C. Lowering the temperature to 100 °C brought a
decrease in the yield (entry 16), yet increasing it to 140 °C did
not exhibit obvious promotion in the reaction yield (entry 17).
It is noteworthy that an inert atmosphere was helpful for the
present transformation. When the reaction took place in air, a
lower yield of 71% was obtained (entry 15).
With the optimal conditions in hand, we next explored the
oxidative thioesterification of various aldehydes with disulfides
(Table 2). For the thioesterification of benzaldehyde, a series
of aryl disulfides and alkyl disulfides were employed as the
coupling partners. Delightedly, aryl disulfides substituted with
both electron-donating groups (Me, OMe) (3ba, 3ca) and elec-
tron-withdrawing groups (Br, Cl) (3da–ga) on the aromatic ring
reacted with benzaldehyde to give the desired thiol esters in
moderate to good yields (3ba–ga), and the connection position
of substituents had no obvious effect on this coupling reaction
(3da–fa). When a heterocyclic compound 2-(2-(benzo[d]thiazol-
2-yl)disulfanyl)benzo[d]thiazole (1i) was used as the thioaryl
reagent, it gave a moderate yield of 58% (3ia). Similar to aryl
disulfides, the reaction of aliphatic disulfides also gave good
yields (3ha, 3ja). The reactions of various aldehydes were
further investigated. As it was revealed in disulfides, the reac-
tion could proceed smoothly whether electron-donating or
electron-withdrawing groups substituted on the benzene ring
of the aldehydes, even though the yields were somewhat lower
when the electron-donating groups existed. When heterocyclic
aromatic aldehydes were used, the reaction gave moderate
yields (3al, 3am). Compared with the aromatic aldehydes, the
aliphatic aldehydes propylaldehyde (2n) and isobutylaldehyde
(2o) gave the corresponding products in lower yields (3an,
3ao).
a Reaction conditions: 1 (0.5 mmol), 2 (1.2 mmol) and TBP (4.0 equiv.),
in EA (1 mL) in a sealed tube under Ar at 120 °C for 12 h. b The
yields are isolated one.
As the congeneric elemento-organic compounds, diselenides
have the similar reactivity with disulfides for some transforma-
tions.12b In the subsequent work, we applied this direct oxidative
coupling protocol for the synthesis of selenol esters. Using
diphenyl diselenide as the reaction partner, for the different sub-
stituted aldehydes, the reaction gave moderate to good yields
under the same reaction conditions as above (Table 3).
In order to study the possible pathway of this reaction, a
radical-trapping reagent 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) was added under the standard reaction conditions.
The results showed that in the presence of 2 equiv. TEMPO,
the yield of 3aa was reduced to 33%, while the amount of
TEMPO was increased to 4 equiv., no target product was found
(Scheme 1). The inhibitory effect of TEMPO on the reaction
indicated that the radicals existed in this transformation.
In the presence of a peroxide, the acyl radical would be pro-
duced from aldehyde, which was proved from a series of
reports.9,13 The high yield based on disulfide or diselenide
showed that a homolytic cleavage of the S–S (or Se–Se) bond
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Table 3 The reaction results of aldehydes with diselenidesa
Priority Academic Program Development of Jiangsu Higher
Education Institutions.
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a Reaction conditions: 1k (0.5 mmol), 2 (1.2 mmol) and TBP (4.0
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Scheme 2 Proposed reaction mechanism.
might exist in this process. On the basis of the present experi-
mental results and previous related reports,9,12b,13 a plausible
mechanism is depicted in Scheme 2. First, the homolytic clea-
vage of TBP produced a tert-butoxyl radical. The tert-butoxyl
radical then abstracted hydrogen from the C(sp2)–H bond of
aldehyde to afford an acyl radical (A), which finally reacted
with RSSR (or RSeSeR) (1) to generate the product 3.
Conclusions
In summary, a convenient C–S and C–Se bond formation
based on the direct oxidative cross-couplings of aldehydes
with disulfides or diselenides under metal-free conditions was
developed. This method provides a very simple, atom-economi-
cal and environmentally friendly route for the syntheses of
thiol and selenol esters.
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Acknowledgements
This work was supported by the National Natural Science 10 S. B. Bandgar, B. P. Bandgar, B. L. Korbad and S. S. Sawant,
Foundation of China (project 21272117 and 20972068) and the
Tetrahedron Lett., 2007, 48, 1287.
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