The direct thioesterification of aldehydes with disulfides via NHC-catalyzed carbonyl umpolung strategy

Article abstract of DOI:10.1016/j.tetlet.2012.07.042

An efficient N-heterocyclic carbene (NHC)-catalyzed direct thioesterification of aldehydes and α,β-unsaturated aldehydes (enals) with diaryl disulfides is reported. The protocol involves carbonyl umpolung reactivity of aldehydes and enals in which the car

Full text of DOI:10.1016/j.tetlet.2012.07.042

Tetrahedron Letters 53 (2012) 5136–5140
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The direct thioesterification of aldehydes with disulfides via NHC-catalyzed
carbonyl umpolung strategy
⇑
Santosh Singh, Lal Dhar S. Yadav
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient N-heterocyclic carbene (NHC)-catalyzed direct thioesterification of aldehydes and a,b-unsat-
urated aldehydes (enals) with diaryl disulfides is reported. The protocol involves carbonyl umpolung
reactivity of aldehydes and enals in which the carbonyl carbon attacks nucleophilically on diaryl disul-
fides to afford thioesters and a,b-unsaturated thioesters, respectively. However, aliphatic aldehydes are
not suitable substrates for this reaction. No by-product formation, complete atom-economy, shorter reac-
tion time, ambient temperature, operational simplicity, and high yields are the salient features of the
present procedure.
Received 17 May 2012
Revised 9 July 2012
Accepted 11 July 2012
Available online 15 July 2012
Keywords:
N-heterocyclic carbenes
Acylation
Ó 2012 Elsevier Ltd. All rights reserved.
Umpolung
Disulfides
Thioesters
Aldehydes
The development of mild and efficient new catalytic methods
for carbon–sulfur (C–S) bond formation without transition-metal
catalyst remains a formidable challenge. Thioesters are important
synthetic intermediates in organic synthesis1 and used as mild acyl
transfer reagents,2 building blocks of heterocyclic compounds,3 for
aldol reactions,4 protecting groups for thiols,5 for peptide cou-
pling,6 for the synthesis of ketones,7 amides,8 and also as coupling
partners in organometallic reactions.9 They are also key intermedi-
ates in various biological processes10 and find broad application in
medicinal chemistry11 (Fig. 1). The biologically active thioesters
play central roles in living cells serving as essential metabolic
intermediates due to their ability to act as excellent acyl group
transfer agents. In addition, biosynthesis of polyketides and non-
ribosomal polypeptides is achieved via thioester intermediates of
fatty acids and amino acids.12
O
N
Cl
i-Pr
O
S
O
N
N
Cl
O
O
S
Ph
O
Me
Cl
Me
Ph
S
O
Me
S
CO2H
O
1-[bis(benzoylthio)acetyl]-L-proline
2-pyridinecarboxylic acid ester
derivative
Figure 1. Examples of medicinally important thioesters.
Due to the chemical and biological importance of thioesters, a
number of methods for their synthesis have been described in the
past few years. The most common method involves the acylation
reaction of thiols with acids, anhydrides, aldehydes, acyl chlorides,
N-acylphthalimides, and N-acylbenzotriazoles.13 Recently, Alper
and co-workers introduced a new procedure for the preparation
of thioesters utilizing palladium-catalyzed thiocarbonylation of
iodoarenes with thiols in ionic liquid.14 However, the use of highly
volatile and unpleasant smelling free thiols leads to serious envi-
ronmental safety problems and also limits the use of these methods
for large-scale operations. Furthermore, these methodologies are
associated with undesirable side reactions owing to the oxidation
of thiols. In order to minimize or eliminate the encountered
problems, the acylation of disulfides with anhydrides or acyl
halides in the presence of various promoting agents, such as In
or InI,15a,15b Sm/CoCl2,15c,15d SmI2,15e–g Sm/Cp2TiCl2,15h Sm/NiCl2,15i
Zn/AlCl3, 15j,15k Zn/ZrCl4,15l V(O)(OTf)2,15m and RhCl(PPh3)3/H2
(1 atm)15n has been developed as an alternative method for the
synthesis of thioesters. Recently, Yamaguchi and co-workers have
reported
a rhodium-catalyzed alkylthio exchange reaction of
thioester with disulfide.16
In view of the above points, the direct synthesis of thioesters
from aldehydes appears to be an interesting target of investigation.
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.042

S. Singh, L.D.S. Yadav / Tetrahedron Letters 53 (2012) 5136–5140
5137
Table 1
Although, a few such synthetic methods are available in the litera-
a
Screening of oxidants for the formation of 4a and 4a0
ture,17 they usually suffer from one or more limitations, such as the
use of unpleasant odorous substrates,14,17b,13a,13d,13e,13h,13k toxic, or
metallic catalysts,15 poor atom-economy,15m low reagent effi-
ciency,17a use of additives,17a,17b as well as elevated temperature.16
Sometimes, a large amount of the aldehyde is required, since the
aldehyde must be used not only as the reagent but also as the
solvent.17a
O
O
R2
(30 mol %)
3a
R2
R1
S
S
R1
H
R2
S
DBU (30 mol %)
THF, 15h, rt
oxidant
4a, R1 = Ph , R2 = Ph
4a', R1 = PhCH=CH,
R2 = Ph
2a
1a, R1 = Ph
R2 = Ph
1a', R1 = PhCH=CH
O
Over the past two decades, NHCs have aroused considerable
interest18 not only because of their extensive use in organocatalyt-
ic transformations, but also due to their characteristic inversion of
the classical carbonyl reactivity, that is, umpolung.19–22 Although
the development of carbonyl anion addition reactions has received
significant attention,19–22 the nucleophilic substitution reactions
catalyzed by NHC have received far less attention.23–26 However,
there has been no report on NHC-catalyzed acylation of disulfides
via acyl anion equivalent of aldehydes and enals. Prompted by this
novel C–S bond formation strategy without transition-metal cata-
lyst and our efforts to develop synthetically useful processes,27
we report herein a novel methodology developed for an efficient
But
tBu
Ph
N
N
O
O
N
N
N
But
tBu
B
D
O
A
Entry
Oxidant
Yieldb (%)
4a
4a0
construction of both thioesters 4 and
a,b-unsaturated thioesters
1
2
3
4c
5
6
7
8
Azobenzene
PhTAD (D)
DEAD
Trace
61
82
71
18
Trace
52
76
Trace
56
81
67
13
Trace
33
58
40. The protocol involves the first example of the NHC-catalyzed
intermolecular acylation of disulfides 2 with aromatic aldehydes
1 and enals 10 (Scheme 1), and it is the best example in which thi-
c
PhI(OAc)2
A
B
oesters and
a,b-unsaturated thioesters can be synthesized by the
same method.
MnO2
Firstly, we investigated the reaction of benzaldehyde 1a or cin-
namaldehyde 10a (1 equiv) with diphenyl disulfide 2a (1 equiv) as
a representative case for the synthesis of thioesters 4a and 4a0.
The reaction underwent satisfactorily at room temperature (Table
1). However, the atom-economy of the reaction was considerably
low because only half part (R2S) of the disulfide (R2SSR2) was incor-
porated in the product and the other half (thiolate anion R2Sꢀ) re-
mained as the by-product. In order to increase the atom-economy
of the reaction, we searched for a selective oxidant which would
oxidize the thiolate anion into the corresponding disulfide without
any interference with Breslow intermediate. For this purpose, we
used different oxidants, viz. azobenzene, PhTAD, DEAD, PhI(OAc)2,
MnO2, IBX, A, and B (Table 1). Out of these, DEAD was the best for
the synthesis of 4a and 40a in terms of yield (Table 1, entry 3),
whereas oxidants PhTAD (D) and MnO2 gave thioesters 4a and 40a
in low to moderate yields (Table 1, entries 2 and 7) because they
were also involved in the oxidation of the Breslow intermediate
IBXc
a
Reaction conditions: 1a (1 mmol), 2a (0.5 mmol), 3a (0.3 mmol), DBU
(0.3 mmol), oxidant (1.2 equiv) in 5 mL of THF at rt.
b
Yield of isolated and purified product.
2.2 equiv of oxidant was used.
c
Table 2
Optimization of reaction conditions for the formation of representative compounds
4a and 4’aa
O
O
(30 mol %)
3
S
Ph
Ph
R1
S
R1
1a, R1 = Ph
H
Ph
S
2a
base (30 mol %)
solvent, 15 h, rt
DEAD
4a, R1 = Ph
4a', R1 = PhCH=CH
1a', R1 = PhCH=CH
Entry
Precatalyst (mol %)
Base
Solvent
Yieldb (%)
4a
40a
1
2
3
4
5
6
7
8
3a (30)
3a (30)
3a (30)
3a (30)
3a (30)
3a (30)
3a (30)
3a (30)
3b (30)
3c (30)
3d (30)
3e (30)
3a (25)
3a (35)
—
TEA
THF
THF
THF
52
58
52
68
61
51
48
82
29
28
35
31
74
82
—
42
53
48
62
57
41
39
81
22
NDd
31
NDd
71
81
—
O
K2CO3
CsCO3
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
O
THF/ButOHc
CH2Cl2
CH3CN
DMF
THF
R1
H
R2
1
R1
S
3, DBU, THF
DEAD, rt, 11-16 h
4
S
R2
9
THF
THF
THF
THF
THF
THF
THF
O
R2
S
10
11
12
13
14
15
O
2
Ar
H
R2
1'
Ar
S
3, DBU, THF
4'
DEAD, rt, 13-16 h
Mes
Ph
Ph
a
b
c
28
Ph
Cl
For the experimental procedure, see Ref.
Yield of isolated and purified product.
THF/ButOH; 10:01 were used.
.
Ph
Cl
N
N
N
Cl
N
N
S
N
Ph
N
N
N
Mes
d
Instead of
a,b-unsaturated thioester, b-aryl/alkylsulfanyl thioesters was
Cl
ClO4
3d
Mes = 2,4,6-trimethylphenyl
Scheme 1. Synthesis of thioesters 4 and
,b-unsaturated thioesters 40.
N
Ph
N
obtained in low yield.
Mes
3e
3c
3a
3b
to some extent. Although PhI(OAc)2 and IBX also give good yield
(Table 1, entries 4 and 8), their 2.2 equiv was required compared
to 1.2 equiv in the case of DEAD. Furthermore, in case of oxidants
a

5138
S. Singh, L.D.S. Yadav / Tetrahedron Letters 53 (2012) 5136–5140
azobenzene and B, only trace amount of thioesters 4a and 40a
were obtained (Table 1, 1 and 6) because they oxidized the Breslow
intermediate selectively instead of the thiolate ion.
Next, we optimized the reaction conditions with regard to NHC-
catalyst base, solvent, and temperature. Thus, different types of
N-heterocyclic carbene precursors 3a–e were tested and 3a was
found to be the most effective pre-catalyst for the preparation of
4a and 40a under the present reaction conditions (Table 2, entry
8). The optimum loading for the pre-catalyst 3a was found to be
30 mol % along with 30 mol % of DBU. When the amount of the
pre-catalyst was decreased from 30 mol % to 25 mol % relative to
substrates 1a and 10a, the yield of the thioesters 4a and 40a reduced
(Table 2, entry 13), but the use of 35 mol % of 3a did not affect the
yield (Table 2, entries 8 and 14). The reaction did not occur without
using the pre-catalyst 3 (Table 2, entry 15). Then, we optimized the
base and found that DBU was the best among TEA, K2CO3, CsCO3,
and DBU (Table 2, entries 1–3 and 8). Optimization of solvents
for the synthesis of 4a and 40a employing the precatalyst 3a was
also undertaken and it was found that among THF, THF/ButOH,
CH2Cl2, CH3CN, and DMF (Table 2, entries 3–7), the best solvent
Table 3
a
Reaction of aldehydes 1 with phenacyl halide 2 yielding thioesters 4 and 40
O
O
R2
R2
(30 mol %)
3a
S
R2
S
R1
H
R1
4 or 4'
S
DBU (30 mol %)
THF, rt
2
1
DEAD
Entry
R1
R2
Product 4 or 40
Timeb (h)
Yieldc (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4’a
4’b
4’c
4’d
4’e
15
12
14
16
15
11
16
15
16
13
16
15
15
13
16
16
16
82
87
85
77
83
91
80
86
78
82
71
79
81
86
82
66
69
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
Ph
4-NO2C6H4
4-MeOC6H4
4-ClC6H4,
Ph
4-NO2C6H4
4-MeOC6H4
4-ClC6H4
PhCH@CH
4-NO2C6H4CH@CH
4-MeOC6H4CH@CH
CH3CH@CH
CH3CH@CH
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
4-ClC6H4
a
b
c
28
For the experimental procedure, see Ref.
Stirring time at room temperature.
Yield of isolated and purified product 4 or 40.
Ph
N
O
R1
O
H
N
R1
H
1
8
Ph
Ph
Ph
Ph
OH
R1
OH
R1
Ph
N
N
N
N
N
N
R2
9'
9
6
Ph
S
S
Ph
Ph
Ph
R2
2
OH
N
DEAD
R1
R2
S
N
O
SR2
R2
R1
S
4
Scheme 2. A plausible mechanism for the formation of thioesters 4 and a
,b-unsaturated thioesters 40.

S. Singh, L.D.S. Yadav / Tetrahedron Letters 53 (2012) 5136–5140
5139
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in terms of yield was THF (Table 2, entry 8) and we used it through-
out the present study. It was also noted that a higher reaction tem-
perature, for example, in a refluxing solvent instead of room
temperature did not increase the yield.
We applied the optimized conditions to the reaction of different
substituted aldehydes and enals with a wide range of disulfides to
produce the desired thioesters in good to excellent yields (Table 3).
The presence of an electron-withdrawing substituent on the aryl
moiety of aldehydes, enals, or disulfides appears to enhance the
yield (Table 3, entries 3, 5, 6, 8, and 14), whereas an electron-
donating group seems to reduce the yield (Table 3, entries 4, 9,
11, and 15). Besides the aromatic enals, we also attempted the
reaction using aliphatic enals such as crotonaldehyde, but yields
were low (66–69%) in these cases. Furthermore, we also attempted
the reaction using aliphatic aldehydes such as, acetaldehyde, and
propionaldehyde, but the yields were poor (10–20%) in these cases.
This might be due to the side reaction like aldol reaction under the
present basic conditions.
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equivalent (Breslow intermediate) 9 which reacts with disulfide
2 to form the desired product thioester 4 and thiophenoxide ion
which further oxidize into disulfide 2 by DEAD (Scheme 2). Simi-
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mediate 70 (d1 nucleophile) to afford
a
,b-unsaturated thioester 40.
To our delight, the NHC 3a mediated reaction of enals 10 with disul-
fide 2 proceeded well via acyl anion to afford a,b-unsaturated thi-
oester 40 in good to excellent yields (Table 3) without the
formation of any appreciable amount of the product through the
homoenolate (d3 nucleophile) of 10.
In conclusion, we have developed a convenient, efficient, and
one-pot route for the synthesis of thioesters and
a,b-unsaturated
thioesters via direct NHC-catalyzed nucleophilic acylation of disul-
fides with aromatic aldehydes and enals in good to excellent yields.
The method benefits from the use of cheap and safe starting mate-
rials and avoids the use of very unpleasant and noxious thiols as
well as corrosive acid chlorides in the course of reaction. This is
the first NHC-catalyzed intermolecular acylation reaction of disul-
fides. This protocol allows the transformation of aldedydes and en-
als to a range of thioesters and
same procedure.
a,b-unsaturated thioesters by the
Acknowledgments
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. S.S. is grateful to the CSIR,
New Delhi, for the award of a Research Associateship (CSIR File
No. 09/001/(0358)/2012/EMR-I).
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1990, 38, 1147.
References and notes
24. He, J.; Zheng, J.; Liu, J.; She, X.; Pan, X. Org. Lett. 2006, 8, 4637.
25. Lin, L.; Li, Y.; Du, W.; Deng, W. P. Tetrahedron Lett. 2010, 51, 3571.
26. Singh, S.; Singh, P.; Rai, V. K.; Yadav, L. D. S. Tetrahedron Lett. 2011, 52, 125.
27. (a) Singh, S.; Yadav, L. D. S. Org. Biomol. Chem. 2012, 10, 3932; (b) Yadav, L. D. S.;
Singh, S.; Rai, V. K. Synlett 2010, 240; (c) Yadav, L. D. S.; Rai, V. K.; Singh, S.;
Singh, P. Tetrahedron Lett. 2010, 51, 1657; (d) Patel, R.; Srivastava, V. P.; Yadav,
L. D. S. Adv. Synth. Catal. 2010, 352, 1610; (e) Yadav, L. D. S.; Singh, S.; Rai, V. K.
Green Chem. 2009, 11, 878.
1. Field, L. Synthesis 1972, 101, 6321.
2. Mukaiyama, T.; Araki, M.; Takei, H. J. Am. Chem. Soc. 1973, 95, 4763.
3. (a) Alvarez-Ibarra, C.; Mendoza, M.; Orellana, G.; Quiroga, M. L. Synthesis 1989,
560; (b) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F. Tetrahedron Lett.
1995, 36, 613.
4. (a) Mukaiyama, T.; Uchiro, H.; Shiina, I.; Kobayashi, S. Chem. Lett. 1990, 1019;
(b) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, I.; Mukaiyama, T. J. Am. Chem.
Soc. 1991, 113, 4247.
5. Christian, F.; Bjorn, S.; Andreas, T. Eur. J. Org. Chem. 2007, 6, 1013.
6. (a) Ficht, S.; Payne, R. J.; Guy, R. T.; Wong, C. H. Eur. J. Org. Chem. 2008, 14, 3620;
(b) Hojo, H.; Aimoto, S. Bull. Chem. Soc. Jpn. 1991, 64, 111; (c) Ozawa, C.;
Katayama, H.; Hojo, H.; Yuko, N.; Yoshiaki, N. Org. Lett. 2008, 10, 3531; (d)
Dawson, P. E.; Muir, T. W.; Lewis, C. I.; Kent, S. B. H. Science 1994, 266, 776; (e)
Dawson, P. E.; Kent, S. B. H. Annu. Rev. Biochem. 2000, 69, 923.
7. (a) McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J. Am.
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28. General procedure for the synthesis of thioesters 4 and 40: A flame-dried round
bottomed flask was charged with benzimidazolium salt 3a (0.3 mmol),
aldehyde
1 2 (0.5 mmol), oxidant DEAD
or 10 (1.0 mmol), disulfide
(1.2 mmol) and 5 mL of THF under positive pressure of nitrogen followed by
addition of DBU (0.3 mmol) with a syringe. The resulting solution was stirred
for 11–16 h at room temperature (Table 3). After completion of the reaction
(monitored by TLC), the reaction mixture was concentrated under reduced
pressure. The residue was purified by silica gel column chromatography using
hexane/EtOAc; (20:1) as eluent to afford analytically pure
4
and 40.
Characterization data of representative compounds. Compound 4a: The 1H

5140
S. Singh, L.D.S. Yadav / Tetrahedron Letters 53 (2012) 5136–5140
NMR spectroscopic data are in agreement with those reported in the
literature.13k IR (KBr): max = 3058, 2931, 1666 cmꢀ1 1H NMR (400 MHz,
CDCl3): d = 7.99 (d, J = 7.5 Hz, 2H, Ar), 7.67 (t, J = 7.5 Hz, 1H, Ar) 7.50–7.42 (m,
7H, Ar). 13C NMR (100 MHz, CDCl3): d = 126.5, 127.2, 128.4, 129.3, 130.1, 134.2,
135.8, 136.7, 189.7. MS (EI): m/z = 214 (M+). Anal. Calcd for C13H10OS: C, 72.87;
(KBr): m .
max = 3062, 2927, 1676 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 8.28 (d,
m
.
J = 7.5 Hz, 2H, Ar), 8.16 (d, J = 7.5 Hz, 2H, Ar), 7.09 (d, J = 7.3 Hz, 2H, Ar), 6.88 (d,
J = 7.3 Hz, 2H, Ar), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3): d = 25.1, 122.8,
129.4, 130.2, 131.4, 132.9, 136.5, 139.7, 154.2, 190.1. MS (EI): m/z = 273 (M+).
Anal. Calcd for C14H11NO3S: C, 61.52; H, 4.06; N, 5.12%. Found: 61.81; H, 4.27;
H, 4.70%. Found: 73.14; H, 4.54%. Compound 4g: IR (KBr):
m
max = 3062, 2925,
N, 4.88%. Compound 40a: IR (KBr): max = 3052, 2965, 2927, 1645 cmꢀ1 1H NMR
m .
1670 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 7.92 (d, J = 8.4 Hz, 2H, Ar), 7.21 (d,
.
(400 MHz, CDCl3): d = 7.65 (d, J = 16.0 Hz, 1H), 7.60–7.49 (m, 3H, Ar), 7.31–7.22
(m, 5H, Ar), 6.88 (d, J = 7.3 Hz, 2H, Ar), 6.61 (d, J = 16.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d = 124.1, 125.9, 126.8, 128.5, 129.2, 130.4, 131.2, 135.8,
136.2, 153.4, 189.6. MS (EI): m/z = 240 (M+). Anal. Calcd for C15H12OS: C, 74.97;
H, 5.03%. Found: C, 74.73; H, 4.88%.
J = 8.3 Hz, 2H Ar), 7.15 (d, J = 8.3 Hz, 2H, Ar), 7.02 (d, J = 8.4 Hz, 2H, Ar), 3.82 (s,
3H). 13C NMR (100 MHz, CDCl3): d = 56.4, 114.8, 127.3, 129.6, 130.4, 131.1,
131.8, 133.8, 168.2, 188.7. MS (EI): m/z = 278, 280 (M+, M+2). Anal. Calcd for
C14H11ClO2S: C, 60.32; H, 3.98%. Found: 59.94; H, 4.22%. Compound 4j: IR