Unprecedented dithiolation of enals via their NHC-catalysed umpolung reaction with organic disulfides

Article abstract of DOI:10.1039/c2ob25238d

A novel one-pot N-heterocyclic carbene (NHC)-catalysed dithiolation of α,β-unsaturated aldehydes (enals) with organic disulfides is reported. The protocol involves homoenolate reactivity of enals, where the homoenolate attacks on the disulfide as a d

Full text of DOI:10.1039/c2ob25238d

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PAPER
Unprecedented dithiolation of enals via their NHC-catalysed umpolung
reaction with organic disulfides†
Santosh Singh and Lal Dhar S. Yadav*
Received 1st February 2012, Accepted 8th March 2012
DOI: 10.1039/c2ob25238d
A novel one-pot N-heterocyclic carbene (NHC)-catalysed dithiolation of α,β-unsaturated aldehydes
(enals) with organic disulfides is reported. The protocol involves homoenolate reactivity of enals, where
the homoenolate attacks on the disulfide as a d3 nucleophile followed by thioesterification to afford β-aryl/
alkylsulfanyl thioesters with complete atom economy.
However, there are only a few reports on the direct synthesis of
β-arylsulfanyl thioesters starting from an enoic acid derivative
Introduction
The development of mild and efficient new catalytic methods for
carbon–sulfur (C–S) bond formation without transition-metal
catalyst remains a formidable challenge. Thiolation is among
fundamental reactions in biochemistry.1 Thioethers and thioesters
play important roles in biological and chemical processes,2a and
also serve as useful building blocks for various organosulfur
compounds.2b Over the past two decades, NHCs have aroused
considerable interest due to their continuously growing number
of successful and novel applications in organic synthesis.3 The
NHC-catalysed umpolung reactivity of α,β-unsaturated alde-
hydes (enals) via Breslow or homoenolate intermediates has
been well documented,3h,i where addition of an appropriate
NHC to an enal renders it a d3 nucleophile. The concept of
homoenolate anions was introduced by Nickon and Lambert4 in
1962. Their application in organic synthesis during the last four
decades, however, was limited, presumably due to the difficulty
in generating homoenolates directly.5 After the introduction of a
conceptually new approach to the generation of homoenolate6
independently by Bode6a and Glorius et al.,6d the synthetic
utility of homoenolate equivalent intermediates of enals has sig-
nificantly increased. This is because they react with various elec-
trophiles, like aldehydes,6a chalcones,7a dienones,7b diazenes,7c
imines,6c alkyl/acyl halides,7d,e epoxides,7f aziridines7g and acti-
vated, polarized CvC double bonds8 to afford an array of useful
products. In the present study organic disulfides have been used,
for the first time, as a new class of electrophiles in NHC-cata-
lysed carbonyl umpolung reactions.
instead of an enal, viz. by conjugate addition of thiols to thiocin-
namates,9a 1-cinnamoyl-3,5-dimethyl pyrazole,9b or an N-cinna-
moylbenzotriazole.10 These methods suffer from limitations such
as the use of malodorous substrates, thiols and moderate yields.
Prompted by our previous efforts to develop synthetically useful
processes in the area of NHC-catalysis7e–g and the surprising
lack of convenient synthetic methods for β-aryl/alkylsulfanyl
thioesters, we herein report a novel methodology for an efficient
access to chemically and pharmaceutically relevant dithiolated
products in a one-pot procedure (Scheme 1). The protocol
involves the NHC-catalysed intermolecular thioaryl-/alkylation
followed by thioesterification of enals 1 with organic disulfides 2
to afford β-aryl/alkylsulfanyl thioesters 4. The reaction proceeds
with complete atom economy and forms two biologically potent
C–S bonds in a one-pot operation.
Thioesters are a useful class of organic compounds due to
their wide range of biological activity and considerable appli-
cations in drug development11 and industry.12 In the past few
years they have found increasingly important applications as
intermediates for the preparation of heterocycles13 and diverse
ketones,14 amides,15 acyl radicals,16 and biologically active
compounds.17 Moreover, the present reaction products β-aryl-/
The literature scan reveals that no method is available for the
direct synthesis of β-aryl/alkylsulfanyl thioesters from enals.
Green Synthesis Lab, Department of Chemistry, University of
Allahabad, Allahabad-211 002, India. E-mail: ldsyadav@hotmail.com;
Fax: +91 5322460533; Tel: +91 5322500652
†This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
Scheme 1 Synthesis of β-aryl/alkylsulfanyl thioesters 4.
3932 | Org. Biomol. Chem., 2012, 10, 3932–3936
This journal is © The Royal Society of Chemistry 2012

Table 1 Optimization of reaction conditions for the formation of
representative compound 4aa
Table 2 Reaction of enals 1 with organic disulfides 2 yielding
β-arylsulfanyl thioesters 4a
Entry
Precatalyst (mol%)
Base
Solventb
Yieldc
Timeb
(h)
Yieldc,d
(%)
Entry
R1
R2
Product 4
1
2
3
4
5
6
7
8
3a (10)
3b (10)
3c (10)
3d (10)
3e (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (7)
DBU
DBU
DBU
DBU
DBU
TEA
K2CO3
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
THF
THF
THF
THF
THF
THF
THF
THF
81
59
51
0e
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
17
12
17
17
18
17
15
12
19
12
18
15
19
18
20
23
22
23
21
22
81
89
84
78
79
88
82
86
77
84
76
82
60
65
57
60
64
79
81
76
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
Ph
4-NO2C6H4
4-MeOC6H4
4-ClC6H4
Ph
4-NO2C6H4
4-MeOC6H4
4-ClC6H4
CH3
CH3
CH3
Ph
4-NO2C6H4
2-Furyl
2-ClC6H4
p-CH3C6H4
56
52
48
34
62
57
38
78
81
81f
81g
0
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
4-ClC6H4
4-MeC6H4
Et
Et
Ph
9
THF–ButOHd
THF–H2Od
CH2Cl2
THF
10
11
12
13
14
15
16
9
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
3a (15)
3d (30)
3a (15)
—
THF
THF
THF
THF
4m
4n
4o
4p
4q
4r
4s
4t
a Reaction conditions: 0.12 mL (1 mmol) cinnamaldehyde, 218 mg
(1 mmol) diphenyl disulfide, solvent (5 mL). b The different N-
heterocyclic ammonium salts and bases are soluble in the solvents
except potassium carbonate. c Yield of isolated and purified product.
d THF–ButOH or THF–H2O; 10 : 01 were used. e Instead of 4a, 35% of
α,β-unsaturated thioester (phenyl thiocinnamate) was obtained. f Yield of
α,β-unsaturated thioester (phenyl thiocinnamate). g Reaction was
performed in refluxing solvent.
Ph
Ph
a Enal 1 (1 mmol) and disulfide 2 (1 mmol) were used for dithiolation in
THF (5 mL) in the presence of bis-1,3-dibenzyl benzimidazolium salt
3d (10 mol%) and DBU (10 mol%). b Stirring time at room temperature.
c Yield of isolated and purified product 4. d All compounds gave C, H
and N analyses within 0.38% and satisfactory spectral (IR, 1H NMR,
13C NMR and EIMS) data.
alkylsulfanyl thioesters 4 incorporate densely populated chemo-
specific functional groups including carbonyl, thioaryl, thioalkyl,
thioester and active methylene groups, thereby provide handles
for further manipulation in a multitude of synthetic organic
transformations.
(Table 1, entries 1 and 9–11), the best solvent in terms of yield
was THF (Table 1, entry 7) and we used this solvent (THF)
throughout the present study. It was also noted that a higher reac-
tion temperature, for example, in a refluxing solvent instead of
room temperature, did not increase the yield (Table 1, entry 15).
Moreover, under the same reaction conditions N-heterocyclic
carbene precursor 3d formed α,β-unsaturated thioester (phenyl
thiocinnamate) in 35% yield but on increasing the loading of 3d
from 10 to 30 mol%, the yield of the thioester was excellent
(81%, Table 1, entry 14).
Encouraged by these results, next, we investigated the scope
of this catalytic method for the synthesis of various β-aryl-/alkyl-
sulfanyl thioester derivatives 4 (Table 2). Under the optimal con-
ditions, cinnamaldehyde scaffolds were varied as shown in
Table 2. Electron-withdrawing substituents such as 4-nitro, and
4-chloro in enals 1 gave the corresponding β-arylsulfanyl thio-
ester derivatives in good to excellent yields (Table 2, entries 2, 3
compared to 4; 6, 8 compared to 7, and 10, 12 compared to 11).
Whereas cinnamaldehyde with an electron-donating substituent
such as 4-MeOC6H4 produced the desired thioesters in relatively
lower yields (Table 2, entries 4, 7, 11 and 20). Aliphatic α,β-un-
saturated aldehydes such as crotonaldehyde also responded well
to this catalytic method, providing the thioesters in moderate
yields (57–65%), under the same reaction conditions (Table 2,
entries 13–15). Besides these aromatic/aliphatic α,β-unsaturated
aldehydes, we also attempted the reaction using heteroaromatic
Results and discussion
Initial efforts were directed towards optimization of reaction con-
ditions in regard with NHC-catalyst, base and solvent. Herein,
cinnamaldehyde 1a and diphenyl disulfide 2a were chosen as
model substrates for the synthesis of representative β-arylsulfanyl
thioester 4a, and the reaction was performed at room temperature
(Table 1). 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 under the present reaction con-
ditions (Table 1, entry 1). Then, we optimized the base and
found that DBU was the best among TEA, K2CO3, DABCO,
DBU, (Table 1, entries 6–8 and 1). The loading of precatalyst 3a
for the reaction was also optimized and was found to be 10 mol
% along with 10 mol% of DBU. When the amount of the pre-
catalyst was decreased from 10 mol% to 7 mol% relative to sub-
strate 1a, the yield of the β-arylsulfanyl thioester 4a decreased
(Table 1, entry 12), but the use of 15 mol% of 3a did not affect
the yield (Table 1, entries 1 and 13). The reaction did not occur
without using the precatalyst 3 (Table 1, entry 16). Optimization
of solvents for the synthesis of 4a employing the precatalyst 3a
revealed that among THF, THF–ButOH, THF–H2O and CH2Cl2
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3932–3936 | 3933

a Perkin-Elmer 993 IR spectrophotometer, 1H NMR spectra
were recorded on a Bruker WM-40 C (400 MHz) FT spec-
trometer in CDCl3 using TMS as internal reference. 13C NMR
spectra were recorded on the same instrument at 100 MHz in
CDCl3 and TMS was used as internal reference. Mass spectra
were recorded on a JEOL D-300 mass spectrometer. Elemental
analyses were carried out in a Coleman automatic carbon, hydro-
gen and nitrogen analyser. All chemicals used were reagent
grade and were used as received without further purification.
Silica gel-G was used for TLC.
General procedure for the synthesis of β-aryl-/alkylsulfanyl
thioesters. A flame-dried round bottom flask was charged with
imidazolium salt 3a (0.1 mmol), α,β-unsaturated aldehyde 1
(1.0 mmol) and 5 mL of THF under positive pressure of nitrogen
followed by addition of DBU (0.1 mmol) with a syringe. After
stirring at rt for 5 min, a solution of diphenyl disulfide 2
(1.0 mmol) in 1 mLTHF was added. The resulting violet-red sol-
ution was stirred for 12–23 h at rt. After completion of the reac-
tion (monitored by TLC), the reaction mixture was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography hexane/EtOAc (20 : 1) to afford analyti-
cally pure 4. The structure of the products was confirmed by
their elemental (C, H and N) analyses and spectral (IR, 1H
NMR, 13C NMR and EIMS) data.
Scheme 2 A plausible mechanism for the formation of β-aryl/alkylsul-
fanyl thioesters 4.
α,β-unsaturated aldehydes such as 3-(furan-2-yl)acrylaldehyde,
and found that yields was also good (79%) in this case, under
the same reaction conditions (Table 2, entry 18). Next, we
extended this catalytic protocol toward other diaryl/dialkyl
disulfide component. Diphenyl-, di-p-chlorophenyl-, di-p-
methylphenyl- and diethyl disulfides smoothly underwent this
catalytic reaction and gave the desired β-aryl/alkylsulfanyl thio-
esters in good yields (Table 2, entries 1–12) except in the case of
aliphatic enals (Table 2, entries 13–15). But diethyl disulfide pro-
duced β-ethylsulfanyl thioesters in moderate yields (Table 2,
entries 16 and 17).
The formation of β-aryl-/alkylsulfanyl thioester 4 may be ten-
tatively rationalized by the postulated catalytic cycle (Scheme 2).
The α,β-unsaturated aldehyde 1 is attacked by the in situ formed
carbene 11 and the resulting zwitterionic intermediate 6 gener-
ates the conjugated Breslow intermediate 7. This in turn attacks
diaryl disulfide 2 as a d3-nucleophile to form the intermediate 8.
The tautomerization of 8 to intermediate 9 is followed by an
intermolecular attack of the aryl/alkyl sulfide anion at the carbo-
nyl function to afford β-aryl-/alkylsulfanyl thioester 4 and the
regeneration of the catalyst 11 (Scheme 2).
S-Phenyl-3-phenyl-3-(phenylsulfanyl)propanethioate(4a; Table 2;
entry 1). Mp 73–75 °C (Lit.10 Mp 74–76 °C), IR (KBr): νmax
=
3051, 2921, 1708, 1615, 1578, 1509, 1453 cm−1 1H NMR
;
(400 MHz, CDCl3): δ = 7.45–7.19 (m, 15H, Ar–H), 4.81 (t, J =
7.0 Hz, 1H), 3.30 (d, J = 7.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ = 195.7, 142.3, 136.7, 134.6, 130.9, 130.1, 129.1,
128.3, 127.5, 126.6, 125.8, 125.0, 124.1, 51.6, 43.2; MS (EI):
m/z = 350 (M+); Anal. Calcd for C21H18OS2: C, 71.96; H,
5.18%. Found: C, 71.58; H, 5.43%.
S-Phenyl-3-(4-nitrophenyl)-3-(phenylsulfanyl)propanethioate
(4b; Table 2; entry 2). Mp 76–77 °C (Lit.10b Mp 77–79 °C), IR
(KBr): νmax = 3125, 3071, 2938, 2855, 1704, 1605, 1519,
1
1349 cm−1; H NMR (400 MHz, CDCl3): δ = 8.17–7.98 (m,
2H, Ar–H), 7.11–7.54 (m, 12H, Ar–H), 4.84 (t, J = 7.7 Hz, 1H),
3.36 (d, J = 7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ =
196.1, 147.2, 136.7, 135.2, 132.9, 130.5, 129.5, 128.6, 127.7,
126.8, 125.4, 124.6, 121.4, 52.4, 42.9; MS (EI): m/z = 395
(M+); Anal. Calcd for C21H17NO3S2: C, 63.77; H, 4.33; N,
3.54%. Found: C, 64.10; H, 4.12; N, 3.25%.
Conclusions
S-Phenyl-3-(4-chlorophenyl)-3-(phenylsulfanyl)propanethioate
(4c; Table 2; entry 3). Mp 85–86 °C (Lit.10b Mp 86–87 °C), IR
In summary, we have developed a novel N-heterocyclic carbene
catalysed direct dithiolation of enals with organic disulfides to
afford β-aryl-/alkylsulfanyl thioesters with complete atom
economy. This is the first catalytic method where thioetherifica-
tion and thioesterification take place in a one-pot operation to
form two biologically potent C–S bonds efficiently.
1
(KBr): νmax = 3052, 2909, 1703, 1614, 1456 cm−1; H NMR
(400 MHz, CDCl3): δ = 7.35–7.11 (m, 14H, Ar–H), 4.79 (t, J =
7.6 Hz, 1H), 3.31 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ = 196.6, 139.2, 136.7, 134.8, 132.7, 131.4, 130.3,
129.5, 128.8, 127.7, 126.8, 125.7, 124.8, 52.7, 43.5; MS (EI):
m/z = 384, 386 (M+, M + 2). Anal. Calcd for C21H17ClOS2: C,
65.52; H, 4.45%. Found: C, 65.86; H, 4.14%.
Experimental
S-Phenyl-3-(4-methoxyphenyl)-3-(phenylsulfanyl)propanethio-
ate (4d; Table 2; entry 4). Mp 92–93 °C (Lit.10b Mp 93–95 °C),
IR (KBr): νmax = 3050, 2904, 1709, 1618, 1454 cm−1; 1H NMR
(400 MHz, CDCl3): δ = 7.24–6.86 (m, 14H, Ar–H), 4.74 (t, J =
General
Melting points were determined by the open glass capillary
method and are uncorrected. IR spectra in KBr were recorded on
3934 | Org. Biomol. Chem., 2012, 10, 3932–3936
This journal is © The Royal Society of Chemistry 2012

7.6 Hz, 1H), 3.82 (s, 3H), 3.30 (d, J = 7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ = 196.5, 159.4, 135.5, 134.2, 132.1,
130.8, 129.5, 128.8, 127.6, 126.8, 125.9, 125.1, 114.4, 55.1,
52.9, 43.8; MS (EI): m/z = 380 (M+). Anal. Calcd for
C22H20O2S2: C, 69.44; H, 5.30%. Found: C, 69.68; H, 5.53%.
2941, 1703, 1618, 1452 cm−1; 1H NMR (400 MHz, CDCl3): δ =
8.11–7.99 (m, 2H, Ar–H), 7.11–7.44 (m, 6H, Ar–H), 6.88–7.13
(m, 4H, Ar–H), 4.79 (t, J = 7.6 Hz, 1H), 3.32 (d, J = 7.6 Hz,
2H), 2.39 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
= 196.5, 147.9, 146.5, 135.4, 134.8, 133.6, 132.4, 129.7, 128.9,
127.7, 126.7, 125.6, 121.4, 52.6, 42.9, 25.2, 24.1; MS (EI): m/z
= 423 (M+); Anal. Calcd for C23H21NO3S2: C, 65.22; H, 5.00;
N, 3.31%. Found: C, 65.58; H, 5.21; N, 3.05%.
S-4-Chlorophenyl-3-(4-chlorophenylsulfanyl)-3-phenyl-propa-
nethioate (4e; Table 2; entry 5). Mp 64–65 °C (Lit.10 Mp
63–65 °C), IR (KBr): νmax = 3058, 2908, 1710, 1618,
1
1448 cm−1; H NMR (400 MHz, CDCl3): δ = 7.18–7.54 (m,
S-p-Tolyl-3-(p-tolylsulfanyl)-3-(4-methoxyphenyl)propanethio-
13H, Ar–H), 4.76 (t, J = 7.6 Hz, 1H), 3.29 (d, J = 7.6 Hz, 2H);
13C NMR (100 MHz, CDCl3): δ = 196.3, 141.6, 134.5, 133.4,
132.6, 131.9, 131.0, 130.2, 129.4, 128.3, 127.5, 126.6, 125.8,
52.4, 43.8; MS (EI): m/z = 418, 420 (M+, M + 2); Anal. Calcd
for C21H16Cl2OS2: C, 60.14; H, 3.85%. Found: C, 59.80; H,
4.09%.
ate (4k; Table 2; entry 11). Mp 78–80 °C, IR (KBr): νmax
=
3055, 2961, 1701, 1619, 1455 cm−1 1H NMR (400 MHz,
;
CDCl3): δ = 7.22–6.87 (m, 12H, Ar–H), 4.78 (t, J = 7.6 Hz,
1H), 3.84 (s, 3H), 3.28 (d, J = 7.6 Hz, 2H), 2.35 (s, 3H), 2.29 (s,
3H); 13C NMR (100 MHz, CDCl3): δ = 196.3, 159.2, 135.7,
134.9, 133.7, 132.8, 131.6, 130.7, 129.9, 128.9, 127.7, 126.8,
114.7, 55.4, 52.6, 42.9, 25.2, 24.1; MS (EI): m/z = 408 (M+);
Anal. Calcd for C24H24O2S2: C, 70.55; H, 5.92%. Found: C,
70.24; H, 5.65%.
S-4-Chlorophenyl-3-(4-chlorophenylsulfanyl)-3-(4-nitrophenyl)-
propanethioate (4f; Table 2; entry 6). Mp 101–102 °C, IR
1
(KBr): νmax = 3110, 3070, 2909, 1709, 1612, 1452 cm−1; H
NMR (400 MHz, CDCl3): δ = 8.16–7.96 (m, 2H, Ar–H),
7.42–7.15 (m, 10H, Ar–H), 4.81 (t, J = 7.6 Hz, 1H), 3.33 (d, J =
7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 196.4, 147.9,
146.2, 134.4, 133.5, 132.6, 131.8, 130.7, 129.4, 128.6, 127.8,
126.9, 121.6, 52.8, 43.6; MS (EI): m/z = 463, 465 (M+, M + 2);
Anal. Calcd for C21H15Cl2NO3S2: C, 54.31; H, 3.26; N, 3.02%.
Found: C, 54.06; H, 3.64; N, 2.78%.
S-p-Tolyl-3-(p-tolylsulfanyl)-3-(4-chlorophenyl)propanethioate
(4l; Table 2; entry 12). Mp 89–90 °C, IR (KBr): νmax = 3053,
2912, 1704, 1618, 1583, 1509, 1449 cm−1; 1H NMR (400 MHz,
CDCl3): δ = 7.28–7.09 (m, 12H, Ar–H), 4.78 (t, J = 7.5 Hz,
1H), 3.32 (d, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.30 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 196.4, 138.8, 134.9, 133.4, 132.5,
131.6, 130.4, 129.6, 128.9, 128.3, 127.6, 126.9, 125.7, 52.0,
43.2, 25.4, 24.5; MS (EI): m/z = 412, 414 (M+, M + 2); Anal.
Calcd for C23H21ClOS2: C, 66.89; H, 5.13%. Found: C, 66.67;
H, 5.33%.
S-4-Chlorophenyl-3-(4-chlorophenylsulfanyl)-3-(4-methoxy-
phenyl)propanethioate (4g; Table 2; entry 7). Mp 81–83 °C,
IR (KBr): νmax = 3105, 2919, 1708, 1614, 1449 cm−1; 1H NMR
(400 MHz, CDCl3): δ = 7.18–6.81 (m, 12H, Ar–H), 4.77 (t, J =
7.5 Hz, 1H), 3.83 (s, 3H), 3.30 (d, J = 7.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ = 196.1, 159.7, 135.2, 134.0, 133.2,
132.1, 131.4, 130.5, 129.8, 128.9, 127.6, 126.8, 114.8, 55.2,
52.4, 43.6; MS (EI): m/z = 448, 450 (M+, M + 2). Anal. Calcd
for C22H18Cl2O2S2: C, 58.80; H, 4.04%. Found: C, 59.07; H,
3.79%.
S-Phenyl-3-(phenylsulfanyl)butanethioate (4m; Table 2; entry
13). Yellow oil, IR (KBr): νmax = 3051, 2960, 2928, 2859,
1706, 1578, 1478, 1436 cm−1; 1H NMR (400 MHz, CDCl3): δ =
7.44–7.18 (m, 10H, Ar–H), 3.71 (m, 1H), 2.99 (dd, J = 15.5, 5.4
Hz, 1H), 2.71 (dd, J = 15.5, 9.0 Hz, 1H), 1.34 (d, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ = 195.9, 137.4, 135.3,
134.7, 129.3, 128.6, 127.9, 126.9, 125.8, 52.3, 37.4, 22.2; MS
(EI): m/z = 288 (M+). Anal. Calcd for C16H16OS2: C, 66.63; H,
5.59%. Found: C, 66.87; H, 5.41%.
S-4-Chlorophenyl-3-(4-chlorophenylsulfanyl)-3-(4-chlorophenyl)-
propanethioate (4h; Table 2; entry 8). Mp 97–98 °C, IR (KBr):
νmax = 3048, 2903, 1709, 1614, 1452 cm−1
;
1H NMR
S-4-Chlorophenyl-3-(4-chlorophenylsulfanyl)butanethioate (4n;
Table 2; entry 14). Yellow oil, IR (KBr): νmax = 3058, 2972,
2932, 2862, 1709, 1584, 1475, 1442 cm−1; 1H NMR (400 MHz,
CDCl3): δ = 7.48–7.24 (m, 8H, Ar–H), 3.74 (m, 1H), 2.96 (dd, J
= 15.4, 5.4 Hz, 1H), 2.75 (dd, J = 15.4, 9.0 Hz, 1H), 1.36 (d, J =
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 196.2, 137.1,
135.8, 134.3, 131.9, 130.8, 129.2, 128.4, 127.2, 52.5, 37.1,
21.8; MS (EI): m/z = 356, 358 (M+, M + 2); Anal. Calcd for
C16H14Cl2OS2: C, 53.78; H, 3.95%. Found: C, 54.05; H, 4.17%.
(400 MHz, CDCl3): δ = 7.31–7.15 (m, 12H, Ar–H), 4.75 (t, J =
7.6 Hz, 1H). 3.31 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ = 196.7, 139.6, 136.5, 134.5, 133.7, 132.4, 131.6,
130.8, 130.0, 129.2, 128.4, 127.1, 126.2, 52.5, 43.4; MS (EI):
m/z = 451, 453 (M+, M + 2); Anal. Calcd for C21H15Cl3OS2: C,
55.58; H, 3.33%. Found: C, 55.23; H, 3.59%.
S-p-Tolyl-3-(p-tolylsulfanyl)-3-phenylpropanethioate (4i; Table 2;
entry 9). Mp 83–84 °C (Lit.10 Mp 82–83 °C), IR (KBr): νmax
=
3051, 2911, 1702, 1621, 1454 cm−1 1H NMR (400 MHz,
;
S-p-Tolyl-3-(p-tolylsulfanyl)butanethioate (4o; Table 2; entry
15). Yellow oil, IR (KBr): νmax = 3047, 2957, 2930, 2861,
1702, 1574, 1475, 1438 cm−1; 1H NMR (400 MHz, CDCl3): δ =
7.11–6.87 (m, 8H, Ar–H), 2.97 (m, 1H), 2.69 (d, J = 7.3 Hz,
2H), 2.38 (s, 3H), 2.32 (s, 3H), 1.43 (d, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ = 196.6, 135.4, 134.8, 132.6, 131.7,
130.9, 130.3, 129.1, 128.6, 52.1, 37.5, 25.8, 25.1, 22.3; MS
(EI): m/z = 316 (M+); Anal. Calcd for C18H20OS2: C, 68.31; H,
6.37%. Found: C, 68.18; H, 6.45%.
CDCl3): δ = 7.41–7.09 (m, 13H, Ar–H), 4.79 (t, J = 7.5 Hz,
1H), 3.34 (d, J = 7.5 Hz, 2H), 2.34 (s, 3H), 2.38 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 196.8, 142.1, 135.8, 134.9, 132.2,
131.1, 130.3, 129.3, 128.5, 127.7, 126.8, 126.0, 125.2, 52.5,
43.1, 25.4, 24.6; MS (EI): m/z = 378 (M+); Anal. Calcd for
C23H22OS2: C, 72.97; H, 5.86%. Found: C, 73.24; H, 6.07%.
S-p-Tolyl-3-(p-tolylsulfanyl)-3-(4-nitrophenyl)propanethioate
(4j; Table 2; entry 10). Mp 92–93 °C, IR (KBr): νmax = 3051,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3932–3936 | 3935

S-Ethyl-3-(ethylsulfanyl)-3phenylpropanethioate (4p; Table 2;
entry 16). Mp 56–57 °C, IR (KBr): νmax = 3051, 2960, 2933,
2842, 1696, 1576, 1453 cm−1; 1H NMR (400 MHz, CDCl3): δ =
7.38–7.06 (m, 5H, Ar–H), 3.81 (t, J = 7.3 Hz, 1H), 3.26 (d, J =
7.3 Hz, 2H), 3.03 (q, J = 7.1 Hz, 2H), 2.49 (q, J = 7.0, 2H), 1.27
(t, J = 7.0, 3H), 1.32 (t, J = 7.1, 3H); 13C NMR (100 MHz,
CDCl3): δ = 198.4, 138.2, 130.6, 129.4, 128.8, 52.2, 42.3, 30.6,
28.4, 15.2, 12.8; MS (EI): m/z = 254 (M+); Anal. Calcd for
C13H18OS2: C, 61.37; H, 7.13%. Found: C, 61.59; H, 6.91%.
Notes and references
1 (a) N. Shigi, Y. Sakaguchi, S. I. Asai, T. Suzuki and K. Watanabe, EMBO
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2 (a) M. E. Peach, Thiols As Nucleophiles, in the Chemistry of the Thiol
Group, ed. S. Patai, John Wiley & Sons, London, 1979, p. 721; (b) R.
J. Cremlyn, An Introduction to Organosulfur Chemistry, Wiley & Sons,
New York, 1996.
3 (a) H. U. Vora and T. Rovis, Aldrichimica Acta, 2011, 44, 3;
(b) K. Hirano, I. Piel and F. Glorius, Chem. Lett., 2011, 40, 786; (c) P.-
C. Chiang and J. W. Bode, TCI Mail, 2011, 149, 2; (d) J. L. Moore and
T. Rovis, Top. Curr. Chem., 2010, 291, 77; (e) V. Nair, S. Vellalath and
B. Pattoorpadi Babu, Chem. Soc. Rev., 2008, 37, 2691; (f) D. Enders,
O. Niemeier and A. Henseler, Chem. Rev., 2007, 107, 5606;
(g) N. Marion, S. Díez-González and S. P. Nolan, Angew. Chem., Int.
Ed., 2007, 46, 2988; (h) C. Burstein, S. Tschan, X. Xie and F. Glorius,
Synthesis, 2006, 2418; (i) M. He, J. R. Struble and J. W. Bode, J. Am.
Chem. Soc., 2006, 128, 8418.
4 A. Nickon and J. L. Lambert, J. Am. Chem. Soc., 1962, 84, 4604.
5 (a) A. S. Bal, A. Marfat and P. Helquist, J. Org. Chem., 1982, 47, 5045;
(b) M. Seppi, R. Kalkofen, J. Reupohl, R. Fröhlich and D. Hoppe,
Angew. Chem., Int. Ed., 2004, 43, 1423; (c) J. Reuber, R. Fröhlich and
D. Hoppe, Org. Lett., 2004, 6, 783; (d) M. C. Whisler and P. Beak, J.
Org. Chem., 2003, 68, 1207.
S-Ethyl-3-(ethylsulfanyl)-3-(4-nitrophenyl)propanethioate (4q;
Table 2; entry 17). Mp 64–65 °C, IR (KBr): νmax = 3062, 2955,
2941, 2848, 1694, 1582, 1455 cm−1 1H NMR (400 MHz,
;
CDCl3): δ = 8.19–8.02 (m, 2H, Ar–H), 7.28–7.41 (m, 2H, Ar–
H), 3.84 (t, J = 7.3 Hz, 1H), 3.23 (d, J = 7.3 Hz, 2H), 3.06 (q, J
= 7.1 Hz, 2H), 2.51 (q, J = 7.0, 2H), 1.26 (t, J = 7.0, 3H), 1.30
(t, J = 7.1, 3H); 13C NMR (100 MHz, CDCl3): δ = 198.7, 145.2,
143.6, 130.4, 122.5, 51.9, 42.1, 30.8, 28.6, 14.8, 13.1; MS (EI):
m/z = 299 (M+); Anal. Calcd for C13H17NO3S2: C, 52.15; H,
5.72; N, 4.68%. Found: C, 51.89; H, 5.57, N, 4.86%.
6 (a) S. S. Sohn, E. L. Rosen and J. W. Bode, J. Am. Chem. Soc., 2004,
126, 14370; (b) M. He and J. W. Bode, Org. Lett., 2005, 7, 3131;
(c) K. Zeitler, Angew. Chem., Int. Ed., 2005, 44, 7506; (d) C. Burstein
and F. Glorius, Angew. Chem., Int. Ed., 2004, 43, 6205.
7 (a) V. Nair, S. Vellalath, M. Poonoth and E. Suresh, J. Am. Chem. Soc.,
2006, 128, 8736; (b) V. Nair, B. P. Babu, S. Vellalath and E. Suresh,
Chem. Commun., 2008, 747; (c) A. Chan and K. A. Scheidt, J. Am.
Chem. Soc., 2008, 130, 2740; (d) L. D. S. Yadav, P. Singh, S. Singh and
V. K. Rai, Synlett, 2010, 2649; (e) S. Singh, P. Singh, V. K. Rai and
L. D. S. Yadav, Tetrahedron Lett., 2011, 52, 125; (f) L. D. S. Yadav,
S. Singh and V. K. Rai, Synlett, 2010, 240; (g) L. D. S. Yadav, V. K. Rai,
S. Singh and P. Singh, Tetrahedron Lett., 2010, 51, 1657.
S-Phenyl 3-(furan-2-yl)-3-(phenylsulfanyl)propanethioate (4r;
Table 2; entry 18). Mp 49–51 °C, IR (KBr): νmax = 3117, 3055,
2942, 1714, 1627, 1569, 1451 cm−1 1H NMR (400 MHz,
;
CDCl3): δ = 7.49–7.18 (m, 13H, Ar–H), 4.97 (t, J = 7.0 Hz,
1H), 3.41 (d, J = 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
= 195.1, 152.7, 141.8, 137.8, 134.7, 134.1, 129.6, 128.5, 127.4,
126.9, 125.5, 111.4, 108.6, 51.7, 43.8; MS (EI): m/z = 340 (M+).
Anal. Calcd for C19H16O2S2: C, 67.03; H, 4.74%. Found: C,
67.28; H, 4.86%.
8 J. R. de Alaniz and T. Rovis, Synlett, 2009, 1189.
9 (a) L. Marzorati, M. C. De Mattos, B. Wladislaw and C. D. Vitta, Synth.
Commun., 2002, 32, 1427; (b) C. Kashima, K. Takahashi and
A. Hosomi, Heterocycles, 1996, 42, 241.
10 (a) S. M. Lin, J. L. Zhang, J. X. Gao, J. C. Ding, W. K. Su and H. Y. Wu,
J. Braz. Chem. Soc., 2010, 21, 1616; (b) Z. Xia, X. Lv, W. Wang and
X. Wang, Tetrahedron Lett., 2011, 52, 4906.
S-Phenyl-3-(2-chlorophenyl)-3-(phenylsulfanyl)propanethioate
(4s; Table 2; entry 19). Mp 71–73 °C, IR (KBr): νmax = 3052,
2917, 1710, 1614, 1580, 1455 cm−1 1H NMR (400 MHz,
;
CDCl3): δ = 7.39–7.18 (m, 14H, Ar–H), 5.30 (t, J = 7.2 Hz,
1H), 3.30 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
= 195.6, 138.2, 135.1, 134.2, 133.4, 132.6, 131.4, 130.1, 129.5,
128.8, 128.2, 127.5, 126.8, 126.1, 125.5, 47.8, 45.5; MS (EI):
m/z = 384, 386 (M+, M + 2). Anal. Calcd for C21H17ClOS2: C,
65.52; H, 4.45%. Found: C, 65.33; H, 4.31%.
11 (a) Y. Kanda, T. Ashizawa, S. Kakita, Y. Takahashi, M. Kono,
M. Yoshida, Y. Saitoh and M. Okabe, J. Med. Chem., 1999, 42, 1330;
(b) E. Mroszczak and R. Runkel, U.S. Pat.,
4 397 862, 1983;
E. Mroszczak and R. Runkel, Chem. Abstr., 1983, 99, 146134; (c) M.
C. Venuti, G. M. Young, P. G. Maloney, D. Johnson and K. McGreevy,
Pharm. Res., 1989, 6, 867; (d) M. L. Greenlee, J. B. Laub, J.
M. Balkovec, M. L. Hammond, G. G. Hammond, D. L. Pompliano and J.
H. Epstein-Toney, Bioorg. Med. Chem. Lett., 1999, 9, 2549; (e) J. Olsen,
I. Bjørnsdottir, J. Tjørnelund and S. H. Hansen, J. Pharm. Biomed. Anal.,
2002, 29, 7.
S-Phenyl-3-(phenylsulfanyl)-3-p-tolylpropanethioate (4t; Table 2;
entry 20). Mp 60–62 °C (Lit.10 Mp 59–61 °C), IR (KBr): νmax
=
3056, 3036, 2910, 1701, 1605, 1578, 1450 cm−1 1H NMR
;
12 (a) K. Matsumoto, E. A. Costner, I. Nishimura, M. Ueda and
C. G. Willson, Macromolecules, 2008, 41, 5674; (b) H. R. Kricheldorf
and G. Schwarz, J. Macromol. Sci., Part A: Pure Appl. Chem., 2007, 44,
625.
13 (a) J. Chen and C. J. Forsyth, Org. Lett., 2003, 5, 1281; (b) C. Brule, J.
P. Bouillon, E. Nicolaï and C. Portella, Synthesis, 2003, 436.
14 (a) T. Shimizu and M. Seki, Tetrahedron Lett., 2002, 43, 1039;
(b) R. K. Dieter, Tetrahedron, 1999, 55, 4177; (c) Z. Ikeda, T. Hirayama
and S. Matsubara, Angew. Chem., Int. Ed., 2006, 45, 8200; (d) J.
M. Villalobos, J. Srogl and L. S. Liebeskind, J. Am. Chem. Soc., 2007,
129, 15734.
(400 MHz, CDCl3): δ = 7.20–7.38 (m, 10H, Ar–H), 7.16 (d, J =
7.6 Hz, 2H), 7.04 (d, J = 7.6 Hz, 2H), 4.72 (t, J = 7.1 Hz, 1H),
3.27 (d, J = 7.1 Hz, 2H), 2.33 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 195.4, 138.1, 136.7, 134.6, 133.5, 132.4, 131.1,
130.3, 129.5, 128.6, 127.8, 127.0, 126.1, 50.6, 48.2, 22.1; MS
(EI): m/z = 364 (M+); Anal. Calcd for C22H20OS2: C, 72.49; H,
5.53%. Found: C, 72.61; H, 5.41%.
15 M. Mizumo, I. Muramuto, T. Kawakami, M. Soike, S. Aimoto,
K. Hanoda and T. Inazu, Tetrahedron Lett., 1998, 39, 55.
16 S. Ozaki, M. Adachi, S. Sekiya and R. Kamikawa, J. Org. Chem., 2003,
68, 4586.
17 J. M. Turpin, Y. Song, J. K. Inman, M. Huang, A. Wallqvist,
A. Maynard, D. G. Covell, W. G. Rice and E. Appella, J. Med. Chem.,
1999, 42, 67.
Acknowledgements
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 Senior Research
Fellowship.
3936 | Org. Biomol. Chem., 2012, 10, 3932–3936
This journal is © The Royal Society of Chemistry 2012