Efficient synthesis of unsymmetrical disulfides

Article abstract of DOI:10.1016/j.tet.2011.09.071

A novel way of synthesizing unsymmetrical disulfides from thiols with DDQ is presented here. This procedure ran in a straightforward manner to give high product yields. Unsymmetrical disulfides were directly synthesized from the corresponding mixture of thiols in equimolar amounts under mild conditions.

Full text of DOI:10.1016/j.tet.2011.09.071

Tetrahedron 67 (2011) 8895e8901
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of unsymmetrical disulfides
,
Jaya Kishore Vandavasi a, Wan-Ping Hu b, Chung-Yu Chen c, Jeh-Jeng Wang a
*
a Department of Medicinal and Applied Chemistry, Life Sciences, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
b Department of Biotechnology, Life Sciences, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
c School of Pharmacy, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Received in revised form 15 September 2011
Accepted 15 September 2011
Available online 22 September 2011
A novel way of synthesizing unsymmetrical disulfides from thiols with DDQ is presented here. This
procedure ran in a straightforward manner to give high product yields. Unsymmetrical disulfides were
directly synthesized from the corresponding mixture of thiols in equimolar amounts under mild
conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Disulfide
DDQ
Thiol
Oxidation
Symmetrical and unsymmetrical
1. Introduction
metal,29 with sulfenic acid and thiosulfenate intermediates as
precursors.30 In some instances, unstable nitroso thiols were
Organic compounds containing disulfides play vital roles in
chemistry and biology.1 Biological transformation of thiols to
disulfides is extremely common and is a critical process for main-
taining the redox state within and without cells for latentiating
thiols in prodrugs.2e8 Perusal of the literature reveals a variety of
methods for synthesizing both symmetric and unsymmetric
disulfides, many of which are based upon the reaction of a thiol
with a sulfenylating reagent (sulfur transfer)9 or from aromatic
sulfonyl chlorides using samarium metal,10 triphenyl phosphine11
or neutral alumina.12 Other areal oxidation reactions include son-
ication,13 or iron metal catalyzed areal oxidation.14 Oxidative cou-
pling of thiols in the presence of Iodine,15 H2O2,16 organometallic
manganese complex17 and electrochemical oxidation of thiols18
have also been reported. Thiols with Burgess reagent,19 strong ba-
ses,20 CAN,21 Al2O3/KF,22 CsF,23 Benzyltriethylammoniumte-
trathiomolybdate,24 Silica sulfuric acid/NaNO2,25 ammonium,26
Polyvinylpyrrolidone/N2O4,27 have also been shown to produce
symmetric dithio compounds. Unsymmetrical disulfides are gen-
erally synthesized using 2,20-dithiobis(benzothiazole),28 where the
benzothiazole is the resultant fragment in the products. Other
methodologies synthesize unsymmetrical dithio compounds from
symmetrical disulfides by oxidative coupling using rhodium
exploited as substrates to form unsymmetrical dithio compounds
via sulfonamide intermediates31 and benzotriazole precursors.32
A
variety of unsymmetrical disulfides have been synthesized via
dialkoxylthiophosphorane sulfenyl halide precursors33 and a series
of unsymmetrical glycosyl disulfides have also been synthesized
using different dialkyl azodicarboxylate through a standard pro-
tocol.34 A combination of diazoniumsalts/CS2,35 N-trifluoroacetyl
arenesulfenamides-thiol36 were also demonstrated to be practical
substrates for the synthesis of unsymmetrical disulfides. Very re-
cently, thiols were protected with [[(tert-Butyl)dimethylsilyl]oxy]-
methyl group during the synthesis of disulfides.37 Chemical in-
teraction studies of 1,3-benzothiazole-2-thiol with
p-acceptors
yielding the formation of corresponding symmetrical compounds
were conducted with DDQ, but unfortunately yields were very
low.38 Early studies in this field describe the synthesis of un-
symmetrical dithio compounds, however toxic reagents, the need
for high temperature, highly unstable reactive intermediates, and
costly reagents diminished the applicability of this technique. In
our previous study, we explored a mild and efficient way to include
SeS bond formation of thioamides in the presence of DDQ.39
Herein, we describe our studies to a more general investigation of
this phenomenon, with the formation of disulfide bonds. Based on
our literature survey, until the present study DDQ has not been
exploited as a reagent for the synthesis of various unsymmetrical
dithio compounds directly from equimolar mixtures of different
thiols.
* Corresponding author. Fax: þ886 7 312 5339; e-mail address: jjwang@kmu.
edu.tw (J.-J. Wang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.071

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J.K. Vandavasi et al. / Tetrahedron 67 (2011) 8895e8901
2. Results and discussion
synthesized various aromatic as well as aliphatic dithio derivatives
by choosing selected commercially available aromatic and aliphatic
thiols listed in Fig. 1.
Over the course of optimization studies, we discovered that we
could generate unsymmetrical disulfide bond formation. First, op-
timization of the reaction conditions for the formation of SeS bond
in symmetrical disulfide 1 with the selected oxidizing reagents is
presented in Table 1.
O
SH
Cl
SH
SH
SH
Br
Cl
SH
SH
B
D
A
C
Table 1
SH
SH
O
N
Optimization of reaction conditions to synthesize disulfides
oxidizing reagent
N
S
H3C
O
S
Br
Br
SH
E
F
G
H
Br
S
solvent
A
1
O
Br
O
Entry
Reagent
Solvent
Equiv
Temp (ꢀC)
Time
Yield (%)
SH
HO
HO
SH
1
2
3
4
5
6
7
8
DDQ
DDQ
DDQ
DDQ
DDQ
CAN
PCC
K3Fe(CN)6
K3Fe(CN)6
Mn(OAc)2
DMP
AgNO3
AgNO3
Mg(NO3)2
IBX
CH2Cl2
THF
0.5
0.5
0.5
0.2
0.4
3.0
1.0
2.0
1.5
1.5
0.5
1.0
1.0
1.5
1.0
0
0
0
0
0
0
0
5 min
5 min
5 min
5 min
5 min
5 min
5 min
12 h
5 h
5 h
5 min
5 h
5 h
95
51
91
40
50
78
86
20
70
84
67
15
35
12
85
SH
SH
SH
I
J
K
M
L
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
O
SH
SH
NH2
HS
HS
OH
O
N
Q
0e28
80
0e28
0
0e28
0e28
0e28
0e28
9
P
10
11
12
13
14
15
Fig. 1. Thiols used for SeS bond formation reactions.
24 h
45 min
A broad range of thiols reacted smoothly under our optimized
reactionconditions. Thereactionwastolerantofvarioussubstituents,
including hydroxy, carboxylic, halides, methoxy, and methyl. These
results are summarized in Table 2. Aromatic thiols from A to H (in
Fig. 1) underwent disulfide formation to furnish desired products
with excellent yields (90e98%, entries 1e8, Table 1). An example of
aliphatic dithio compound was synthesized in 92% yield (entry 9,
Table 1). It is noteworthy to mention that the aliphatic thio com-
pounds underwent reaction in the presence of unprotected hydroxyl
groups. We also observed dithio compound formationwith 82% yield
from corresponding thiocarboxylic acid (entry 10, Table 1).
Further, to investigate the synthesis of unsymmetrical disul-
fides, various reaction conditions were screened with compounds E
and G serving as initial substrates (Table 3). Dichloromethane with
PCC at 0e28 ꢀC for 1 h gave the corresponding unsymmetrical
disulfide at a 65% yield (entry 1, Table 3). The reaction was not
successful with many of the other reagents including Mn(OAc)2,
K3Fe(CN)6, Mg(NO3)2, and AgNO3 (entries 2, 3, 8, and 9, Table 3).
Only a 23% yield was obtained with CAN. Moderate to high
yields were observed with IBX, DMP and DDQ (85%, 77% and 89%,
respectively) (entries 5, 6, and 7, Table 3). With these results in
mind, we concluded that the reaction was not successful with in-
organic reagents like Mn(OAc)2, K3Fe(CN)6, Mg(NO3)2, and AgNO3.
Likewise the yield was also quite low when CAN was utilized. In-
terestingly, with symmetrical disulfide synthesis, congruent with
our previous work,39 we found that the DDQ to be an efficient re-
agent for this reaction. These results are presented with relevant
details in Table 4.
Reactions with mixture of different aromatic mercaptans (en-
tries 1, 2, and 8e10, Table 4) led to the formation of the dithio
compounds in relatively high yields (81e92%) as compared to re-
actions between aromatic and aliphatic substrates (entries 3e7 and
11e22, Table 4). The reaction was successful using a secondary
thiol, and afforded a moderate yield (75%) (entry 23, Table 4),
whereas reactions utilizing a tertiary thiol were not successful
(entry 29, Table 4) perhaps due to steric hindrance. Reaction mass
was decomposed when amine substituted thiol was reacted with
substituted thiols like para-OMe/meta-Cl/ortho-Br/para-Cl (entries
24e28, Table 4). Low yield was obtained with a carboxylic acid
substituted thiol (37%) (entry 30, Table 4).
The study began with compound A and commercially available
DDQ (0.5 equiv) in dichloromethane solvent at 0 ꢀC for 5 min to
create disulfide 1 with a 95% yield. In contrast, utilizing tetrahy-
drofuran gave significantly less yield (51%, entry 2) under similar
reaction conditions. To compare, conducting the reaction in ace-
tonitrile solvent yielded 91% (entry 3) of the desired product 1a.
Furthermore, reactions were also carried out while varying the
amount of DDQ from 0.2 to 0.4 equiv in dichloromethane under
similar reaction conditions. These reactions gave 40% and 50%
yields, respectively (entries 4 and 5).
We were curious to continue our investigation with other pos-
sible oxidizing reagents, such as ceric(IV) ammonium nitrate (CAN),
pyridiniumchlorochromate
(PCC),
potassium
ferricyanide
K3Fe(CN)6, manganese (II) acetate (Mn(OAc)2), Dessemartin peri-
odinane (DMP), silver nitrate (AgNO3), magnesium nitrate
Mg(NO3)2 and 2-iodoxybenzoic acid (IBX) under different reaction
conditions. The CAN mediated reaction was performed with excess
(3.0 equiv) of reagents and resulted in a 78% yield of 1a. Reaction
with 1.0 equiv of PCC was also found to be effective and produced
86% of the desired product. K3Fe(CN)6 in dichloromethane required
a longer reaction time and excess reagent at 0ꢀꢁ28 ꢀC but only
yielded 20% of the desired disulfide 1a (entry 8). In this particular
case, a change of the solvent from dichloromethane to acetonitrile
increased the yield of disulfide 1a to 70% at higher temperature
(80 ꢀC for 5 h) (entry 9). With Mn(OAc)2 in dichloromethane at
28 ꢀC for 5 h we were able to obtain 84% yield (entry 10). The DMP
catalyzed reaction in dichloromethane yielded 67% of 1a (entry 11).
Reactivity of AgNO3 in dichloromethane (entry 12) was consider-
ably worse than other reagents with a 35% yield even by switching
over to other solvent, like acetonitrile (entry 13). An attempted
reaction with Mg(NO3)2 in dichloromethane was found to produce
very less yield, 12% (entry 14). 2-Iodoxybenzoic acid in dichloro-
methane was also found to be effective, but with moderate yield of
85% as compared to DDQ (entry 15). Comparative study of the
optimization reaction conditions mentioned in Table 1 clearly in-
dicated that DDQ in dichloromethane could be a versatile reagent
for the synthesis of disulfides from the corresponding thiols. We

J.K. Vandavasi et al. / Tetrahedron 67 (2011) 8895e8901
8897
Table 2
Table 4
Formation of disulfides from thiols and thiocarboxylic acids
Scope and limitations of unsymmetrical disulfides formation from thiols
DDQ, CH2Cl2, 0 oC, 5 min.
R2
DDQ, CH2Cl2
0 oC, 5 min.
S
R1 SH
R2 SH
R1
S
R
R
SH
S
+
R
S
Entry
1
Substrate
A
Product
1
Yield (%)
95
Entry
1
Substratesa
Product
2 [Yield (%)]b
N
S
Br
Cl
S
S
1a
1b
1c
Br
Cl
AþE
2a (83)
2b (81)
2c (80)
S
S
S
Br
S
S
N
O
2
3
B
C
94
93
S
2
3
AþF
AþI
Br
S
S
Cl
S
OH
Cl
S
Br
S
N
S
S
O
4
D
1d
91
S
O
4
5
EþI
FþI
2d (83)
2e (82)
S
S
OH
OH
O
N
S
N
S
S
S
S
N
5
6
E
F
1e
1f
90
92
Br
S
6
7
AþM
FþM
2f (91)
2g (88)
O
N
S
OH
S
S
O
N
O
S
N
S
OH
O
S
S
7
8
9
G
H
I
1g
1h
1i
97
98
92
S
O
S
8
EþG
EþH
FþH
2h (89)
2i (92)
2j (90)
N
S
O
S
S
S
S
S
9
N
S
S
S
S
OH
HO
O
N
10
O
S
S
S
S
OH
10
J
1j
82
11
12
13
HþM
DþM
BþM
2k (83)
2l (82)
O
O
S
S
OH
S
Table 3
S
OH
OH
2m (80)
Screening different oxidizing reagents to synthesize the unsymmetrical disulfides
Cl
Cl
S
N
S
N
oxidizing reagent
solvent
SH HS
+
O
S
S
S
O
S
S
14
15
CþM
JþM
2n (83)
2o (85)
E
2h
G
S
Entry
Reagent
Solvent
Equiv
Temp (ꢀC)
Time
Yield (%)
O
OH
1
2
3
4
5
6
7
8
9
PCC
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
3
4
6
2
1
1
3
2
0e28
0e28
0e28
0e28
0e28
0
1 h
4 h
24 h
1 h
1 h
5 min
5 min
24 h
24 h
65
Mn(OAc)2
K3Fe(CN)6
CAN
IBX
DMP
DDQ
Mg(NO3)2
AgNO3
N.R.
N.R.
23
85
77
89
N.R.
N.R.
Br
S
O
16
17
AþL
IþJ
2p (81)
2q (72)
S
S
S
OH
0
O
0e28
0e28
Cl
S
18
19
BþI
CþI
2r (65)
2s (68)
OH
S
Cl
S
OH
OH
Our data show that the position of the substituents on the ar-
omatic ring does not play a vital role in the yield of the product.
Chain length in aliphatic thiols play a significant role e.g., yield of
dithio compounds 2qet and 2v (Table 3) with a 4-carbon aliphatic
chain produced less yield (65e72%) when compared with that of
2keo (80e85%) having a 3-carbon aliphatic thiol. By compiling the
above results we came to the determination that hydroxy
substituted thiols are favorable to the formation of SeS bonds.
S
O
S
S
20
21
DþI
2t (70)
2u (68)
S
S
OH
KþM
Br
(continued on next page)

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J.K. Vandavasi et al. / Tetrahedron 67 (2011) 8895e8901
Table 4 (continued )
3. Conclusions
Entry
Substratesa
Product
2 [Yield (%)]b
In conclusion, we have developed a mild and efficient ‘one pot’
method for the synthesis of unsymmetrical dithio compounds di-
rectly from corresponding thiols and thiocarboxylic acids in the
presence of DDQ. This method may be useful for the preparation of
both classes of dithio compounds in a single step. Further biological
studies of these molecules are in progress.
OH
S
S
22
23
IþK
2v (65)
2w (75)
Br
Cl
BþN
S
S
4. Experimental section
4.1. General information
Cl
24
25
BþO
GþO
2x (N.R.)
2y (N.R.)
S
S
NH
2
Melting points are uncorrected. 1H NMR and 13C NMR spectra
were recorded at 400 and 100 MHz, respectively, using CDCl3 as
a solvent. 1H NMR chemical shifts are referenced to TMS or residual
chloroform in CDCl3 (7.26 ppm). 13C NMR was referenced to re-
sidual chloroform in CDCl3 (77.0 ppm). Mass spectra and high-
resolution mass spectra (HRMS) were obtained using the
electron-impact (EI, 70 eV) technique. Raman Spectroscopy were
recorded on an iHR-320- monochromometer, HeeNe laser excita-
tion was set to 632.8 nm, power was 15 MW per to sample, tem-
perature was ꢁ133 ꢀC and exposure time was 1 s with 10
accumulations. Flash chromatography was carried out on silica gels
(230e400 mesh).
O
S
S
NH
2
26
CþO
2z (N.R.)
Br
S
27
28
29
KþO
BþO
BþP
2aa (N.R.)
2ab (N.R.)
2ac (N.R.)
S
NH
2
Cl
NH2
S
S
S
Cl
4.2. General procedure for the synthesis of disulfides
S
Procedure for symmetrical molecules: DDQ (0.5 mmol) was added
to an ice-cooled solution of thiol (1 mmol) in dichloromethane
(3.0 mL). The reaction mixture stirred for 5 min at 0 ꢀC and moni-
tored by TLC analysis. The reaction mixture was concentrated under
reduced pressure and directly purified by column chromatography
by gradient elution of ethyl acetate in hexanes to give the title
compounds.
Cl
30
BþQ
S
OH
2ad (37)
S
O
a
Equimolar ratio of thiols were used in all reactions (entries 1e22).
Minor amounts of symmetrical dithio compounds were observed by analytical
b
Procedure for unsymmetrical molecules: Thiol A (1.0 mmol) and
thiol B (1.0 mmol) were dissolved in 3.0 ml of dichloromethane
and cooled to 0 ꢀC. DDQ (1.0 mmol) was added slowly to the re-
action mixture and stirred for 5 min at 0 ꢀC. The reaction was
monitored by TLC analysis. Solvents were removed under re-
duced pressure and the crude compound was directly purified by
column chromatography by gradient elution of ethyl acetate in
hexanes to give the title compounds along with the side
products.
TLC.
The structure of the resultant SeS bonds was confirmed by
X-ray crystallographic analysis of single crystals of unsymmetrical
disulfide 2m (Fig. 2A) and symmetrical disulfide 1j (Fig. 2B). In
addition, Raman spectral data of 15 examples were selected from
both Tables 2 and 3 to demonstrate SeS bond stretching vibration
in the range of 528e558 cmꢁ1 (see Supplementary data).
4.2.1. Compound 1a. White solid; 95% yield; mp 94e95 ꢀC (lit40
mp¼95 ꢀC); 1H NMR (CDCl3, 400 MHz)
d 7.40e7.42 (m, 4H, Ph),
7.31e7.33 (m, 4H, Ph); 13C NMR (CDCl3, 100 MHz):
d 121.5, 129.3,
132.2, 135.6.
4.2.2. Compound 1b. White solid, 94% yield, mp 71e73 ꢀC (lit41
mp¼69e71 ꢀC), 1H NMR (CDCl3, 400 MHz):
d
7.25e7.27 (m, 4H,
129.2,
Ph), 7.38e7.40 (m, 4H, Ph); 13C NMR (CDCl3, 100 MHz):
d
133.5, 135.0; LRMS (EI, m/z)¼286 [Mþ]; HRMS (EI, m/z) calcd for
C12H8Cl2S2 [Mþ] 285.9444, found 285.9449.
4.2.3. Compound 1c. Colorless oil, 93% yield, 1H NMR (CDCl3,
400 MHz): d 7.18e7.24 (m, 2H, Ph), 7.32e7.35 (m, 1H, Ph), 7.46e7.47
(m, 1H, Ph), 13C NMR (CDCl3, 100 MHz):
d 125.2, 126.9, 127.5, 130.1,
135.0, 138.3; LRMS (EI, m/z)¼286 [Mþ]; HRMS (EI, m/z) for
C12H8Cl2S2 calcd 285.9440, found 285.9450; Raman spectra: SeS
530 cmꢁ1
.
4.2.4. Compound 1d. White solid, 91% yield, mp 105e107 ꢀC (Lit42
mp¼114 ꢀC), 1H NMR (CDCl3, 400 MHz):
d 3.75 (s, 6H, CH3),
6.73e6.76 (m, 2H, Ph), 7.05e7.08 (m, 4H, Ph), 7.18e7.24 (m, 2H, Ph);
Fig. 2. ORTEP diagram of 1j and 2m (crystals were obtained from a mixture of chlo-
roform and hexane at low temperature).

J.K. Vandavasi et al. / Tetrahedron 67 (2011) 8895e8901
8899
13C NMR (CDCl3, 100 MHz):
159.9, HRMS (EI, m/z) for C14H14O2S2 [Mþ] calcd 278.0435, found
278.0432, Raman spectra: SeS 540 cmꢁ1
d
55.2, 112.4, 113.0, 119.5, 129.8, 138.2,
[Mþ]; HRMS (EI, m/z) for C10H13BrOS2Na [MþNa]þ calcd 314.9489,
found 314.9487.
.
4.2.14. Compound 2d. Oil, 83% yield, 1H NMR (CDCl3, 400 MHz):
d 1.62e1.69 (m, 2H, CH2), 1.79e1.87 (m, 2H, CH2), 2.19 (br s, 1H, OH),
4.2.5. Compound 1e. Off white solid, 90% yield, mp 181e183 ꢀC
(lit43 mp¼182e183.5 ꢀC); 1H NMR (CDCl3, 400 MHz):
2.95 (t, J¼7.2 Hz, 2H, CH2), 3.62 (t, J¼6.4 Hz, 2H, CH2), 7.27e7.31
d
7.76e7.78 (m, 2H, Ph), 7.44e7.48 (m, 2H, Ph), 7.76e7.78 (m, 2H,
(1 m, 1H, Ph), 7.37e7.41 (m, 1H, Ph), 7.74e7.83 (m, 2H, Ph); 13C NMR
Ph), 7.93e7.95 (m, 2H, Ph); 13C NMR (CDCl3, 100 MHz):
d
121.2,
(CDCl3, 100 MHz): d 25.3 (eCH2), 31.2 (eCH2), 39.1 (eCH2), 61.8
122.6, 125.2, 126.5, 136.1, 154.5, 167.8; LRMS (EI, m/z)¼333 [Mþ];
HRMS (EI, m/z) for C14H8N2S4 [MþH]þ calcd 332.9649, found
332.9647.
(eCH2), 121.0, 121.9, 124.5, 126.1, 135.6, 154.8172.9; LRMS (EI, m/z)¼
294 [Mþ]; HRMS (EI, m/z) for C11H13NOS3Na [MþNa]þ calcd
294.0057, found 294.0055. Raman spectra: SeS 528 cmꢁ1
.
4.2.6. Compound 1f. Yellow sticky mass, 92% yield, mp 111e113 ꢀC
4.2.15. Compound 2e. Colorless oil, 82% yield, 1H NMR (CDCl3,
400 MHz) 1.67e1.74 (m, 2H, CH2), 1.84e1.91 (m, 2H, CH2), 2.63 (br
ꢀ
(lit44 mp: 114 C); 1H NMR (CDCl3, 400 MHz)
d
7.27e7.34 (m, 4H,
d
Ph), 7.48e7.54 (m, 2H, Ph), 7.67e7.70 (m, 2H, Ph);13C NMR (CDCl3,
s, 1H, OH), 3.02 (t, J¼7.2 Hz, 2H, CH2), 3.67 (t, J¼6.4 Hz, 2H, CH2),
100 MHz):
d 110.5, 119.7, 124.9, 125.4, 141.7, 152.5, 159.8; LRMS (EI,
7.27e7.33 (m, 1H, Ph), 7.45e7.50 (m, 1H, Ph), 7.64e7.68 (m, 1H, Ph);
m/z)¼301 [Mþ]; HRMS (EI, m/z) for C14H8N2O2S2 [MþH]þ calcd
13C NMR (CDCl3, 100 MHz):
d 24.9 (eCH2), 31.0 (CH2), 39.0 (CH2),
301.0105, found 301.0103.
61.8 (CH2), 110.1, 119.1, 124.5, 124.7, 141.6, 152.2, 163.5; LRMS (EI, m/
z)¼278 [Mþ]; HRMS (EI, m/z) for C11H13NO2S2Na [MþNa]þ calcd
278.0285, found 278.0284.
4.2.7. Compound 1g. Off white solid, 97% yield, mp 33e34 ꢀC (lit41
mp¼31e34 ꢀC), 1H NMR (CDCl3, 400 MHz):
d 3.76 (s, 1H, CH3),
6.82e6.80 (m, 2H, Ph), 7.39e7.37 (m, 2H, Ph); 13C NMR (CDCl3,
4.2.16. Compound 2f. Colorless oil, 91% yield; 1H NMR (CDCl3,
100 MHz):
d
55.2, 114.5, 128.2, 132.5159.8; LRMS (EI, m/z)¼278.1
400 MHz):
d
1.87e1.94 (m, 3H, CH2), 2.82 (t, J¼7.2 Hz, 2H, CH2), 3.69
[Mþ]; HRMS (EI, m/z) for C14H14O2S2Na [MþNa]þ calcd 301.0331,
(t, J¼6.0 Hz, 2H, CH2), 7.37e7.45 (m, 4H, Ph); 13C NMR (CDCl3,
found 301.0331.
100 MHz); d 31.3 (eCH2), 35.0 (eCH2), 60.7 (eCH2), 120.6, 128.9,
131.9, 136.4; HRMS (EI, m/z) for C9H11BrOS2 [Mþ] calcd 277.9435,
4.2.8. Compound 1h. Off white solid, 98% yield, mp 38e40 ꢀC (lit41
found 277.9428.
mp¼40e42 ꢀC), 1H NMR (CDCl3, 400 MHz):
d 2.30 (s, 3H, CH3),
7.08e7.10 (m, 4H, Ph), 7.35e7.39 (m, 4H, Ph); 13C NMR (CDCl3,
4.2.17. Compound 2g. Colorless oil, 88% yield, 1H NMR (CDCl3,
400 MHz):
100 MHz):
d
21.0, 128.5, 129.7, 133.8, 137.4; LRMS (EI, m/z)¼[Mþ];
d
1.97e2.04 (m, 2H, CH2), 3.16 (t, J¼7.2 Hz, 2H, CH2), 3.23
HRMS (EI, m/z) for C14H14S2 [Mþ] calcd 246.0537, found 246.0535;
(br s, 1H, OH), 3.82 (t, J¼5.6 Hz, 2H, CH2), 7.27e7.33 (m, 2H, Ph),
Raman spectra: SeS 540 cmꢁ1
4.2.9. Compound 1i. Light yellow oil, 92% yield, 1H NMR (CDCl3,
.
7.45e7.50 (m, 1H, Ph), 7.64e7.68 (m, 1H, Ph); 13C NMR (CDCl3,
100 MHz)
d 30.9 (eCH2), 36.0 (eCH2), 60.1 (eCH2), 110.2, 119.0,
124.6, 124.7, 141.3, 152.3163.9; HRMS (ESI, m/z) for C10H11NO2S2
400 MHz): d 1.62e1.69 (m, 2H, CH2), 1.74e1.81 (m, 2H, CH2), 2.72 (t,
[MþH]þ calcd 242.0304, found 242.0304; Raman spectra: SeS
J¼7.2 Hz, 2H, CH2), 3.02 (br s,1H, OH),3.64 (t, J¼6.4 Hz, 2H, CH2); 13
C
544 cmꢁ1
.
NMR (CDCl3, 100 MHz):
d
25.4, 31.1, 38.6, 61.9; LRMS (EI, m/z)¼233
[Mþ]; HRMS (EI, m/z) for C8H18O2S2Na [MþNa]þ calcd 233.0646,
4.2.18. Compound 2h. Yellow solid, 89% yield, mp 59e61 ꢀC (lit33
temp 61e62 ꢀC); 1H NMR (CDCl3, 400 MHz):
3.77 (s, 3H,),
found 233.0644; Raman spectra: SeS 540 cmꢁ1
.
d
6.82e6.86 (m, 2H), 7.29e7.33 (m, 1H), 7.39e7.43- (m, 1H),
4.2.10. Compound 1j. White solid, 82% yield, mp 127e129 ꢀC (lit45
temp 127e128 ꢀC); 1H NMR (CDCl3, 400 MHz):
7.49e7.53 (m, 4H,
Ph), 7.62e7.66 (m, 2H, Ph), 8.06e8.08 (m, 4H, Ph); 13C NMR (CDCl3,
7.60e7.63 (m, 2H), 7.78e7.80 (m, 1H), 7.84e7.87 (m, 1H); 13C NMR
d
(CDCl3, 100 MHz): d 55.3, 114.9, 121.0, 122.1, 124.5, 125.7, 126.1,
133.3, 135.7, 154.8, 160.7, 171.9; LRMS (EI, m/z)¼305.1 [Mþ]; HRMS
100 MHz):
d 128.0, 128.9, 134.3, 135.1, HRMS (EI, m/z) for
(EI, m/z) for C14H11NOS3 [Mþ] calcd 305.0003, found 305.0000,
C14H10O2S2Na [MþNa]þ calcd 297.0020, found 297.0022.
Raman spectra: SeS 532 cmꢁ1
.
4.2.11. Compound 2a. Off white solid, 83% yield, mp 65e67 ꢀC
4.2.19. Compound 2i. Off white solid, 89% yield, mp 37e38 ꢀC (lit28
temp 61e62 ꢀC); 1H NMR (CDCl3, 400 MHz):
2.27 (s, 3H, CH3), 7.09
(lit28 temp 67e68 ꢀC), 1H NMR (CDCl3, 400 MHz):
d
7.31e7.35 (m,
1H, Ph), 7.41e7.50 (m, 5H, Ph), 7.76e7.78 (m, 1H, Ph), 7.87e7.89
(m, 1H, Ph); 13C NMR (CDCl3, 100 MHz):
121.1, 122.3, 122.7, 124.8,
d
(d, J¼8.4 Hz, 2H, Ph), 7.24e7.28 (m, 1H, Ph), 7.35e7.39 (m, 1H, Ph),
d
7.40e7.51 (m, 2H, Ph), 7.70e7.72 (m, 1H, Ph), 7.83e7.85 (m, 1H, Ph);
126.3, 130.5, 132.4, 134.1, 135.8, 154.7, 170.5; LRMS (EI, m/z)¼354
[M]þ; HRMS (EI, m/z) for C13H8BrNS3 [Mþ] calcd 353.9080, found
353.9079.
13C NMR (CDCl3, 100 MHz):
d 21.0, 120.9, 122.0, 124.4, 126.0, 129.7,
129.9, 131.3, 135.7, 138.9, 154.8, 171.8; LRMS (EI, m/z)¼289 [Mþ];
HRMS (EI, m/z) for C14H11NS3 [Mþ] calcd 289.0054, found 289.0063;
Raman spectra: SeS 532 cmꢁ1
.
4.2.12. Compound 2b. Colorless oil, 81% yield, 1H NMR (CDCl3,
400 MHz):
d
7.29e7.35 (m, 1H, Ph), 7.45e7.57 (m, 5H, Ph), 7.62e7.71
110.3, 119.6, 123.2, 124.7,
4.2.20. Compound 2j. Light yellow sticky solid, 90% yield, 1H NMR
(CDCl3, 400 MHz):
2.32 (s, 3H, CH3), 7.13 (d, J¼8 Hz, 2H, CH2),
7.24e7.33 (m, 2H, Ph), 7.46e7.50 (m, 1H, Ph), 7.56e7.60 (m, 2H, Ph),
7.66e7.70 (m, 1H, Ph); 13C NMR (CDCl3, 100 MHz);
21.1, 110.2,
(m, 1H, Ph); 13C NMR (CDCl3, 100 MHz):
d
d
125.0, 131.7, 132.4, 134.4, 141.8, 152.4, 162.2; LRMS (EI, m/z)¼338
[M]þ; HRMS (EI, m/z) for C13H8BrNOS2 [MþH]þ calcd 337.9309,
found 337.9311.
d
119.5, 124.5, 124.7, 130.0, 131.2, 131.8, 139.4, 141.9, 152.4, 162.9;
LRMS (EI, m/z)¼273.1 [Mþ]; HRMS (EI, m/z) for C14H11NOS2 [Mþ]
4.2.13. Compound 2c. Colorless oil, 80% yield, 1H NMR (CDCl3,
calcd 273.0282, found 273.0276; Raman spectra: SeS 529 cmꢁ1
.
400 MHz):
J¼6.8 Hz, 2H, CH2), 3.62 (t, J¼6.4 Hz, 2H, CH2), 7.38e7.45 (m, 4H,
Ph); 13C NMR (CDCl3, 100 MHz):
25.0 (eCH2), 31.2 (eCH2), 38.5
(eCH2), 62.2 (eCH2), 120.5, 128.9, 131.9136.7; LRMS (EI, m/z)¼315
d 1.59e1.67 (m, 2H, CH2), 1.72e1.79 (m, 2H, CH2), 2.75 (t,
4.2.21. Compound 2k. Yellow oil, 83% yield; 1H NMR (CDCl3,
400 MHz): 1.89e1.96 (m, 2H, CH2), 2.33 (s, 3H, CH3), 2.82 (t,
J¼6.8 Hz, 2H, CH2), 3.69 (t, J¼6.4 Hz, 2H, CH2), 7.12 (d, J¼7.6 Hz, 2H,
d
d

8900
J.K. Vandavasi et al. / Tetrahedron 67 (2011) 8895e8901
Ph), 7.41e7.43 (m, 2H, Ph); 13C NMR (CDCl3, 100 MHz):
d
20.9
CH2), 3.62 (t, J¼6.4 Hz, 2H, CH2), 7.16e7.26 (m, 2H, Ph), 7.36e7.39
(m, 1H, Ph), 7.53 (t, J¼2 Hz, 1H, Ph); 13C NMR (CDCl3, 100 MHz)
(eCH2), 31.3 (eCH2), 35.0 (eCH2), 60.9 (eCH2), 128.5, 129.7, 133.76,
137.1; LRMS (EI, m/z)¼214.2 [Mþ]; HRMS (EI, m/z) for C10H14OS2
[Mþ] calcd 214.0486, found 214.0482; Raman spectra: SeS
d
25.0 (eCH2), 31.2 (eCH2), 38.5 (eCH2), 62.2 (eCH2), 125.0, 126.5,
126.7, 129.9, 134.9, 139.6; LRMS (EI, m/z)¼248.1 [M]þ; HRMS (EI, m/
532 cmꢁ1
.
z) for C10H13ClO2S2 [Mþ] calcd 248.0096, found 248.0101; Raman
spectra: SeS 533 cmꢁ1
.
4.2.22. Compound 2l. Colorless oil, 82% yield; 1H NMR (CDCl3,
400 MHz): 1.79 (br s, 1H, OH), 1.89e1.95 (m, 2H, CH2), 2.83 (t,
d
4.2.30. Compound 2t. Colorless oil, 70% yield, 1H NMR (CDCl3,
400 MHz): 1.48 (br s, 1H, OH), 1.60e1.67 (m, 2H, CH2), 1.73e1.80
J¼6.8 Hz, 2H, CH2), 3.70 (t, J¼6.0 Hz, 2H, CH2), 3.81 (s, 3H, OCH3),
d
6.73e6.76 (m, 1H, Ph), 7.08e7.11 (m, 2H, Ph), 7.20e7.25 (m, 1H, Ph);
(m, 2H, CH2), 2.77 (t, J¼6.8 Hz, 2H, CH2), 3.61 (t, J¼6.4 Hz, 2H, CH2),
13C NMR (CDCl3, 100 MHz)
d 31.4 (eCH2), 35.0 (eCH2), 55.2, 60.8
3.81 (s, 3H, CH3), 6.73e6.76 (m, 1H, Ph), 7.08e7.12 (m, 2H, Ph),
(eCH2), 112.4, 112.5, 119.4, 129.7, 138.5, 159.9; LRMS (EI, m/z)¼230.1
7.20e7.24 (m, 1H, Ph); 13C NMR (CDCl3, 100 MHz):
d 25.0 (eCH2),
[Mþ]; HRMS (EI, m/z) for C10H14O2S2 [Mþ] calcd 230.044, found
31.3 (eCH2), 38.5 (eCH2), 55.2 (eCH2), 62.2 (eCH2), 112.4, 112.4,
119.4, 129.7, 138.7, 160.0; LRMS (EI, m/z)¼244.0 [Mþ]; HRMS (EI, m/
z) for C11H16O2S2 [Mþ] calcd 244.0592, found 244.0586; Raman
230.043; Raman spectra: SeS 538 cmꢁ1
.
4.2.23. Compound 2m. Off white solid, 80% yield, mp 36e38 ꢀC, 1H
NMR (CDCl3, 400 MHz):
1.89e1.95 (m, 2H, CH2), 2.83 (t, J¼6.8 Hz,
2H, CH2), 3.71 (t, J¼6.0 Hz, 2H, CH2), 7.28e7.30 (m, 2H, Ph),
7.45e7.47 (m, 2H, Ph); 13C NMR (CDCl3, 100 MHz):
31.4 (eCH2),
spectra: SeS 533 cmꢁ1
.
d
4.2.31. Compound 2u. Colorless oil, 70% yield, 1H NMR (CDCl3,
400 MHz): 1.66 (br s, 1H, OH), 1.91e1.97 (m, 2H, CH2), 2.83 (t,
d
d
35.0 (eCH2), 60.8 (eCH2), 128.9, 129.0, 132.8, 135.8; LRMS (EI, m/z)¼
234 [Mþ]; HRMS (EI, m/z) for C9H11ClOS2 [Mþ] calcd 233.994, found
233.994.
J¼7.2 Hz, 2H, CH2), 3.73 (t, J¼6.4 Hz, 2H, CH2), 7.05e7.09 (m,1H, Ph),
7.33e7.37 (m, 1H, Ph), 7.49e7.51 (m, 1H, Ph), 7.79 (dd, J¼1.6, 8 Hz,
1H, Ph); 13C NMR (CDCl3, 100 MHz):
d 31.5 (eCH2), 34.7 (eCH2),
60.8 (eCH2), 121.3, 127.1, 127.4, 127.8, 132.8, 137.6; LRMS (EI, m/z)¼
278.1 [M]þ; HRMS (EI, m/z) for C9H11BrOS2 [Mþ] calcd 277.9435,
found 277.9429; Raman spectra: SeS 533 cmꢁ1
4.2.24. Compound 2n. Colorless oil, 83% yield; 1H NMR (CDCl3,
400 MHz):
d 1.63 (br s, 1H, OH), 1.89e1.96 (m, 2H, CH2), 2.84 (t,
J¼6.8 Hz, 2H, CH2), 3.72 (t, J¼6.0 Hz, 2H, CH2), 7.16e7.26 (m, 2H, Ph),
7.36e7.39 (m, 1H, Ph), 7.53 (t, J¼2 Hz, 1H, Ph); 13C NMR (CDCl3,
4.2.32. Compound 2v. Colorless oil, 65% yield, 1H NMR (CDCl3,
400 MHz): d 1.46 (br s, 1H, OH), 1.62e1.69 (m, 2H, CH2), 1.75e1.82
100 MHz):
d
31.4 (eCH2), 35.1 (eCH2), 60.8 (eCH2), 125.0, 126.6,
126.8, 129.9, 134.9, 139.4; LRMS (EI, m/z)¼234.1 [M]þ; HRMS (EI, m/
(m, 2H, CH2), 2.77 (t, J¼7.2 Hz, 2H, CH2), 3.64 (t, J¼6.4 Hz, 2H, CH2),
z) for C9H11ClOS2 [Mþ] calcd 233.994, found 233.995; Raman
7.05e7.09 (m, 1H, Ph), 7.33e7.37 (m, 1H, Ph), 7.50 (dd, J¼1.6, 7.8 Hz,
spectra: SeS 550 cmꢁ1
.
1H, Ph), 7.79 (dd, J¼1.6 Hz,1H, 8); 13C NMR (CDCl3, 100 MHz):
d 25.2
(eCH2), 31.3 (eCH2), 38.2 (eCH2), 62.2 (eCH2), 121.2, 127.1, 127.4,
127.8, 132.8, 137.8; LRMS (EI, m/z)¼292.0 [M]þ; HRMS (EI, m/z) for
C10H13BrOS2 [Mþ] calcd 291.9591, found 291.9596; Raman spectra:
4.2.25. Compound 2o. Colorless oil, 82% yield, 1H NMR (CDCl3,
400 MHz): 1.89e1.95 (m, 2H, CH2), 2.50 (br s, 1H, OH), 2.92 (t,
d
J¼7.2 Hz, 2H, CH2), 3.81 (t, J¼6.0 Hz, 2H, CH2), 7.45e7.50 (m, 2H,
SeS 558 cmꢁ1
.
Ph), 7.59e7.63 (m, 1H, Ph), 7.97e8.00 (m, 2H, Ph); 13C NMR (CDCl3,
100 MHz)
134.0, 135.4, 190.7; HRMS (EI, m/z) for C10H12O2S2Na [Mþ] calcd
251.0176, found 251.0174; Raman spectra: SeS 540 cmꢁ1
d
31.3 (eCH2), 35.4 (eCH2), 60.6 (eCH2), 127.6, 128.8,
4.2.33. Compound 2w. Colorless oil, 75% yield, 1H NMR (CDCl3,
400 MHz):
d
0.943 (t, J¼7.2 Hz, 3H, CH3), 1.26 (d, J¼6.4 Hz, 3H, CH3),
.
1.45e1.56 (m, 1H, CH2), 1.63e1.74 (m, 1H, CH2), 2.77e2.85 (m, 1H,
CH), 7.24e7.28 (m, 2H, Ph), 7.44e7.48 (m, 2H, Ph); 13C NMR (CDCl3,
4.2.26. Compound 2p. Sticky solid, 81% yield; 1H NMR (CDCl3,
400 MHz):
2.47 (s, 3H, CH3), 7.32e7.44 (m, 4H, Ph); 13C NMR
(CDCl3, 100 MHz):
100 MHz): d 11.4 (eCH3), 19.8 (eCH3), 28.7 (eCH2), 48.5(eCH),
d
128.4, 128.8, 129.2, 129.3, 132.3, 136.9; HRMS (ESI, m/z) for
d
29.6, 122.6, 122.9, 129.3, 132.1, 132.1, 134.8,
C10H13ClS2 [MꢁH]ꢁ calcd 231.0063, found 231.0069.
193.3; LRMS (EI, m/z)¼262 [M]þ; HRMS (EI, m/z) for C8H7BrOS2
[Mþ] calcd 261.9122, found 261.9117, Raman spectra: SeS 528 cmꢁ1
.
4.2.34. Compound 2ad. Pale pink Solid, 37% yield, mp 89e91 ꢀC, 1H
NMR (CDCl3, 400 MHz):
d
2.78 (t, J¼6.8 Hz, 2H, CH2), 2.95 (t,
4.2.27. Compound 2q. Colorless oil, 72 % yield; 1H NMR (CDCl3,
400 MHz): 1.72e1.74 (m, 4H, CH2), 2.32 (br s, 1H, OH), 2.81 (t,
J¼6.8 Hz, 2H, CH2), 1.75e1.82 (m, 2H, CH2), 2.77 (t, J¼7.2 Hz, 2H,
d
CH2), 3.64 (t, J¼6.4 Hz, 2H, CH2), 7.28e7.31 (m, 2H, Ph), 7.45e7.47
J¼6.8 Hz, 2H, CH2), 3.66 (t, J¼6.0 Hz, 2H, CH2), 7.45e7.49 (m, 2H,
(m, 2H, Ph); 13C NMR (CDCl3, 100 MHz):
d 32.7 (eCH2), 33.4 (eCH2),
Ph), 7.59e7.63 (m, 1H, Ph), 7.97e7.99 (m, 2H, Ph); 13C NMR (CDCl3,
129.1, 129.2, 133.1, 135.3, 177.0; HRMS (ESI, m/z) for C9H9ClO2S2
100 MHz):
d 25.1 (eCH2), 31.1 (eCH2), 38.5 (eCH2), 61.9 (eCH2),
[MꢁH]ꢁ calcd 246.9654, found 246.9648.
127.5, 128.7, 133.9, 135.5, 190.6; HRMS (EI, m/z) for C11H14O2S2Na
[MþNa]þ calcd 265.0333, found 265.0334, Raman spectra: SeS
Acknowledgements
550 cmꢁ1
.
We thank the National Science Council of the Republic of China,
and the KMU Center of Excellence for Environmental Medicine for
financial support. We gratefully acknowledge Mr. Yu-Lung Lin for
recording the Raman spectral data. The authors would like to thank
Dr. Jennifer S. Dickey for helpful discussions during the preparation
of this manuscript.
4.2.28. Compound 2r. Colorless oil, 65% yield; 1H NMR (CDCl3,
400 MHz): 1.46 (br s, 1H, OH), 1.60e1.67 (m, 2H, CH2), 1.71e1.79
d
(m, 2H, CH2), 2.75 (t, J¼7.2 Hz, 2H, CH2), 3.62 (t, J¼6.4 Hz, 2H, CH2),
7.26e7.30 (m, 2H, Ph), 7.44e7.48 (m, 2H, Ph); 13C NMR (CDCl3,
100 MHz)
d 25.0 (eCH2), 31.2 (eCH2), 38.5 (eCH2), 62.2 (eCH2),
128.8, 129.0, 132.7, 136.0; LRMS (EI, m/z)¼248.1 [M]þ; HRMS (EI, m/
z) for C10H13ClOS2 [Mþ] calcd 248.0086, found 248.0099; Raman
spectra: SeS 545 cmꢁ1
.
Supplementary data
4.2.29. Compound 2s. Oil, 68% yield; 1H NMR (CDCl3, 400 MHz):
1.48 (br s, 1H, OH), 1.61e1.69 (m, 2H, CH2), 2.77 (t, J¼7.2 Hz, 2H,
1H, 13C, DEPT, and Raman spectra of all compounds and crys-
tallographic data tables of 1b, 1j, and 2m. Supplementary data
d

J.K. Vandavasi et al. / Tetrahedron 67 (2011) 8895e8901
8901
12. Jerome, K. D.; Rucker, P. V.; Xing, L.; Shieh, H. S.; Baldus, J. E.; Selness, S. R.;
Letavic, M. A.; Braganza, J. F.; McClure, K. F. Bioorg. Med. Chem. Lett. 2010, 20,
469e473.
associated with this article can be found, in the online version, at
doi:10.1016/j.tet.2011.09.071.
ꢀ
13. Ruano, J. L. G.; Parra, A.; Aleman, J. Green Chem. 2008, 10, 706e711.
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