Benzoyloxymethyl p-toluenethiosulfonate: A crystalline, stable synthetic equivalent for+CH2S+

Article abstract of DOI:10.1071/CH04170

Benzoyloxymethyl p-toluenethiosulfonate has been developed as a reagent for the one-pot preparation of α-sulfide disulfides and the corresponding symmetrical bissulfide disulfides. The reagent is effective for systems bearing terminal aryl groups. CSIRO 2005.

Full text of DOI:10.1071/CH04170

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2005, 58, 362–367
www.publish.csiro.au/journals/ajc
Benzoyloxymethyl p-Toluenethiosulfonate: a Crystalline,
+
+
Stable Synthetic Equivalent for CH S
2
A
A,B
S. M. Humayun Kabir and Richard F. Langler
A
Department of Chemistry, Mount Allison University, Sackville, New Brunswick E4L 1G8, Canada.
Corresponding author. Email: rlangler@mta.ca
B
Benzoyloxymethyl p-toluenethiosulfonate has been developed as a reagent for the one-pot preparation of α-sulfide
disulfides and the corresponding symmetrical bissulfide disulfides. The reagent is effective for systems bearing
terminal aryl groups.
Manuscript received: 20 July 2004.
Final version: 11 February 2005.
Introduction
Stemming from earlier reports[1,2] that dysoxysulfone 1
Compound 3 has proved to be a useful platform from which
to construct an assortment of α-sulfone disulfides.
[
8,9]
Treatment of 2a with sulfuryl chloride/methylene chloride
provides 3 as the major component in a mixture. Bulb-to-bulb
distillation produces 3 which has been improved in purity but
retains a persistent impurity. Furthermore, sulfenyl chlorides
are often unstable so that prudent storage of unused 3 requires
a freezer.This report describes the preparation of a new, stable
(
Scheme 1) shows both antifungal and anticancer activity
[3–5]
and our reports
that antifungal and antileukemic activ-
ity for structural relatives require the presence of a disulfide
linkage, we have targeted disulfides for biological activity
assessments. Related disulfides are now known to exhibit
antimalarial activity as well.[
6]
+
+
synthetic equivalent for CH2S . The new reagent has been
appliedtotheone-potconversionofmercaptansintoα-sulfide
disulfides.
Like dysoxysulfone 1 itself, many of our synthetic targets
ꢀ
havebeenα-substitutedandunsymmetricalα,α -disubstituted
disulfides. A straightforward retrosynthetic analysis leads to
the conclusion that a disulfide bearing a suitable leaving
group on an α-carbon, such as 2, would serve as a flexi-
ble intermediate from which an assortment of α-substituted
disulfides might be accessed by means of simple substitution
reactions.
Results and Discussion
In order to conserve electrophilicity at sulfenyl sulfur while
introducing the possibility that a new reagent might be nicely
crystalline, we elected to replace the sulfenyl chloride moi-
ety in 3 with a thiosulfonate linkage. A pair of thiosulfonate
propionates 4 (Scheme 3) were prepared and found to be
persistent oils. Propionates were abandoned.
Earlier work has shown that the α-ester disulfides 2a and
thus, probably, 2b are suitable precursors for the synthesis
[
7,8]
of α-sulfone disulfides, i.e. X = O2SR in 2.
At this stage,
only target methyl disulfides could be conveniently made.
A previous report[ described the successful preparation of
the sulfenyl chloride ester 3 (Scheme 2), which is, to the best
Because the yield of 2a is quite low (15%), we had devel-
8]
[8]
opedconditions thataffordtheα-benzoate2binbetteryield
(see Scheme 4).
Aspartofthecurrentstudy, apairofmethyldisulfideswere
treated with dibenzoyl peroxide in an attempt to obtain the
+
+
of our knowledge, the first synthetic equivalent for CH2S .
O
S
H
C
H
C
H
C
2
2
2
2
S
CH3
S
H C
C
H
S
S
S
O
H C
S
X
O
3
3
O
S
H
C
2
2
2
2
C
1
2a X ϭ O CC H
5
R
S
O
C2H5
2
2
2
b X ϭ O CPh
4
2
Scheme 3.
Scheme 1.
O
O
C
H
C
2
Cl
C
CHCl3
S
O
C H
CH3SSCH3
ϩ
(PhCO2)2
CH3SSCH2O
Ph
2
5
3
2b 24%
Scheme 2.
Scheme 4.
10.1071/CH04170
©
CSIRO 2005
0004-9425/05/050362

Benzoyloxymethyl p-Toluenethiosulfonate
363
corresponding α-benzoate disulfides. In accord with our ear-
lier report of the transition metal oxidation of phenyl methyl
disulfide,[ the α-benzoate was formed in very low yield
Scheme 10 presents the results of the first application of 7
to the one-pot preparation of the simple α-sulfide disulfide 8.
The unexpected formation of the bissulfide disulfide 9
might be rationalized by a phenyl mercaptide-catalyzed dis-
proportionation reaction which converts 8 into 9. In an
attempt to enrich the product ratio to favour 8, a second
reaction was done. The second reaction, presented in Table 1,
potentially disfavored the formation of 9 by significantly
shortening the reaction time and diminishing the availability
of SPh groups. Nonetheless, the relative yield of 9 was
increased, albeit probably within experimental error, so that
clean preparation of 8, under these reaction conditions, is not
possible. On the other hand, one-pot preparation of bissulfide
disulfides like 9 is very economical. Such compounds will be
of interest for biological testing.
10]
(
seeScheme5). Incontrast, benzylmethyldisulfidefurnished
benzaldehyde (see Scheme 6).
We turned, then, to work on the elaboration of a new thio-
sulfonate carboxylic acid ester. Prior to employing 2b as a
possible precursor for new reagent development, we con-
firmed that the benzoate group was comparable to propionate
as a leaving group (see Scheme 7).
Thereafter, 2b was smoothly transformed into the very
nicely crystalline thiosulfonate benzoate 7 (see Scheme 8).
Thiosulfonate carboxylic acid ester 7, so produced, was
isolated in excellent purity after simple recrystallization.
Support for the presence of the thiosulfonate linkage in
7
was obtained by mass spectrometry (chemical ionization)
In a brief examination of their chemistry, 8 and 9 were each
subjected to oxidation with m-chloroperoxybenzoic acid as
shown in Scheme 11.
Reactions between thiosulfonate benzoate 7 and a variety
of mercaptide anions, both aryl and non-aryl, are summarized
in Table 2. From the preparative standpoint, Table 2 results
show that aryl mercaptide anions provide a richer array of
useful products. The alkyl mercaptide anions did not furnish
which showed major ions as depicted in Scheme 9.
We have established a range of biological activity for
α-sulfone disulfides[
3–9,11–13]
which includes pronounced
antithrombotic activity.[ In the search for new functional-
ity, α-sulfidedisulfides, whichcontainanothermoietypresent
in dysoxysulfone 1 (Scheme 1), were selected as synthetic
targets to which the new reagent 7 (Scheme 8) might be
applied.
11]
ϩ
ϩ
H C
SO SCH O
Ph H
H C
SO SϭCH
3
2
2
3
2
2
O
CHCl3
C
m/z 323 (2%)
m/z 201 (100%)
PhSSCH3
ϩ
(PhCO2)2
PhSSCH O
Ph
O
2
5
3.3%
Scheme 5.
ϩ
SO2
H C
3
O
C
m/z 155 (32%)
CHCl3
PhCH SSCH
ϩ
(PhCO2)2
Ph
H
2
3
Scheme 9. Chemical ionization processes of 7 during mass spectrom-
1
5%
etry.
Scheme 6.
Acetone
PhSNa
ϩ
H C
SO SCH O Ph
2 2
3
O
C
Water
1h
C
ϩ
H C
SO Na
2
3
CH SSCH O
Ph
3
2
O
7
O
C
Acetone
Water
CH SSCH SO
2
CH3
3
2
PhSCH SSPh
ϩ
PhSCH SSCH SPh
ϩ
PhSSCH O
Ph
2
2
2
2
6
69%
8
39%
9 35%
5 13%
Scheme 7.
Scheme 10.
O
C
O
C
CH Cl
Table 1. Reactions between phenyl mercaptide anions and 7 in
aqueous acetone
2
2
ϩ
SO Cl
2 2
CH SSCH O
Ph
3
2
ClSCH O
Ph
2
Ratio of PhSNa to 7
Reaction time [min]
Mole ratio 8 : 9
2b
2
1
: 1 (Scheme 10)
: 1
60
10
2.2 : 1
1.8 : 1
H C
SO Na
2
3
H C
SO SCH O Ph
2 2
3
Acetone/water
m-CPBA
C
PhSCH S(SCH ) SPh
2
PhSO SPh
2
2 x
20% from 8; x ϭ 0
O
7
Overall yield: 51%
13% from 9; x ϭ 1
Scheme 8.
Scheme 11.

3
64
S. M. H. Kabir and R. F. Langler
Table 2. Reactions between mercaptide anions and 7 in aqueous acetone
RSNa + 7 → RSSCH2OC(O)Ph + RSCH2SSR + RSCH2SSCH2SR + RSSR
R
Yields
RSSCH2OC(O)Ph
RSCH2SSR
RSCH2SSCH2SR
RSSR
A
A
A
Ph-
13% of 5
7% of 10
0%
14% of 15
11% of 16
0%
39% of 8
40% of 11
45% of 13
0%
0%
6% of 17
35% of 9
30% of 12
25% of 14
0%
0%
0%
p-Cl(C6H4)-
o-CH3O2C(C6H4)-
CH3CH2CH2-
–
–
59%
(CH3)2CH-
B
PhCH2-
A
Typically, symmetrical aryl disulfides were recovered from product mixtures in approx. 15% yield. Air
oxidation may account for some of that.
GC-MS showed that starting benzyl thiol contained no detectable dibenzyl disulfide.
B
H C
CH3
CH3
3
Acetone
HC
H C
SNa
ϩ
H C
SO SCH O Ph
H C
SCH SCH S
CH
ϩ
H C
SCH SCH SCH S HC
3
2
2
3
2
2
3
2
2
2
Water
C
CH
S
CH3
CH
S
CH3
3
CH3
CH3
O
7
18 1%
19 1%
Scheme 12.
CO CH
2
3
O
O
CO CH
2
3
CH Cl
SH
2
2
3
CH SSCH2
C
ϩ
SO Cl
2
2
CISCH2
C
O
Ph
O
Ph
CH2Cl2 pyridine
O
Ph
SSCH2
C
O
2
b
20
Scheme 13.
target α-sulfide disulfides upon reaction with 7. From the
standpoint of reaction pathways, the isopropyl mercaptide
anion reaction provided a useful result. Nucleophilic attack
by mercaptide anions on disulfides like 8 or 9 would produce
α-sulfide mercaptide anions which are reasonable interme-
diates for these reactions. Such intermediates are known
to extrude/add thioformaldehyde leading to a mixture of
alternating carbon/sulfur frameworks.[ Column chromatog-
raphy of the product from the reaction between isopropyl
mercaptide anions and 7 produced the benzoate disulfide 16
as shown in Table 2 and a pair of minor products as shown in
Scheme 12.
produced therefrom failed to furnish any benzoate disulfide
upon reaction with 7 (entry 3,Table 2). However, the disulfide
benzoate2bwassmoothlytransformedintothedisulfideester
20 as outlined in Scheme 13.
The disulfide diester 20 reacted with methyl o-mercap-
tobenzoate-derived anions to afford the expected mixture of
products (see Scheme 14) in a result strongly reminiscent of
the Table 2 results (entry 3).
Finally, reaction of the sulfide disulfide 13 with methyl
o-mercaptobenzoate-derived anions produced virtually the
same outcome as that shown in Scheme 14.A proposed mech-
anism for the reaction of aryl mercaptide anions with 7 is
presented in Scheme 15.
2]
1
Structural assignments for 18 and 19 rest upon H NMR
and mass spectra. The NMR spectra showed signals arising
from non-equivalent isopropyl methyl protons (two dou-
blets) and coincident isopropyl methine protons. The NMR
spectrum of 18 showed a pair of non-equivalent methylene
groups while the corresponding spectrum of 19 showed a trio
of non-equivalent methylene groups.The mass spectra exhib-
ited a common fragmentation pathway initiated by the loss of
the disulfide moiety along with its isopropyl group, followed
by sequential loss of thioformaldehyde units to produce the
In conclusion, we have prepared and examined 7, a new
+
+
syntheticequivalentfor CH2S .Withit, α-sulfidedisulfides
and bissulfide disulfides that bear terminal aryl groups are
conveniently accessed.
Experimental
Infrared spectra were recorded on a Thermo Nicolet 2000 spectrom-
eter. 1H NMR (270 MHz) and 13C NMR spectra were obtained on a
JEOLJNM-GSX270Fourier-transformNMRsystem. Unlessotherwise
specified, all NMR spectra were obtained for compounds in deuterated
chloroform using tetramethyl silane as an internal standard. Routine
mass spectra (MS) were obtained on a Hewlett–Packard 5988A gas–
+
base peak at m/z 89 [(CH3)2CHS CH ].
2
To obtain support for our view that aryl mercaptide anions
would transform 7 into an α-benzoate disulfide, thence into
an α-sulfide disulfide and finally into a bissulfide disulfide,
wechosetoworkwithmethyl o-mercaptobenzoate.Theanion
[6]
liquid chromatography mass spectrometer (GLC-MS) system. The
CI(CH4) spectrum for 7 was obtained on a Varian CP-3800 gas chro-
matograph equipped with a CP-8410 autoinjector and connected to a

Benzoyloxymethyl p-Toluenethiosulfonate
365
CO CH
CO CH
2
3
2
3
Acetone
Water
ϩ
O
Ph
SSCH2
C
O
SNa
20
CO CH
CO CH
2
3
2
3
CO CH3
CO CH
CO CH
CO CH
2 3
2
2
3
2
3
H
C
H
C
2
2
S
S
S
S
S
ϩ
ϩ
S
S
S
S
C
H2
21 20%
13 40%
14 30%
Scheme 14.
O
C
H C
SO SCH O Ph
ϩ
ArSNa
H C
SO Na
ϩ
ArSSCH2
3
2
2
3
2
O
Ph
C
O
ArSNa
7
H
C
2
S
Ar
Ϫ
ϩ
(ArS)2
ϩ
Na
SCH SAr
Ar
S
S
2
Ϫ
ArS
ArSSCH SAr
ϩ
2
Na
ArSCH SSCH SAr ϩ ArSNa
2
2
Scheme 15.
Saturn 2000 mass-selective detector. Melting points were determined
on a Gallenkamp MFB-595 capillary melting point apparatus and are
uncorrected. Chloroform extracts were routinely dried over magnesium
sulfate and filtered before solvent evaporation.
Preparation of Benzoyloxymethyl p-Toluenethiosulfonate 7
Procedure A
A solution of distilled sulfuryl chloride (0.626 g, 4.7 mmol) in dry
methylene chloride (1 mL) was added to a solution of the disulfide ben-
[
8]
Reaction of Phenyl Methyl Disulfide with Dibenzoyl Peroxide
zoate 2b (1.0 g, 4.7 mmol) in dry methylene chloride (6 mL). The
reaction mixture was refluxed for 0.5 h. The solvent was evaporated and
dry methylene chloride (7 mL) added.
Phenyl methyl disulfide (1.0 g, 6.4 mmol) and dibenzoyl peroxide (2.2 g,
6
.4 mmol) were added to chloroform (75 mL). The reaction mixture was
refluxed for 24 h. Chloroform (75 mL) was added and the resultant mix-
ture extracted with 2.5% w/v sodium hydroxide (2 × 125 mL aliquots).
The solvent was evaporated and the residue chromatographed on sil-
ica gel employing 4 : 1 light petroleum/chloroform followed by 3 : 2
light petroleum/chloroform. The oily benzoate disulfide 5 was eluted
Procedure B
The sodium salt of p-toluenesulfinic acid (0.814 g, 4.6 mmol) was
covered with 4 : 1 acetone/water (25 mL). The final methylene chloride
solution from part A was added and the reaction mixture immersed in a
−
1
◦
(
60 mg, 0.22 mmol, 3%). νmax (neat)/cm 1722. δH (270 MHz) 5.55
constant temperature bath (50 C) for 4 h. The reaction mixture did not
(
2H, s, SSCH2O), 7.22 (4H, m, ArH), 7.37 (2H, m, ArH), 7.54 (2H,
become homogeneous.
m, ArH), 7.83 (2H, m, ArH). δC (68 MHz) 73.2, 127.4, 128.4, 128.7,
Chloroform (200 mL) was added and the resultant mixture washed
with water (100 mL).The solvent was evaporated furnishing crude prod-
uct (1.248 g). Crude product was recrystallized from methanol (16 mL)
whichgavethebenzoatethiosulfonate7 (0.571 g).Asecondcropofgood
+
•
1
M
29.0, 129.3, 129.8, 133.4, 137.1, 165.8. m/z 276 (1%, M ), 246 (4,
+
•
− 30), 105 (100). Note that the loss of 30 awu from the molecular
[10]
ion is characteristic of C–O linked α-ester disulfides.
◦
purity 7 was obtained (0.199 g) from methanol (2 mL), mp 131–132 C
Reaction of Benzyl Methyl Disulfide with Dibenzoyl Peroxide
(
(
(
Found: C 56.1, H 4.2%. C15H14O4S2 requires C 55.9, H 4.4%). νmax
KBr)/cm 1726, 1329, 1142. δH (270 MHz) 2.34 (3H, s,ArCH3), 5.83
2H, s, OCH2SS), 7.22 (2H, d, ArH), 7.35 (2H, t, ArH), 7.55 (1H, m,
−
1
Benzyl methyl disulfide was reacted with dibenzoyl peroxide and
the products purified as described above for the reaction of phenyl
methyl disulfide. Column fractions furnished benzaldehyde (90 mg,
ArH), 7.70 (2H, d, J 8.1, ArH), 7.82 (2H, d, J 8.1, ArH). δC (68 MHz)
2
1
1.6, 67.8, 127.2, 128.3, 128.6, 129.85, 129.93, 133.7, 143.0, 145.0,
65.3. m/z CI(CH4) 323 (2%, MH ), 201 (100), 155 (32), 105 (54).
0
.85 mmol, 15%).
+
A fragmentation pathway is proposed in Scheme 9.
Reaction of 2b with the Sodium Salt of p-Toluenesulfinic Acid
The disulfide benzoate 2b[8] (0.5 g, 2.3 mmol) and the sodium salt of p-
Reaction of Mercaptide Anions with Benzoyloxymethyl
p-Toluenethiosulfonate 7
toluenesulfinic acid (0.5 g, 2.6 mmol) were added to 4 : 1 acetone/water
◦
(
10 mL). The reaction mixture was heated at 50 C for 2 h. Chloro-
form (40 mL) was added and the resultant mixture extracted with water
25 mL). The solvent was evaporated and the residue chromatographed
on silica gel employing 4 : 1 light petroleum/chloroform followed by
: 1 light petroleum/chloroform for elution. Chromatography furnished
the α-sulfone disulfide 6 (0.40 g, 1.61 mmol, 70%) which was identical
A series of mercaptide anions were reacted with 7. Results are summa-
rized in Scheme 10 and Table 2. Details are provided for the reaction of
p-chlorothiophenol (Table 2, entry 2).
Sodium metal (36 mg, 1.56 mmol) was dissolved in methanol (2 mL)
and p-chlorothiophenol (226 mg, 1.56 mmol) added. The solvent was
evaporated and the residue dried under vacuum. The residue was
(
1
[
7]
1
13
to previously obtained material by H and C NMR spectra.

3
66
S. M. H. Kabir and R. F. Langler
dissolved in acetone (7 mL) and a solution of the benzoate thiosulfonate
(250 mg, 0.78 mmol) in acetone (5 mL) was added. The reaction mix-
petroleum/chloroform, 4 : 1 light petroleum/chloroform, and 1 : 1 light
petroleum/chloroform.
7
ture was stirred at ambient temperature for 1 h.Water (10 mL) was added
and the resultant mixture extracted with chloroform (100 mL). The sol-
vent was evaporated and the residue was chromatographed on silica gel
employing light petroleum followed by 1 : 9 methylene chloride/light
petroleum for elution. Di-p-chlorophenyl disulfide (33 mg, 0.12 mmol,
Column elution furnished the oily bissulfide disulfide 18 (1.3 mg,
0.0053 mmol, 1.4%). δH (270 MHz) 1.27 (6H, d, CH3), 1.31 (6H,
d, CH3), 3.11 (2H, septet, CH), 3.84 (2H, s, SCH2S), 3.97 (2H, s,
SCH2SS). m/z 242 (2.1%, M ), 167 (12, M − (CH3)2CHS), 135
+
•
+•
+
•
+•
(26, M − (CH3)2CHSS), 89 (100, M − (CH3)2CHSSCH2S). Fur-
ther elution gave the oily trissulfide disulfide 19 (1.0 mg, 0.0034 mmol,
1.3%). δH (270 MHz) 1.27 (6H, d, CH3), 1.31 (6H, d, CH3), 3.11
(2H, sept, CH), 3.79 (2H, s, SCH2S), 3.94 (2H, s, SCH2S), 3.98 (2H,
1
5%) was obtained. Further elution gave the sulfide disulfide 11
◦
(
104 mg, 0.31 mmol, 40%), mp 99–101 C (Found: C 47.0, H 3.4%.
−
1
C13H10Cl2S3 requires C 46.8, H 3.0%). νmax (KBr)/cm 1474. δH
270 MHz) 4.09 (2H, s, SCH2SS), 7.27 (8H, m, ArH). δC (68 MHz,
+
•
+•
(
s, SCH2SS). m/z 181 (34%, M − (CH3)2CHSS), 135 (7, M
−
+
•
CDCl3, Me4Si) 43.9, 129.25, 129.34, 129.6, 132.3 (shoulder observed),
(CH3)2CHSSCH2S), 89 (100, M − (CH3)2CHSSCH2SCH2S). Fur-
+
•
+•
1
1
0
33.5, 133.8, 135.1. m/z 334 (2.2%, M + 2), 332 (2.8, M ), 159 (36),
ther elution furnished the disulfide ester 16 (20 mg, 0.082 mmol, 11%).
−
1
57 (100). Futher elution gave the oily bissulfide disulfide 12 (44 mg,
.12 mmol, 30%). νmax (film)/cm 1475, 1398. δH (270 MHz) 4.18
νmax (neat)/cm 1724. δH (270 MHz) 1.30 [6H, d, C(CH3)2], 3.08 (1H,
septet, CH) 5.47 (2H, s, OCH2SS), 7.45 (2H, t, ArH), 7.58 (1H, t, ArH),
8.04 (2H, d, ArH). δC (68 MHz) 22.6, 41.6, 74.7, 128.6, 129.6, 129.9,
−
1
(
4H, s, SCH2SS), 7.29 (4H, d, ArH), 7.36 (4H, d, ArH). δC (68 MHz)
1.2, 129.4, 131.9, 132.7, 133.6. m/z 159 (38%), 157 (100). Later frac-
tions gave the disulfide benzoate 10 (18 mg, 0.058 mmol, 7%). νmax
+
•
+•
[10]
4
133.4, 165.9. m/z 242 (0.6%, M ), 212 (7, M − 30),
105 (100).
The sodium salt of benzyl thiol was treated with 7 as described above
for p-chlorothiophenol. Crude product was chromatographed on sil-
ica gel employing light petroleum and 9 : 1 light petroleum/chloroform.
Elution gave dibenzyl disulfide (112.9 mg, 0.46 mmol, 59%). Further
elution afforded the sulfide disulfide 17 (12.6 mg, 0.043 mmol, 6%). δH
(270 MHz) 3.29 (2H, s, CH2), 3.77 (2H, s, CH2), 3.95 (2H, s, CH2),
7.28 (10H, m, ArH). δC (68 MHz) 35.2, 40.9, 43.7, 127.3, 127.6, 128.6,
129.1, 129.4, 137.2, 137.4. m/z 137 (43%), 91 (100).
−1
(
neat)/cm 3062, 1727. δH (270 MHz) 5.53 (2H, s, OCH2SS), 7.12
(
2H, d, ArH), 7.36 (2H, t, ArH), 7.45 (3H, m, ArH), 7.78 (2H, d, ArH).
δC (68 MHz) 73.2, 128.4, 129.1, 129.2, 129.7, 130.1, 133.5, 135.8,
+
•
+•
[10]
1
M
65.7. m/z 312 (0.4%, M + 2), 310 (1.1, M ), 282 (1),
280 (2.5,
+
•
− 30), 159 (3), 157 (8), 105 (100).
The sodium salt of thiophenol was treated with 7 as described above
for p-chlorothiophenol. Crude product was chromatographed on sil-
ica gel employing light petroleum then 1 : 9 methylene chloride/light
petroleum and 1 : 1 methylene chloride/light petroleum for elution. Elu-
Oxidations of 8 and 9 with m-Chloroperoxybenzoic Acid
tion furnished the sulfide disulfide 8 (160 mg, 0.61 mmol, 39%), mp
Each compound was oxidized following the procedure outlined for the
sulfide disulfide 8. The sulfide disulfide 8 (100 mg, 0.38 mmol) and m-
chloroperoxybenzoic acid (50%, 328 mg) were dissolved in chloroform
◦
5
4
7
1
1.9–52.3 C (Found: C 59.1, H 4.6%. C13H12S3 requires C 59.0, H
−1
.6%). νmax (KBr)/cm 1435. δH (270 MHz) 4.16 (2H, s, SCH2SS),
.27 (10H, m, ArH). δC (68 MHz) 43.5, 127.2, 127.4, 128.1, 129.1,
(
10 mL), and the reaction mixture was stirred at ambient temperature
+
•
30.7, 134.1, 136.6. m/z 264 (3.8%, M ), 123 (100). Further elution
for 7 days. Chloroform (100 mL) was added and the resultant mixture
extracted with 2.5% w/v sodium hydroxide (2 × 100 mL portions). The
solvent was evaporated and the residue chromatographed on silica gel
employing light petroleum and 1 : 1 light petroleum/methylene chloride.
Phenyl benzenethiosulfonate (19 mg, 0.076 mmol, 20%) was eluted.
Oxidation of 9 furnished phenyl benzenethiosulfonate (13%).
gave the oily bissulfide disulfide 9 (85 mg, 0.274 mmol, 35%). νmax
−
1
(
(
1
neat)/cm 1581, 1479. δH (270 MHz) 4.23 (4H, s, SCH2SS), 7.31
10H, m, ArH). δC (68 MHz, CDCl3, Me4Si) 45.1, 127.3, 129.2, 130.4,
+
•
34.4. m/z 310 (2.8%, M ), 123 (100). Further elution furnished the
oily disulfide ester 5 (71 mg, 0.257 mmol, 17%) which was identical to
1
13
previously isolated material by IR and H, and C NMR spectroscopy.
The properties of 5 are described under above.
In each case, the phenyl benzenethiosulfonate was identical with
freshly prepared authentic material (compare m-chloroperbenzoic acid
The sodium salt of methyl o-mercaptobenzoate was treated with 7
as described above for p-chlorothiophenol. Crude product was chro-
matographed on silica gel employing 4 : 1 light petroleum/chloroform,
followed by 7 : 3 light petroleum/chloroform and 1 : 1 light petroleum/
chloroform for elution. Elution afforded di-o-carbomethoxyphenyl
disulfide (52 mg, 0.16 mmol, 20%). Further elution gave the sul-
1
13
oxidation of diphenyl disulfide) by IR, H, and C NMR spectra.
Preparation of Disulfide Diester 20
Procedure A
The disulfide benzoate 2b (1.0 g) was converted into a solution of
the ester sulfenyl chloride as described in Procedure A above for the
preparation of 7.
◦
fide disulfide 13 (133 mg, 0.35 mmol, 45%), mp 108–109 C. νmax
(
−1
KBr)/cm 1708. δH (270 MHz) 3.88 (3H, s, CO2CH3), 3.92 (3H, s,
CO2CH3), 4.19 (2H, s, SCH2SS), 7.25 (2H, d,ArH), 7.52 (2H, m,ArH),
7
1
1
.99 (2H, t,ArH), 8.06 (2H, t,ArH). δC (68 MHz) 40.7, 52.3, 52.4, 125.1,
25.6, 125.9, 126.6, 127.2, 128.4, 131.48, 131.55, 132.7, 132.9, 138.7,
Procedure B
The solution from Procedure A was added to a solution of methyl 2-
mercaptobenzoate (785 mg, 4.67 mmol) in methylene chloride (3 mL).
Dry pyridine (0.8 mL) was added and the reaction stirred at ambient tem-
perature, overnight. Chloroform (100 mL) was added and the resultant
mixture extracted with 2.5% hydrochloric acid (100 mL). The solvent
was evaporated affording crude 20 which was chromatographed on sil-
ica gel employing 1 : 1 light petroleum/chloroform for elution. Clean
40.9, 166.7, 166.8. m/z 181 (100%). Additional elution furnished the
◦
bissulfide disulfide 14 (42 mg, 0.097 mmol, 25%), mp 88–89 C. νmax
−1
(
KBr)/cm 1710. δH (270 MHz) 3.88 (6H, s, CO2CH3), 4.32 (4H, s,
SCH2SS), 7.21 (2H, t, ArH), 7.50 (4H, m, ArH), 7.97 (2H, d, ArH). δC
68 MHz) 42.5, 52.3, 125.0, 126.6, 128.1, 131.4, 132.7, 139.1, 166.8.
(
m/z 181 (100%).
The sodium salt of propane-1-thiol was treated with 7 as described
above for p-chlorothiophenol. Crude product was chromatographed on
silica gel employing light petroleum, 9 : 1 light petroleum/methylene
chloride, 1 : 1 light petroleum/methylene chloride and methylene chlo-
ride. Elution gave the liquid disulfide ester 15 (26 mg, 0.11 mmol, 14%).
◦
disulfide diester 20 (1.153 g, 3.45 mmol, 74%), mp 57–59 C. νmax
−
1
(
KBr)/cm 1716, 1699. δH (270 MHz) 3.93 (3H, s, OCH3), 5.52 (2H,
s, OCH2SS), 7.13 (1H, t, ArH), 7.35 (3H, m, ArH), 7.53 (1H, t, ArH),
.85 (2H, d, ArH), 7.96 (1H, d, ArH), 8.12 (1H, d, ArH). δC (68 MHz)
7
−1
52.4, 73.1, 125.4, 126.2, 127.1, 128.4, 129.2, 129.9, 131.3, 132.7, 133.4,
νmax (neat)/cm 1724. δH (270 MHz) 0.91 (3H, t, CH3),1.68 (2H, sex-
tet, CH2), 2.75 (2H, t, CH2), 5.50 (2H, s, SSCH2O), 7.46 (2H, t, ArH),
+
•
+•
[10]
1
(
41.5, 165.7, 166.9. m/z 334 (0.8%, M ), 304 (3, M − 30),
105
100) was obtained.
7
.58 (1H, t, ArH), 8.06 (2H, d, ArH). δC (68 MHz) 13.0, 22.4, 41.8,
+
•
7
6.6, 128.6, 129.6, 129.9, 133.4, 165.9. m/z 242 (0.5%, M ), 212 (6,
+
•
[10]
Reaction of Disulfide Diester 20 with the Sodium Salt of Methyl
-Mercaptobenzoate
M
− 30),
105 (100).
2
The sodium salt of 2-mercaptopropane was treated with 7 as
described above for p-chlorothiophenol. Crude product was chro-
matographed on silica gel employing light petroleum, 9 : 1 light
Sodiummetal(36 mg, 1.56 mmol)wasdissolvedinmethanol(2 mL)and
methyl 2-mercaptobenzoate (262 mg, 1.56 mmol) added. The solvent

Benzoyloxymethyl p-Toluenethiosulfonate
367
was evaporated and the residue dried under vacuum. The residue was
dissolved in acetone (15 mL) and a solution of the disulfide diester 20
C. Chaulk, and E. O’Brien. High-field NMR spectra were
obtained by D. Durant. Mass spectra were run by R. Smith.
(
521 mg, 1.56 mmol) in acetone (3 mL) was added.The reaction mixture
was stirred at ambient temperature for 1 h.
Water (10 mL) was added and the resultant mixture extracted
with chloroform (100 mL). The solvent was evaporated and the
residue was chromatographed on silica gel employing 7 : 3 light
petroleum/chloroform and 1 : 1 light petroleum/chloroform for elution.
Elution gave the simple symmetrical disulfide 21 (104 mg, 0.311 mmol,
References
[
[
[
1] M. K. Jogia, R. J. Andersen, E. K. Mantus, J. Clardy, Tetrahedron
Lett. 1989, 30, 4919. doi:10.1016/S0040-4039(01)80542-6
2] E. Block, R. DeOrazio, M. Thiruvazhi, J. Org. Chem. 1994, 59,
2
273.
2
0%). Further elution furnished the sulfide disulfide 13 (237 mg,
3] F. J. Baerlocher, R. F. Langler, M. U. Frederiksen, N. M. Georges,
0
.62 mmol, 40%) which was identical to described previously mate-
R. D.Witherell, Aust. J. Chem. 1999, 52, 167. doi:10.1071/C98141
[4] W. W.-L. Wong, S. MacDonald, R. F. Langler, L. Z. Penn,
Anticancer Res. 2000, 20, 1367.
rial (see above description of the reaction of mercaptide anions with 7)
1
13
by H NMR, C NMR, and IR spectroscopy. Further elution gave the
bissulfide disulfide 14 (101 mg, 0.24 mmol, 30%) which was identical
1
13
[5] J. Anderson, R. F. Langler, F. J. Baerlocher, Sydowia 2002,
to described previously material (see above) by H NMR, C NMR,
and IR spectroscopy.
5
4, 121.
6] G. Kong, K. C. Kain, I. Crandall, R. F. Langler, Sulfur Lett. 2003,
6, 149. doi:10.1080/02786110310001612272
7] R. F. Langler, S. L. MacQuarrie, R.A. McNamara, P. E. O’Connor,
Aust. J. Chem. 1999, 52, 1119. doi:10.1071/CH99086
8] F. J. Baerlocher, M. O. Baerlocher, C. L. Chaulk, R. F. Langler,
E. M. O’Brien, Sulfur Lett. 2000, 24, 101.
9] F. J. Baerlocher, M. O. Baerlocher, R. F. Langler,
S. L. MacQuarrie, P. E. O’Connor, Sulfur Lett. 2002, 25, 135.
doi:10.1080/02786110213980
[
[
[
[
2
Reaction of Sulfide Disulfide 13 with the Sodium Salt of Methyl
2
-Mercaptobenzoate
The sodium salt of methyl 2-mercaptobenzoate, prepared from methyl
-mercaptobenzoate (131 mg, 0.78 mmol), was reacted with the sulfide
2
disulfide 13 (296 mg, 0.78 mmol) as in the preceding procedure and the
crude product chromatographed on silica gel. Elution with 7 : 3 light
petroleum/chloroform followed by 1 : 1 light petroleum/chloroform
gave symmetrical disulfide 21 (55 mg, 0.16 mmol, 21%) followed by
unchanged disulfide 13 (113 mg, 38%) and then bissulfide disulfide 14
[
[
10] R. F. Langler, D. A. Ryan, S. D. Verma, Sulfur Lett. 2000, 24, 51.
11] J. A. MacDonald, R. F. Langler, Biochem. Biophys. Res. Commun.
(
53 mg, 0.124 mmol, 32%).
2
000, 273, 421. doi:10.1006/BBRC.2000.2950
[
[
12] F. J. Baerlocher, M. O. Baerlocher, K. D. Guckert, R. F. Langler,
Acknowledgments
S. L. MacQuarrie, P. E. O’Connor, G. C. Y. Sung, Aust. J. Chem.
2
001, 54, 397. doi:10.1071/CH01046
The authors gratefully acknowledge Mount Allison Univer-
sity for the award of a McCain postdoctoral fellowship to
S.M.H.K. Technical assistance was provided by S. Duffy,
13] S. A. Bewick, S. Duffy, S. P. Fletcher, R. F. Langler,
H. G. Morrison, E. M. O’Brien, C. Ross, V. C. Stephenson, Aust.
J. Chem. 2005, 58, 218. doi:10.1071/CH03253