New and more potent antifungal bisulfides

Article abstract of DOI:10.1071/ch99139

From a design principle described in an earlier paper, a new series of substituted aryl methyl disulfides have been prepared and tested against Aspergillus niger and Aspergillus flavus. Methyl p-nitrophenyl disulfide is more potent (by an order of magnitude) than the fungitoxic natural product (CH₃SCH₂S)₂. With the present rationale in hand, one can anticipate which Polycarpamine is an effective antifungal agent. CSIRO 2000.

Full text of DOI:10.1071/ch99139

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 53, 2000
© CSIRO Australia 2000
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Aust. J. Chem., 2000, 53, 1–5
New and More Potent Antifungal Disulfides
Felix Jakob Baerlocher,A,B Mark Otto Baerlocher,A Richard Francis Langler,C,D
Stephanie Lee MacQuarrieC and Maurice Emile MarchandC
A Department of Biology, Mount Allison University,
Sackville, New Brunswick, Canada E4L 1G7.
B To whom correspondence should be addressed about
the biological testing.
C Department of Chemistry, Mount Allison University,
Sackville, New Brunswick, Canada E4L 1G8.
D To whom correspondence should be addressed about
the organic chemistry.
From a design principle described in an earlier paper, a new series of substituted aryl methyl disulfides have been
prepared and tested against Aspergillus niger and Aspergillus flavus. Methyl p-nitrophenyl disulfide is more potent
(by an order of magnitude) than the fungitoxic natural product (CH3SCH2S)2. With the present rationale in hand,
one can anticipate which Polycarpamine is an effective antifungal agent.
Keywords. Antifungal; disulfides; structure–activity relationship; synthesis.
(compound/pKa(Me2SO):14 C6H5SO2H/7.1; CH3CO2H/12.3;
CH3(CH2)3SH/16.9).
Introduction
Reports of the isolation and/or synthesis of antifungal
compounds continue to appear in the literature.1–13 Some
contain sulfur atoms1–4 and some do not.5–13 Initially, our
interest centred on determining what portions of the fungi-
toxic natural product Dysoxysulfone (1) were responsible for
its antifungal activity.
Replacing the methylene in (2) (Scheme 1) with a CC
double bond would still permit nucleophilic attack at the SS
linkage to induce negative charge on appropriate X groups.
Moreover, such structures might have enhanced reactivity
because the costly requirement for CX ꢁ bond rupture (pic-
tured in Scheme 1) would be replaced by the less
unfavourable requirement of CC ꢂ bond rupture. For ease of
preparation, we have targeted substituted aromatic methyl
disulfides for synthesis and antifungal testing. Scheme 2 pre-
sents the proposed mechanism of action for aromatic disul-
fides.
Our first study1 concluded that simple ꢀ-sulfone disul-
fides were fungicidal and proposed a mechanism of action
which fitted structure–activity results for 14 sulfur com-
pounds. Our proposed mechanism is presented in Scheme 1.
Scheme 2. Proposed antifungal reactivity for substituted aryl disul-
fides (3).
Results and Discussion
Scheme 1. Proposed antifungal reactivity for some fungicidal disul-
Our current antifungal test results are presented in Table
1. Consistent with our earlier report,1 the simple disulfides
(4) and (5) are completely inactive against Aspergillus niger
and A. flavus at a dose of 100 ꢃg/disk.
fides.
The Scheme 1 proposal assumes that ꢀ-sulfone disulfides
or ꢀ-carboxylate disulfides (2) are activated fungitoxins
because the ꢀ-substituents function as leaving groups. Thus
negative charge develops on X which is better able to handle
it than a simple mercaptide (thiolate) anion would be
We have reported1 that the ester disulfide (2;
R = CH3, X = OAc) had clear zone diameters of 2.3 mm
(dose 100 ꢃg/disk) against both of our test fungi. The linkage
Manuscript received 13 October 1999
© CSIRO 2000
10.1071/CH99139
0004-9425/00/010001

2
F. J. Baerlocher et al.
isomeric disulfide ester CH3SSCH2C(O)OCH3 was inactive.
For those structural isomers, fungitoxic activity required the
ester ether oxygen be closer to the disulfide linkage.
However, the Scheme 2 mechanism requires that antifungal
aryl ester disulfides have the ester carbonyl closer to the
disulfide linkage (i.e. the ester group should act as a
ꢂ-acceptor). In complete accord with this proposal, the
disulfide ester (6) (Table 1) shows substantially enhanced
antifungal activity relative to (2; R = CH3, X = OAc).
anism, should be the most potent antifungal disulfides we
have described. Furthermore, meta disposition of the nitro
group should diminish fungitoxic activity for that disulfide.
The results for those compounds [(9–11) in Table 1] are in
complete accord with our expectations.
Both presumed mechanisms (Schemes 1 and 2) assume
that our antifungal disulfides are activated sulfenylating
agents. However, the more complex disulfides examined in
this paper could conceivably be more potent fungitoxins
because they exploit a completely different mode of action.
Appropriately substituted nitrophenyl or methylsul-
fonylphenyl aromatics can undergo smooth nucleophilic aro-
matic substitutions which arylate thiolate anions16,17 in
dimethyl sulfoxide or hexamethylphosphoramide (e.g. see
Scheme 4).
Table 1. Sulfur compounds as antifungal agents
Each compound was introduced onto a small paper disk which was
placed in a culture medium. The diameter of the clear zone (the area
where fungus—Aspergillus niger or Aspergillus flavus—did not grow)
around each disk indicated antifungal activity
Sulfur
compound
tested
Dose
(ꢃg/
disk)
Diameter (mm) of
clear zone
A. niger
A. flavus
C6H5SSCH3 (4)
C6H5SSC6H5 (5)
100
100
25
25
25
10
10
10
100
100
0
0
0
0
o-CH3OC(O)(C6H4)SSCH3 (6)
[o-CH3SO2(C6H4)S]2 (7)
[p-CH3SO2(C6H4)S]2 (8)
m-O2N(C6H4)SSCH3 (9)
o-O2N(C6H4)SSCH3 (10)
p-O2N(C6H4)SSCH3 (11)
p-CH3SO2(C6H4)OSO2CH3 (12)
p-O2N(C6H4)OSO2CH3 (13)
2.8
3.3
4.0
1.7
2.8
3.9
0
4.3
3.0
6.9
1.8
1.9
4.0
0
Scheme 4. Nitrophenylation of a mercaptide anion.
0
0
The test results (Table 1) for compounds (12) and (13)
demonstrate that potential nucleophilic aromatic substitu-
tions which arylate by displacement of the entire disulfide
linkage would not inhibit fungal growth.
The next targets selected were (3; X = o-SO2CH3) and (3;
X = p-SO2CH3). Given that benzenesulfonyl chlorides can
generally be reduced (LiAlH4) to the corresponding mercap-
tans,15 we elected to prepare the appropriate methylsulfonyl-
substituted benzenesulfonyl chlorides (14) and (15).16
Lithium aluminum hydride reduction of (14) and (15), fol-
lowed by attempted thiomethylation, as shown in Scheme 3,
gave none of the target methyl disulfides, but instead fur-
nished the symmetrical disulfides (7) and (8).
A 1990 report18 of the structure proof and isolation of the
Polycarpamines, from Polycarpa auzata, provides a nice test
of our proposed structure–activity relationship for potential
fungitoxic aryl methyl disulfides and a related sulfenate
ester. Of the Polycarpamines (16)–(19), only (16) was found
to be ‘a significant inhibitor in vitro of the fungi
Saccharomyces cerevisiae and Candida albicans’.
Happily, the disulfone disulfides (7) and (8) had appropri-
ate functionality to warrant testing and proved to be fungi-
toxic (see Table 1).
The next set of target disulfides included (3; X = o-NO2),
(3; X = m-NO2) and (3; X = p-NO2). Each of these molecules
contained the most powerful electron-withdrawing group we
have examined and so, following from the Scheme 2 mech-
Only (16) has a reasonably potent ꢂ-acceptor positioned
to activate the disulfide linkage in the manner which has now
been validated for the related fungitoxic ester disulfide (6)
(Table 1).
Our interest in the chemistry of sulfur-rich antifungal
compounds was stimulated, in part, by the recent observa-
tions19–21 that nosocomial fungal infections frequently prove

Antifungal Disulfides
3
and the resultant mixture extracted with water (two 100-ml aliquots)
and 1% sodium hydroxide (two 100-ml aliquots). The combined
aqueous layers were added to chloroform (75 ml), ice (100 ml) and con-
centrated hydrochloric acid (8 ml). Chloroform (150 ml) was added, the
layers were separated, the organic layer was dried (MgSO4) and filtered.
The solvent was evaporated and the residue rectified at reduced pres-
sure affording clean methyl o-mercaptobenzoate (6.9 g, 41.0 mmol,
to be lethal for immunocompromised patients. We note that
aryl disulfides, including (20), which bear suitably posi-
tioned electron-withdrawing groups also show significant
antiviral activity against HIV-1 in proliferating T cell cul-
tures.22
1
64%), b.p. 103–108°C/2.7 Torr. I.r. (liquid film) 1710 cm–1. H n.m.r.
(270 MHz) ꢄ 7.99, d, 1H; 7.29, d, 1H; 7.14, m, 2H; 4.68, s, 1H; 3.90, s,
3H. 13C n.m.r. ꢄ 167.09, 138.27, 132.45, 131.65, 130.86, 125.74,
124.62, 52.19. m/z 168 (21%, M+•), 136 (100), 108 (35).
Preparation of Methyl o-(Methyldithio)benzoate (6)
Powdered sodium hydroxide (0.24 g, 6 mmol) was suspended in
dimethyl sulfoxide (8 ml) and a solution of methyl o-mercaptobenzoate
(1.0 g, 5.9 mmol) in dimethyl sulfoxide (5 ml) added. The reaction
mixture was stirred for 5 min and a solution of dimethyl disulfide (1.7
g, 18 mmol) in dimethyl sulfoxide (7 ml) added. The reaction mixture
was stirred for 24 h at ambient temperature.
Hydrochloric acid (2.5%, 150 ml) was added to the reaction and the
resultant mixture extracted with diethyl ether (three 100-ml aliquots).
The organic layers were combined and concentrated. Hydrochloric acid
(2.5%, 150 ml) was added to the concentrate and the resultant mixture
washed with diethyl ether (three 100-ml aliquots). The organic layers
were combined and concentrated. Sodium hydroxide solution (25%
w/v, 150 ml) was added to the residue and the resultant mixture
extracted with diethyl ether (three 100-ml aliquots). The combined
organic layers were dried (MgSO4), filtered and the solvent was evapo-
rated. The crude product was chromatographed on silica gel (100 g)
employing 3: 2 chloroform/light petroleum (100-ml fractions).
Fractions 3 and 4 were combined and concentrated and the product rec-
tified at reduced pressure giving clean (6) (0.09 g, 0.4 mmol, 7%), b.p.
141–142°C/2.1 Torr (Found: C, 50.5; H, 4.6. C9H10O2S2 requires C,
50.4; H, 4.7). I.r. (liquid film) 1705 cm–1. 1H n.m.r. (270 MHz) ꢄ 8.15,
Experimental
Infrared spectra were recorded on a Perkin–Elmer 710B grating
spectrophotometer for chloroform solutions unless otherwise specified.
1H n.m.r. spectra (60 MHz) were obtained on a Varian EM360L instru-
1
ment. H n.m.r. (270 MHz) and 13C n.m.r. spectra were obtained on a
JEOL JNM-GSX 270 Fourier-transform n.m.r. system. Unless other-
wise specified, all n.m.r. spectra were obtained for (D)chloroform solu-
tions with tetramethylsilane as internal standard. Most mass spectra
were obtained on a Hewlett–Packard 5988A g.l.c./m.s. system. Mass
spectra for the disulfone disulfides (7) and (8) were obtained on a CEC
21-110 mass spectrometer. Melting points were determined on a
Gallenkamp MFB-595 capillary melting point apparatus and are uncor-
rected.
d, 1H; 8.04, d, 1H; 7.58, t, 1H; 7.25, t, 1H; 3.93, s, 3H; 2.40, s, 3H. 13
C
n.m.r. ꢄ 166.80, 141.30, 132.92, 131.57, 126.90, 125.09, 52.29, 21.99.
m/z 214 (35%, M+•), 167 (100), 152 (37), 136 (41).
Preparation of o-Chlorophenyl Methyl Sulfide
Sodium metal (0.80 g, 34 mmol) was dissolved in methanol (80 ml)
and a solution of o-chlorobenzenethiol (5.1 g, 35 mmol) in methanol
(10 ml) added. The reaction mixture was cooled with an ice/water bath
and a solution of methyl iodide (5.0 g, 35 mmol) in methanol (10 ml)
was added dropwise. The reaction mixture was stirred at ambient tem-
perature for 24 h. Water (100 ml) was added and the resultant mixture
extracted with chloroform (three 100-ml aliquots). The organic layers
were combined, dried (MgSO4) and the solvent was evaporated. The
residue was distilled at reduced pressure yielding o-chlorophenyl
Biological Testing
Details have been provided earlier.1
Previously Prepared Compounds (Table 1)
Compound (12) was prepared as described in ref. 16 and compound
(13) was prepared as outlined in ref. 17.
Preparation of Methyl Phenyl Disulfide
1
methyl sulfide (4.7 g, 29.7 mmol, 85%), b.p. 80–86°C/3.0 Torr. H
Sodium metal (0.02 g, 0.69 mmol) was dissolved in methanol (1 ml)
and benzenethiol (0.1 ml) added. The solvent was evaporated and the
sodium benzenethiolate dried in vacuum. The benzenethiolate salt was
dissolved in dimethyl sulfoxide (10 ml). A portion of the resultant solu-
tion (1 ml) was added to a mixture of diphenyl disulfide (1.98 g, 9.1
mmol) and dimethyl disulfide (12 ml). The reaction mixture was stirred
at ambient temperature for 8 days.
Hydrochloric acid (2.5%, 70 ml) was added and the resultant
mixture washed with diethyl ether (three 50-ml aliquots). The organic
layers were combined, dried (MgSO4), filtered and the solvent was
evaporated. The concentrate was rectified at reduced pressure affording
methyl phenyl disulfide (2.38 g, 15.2 mmol, 84%), b.p. 82–86°C/1.8
Torr. 1H n.m.r. (270 MHz) ꢄ 7.51, d, 2H; 7.30, t, 2H; 7.20, t, 1H; 2.40,
s, 3H. 13C n.m.r. ꢄ 22.82, 126.77, 127.47, 128.96, 136.83. m/z 156
(100%, M+•), 141 (65), 109 (57).
n.m.r. (270 MHz) ꢄ 7.33, d, 1H; 7.22, t, 1H; 7.12, d, 1H; 7.07, t, 1H;
2.47, s, 3H. 13C n.m.r. ꢄ 137.70, 131.75, 129.69, 129.34, 127.18,
125.46, 15.13. m/z 160 (33%),158 (100, M+•), 145 (24), 143 (66).
Preparation of o-Chlorophenyl Methyl Sulfone
o-Chlorophenyl methyl sulfide (4.1 g, 25.9 mmol) in chloroform (86
ml) was added dropwise to 10% sulfuric acid (120 ml). Simultaneously,
potassium permanganate (13.9 g) was added in small portions. The
double addition took 45 min. Upon completion of the addition, the reac-
tion mixture was stirred at ambient temperature for 1 h. The reaction
mixture was cooled in an ice/water bath and sodium bisulfite added
until the reaction mixture became colourless. The layers were separated
and the aqueous layer was extracted with chloroform (three 100-ml por-
tions). The combined organic layers were dried (MgSO4), filtered and
the solvent was evaporated. Crude chloro sulfone was recrystallized
(methanol) affording clean chloro sulfone (4.0 g, 21.0 mmol, 81%),
m.p. 93.5–95.1°C. I.r. 1330, 1165 cm–1. 1H n.m.r. (270 MHz) ꢄ 8.15, d,
1H; 7.58, m, 2H; 7.48, m, 1H; 3.29, s, 3H. 13C n.m.r. ꢄ 138.03, 134.79,
131.91, 130.84, 127.52, 42.73. m/z 192 (7%), 190 (20, M+•), 113 (33),
111 (100).
Preparation of Methyl o-Mercaptobenzoate
o-Mercaptobenzoic acid (9.9 g, 64.2 mmol) was dissolved in
methanol (300 ml) and concentrated sulfuric acid (0.5 ml) added. The
reaction mixture was refluxed for 72 h. Chloroform (300 ml) was added

4
F. J. Baerlocher et al.
3.44, s, 3H. 13C n.m.r. (CD3SOCD3) ꢄ 138.22, 135.67, 134.92, 130.04,
127.90, 127.64, 42.52. m/z 374 (21%, M+•), 296 (11), 234 (15), 188
(100).
Clean disulfone disulfide (8) (22% from the sulfonyl chloride) had
m.p. 183–185°C (Found: C, 45.2; H, 3.9. C14H14O4S4 requires C, 44.9;
H, 3.8%). I.r. (KBr) 1308, 1155 cm–1. 1H n.m.r. (CD3SOCD3, 270 MHz)
ꢄ 7.93, d, 4H; 7.80, d, 4H; 3.22, s, 6H. 13C n.m.r. (CD3SOCD3) ꢄ 141.61,
139.52, 128.05, 126.45, 43.33. m/z 374 (31%, M+•), 234 (18), 188
(100).
Preparation of Benzyl o-Methylsulfonylphenyl Sulfide
Sodium metal (0.24 g, 10.4 mmol) was dissolved in methanol (5 ml)
and phenylmethanethiol (1.3 ml) added. The solvent was evaporated
and sodium phenylmethanethiolate dried in vacuum. The sodium thio-
late salt was dissolved in dimethyl sulfoxide (50 ml) and o-
chlorophenyl methyl sulfone (2.0 g, 10.6 mmol) added. The reaction
mixture was stirred at ambient temperature for 19 h. Hydrochloric acid
(10%, 200 ml) was added and the product filtered off. Dried sulfone
sulfide (2.0 g) was recrystallized (methanol) furnishing benzyl o-
methylsulfonylphenyl sulfide (1.6 g, 5.8 mmol, 55%), m.p.
Preparation of the Nitrophenyl Disulfides (9)–(11)
1
132.0–133.4°C. I.r. 1315, 1155 cm–1. H n.m.r. (270 MHz) ꢄ 8.07, d,
1H; 7.50, m, 2H; 7.37, m, 6H; 4.24, s, 2H; 3.17, s, 3H. 13C n.m.r. ꢄ
139.47, 137.15, 136.08, 133.59, 131.05, 130.10, 128.93, 128.70,
127.67, 126.42, 42.05, 39.28. m/z 278 (3%, M+•), 91 (100).
The methyl nitrophenyl disulfides were prepared from the appropri-
ate symmetrical di(nitrophenyl) disulfides as described below for the
para-nitro case.
Sodium metal (0.018 g, 0.78 mmol) was dissolved in methanol (10
ml) and methanethiol (20 ml) bubbled into the solution. The solvent
was evaporated and the sodium methanethiolate dried in vacuum.
The sodium methanethiolate was dissolved in dimethyl sulfoxide
(10 ml). Di(p-nitrophenyl) disulfide (2.0 g, 6.6 mmol) was added to
dimethyl sulfoxide (2 ml) and a portion of the methanethiolate solution
(1 ml) added. Dimethyl disulfide (12 ml) was added and the reaction
mixture stirred at ambient temperature for 8 days. The reaction mixture
became homogeneous after stirring for 24 h.
Hydrochloric acid (2.5%, 70 ml) was added and the resultant
mixture extracted with diethyl ether (three 50-ml aliquots). The organic
layers were combined, dried (MgSO4), filtered and rotary evaporated.
The residue was chromatographed on silica gel (50 g) employing light
petroleum (twelve 50-ml fractions) followed by 1: 1 light
petroleum/chloroform (50-ml fractions) for elution. Fractions 13–22
were combined and rectified at reduced pressure affording methyl p-
nitrophenyl disulfide (11) (1.2 g, 5.9 mmol, 45%), b.p. 146–149°C/0.9
Torr. Disulfide (11) crystallized on standing and after recrystallization
(methanol) had m.p. 42.9–44.3°C.
Clean methyl o-nitrophenyl disulfide (10) (31%) had m.p. 49–51°C
(Found: C, 41.9; H, 3.3. C7H7NO2S2 requires C, 41.8; H, 3.5%). I.r.
1524, 1340 cm–1. 1H n.m.r. (270 MHz) ꢄ 8.29, t, 2H; 7.71, t, 1H; 7.37,
t, 1H; 2.43, s, 3H. 13C n.m.r. ꢄ 137.25, 134.10, 126.79, 126.27, 126.09,
21.89. m/z 201 (14%, M+•), 136 (100), 122 (41).
Clean methyl m-nitrophenyl disulfide (9) (74%) had b.p.
152–158°C/2 Torr (Found: C, 42.0; H, 3.6. C7H7NO2S2 requires C, 41.8;
H, 3.5%). I.r. 1530, 1350 cm–1. 1H n.m.r. (270 MHz) ꢄ 8.39, s, 1H; 8.04,
d, 1H; 7.80, d, 1H; 7.52, t, 1H; 2.49, s, 3H. 13C n.m.r. ꢄ 148.78, 140.10,
132.26, 129.79, 121.37, 121.07, 22.85. m/z 201 (100%, M+•), 140 (48).
Clean methyl p-nitrophenyl disulfide (11) (45%) had the following
properties (Found: C, 41.9; H, 3.5. C7H7NO2S2 requires C, 41.8; H,
3.5%). I.r. 1515, 1340 cm–1. 1H n.m.r. (270 MHz) ꢄ 8.20, d, 2H; 7.66, d,
2H; 2.48, s, 3H. 13C n.m.r. ꢄ 146.43, 125.73, 124.15, 22.71. m/z 201
(100%, M+•), 140 (56).
Preparation of o-Methylsulfonylbenzenesulfonyl Chloride (14)
Benzyl o-methylsulfonylphenyl sulfide (1.0 g, 3.5 mmol) was sus-
pended in glacial acetic acid (35 ml) and water (3ml). Cl2 (c. 200
ml/min) was bubbled into the reaction mixture for 45 min. Ice/water
cooling was employed, as necessary, to maintain the reaction tempera-
ture below 30°C. Chloroform (100 ml) was added and the resultant
mixture extracted with 2.5% (w/v) sodium hydroxide (three 50-ml
aliquots). The organic layer was dried (MgSO4), filtered and the solvent
evaporated. The sulfone sulfonyl chloride was recrystallized (dry
carbon tetrachloride) yielding (14) (0.64 g, 2.5 mmol, 71%),
m.p.140.4–142.2°C. I.r. 1380, 1330, 1155 cm–1. 1H n.m.r. (270 MHz) ꢄ
8.42, t, 2H; 7.95, m, 2H; 3.41, s, 3H. 13C n.m.r. ꢄ 142.80, 139.08,135.99,
134.64, 133.18, 131.72, 45.12.
Preparation of the Disulfone Disulfides (7) and (8)
Both sulfone disulfides were prepared as described below for bis-o-
methylsulfonylphenyl disulfide (7). Note that the preparation of p-
methylsulfonylbenzenesulfonyl chloride (15) has been described
earlier.16
(A) Lithium aluminum hydride (1.2 g, 31.5 mmol) was added to
tetrahydrofuran (20 ml). A solution of (14) (2.0 g, 7.8 mmol) in tetrahy-
drofuran (80 ml) was added dropwise over 25 min. The reaction
mixture was refluxed for 1 h. After cooling to ambient temperature the
following chemicals were added sequentially in a dropwise manner:
ethyl acetate (20 ml), methanol (10 ml), water (10 ml), 1% hydrochlo-
ric acid (40 ml) and concentrated hydrochloric acid (12 ml).
Chloroform (250 ml) was added and the resultant mixture washed with
water (two 150-ml aliquots). The organic layer was dried (MgSO4), fil-
tered and concentrated affording crude methyl phenyl sulfone (0.33 g).
Methyl phenyl sulfone was recrystallized (methanol) and shown to be
identical to authentic material by m.p., mixture m.p., i.r. and 1H n.m.r.
(60 MHz).
The aqueous layer from the extraction procedure was acidified (12
ml of concentrated hydrochloric acid) and the resultant mixture
extracted with chloroform (three 100-ml aliquots). The combined
organic layers were dried (MgSO4), filtered and the solvent was evap-
orated affording crude oily o-methylsulfonylbenzenethiol (0.6 g).
(B) Sodium metal (0.25 g, 10.7 mmol) was dissolved in methanol
(25 ml) and methanethiol (250 ml) bubbled into the solution. The
solvent was evaporated and the sodium methanethiolate dried in
vacuum. The sodium methanethiolate was dissolved in dimethyl sul-
foxide (15 ml) and a solution of oily o-methylsulfonylbenzenethiol (1.9
g, 10 mmol), dimethyl disulfide (3.0 g, 31 mmol) and dimethyl sulfox-
ide (5 ml) added. The reaction mixture was stirred at ambient tempera-
ture for 20 h. Hydrochloric acid (2.5%, 150 ml) was added and the
resultant mixture extracted with diethyl ether (three 100-ml aliquots).
The organic layers were combined, dried (MgSO4), filtered and the
solvent was evaporated. Crude disulfone disulfide (7) was recrystal-
lized from methanol (175 ml).
Acknowledgments
The authors acknowledge financial support from Mount
Allison University and from the Medical Research Fund of
New Brunswick. Mass spectra on (7) and (8) were kindly
provided by Dr J. S. Grossert. All other mass spectra were
obtained by R. Smith. High-field n.m.r. spectra were
obtained by D. Durant.
References
1
Baerlocher, F. J., Langler, R. F., Frederiksen, M. U., Georges, N. M.,
and Witherell, R. D., Aust. J. Chem., 1999, 52, 167, and references
therein.
2
Martin, B. J., Clough, J. M., Pattenden, G., and Waldron, I. R.,
Tetrahedron Lett., 1993, 34, 5151.
Issacs, S., Hizi, A., and Kashman, Y., Tetrahedron, 1993, 49, 4275.
Cole, E. R., Nature (London), 1963, 198, 1083.
Tabuchi, H., Hamamoto, T., Miki, S., Tejima, T., and Ichihara, A.,
3
Clean disulfone disulfide (7) (0.69 g, 1.8 mmol, 46% from the sul-
fonyl chloride) had m.p. 225–227°C (Found: C, 45.0; H, 3.8.
C14H14O4S4 requires C, 44.9; H, 3.8%). I.r. (KBr) 1300, 1140 cm–1. 1H
n.m.r. (CD3SOCD3, 270 MHz) ꢄ 8.06, d, 1H; 7.86, m, 2H; 7.65, t, 1H;
4
5
Tetrahedron Lett., 1993, 34, 2327.

Antifungal Disulfides
5
6
15
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