A new synthesis for antifungal α-sulfone disulfides

Article abstract of DOI:10.1071/CH99086

An α-ester disulfide is shown to be a useful precursor for the preparation of several α-sulfone disulfides. These new α-sulfone disulfides are all fungitoxic against Aspergillus niger and Aspergillus flavus. CSIRO 1999.

Full text of DOI:10.1071/CH99086

C S I R O P U B L I S H I N G
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Volume 52, 1999
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Aust. J. Chem., 1999, 52, 1119–1121
␣
A New Synthesis for Antifungal -Sulfone Disulfides
Richard Francis Langler,A,B Stephanie Lee MacQuarrie,A
Robert Antle McNamaraA and Paul Eric O’ConnorA
A Department of Chemistry, Mount Allison University,
Sackville, New Brunswick, Canada E4L 1G8.
B To whom correspondence should be addressed.
An ␣-ester disulfide is shown to be a useful precursor for the preparation of several ␣-sulfone disulfides. These new
␣-sulfone disulfides are all fungitoxic against Aspergillus niger and Aspergillus flavus.
Introduction
Results and Discussion
Recently, we provided evidence that sulfone disulfides in
which both functional groups are attached to a common
carbon, i.e. (1), are fungitoxic.1
Reaction of the disulfide propionate (2) with the sodium
salt of p-toluenesulfinic acid in either aqueous acetonitrile or
aqueous acetone led to smooth displacement of the propi-
onate group (see Scheme 2).
Each ␣-sulfone disulfide (1) tested in our initial report
was prepared in six steps [complete experimental details for
(1; R = CH3, Rꢀ = C6H5) have been provided earlier2]. Our
growing interest in structure–activity studies of compounds
(1) demands the development of more efficient and more
flexible synthetic methodologies for them.
The discovery3 that transition-metal oxidants can convert
dimethyl disulfide into ␣-ester disulfides (e.g. see Scheme 1)
has provided us with a little-known class of disulfides which
might be suitable for the preparation of antifungal disulfides
(1).
Sequential reaction of (4) with benzenethiolate ions and
acetyl chloride produced the thioacetate (6) as depicted in
Scheme 3.
A priori, attempted preparation of a sulfone disulfide (1;
Rꢀ = CH3) by reaction of the disulfide propionate (2) with a
sulfinate anion raises two questions—(A) will the ester group
have inadequate nucleofugality (precludes sulfone disulfide
formation) and (B), if the ester group is displaceable, will an
ambident nucleophilic sulfinate anion4–6 attack carbon using
an oxygen atom (leads to unwanted sulfinate ester formation)
or using the sulfur atom (leads to target ␣-sulfone disulfide
formation)?
This report provides answers to these questions and in so
doing outlines the first successful application of (2) to the
preparation of several ␣-sulfone disulfides (1; Rꢀ = CH3).
An unambiguous synthesis (see Scheme 4) of the sulfone
thioacetate corresponding to (6) proved that (6) is not a
thioacetate sulfinate ester.
Manuscript received 15 July 1999
© CSIRO 1999
10.1071/CH99086
0004-9425/99/121119

1120
R. F. Langler et al.
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
(␮g/
disk)
Diameter (mm) of
clear zone
A. niger
A. flavus
p-CH3(C6H4)SO2CH2SSCH3 (4)
C6H5SO2CH2SSCH3
25
25
10.9
5.5
2.7
0
8.0
4.2
3.8
0
CH3SO2CH2SSCH3
25
p-CH3(C6H4)SO2CH2SH (5)
CH3CH2C(O)OCH2SSCH3 (2)
100
25
14.8
7.6
Qualitatively, the observed toxicity of the compounds in
Table 1 is in complete accord with our earlier proposal1 that
activated antifungal disulfides (those with a reasonable
leaving group attached to the ␣-carbon) will have pro-
nounced antifungal activity. Quantitatively, the first and last
compounds in Table 1 are the most potent fungitoxic disul-
fides we have described to date.
In connection with a related synthetic problem, we
decided to react the disulfide ester (2) with potassium p-
toluenethiosulfonate. To our surprise, this reaction (see
Scheme 6) produced the ␣-sulfone disulfide (4).
Clearly, sulfinate anion attack on (2) has occurred exclu-
sively with the sulfur atom under our reaction conditions
(see Scheme 2).
We note in passing that Schemes 3 and 4 not only estab-
lish that (4) is the target ␣-sulfone disulfide but also establish
that (5) is an ␣-mercapto sulfone. To the best of our knowl-
edge, our earlier report7 describes the first synthesis of an ␣-
mercapto sulfone (CH3SO2CH2SH). Unfortunately, that oily
␣-mercapto sulfone was unstable (t1/2 = 6 days), this property
making it awkward to study. In contrast, the crystalline ␣-
mercapto sulfone (5) is stable at ambient temperature for at
least 10 months (no observable change in the proton n.m.r.
spectrum). Convenient exploration of the chemistry of an ␣-
mercapto sulfone is now possible.
Typically, preparation of the disulfide ester (2) produces
disulfide contaminated with the corresponding sulfide ester
(3) (see Scheme 1). Fractional distillation usually leaves a
small amount of sulfide ester (3) contaminating distilled
disulfide ester (2). It seemed likely that preparation of a
sulfone disulfide [e.g. (4), Scheme 2] from (2) would also
produce the corresponding sulfone sulfide which would be
difficult to remove. However, neither the sulfide propionate
(3)3 nor the sulfide acetate (9)3 react with sulfinate anions in
warm aqueous acetonitrile (see Scheme 5).
Apparently the reagent is transformed, under our reaction
conditions, into the potassium salt of p-toluenesulfinic acid.
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-
ment. 1H n.m.r. spectra (270 MHz) and 13C n.m.r. spectra were obtained
on a JEOL JNM-GSX 270 Fourier-transform n.m.r. system. Unless oth-
erwise specified, all n.m.r. spectra were obtained for (D)chloroform
solutions with tetramethylsilane as internal standard. Mass spectra were
obtained on a Hewlett–Packard 5988 A g.l.c./m.s. system. Melting
points were determined on a Gallenkamp MFB-595 capillary melting
point apparatus and are uncorrected.
Biological Testing
Details have been provided earlier.1
Thus, ␣-sulfone disulfides (1; Rꢀ = CH3), prepared as
shown in Scheme 2, are readily purified.
Several other ␣-sulfone disulfides (1) have been prepared
from (2) and tested for fungitoxic activity. Antifungal test
results for these ␣-sulfone disulfides and both disulfide pro-
pionate (2) and the ␣-mercapto sulfone (5) are presented in
Table 1.
Previously Prepared Compounds (Table 1)
Compound (2) was prepared as described in ref. 3.
Preparation of ␣-Sulfone Disulfides (1; Rꢀ = CH3)
Table 1 ␣-sulfone disulfides were prepared in the manner described
below for (4).

1121
Antifungal ␣-Sulfone Disulfides
A solution of sodium p-toluenesulfinate (2.4 g, 13.4 mmol) and the
disulfide propionate (2) (2.0 g, 12.0 mmol) in 1: 4 water/acetone (30
ml) was immersed in a constant-temperature bath at 50°C for 2 h.
Chloroform (150 ml) was added and the resultant mixture washed with
water (100 ml). The organic layer was dried (MgSO4), filtered and the
solvent evaporated. The residue was chromatographed on silica gel
(200 g) with 1 : 1 chloroform/light petroleum (100-ml fractions) for
elution. Fractions 13–28 were combined and concentrated furnishing
the ␣-sulfone disulfide (4) (1.6 g, 6.4 mmol, 53%). Recrystallized
(methanol) ␣-sulfone disulfide (4) had m.p. 46.2–48.6°C (Found: C,
44.1; H, 5.1. C9H12O2S3 requires C, 43.5; H, 4.9%). I.r. 1342, 1148 cm–1.
1H n.m.r. (270 MHz) ␦ 2.46, s, 3H; 2.50, s, 3H; 4.20, s, 2H; 7.38, d, 2H;
7.83, d, 2H. 13C n.m.r. ␦ 21.70, 23.69, 64.38, 128.98, 129.92, 134.67,
145.36. m/z 248 (6%, M+•), 139 (56), 93 (100).
(B) Thioacetic S-acid (0.4 g, 5.8 mmol) was dissolved in dry pyridine
(25 ml) and chloromethyl p-tolyl sulfide (1.0 g, 5.8 mmol) added. The
reaction mixture was stirred at ambient temperature for 23 h.
Chloroform (100 ml) was added and the resultant mixture extracted
with 5% HCl (50-ml aliquots) until the aqueous pH remained acidic.
The organic layer was extracted with 2.5% NaOH (50 ml), dried
(MgSO4), filtered and the solvent evaporated. The residue was rectified
at reduced pressure furnishing the sulfide thioacetate (7) (0.8 g, 3.7
mmol, 64%), b.p. 138–140°C/1.7 Torr. I.r. (liquid film) 1700 cm–1. 1H
n.m.r. (270 MHz) ␦ 2.29, s, 3H; 2.33, s, 3H; 4.29, s, 2H; 7.12, d, 2H;
7.32, d, 2H. 13C n.m.r. ␦ 21.11, 30.39, 34.75, 129.82, 130.62, 131.46,
137.69, 194.34. m/z 212 (55%, M+•), 124 (100), 91 (55), 43 (65).
Conversion of (8) into the Sulfone ␣-Thioacetate (6)
Oily C6H5SO2CH2SSCH3 (obtained in 58% yield) has i.r. 1325,
1155 cm–1. 1H n.m.r. (270 MHz) ␦ 2.49, s, 3H; 4.22, s, 2H; 7.60, t, 2H;
7.70, t, 1H; 7.96, d, 2H. 13C n.m.r. ␦ 23.68, 64.32, 128.96, 129.30,
134.23, 137.62. m/z 234 (5%, M+•), 125 (28), 93 (100).
The sulfide ␣-thioacetate (8) (1.0 g, 4.7 mmol) and hydrogen per-
oxide (30%, 1.1 g) were added to 1,4-dioxan (25 ml) and the reaction
mixture was refluxed for 0.5 h. The solvent was evaporated and chloro-
form (150 ml) added. The chloroform solution was dried (MgSO4), fil-
tered and concentrated. The residue was chromatographed on silica gel
(100 g) with chloroform (100-ml fractions) for elution. Fractions 4 and
5 were combined and concentrated affording clean sulfone ␣-thioac-
etate (6) (0.34 g, 1.4 mmol, 30%). The product was identical to material
described under ‘Conversion of (5) into the Sulfone ␣-Thioacetate (6)’
by i.r., 1H n.m.r. (270 MHz) and 13C n.m.r. spectroscopy.
8,9
Oily CH3SO2CH2SSCH3 (obtained in 53% yield) had i.r. 1320,
1145 cm–1. 1H n.m.r. (270 MHz) ␦ 2.60, s, 3H; 3.05, s, 2H; 4.16, s, 2H.
13C n.m.r. ␦ 23.61, 39.33, 61.38. m/z 172 (10%, M+•), 93 (100).
Conversion of (4) into the ␣-Mercato Sulfone (5)
The ␣-sulfone disulfide (4) (0.20 g, 0.81 mmol) was dissolved in a
solution of benzenethiol (0.19 g, 1.7 mmol) in dry methylene chloride
(10 ml). Dry pyridine (0.1 ml) was added and the reaction mixture
stirred at ambient temperature for 2 h and 10 min. The solvent was
evaporated and the residue chromatographed on silica gel (10 g) with
chloroform (5-ml fractions) for elution. Fractions 3 and 4 were com-
bined and dissolved in chloroform (100 ml). The chloroform layer was
washed with 2.5% sodium hydroxide (two 50-ml portions), dried
(MgSO4), filtered and the solvent evaporated. G.l.c./m.s. established the
presence of methyl phenyl disulfide and diphenyl disulfide in these
fractions. Column fraction 5 furnished a mixture (0.06 g) of unchanged
(4) and the ␣-mercapto sulfone (5). Fractions 6–9 were combined and
concentrated yielding clean ␣-mercapto sulfone (5) (0.09 g, 0.44 mmol,
54%). Recrystallized (5) (methanol) had m.p. 86.4–87.4°C (Found: C,
47.3; H, 5.0. C8H10O2S2 requires C, 47.5; H, 5.0%). I.r. 2500, 1330,
1170 cm–1. 1H n.m.r. (270 MHz) ␦ 2.21, t, 1H; 2.46, s, 3H; 3.94, d, 2H;
7.38, d, 2H; 7.83, d, 2H. 13C n.m.r. ␦ 21.68, 49.43, 129.08, 129.85,
133.67, 145.37.
Reaction of the Disulfide Ester (2) with Potassium
p-Toluenethiosulfonate
The disulfide propionate (2) (2.0 g, 12.0 mmol) and potassium p-
toluenethiosulfonate (2.7 g, 11.9 mmol) were dissolved in 1 : 4
water/acetone (30 ml) and the reaction mixture was heated at 50°C for
2 h. Chloroform (200 ml) was added and the resultant mixture extracted
with water (100 ml). The organic layer was dried (MgSO4), filtered and
the solvent evaporated. The residue was chromatographed on silica gel
(200 g) with 1: 1 chloroform/light petroleum (100-ml fractions) for
elution. Fractions 17–22 were combined and concentrated affording the
␣-sulfone disulfide (4) (0.38 g, 1.5 mmol, 13%) which was identical to
(4) described under ‘Preparation of ␣-Sulfone Disulfides (1; Rꢀ = CH3)’
by i.r., 1H n.m.r. (270 MHz) and 13C n.m.r. spectroscopy.
Acknowledgments
The authors acknowledge technical assistance by F.
Baerlocher and C. Chaulk. Financial support was provided
by the Mount Allison Research Committee. High-field n.m.r.
spectra were obtained by D. Durant and mass spectra by R.
Smith.
Conversion of (5) into the Sulfone ␣-Thioacetate (6)
The ␣-mercapto sulfone (5) (0.06 g, 0.29 mmol) was covered with
acetyl chloride (10 ml) and the reaction mixture refluxed for 1 h. The
solvent was evaporated and the residue chromatographed on silica gel
(5 g) with 1: 4 light petroleum/methylene chloride (5-ml fractions) for
elution. Fractions 6–8 were combined and concentrated giving the
sulfone thioacetate (6) (0.024 g, 0.10 mmol, 34%) (Found: C, 49.3; H,
5.1. C10H12O3S2 requires C, 49.2; H, 5.0%). I.r. 1720, 1335, 1165 cm–1.
1H n.m.r. (270 MHz) ␦ 2.30, s, 3H; 2.45, s, 3H; 4.44, s, 2H; 7.34, d, 2H;
7.81, d, 2H. 13C n.m.r. ␦ 21.70, 29.94, 52.09, 128.93, 129.71, 134.20,
145.39, 190.41. m/z 244 (1%, M+•), 150 (31), 43 (100).
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