A versatile and convenient preparation of unsymmetrical diaryl disulfides

Article abstract of DOI:10.1055/s-2008-1067118

We have developed a convenient method for the synthesis of unsymmetrical diaryl disulfides under mild conditions in excellent yields. The described method is based on the straightforward preparation of 5,5-dimethyl-2-thioxo-1,3, 2-dioxaphosphorinane-2-sulfenyl bromide from readily available 5,5-dimethyl-2-sulfanyl-2-thioxo-l,3,2-dioxaphosphorinane or bis(5,5-dimethyl-2-thioxo-l,3,2-dioxaphosphorinan-2-yl) disulfide. The unsymmetrical diaryl disulfides can be obtained from aromatic thiol derivatives bearing electron-withdrawing or electron-donating groups. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067118

PAPER
2033
A Versatile and Convenient Preparation of Unsymmetrical Diaryl Disulfides
P
reparationof
e
U
nsymmet
b
rica
l
D
iaryl
D
a
isulfide
s
stian Demkowicz, Janusz Rachon, Dariusz Witt*
Department of Organic Chemistry, Chemical Faculty, Gdansk University of Technology, Narutowicza 11/12, 80952 Gdansk, Poland
Fax +48(58)3472694; E-mail: dwitt@chem.pg.gda.pl
Received 5 February 2008; revised 4 March 2008
to extend the strategy to the preparation of unsymmetrical
Abstract: We have developed a convenient method for the synthe-
diaryl disulfides based on organophosphorus sulfenyl bro-
mides as activating agents for unsymmetrical disulfide
bond formation.
sis of unsymmetrical diaryl disulfides under mild conditions in ex-
cellent yields. The described method is based on the straightforward
preparation of 5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinane-2-
sulfenyl bromide from readily available 5,5-dimethyl-2-sulfanyl-2-
thioxo-1,3,2-dioxaphosphorinane or bis(5,5-dimethyl-2-thioxo-
1,3,2-dioxaphosphorinan-2-yl) disulfide. The unsymmetrical diaryl
disulfides can be obtained from aromatic thiol derivatives bearing
electron-withdrawing or electron-donating groups.
Treatment of the stable and readily available bis(5,5-di-
methyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl) disulfide
(1)15 with bromine at –30 °C quantitatively affords 5,5-
dimethyl-2-thioxo-1,3,2-dioxophosphorinane-2-sulfenyl
bromide (3) (Table 1). Subsequent treatment, without
prior isolation, of sulfenyl bromide 3 with arenethiols pro-
vides the corresponding aryl 5,5-dimethyl-2-thioxo-1,3,2-
dioxaphosphorinan-2-yl disulfides 4a–f, which can be
isolated in very good yields (Table 1, method A, entries
1–6). These compounds are stable at room temperature for
several months; formation of symmetrical disulfides or
decomposition by moisture was not observed. Moreover,
compounds 4a–f can be prepared from 5,5-dimethyl-2-
sulfanyl-2-thioxo-1,3,2-dioxaphosphorinane (2)15 in sim-
ilar, very high yields (Table 1, method B, entries 1–6). Al-
though the use of dithiophosphoric acid derivative 2 is
simpler with regard to the availability of reagents required
for the preparation of sulfenyl bromide 3, the formation of
hydrogen bromide as side product was observed. In some
cases strong acidic conditions are responsible for the re-
moval of protective group and poor reaction yield.14 From
this point of view, method B can only be applied to the
preparation of disulfide derivatives 4 from thiols without
acid-sensitive groups. The results for both methods are
summarized in Table 1.
Key words: unsymmetrical diaryl disulfides, sulfenyl bromide,
aromatic thiols, arenes, heterocycles
The synthesis of unsymmetrical disulfides is an important
transformation in modern organic synthesis and medicinal
chemistry.1 Although there are many different approaches
for the preparation of disulfides, the majority of them are
not applicable to the synthesis of unsymmetrical diaryl
disulfides, due to the fast thiol–disulfide exchange reac-
tion. Furthermore, preparative methods that are efficient
for the preparation of symmetrical diaryl disulfides are
very often ineffective for the preparation of unsymmetri-
cal diaryl disulfides. The most common methods for ob-
taining unsymmetrical diaryl disulfides include the
thioalkylation of a thiol or its derivative by sulfenyl deriv-
atives: sulfenyl chlorides,2 N-(trifluoroacetyl)arenesulfe-
namides,3 benzotriazolyl sulfides,4 S-arylarenothio-
sulfonates,5 4-nitroarenesulfenanilides,6 and toluene-4-
sulfinic acid.7 Other practical procedures involve disul-
fide exchange catalyzed by rhodium,8 triphenylphos-
phine,9 or tetrathiomolybdate.10
The reaction of disulfide 4a with one equivalent of 4-
methylbenzenethiol in the presence of triethylamine afford-
ed unsymmetrical disulfide 5a in moderate yield (67%),
together with the other symmetrical disulfides. However,
in the presence of a 5% excess of 4a relative to 4-methyl-
benzenethiol, the same reaction gave product 5a in excel-
lent yield (97%) (Table 2). These observations show that
unsymmetrical disulfide 5a forms very fast from 4-meth-
ylbenzenethiol and compound 4a, and that further disul-
fide exchange takes place in the presence of thiolate
anion. Therefore, unsymmetrical disulfides 5 need to be
prepared in the presence of only a small excess of reagent
4. The influence of the thiolate anion on the disulfide ex-
change reaction was confirmed by treatment of isolated
unsymmetrical disulfide 5a with 4-methylbenzenethiol (5
mol%) in the presence of triethylamine. After 15 minutes
an equal amount of both symmetrical disulfides was ob-
served and after 30 minutes only 65% of starting 5a was
present in the reaction mixture (confirmed by TLC and 1H
NMR).
Several unsymmetrical substituted aromatic donor–
acceptor disulfides have been analyzed for their second-
order nonlinear optical properties. These compounds ex-
hibit moderately high first hyperpolarizability with excel-
lent transparency in the visible region.11 Although this
class of molecules has potential application in optical data
processing and communication, these disulfides are pro-
vided in only moderate or poor yield by the available syn-
thetic methods.
We have previously demonstrated the preparation of func-
tionalized unsymmetrical molecules, such as dialkyl di-
sulfides, alkyl aryl disulfides,12 ‘bioresistant’ disulfides,13
and unsymmetrical disulfides based on L-cysteine and L-
cystine derivatives.14 The excellent results encouraged us
SYNTHESIS 2008, No. 13, pp 2033–2038
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067118; Art ID: P01308SS
© Georg Thieme Verlag Stuttgart · New York

2034
S. Demkowicz et al.
PAPER
Table 1 Synthesis of Aryl 5,5-Dimethyl-2-thioxo-1,3,2-dioxaphos-
phorinan-2-yl Disulfides 4
O
O
S
S
P
S
Et3N
O
O
+
S
S
S
S
O
S
P
P
OH
4f
P
O
O
SH
O
1
2
O
S
S
method B
method A
Br2
CH2Cl2, –30 °C
P
S
O
S
S
O
HNEt3
+
Br2
CH2Cl2, –30 °C
P
Br
O
O
3
Ar1SH
S
O
S
S
O
O
P
P
S
S
S
O
Ar1
O
Scheme 1 The reaction of 4f with triethylamine
4
Entry Ar1
Product 4
Yield (%) by Yield (%) by
sion into the unsymmetrical disulfide 5 takes place, with-
out significant formation of either symmetrical disulfide
or 4-thioxocyclohexa-2,5-dienone (Table 2). In general,
because arenethiols are stronger acids than the corre-
sponding phenols, triethylamine abstracts the proton from
the thiol group, and the intramolecular elimination shown
in Scheme 1 is not observed. The thiolate anion is gener-
ated in the presence of a small excess of 4f, so that thiol–
disulfide exchange is limited, and unsymmetrical product
5 forms exclusively. Finally, after modification of the
conditions, unsymmetrical disulfides 5e, 5j, 5n, 5r, 5t,
and 5w were obtained from 4f in excellent yields
(Table 2).
method A
method B
1
2
3
4
5
6
2-MeO2CC6H4
4-Tol
4a
4b
4c
4d
4e
4f
94
95
92
97
91
93
92
91
95
92
94
97
Ph
2-Naph
PMP
4-HOC6H4
The development of an effective protocol for the reliable
synthesis of unsymmetrical disulfides 5 from 4f was the
most challenging. When triethylamine was added to the
solution of 4f in dichloromethane, a yellow and then
brownish color appeared very fast. Further treatment with
Compounds 4a–f were treated with a variety of arene-
thiols to examine the scope and limitation of this method
for the preparation of 5 (Table 2).
a benzenethiol did not afford the corresponding unsym- As shown in Table 2, the same unsymmetrical disulfide
metrical disulfide 5. This is probably because compound can be obtained by two different ways. For example, 5a
4f reacted with triethylamine to form 4-thioxocyclohexa- can be prepared from 4a and 4-methylbenzenethiol or
2,5-dienone (Scheme 1).
from 4b and methyl 2-sulfanylbenzoate. Both approaches
gave product 5a in excellent yield (Table 2). Moreover, it
seems that steric hindrance and the presence of electron-
However, when triethylamine is added to a mixture of 4f
and the arenethiol in dichloromethane, complete conver-
Table 2 Synthesis of Unsymmetrical Diaryl Disulfides 5a
O
S
Ar1
Ar2SH
S
Ar2
P
S
S
Ar1
S
4
O
CH2Cl2, Et3N, r.t., 15 min
5
Ar1
Ar2
2-MeO2CC6H4 4-Tol
5a (97)
Ph
2-Naph
5c (100)
5h (100)
5l (96)
PMP
4-HOC6H4
5e (90)
5j (98)
4-O2NC6H4
5f (93)
4a
4b
4c
4d
4e
4f
2-MeO2CC6H4
4-Tol
5b (86)
5g (98)
5d (100)
5i (100)
5m (82)
5p (92)
5a (93)
5k (100)
5o (100)
5s (98)
Ph
5b (100)
5c (100)
5d (99)
5g (97)
5h (97)
5i (95)
5j (95)
5n (98)
5r (84)
5t (87)
2-Naph
PMP
5l (96)
5m (99)
5n (99)
5p (100)
5r (100)
5u (93)
4-HOC6H4
5e (100)
5t (100)
5w (100)
a The yields (%) of the isolated product are reported in parentheses.
Synthesis 2008, No. 13, 2033–2038 © Thieme Stuttgart · New York

PAPER
Preparation of Unsymmetrical Diaryl Disulfides
2035
4-[(5,5-Dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)disul-
fanyl]toluene (4b)
Chromatography (CH2Cl2–hexane, 1:1); yield: 95%; mp 83–85 °C.
1H NMR (200 MHz, CDCl3): d = 0.97 (s, 3 H, CH3), 1.20 (s, 3 H,
CH3), 2.36 (s, 3 H, ArCH3), 3.90–4.10 (m, 4 H, POCH2), 7.15 (d,
J = 8.2 Hz, 2 H, Ar), 7.58 (d, J = 8.2 Hz, 2 H, Ar).
withdrawing or electron-donating groups did not affect
the formation of unsymmetrical disulfides 5. The success
of the method depends on the very fast formation of 5
from 4a–f so that further disulfide exchange is avoided
and unsymmetrical diaryl disulfides 5 form exclusively.
In conclusion, a convenient and versatile method for the
preparation of unsymmetrical diaryl disulfides 5 has been
developed. Compounds 4 were readily prepared, and
these stable crystalline solids were effective precursors
for the synthesis of 5. Reactions of 4 with a variety of
arenethiols in dichloromethane at room temperature were
generally complete within 15 minutes and gave unsym-
metrical diaryl disulfides 5 exclusively in excellent yield
after isolation. Since the reactions of the arenethiols pro-
ceeded with a small excess of 4 under mild reaction con-
ditions in a short time, thiol–disulfide exchange did not
occur during the reaction. The simplicity and excellent
yields make this method one of the most attractive ap-
proaches to the preparation of unsymmetrical diaryl disul-
fides.
13C NMR (50 MHz, CDCl3): d = 139.3, 131.7, 129.8, 77.8 (d,
3
2JP–C = 9.1 Hz), 32.5 (d, JP–C = 7.3 Hz), 22.0, 21.2, 21.1. Signals:
expected, 9; observed, 8.
31P NMR (202 MHz, CDCl3): d = 84.56.
ESI-HRMS: m/z [M + Na]+ calcd for C12H17NaO2PS3: 343.0026;
found: 343.0027.
[(5,5-Dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)disul-
fanyl]benzene (4c)
Chromatography (hexane, then CH2Cl2); yield: 92%; mp 56–58 °C.
1H NMR (200 MHz, CDCl3): d = 0.97 (s, 3 H, CH3), 1.19 (s, 3 H,
CH3), 3.92–4.09 (m, 4 H, POCH2), 7.28–7.42 (m, 3 H, Ar), 7.62–
7.73 (m, 2 H, Ar).
13C NMR (50 MHz, CDCl3): d = 130.7, 129.1, 128.6, 77.9 (d,
2JP–C = 9.0 Hz), 32.5 (d, 3JP–C = 7.4 Hz), 22.0, 21.0. Signals: expect-
ed, 8; observed, 7.
31P NMR (202 MHz, CDCl3): d = 83.87.
ESI-HRMS: m/z [M + Na]+ calcd for C11H15NaO2PS3: 328.9869;
4-Methylbenzenethiol, thiophenol, naphthalene-2-thiol, 4-methoxy-
benzenethiol, 4-sulfanylphenol, and 4-nitrobenzenethiol are avail-
able from Aldrich. Methyl 2-sulfanylbenzoate,16 bis(5,5-dimethyl-
2-thioxo-1,3,2-dioxaphosphorinan-2-yl) disulfide (1),15 and 5,5-
dimethyl-2-sulfanyl-2-thioxo-1,3,2-dioxaphosphorinane (2)15 were
synthesized by previously described procedures. CH2Cl2 was dried
and distilled by standard procedures. Melting points are uncorrect-
ed. NMR spectra were recorded on a Varian Gemini 500-MHz or
200-MHz spectrometer. The residual solvent peak was used as in-
found: 328.9858.
2-[(5,5-Dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)disul-
fanyl]naphthalene (4d)
Chromatography (hexane–CH2Cl2, 1:0, then 3:1); yield: 97%; mp
86–88 °C.
1H NMR (200 MHz, CDCl3): d = 0.95 (s, 3 H, CH3), 1.19 (s, 3 H,
CH3), 3.90–4.10 (m, 4 H, POCH2), 7.40–7.60 (m, 2 H, Ar), 7.70–
7.93 (m, 4 H, Ar), 8.12–8.20 (m, 1 H, Ar).
1
ternal reference (CDCl3: d = 7.26 for H, d = 77.0 for 13C; metha-
nol-d4: d = 4.78 for 1H, d = 49.0 for 13C); for 31P NMR spectroscopy
an external standard was used as reference (85% H3PO4: d = 0).
ESI-MS spectra were recorded on a Mariner PerSeptve Biosystem
spectrometer. Column chromatography was performed on silica gel
60 (230–400 mesh, Merck). Preparative TLC was performed on sil-
ica gel Polygram SIL G/UV254 (Macherey-Nagel).
13C NMR (50 MHz, CDCl3): d = 133.2, 132.9, 130.1, 130.0, 129.0,
127.7, 127.5, 127.4, 126.9, 77.9 (d, 2JP–C = 9.0 Hz), 32.4 (d, 3JP–C
=
7.4 Hz), 21.9, 21.0. Signals: expected, 14; observed, 13.
31P NMR (202 MHz, CDCl3): d = 83.87.
ESI-HRMS: m/z [M + Na]+ calcd for C15H17NaO2PS3: 379.0026;
found: 379.0013.
Methyl 2-[(5,5-Dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-
yl)disulfanyl]benzoate (4a); Typical Procedure (Method A)
Br2 (0.96 g, 6.0 mmol) was added to a soln of 1 (2.76 g, 7.0 mmol)
in anhyd CH2Cl2 (50 mL) at –30 °C and under N2. After 15 min, a
soln of methyl 2-sulfanylbenzoate (1.85 g, 11 mmol) in anhyd
CH2Cl2 (5 mL) was added. Then the mixture was stirred at r.t. for
30 min, diluted with CH2Cl2 (50 mL), washed with H2O (50 mL),
dried (MgSO4), filtered, and evaporated under vacuum. The residue
was purified by column chromatography (silica gel, CH2Cl2–hex-
ane, 1:1); this yielded 4a.
4-[(5,5-Dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)disul-
fanyl]anisole (4e)
Chromatography (CH2Cl2–hexane, 1:1); yield: 91%; mp 51–53 °C.
1H NMR (200 MHz, CDCl3): d = 0.97 (s, 3 H, CH3), 1.21 (s, 3 H,
CH3), 3.82 (s, 3 H, OCH3), 3.90–4.10 (m, 4 H, POCH2), 6.80–6.95
(m, 2 H, Ar), 7.60–7.72 (m, 2 H, Ar).
13C NMR (50 MHz, CDCl3): d = 160.9, 135.2, 125.2, 114.6, 77.7 (d,
3
2JP–C = 9.0 Hz), 55.4, 32.4 (d, JP–C = 7.2 Hz), 22.0, 21.0. Signals:
Yield: 3.77 g (94%); white solid; mp 106–108 °C.
1H NMR (200 MHz, CDCl3): d = 0.95 (s, 3 H, CH3), 1.19 (s, 3 H,
CH3), 3.94 (s, 3 H, OCH3), 3.98–4.30 (m, 4 H, POCH2), 7.20–7.36
(m, 1 H, Ar), 7.52–7.66 (m, 1 H, Ar), 8.02 (dd, J = 1.5, 7.8 Hz, 1 H,
Ar), 8.16 (d, J = 8.1 Hz, 1 H, Ar).
expected and observed, 9.
31P NMR (202 MHz, CDCl3): d = 85.35.
ESI-HRMS: m/z [M + Na]+ calcd for C12H17NaO3PS3: 358.9975;
found: 358.9977.
13C NMR (50 MHz, CDCl3): d = 166.8, 133.0, 131.0, 127.3, 125.8,
2
3
78.2 (d, JP–C = 9.2 Hz), 52.4, 32.5 (d, JP–C = 7.4 Hz), 22.0, 21.0.
4-[(5,5-Dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)disul-
fanyl]phenol (4f)
Signals: expected, 12; observed, 10.
31P NMR (202 MHz, CDCl3): d = 81.31.
ESI-HRMS: m/z [M + Na]+ calcd for C13H17NaO4PS3: 386.9924;
Chromatography (CH2Cl2); yield: 93%; mp 110–112 °C.
1H NMR (200 MHz, CDCl3): d = 0.96 (s, 3 H, CH3), 1.21 (s, 3 H,
CH3), 3.90–4.05 (m, 4 H, POCH2), 5.10 (br s, 1 H, OH), 6.76–6.87
(m, 2 H, Ar), 7.57–7.68 (m, 2 H, Ar).
found: 386.9946.
Synthesis 2008, No. 13, 2033–2038 © Thieme Stuttgart · New York

2036
S. Demkowicz et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 157.2, 135.4, 125.3, 113.2, 77.8 (d,
2JP–C = 9.1 Hz), 32.5 (d, 3JP–C = 7.2 Hz), 22.0, 21.0. Signals: expect-
ed and observed, 8.
13C NMR (50 MHz, CDCl3): d = 167.2, 155.8, 141.6, 133.0, 132.9,
131.4, 131.0, 125.9, 125.4, 116.3, 116.1, 52.5. Signals: expected
and observed, 12.
31P NMR (202 MHz, CDCl3): d = 85.71.
ESI-HRMS: m/z [M + Na]+ calcd for C11H15NaO3PS3: 344.9819;
ESI-HRMS: m/z [M + Na]+ calcd for C14H12NaO3S2: 315.0126;
found: 315.0122.
found: 344.9823.
Methyl 2-[(4-Nitrophenyl)disulfanyl]benzoate (5f)
Chromatography (CHCl3); yield: 93%; mp 128–130 °C.
Methyl 2-[(5,5-Dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-
yl)disulfanyl]benzoate (4a); Typical Procedure (Method B)
Br2 (1.92 g, 12.0 mmol) was added to a soln of 2 (2.78 g, 14.0 mmol)
in anhyd CH2Cl2 (50 mL) at –30 °C and under N2. After 15 min, a
soln of methyl 2-sulfanylbenzoate (1.85 g, 11 mmol) in anhyd
CH2Cl2 (5 mL) was added. The mixture was stirred at r.t. for 30 min,
diluted with CH2Cl2 (50 mL), washed with H2O (50 mL), dried
(MgSO4), filtered, and evaporated under vacuum. The residue was
purified by column chromatography (silica gel, CH2Cl2–hexane,
1:1); this gave 4a.
1H NMR (200 MHz, CDCl3): d = 4.00 (s, 3 H, OCH3), 7.23–7.35
(m, 1 H, Ar), 7.44–7.66 (m, 3 H, Ar), 7.76–7.84 (m, 1 H, Ar), 8.06–
8.24 (m, 3 H, Ar).
13C NMR (50 MHz, CDCl3): d = 166.8, 145.4, 139.5, 133.3, 131.6,
126.3, 126.1, 126.1, 125.3, 124.4, 124.1, 52.5. Signals: expected
and observed, 12.
ESI-HRMS: m/z [M + Na]+ calcd for C14H11NNaO4S2: 344.0027;
found: 344.0021.
Yield: 3.69 g (92%); white solid; mp 106–108 °C.
4-(Phenyldisulfanyl)toluene (5g)
Compounds 4b–f were prepared similarly from 2, and the yields are
Chromatography (CH2Cl2–hexane, 1:2); yield: 98%; oil.
reported in Table 1.
1H and 13C NMR spectra identical to those reported previously.3,8a
Unsymmetrical Diaryl Disulfides 5 from 4a-e; General Proce-
dure
4-(2-Naphthyldisulfanyl)toluene (5h)
Chromatography (CH2Cl2–hexane, 1:2); yield: 100%; mp 93–
96 °C.
1H NMR (200 MHz, CDCl3): d = 2.32 (s, 3 H, CH3), 7.05–7.16 (m,
2 H, Ar), 7.37–7.55 (m, 4 H, Ar), 7.56–7.66 (m, 1 H, Ar), 7.70–7.86
(m, 3 H, Ar), 7.93–8.00 (m, 1 H, Ar).
13C NMR (50 MHz, CDCl3): d = 129.8, 129.7, 128.9, 128.8, 128.6,
128.5, 127.7, 127.4, 126.6, 126.5, 126.3, 126.2, 126.1, 125.6, 21.0.
Signals: expected and observed, 15.
A soln of the appropriate arenethiol Ar2SH (5.0 mmol) and Et3N
(0.84 mL, 6.0 mmol) in CH2Cl2 (10 mL) was added to a soln of one
of 4a–e (5.25 mmol) in CH2Cl2 (25 mL). After stirring for 15 min at
r.t., the mixture was diluted with CH2Cl2 (50 mL), washed with H2O
(35 mL), dried (MgSO4), filtered, and evaporated under vacuum.
The residue was purified by column chromatography.
Methyl 2-(4-Tolyldisulfanyl)benzoate (5a)
Chromatography (CH2Cl2–hexane, 1:1); yield: 97%; mp 60–62 °C
(Lit.4 59–62 °C).
1H and 13C NMR spectra identical to those reported previously.
ESI-HRMS: m/z [M + H]+ calcd for C17H15S2: 283.0615; found:
283.0623.
4-(4-Tolyldisulfanyl)anisole (5i)
Methyl 2-(Phenyldisulfanyl)benzoate (5b)
Chromatography (CH2Cl2–hexane, 1:2); yield: 86%; mp 53–55 °C
(Lit.3,17 54–55 °C).
1H and 13C NMR spectra identical to those reported previously.
Chromatography (CH2Cl2–hexane, 1:2); yield: 100%; mp 43–45 °C
(Lit.5b 44–45 °C).
1H and 13C NMR spectra identical to those reported previously.
4-(4-Tolyldisulfanyl)phenol (5j)
Chromatography (CH2Cl2–hexane, 1:1); yield: 98%; mp 59–62 °C.
1H NMR (200 MHz, CD3OD): d = 2.33 (s, 3 H, CH3), 6.65–6.80 (m,
2 H, Ar), 7.10–7.40 (m, 2 H, Ar), 7.42–7.82 (m, 4 H, Ar).
13C NMR (50 MHz, CD3OD): d = 159.5, 139.0, 135.4, 133.9, 130.7,
130.6, 127.7, 117.1, 21.1. Signals: expected and observed, 9.
ESI-HRMS: m/z [M + Na]+ calcd for C13H12NaOS2: 271.0227;
found: 271.0223.
Methyl 2-(2-Naphthyldisulfanyl)benzoate (5c)
Chromatography (CH2Cl2–hexane, 1:2); yield: 100%; mp 70–
72 °C.
1H NMR (200 MHz, CDCl3): d = 3.99 (s, 3 H, OCH3), 7.17–7.30
(m, 1 H, Ar), 7.40–7.64 (m, 4 H, Ar), 7.70–7.84 (m, 3 H, Ar), 7.92–
8.10 (m, 3 H, Ar).
13C NMR (50 MHz, CDCl3): d = 166.8, 141.2, 133.5, 133.4, 133.0,
132.3, 131.3, 128.9, 127.7, 127.3, 127.0, 126.7, 126.0, 125.9, 125.5,
124.9, 52.3. Signals: expected, 18; observed, 17.
4-[(4-Nitrophenyl)disulfanyl]toluene (5k)
Chromatography (CHCl3); yield: 100%; mp 61–63 °C (Lit.18 63–
63.5 °C).
ESI-HRMS: m/z [M + Na]+ calcd for C18H14NaO2S2: 349.0333;
found: 349.0337.
1H and 13C NMR spectra identical to those reported previously.
Methyl 2-[(4-Methoxyphenyl)disulfanyl]benzoate (5d)
Chromatography (CH2Cl2–hexane, 1:1); yield: 100%; mp 48–50 °C
(Lit.4 49–50 °C).
1H and 13C NMR spectra identical to those reported previously.
2-(Phenyldisulfanyl)naphthalene (5l)
Chromatography (CHCl3–hexane, 1:1); yield: 96%; mp 88–90 °C.
1H NMR (200 MHz, CDCl3): d = 7.18–7.38 (m, 3 H, Ar), 7.40–7.67
(m, 5 H, Ar), 7.70–7.88 (m, 3 H, Ar), 7.74–8.02 (m, 1 H, Ar).
13C NMR (50 MHz, CDCl3): d = 129.0, 128.9, 128.9, 127.7, 127.5,
127.4, 127.2, 127.1, 126.7, 126.5, 126.2, 126.1, 125.6, 125.4. Sig-
nals: expected and observed, 14.
ESI-HRMS: m/z [M + H]+ calcd for C16H13S2: 269.0459; found:
269.0467.
Methyl 2-[(4-Hydroxyphenyl)disulfanyl]benzoate (5e)
Chromatography (CH2Cl2); yield: 90%; oil.
1H NMR (200 MHz, CDCl3): d = 3.93 (s, 3 H, OCH3), 5.30 (br s, 1
H, OH), 6.70–6.87 (m, 2 H, Ar), 7.15–7.30 (m, 1 H, Ar), 7.30–7.45
(m, 2 H, Ar), 7.47–7.62 (m, 1 H, Ar), 7.95–8.07 (m, 1 H, Ar), 8.11–
8.20 (m, 1 H, Ar).
Synthesis 2008, No. 13, 2033–2038 © Thieme Stuttgart · New York

PAPER
Preparation of Unsymmetrical Diaryl Disulfides
2037
4-(Phenyldisulfanyl)anisole (5m)
1H and 13C NMR spectra identical to those reported previously.
Chromatography (CH2Cl2–hexane, 2:1); yield: 82%; oil.
4-[(4-Nitrophenyl)disulfanyl]phenol (5w)
Chromatography (CHCl3); yield: 100%; mp 117–119 °C (Lit.2b
118–120 °C).
1H and 13C NMR spectra identical to those reported previously.
1H and 13C NMR spectra identical to those reported previously.8b
4-(Phenyldisulfanyl)phenol (5n)
Chromatography (CH2Cl2–hexane, 1:1); yield: 98%; mp 133–
134 °C (Lit.19 134–135 °C).
Unsymmetrical Diaryl Disulfides 5 from 4f; Typical Procedure
Et3N (0.84 mL, 6.0 mmol) was added to a soln of 4f (1.69 g, 5.25
mmol) and the appropriate arenethiol Ar2SH (5.0 mmol) in CH2Cl2
(35 mL). After stirring for 15 min at r.t., the mixture was diluted
with CH2Cl2 (50 mL), washed with H2O (35 mL), dried (MgSO4),
filtered, and evaporated under vacuum. The residue was purified by
column chromatography; this gave 5e, 5j, 5n, 5r, 5t, or 5w (see
Table 2 for yields).
1H and 13C NMR spectra identical to those reported previously.
1-Nitro-4-(phenyldisulfanyl)benzene (5o)
Chromatography (CHCl3); yield: 100%; mp 57–59 °C (Lit.20 58–
59 °C).
1H and 13C NMR spectra identical to those reported previously.
4-(2-Naphthyldisulfanyl)anisole (5p)
Chromatography (CH2Cl2–hexane, 1:3); yield: 92%; mp 116–
118 °C.
1H NMR (200 MHz, CDCl3): d = 3.78 (s, 3 H, OCH3), 6.77–6.87
(m, 2 H, Ar), 7.38–7.52 (m, 4 H, Ar), 7.58–7.66 (m, 1 H, Ar), 7.70–
7.86 (m, 3 H, Ar), 7.92–7.98 (m, 1 H, Ar).
Acknowledgment
We gratefully acknowledge the Polish Ministry of Science and
Higher Education for financial support (grant no N N204 4511 33).
13C NMR (50 MHz, CDCl3): d = 159.8, 132.6, 132.0, 128.8, 127.7,
127.4, 126.9, 126.7, 126.6, 126.5, 126.1, 114.7, 114.6, 55.3. Sig-
nals: expected, 15; observed, 14.
ESI-HRMS: m/z [M + Na]+ calcd for C17H14NaOS2: 321.0384;
found: 321.0390.
References
(1) (a) Cremlyn, R.; An, J. Introduction to Organosulfur
Chemistry; Wiley: New York, 1996. (b) Organic Sulfur
Chemistry: Structure and Mechanism; Oae, S., Ed.; CRC
Press: Boca Raton FL, 1991. (c) Vruhula, V. M.;
MacMaster, J. F.; Zhengong, L.; Kerr, D. E.; Senter, P. D.
Bioorg. Med. Chem. Lett. 2002, 12, 3591. (d) Mu, Y.;
Nodwell, M.; Pace, J. L.; Shaw, J. P.; Judice, J. K. Bioorg.
Med. Chem. Lett. 2004, 14, 735.
(2) (a) Field, L.; Banks, C. H. J. Org. Chem. 1975, 40, 2774.
(b) Oae, S.; Yoshihara, M. Bull. Chem. Soc. Jpn. 1968, 41,
2082.
(3) Bao, M.; Shimizu, M. Tetrahedron 2003, 59, 9655.
(4) Hunter, R.; Caira, M.; Stellenboom, N. J. Org. Chem. 2006,
71, 8268.
4-(2-Naphthyldisulfanyl)phenol (5r)
Chromatography (CH2Cl2–hexane, 1:3, then 1:0); yield: 84%; mp
110–112 °C.
1H NMR (200 MHz, CDCl3): d = 4.75 (br s, 1 H, OH), 6.70–6.82
(m, 2 H, Ar), 7.31–7.56 (m, 4 H, Ar), 7.58–7.67 (m, 1 H, Ar), 7.70–
7.88 (m, 3 H, Ar), 7.92–8.02 (m, 1 H, Ar).
13C NMR (50 MHz, CDCl3): d = 155.8, 132.2, 129.0, 127.7, 127.4,
126.7, 126.7, 126.6, 126.2, 126.2, 125.6, 116.2, 116.1. Signals: ex-
pected, 14; observed, 13.
ESI-HRMS: m/z [M + Na]+ calcd for C16H12NaOS2: 307.0227;
found: 307.0221.
(5) (a) Capozzi, G.; Menichetti, S.; Rosi, A. J. Chem. Soc.,
Perkin Trans. 2 1992, 2247. (b) Caputo, R.; Ferreri, C.;
Palumbo, G. Tetrahedron 1986, 42, 5377. (c) Capozzi, G.;
Capperucci, A.; Degl’Inocenti, A.; Duce, R. D.; Menichetti,
S. Gazz. Chim. Ital. 1990, 120, 421.
(6) Benati, L.; Montevecchi, P. C.; Spagnolo, P. Tetrahedron
Lett. 1986, 27, 1739.
(7) Oae, S.; Togo, H.; Numata, T.; Fujimori, K. Chem. Lett.
1980, 1193.
(8) (a) Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc. 2003,
125, 6624. (b) Tanaka, K.; Ajiki, K. Tetrahedron Lett. 2004,
45, 5677.
1-(2-Naphthyldisulfanyl)-4-nitrobenzene (5s)
Chromatography (CHCl3); yield: 98%; mp 78–80 °C.
1H NMR (200 MHz, CDCl3): d = 7.43–7.60 (m, 3 H, Ar), 7.64–7.78
(m, 5 H, Ar), 7.92–7.98 (m, 1 H, Ar), 8.10–8.22 (m, 2H, Ar).
13C NMR (50 MHz, CDCl3): d = 146.1, 133.4, 132.6, 132.4, 129.4,
127.8, 127.4, 127.0, 126.8, 126.7, 126.2, 125.3, 124.1. Signals: ex-
pected, 14; observed, 13.
ESI-HRMS: m/z [M + Na]+ calcd for C16H11NNaO2S2: 336.0129;
found: 336.0137.
(9) Harpp, D. N.; Smith, R. A. J. Am. Chem. Soc. 1982, 104,
6045.
(10) (a) Prabhu, K. R.; Devan, N.; Chandrasekaran, S. Synlett
2002, 1762. (b) Prabhu, K. R.; Sivanand, P. S.;
Chandrasekaran, S. Angew. Chem. Int. Ed. 2000, 39, 4316.
(11) Sudharsanam, R.; Chandrasekaran, S.; Das, P. K. J. Mater.
Chem. 2002, 12, 2904.
(12) Antoniow, S.; Witt, D. Synthesis 2007, 363.
(13) Kowalczyk, J.; Barski, P.; Witt, D.; Grzybowski, B. A.
Langmuir 2007, 23, 2318.
4-[(4-Methoxyphenyl)disulfanyl]phenol (5t)
Chromatography (CH2Cl2); yield: 87%; mp 128–130 °C.
1H NMR (200 MHz, CDCl3): d = 3.81 (s, 3 H, OCH3), 4.96 (br s, 1
H, OH), 6.68–6.92 (m, 4 H, Ar), 7.30–7.55 (m, 4 H, Ar).
13C NMR (50 MHz, CDCl3): d = 159.7, 155.8, 133.9, 133.6, 132.8,
132.6, 116.1, 114.6, 55.4. Signals: expected and observed, 9.
ESI-HRMS: m/z [M + Na]+ calcd for C13H12NaO2S2: 287.0176;
found: 287.0168.
(14) Szymelfejnik, M.; Demkowicz, S.; Rachon, J.; Witt, D.
Synthesis 2007, 3528.
(15) Edmundson, R. S. Tetrahedron 1965, 21, 2379.
(16) Sukanta, K.; Omair, K.; Hongming, Z.; Edward, B. Synth.
Commun. 2006, 36, 1419.
4-[(4-Nitrophenyl)disulfanyl]anisole (5u)
Chromatography (CHCl3); yield: 93%; mp 69–71 °C (Lit.21 67–
68 °C).
Synthesis 2008, No. 13, 2033–2038 © Thieme Stuttgart · New York

2038
S. Demkowicz et al.
PAPER
(17) Modena, T.; Pavanetto, F.; Montanari, L.; Mazza, M.; Conti,
B. Farmaco, Ed. Sci. 1985, 40, 803.
(18) Campaigne, E.; Tsurugi, J.; Meyer, W. W. J. Org. Chem.
1961, 26, 2486.
(19) Stepanov, B. I.; Robinov, V. A.; Chibisova, T. A.; Yagobina,
L. A.; Stankevich, A. D. J. Org. Chem. USSR 1977, 13, 334.
(20) Mukaiyama, T.; Takahashi, K. Tetrahedron Lett. 1968,
5907.
(21) Oae, I. Tetrahedron Lett. 1968, 3791.
Synthesis 2008, No. 13, 2033–2038 © Thieme Stuttgart · New York