Novel and efficient synthesis of unsymmetrical trisulfides

Article abstract of DOI:10.1055/s-0030-1259033

We have developed a convenient method for the synthesis of unsymmetrical trisulfides under mild conditions in very good yields. The designed method is based on the straightforward preparation of 1-[(5,5-dimethyl-2-thioxo-1,3,2- dioxaphosphorinan-2-yl)trisulfanyl]dodecane from readily available 5,5-dimethyl-2-sulfanyl-2-thioxo-1,3,2-dioxaphosphorinane, sulfur dichloride (SCl₂) and dodecane-1-thiol. The unsymmetrical trisulfides can be obtained from aliphatic, aromatic thiols and l-cysteine derivatives as well. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259033

LETTER
2857
Novel and Efficient Synthesis of Unsymmetrical Trisulfides
N
ovel and Eff
l
icient
S
a
ynthesis of
w
U
nsymmetrical
T
o
risulfides mir Lach, Magdalena Sliwka-Kaszynska, Dariusz Witt*
Department of Organic Chemistry, Chemical Faculty, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland
Fax +48(58)3472694; E-mail: dwitt@chem.pg.gda.pl
Received 9 August 2010
Although the preparation of symmetrical, acyclic trisul-
Abstract: We have developed a convenient method for the synthe-
fides is well documented,17 the synthesis of unsymmetri-
cal trisulfides is more complex. There are known
sis of unsymmetrical trisulfides under mild conditions in very good
yields. The designed method is based on the straightforward prepa-
ration of 1-[(5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-
procedures based on the coupling of chlorodisulfides with
yl)trisulfanyl]dodecane from readily available 5,5-dimethyl-2-sul- N-arylamidothiosulfites18 or thiols19,20 or the sequential
coupling of two thiols using sulfur dichloride.21 Other
fanyl-2-thioxo-1,3,2-dioxaphosphorinane, sulfur dichloride (SCl2)
and dodecane-1-thiol. The unsymmetrical trisulfides can be ob-
procedures involve the desulfurization of unsymmetrical
tained from aliphatic, aromatic thiols and L-cysteine derivatives as
dialkanesulfonic thioanhydrides,11 or the use of (often)
well.
unstable hydrodisulfides.22
Key words: unsymmetrical trisulfides, sulfur dichloride, thiols,
Most of the above methods suffer from either moderate
yields or the formation of undesirable polysulfide side
products. The removal of these impurities in most cases is
not possible. The best method of purification is crystalli-
zation, but clearly this can only be applied to solid trisul-
fides. Other methods require the multistep synthesis of
appropriate precursors or using freshly distilled sulfur
dichloride.5 Additionally, various functional groups are
not compatible with the reagents and reaction conditions.
L-cysteine, phosphorodithioic acid
Organic polysulfides have attracted significant interest
during the past years, initially because of their interesting
physical properties and potential for synthetic utility.
More recently, several unprecedented classes of biologi-
cally active natural products containing polysulfide func-
tionality have been discovered. Varacin the first naturally
occurring compound determined to contain the 1,2,3,4,5-
pentathiepin ring system, was isolated from a marine as-
cidian and exhibited significant antifungal and cytotoxic
activities. It was as much as 100 times more potent than 5-
fluorouracil toward the human colon cancer cell line HCT
116. The synthesis, reactivity, and biological activity of
pentathiepins has been recently reviewed by Rakitin and
Rees.1 The trisulfide functionality is found in the tumor
inhibitors calicheamicin2 and esperamicin,3 members of
the enediyne group of antibiotics. The trisulfide function-
ality is also observed in lissoclinotoxin A.4
We have previously demonstrated the preparation func-
tionalized unsymmetrical molecules, such as dialkyl dis-
ulfides, alkyl-aryl disulfides,23 ‘bioresistant’ disulfides,24
unsymmetrical disulfides based on L-cysteine and L-cys-
tine derivatives,25 and diaryl disulfides.26 The excellent re-
sults encouraged us to extend the strategy to the
preparation of symmetrical trisulfides based on the readily
available 5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphori-
nane-2-disulfanyl derivatives.27
We report a modification our latest extension of the strat-
egy for preparation of unsymmetrical trisulfides. The
treatment of a mixture of 5,5-dimethyl-2-sulfanyl-2-
thioxo-1,3,2-dioxaphosphorinane (1)28 and dodecane-1-
thiol with sulfur dichloride SCl2 at –30 °C afforded 1-
[(5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)-
trisulfanyl]dodecane (2) in 68% yield after column chro-
matography (Scheme 1).
The most common methods for obtaining symmetrical
trisulfides include the reaction of thiols with sulfur dichlo-
ride,5 the coupling of alkyl halides with sodium trisulfide,6
and the reaction of thiols or disulfides with sulfur.7 Thio-
alkylation of various thiosulfenate species can also pro-
duce trisulfides. The most suitable substrates include
Bunte salts,8 metal sulfides,9 and thiosulfenyl chloride.10
The latter can also be used for preparation of unsymmet-
rical trisulfides. Other procedures involve the reduction of
thiosulfonates and disulfonyl sulfides with phosphines,11
sulfur insertion reactions into thiosulfinates, thiosul-
fonates,12 and disulfides,13 alkoxide decomposition of
sulfenylthiocarbonates,14 and reactions of thiols with 1,1¢-
thiobis(benzimidazole)15 or diimidazolylsulfide.16
O
S
P
HS
SH
O
1
SCl2 CH2Cl2, –30 °C
O
S
S
P
S
S
O
2
Scheme 1 The preparation of 1-[(5,5-dimethyl-2-thioxo-1,3,2-
dioxaphosphorinan-2-yl)trisulfanyl]dodecane (2)
SYNLETT 2010, No. 19, pp 2857–2860
Advanced online publication: 10.11.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1259033; Art ID: D21710ST
© Georg Thieme Verlag Stuttgart · New York

2858
S. Lach et al.
LETTER
The preparation of a wider range of trisulfanyl derivatives
2 is limited by the use of sulfur dichloride. The presence
of olefinic, hydroxylic, or aminoaryl groups in the appro-
priate thiol structure led to side reactions. We also ob-
served that benzenethiol under the above conditions
provided a mixture of trisulfanyl and disulfanyl deriva-
tives in 85% and 15% yield, respectively. These com-
pounds could not be separated and further exposure of the
mixture to light caused decomposition of the (5,5-dimethyl-
2-thioxo-1,3,2-dioxaphosphorinan-2-yl)trisulfanylbenzene,
forming polysulfides.
Table 1 Synthesis of Unsymmetrical Trisulfides 3
O
S
S
P
S
S
O
2
CH2Cl2, Et3N, r.t., 15 min
R
SH
R
S
S
S
3
Entry
R
Product
3a
Yield (%)
The reaction of trisulfide 2 with one equivalent of 11-sul-
fanylundecanol and one equivalent of Et3N afforded a
complex mixture of products, the formation of symmetri-
cal and unsymmetrical di- and trisulfides being observed.
It is known that the preparation of polysulfides is fre-
quently hampered by the formation of their homologues
with a variable number of sulfur atoms.20 The purification
of such mixture is at best difficult and in most cases im-
possible due to similar properties of the products. We
were interested in finding a new clean approach to the
synthesis of the trisulfide functionality, so the above reac-
tion was repeated and 1.1 equivalents of 2 were treated
with 1.0 equivalent of 11-sulfanylundecanol and 1.1
equivalents of Et3N. When a small excess of reagent 2 was
used the only isolated product was unsymmetrical trisul-
fide 3b in 99% yield (Table 1, entry 2). These observa-
tions show that unsymmetrical trisulfide 3b is formed
very rapidly from 11-sulfanylundecanol and compound 2,
and that further exchange takes place in the presence of
thiolate anion. The influence of the thiolate anion on the
exchange reaction and extrusion of sulfur was confirmed
by treatment of isolated unsymmetrical trisulfide 3b with
11-sulfanylundecanol (5 mol%) in the presence of trieth-
ylamine. After 15 minutes a mixture of symmetrical and
unsymmetrical di- and trisulfides was observed (con-
1
2
3
4
5
6
7
8
9
(CH2)11NHBoc
(CH2)11OH
99
99
86
75
97
90
99
98
99
3b
(CH2)10CO2H
(CH2)10CO2Me
(R)-CH2CH(NH2)CO2Et
(R)-CH2CH(NHAc)CO2H
Ph
3c
3d
3e
3f
3g
4-MeOC6H4
3h
2-naphthyl
3i
compounds afforded, after purification, unsymmetrical
trisulfides 3 in excellent yield (Table 1). The presence of
electron-withdrawing and electron-donating groups or un-
protected hydroxy, carboxy, and amino groups did not af-
fect the formation of unsymmetrical trisulfides 3. The
success of the method depends on the very fast formation
of 3 from 2 and thiolates so that further exchange and sul-
fur extrusion reactions can be avoided. The versatility of
the method is limited by the availability of the trisulfanyl
derivatives 2 wherein the olefinic, hydroxy, or aromatic
groups cause side reactions (Scheme 2).
1
firmed by TLC and H NMR).Therefore, unsymmetrical
trisulfides 3 need to be prepared in the presence of excess
of reagent 2 to avoid formation of symmetrical products
and homologues.
O
O
S
S
Et3N
P
S
(CH2)11Me
R
S
+
Subsequent treatment of trisulfanyl derivative 2 with a va-
riety of thiols provided the corresponding unsymmetrical
trisulfides 3a–i, which could be isolated in very good
yields (Table 1, entries 1–9). These compounds are stable
at room temperature in the darkness for several weeks; de-
composition by moisture or formation of symmetrical
products was not observed. However, exposure to the day-
light at room temperature for extended times resulted in
the extrusion of the sulfur and formation of a mixture of
the corresponding disulfides and trisulfides. This process
was most rapid for aromatic trisulfides 3g–i; whereas for
aliphatic compounds and L-cysteine derivatives extrusion
of sulfur was very slow.
We selected thiols bearing tert-butoxycarbonylamino,29
hydroxy, carboxy, methyl ester,30 aromatic functional-
ities, L-cysteine ethyl ester, and N-acetyl-L-cysteine to ex-
amine the scope and limitations of this method for the
preparation of unsymmetrical trisulfides 3. All the above
R
SH
S
2
O
S
S
R
S
(CH2)11Me
P
S
S
+
O
3
Scheme 2 Plausible reaction mechanism
Further studies on the exact details of the reaction mecha-
nism are now under investigation.
In conclusion, we have achieved the synthesis of pure un-
symmetrical trisulfides. These compounds can be ob-
tained from aliphatic, aromatic thiols, and L-cysteine
derivatives. The presence of functional groups such as
amino, hydroxy, or carboxy did not disrupt the course of
the reaction. The advantages of this new method are the
Synlett 2010, No. 19, 2857–2860 © Thieme Stuttgart · New York

LETTER
Novel and Efficient Synthesis of Unsymmetrical Trisulfides
2859
39.2, 38.9, 34.0, 31.9, 29.6, 29.6, 29.5, 29.3, 29.2, 29.1, 29.0, 28.8,
28.7, 28.5, 24.6, 22.7, 14.1. Signals: 23 expected; 18 observed. ESI-
HRMS: m/z [M + Na]+ calcd for C23H46NaO2S3: 473.2558; found:
473.2553.
readily accessible starting materials, convenient manipu-
lation, short reaction times, very high purities, and high
yields. From this point of view, the method presented
above for the synthesis of unsymmetrical trisulfides
seems to be currently one of the most versatile and conve-
nient approaches to preparation of functionalized trisul-
fides. The limitation in the preparation of trisulfanyl
derivatives 2 has encouraged us to develop two new syn-
thetic strategies for the preparation of unsymmetrical
trisulfides bearing the additional functionalities at both
sides. These results will be reported in due course.
Ethyl (R)-2-Amino-3-(dodec-1-yl-trisulfanyl)-propanoate (3e)
Chromatography (CH2Cl2–MeOH, 25:1); yield: 97%; yellow oil.
20
[a]D +10 (c 1.0, CHCl3). IR (film): n = 3382 (w, NH), 3315 (w,
NH), 2924 (s), 2853 (s), 1738 (m, C=O), 1597 (w, NH), 1375 (w,
CH3), 1183 (m), 722 (w, CH2) cm–1.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.4 Hz, 3 H, CH3),
1.26–1.38 (m, 21 H, CH2, OCCH3), 1.70–1.74 (m, 2 H, SCCH2),
2.41 (br s, 2 H, NH2), 2.89 (t, J = 7.2 Hz, 2 H, SCH2), 3.10 (dd,
J = 13.9, 7.5 Hz, 1 H, SCH), 3.32 (dd, J = 17.7, 4.4 Hz, 1 H, SCH),
3.85–3.95 (m, 1 H, NCH), 4.22 (q, J = 7.1 Hz, 2 H, OCH2). 13C
NMR (50 MHz, CDCl3): d = 173.3, 61.3, 53.2, 43.6, 38.8, 31.8,
29.5, 28.4, 22.6, 14.1. Signals: 17 expected; 10 observed. ESI-
HRMS: m/z [M + H]+ calcd for C17H36NO2S3: 382.1908; found:
382.1902.
1-[(5,5-Dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)trisul-
fanyl]dodecane (2)
Sulfur dichloride (2.573 g, 25.0 mmol) was added dropwise to a
soution of 1 (4.956 g, 25.0 mmol) and 1-dodecanethiol (5.06 g,
24.95 mmol) in anhyd CH2Cl2 (50 mL) at –30 °C under N2. The
mixture was allowed to warm to r.t. and evaporated under reduced
pressure. The residue was purified by column chromatography (sil-
ica gel, PE–CH2Cl2, 2:1) and yielded compound 2.
(Dodec-1-yl-trisulfanyl)benzene (3g)
Chromatography (PE); yield: 99%; yellow oil. IR (film): n = 2923
(s), 2852 (s), 1581, (w, C=C), 1464 (m, C=C), 1376 (w, CH3), 738
(m, CH2) cm–1. 1H NMR (200 MHz, CDCl3): d = 0.91 (t, J = 6.8 Hz,
3 H, CH3), 1.28–1.37 (m, 18 H, CH2), 1.69 (quin, J = 7.3 Hz, 2 H,
S-C-CH2), 2.84 (t, J = 7.3 Hz, 2 H, SCH2), 7.33–7.65 (m, 5 H, Ph).
13C NMR (50 MHz, CDCl3): d = 137.6, 130.6, 129.5, 128.5, 39.5,
32.4, 30.1, 30.1, 30.0, 29.9, 29.6, 29.4, 29.3, 29.0, 23.2, 14.6. Sig-
nals: 18 expected; 16 observed. ESI-HRMS: m/z [M + Na]+ calcd
for C18H30NaS3: 365.1407; found: 365.1412.
Yield: 7.1 g (66%); white solid; mp 36–40 °C. IR (KBr): n = 2970
(m), 2916 (s), 2847 (w, CH), 1043 (s), 987 (s, POC), 683 (s, P=S)
1
cm–1. H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 6.8 Hz, 3 H,
CH3), 1.04 (s, 3 H, CH3), 1.27–1.32 (m, 19 H,CH2, CH3), 1.39–1.43
(m, 2 H, CH2), 1.77 (quin, J = 7.3 Hz, SCCH2, 2 H), 3.01 (t, J = 7.3
Hz, PSSCH2, 2 H), 4.09 (dd, J = 20.0, 4.1 Hz, POCH, 2 H), 4.21 (t,
J = 10.0 Hz, POCH, 2 H). 13C NMR (125 MHz, CDCl3): d = 77.5
(d, 2JP–C = 8.9 Hz), 39.9, 33.0 (d, 3JP–C = 7.2 Hz), 31.8, 29.5, 29.5,
29.4, 29.2, 29.1, 28.6, 22.6, 22.0, 14.0. Signals: 17 expected; 13 ob-
served. 31P NMR (202 MHz, CDCl3): d = 84.81. ESI-HRMS: m/z
[M + Na]+ calcd for C17H35NaO2PS4: 453.1155; found: 453.1161.
Acknowledgment
We gratefully acknowledge the Polish Ministry of Science and
Higher Education for financial support.
Typical Procedure for Trisulfide Preparation
A solution of the appropriate thiol (1.0 mmol) in CH2Cl2 (10 mL)
was added to a solution of 2 (0.473 g, 1.1 mmol) and Et3N (0.153 References
mL, 1.1mmol) in CH2Cl2 (10 mL) at r.t. under an air atmosphere.
(1) Konstantinova, L. S.; Rakitin, O. A.; Rees, C. W. Chem. Rev.
The mixture was stirred for 15 min and evaporated under reduced
pressure. The residue was purified by column chromatography. Ad-
dition of a small amount of AcOH prior to purification on silica gel
column inhibited sulfur extrusion during separation.
2004, 104, 2617.
(2) Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama,
K.; Pitsinos, E. N.; Saimoto, H.; Mizuno, Y.; Baldenius,
K.-U.; Smith, A. L. J. Am. Chem. Soc. 1993, 115, 7625.
(3) Kumar, R. A.; Ikemoto, N.; Patel, D. J. J. Mol. Biol. 1997,
265, 173.
Representative Analytical Data
(4) Litaudon, M.; Guyot, M. Tetrahedron Lett. 1991, 32, 911.
(5) (a) Zysman-Colman, E.; Harpp, D. N. J. Org. Chem. 2003,
68, 2487. (b) Clayton, J. O.; Etzler, D. H. J. Chem. Soc.
1974, 69, 974.
(6) Fuson, R. C.; Price, C. C.; Burness, D. M.; Foster, R. E.;
Hatchard, W. R.; Lipscomb, R. D. J. Org. Chem. 1946, 11,
487.
(7) Sato, R.; Saito, S.; Chiba, H.; Goto, T.; Saito, M. Chem. Lett.
1986, 349.
(8) Schimmelschmidt, K.; Hoffmann, H.; Mundlos, E. Chem.
N-(tert-Butoxycarbonyl)-11-(dodec-1-yl-trisulfanyl)-1-undecyl-
amine (3a)
Chromatography (PE–CH2Cl2, 1:1); yield: 99%; white solid; mp
32–34 °C. IR (KBr): n = 3381 (m, NH), 2919 (s), 2849 (s, CH),
1682 (s, C=O), 1638 (m, NH), 1170 (m, CN), 720 (w, CH2) cm–1.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 6.3 Hz, 3 H, CH3),
1.20–1.44 (m, 34 H, CH2), 1.46 (s, 9 H, t-Bu), 1.66–1.76 (m, 4 H,
SCCH2), 2.87 (t, J = 7.3 Hz, 4 H, SCH2), 3.11 (m, 2 H, NCH2), 4.46
(s, 1 H, NH). 13C NMR (50 MHz, CDCl3): d = 155.9, 78.9, 40.7,
39.2, 38.9, 31.9, 30.0, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0, 28.8,
28.5, 28.4, 26.8, 22.7, 14.1. Signals: 28 expected; 20 observed. ESI-
HRMS: m/z [M + Na]+ calcd for C28H57NNaO2S3: 558.3449; found:
558.3452.
Ber. 1963, 96, 38.
(9) Buckman, J. D.; Field, L. J. Org. Chem. 1967, 32, 2.
(10) Mott, A. W.; Barany, G. Synthesis 1984, 657.
(11) Hayashi, S.; Furukawa, M.; Yamamoto, J.; Hamamura, K.
Chem. Pharm. Bull. 1967, 15, 1310.
(12) Capozzi, G.; Capperucci, A.; Degl’Innocenti, A.; Del Duce,
R.; Menichetti, S. Tetrahedron Lett. 1989, 30, 2991.
(13) (a) Arisawa, M.; Tanaka, K.; Yamaguchi, M. Tetrahedron
Lett. 2005, 46, 4797. (b) Hou, Y.; Abu-Yousef, I. A.;
Doung, Y.; Harpp, D. N. Tetrahedron Lett. 2001, 42, 8607.
(14) Harpp, D. N.; Granata, A. Tetrahedron Lett. 1976, 3001.
11-(Dodec-1-yl-trisulfanyl)undecanoic Acid (3c)
Chromatography (CH2Cl2); yield: 86%; white solid; mp 43–46 °C.
IR (KBr): n = 3413 (m, OH), 2919 (s), 2848 (s), 1893 (m, C=O),
738 (w, CH2) cm–1. 1H NMR (200 MHz, CDCl3): d = 0.90 (t, J = 6.6
Hz, 3 H, CH3), 1.23–1.42 (m, 30 H, CH2), 1.66 (m, 2 H, CH2), 1.76
(m, 5 H, CH2, COOH), 2.37 (t, J = 7.3 Hz, 2 H, CH2COO), 2.89 (t,
J = 7.3 Hz, 4 H, SCH2). 13C NMR (50 MHz, CDCl3): d = 180.0,
Synlett 2010, No. 19, 2857–2860 © Thieme Stuttgart · New York

2860
S. Lach et al.
LETTER
(15) Wu, Z.; Back, T. G.; Ahmad, R.; Yamdagni, R.; Amstrong,
D. A. J. Phys. Chem. 1982, 86, 4417.
(16) An, H.; Zhu, J.; Wang, X.; Xu, X. Bioorg. Med. Chem. Lett.
2006, 16, 4826.
(23) Antoniow, S.; Witt, D. Synthesis 2007, 363.
(24) Kowalczyk, J.; Barski, P.; Witt, D.; Grzybowski, B. A.
Langmuir 2007, 23, 2318.
(25) Szymelfejnik, M.; Demkowicz, S.; Rachon, J.; Witt, D.
(17) Schöberl, A.; Wagner, A. In Methoden der Organischen
Chemie (Houben-Weyl), 4th ed., Vol. 9; Müller, E., Ed.;
Thieme: Stuttgart, 1955, 87.
(18) Nakabayashi, T.; Tsurugi, J. J. Org. Chem. 1961, 26, 2482.
(19) Böhme, H.; Van Ham, G. Justus Liebigs Ann. Chem. 1958,
617, 62.
(20) Abu-Yousef, I. A.; Rys, A. Z.; Harpp, D. N. J. Sulfur Chem.
2006, 27, 15.
(21) Harpp, D. N.; Derbesy, G. Tetrahedron Lett. 1994, 35, 5381.
Synthesis 2007, 3528.
(26) Demkowicz, S.; Rachon, J.; Witt, D. Synthesis 2008, 2033.
(27) Kertmen, A.; Lach, S.; Rachon, J.; Witt, D. Synthesis 2009,
1459.
(28) Edmundson, R. S. Tetrahedron 1965, 21, 2379.
(29) Ng, S. C.; Sun, T.; Chan, H. S. O. Tetrahedron Lett. 2002,
43, 2863.
(30) Koenig, N. H.; Sasin, G. S.; Swern, D. J. Org. Chem. 1958,
23, 1525.
(22) Kresze, G.; Patzscheke, J. Chem. Ber. 1960, 93, 380.
Synlett 2010, No. 19, 2857–2860 © Thieme Stuttgart · New York