Efficient synthesis of functionalized unsymmetrical dialkyl trisulfanes

Article abstract of DOI:10.1055/s-0033-1338966

We have developed a convenient method for the synthesis of functionalized unsymmetrical dialkyl trisulfanes under mild conditions in very good yields. The designed method is based on the reaction of (5,5-dimethyl-2-thioxo-1,3,2- dioxaphosphorinan-2-yl)-di

Full text of DOI:10.1055/s-0033-1338966

LETTER
▌1927
letter
Efficient Synthesis of Functionalized Unsymmetrical Dialkyl Trisulfanes
Functionalized Unsymmetrical Dialkyl Trisulfanes
Slawomir Lach, 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: 22.05.2013; Accepted after revision: 27.06.2013
alkylation reactions of various thiosulfenate species can
also produce trisulfanes. The most suitable substrates in-
clude Bunte salts,21 metal sulfides,22 and thiosulfenyl
chloride.23 The latter can also be used for the preparation
Abstract: We have developed a convenient method for the synthe-
sis of functionalized unsymmetrical dialkyl trisulfanes under mild
conditions in very good yields. The designed method is based on the
reaction of (5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)-
disulfanyl derivatives with alkyl disulfanyl anions generated in situ of unsymmetrical trisulfanes. Other practical procedures
from S-acetyl disulfanyl derivatives and sodium methoxide. The de-
veloped method allows for the preparation of unsymmetrical tri-
sulfanes bearing additional hydroxyl, carboxyl, or amino
thiosulfinates, thiosulfonates,25 and disulfanes,26 alkoxide
functionalities on both sides of the trisulfane functionality.
involve the reduction of thiosulfonates and disulfonyl sul-
fides with phosphines,24 sulfur insertion reactions into
decomposition of sulfenylthiocarbonates,27 and reactions
of thiols with 1,1-thiobis(benzimidazole)28 or diimidazol-
Key words: unsymmetrical trisulfanes, thiols, hydrodisulfanes,
S-acetyl alkyldisulfanes, phosphorodithioic acid
ylsulfide.29
Preparative methods that are efficient for the preparation
of symmetrical trisulfanes are very often ineffective for
Our interest in the chemistry of diorganyl trisulfanes (tri-
the preparation of unsymmetrical compounds. Indeed, the
sulfides) arises from their diverse roles in living organ-
synthesis of unsymmetrical trisulfanes is more complex.
isms and their occurrence in natural sources.1,2 In the
There are known procedures based on the coupling of
literature, these compounds are often termed as organic
trisulfides, but the IUPAC recommended nomenclature is
chlorodisulfanes with N-arylamidothiosulfites30 or
thiols31,32 or the sequential coupling of two thiols using
trisulfanes.3 The name trisulfide should only be applied to
sulfur dichloride.33 Other procedures involve the desulfur-
ionic compounds, such as Na2S3. Organic trisulfanes have
ization of unsymmetrical dialkanesulfonic thioanhy-
been isolated from shiitake mushrooms,4 oil made
drides,24 or the use of (often) unstable hydrodisulfanes.34
from erula asafetida,5 durian fruit,6 garlic oil,7,8 and Ha-
waiian algae.9 It also should be mentioned that dialanyltri-
sulfane has been detected in acidic wool hydrolysates, but
it is not clear whether the related amino acid
(HOOCCH(NH2)CH2)S3 is a part of the wool structure or
is formed from cysteine during hydrolysis.10 In the bio-
chemical literature, dialanyltrisulfane is often incorrectly
termed as ‘cysteine trisulfide’. A natural peptide contain-
ing a trisulfane group in place of a disulfane bridge has
been isolated from genetically engineered Escherichia
coli bacteria.11 It is a derivative of the human growth hor-
mone consisting of 191 amino acids in a single chain with
a trisulfane bridge between cysteine (alanyl) residues 182
and 189.12 A trisulfanyl functionality has also been ob-
served in recombinant DNA-derived methionyl human
growth hormone in the bridge between cysteine residues
53 and 165.13 Calicheamicin14,15 and esperamicins A1 and
A2,16,17 members of the enediyne class of antibiotics, also
contain the trisulfanyl functionality. These natural prod-
ucts are very potent antitumor antibiotics.
Moderate yields and/or the formation of undesirable poly-
sulfane side products are the major drawbacks of the
methods presented above. The likelihood that pure trisul-
fanes can be separated from the reaction mixture is very
poor. The best purification method is crystallization, but
clearly this can only be applied to solid products. More-
over, the scopes of the presented methods are limited by
the availability of reagents and the chemical reactivity of
the additional functional groups.
We have previously demonstrated the preparation of func-
tionalized unsymmetrical molecules such as dialkyl disul-
fanes, alkyl-aryl disulfanes,35 ‘bioresistant’ disulfanes,36
unsymmetrical disulfanes of L-cysteine and L-cystine,37
and diaryl disulfanes38 based on the readily available 5,5-
dimethyl-2-thioxo-1,3,2-dioxaphosphorinane-2-disulfa-
nyl derivatives 1. These disulfanyl derivatives 1 of phos-
phorodithioic acid were also convenient for the
preparation of α-sulfenylated carbonyl compounds39 and
symmetrical trisulfanes.40
There are numerous reactions that can be used to prepare
symmetrical organic trisulfanes. The most common meth-
ods include the reaction of thiols with sulfur dichloride,18
the coupling of alkyl halides with sodium trisulfide,19 and
the reaction of thiols or disulfanes with sulfur.20 Thio-
The limitations of our previous method for the preparation
of unsymmetrical trisulfanes41 have encouraged us to de-
velop a new synthetic strategy for the preparation of un-
symmetrical trisulfanes bearing additional functionalities
on either side of the trisulfane. The idea is based on the re-
action of electrophilic disulfanyl derivatives of phospho-
SYNLETT 21709013, 2415, 1927–1930
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DOI: 10.1055/s-0033-1338966; Art ID: ST-2013-D0472-L
© Georg Thieme Verlag Stuttgart · New York

1928
S. Lach, D. Witt
LETTER
rodithioic acid 1 with a nucleophilic dodecyldisulfanyl
anion generated in situ from S-acetyl dodecyldisulfane
(2a) and sodium methoxide (Table 1).
Table 2 Preparation of S-Acetyl Alkyldisulfanes 2
O
O
S
S
AcSK (1.05 equiv)
MeOH, r.t., 30 min
P
S
S
S
R
R
O
Table 1 Formation of Unsymmetrical Trisulfanes 3 from S-Acetyl
Dodecyldisulfane (2a)
2
1
Entry
R
2
Yield (%)
O
O
S
S
P
S
S
S
(CH2)11Me
R
1
2
3
4
(CH2)11Me
(CH2)11OH
2a
2b
2c
2d
99
80
87
91
O
2a
1
MeONa (2 equiv)
MeOH, 0 °C
r.t., 15 min
(CH2)10CO2H
(CH2)11NHBoc
S
S
R
S
(CH2)11Me
3
We selected disulfanyl derivatives 1 and S-acetyl alkyldi-
sulfanes 2 bearing hydroxy, carboxy, methyl ester, tert-
butoxycarbonylamino, and phenyl functionalities to ex-
amine the scope and limitations of this method for the
preparation of functionalized unsymmetrical trisulfanes 3.
All of the above alkyl derivatives afforded, after purifica-
tion, unsymmetrical trisulfanes 3 in very good yield (Ta-
ble 3).
Entry
R
3
Yield (%)
1
2
3
4
5
(CH2)11OH
(CH2)10CO2H
(CH2)11NHBoc
(CH2)10CO2Me
Ph
3a
3b
3c
3d
3e
99
99
96
75
63
As shown in Table 3, the same unsymmetrical trisulfane 3
can be obtained in two different ways. For example, 3b
can be prepared from 1c and 2a or from 1a and 2b. Both
approaches gave product 3b in very good yield (Table 3).
However, the reaction of disulfanyl derivative 1f
(R1 = Ph) with S-acetyl alkyldisulfanes 2 was successful
only for compound 2a. Unfortunately, the other S-acetyl
alkyldisulfanes 2b–d provided products 3i, 3l, and 3n that
were contaminated with symmetrical and unsymmetrical
di- and tetrasulfanes, respectively. Although di-, tri-, and
tetrasulfanes could not be separated by column chroma-
tography, the presence of these impurities can be easily
confirmed by 1H NMR spectroscopy. The chemical shift
of the methylene group (triplet in CDCl3) adjacent to the
sulfur for di-, tri-, and tetrasulfanes are 2.66, 2.87, and
3.05, respectively. The versatility of the method is limited
It is known that the preparation of polysulfanes is fre-
quently hampered by the formation of their homologues
with a variable number of sulfur atoms.32 The purification
of such a mixture is, at best, difficult and, in most cases,
impossible due to the similar properties of the products.
We were able to avoid the formation of side products by
using a small excess of the disulfanyl derivatives 1 (1.05
equiv). In this case, the potentially unstable dodecyldisul-
fanyl anion was consumed very quickly and sulfur extru-
sion or exchange with product 3 was not observed.
The S-acetyl alkyldisulfanes 2 are readily available from
disulfanyl derivatives 1 and potassium thioacetate (Table
2).
Table 3 Synthesis of Unsymmetrical Trisulfanes 3a
O
O
S
S
NaOMe (2 equiv)
S
S
+
P
R1
S
R2
S
S
MeOH, 0 °C
r.t., 30 min
R1
S
R2
O
1
2
3
R1 (CH2)11Me 1a R1 (CH2)11OH 1b R1 (CH2)10CO2H 1c R1 (CH2)11NHBoc R1 (CH2)10CO2Me R1 Ph 1f
1d
1e
R2 (CH2)11Me 2a
R2 (CH2)11OH 2b
–
3a (99)
–
3b (99)
3f (72)
–
3c (96)
3g (78)
3j (73)
–
3d (75)
3h (60)
3k (62)
3m (77)
3e (63)
3i (0)
3a (71)
R2 (CH2)10CO2H 2c 3b (85)
R2 (CH2)11NHBoc 2d 3c (87)
3f (70)
3g (76)
3l (0)
3j (74)
3n (0)
a The yields (%) of the isolated product are reported in parentheses.
Synlett 2013, 24, 1927–1930
© Georg Thieme Verlag Stuttgart · New York

LETTER
Functionalized Unsymmetrical Dialkyl Trisulfanes
1929
(m, CH2) cm–1. 1H NMR (200 MHz, CDCl3): δ = 1.02–1.77 (m, 35
H, CH2, OH), 2.22–2.34 (m, 2 H, CH2), 2.87 (t, J = 7.3 Hz, 4 H,
by very fast sulfur extrusions and exchange reactions in
the case of aryl alkyl trisulfanes 3i, 3l, and 3n. It seems
that aromatic groups can promote these side reactions be-
cause the arylthiolate anion is a very good leaving group.
SCH2), 3.64 (t, J = 6.5 Hz, 2 H, OCH2), 3.67 (s, 3 H, COOCH3). 13
C
NMR (50 MHz, CDCl3): δ = 174.7, 63.0, 51.4, 39.4, 39.2, 38.8,
34.4, 34.0, 32.7, 29.7, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0, 28.8, 28.6,
28.5, 28.4, 25.7, 24.9; signals: 23 expected, 22 observed. ESI-
HRMS: m/z [M + H]+ calcd for C23H47O3S3: 467.2687; found:
467.2691.
In conclusion, a convenient method for the preparation of
unsymmetrical dialkyl trisulfanes 3, bearing hydroxy, car-
boxy, methyl ester, or tert-butoxycarbonylamino groups
on either or both sides of the trisulfane has been devel-
oped. Reactions of 1 with a variety of 2 in the presence of
sodium methoxide in methanol at room temperature were
generally complete within 30 minutes and gave exclusive-
ly unsymmetrical dialkyl trisulfanes 3 in very good yields
11-[11-(N-tert-Butoxycarbonylamino)undec-1-yl-trisulfa-
nyl]undecanoic Acid (3j)
Chromatography (CH2Cl2–EtOAc = 10:1); yield: 0.403 g (73%),
white solid, mp 54–56 °C. IR (KBr): ν = 3381 (m, NH), 2920 (s),
2850 (s, CH), 1895, (m, C=O), 1684, (s, C=O), 1639 (m, NH), 1172
(m, CN), 730 (w, CH2) cm–1. 1H NMR (200 MHz, CDCl3):
after purification. Because the reactions of the S-acetyl al- δ = 1.20–1.44 (m, 30 H, CH2), 1.46 (s, 9 H, t-Bu), 1.66–1.76 (m, 4
H, SCCH2), 2.36 (t, J = 7.3 Hz, 2 H, CH2COO), 2.88 (t, J = 7.3 Hz,
kyldisulfanes 2 proceeded with a small excess of 1 under
4 H, SCH2), 3.00–3.20 (m, 2 H, NCH2), 4.48 (br s, 1 H, NH). 13
C
mild reaction conditions and in a short time, thiol–trisul-
fane exchange and sulfur extrusion did not occur during
the reaction. The simplicity and very good yields of this
method make it one of the most attractive approaches for
the preparation of functionalized unsymmetrical dialkyl
trisulfanes.
NMR (50 MHz, CDCl3): δ = 179.9, 156.0, 78.9, 40.7, 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; signals: 25 expected, 20 observed. ESI-HRMS: m/z [M
+ H]+ calcd for C27H54NO4S3: 552.3215; found: 552.3220.
Acknowledgment
We gratefully acknowledge the Polish Ministry of Science and Hig-
her Education for financial support (grant No. N N204 208440).
Typical Procedure for Trisulfane Preparation
A solution of NaOMe (2.0 mmol) in dry MeOH (2 mL) was added
to a solution of 1 (1.05 mmol) and 2 (1.0 mmol) in dry MeOH
(20 mL) at 0 °C under N2 atmosphere. Then, the ice bath was re-
moved, and the mixture was stirred for 30 min at r.t. After evapora-
tion of the solvent under reduced pressure, the residue was purified
by column chromatography. The addition of small amount of AcOH
prior to purification on a silica gel column inhibited sulfur extrusion
during separation. The yields are reported in Table 3.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
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iornat
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© Georg Thieme Verlag Stuttgart · New York
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S. Lach, D. Witt
LETTER
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