Direct synthesis of functionalized unsymmetrical β-sulfonamido disulfides by tetrathiomolybdate mediated aziridine ring-opening reactions

Article abstract of DOI:10.1021/jo901528e

(Chemical Equation Presented) Direct synthesis of unsymmetrical β-sulfonamido disulfides by ring-opening of aziridines by using benzyltriethylammonium tetrathiomolybdate 1 as a sulfur transfer reagent in the presence of symmetrical disulfides as thiol equ

Full text of DOI:10.1021/jo901528e

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reported to obtain mixed disulfides,2,4-14 most of the meth-
Direct Synthesis of Functionalized Unsymmetrical
β-Sulfonamido Disulfides by Tetrathiomolybdate
Mediated Aziridine Ring-Opening Reactions
ods suffer from disadvantages like harsh conditions and the
disulfide-thiol exchange reaction.3 The most prominent and
widely explored methods to achieve the synthesis of mixed
disulfides are via sulfenyl derivatives of a thiol, viz., sulfenyl
chloride,4 dithioperoxy ester,5 thiosulfonates,6 thiosulfates
(Bunte salts),7 thioimides,8 alkylthiodialkylsulfonium salts,9
thiocarbonates,10 thiocyanates,11 N-trifluoroacetylsulfena-
mides,12 and benzotriazoles13 of the corresponding thiols,
using a variety of reagents that are capable of forming an
activated intermediate. These intermediates would readily
undergo nucleophilic substitution with another thiol partner
to give the desired mixed disulfide. These methods involve
the formation and isolation of the activated sulfenyl deriva-
tive followed by the treatment with thiols. In addition to the
number of steps, the usage of free thiols is not preferred
because of the handling issues.
Devarajulu Sureshkumar,† Venkataraman Ganesh,†
Ravindran Sasitha Vidyarini,† and
Srinivasan Chandrasekaran*,‡
Department of Organic Chemistry, Indian Institute of Science,
Bangalore-560012, Karnataka, India. †Authors contributed
equally. ‡Honorary Professor, Jawaharlal Nehru Center for
Advanced Scientific Research, Jakkur, Bangalore
scn@orgchem.iisc.ernet.in
Received July 16, 2009
Earlier, we reported our work on the ring-opening
of aziridines in the presence of tetrathiomolybdate 1 using
disulfides containing electron-withdrawing groups (p-NO2,
p-Cl) which yielded the corresponding β-sulfonamido sul-
fides exclusively (Scheme 1).14e We now report a direct
synthesis of unsymmetrical β-sulfonamido disulfides
mediated by benzyltriethylammonium tetrathiomolybdate
[BnNEt3]2MoS4 (1)14 involving the ring-opening of aziri-
dines by using symmetrical disulfides as thiol equivalents.
The versatility of reagent 1 in organic synthesis as a sulfur
transfer agent has been explored extensively in recent
years.14 Moreover, it effects the reductive cleavage of the
disulfide bond to give thiolate anion in situ which can act as a
nucleophile as well.14a Reagents commonly reported in the
literature for reducing the disulfide bond are, viz., SmI2,15
Directsynthesis of unsymmetricalβ-sulfonamido disulfides
by ring-opening of aziridines by using benzyltriethyl-
ammonium tetrathiomolybdate 1 as a sulfur transfer reagent
in the presence of symmetrical disulfides as thiol equiva-
lents has been reported. Reaction of benzyl and alkyl
disulfides gave unsymmetrical β-sulfonamido disulfides as
the only product in very good yields. From the study, it has
been observed that aryl disulfides containing p-NO2, p-Cl,
and p-CN led to the formation of the corresponding
β-aminosulfides as the exclusive products. However, un-
substituted aryl disulfides and the one containing electron-
donating substituents (p-Me) provide a mixture of β-sulfo-
namido mono- and disulfides as the products.
(2) (a) Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc. 2003, 125, 6624.
(b) Tanaka, K.; Ajiki, K. Tetrahedron Lett. 2004, 45, 5677.
(3) (a) For a review on this topic see: Parker, A.; Kharasch, N. Chem. Rev.
1959, 59, 583. (b) Gorin, G.; Dougherty, G.; Tobolsky, A. V. J. Am. Chem.
Soc. 1949, 71, 3551.
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(b) Harpp, D. N.; Friedlander, B. T.; Larsen, C.; Steliou, K.; Stockton, A.
J. Org. Chem. 1978, 43, 3481. (c) Brown, C.; Evans, G. R. Tetrahedron Lett.
1996, 37, 9101.
(5) Leriverend, C.; Metzner, P. Synthesis 1994, 761.
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Menichetti, S. Tetrahedron Lett. 1989, 30, 2995. (b) Rajca, A.; Wiessler, M.
Tetrahedron Lett. 1990, 31, 6075.
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(8) (a) Harpp, D. H.; Ash, D. K.; Back, T. G.; Gleason, J. G.; Orwig, B.
A.; VanHorn, W. F.; Snyder, J. P. Tetrahedron Lett. 1970, 11, 3551.
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The disulfide bond plays an important role in natural
product chemistry, drug targets and in controlling and
stabilizing the protein folding phenomena. These disulfides
are generally unsymmetrical in nature.1a,b Development of
new synthetic routes to unsymmetrical disulfides is challen-
ging and has attracted considerable interest among the
synthetic organic chemists for the past few decades because
of their practical applications.1 Generally, symmetrical dis-
ulfides are obtained by direct oxidation of the corresponding
thiols but, in the case of unsymmetrical disulfides, oxidation
of two different thiols would lead to a mixture of disulfides.
In the literature, although different approaches have been
(12) Bao, M.; Shimizu, M. Tetrahedron 2003, 59, 9655.
(13) Hunter, R.; Caira, M.; Stellenboom, N. J. Org. Chem. 2006, 71, 8268.
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K. R.; Chandrasekaran, S. J. Org. Chem. 2002, 67, 9417. (c) Prabhu, K. R.;
Devan, N.; Chandrasekaran, S. Synlett 2002, 11, 1762. (d) Sureshkumar, D.;
Koutha, S. M.; Chandrasekaran, S. J. Am. Chem. Soc. 2005, 127, 12760.
(e) Sureshkumar, D.; Gunasundari, T.; Ganesh, V.; Chandrasekaran, S.
J. Org. Chem. 2007, 72, 2106.
(1) (a) Chang, S. H.; Wilken, D. R. J. Biol. Chem. 1966, 241, 4251. (b) Mu,
Y.; Nodwell, M.; Pace, J. L.; Shaw, J. P.; Judice, J. K. Bioorg. Med. Chem.
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Kleindl, P. J.; You, F.; Howard, S. J.; Westrick, E.; Reddy, J. A.; Leamon, C.
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Published on Web 09/15/2009
DOI: 10.1021/jo901528e
r
2009 American Chemical Society

Sureshkumar et al.
JOCNote
SCHEME 1. Reaction of Aryl Disulfides Bearing Electron-
Withdrawing Groups with Aziridines in the Presence of 1
TABLE 1. Ring-Opening Reaction of Phenylalanine-Derived Aziridine
with Various Disulfides
SCHEME 2. Reaction of Aziridines with Organic Disulfides in
the Presence of 1
LiCl/NaBH4, ZrCl2/NaBH4,16 Zn/AlCl3,17 InI,18 ronga-
lite,19 tranistion metal complexes,2,20 sodium hydrogen tell-
uride (NaHTe),21 etc. However, these reagents suffer from
disadvantages of incompatibilitywith otherfunctional groups
capable of undergoing reduction. The present study focuses
on the reaction of alkyl disulfides with aziridines mediated by
1. Interestingly, the reaction of alkyl disulfides with aziridines
in the presence of 1 formed the β-sulfonamido disulfides B as
the only product (Scheme 2). A detailed study of the electronic
effect of substituents on the organic disulfide has been carried
out to determine the product selectivity. Further, the study
resulted in a versatile methodology for the synthesis of a
variety of functionalized unsymmetrical disulfides.
Ring-Opening of Phenylalanine-Derived Aziridine 2 with
Various Organic Disulfides Mediated by 1. Our investigation
began with a study of the ring-opening of optically pure
phenylalanine-derived aziridine 2 with benzyl disulfide
mediated by tetrathiomolybdate 1. Aziridine 2 (1 equiv)
was treated with a well-stirred solution of benzyl disulfide
(1 equiv) and tetrathiomolybdate 1 (2 equiv) in acetonitrile
(28 °C, 3 h) to afford the unsymmetrical disulfide 3 as the
exclusive product in 83% yield. The studies were then
extended to the reaction of various alkyl and aryl disulfides
with aziridine 2 in the presence of 1. The results of this
investigation are presented in Table 1.
To study the effect of substituents in the disulfide pre-
cursors on the course of the reaction, phenylalanine-derived
aziridine 2 was taken as reference starting material. Reaction
of aziridine 2 with p-methoxybenzyl disulfide and 1 (entry 2)
resulted in the formation of disulfide 4 exclusively in 78%
yield. Further, reaction of 2-aminoethanethiol derived disul-
fide (entry 3) with 1 in the presence of aziridine 2 successfully
gave the corresponding mixed disulfide 5 as the only product
in 80% yield. Following the results obtained, when the reac-
tion was carried out with diphenyl disulfide (entry 4), to our
surprise it resulted in an inseparable mixture of monosulfide
6a and disulfide 6b (72%). Similarly, with p-tolyl disulfide
(entry 5) the reaction led to an inseparable mixture of
monosulfide 7a and disulfide 7b (69%). Summing up the
results from the earlier report14b and the present study, it
clearly shows the product dependence on the electronic
environment on disulfide substrates. Thus, in the case of aryl
disulfides carrying electron-withdrawing substituents (entry
6)14e it resulted in the formation of the corresponding
β-sulfonamido sulfides, whereas, other aryl disulfides led to
the formation of an inseparable mixture of the corresponding
mono- and disulfides (entries 4 and 5). In the case of aliphatic
disulfides (entries 1-3), the reaction led to the formation of
the corresponding β-sulfonamido disulfides exclusively.
Ring-Opening of Various N-Tosylaziridines with Benzyl
Disulfides Mediated by 1. To explore this methodology
further, we studied tetrathiomolybdate 1 mediated ring-open-
ing of various monosubstituted aziridines in the presence
of benzyl disulfide. Optically pure S-(þ)-2-aminobutanol
derived aziridine 9a when treated with a mixture of benzyl
disulfide and tetrathiomolybdate 1 in acetonitrile under the
same reaction conditions resulted in the ring-opening of
aziridinefromthe lesshinderedside followinganSN2pathway
to give the corresponding mixed disulfide 9b in 81% yield.
Similarly, various monosubstituted aziridines (10a-13a) were
subjectedtoring-openingwithbenzyldisulfideunder the same
conditions and in all the cases ring-opening took place at the
less hindered site as expected to offer the corresponding mixed
disulfides 10b-13b in good yields (Table 2, entries 3-7).
3-Buten-1-ol derived aziridine 12a on treatment with a
mixture of benzyl disulfide and tetrathiomolybdate 1 furnished
the corresponding mixed disulfide 12b as a crystalline white solid
in 69% yield. Similarly, when carbohydrate derived aziridine
13a14e was treated with a mixture of benzyl disulfide and tetra-
thiomolybdate 1, the reaction led to the formation of the car-
bohydrate-derived β-sulfonamido disulfide 13b in 83% yield.
Proposed Mechanism for the Formation of β-Amino Sul-
fides and β-Amino Disulfides Mediated by 1. From the reac-
tivity pattern of various aziridines toward benzyl disulfide
(16) Rajaram, S.; Chary, K. P.; Iyengar, D. S. Indian J. Chem., Sect. B
2001, 40, 622 and references cited therein.
(17) Movassagh, B.; Sobhani, S.; Kheirdoush, F.; Fadaei, Z. Synth.
Commun. 2003, 33, 3103.
(18) Ranu, B. C.; Mandal, T. J. Org. Chem. 2004, 69, 5793.
(19) Tang, R.; Zhong, P.; Lin, Q. Synthesis 2007, 1, 85.
(20) (a) Alexakis, A.; Normant, J. F. Synthesis 1985, 72. (b) Chowdhury,
S.; Roy, S. Tetrahedron Lett. 1997, 38, 2149.
(21) Kong, F.; Zhou, X. Synth. Commun. 1989, 19, 3143.
J. Org. Chem. Vol. 74, No. 20, 2009 7959

Sureshkumar et al.
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TABLE 2. Ring-Opening of Monosubstituted Aziridines with Benzyl
Disulfide Mediated by Tetrathiomolybdate 1
SCHEME 3. Proposed Mechanistic Pathway for the Formation
of β-Sulfonamido Sulfides
SCHEME 4. Proposed Mechanistic Pathway for the Formation
of Unsymmetrical Disulfides Mediated by 1
mediated by tetrathiomolybdate 1, the formation of unsym-
metrical disulfide was observed consistently. Though a de-
tailed study of the mechanism of this interesting observation
has not been carried out, a tentative mechanism has been
proposed on the basis of the pioneering work of Stiefel et
al.,22 on the cleavage of aromatic disulfides mediated by
tetrathiomolybdate as well as our own studies of reactivity of
1 and its utility in organic synthesis.14 To place the present
work in the right perspective the mechanism that we pro-
posed earlier for the formation of β-sulfonamidosulfides
from aziridines and aryl disulfides in the presence of 1 is
discussed first.
On the basis of the investigation by Stiefel et al.22b on the
kinetics of tetrathiomolybdate-mediated disulfide cleavage
reactions, aromatic disulfides bearing electron-withdraw-
ing groups (EWG) undergo disulfide cleavage faster than
diphenyl disulfide and the equilibrium is largely shifted
toward the formation of thiolate (step 1, Scheme 3). In
the case of aziridine ring-opening with disulfides mediated
by tetrathiomolybdate 1, one of the competing reactions
is the direct ring-opening by tetrathiomolybdate leading
to the formation of a symmetrical disulfide (D).14e In the
case of aromatic disulfides bearing EWG, since the clea-
vage of the disulfide with 1 is much faster than the com-
peting aziridine ring-opening reaction, the thiolate formed
in situ acts as a nucleophile to open the aziridine ring
to form the β-sulfonamido sulfide as depicted in step 2,
Scheme 3.
When the reaction of 1 with an aziridine in the presence of
an aliphatic disulfide is carried out, the cleavage of the S-S
bond is very slow (step 1, Scheme 4). Therefore, the compet-
ing direct attack of tetrathiomolybdate 1 on the aziridines
takes over leading to the ready formation of symmetrical
disulfide. The intermediate (D) and the aliphatic disulfide in
the presence of tetrathiomolybdate 1 undergo a disulfide
exchange reaction to form the unsymmetrical disulfide as the
product.
The aromatic disulfides bearing no electron-withdrawing
group (diphenyl disulfide and p-tolyl disulfide) fall in-
between the two cases. The disulfide cleavage and the direct
ring-opening of aziridine with tetrathiomolybdate 1 become
equally facile, which leads to the formation of a mixture of
the corresponding β-sulfonamido sulfide and β-sulfonamido
disulfide.
Reactivity of Substituted Aziridines with Benzyl Disulfide in
the Presence of 1. It was then decided to study the reactivity
of a number of substituted aziridine derivatives. In the case
of symmetrically disubstituted aziridines, the reaction was
generally slower than that of the monosubstituted aziridines
(Table 3, entry 1 and 2). In the case of unsymmetrically
disubstituted aziridines like cis-isopropylmethyl-N-tosyla-
ziridines 16a and trans-isopropylmethyl-N-tosylaziridines
17a, the ring-opening occurred generally at the less hindered
side due to steric hindrance offered by the bulky isopropyl
group, to yield unsymmetrical disulfide 16b and 17b respec-
tively in good yields with full regio- and stereocontrol. In the
same fashion, gem-disubstituted aziridine 19a was expected
to open from the less hindered side. But, the reaction led
to a mixture of (1:1 regioisomer) unsymmetrical disulfides
19b (78% overall conversion), due to equally facile ring-
opening at the more substituted site. Then, the reaction
was carried out with trisubstituted aziridine 20a, which led
(22) (a) Pan, W. H.; Harmer, M. A.; Halbert, T. R.; Stiefel, E. I. J. Am.
Chem. Soc. 1984, 106, 459. (b) Coyle, C. L.; Harmer, M. A.; George, G. N.;
Daage, M.; Stiefel, E. I. Inorg. Chem. 1990, 29, 14.
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Sureshkumar et al.
JOCNote
TABLE 3. Ring-Opening of Di- and Trisubstituted Aziridines with
Benzyl Disulfide Mediated by 1
TABLE 4. Ring-Opening of Cyclic Aziridines with Benzyl Disulfide
Mediated by 1
aziridines using tetrathiomolybdate 1 in the presence of
symmetrical disulfides.
to ring-opening at the more substituted site giving 20b as the
only product in 68% yield. This kind of selectivity in the ring-
opening at the more hindered site can be rationalized by
considering a larger polarization of the carbon-nitrogen
bond along the disubstituted side, due to the stabilization of
the positive charge at the tertiary center. This facilitates the
nucleophile to attack at the more substituted site with equal
facility.23
The methodology was further explored by studying the
ring-opening of aziridines attached to cyclic structures.
The aziridines 21a-24a and 27a were prepared from the
corresponding alkenes. When cyclopentene and cyclo-
hexene derived aziridines 21a-27a were treated with
tetrathiomolybdate 1 in the presence of benzyl disulfide,
as expected, the corresponding unsymmetrical disul-
fides 21b-27b respectively were formed in good yields
(Table 4). It is pertinent to mention the chemoselective ring-
opening of aziridines in the presence of epoxide (entries
5 and 6) to obtain the corresponding mixed disulfides
leaving the epoxide untouched. In the methylcyclohexene
derived aziridine 27a, the ring-opening took place at the
more hindered side as in the case of trisubstituted aziridines
to afford the mixed disulfide 27b as the only product in 72%
yield.
Experimental Section
Typical Procedure for the Synthesis of 3. To a stirred solution
of benzyl disulfide (43 mg, 0.17 mmol, 1 equiv) in CH3CN
(2 mL) was added [BnEt3N]2MoS4 (1) (213 mg, 0.35 mmol, 2
equiv). The mixture was allowed to stir for 1 h, followed by the
addition of a solution of 2 in acetonitrile (1 mL) in one portion.
The reaction was allowed to stir for 3 h at room temperature (28
°C). When the starting material disappeared (TLC), the solvent
was removed in vacuo and the residue was extracted repeatedly
(3 ꢀ 5 mL) with a DCM/ether mixture (4:1). The extract was
filtered through a thin pad of Celite and the filtrate was
concentrated in vacuo. The reaction mixture was further pur-
ified by column chromatography to yield the mixed disulfide 3
(64 mg, yield 83%): pale yellow gummy liquid; IR (neat) νmax
3280, 1497, 1326, 1157, 813, 700, 665 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.61 (d, J = 8.1 Hz, 2H), 7.32-7.18 (m, 10H),
6.98-6.95 (m, 2H), 4.61 (d, J = 6.9 Hz, 1H), 3.84 (s, 2H),
3.64-3.57 (m, 1H), 2.90 (dd, J = 13.8, 6.3 Hz, 1H), 2.70 (dd, J =
13.8, 6.3 Hz, 1H), 2.54 (dd, J = 14.0, 6.0 Hz, 1H), 2.40 (dd, J =
14.0, 6.6 Hz, 1H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
143.3, 136.9, 136.7, 136.3, 129.6, 129.4, 129.3, 128.6, 127.6,
127.1, 126.7, 54.1, 42.9, 42.0, 39.6, 21.5; HRMS calcd for
C23H25NO2S3 (M þ Naþ) 466.0945, found 466.0940.
In the case of gem-disubstituted aziridines, the nucleophile
ring-opening at the more hindered side has been observed.
The versatility of the reaction has been demonstrated in the
presence of two different functionalities. In summary, we
have developed optimized conditions to the number of func-
tionalized unsymmetrical disulfides through ring-opening of
Acknowledgment. We thank CSIR, New Delhi for the
award of a Senior Research Fellowship to D.S. and a
Shyama Prasad Mukherjee Fellowship to V.G., and DST,
New Delhi is thanked for the CCD X-ray facility and for the
JC Bose National Fellowship to S.C.N.
Supporting Information Available: 1H, 13C spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
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J. Am. Chem. Soc. 2007, 129, 14463.
J. Org. Chem. Vol. 74, No. 20, 2009 7961