An efficient and convenient synthesis of unsymmetrical disulfides from thioacetates

Article abstract of DOI:10.1016/j.tetlet.2013.10.056

We have developed convenient methods for the synthesis of functionalized unsymmetrical dialkyl disulfides 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)-disu

Full text of DOI:10.1016/j.tetlet.2013.10.056

Tetrahedron Letters 54 (2013) 7021–7023
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient and convenient synthesis of unsymmetrical disulfides
from thioacetates
⇑
Slawomir Lach, Sebastian Demkowicz, Dariusz Witt
Department of Organic Chemistry, Chemical Faculty, Gdansk University of Technology, Narutowicza 11/12, Gdansk 80-233, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed convenient methods for the synthesis of functionalized unsymmetrical dialkyl disul-
fides under mild conditions in very good yields. The designed method is based on the reaction of (5,5-
Received 21 August 2013
Revised 30 September 2013
Accepted 11 October 2013
Available online 18 October 2013
dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)-disulfanyl derivatives
1 with functionalized alkyl
thiolate anions, generated in situ from thioacetates 2 and sodium methoxide or butylamine. The devel-
oped method allows the preparation of unsymmetrical disulfides bearing additional hydroxy, carboxy,
amino, azido, biotin, or maleimide functionalities.
Keywords:
Unsymmetrical disulfides
Thiolate
Ó 2013 Elsevier Ltd. All rights reserved.
Phosphorodithioic acid
Thioacetates
Biotin
The synthesis of unsymmetrical disulfides is an important
transformation in modern organic synthesis and medicinal chem-
istry.1 The recent developments in disulfide bond formation have
been reviewed.2 Disulfides have also been used for the preparation
of self-assembled monolayers (SAMs)3 and monolayer-protected
clusters (MPCs) with a number of versatile properties.4
have presented the preparation of S-nucleosidyl S-aryl disulfides11
from the corresponding S-nucleosidyl thiobenzoates.
We have previously demonstrated the preparation of functional-
ized unsymmetrical molecules such as dialkyl disulfides, alkyl-aryl
disulfides,12 ‘bioresistant’ disulfides,13 unsymmetrical disulfides of
L
-cysteine and L
-cystine,14 and diaryl disulfides15 based on the
Thioesters are readily available from alcohol, alkyl halide, or
alkene derivatives,5 and traditionally are converted into the corre-
sponding thiols. Deprotection of the thiol group by removal of the
acyl group can occur under basic, acidic, or neutral conditions.
However, the formation of symmetrical disulfides, instead of the
expected thiol, is observed very frequently when deprotection is
performed under basic conditions, when open to the atmosphere
or when solvent with dissolved oxygen from air is used.6
Thiols are relatively labile under ambient atmosphere and thus
a transformation is highly desired in which protected thiols can be
directly converted into disulfides, especially unsymmetrical exam-
ples. Convenient one-pot syntheses of symmetrical disulfides from
thioacetates by nickel boride catalyzed methanolysis and disprop-
otionation,7 hydrolysis catalyzed by sodium azide6b or treatment
with alkoxystannanes and ferric chloride8 have been reported.
Treatment of thiobenzoates with piperidine9 or samarium diio-
dide10 can also afford symmetrical disulfides. Much more interest-
ing from the synthetic point of view is the direct conversion of
thioesters into unsymmetrical disulfides. Cosstick and co-workers
readily available 5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphor-
inane-2-disulfanyl derivatives 1. These disulfanyl derivatives 1 of
phosphorodithioic acid were also convenient for the preparation
of
a
-sulfenylated carbonyl compounds,16 and symmetrical17 and
unsymmetrical18 trisulfides. In continuation of our interest in using
disulfanyl derivatives 1 of phosphorodithioic acid for the prepara-
tion of functionalized unsymmetrical disulfides, herein we report
an efficient and convenient synthesis of unsymmetrical disulfides
directly from thioacetates (Table 1).
The idea is based on the chemoselective deprotection of thioac-
etates with sodium methoxide (method A, Table 1) or butylamine
(method B, Table 1) in the presence of disulfanyl derivatives 1. The
generated thiolate anion reacts quickly with electrophilic disulfa-
nyl derivative 1 to produce the corresponding functionalized
unsymmetrical disulfide 3. We have found that the use of a small
excess of compound 1 (1.05 equiv) was required to avoid potential
disulfide–thiol exchange and formation of symmetrical disulfides.
This is important, especially in the case when the symmetrical
product cannot be separated from the unsymmetrical derivative
by column chromatography.
Under the optimized reaction conditions, the scope and gener-
ality of the disulfide formation were explored (Table 1).19 In gen-
eral, the yields of the unsymmetrical dialkyl disulfides 3 were
⇑
Corresponding author. Tel.: +48 58 347 1851; fax: +48 58 347 2694.
E-mail address: dwitt@chem.pg.gda.pl (D. Witt).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.056

7022
S. Lach et al. / Tetrahedron Letters 54 (2013) 7021–7023
Table 1
Reaction of disulfanyl derivatives 1 with thioacetates 2a
Entry
R1
1
R2
2
Product
Yieldb (%)
Method A
Method B
1
2
3
4
5
6
7
8
9
(CH2)11CH3
(CH2)11CH3
(CH2)11CH3
(CH2)11OH
(CH2)11NHBoc
(CH2)10CO2H
(CH2)11N3
1a
1a
1a
1b
1c
1d
1e
1f
(CH2)11OH
(CH2)11NHBoc
(CH2)10CO2H
(CH2)11CH3
(CH2)11CH3
(CH2)11CH3
(CH2)11OH
(CH2)11(OCH2CH2)3OH
(CH2)11(OCH2CH2)6OH
(CH2)11(OCH2CH2)6OCH2CO2H
2a
2b
2c
2d
2d
2d
2a
2e
2f
3a
3b
3c
3a
3b
3c
3d
3e
3f
86
91
92
87
89
89
90
65
95
85
92
95
94
94
93
91
92
70
97
89
Ph
(CH2)11(OCH2CH2)3OH
(CH2)11(OCH2CH2)3OH
1g
1g
10
2g
3g
11
(CH2)11(OCH2CH2)3OH
1g
2h
3h
89
.92
12
13
(CH2)11(OCH2CH2)3OH
(CH2)11OH
1g
1b
2i
2j
3i
3j
65
74
—
—
(CH2)10CHO
a
Conditions. Method A: 1 (1.05 mmol), 2 (1.0 mmol), MeONa (2.0 mmol), MeOH (20 mL), 0 °C then rt, 15–30 min, under nitrogen. Method B: 1 (1.05 mmol), 2 (1.0 mmol),
BuNH2 (4.0 mmol), MeOH (20 mL), 0 °C then rt, 15–30 min, under nitrogen.
Isolated yield based on 2.
b
very high. Functional groups such as hydroxy, carboxy, azido, or
Boc-protected amino were very well tolerated. Protection of the
amino group was recommended to avoid potential acetyl transfer
from thioacetates 2. As shown in Table 1, the same unsymmetrical
disulfide 3 can be obtained in two different ways. For example, 3a
can be prepared from 1a and 2a (entry 1), or from 1b and 2d (entry
4). Both approaches gave product 3a in very good yield (Table 1).
However, the formation of aryl alkyl disulfide 3e was accomplished
in moderate yield. It seems that the versatility of the method is
limited by a very fast thiol–disulfide exchange reaction in the case
of aryl alkyl disulfides. Probably, aromatic groups can promote this
side reaction because the arylthiolate anion is a very good leaving
group, and the generated thiolates from thioacetates 2 can react
with either disulfanyl derivatives 1 or unsymmetrical product 3
to produce symmetrical disulfides.
In summary, we have developed efficient and convenient meth-
ods for the preparation of unsymmetrical dialkyl disulfides 3 bear-
ing hydroxy, carboxy, amino, azido, biotin, or maleimide
functionalities. Reactions of 1 with various thioacetates 2 in the
presence of sodium methoxide or butylamine in methanol at room
temperature were generally complete within 30 min, and gave
unsymmetrical dialkyl disulfides 3 exclusively, in good or very
good yields after isolation. Since the reactions of thioacetates 2
proceeded with a small excess of 1 under mild reaction conditions
in a short time, thiol–disulfide exchange did not occur during the
reaction. The simplicity and good yields should make this method
an attractive approach for the preparation of functionalized
unsymmetrical dialkyl disulfides, especially when the presence of
functionalities highly reactive toward thiol groups cannot be
avoided.
To further explore the scope of the reaction, thioacetates 2i,j
were employed in reactions with 1g and 1b, respectively (Table 1,
entries 12 and 13). In these cases only method A could be applied
because butylamine can react with the aldehyde or maleimide
groups in the starting materials 2i,j or products 3i,j. Under the opti-
mized reaction conditions (method A), both thioacetates 2i and 2j
provided unsymmetrical disulfides 3i and 3j, respectively, in mod-
erate yields. The corresponding thiols from deprotection of 2i and
2j could not be isolated due to the reaction of the thiol group with
the aldehyde20 or maleimide21 functionalities. Although these thi-
ols cannot be isolated, their formation in the reaction mixture and
reaction with electrophilic disulfanyl derivatives 1 to produce
disulfides 3i,j can be accomplished. It appears that the reaction
of the generated thiolate from thioacetates 2i,j is faster with dis-
ulfanyl derivatives 1 than with aldehyde or maleimide functional-
ities. A major advantage of the developed method is the possibility
of disulfide bond formation in the presence of functionalities that
are highly reactive toward thiol groups.
Acknowledgment
We gratefully acknowledge the Polish Ministry of Science and
Higher Education for financial support (Grant No. N N204 208440).
Supplementary data
Supplementary data (experimental details and spectroscopic
data for all compounds 3) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.
056.
References and notes
1. (a) Cremlyn, R.; An, J. Introduction to Organosulfur Chemistry; Wiley: New York,
1996; (b) Oae, S. Organic Sulfur Chemistry: Structure and Mechanism; CRC Press:
Boca Raton FL, 1991; (c) Vruhula, V. M.; MacMaster, J. F.; Zhengong, L.; Kerr, D.

S. Lach et al. / Tetrahedron Letters 54 (2013) 7021–7023
7023
E.; Senter, P. D. Bioorg. Med. Chem. Lett. 2002, 12, 3591; (d) Mu, Y.; Nodwell, M.;
15. Demkowicz, S.; Rachon, J.; Witt, D. Synthesis 2008, 2033.
16. Okragla, E.; Demkowicz, S.; Rachon, J.; Witt, D. Synthesis 2009, 1720.
17. Kertmen, A.; Lach, S.; Rachon, J.; Witt, D. Synthesis 2009, 1459.
18. Lach, S.; Sliwka-Kaszynska, M.; Witt, D. Synlett 2010, 2857.
Pace, J. L.; Shaw, J. P.; Judice, J. K. Bioorg. Med. Chem. Lett. 2004, 14, 735.
2. (a) Shcherbakova, I.; Pozharskii, A. F. In Comprehensive Organic Functional Group
Transformations II; Katritzky, A. R., Taylor, R., Ramsden, Ch., Eds.; Pergamon:
Oxford, 2004; Vol. 2, pp 177–187; (b) Sato, R.; Kimura, T. In Science of Synthesis;
Kambe, N., Drabowicz, J., Molander, G. A., Eds.; Thieme: Stuttgart-New York,
2007; Vol. 39, pp 573–588; (c) Witt, D. Synthesis 2008, 2491.
3. (a) Ulman, A. Chem. Rev. 1996, 96, 1533; (b) Witt, D.; Klajn, R.; Barski, P.;
Grzybowski, B. A. Curr. Org. Chem. 2004, 8, 1763.
4. (a) Porter, L. A., Jr.; Ji, D.; Westcott, S. L.; Graupe, M.; Czernuszewicz, R. S.; Halas,
N. J.; Lee, T. R. Langmuir 1998, 14, 7378; (b) Shon, Y. S.; Mazzitelli, C.; Murray, R.
W. Langmuir 2001, 17, 7735.
5. Shcherbakova, I.; Pozharskii, A. F. In Comprehensive Organic Functional Group
Transformations II; Katritzky, A. R., Taylor, R., Ramsden, Ch., Eds.; Pergamon:
Oxford, 2004; Vol. 2, pp 92–98.
6. (a) Lee, S.; Rosazza, J. P. N. Org. Lett. 2004, 6, 365; (b) Cha, M. J.; Song, Y. S.; Lee,
K.-J. Bull. Korean Chem. Soc. 2006, 27, 1900.
7. Choi, J.; Yoon, N. M. Synlett 1995, 1073.
8. Sato, T.; Otera, J.; Nozaki, H. Tetrahedron Lett. 1990, 31, 3595.
9. Kakehi, A.; Suga, H.; Okuno, H.; Okuhara, M.; Ohta, A. Chem. Pharm. Bull. 2007,
55, 1458.
10. Yoo, B. W.; Baek, H. S.; Keum, S. R.; Yoon, C. M.; Nam, G. S.; Kim, S. H.; Kim, J. H.
Synth. Commun. 2000, 30, 4317.
19. Method A. A solution of MeONa (2.0 mmol) in dry MeOH (2 mL) was added to a
solution of 1e (447 mg, 1.05 mmol) and 2a (246 mg, 1.0 mmol) in dry MeOH
(20 mL) at 0 °C under an N2 atmosphere. The ice bath was removed and the
mixture was stirred for 15–30 min at rt. The progress of the reaction was
monitored by TLC. The volatiles were removed under vacuum and the residue
was purified by column chromatography (silica gel, CH2Cl2) to give 3d as a
colorless oil; yield: 388 mg (90%). All compounds were characterized by means
of IR, 1H NMR, 13C NMR, and HRMS. Compound 3d: IR (KBr):
(OH), 2921 (s), 2851 (s), 2098 (m), (N3), 1055, (m), 720 (w) cmÀ1
m
= 3413 (m),
.
1H NMR
(200 MHz, CDCl3): d = 3.64 (t, J = 6.5 Hz, OCH2, 2H), 3.28 (t, J = 7.1 Hz, CH2N3,
2H), 2.69 (t, J = 7.3 Hz, SCH2, 4H), 1.50–1.76 (m, CH2, OH, 5H), 1.20–1.48 (m,
CH2, 32H). 13C NMR (50 MHz, CDCl3): d = 63.0, 51.5, 39.2, 32.7, 31.9, 29.6, 29.5,
29.4, 29.3, 29.2, 28.5, 28.6, 25.6, 22.8. Signals: expected, 22; observed, 14.
HRMS (ESI): m/z [M+H]+ calcd for C22H46N3OS2: 432.3082; found: 432.3084.
Method B. A solution of n-butylamine (290 mg, 0.4 mL, 4.0 mmol) in dry MeOH
(2 mL) was added to a solution of 1e (447 mg, 1.05 mmol) and 2a (246 mg,
1.0 mmol) in dry MeOH (20 mL) at 0 °C under an N2 atmosphere. The ice bath
was removed and the mixture was stirred for 15–30 min at rt. The progress of
the reaction was monitored by TLC. After evaporation of the volatiles under
reduced pressure, the residue was purified by column chromatography on a
silica gel column to yield 3d as a colorless oil; 397 mg (92%).
11. Higson, A. P.; Scott, G. K.; Earnshaw, D. J.; Baxter, A. D.; Taylor, R. A.; Cosstick, R.
Tetrahedron 1996, 52, 1027.
12. Antoniow, S.; Witt, D. Synthesis 2007, 363.
20. Cox, J. M.; Owen, L. N. J. Chem. Soc. C 1967, 1130.
13. Kowalczyk, J.; Barski, P.; Witt, D.; Grzybowski, B. A. Langmuir 2007, 23, 2318.
14. Szymelfejnik, M.; Demkowicz, S.; Rachon, J.; Witt, D. Synthesis 2007, 3528.
21. Houseman, B. T.; Gawalt, E. S.; Mrksich, M. Langmuir 2003, 19, 1522.