Sulfenylation chemistry using polymer-supported sulfides

Article abstract of DOI:10.1016/j.tetlet.2009.02.009

Clean sulfenylations are observed upon reaction of activated methylenes with phenyl succinimidyl sulfide. When working with diethyl benzylmalonate, the sulfenylated product can be selectively oxidized and thermally fragmented affording phenylsulfenic acid

Full text of DOI:10.1016/j.tetlet.2009.02.009

Tetrahedron Letters 50 (2009) 1855–1857
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sulfenylation chemistry using polymer-supported sulfides
a
a
b
a
David C. Forbes a, , Sampada V. Bettigeri , Nahla N. Al-Azzeh , Brian P. Finnigan , Joseph A. Kundukulam
*
a Department of Chemistry, University of South Alabama, Mobile, AL 36688, USA
b Murphy High School, 100 S. Carlen St., Mobile, AL 36606, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Clean sulfenylations are observed upon reaction of activated methylenes with phenyl succinimidyl sul-
fide. When working with diethyl benzylmalonate, the sulfenylated product can be selectively oxidized
and thermally fragmented affording phenylsulfenic acid, initially, and diethyl benzylidenemalonate.
The developed method was applied using a polymer-supported thioanisole derivative (JandaJel). Forma-
tion of the enedicarboxylate documents proof of principle of polymer-supported sulfides as sulfenylating
agents onto activated methylenes.
Received 20 August 2008
Revised 3 February 2009
Accepted 4 February 2009
Available online 8 February 2009
Keywords:
Polymer-supported synthesis
Sulfenylation
Ó 2009 Elsevier Ltd. All rights reserved.
Since Groebel’s seminal work almost 50 years ago (Scheme 1),1
there have been numerous reports on the preparation and use of
N-(organothio)succinimide derivatives.2,3 These activated organo-
sulfides are most commonly used as sulfenylating reagents. While
not all N-(organothio)succinimide derivatives are prepared via a
demethylation process as first reported by Groebel, subsequent re-
ports do present strategies based upon convenience, such as the
avoidance of sulfenyl chloride, or use of readily accessible starting
materials.
Sulfenylations using either N-(organothio)succinimide or
N-(organothio)phthalimide derivatives with a host of nucleophiles
(neutral, anionic, and heteroatomic) have been shown to proceed
with high efficiency.3 The most common class of nucleophiles em-
ployed are activated methylenes. When considering cost, stability
of the activated organosulfide, and the avoidance of toxic materi-
als, the use of an S-imido derivative is the reagent of choice when
performing sulfenylation chemistry.
jor synthetic use is in the preparation of
our research centers on the use of
a
-thiocarboxylates.4 Since
-thiocarboxylates in S-ylide
a
aziridination and epoxidation reactions,5 the recent commercial
availability of polymer-supported thioanisole derivatives caught
our attention, and reported herein are our findings on the proof
of concept of polymer-supported sulfides as sulfenylating agents
onto activated methylenes.
The advantages of developing such technologies are clear. The
materials needed for this process are cheap, readily available,
and easy to work with even when considering on scale. The strat-
egy utilizing polymer-supported technologies (polymer-supported
organic synthesis (PSOS)) is evident given the numerous benefits
associated with a process involving solid-phase chemistry. While
we have made great progress with S-methylene transfers onto a
host of carbonyl derivatives, limitations do exist. One significant
advancement in the development of S-ylide chemistries would be
the incorporation of polymer-supported technologies in the
The novelty of this process is how the sulfur atom can serve the
role of both nucleophile and electrophile. Upon formation of phe-
nyl succinimidyl sulfide using a demethylation process, the sulfur
atom of thioanisole serves the role of nucleophile upon bromina-
tion with NBS. This role is then reversed upon expulsion of the bro-
mide with succinimide. Similar strategies have been used toward
the preparation of not only S-imidosulfides but also S-thio-, S-sele-
no-, S-stannyl-, and S-halosulfides. As activated organosulfides, the
relatively weak S-linkage is then exploited upon reaction with a
wide spectrum of nucleophiles.
assembly of a-thiocarboxylates.
Prior to exploring the use of solid-phase chemistry (polymer-
supported sulfide), we embarked upon a solution-phase study
(Scheme 2).
Using as our baseline the demethylation chemistry first re-
ported by Groebel, we were successful in improving the isolated
yield of organosulfide 1 from 69% to 98%. After examining solvent
O
O
The use of organosulfides has been a very attractive strategy in
assembly of both complex and simple organic molecules. The ma-
S
S
CCl4
N
CH3
+
N Br
+ CH3Br
(69%)
O
O
* Corresponding author. Fax: +1 251 460 7359.
E-mail address: dforbes@jaguar1.usouthal.edu (D.C. Forbes).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.009

1856
D. C. Forbes et al. / Tetrahedron Letters 50 (2009) 1855–1857
O
S
NBS
S
N
O
CH3
O
S
O
CH2Cl2
rt
(98%)
O
EtO
OEt
CH3CN
1
rt
O
O
O
(93%)
K2CO3
EtO
K
OEt
EtO
OEt
CH3CN
rt
2
Scheme 2.
systems, stoichiometry, and temperature, we found that upon
reaction of a slight excess of NBS with thioanisole in dichlorometh-
ane at room temperature, we were successful in obtaining the de-
sired product in excellent yield when allowed to react over a
period of 24 h. While higher reaction temperatures (>50 °C) did re-
sult in shorter reaction times based upon the consumption of thio-
anisole, the higher reaction temperatures did result in
decomposition of organosulfide 1. Furthermore, using either excess
quantities of NBS or alternative dipolar aprotic solvents did not re-
sult in significant improvements when considering reaction time.
Diethylbenzylmalonate was one of several activated methyl-
enes we surveyed. When working with diethylmalonate, bis(sulfe-
nylation), not surprising, using phenyl succinimidyl sulfide was
observed. Surprising, however, was bis(sulfenylation) of diethyl-
malonate using just 0.5 equiv of organosulfide 1. For this example,
we confirmed the challenges associated with monosulfenylations
with systems bearing two acidic protons. Observed with this
example was bis(sulfenylation) in 44% conversion using phenyl
succinimidyl sulfide and diethylmalonate. This, however, does
not detract from the chemistry at hand. Even with the predisposi-
tion of double sulfenylation, reaction of sodium ethanethiolate
with the bissulfenylated product has been shown to cleanly reduce
the material to the corresponding monosulfenylated derivative.6
With our model system, the desired sulfenylated product (2)
was obtained in excellent yield starting from the diethylbenzyl-
malonate and organosulfide 1.7 For this transformation, the order
of addition and allowing for formation of the potassium salt prior
to addition of the activated organosulfide was key.
n-Bu3SnH/AIBN or Na/NH3, which can as well be used to perform
cleavage of the C–S bond directly.
Sulfide 2 was oxidized using mCPBA, and resulted in formation
of sulfoxide 3 in 98% isolated yield.8 While high boiling solvents are
most commonly used to perform fragmentation processes involv-
ing b-eliminations,9 we found this process with our system (sulfox-
ide 3) to be sluggish. Using toluene as solvent, the percent
conversion of 3 to 4 never exceeded 50%. This was observed while
monitoring the reaction at three separate intervals (3 h, 12 h, and
48 h). Odd was that the mass balance of the reaction mixture ex-
ceeded 90% on the 1.0 mmol scale and when monitoring the reac-
tion, no evidence of any secondary processes was observed. One
known process being polymerization of enedicarboxylate 4.10
While disappointed with the overall levels of conversion, the reac-
tion conditions are unoptimized. As stated above, while we did not
observe any secondary processes, we cannot dismiss the fact that
as the reaction proceeds, the buildup of phenylsulfenic acid
(PhSOH) may play an important role in the overall outcome of this
process. While secondary when considering the proof of principle
of sulfenylation chemistry using polymer-supported materials, ef-
forts which address the failure of this reaction to complete are
underway.
Using solution-phase chemistry, we developed a method of
sulfenylation using activated organosulfides and cleavage upon
thermolysis of sulfoxide 3. For the polymer-supported chemistry,
we explored the use of commercially available thioanisole func-
tionalized JandaJel 5 (Fig. 1). Aside from the commercial availabil-
ity of this material, we were excited about the potential of using
this material in particular given its homogeneous properties when
compared to traditional solid-phase synthesis supports.11
Duplicating the reaction sequence presented in Schemes 2 and 3
resulted in isolation of enedicarboxylate 4 upon heating the toluene
suspension containing the oxidized JandaJel derivative. Starting
with 1.0 g of the thioanisole derived JandaJel 5 we obtained 30 mg,
unoptimized, of enedicarboxylate 4. The only difference with this
work when considering the mechanics of running the reaction itself
was that once the beads were given sufficient time to drop to the
bottom of the flask, the solvent system containing unreacted start-
ing material and by-product were removed by pipet.
With a series of organosulfides in hand, we next explored the
aspect of cleaving the C–S bond. The development of a fragmenta-
tion process was needed in that once a solution-phase method was
established; we were to go blind using identical reaction proce-
dures with not thioanisole but a polymer-supported thioanisole
derivative. Scheme 3 presents the key steps of our approach. While
a b-hydrogen is needed for a b-elimination, selective cleavage of
the C–S bond using an oxidant which preferentially reacts with
the sulfur atom makes this an attractive method. Even though this
strategy results in the formation of an alkene upon b-elimination, it
does avoid the use of less than desirable reagents such as
O
S
O
O
S
O
O
O
EtO
OEt
EtO
O
OEt
mCPBA
toluene
110oC
EtO
OEt
+
3
CH2Cl2
0oC
(98%)
15:85 (4:3) after 3h
44:53 (4:3) after 12h
2
3
4
Scheme 3.

D. C. Forbes et al. / Tetrahedron Letters 50 (2009) 1855–1857
1857
References and notes
CH3
1. Groebel, W. Chem. Ber. 1959, 92, 2887.
S
2. For preparation, see: (a) Abe, Y.; Nakabayashi, T.; Tsurugi, J. Bull. Chem. Soc. Jpn.
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B. C.; Noltes, J. G. Inorg. Nucl. Chem. Lett. 1971, 7, 63; (d) Harpp, D. N.; Aida, T.;
DeCesare, J.; Tisnes, P.; Chan, T. H. Synth. Commun. 1984, 1037.
3. For synthetic use, see: (a) Mukaiyama, T.; Kobayashi, S.; Kumamoto, T.
Tetrahedron Lett. 1970, 59, 5115; (b) Furukawa, M.; Suda, T.; Hayashi, S.
Synthesis 1974, 282; (c) Mukaiyama, T.; Kobayashi, S.; Kamio, K.; Takei, H.
Chem. Lett. 1972, 237; (d) Walker, K. A. M. Tetrahedron Lett. 1977, 51, 4475; (e)
Torii, S.; Sayo, N.; Hideo, T. Chem. Lett. 1980, 695; (f) Huang, C.-H.; Liao, K.-S.;
De, S. K.; Tsai, Y.-M. Tetrahedron Lett. 2000, 41, 3911.
4. (a) Shcherbakova, I.; Pozharskii, A. F.. In Comprehensive Organic Functional
Group Transformations II; Katritzky, A. R., Taylor, R. J. K., Eds.; Elsevier Ltd:
Oxford, UK, 2005; Vol. 2, p 89; (b) Taylor, P. C.; Parrett, M. R. Annu. Rep. Prog.
Chem. Sect. B: Org. Chem. 2007, 103, 47; (c) Skabara, P. J. Annu. Rep. Prog. Chem.
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H3C
S
CH3
S
O
5
O
Figure 1. Commercially available thioanisole functionalized JandaJel 5.
5. (a) Forbes, D. C.; Standen, M. C.; Lewis, D. L. Org. Lett. 2003, 5, 2283; (b) Forbes,
D. C.; Amin, S. R.; Bean, C. J.; Standen, M. C. J. Org. Chem. 2006, 71, 8287; (c)
Forbes, D. C.; Bettigeri, S. V.; Patrawala, S. A.; Pischek, S. C.; Standen, M. C.
Tetrahedron 2009, 65, 70; (d) Forbes, D. C.; Bettigeri, S. V.; Amin, S. R.; Bean, C. J.;
Law, A. M.; Stockman, R. A. Synth Commun., in press.
While it is unfortunate that the by-product of the thermolysis
reaction, phenylsulfenic acid, does rapidly dimerize to form a thio-
sulfinate,12 we were pleased to see that each malonate intermedi-
ate prepared in solution could be unambiguously identified using
just the benzylic proton(s) by 1H NMR thus adding the value of this
synthetic sequence as a teaching exercise. Had the dimerization
process be slower under these reaction conditions, a direct method
toward the regeneration of organosulfide 1 both in solution and as
a derivative bound to polymer-support would be possible. Efforts
which address reuse of this polymer-supported material and appli-
cation toward the grafting, assembly, and releasing of materials in
multi-step processes are currently underway, and will be reported
in due course.
6. Grossert, J. S.; Dubey, P. K. J. Chem. Soc., Chem. Commun. 1982, 1183.
7. Representative reaction procedure: To
a dichloromethane (5 mL) solution
consisting of thioanisole (0.12 g, 1.0 mmol) was added NBS (0.27 g, 1.5 mmol)
portionwise at room temperature. The reaction mixture was allowed to stir for
a period of 24 h at room temperature at which time all volatiles were removed
in vacuo. The resulting slurry was then recrystallized using CH2Cl2/hexanes
(1:6) to afford 0.20 g (0.98 mmol) of phenyl succinimidyl sulfide (1) in 98%
yield. Organosulfide 1 was then added neat to a solution of acetonitrile (5 mL)
containing diethyl benzylmalonate (0.25 g, 1.0 mmol) and potassium
carbonate (0.20 g, 1.5 mmol) having been allowed to react for a period of
30 min at room temperature. After addition of the sulfide (1.0 mmol), the
reaction mixture was allowed to stir at room temperature for a period of 60 h
at which time 30 mL of dichloromethane was added and subsequently washed
with water. The organic phase was then dried using MgSO4, concentrated in
vacuo, and purified by column chromatography to afford 0.34 g (0.93 mmol)
diethyl benzyl(phenylthio)malonate in 93% yield.
8. Representative reaction procedure:
A
dichloromethane (5 mL) solution
Acknowledgments
consisting of organosulfide 2 (0.36 g, 1.0 mmol) was cooled to 0 °C at which
time mCPBA (0.21 g, 1.2 mmol) was added portionwise. The reaction mixture
was allowed to gradually warm to room temperature and stir for a period of
30 min. The reaction mixture was then neutralized using NaHCO3 and washed
with water. The organic phase was dried using MgSO4, concentrated in vacuo,
and purified by column chromatography to afford 0.37 g (0.98 mmol) of
organosulfoxide 3 in 98% yield. Organosulfoxide 1 was then redissolved in
D.C.F. would like to thank the helpful suggestions made during
the review process of this Letter. DCF would like to recognize NIG-
MS (NIH NIGMS 1R15GM085936), NSF (CHE 0514004), and the Ca-
mille and Henry Dreyfus Foundation (TH-06-008) for partial
funding of this research. D.C.F would like to thank Professor Patrick
Toy (University Hong Kong) for his generous donation of a thioani-
sole grafted JandaJel. B.P.F. would like to thank NSF for summer
sponsorship over the 2007 and 2008 summer months. J.A.K. would
like to acknowledge financial support through the Alabama Space
Grant Scholars Program and the University of South Alabama
(UCUR and University Honors Program).
toluene (5 mL) and externally warmed to reflux using
a sand bath. The
refluxing solution was monitored by NMR. After 12 h, NMR analysis revealed
44% conversion to the desired product. The analytical data of
diethylbenzylidenemalonate obtained matched that of commercial material.
9. Kametani, T.; Yukawa, H.; Honda, T. J. Chem. Soc., Chem. Commun. 1988, 685.
10. Hoye, T. R.; Caruso, A. J.; Magee, A. S. J. Org. Chem. 1982, 47, 4152.
11. (a) Solinas, A.; Taddei, M. Synthesis 2007, 16, 2409; (b) Kan, J. W.; Toy, P. H. J.
Sulfur Chem. 2005, 26, 509. and references cited therein.
12. Davis, F. A.; Billmers, R. L. J. Org. Chem. 1985, 50, 2593.