Iodine-Catalyzed Facile Approach to Sulfones Employing TosMIC as a Sulfonylating Agent

Article abstract of DOI:10.1021/acs.orglett.7b00896

A novel iodine-catalyzed functionalization of a variety of olefins and alkynes and direct decarboxylative functionalization of cinnamic and propiolic acids with TosMIC to provide access to various vinyl, allyl, and β-iodo vinylsulfones is described. This simple, efficient, and environmentally benign approach employing inexpensive molecular iodine as a catalyst demonstrates a versatile protocol for the synthesis of highly valuable sulfones, rendering it attractive to both synthetic and medicinal chemistry.

Full text of DOI:10.1021/acs.orglett.7b00896

Letter
pubs.acs.org/OrgLett
Iodine-Catalyzed Facile Approach to Sulfones Employing TosMIC as a
Sulfonylating Agent
Lingaswamy Kadari, Radha Krishna Palakodety,* and Lakshmi Prapurna Yallapragada*
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500007, India
S
* Supporting Information
ABSTRACT: A novel iodine-catalyzed functionalization of a variety of
olefins and alkynes and direct decarboxylative functionalization of
cinnamic and propiolic acids with TosMIC to provide access to various
vinyl, allyl, and β-iodo vinylsulfones is described. This simple, efficient,
and environmentally benign approach employing inexpensive molecular
iodine as a catalyst demonstrates a versatile protocol for the synthesis of
highly valuable sulfones, rendering it attractive to both synthetic and
medicinal chemistry.
Scheme 1. Diversity of Reaction of TosMIC with Unsaturated
Compounds
he widespread popularity of sulfur-containing compounds
Tcan be attributed to their potential biological activity,
pharmaceutical significance, and synthetic utility.1 Among them,
organosulfone compounds are an important class of function-
alities and have drawn considerable interest of chemists owing to
their versatility as intermediates in organic synthesis and ability
to serve as building blocks in the construction of biologically
active molecules or functional materials.2 The sulfone function-
ality can serve as an activating, an electron-withdrawing, or a
good leaving group and can be employed as a temporary
modulator of chemical reactivity. Therefore, a variety of different
transformations are feasible with this functional group, so aptly
been described as a chemical chameleon by Trost.3 Traditionally,
sulfones are synthesized by the oxidation of corresponding
sulfides or sulfoxides, alkylation of sulfinate salts, Friedel−Crafts-
type sulfonylation of arenes, and addition reactions to alkenes
and alkynes.4 Because of their distinctive electronic and
structural features, the development of efficient approaches for
the synthesis of these molecules is an appealing and valuable task
in synthetic community.
Over the past decade, our group has been working to expand
the synthetic applications of TosMIC chemistry.8 In continu-
ation of that work, a novel access to various vinyl, allyl, and β-iodo
vinylsulfones employing TosMIC as a sulfonyl source is
described herein (Scheme 2). In this newly developed protocol,
Scheme 2. TosMIC-Mediated Synthesis of Various Sulfones
p-Toluenesulfonylmethyl isocyanide (TosMIC), a unique
isocyanide, is the most versatile synthon in organic chemistry.5
It could be used to prepare quite different products from the
same substrates by changing the reaction conditions. Therefore,
it has long been renowned for its diversity in numerous synthetic
transformations. In general, TosMIC undergoes base-mediated
1,3-dipolar cycloadditions with activated alkenes to provide
pyrroles as products (Scheme 1).6 We previously reported the
first examples of synthesis of oxazoles and pyrroles C-nucleosides
using TosMIC.7 This report details the synthesis of sulfones from
the same substrate molecules in the presence of iodine,
demonstrating the diversity of TosMIC.
Received: March 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00896
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Organic Letters
Letter
the addition of sulfonyl radical to unsaturated carbon takes place,
which is the most popular approach for synthesis of sulfones in
which sulfonyl halides,9 sulfonyl hydrazides,10 sulfinic acid,11 and
sodium sulfinate12 are generally used as precursors of sulfonyl
radicals. However, the notable advantages of the present reaction
such as TosMIC as a rapid sulfonyl source, simple, cheap, and
readily available iodine as an efficient catalyst, common and
nontoxic DMSO as a solvent medium, wide applicability, and
mild reaction conditions could make it as an effective
complement for current methods.
of the expected vinyl sulfone (Scheme 4). The formation of
allylic sulfone could be rationalized by the sulfonylation at the
a,b
Scheme 4. Synthesis of Allyl Sulfones from Methyl Styrenes
Based on the recent development of iodine mediated
reactions, we initiated our investigation with the reaction of
styrene 1aa and TosMIC 2 in the presence of 1 equiv of
molecular iodine using DMSO as a solvent. To our delight, the
corresponding vinyl sulfone 3aa was observed with 90% yield.
This promising result prompted us to optimize the reaction
conditions. The screening of various iodine sources (NIS,
PhI(OAc)2, CuI) and solvents (CH3CN, DCE, THF) shows no
product formation except with NIS, albeit in low yield. Thus, the
I2/DMSO system was found to be irreplaceable for sulfonylation
of olefins. Pleasingly, the transformation worked well even with a
catalytic amount of iodine (40 mol %) without a significant effect
on reaction time and yield. The increase in amount of TosMIC
did not improve the yield of 3aa.
a
Reaction conditions: 1ba (1.0 equiv), TosMIC (1.0 equiv) and I2
b
(0.4 equiv) in DMSO solvent at rt. Yields refer to isolated products
purified by column chromatography.
terminal double bond with the migration of the double bond.10b
The versatility of allylic sulfones to form C−C bonds via sulfonyl
carbanions motivated us to test a series of substituted α-
methylstyrenes (1bb−bi) under the standard conditions.
Gratifyingly, the reactions proceeded smoothly with high
regioselectivity, leading to the formation of the corresponding
allylic sulfones (3bb−bi) exclusively. Moreover, the reaction
shows high stereoselectivity. Thus, the α-ethylstyrenes 1bj gave
rise to the allyl sulfone 3bj as a single Z-isomer in 91%
yield.10b,11g The reaction of 3-chloro-α-ethylstyrenes 1bk
afforded 3bk in 88% yield. Similarly, when 1-cyclopropylvinyl-
benzene 1bl was used as the substrate 3bl was obtained as
product. This result demonstrates the sulfonylation at terminal
double bond with migration of the double bond followed by
cyclopropyl ring opening with iodine. The configuration of 3bk
and 3bl was established as “Z” on the basis of the same analogy.
Next, the present approach, i.e., sulfono functionalization
using TosMIC, was extended to acetylene functionality. The
iodine-catalyzed reaction of phenyl acetylene with TosMIC
resulted in the formation of the corresponding (E)-β-iodo vinyl
sulfone in 92% yield (Scheme 5). The recent report by Tiwari
and co-workers revealed nanocopper-catalyzed synthesis of (E)-
vinyl sulfones from the same substrates, i.e., terminal acetylenes
and TosMIC.13 However, the current approach provides a good
illustration of the diversity of TosMIC. A range of alkynes (4ab−
ai) bearing electronically varied groups (e.g., Me, Et, OMe, Cl,
Br, OMe, Ph, CN, CO2Me) on the phenyl ring were found to be
tolerant in these transformations, and the corresponding
products (5ab−ai) were obtained in good yields. The
sulfonylation of sterically hindered substrate 1-ethynylnaphtha-
lene 4aj with TosMIC also afforded the desired sulfone 5aj
effectively. (E)-But-1-en-3-yn-1-yl benzene 4ak could also be
successfully employed to afford the desired iodosulfonylation
product 5ak in 90% yield. However, the reaction of hex-1-yne did
not afford the desired product. Pleasingly, 3-ethynylthiophene
4al could be employed in the reaction to furnish the desired
product 5al in 82% yield. Notably, the internal alkynes 4ba−bc
could be converted to the corresponding products 5ba−bc,
although they are less reactive than others.
With the optimized reaction conditions in hand, a series of
styrenes were applied in the reaction to establish the scope and
generality of this protocol (Scheme 3). The results indicated that
a,b
Scheme 3. Synthesis of Vinyl Sulfones from Styrenes
a
Reaction conditions: 1aa (1.0 equiv), TosMIC (1.0 equiv), and I2
b
(0.4 equiv) in DMSO solvent at rt. Yields refer to isolated products
purified by column chromatography.
a wide range of substituted groups, such as methyl, chloro, fluoro,
bromo, methoxy, nitro, cyano, and ester (1ab−ak), were well
tolerated under the present conditions and afforded the
corresponding vinyl sulfones (3ab−ak) in good yields. The 2-
vinyl naphthalene 1al and α-phenyl styrene 1am were also
applied in the reaction successfully to provide the corresponding
vinyl sulfones 3al and 3am in 95 and 93% yields, respectively.
The heterocycle-derived alkene, 2-vinyl thiophene 1an, is well
tolerated and afforded 3an in 87% yield. However, the reactions
of 4-hydroxy styrene and N,N-dimethyl-4-vinylaniline failed to
give the corresponding products.
Interestingly, the reaction of α-methylstyrene 1ba provided
the corresponding allylic sulfone 3ba as the sole product instead
B
DOI: 10.1021/acs.orglett.7b00896
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Letter
(Scheme 7). To the best of our knowledge, this is the first
example of direct synthesis of halogenated vinyl sulfones from
Scheme 5. Synthesis of Iodo Vinyl Sulfones from
Acetylenes
a,b
Scheme 7. Synthesis of Iodo Vinyl Sulfones from Phenyl
a,b
Propiolic Acid
a
Reaction conditions: 4ca (1.0 equiv), TosMIC (1.0 equiv) and I2 (0.4
b
equiv) in DMSO solvent at 80 °C. Yields refer to isolated products
purified by column chromatography. No significant improvement in
c
the yield of the product was observed with further increase of the
amount of catalyst.
arylacetylenic acid. The previous related work shows synthesis of
either vinyl or acetylenic sulfones as the products.12e,14 The
phenyl propiolic acids bearing substituents on the aromatic ring
such as CH3, Cl and OMe participated in the reaction to deliver
the products 5ab−af in 61−69% yields. It is worth mentioning
that the reactions were performed on each set of model
substrates, i.e., on a 1.0 g scale, to afford the corresponding
sulfones without significant effect on the yield, indicating that the
present reaction is scalable and practical.
a
Reaction conditions: 4aa (1.0 equiv), TosMIC (1.0 equiv) and I2 (0.5
b
equiv) in DMSO solvent at rt. Yields refer to isolated products
purified by column chromatography. No significant improvement in
the yield of the product was observed with further increase of the
amount of catalyst. The yield in parentheses refer to the yield
c
d
obtained with 0.4 equiv of iodine.
In general, the decarboxylative sulfonylation of cinnamic acid
requires harsh conditions and long reaction time. Intrigued by
the above results, we envisioned TosMIC-mediated decarbox-
ylative sulfono functionalization of cinnamic acid 1ca under the
standard conditions. Nonetheless, we did not obtain any product
in the absence of base. To our delight, the desired (E)-1-methyl-
4-(styrylsulfonyl)benzene 3aa was obtained in the presence of
K2CO3, while the other bases (DBU, Cs2CO3) failed to furnish
the product. The optimum amount of K2CO3 was found to be 1
equiv. Next, the scope of substrates was investigated, and the
results are summarized in Scheme 6. Various cinnamic acid
To explore the mechanism for TosMIC-mediated sulfono
functionalization, we carried out some control experiments
(Scheme 8). In the presence of TEMPO, a common radical
Scheme 8. Control Experiments
a,b
Scheme 6. Synthesis of Vinyl Sulfones from Cinnamic Acid
scavenger the reaction of styrene and TosMIC under standard
conditions was almost ceased. This result suggests that the
reaction have proceeded through a radical mechanism. It is worth
pointing out that, during the optimization studies, the reaction of
styrene and TosMIC mediated by NIS (instead of iodine)
resulted in the formation of 3aa, attesting the generation of
sulfonyl radical from TosMIC. The reaction of styrene with 4-
methylbenzene 1-sulfonyl iodide (A)15 without TosMIC and
iodine furnished 3aa in 78% yield. The result suggested that A
might be the possible intermediate in this transformation.
On the basis of the control experiments, we propose a possible
mechanism as shown in Scheme 9. Initially, the interaction of
iodine with TosMIC generates p-toluenesulfonyl iodide A with
the concomitant formation of iodine radical. Thus, formed p-
toluenesulfonyl iodide underwent homolytic clevage to generate
sulfonyl radical B, which then reacted with styrene 1aa to
generate the reactive alkyl radical C. Subsequently, the radical C
is combined with iodine radical to give the intermediate D.
Finally, the intermediate D undergoes elimination of HI to
a
Reaction conditions: 4ca (1.0 equiv), TosMIC (1.0 equiv), and I2
b
(0.4 equiv) in DMSO solvent at 80 °C. Yields refer to isolated
products purified by column chromatography
derivatives 1cb−ch, which have substituents on the phenyl ring
(CH3, Cl, F, Br, OMe, NO2, CN), could proceed smoothly to
afford the corresponding products 3ab−ah in good yields.
Moreover, (E)-3-(thiophene-2-yl)acrylic acid 1cn, was also good
substrate for this transformation, affording the corresponding
product 3an in 84% yield.
The synthetic utility of the present protocol was further
extended to the decarboxylative coupling of phenyl propiolic acid
4ca. The reaction resulted in the formation of 5aa in 65% yield
C
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Letter
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restore the unsaturation to afford the desired vinyl sulfone 3aa.
The regeneration of molecular iodine takes place by the
oxidation of HI into molecular iodine along with the generation
of dimethyl sulfide and water.
In summary, we have demonstrated TosMIC-mediated novel
protocol that offers a convenient synthetic route to sulfones
under metal-free conditions. Mechanistically the formation of
sulfone is suggested to proceed via a radical mechanism. The
protocol exhibited experimental simplicity, short reaction time,
and high regio- and stereoselectivity with a broad substrate scope,
which suggests that this approach has potential applications in
organic synthesis. Further efforts to expand the substrate scope
and applications are currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ylprapurna.iict@gov.in.
*E-mail: prkgenius@iict.res.in.
ORCID
Lakshmi Prapurna Yallapragada: 0000-0002-8302-5582
Notes
The authors declare no competing financial interest.
(12) (a) Singh, A. K.; Chawla, R.; Yadav, L. D. S. Tetrahedron Lett.
2014, 55, 4742. (b) Taniguchi, N. Synlett 2012, 23, 1245. (c) Chawla, R.;
Singh, A. K.; Yadav, L. D. S. Eur. J. Org. Chem. 2014, 2014, 2032.
(d) Zhang, N.; Yang, D.; Wei, W.; Yuan, L.; Cao, Y.; Wang, H. RSC Adv.
2015, 5, 37013. (e) Meesin, J.; Katrun, P.; Pareseecharoen, C.;
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Chem. 2016, 81, 2744. (f) Sun, Y.; Abdukader, A.; Lu, D.; Zhang, H.; Liu,
C. Green Chem. 2017, 19, 1255.
ACKNOWLEDGMENTS
■
Dr. Y. Lakshmi Prapurna thanks Department of Science and
Technology (DST) for a financial grant under Women Scientists
Scheme-A (WOS-A), Grant No. SR/WOS-A/CS-1034/2014
(G). K.L.S. acknowledges UGC, New Delhi, for fellowship
support.
(13) Phanindrudu, M.; Tiwari, D. K.; Sridhar, B.; Likhar, P. R.; Tiwari,
D. K. Org. Chem. Front. 2016, 3, 795.
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D
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