Transition-Metal-Free Selective Oxidative C(sp3)-S/Se Coupling of Oxindoles, Tetralone, and Arylacetamides: Synthesis of Unsymmetrical Organochalcogenides

Article abstract of DOI:10.1021/acs.orglett.6b03735

Transition-metal-free synthetic methods have been developed for the preparation of unsymmetrical diaryl and aryl alkyl chalcogenides: sulfones, sulfides, and selenides from the sp³-C-H bond of oxindole, tetralone, arylacetamide, and aryl chalco

Full text of DOI:10.1021/acs.orglett.6b03735

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Selective Oxidative C(sp3)−S/Se Coupling of
Oxindoles, Tetralone, and Arylacetamides: Synthesis of
Unsymmetrical Organochalcogenides
Ch. Durga Prasad, Moh. Sattar, and Sangit Kumar*
Department of Chemistry, Indian Institute of Science Education and Research (IISER), Bhopal, MP 462 066, India
S
* Supporting Information
ABSTRACT: Transition-metal-free synthetic methods have been developed for the preparation of unsymmetrical diaryl and aryl
alkyl chalcogenides: sulfones, sulfides, and selenides from the sp3-C−H bond of oxindole, tetralone, arylacetamide, and aryl
chalcogenide precursors. Sulfones were obtained from sodium sulfinates using potassium iodide, tert-butyl hydroperoxide in
DMSO, and acetic acid. Sulfides and selenides were prepared from diaryl disulfides or diselenides employing potassium tert-
butoxide in DMSO. α-Tetralone underwent concomitant chalcogenation and aromatization resulting in 2-chalcogenyl-1-
naphthols in one pot.
Scheme 1. Chalcogenation and Sulfonylation of Amides
he formation of the aryl C−E (S/Se) bond is one of the
Tfundamental reactions in synthetic chemistry, and it
constitutes a key step toward accessing a broad range of organic
molecules, which are prevalent in drugs, antioxidants, and metal
complexes.1−3 3-Chalcogenated, particularly thiolated and
sulfonated oxindoles are known to have promising anticancer,
antifungal, and antitubercular activities.4 For example, 3-
spirothiazolidinones are potent and selective inhibitors of
Mycobacterium tuberculosis protein tyrosine phosphatase B.4d 2-
Phenylchalcogenyl-l-naphthols have been proven to be potent 5-
lipoxygenase inhibitors and promising antioxidants.2c
The carbon−chalcogen coupling reactions were mainly
achieved in the following modes: (a) TM-catalyzed coupling of
aryl/alkyl halides with organochalcogenides (eq 1, Scheme 1)5
and (b) a conventional route in which aryl/alkyl dichalcogenides
were reacted with organolithium/Grignard reagents (eq 2) or in
another approach where lithium or magnesium organochalcoge-
nolatesweretreated withorganichalides(eq3).6 Thepreparation
of organolithium and Grignard reagents involves strict inert
conditions and often requires organohalide substrates. Moreover,
an excess of aryl dichalcogenide is required as the reaction
provides unsymmetrical diorganochalcogenide and lithium or
magnesium organochalcogenolate as the byproduct (eq 2). In
fact, sulfonylation7 and chalcogenation8 of the sp2 or sp3 C−H
bond of aromatic/aliphatic functionalities via direct C−H
functionalization were reported in the literature, while that of
the oxindole framework has not been reported to date.
using potassium tert-butoxide (KOtBu) as a base in dimethyl
sulfoxide (DMSO) for the synthesis of biologically important
organochalcogenides and also generated organothiolate or
selenolate oxidized in situ into the respective disulfide or
diselenide (eq 4). On the other hand, organosulfones were
obtained by enolization of amide followed by the addition of
sulfonyl radical, which was generated from the reaction of tert-
butyl hydroperoxide (TBHP) and potassium iodide (KI) with
sodium sulfinate (eq 5).
Here, we report the organochalcogenation of an sp3-C−H
bond of oxindole, phenylacetamide, and tetralone substrates by
Received: December 15, 2016
© XXXX American Chemical Society
A
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Letter
Owing to our continued interest in organochalcogen
chemistry9 and TM-free C−H functionalization,10 we attempted
the synthesis of 3-sulfonated oxindole using KOtBu by direct sp3
C−Hfunctionalizationofoxindoleemploying sodiumsulfinateas
the sulfonylating agent. However, the reaction failed to yield the
desired 3-sulfonated oxindole 1a despite several attempts (Table
1, entry 1). Next, we envisioned that an oxidant in the presence of
acidic conditions would accomplish the sulfonylation reaction.
one 1b in 47% yield, whereas the reaction with methanesulfinate
gave 3-methyl-3-(methylsulfonyl)indolin-2-one 1c in 39% yield.
The reaction of oxindole with methanesulfinate afforded 3-
(methylsulfonyl)indolin-2-one 1d in 57% yield. Next, the
reaction of N-methyloxindole with sodium p-toluenesulfinate
gave 1-methyl-3-tosylindolin-2-one 1e in 58% yield, while the
reaction with sodium benzenesulfinate provided 1-methyl-3-
(phenylsulfonyl)indolin-2-one 1f in 70% yield.
Later, the scope of N-methyloxindoles having substituents on
the phenyl ring was investigated under the optimized reaction
conditions of the sulfonylation reaction. Irrespective of the
electronic effect of the substituent attached to the phenyl ring, the
corresponding sulfonated products were formed in decent yields.
The reaction of N-methyloxindoles with electron-deficient
substituents such as bromo and chloro resulted in 59−66% yields
of the respective sulfonated products 1g, 1i−1k. In the case of the
reaction with an electron-rich methoxy group substituted N-
methyloxindole, a poor yield of the product 1h was obtained. The
same reaction of oxindole with a free N-H group gave a 58% yield
of the sulfonated indole 1l. 3-Benzyl-substituted oxindole was not
compatible in the sulfonylation reaction to form quaternary-
centered 3-sulfonated oxindole.
a
Table 1. Survey of Reaction Conditions
entry
iodine source
−/KOtBu
solvent
DMSO
yield (%)
1
2
ND
ND
32
−
KI
DMSO/AcOH (1:1)
DMSO/AcOH (1:1)
DMSO/AcOH (1:1)
b
3
4
KI
70
a
Reaction was carried out using oxindole (0.2 mmol), sodium p-
Next, we turned our attention to the synthesis of another class
of biologically important 3-chalcogenyl oxindoles (Scheme 3).
toluene sulfinate (0.4 mmol), iodine source (1 equiv), and TBHP (1
b
equiv) in solvent (1 mL) at 80 °C for 4 h. TBHP was not added. ND
= not detected.
a
Scheme 3. Synthesis of 3-Chalcogenyloxindoles
Unfortunately, with TBHP alone as an oxidant, the reaction did
not occur (entry 2, Table 1). The addition of 1 equiv of KI along
with TBHP gave 70% yield of the desired product 1a (entry 4,
Table 1; for details on optimization of reaction conditions, see the
SI). The structure of 1a was also confirmed by single-crystal X-ray
diffraction study (CCDC No. 1474948).
With the optimized reaction conditions in hand, we
investigated the scope of oxindoles in the reaction system
(Scheme 2). In most cases, oxindoles were smoothly converted to
the corresponding sulfonated oxindoles in moderate to good
yields. Oxindoles with a free N-H group as well as N-protected
groupsreactedwell, andtherespectivesulfonated products1a−1l
were obtained. For example, the reaction of 3-methyloxindole
with sodium p-toluenesulfinate gave 3-methyl-3-tosylindolin-2-
a
Scheme 2. Scope of 3-Sulfonated Oxindoles
a
Reaction was performed using aryl disulfide (0.3 mmol), oxindole
(0.6 mmol), and KOtBu (0.66 mmol) in DMSO (1 mL) at rt for 6 h
b
unless otherwise mentioned. Crystal structure of 2k (CCDC No.
1500696).
We attempted the sulfenylation reaction with phenyl disulfide
under the optimized KI-mediated conditions. Unfortunately, the
sulfenylation reaction was not clean, and formation of the
complex reaction mixture was observed. Next, we thought a base
could promote the sulfenylation reaction by a nucleophilic attack
a
Reaction was performed using oxindole (0.5 mmol), sulfinate salt (1
mmol), KI (1 equiv), and TBHP (1 equiv) in AcOH/DMSO = 1:1 (1
mL) at 80 °C for 4 h unless otherwise mentioned.
B
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a
of in situ generated carbanion from oxindole to disulfides or thiols
(Scheme 1, eq 4).
Scheme 4. Chalcogenation of Acetamides and α-Tetralone
As we have already explored KOtBu as a promoter in carbon−
carbon coupling reactions,10 we attempted the sulfenylation
reaction of oxindole with benzenethiol using the same conditions.
Benzenethiol gave the 3-sulfenylated oxindole 2a in low yield
(20%). However, the complete conversion of benzenethiol into
disulfide was noticed. Hence, phenyl disulfide was used as the
source of sulfur. Indeed, a considerable increase in the yield of 2a
was observed. Tuning the stoichiometry to 0.3 mmol of phenyl
disulfide, 0.6 mmol of oxindole, and 1.1 equiv of KOtBu inDMSO
at room temperature resulted in the respective 3-sulfenyloxindole
2a in 85% yield.
With these conditions in hand, we then explored the scope of
this method utilizing various disulfides. It was found that different
substituted disulfides are compatible in this reaction and afforded
structurally diverse 3-sulfenyloxindoles in 43−92% yields
(Scheme 3). At first, various aromatic disulfides were tested
under our reaction conditions. For example, the reaction of 2-
oxindole with p-tolyl disulfide provided 3-(p-tolylthio)indolin-2-
one 2b in 79% yield. The reaction of substituted phenyl disulfides,
especially with electron-poor substituents such as chloro and
fluoro groups, resulted in an excellent outcome of the
corresponding 3-sulfenylindoles 2c and 2d. An attempted
reaction of oxindole with an aliphatic substrate, n-hexyl disulfide,
was also successful to afford 3-(hexylthio)indolin-2-one 2e, albeit
in low yield. Likewise, a reaction of oxindole with a
heteroaromatic substrate, 2-pyridyl disulfide, gave 3-(pyridin-2-
ylthio)indolin-2-one2fin85%yield. Thenthescopeofthephenyl
ring substituted oxindoles were tested to check the viability of the
reaction system. The reaction of oxindoles with electron-deficient
substituents such as bromo and chloro resulted in 72−92% yields
of the respective sulfenylated products 2g−2i.
a
Aryl dichalcogenide (0.5 mmol), substrates (1 mmol), and KOtBu
(1.1 mmol for 3a−3c and 2.2 mmol for 4a−4c) were used unless
otherwise mentioned.
conditions are also required to generate the aryl chalcogenenium
ion (ArS+/ArSe+).
Here, we could access 2-chalcogenyl-1-naphthols 4a−4c using
this method in decent yields. Moreover, the addition of selenium
powder to 3-methyloxindole under the present reaction
conditions provided 3,3′-diselanediylbis(3-methylindolin-2-
one) 5 in 64% yield (Scheme 5).
Scheme 5. Formation of Diselenide 5 and 3-Sulfonylindoles
The beauty of this method lies in the successful extension to
prepare the quaternary-centered 3-sulfenyloxindoles. 3-Benzy-
loxindole, on reaction with phenyl disulfide, provided 3-benzyl-3-
(phenylthio)indolin-2-one 2j in 91% yield. The substituents on
either phenylring ofoxindoleorthatofaryldisulfidedidnotaffect
the elegance of the current reaction system in affording the
corresponding 3,3-disubstituted sulfenyloxindoles 2k, 2l. Gratify-
ingly, phenyl diselenide was also compatible with the reaction
system (Scheme 3). 3-Benzyloxindoles, on reaction with phenyl
diselenide, gave the respective selenenyl products 2m−2o in
modest yields. Unfortunately, phenyl ditelluride could not afford
the respective tellurated oxindole; instead, 3-hydroxyoxindole
was formed as the major product.
To check the versatility of the present reaction, we attempted a
reaction of linear amide (2-phenylacetamide) with phenyl
dichalcogenide (Scheme 4). Indeed, chalcogenated phenyl-
acetamides 3a−c were obtained in moderate to good (55−
75%) yields.
α-Tetralone, a cyclic ketone, was also tested under the reaction
conditions(Scheme4). Unexpectedly, itresultedintheformation
of 2-chalcogenyl-1-naphthols 4a−4c by concomitant chalcoge-
nation and aromatization (Scheme 4). 2-Hydroxyaryl chalcoge-
nides were proven to be good antioxidants.2c The previous routes
for the synthesis of these compounds involve two steps: lithiation
of 2-bromoaryl alcohol followed by addition of diaryl
dichalcogenide to the resulting dianion.2e In another approach,
electrophilic selenation of phenol provided 2-hydroxyaryl
selenide.9a Nonetheless, the para-position needs to be blocked
in order to obtain ortho as a major product, and harsh reaction
Thesynthetic utilityof the synthesized 3-sulfonyloxindoles was
then explored by using Schwartz reagent to obtain the respective
3-sulfonylindoles (Scheme 5). 3-Tosylindolin-2-ones 1a and 1g,
on reaction with Schwartz reagent, provided 3-tosyl-1H-indoles
6a and 6b in 64 and 60% yields, respectively.
A plausible mechanism for the sulfonylation reaction is
depicted in Scheme 6 based on the obtained results and control
experiments. OxindolecanreversiblyexistinanenolformAinthe
presence of acetic acid. TBHP converts iodide into iodine radical.
Aryl sulfinate ion could be transformed by a single-electron
transfer (SET) to a sulfinate radical at the expense of the iodine
radical. Sulfinateradicals exhibit reactivity bywayof sulfurtoform
a sulfonate radical, which then added to the CC bond of enol A
to form radical intermediate B, which would undergo the transfer
of electron followed by proton transfer to the iodine radical
leading an elimination of HI and concomitant generation of 3-
arylsulfonated indole (1a).
In an aryl chalcogenation reaction, oxindole undergoes
deprotonation in the presence of KOtBu to form α-carbanion C
that can reversibly exist in an oxy anion, which on reaction with
dichalcogenide forms 3-chalcogenyloxindole. On the other hand,
phenyl chalcogenolate anion would oxidize back to the aryl
C
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Scheme 6. Mechanism for the Sulfonylation and
Chalcogenation
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ASSOCIATED CONTENT
■
S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b03735.
Experimental details, NMR spectra, and X-ray crystallo-
graphic data (PDF)
X-ray data for compound 1a (CIF)
X-ray data for compound 2k (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sangitkumar@iiserb.ac.in.
ORCID
Ch. Durga Prasad: 0000-0002-6473-8405
Sangit Kumar: 0000-0003-0658-8709
Notes
(9) (a) Prasad, C. D.; Balkrishna, S. J.; Kumar, A.; Bhakuni, B. S.;
Shrimali, K.; Biswas, S.; Kumar, S. J. Org. Chem. 2013, 78, 1434.
(b) Kumar, A.; Kumar, S. Tetrahedron 2014, 70, 1763. (c) Prasad, C. D.;
Verma, A.; Sattar, M.; Kumar, S. RSC Adv. 2015, 5, 75881.
(10) (a) Kumar, S.; et al. Org. Lett. 2015, 17, 82. (b) Rathore, V.; Sattar,
M.; Kumar, R.; Kumar, S. J. Org. Chem. 2016, 81, 9206. (c) Kumar, S.;
Kadu, R.; Kumar, S. Org. Biomol. Chem. 2016, 14, 9210.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.K. thanks DST-SERB (EMR/2015/000061), New Delhi, and
IISER Bhopal for generous funding. C.D.P. and M.S. thank UGC,
CSIR, New Delhi, for their fellowships.
D
DOI: 10.1021/acs.orglett.6b03735
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