Iodine-catalyzed thioallylation of indoles using Bunte salts prepared from Baylis-Hillman bromides

Article abstract of DOI:10.1039/d1ob00377a

Metal-free iodine-catalyzed regioselective thioallylation of indoles has been accomplished at room temperature using Bunte salts prepared from Baylis-Hillman bromides. The resulting multi-functional C3 thioallylated indoles exhibit ample structural divers

Full text of DOI:10.1039/d1ob00377a

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Iodine-catalyzed thioallylation of indoles using
Bunte salts prepared from Baylis–Hillman
bromides†
Cite this: Org. Biomol. Chem., 2021,
9, 3484
1
Prince Kumar Gupta, Arvind Kumar Yadav, Anup Kumar Sharma and
Krishna Nand Singh
*
Received 26th February 2021,
Accepted 19th March 2021
Metal-free iodine-catalyzed regioselective thioallylation of indoles has been accomplished at room temp-
erature using Bunte salts prepared from Baylis–Hillman bromides. The resulting multi-functional C3
thioallylated indoles exhibit ample structural diversity and good functional group tolerance.
DOI: 10.1039/d1ob00377a
rsc.li/obc
suffer from poor substrate scope with undesired by-product
formation. The idea of the present work stemmed from the
Introduction
Indoles constitute a vital core of many natural products and work of Zhang and Luo’s group, who recently developed a cata-
biologically active compounds capable of binding to many lytic synthesis of 3-thioindoles using a Bunte salt as the
1
11
receptors with high affinity. Indole thioethers are particularly sulphur source under metal-free conditions. Bunte salts
important due to their therapeutic value in treating obesity, (RSSO Na) are stable crystalline solids with no foul odour, are
3
2
,3
cancer and allergies. For instance, MCF-7 (I) is used as a cell easy to handle, can be conveniently prepared by the reaction of
growth inhibitor, 5-chloro-3-(phenylthio)-1H-indole-2-carboxa- inexpensive sodium thiosulfate with alkyl/aryl halides, and are
mide (II) as a HIV inhibitor, and 3-((4-fluorophenyl)thio)-2- valuable synthetic intermediates. In view of the above, it was
methyl-6-(methylsulfonyl)-1H-indole as a COX-2 inhibitor (III) envisioned that Bunte salts of Baylis-Hillman bromides could
4
5
12
(Fig. 1).
be prepared, followed by their reaction with indoles to accom-
Therefore, the synthesis and functionalization of indoles plish diverse thioallylated products with multi-reactive sites.
6
has always been a focal point of research in organic synthesis.
The Baylis–Hillman (BH) reaction has undergone intensive
Indoles readily undergo electrophilic substitution to form research to access various functionalized organic molecules
7
carbon–carbon and carbon–heteroatom bonds; however, the employing BH-alcohols, BH-bromides, BH-acetates, aza-BH
1
3
selective functionalization of indoles is somewhat difficult. In adducts etc. Baylis–Hillman (BH) bromides are widely used
particular, the C3 functionalization of indoles in an efficient as functionalized α,β-unsaturated olefin derivatives and are
way is exigent as it provides easy access to pharmaceutically amenable to many alterations due to the presence of multi-
8
active molecules. In this perspective, the sulfenylation of reactive functionalities.
indoles is immensely important because of the broad spec-
trum biological activities of the resulting products. The C3 C–S bond formation, we report herein a facile molecular
sulfenylation of indoles has been accomplished by the use of iodine-catalyzed synthesis of thioallylated indoles (3) by the
In view of the above and as part of our ongoing research on
9
14
1
0a
many sulfenylating reagents such as sulfonyl hydrazides,
reaction of indoles (1) with Bunte salts (2) derived from Baylis–
Hillman bromides in DMSO at room temperature (Scheme 1).
1
0b
10c
10d,e
sulfenyl halides,
N-thioimides,
sulfonium salts,
1
0f,g
10h
10i
thiols,
finic acid.
disulfides,
quinone mono-O,S-acetals, and sul-
However, most of these reagents are expensive,
1
0j,k
foul-smelling, and unstable towards air or moisture. Moreover,
the sulfenylation reactions of indoles frequently require an
excess of the reagents/additives with harsh conditions and
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi
221005, India. E-mail: knsinghbhu@yahoo.co.in, knsingh@bhu.ac.in
†
Electronic supplementary information (ESI) available. CCDC 2056356. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1ob00377a
Fig. 1 Some biologically active thiolated indoles.
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(
entry 11); however, a decrease in the catalyst loading from
20 mol% to 10 mol% diminished the product yield appreciably
(
entry 12). Markedly, the reaction in the absence of I
2
remained ineffective (entry 13). Some other iodine based cata-
lysts viz., TBAI, KI, NH I and NIS were also tried in DMSO
4
(
entries 14–17) but they could not surpass the efficacy of mole-
cular iodine.
Scheme 1 C3-thioallylation of indoles.
After having established the optimized conditions (entry 6),
the scope of the reaction was then scrutinized using different
indoles (1) and the Bunte salts (2). The outcome is shown in
Table 2.
A diverse array of both reacting partners participated nicely
under the optimized conditions to afford the desired products
Results and discussion
The study was commenced by using a mixture of indole 1a
(1.0 mmol), Bunte salt 2a (1.0 mmol) obtained from BH- 3a–3v in reasonably high yields. Although indoles having sub-
bromide, and molecular iodine (20 mol%) in methanol while
stituents such as Me, OMe, and Br worked exceedingly well in
stirring in open air at room temperature for 10 h, which led to
the reaction to afford the corresponding products, C2-substi-
the formation of the desired product (E)-2-(((1H-indol-3-yl) tuted indoles such as 2-methylindole and 2-phenylindole
thio)methyl)-3-(p-tolyl)acrylonitrile (3a) as a single regioisomer
in 30% yield (Table 1, entry 1). Intrigued by this observation,
remained especially impressive. When 5-cyanoindole,
-nitroindole, 7-azaindole and C3-substituted indoles such as
5
the model reaction was thoroughly investigated using different 3-methylindole were employed under the stipulated con-
catalysts and solvents (Table 1).
ditions, no conversion to the expected product occurred. 1,3,5-
Using I (20 mol%) in solvents such as DMF, CH CN, THF
2
3
and 1,4-dioxane brought about a substantial increase in the
product yield (entries 2–5); but to our utmost pleasure, the use
of DMSO made a phenomenal improvement in the yield (entry
a,b
Table 2 Scope and versatility of the reaction
6
). Nevertheless, the use of solvents like DCE, DCM, toluene
and p-xylene remained poor (entries 7–10). Then the effect of
catalyst loading was explored. Increasing the catalyst concen-
tration (30 mol%) could not enhance the product yield further
a
Table 1 Optimization of reaction conditions
b
Entry
Catalyst (mol%)
Solvent
CH OH
Yield (%)
1
2
3
4
5
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
(20.0)
(20.0)
(20.0)
(20.0)
(20.0)
(20.0)
(20.0)
(20.0)
(20.0)
(20.0)
(30.0)
(10.0)
3
30
50
60
62
70
90
32
29
30
28
90
80
0
DMF
CH CN
3
THF
1,4-Dioxane
DMSO
DCE
c
6
7
8
9
DCM
Toluene
p-Xylene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
—
TBAI (20.0)
KI (20.0)
30
20
35
25
4
NH I (20.0)
NIS (20.0)
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), catalyst
a
(
20 mol%), solvent (1.5 mL), room temperature (in open air), 10 h.
2
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), I (20 mol%),
b
b
c
Isolated yield after column chromatography. The bold entry 6 rep- DMSO (1.5 mL), room temperature (in an open air), 10 h. Isolated
resents the optimized reaction conditions.
yield after column chromatography.
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Trimethoxybenzene and other heterocyclic compounds like
imidazole, benzothiazole, and isoquinoline were also tried but
did not work under the established conditions. The Bunte
salts 2 prepared from the corresponding BH-bromides having
substituents such as Me, OMe, Cl on the aryl part and CN on
the alkene component participated well to afford the corres-
ponding products. It was observed that the presence of an elec-
tron donating group on the aromatic ring of the Bunte salts 2
afforded a somewhat higher yield in comparison with those
bearing an electron-withdrawing group. Interestingly, the reac-
Scheme 3 Control experiments.
tion proceeds with complete Z-stereochemistry of the product
1
3
which was assigned on the basis of the H chemical shifts of
the vinylic/allylic protons and NOESY spectrum (see the ESI†).
To demonstrate the synthetic utility of the method, a gram
scale reaction using 1a (0.585 g, 5 mmol) and 2a (1.455 g,
5
mmol) was carefully carried out under the optimized con-
ditions (Scheme 2), which led to the formation of the product
3
a with a slightly diminished yield (1.247 g, 82%).
All the products are new and have been fully characterized
1
13
based on their NMR ( H & C), NOESY and HRMS data. The
PMR spectrum of the D O exchanged product 3a (ESI†)
2
excludes the possibility of NH substitution in the indole.
Furthermore, the structure of the representative product 3v
was conclusively confirmed by single crystal X-ray analysis
Scheme 4 Plausible mechanism.
(Fig. 2).
To get an insight into the reaction mechanism, some
control experiments were carried out (Scheme 3). Bunte salt 2a
alone (without 1a) under the standard conditions gave rise to a
dimeric intermediate A (Scheme 3, eqn (1)), which was con-
firmed by NMR and HRMS. The isolated intermediate A, when
discretely allowed to react with 1a under the standard con-
ditions, afforded the desired product 3a (85%, eqn (2)),
suggesting the intermediacy of A. However, when the standard
reaction proceeded under an inert atmosphere, the product 3a
was obtained only in 18% yield (Scheme 3, eqn (3)).
11
Based on product isolation and the existing literature,
plausible mechanism is outlined in Scheme 4. The Bunte salt
is presumed to react with H O to form the corresponding di-
a
2
2
sulfide intermediate A, which on subsequent reaction with
molecular iodine forms the electrophilic sulfenyl iodide (R–S–
I) B. The intermediate B then undergoes the regioselective
Friedel–Crafts reaction with indole 1 to form the intermediate
C, which on aromatization finally affords the thioallylated
indole 3. Oxidation of iodide by oxygen to molecular iodine
2
(I ) with in situ superoxide ion generation completes the cata-
1
5
lytic cycle.
Scheme 2 Gram scale synthesis of the product 3a.
Conclusions
In conclusion, a simple and regioselective C3-thioallylation of
indoles has been accomplished using easy to prepare Bunte
salts of Baylis–Hillman bromides at room temperature. The
methodology is endowed with a wide range of substrate scope
and functional group tolerance.
Conflicts of interest
Fig. 2 ORTEP diagram of the product 3v (CCDC: 2056356†).
There are no conflicts to declare.
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