Design and application of intramolecular vinylogous Michael reaction for the construction of 2-alkenyl indoles

Article abstract of DOI:10.1039/d0cc06564a

A base-mediated transformation based on a designed intramolecular vinylogous Michael addition (intra-VMA) is presented to access 3-substituted 2-alkenyl indole derivatives. The reaction represents the first example of the intra-VMA for the construction of

Full text of DOI:10.1039/d0cc06564a

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DOI: 10.1039/D0CC06564A
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Design and Application of Intramolecular Vinylogous Michael
Reaction for the Construction of 2-Alkenyl Indoles
Battu Harish,a,b Sanjay Yadav,a,b and Surisetti Suresh*,a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A
base-mediated transformation planned on a designed
intramolecular vinylogous Michael addition (intra-VMA) is
presented to access 3-substituted 2-alkenyl indole derivatives. The
reaction represents the first example of the intra-VMA for the
construction of indoles. One-pot N-allylation of ortho-
tosylamidocinnamates/congeners
with
γ-bromocrotonates
followed by intra-VMA has been described to provide access to a
diverse range of 2-alkenyl indole derivatives in high yields. The
synthetic value of the developed intra-VMA has been
demonstrated by gram-scale synthesis of a representative indole
derivative and also in the formal synthesis of MK-7246: a Merck’s
clinical CRTH2 antagonist.
Fig
1
Representative biologically/therapeutically
important 2-alkenyl-3-substituted indoles.
oxidative amination of furans to produce 2-alkenyl indoles.8
Seo and Cheon reported a cyanide-catalyzed intramolecular
imino-Stetter reaction for the synthesis of 2-alkenyl indoles.9
Recently, we disclosed an NHC-catalyzed imine umpolung
strategy for the synthesis of 2-alkenyl indoles.10 On the other
hand, the vinylogous principle has emerged as one of the
important reaction strategies to construct C‒C bonds and the
resulted structural motifs are embedded with an additional
alkenyl functionality.11 Although the vinylogous variant of the
Michael (conjugate) addition reaction has been well-explored,
most of the reported methods describe the intermolecular
versions (Scheme 1a).12 The intra-VMA is still an
underexplored reaction in spite of its potential to access useful
carbo- and heterocyclic systems comprising an intact double
bond that can be applicable to further organic
transformations.13 We have previously shown that intra-VMA
followed by aromatization of ortho-O-allyl cinnamates resulted
in the generation of substituted benzofurans involving the
migration of the exo-double bond (Scheme 1b).14
The indole core has been inspiring organic chemists and drug
discovery research teams from the academia and industry.1
This is due to the reasons that indole framework is of
paramount importance owing to its ubiquitous presence in the
natural products, the molecules essential for life-processes
and life-saving drugs.2 Probably, the construction of the indole
nucleus has ranked as the highly attracted problems and
resulted in the development of several 'named' reactions.3 The
development of new methods to construct 2,3-disubstituted
indoles has received significant attention from the synthetic
community.4 Among them, in particular, 2-alkenyl substituted
ones have received considerable attraction due their
interesting chemistry and potential biological profiles (Figure
1).5 The methods to access 2-alkenyl-3-substituted indoles
include transition metal-mediated C‒H functionalization of
indoles at C2-position with alkenyl partners.6 The groups of
Fukuyama and Chatani, independently, reported palladium-
catalyzed cross coupling of C2 pre-functionalized indole and
alkenyl partners to access 2-alkenyl indoles.7 Gevorgyan and
co-workers reported an intramolecular palladium-catalyzed
We became interested to explore the intra-VMA chemistry to
construct indole core (Scheme 1c). The indole nucleus has
earned “privileged structure” status in medicinal
chemistry/drug discovery processes.15 We envisaged and
designed the precursor 3a possessing essential elements for the
intra-VMA and 3a can in turn be accessed from the reaction of o-
tosylamidocinnamate 1a and γ-bromocrotonate 2a.
a. Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of
Chemical Technology (CSIR-IICT), Hyderabad 500 007, India. E-mail:
surisetti@iict.res.in; suresh.surisetti@yahoo.in.
b. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India .
Electronic Supplementary Information (ESI) available: Electronic Supplementary
Information (ESI) available: Experimental procedures, spectral data, copies of NMR
spectra for products. See DOI: 10.1039/x0xx00000x
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DOI: 10.1039/D0CC06564A
Scheme 2 The base-mediated intra-VMA.
Table 1 Optimization studya
Scheme 1 Intermolecular- and intramolecular-vinylogous
Michael addition reactions
Entry
Base
Solvent Temp
(oC)
%yield
of 5ab
%yield of
3ab
According to our hypothesis, treatment of 3a with a base would
generate a carbanion on the active methylene adjacent to nitrogen,
which can be stabilized by the double bond of the α,β-unsaturated
ester moiety. Intramolecular addition of the carbanion to the other
conjugate acceptor in 3a would produce dihydroindole 4a. Thus
generated dihydroindole 4a (i) would undergo a base-mediated
elimination of tosyl group followed by aromatization to lead to 3-
subsituted 2-alkenyl indole derivative 5a (or) (ii) 2-exo-double bond
migration of 4a involving aromatization would provide 2,3-
disubstituted indole 5a’, akin to the reported synthesis of 2,3-
disubstituted benzofurans14 involving intra-VMA. We commenced
our study by treating 3a with K2CO3 base in DMF at 80 oC. The
reaction resulted in the formation of 2-acryl substituted indole-3-
acetate 5a in 21% yield with the retention of the (E)-geometry of
the exo-double bond. However, the other products 4a/5a’ were not
observed (Scheme 2). Probably, under the basic conditions
aromatization involving tosyl group elimination is more feasible.
We next conducted a sequential transformation involving N-
allylation―intra-VMA by using o-tosylamidocinnamate 1a and
γ-bromocrotonate 2a in one-pot. The reaction of 1a and 2a in
the presence of K2CO3 provided the desired product 5a in 30%
yield along with N-allylated intermediate 3a in 42% yield
(Table 1, entry 1). Note that the one-pot approach is more
efficient than the step-wise process to produce 2-alkenyl
substituted indole-3-acetate 5a with complete control of the
stereochemistry of the exo-double bond. Invigorated by the
one-pot transformation, we carried out an optimization assay,
using 1a and 2a, with an objective to improve the yield of 5a
and mitigate the formation of the N-allylated intermediate 3a
(Table 1). Accordingly, we screened different bases, solvents
and reaction conditions. The use of bases like K3PO4, NaH, and
DBU did not provide better results (Table 1, entries 2-4). The
reaction of 1a and 2a in NMP or DMSO afforded slightly better
results (Table 1, entries 5 and 6). An increase in the
temperature from 80 oC to 120 oC in the one-pot reaction of 1a
and 2a, in the presence of K2CO3 in DMSO, resulted in drastic
improvement in the yield of 5a while diminishing the
formation of 3a (Table 1, entries 7 and 8). Further increase in
the temperature was not found to be useful (Table 1, entry 9).
As it was expected this reaction failed in the absence of base
(Table 1, entry 10) (see SI for an extensive optimization study).
1
2
K2CO3
K3PO4
NaH
DMF
DMF
80
80
30
10
12
24
34
40
72
86
80
―
42
28
32
30
28
32
14
10
08
―
3
DMF
80
4
DBU
DMF
80
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
―
NMP
80
6
DMSO
DMSO
DMSO
DMSO
DMSO
80
7
100
120
150
120
8
9
10
aReaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), base
(1.50 mmol), solvent (3 mL); Isolated yields
b
Scheme 3
derivatives.
Synthesis of 2-alkenyl-3-indole acetate
Later, we tested this transformation by using different
departing groups on the nitrogen atom in place of tosyl (Ts)
group in 1a. It turned out that the tosyl group stood out to be
the best among the groups tested including acetyl (Ac),
2 | J. Name., 2012, 00, 1-3
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benzenesulfonyl
mesitylenylsulfony (Mts) and methanesulfonyl (Ms) (see, SI for
more details).
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(Bs),
p-nitrobenzenesulfonyl
(Ns),
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DOI: 10.1039/D0CC06564A
By applying the suitable conditions from the optimization
assay (Table 1, entry 8); we intended to evaluate the scope of
the one-pot transformation involving sequential N-allylation
followed by intra-VMA‒elimination‒aromatization to generate
diverse 2-alkenyl indole derivatives (Scheme 3). Initially, o-
tosylamidocinnamates and γ-bromocrotonates bearing
different alkyl groups present on their ester parts were
examined in the one-pot process. Despite the corresponding 2-
alkenyl indole derivatives 5a-e were obtained in high yields,
the combination of methyl ester 1a and ethyl ester 2a proved
to give better results. We then employed precursors bearing
different substitutions on the benzene ring of the methyl o-
tosylamidocinnamates 1 and ethyl 4-bromocrotonate 2a in this
one-pot sequential transformation. The reaction of 2a and o-
tosylamidocinnamate having methyl group on the benzene
ring provided the corresponding 2-alkenyl indole derivative 5f
in high yield. o-Tosylamidocinnamates bearing halogen groups
on the benzene ring were also employed. Although the
substrate containing fluoro-substituent returned a low yield of
the corresponding 2-alkenyl indole derivative 5g, the chloro-
and bromo-substituents tolerated well to furnish the
respective 2-alkenyl indole derivatives 5h-i in good yields.
Having an α-methyl substituent on the conjugate ester part of
1 also successfully delivered the respective 2-alkenyl indole
product 5j in 80% yield.
Scheme 4
derivatives
Synthesis of 3-substituted 2-alkenyl indole
Scheme 5 Plausible mechanism
We then examined the scope of the substrates containing
other electron-withdrawing groups (EWGs) in the place of the
ester group in 1a. Accordingly, we performed the sequential N-
allylation followed by intra-VMA–elimination–aromatization
cascade using different o-tosylamidochalcones and 2a
(Scheme 4). The reaction of 2a and o-tosylamidophenyl
substituted α,β-unsaturated ketone, having an enolizable
methyl group, afforded the corresponding 2-alkenyl indole
derivative 5k in 74% yield. o-Tosylamidochalcones comprising
different substitutions on the carbonyl side were employed in
the present one-pot sequential transformation. The
corresponding 2-alkenyl indole derivatives 5l-r were obtained
in high yields. The treatment of 2a and α,β-unsaturated ketone
having heteroaryl group such as 2-furyl group on the carbonyl
side afforded the corresponding 2-alkenyl indole derivative 5s
in good yield. We also examined nitrile as an EWG on the
Michael acceptor part as the reaction of o-
tosylamidocinnamonitrile and 2a provided the respective
indole derivative 5t in 72% yield. Having amide moiety as an
EWG on the alkene part of 1 also tolerated to furnish the
respective 2-alkenyl-3-indole acetamide 5u in 64% yield.
However, having nitro group as an EWG on the Michael
acceptor part of 1 proved to be unsuccessful starting material,
which got decomposed.
Scheme 6 Hydrolysis of ester groups of 5b
Scheme 7 Gram-scale synthesis of 5b and Formal synthesis
of MK-7246
3a. Base would abstract a proton on the active methylene
group, next to the conjugate ester moiety, to give a carbanion
intermediate A. Note that the intermediate A can also exist in
the form of its resonance structure A'. The intermediate A'
could act as a vinylogous Michael donor. The thus generated
carbanion of 3a would add to the other electrophilic β-carbon
of the Michael acceptor in the same molecule via an intra-
VMA process to provide intermediate 4a. Base-mediated
elimination of the tosyl group from 4a would give intermediate
B, which upon isomerization could provide the 2-alkenyl-3-
indole acetate 5a.
Considering the literature reports13-14 and above experiments,
we proposed a plausible reaction mechanism (Scheme 5) for
the present one-pot sequential N-allylation followed by intra-
VMA–elimination–aromatization cascade. Base-mediated
reaction of 1a and 2a provides the N-allylation intermediate
The diester 5b was subjected to base-mediated hydrolysis to
obtain the corresponding 4,5-indole-fused (E)-hept-2-enedioic
acid 6 in 90% yield (Scheme 6).
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Kobayashi and T. Fukuyama, J. Heterocyclic Chem., 1998, 35,
To demonstrate the synthetic power of the present protocol,
we embarked on to apply it in the formal synthesis of an
intermediate of Merck’s clinical agent MK-7246 (Scheme 7),
which is a potent and selective CRTH2 [chemo-attractant
receptor expressed on T helper type 2 (Th2) cells] antagonist,
for the treatment of respiratory diseases.16 Initially, to prove
the practicality of the present one-pot sequential method, we
carried out a multi-gram scale reaction of 1b and 2a to afford
the representative 2-alkenyl-3-indole acetate 5b in high yield
(Scheme 7). The indole 5b was subjected to palladium-
catalyzed hydrogenation to effect the reduction of the exo-
alkenyl moiety of 5b to give 7. The compound 7 was treated
with t-butyl bromoacetate to give the corresponding N-
alkylated intermediate 8 (Scheme 7). The agent MK-7246 can
formally be synthesized from 8 using the literature reports.16
In summary, we have presented an unprecedented strategy
involving intra-VMA–elimination–aromatization cascade for
the construction of indoles. The one-pot sequential
transformation based on the base-mediated N-allylation
followed by intra-VMA–elimination–aromatization cascade
1043; For selected important papers, see: (c) R.VCie.wLaArrtioclcekO,nEli.ne
DOI: 10.1039/D0CC06564A
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7
For cross-coupling of indoles and alkenyl partners, see: (a) T.
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using
o-tosylamidocinnamates/congeners
and
γ-
8
9
bromocrotonates has been described for the synthesis of 2-
alkenyl indole derivatives in reasonable to high yields. The
synthesis of 2-alkenyl indole derivatives has been
accomplished using a one-pot, transition metal-free process.
The present one-pot protocol has been demonstrated in the
formal synthesis of selective CRTH2 antagonist MK-7246, a
Merck’s clinical agent. Further explorations on the intra-VMA
chemistry and its applications are in progress in our laboratory.
We thank the Science & Engineering Research Board (SERB),
Department of Science and Technology (DST), India for an
Extra-mural Research grant (EMR/2017/002601). BH and SY
thank CSIR, New Delhi, for fellowships. We thank the Director,
H.-A. Seo and C.-H. Cheon, J. Org. Chem. 2016, 81, 7917.
10 B. Harish, M. Subbireddy and S. Suresh, Chem. Commun.
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4 | J. Name., 2012, 00, 1-3
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