One-Pot Allylation-Intramolecular Vinylogous Michael Addition-Isomerization Cascade of o-Hydroxycinnamates and Congeners: Synthesis of Substituted Benzofuran Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b00414

A unique intramolecular vinylogous Michael addition leading to the synthesis of heterocycles has been disclosed. Base-promoted one-pot sequential O-allylation of o-hydroxy-cinnamates or -cinnamonitrile or -chalcones with γ-bromocrotonates followed by an intramolecular conjugate addition of vinylogous Michael donors resulted in the formation of highly substituted benzofuran derivatives in good to excellent yields. The intramolecular event followed by two [1,3]-H shifts leading to aromatization appears to be the key to the success of this unprecedented transformation.

Full text of DOI:10.1021/acs.orglett.9b00414

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Allylation−Intramolecular Vinylogous Michael Addition−
Isomerization Cascade of o‑Hydroxycinnamates and Congeners:
Synthesis of Substituted Benzofuran Derivatives
Battu Harish,†,‡ Manyam Subbireddy,† Owk Obulesu,†,‡ and Surisetti Suresh*,†,‡
†Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500 007, India
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
S
* Supporting Information
ABSTRACT: A unique intramolecular vinylogous Michael
addition leading to the synthesis of heterocycles has been
disclosed. Base-promoted one-pot sequential O-allylation of o-
hydroxy-cinnamates or -cinnamonitrile or -chalcones with γ-
bromocrotonates followed by an intramolecular conjugate
addition of vinylogous Michael donors resulted in the
formation of highly substituted benzofuran derivatives in
good to excellent yields. The intramolecular event followed by
two [1,3]-H shifts leading to aromatization appears to be the
key to the success of this unprecedented transformation.
he development of efficient approaches for C−
heteroatom, C−C bond formations leading to the
construction of heterocycles has been one of the most sought
after research areas for organic chemists.1 Michael reaction
(conjugate addition) is among the most fundamental, classical
C−C and C−heteroatom bond forming reactions in organic
synthesis (Scheme 1, eq 1).2 The vinylogous variant of the
vinylogous donors.4a−f In rare cases, intra-VMA of vinylogous
donors is operative.4g,h
T
Benzofurans are one of the “privileged” scaffolds in
medicinal chemistry and drug discovery research programs.
Several of the molecules containing a benzofuran core have
shown potential biological activities, and many have become
marketed drugs while few of them are on the World Health
Organization’s List of Essential Medicines.5 In particular, 2,3-
disubstituted benzofurans are among the important benzofuran
derivatives that have exhibited excellent biological and
therapeutic activities.5 Hence, there has been significant
attention from organic chemists to access these scaffolds.5
However, direct methods to access 2,3-disubstituted benzofur-
an derivatives have been less explored, obviating the use of
transition metals.6 One of the traditional ways to access
benzofurans is based on the century-plus-old Rap−Stoermer
reaction, which is essentially a base-meditated reaction of
salicylaldehydes/o-hydroxyphenyl ketones and α-haloketones
involving an intramolecular aldol-type reaction.7 Herein, we
report the development of a base-mediated intra-VMA−
isomerization cascade to access 2,3-disubstituted benzofuran
derivatives.
Scheme 1. Michael Addition and Its Vinylogous Variants
Michael reaction has attracted considerable attention since it
can provide the product with the retained C−C double bond
from the vinylogous partner (Scheme 1, eq 2).3 The olefin
functionality is usually intact and can be useful for further/
deliberate organic transformations. Though the intermolecular
version of this reaction has been well-studied, the intra-
molecular vinylogous Michael addition (intra-VMA) reaction
remains underexplored (Scheme 1, eq 3).4 In many ring-
forming events, the key VMA is intermolecular.3k−o In some
cases, the ring closure of an intra-VMA to the carbo- or
heterocyclic ring features a 1,6-conjugate addition of non-
In continuation of our research program for the develop-
ment of novel methods leading to the synthesis of fused
heterocycles,8 we envisaged and considered an opportunity to
develop intra-VMA to generate useful heterocyclic scaffolds.
We have designed o-O-allyl cinnamate derivative 1a as a model
substrate to test the intra-VMA hypothesis. Initially, the
reaction of 1a with a base such as K2CO3 was performed.
Received: January 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00414
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Letter
a,b
Gratifyingly, we have observed the formation of the
corresponding 2,3-disubstituted benzofuran derivative 3a in
excellent yield, while the possible 2,3-dihydrobenzofuran
derivative 2a was not detected (Scheme 2). This reaction
appears to go through intra-VMA. However, we did not
observe a Dieckmann condensation product of 3a under the
reaction conditions.
Scheme 3. Synthesis of 2,3-Disubstituted Benzofurans
Scheme 2. Base-Mediated Intra-VMA
We next performed a one-pot sequential allylation followed
by intra-VMA using methyl o-hydroxycinnamate 4a and methyl
4-bromocrotonate 5a as precursors. Delightfully, this sequen-
tial transformation provided the corresponding 2,3-disubsti-
tuted benzofuran 3a in 72% yield. Interestingly, in this one-pot
reaction, we have also observed the formation of O-alkenyl
derivative9 1a′ in 23% yield, which is an isomer (tautomer) of
the allylated product 1a (Table 1, entry 1). We then conducted
a
Table 1. Optimization Study
temp time % yield % yield % yield
b
b
b
entry
base
solvent
(°C)
(h)
of 3a
of 1a
of 1a′
1
2
3
4
5
6
7
8
9
10
K2CO3
K3PO4
DBU
DMF
DMF
DMF
DMF
NMP
CH3CN
tBuOH
NMP
NMP
NMP
80
80
80
80
80
24
24
24
24
24
24
24
24
8
72
49
62
23
21
17
a
Reaction conditions: 4 (0.5 mmol), 5 (0.75 mmol), K2CO3 (1.5
b
mmol), NMP (3 mL). Isolated yields.
NaH
34
24
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
78
8
39
67
6
80
80
different alkyl groups on their ester parts have been subjected
to the sequential allylation−intra-VMA (Scheme 3). Although
the corresponding benzofuran derivatives 3a−e were obtained
in good to excellent yields, the precursors bearing methyl esters
were found to provide the highest yield of the benzofuran, 3a.
We then used differently substituted methyl o-hydroxycinna-
mates 4 and methyl 4-bromocrotonate 5a in this sequential
transformation. Methyl (E)-3-(2-hydroxynaphthalen-1-yl)-
acrylate as a substrate provided the corresponding naphthofur-
an 3f in good yield. Methyl o-hydroxycinnamates containing
electron-donating groups produced the corresponding benzo-
furan derivatives 3g−i in good yields. Halogen-substituted o-
hydroxycinnamates furnished the corresponding benzofuran
derivatives 3j−n in slightly lower yields, which may be
attributed to the lower electron density on the OH group of 4
to undergo O-allylation. The structure of the benzofuran 3k
was further confirmed by an X-ray crystal structure in addition
to the standard spectroscopic methods. o-Hydroxycinnamate
bearing both halogen and electron-donating substituents gave
the corresponding benzofuran derivative 3o in high yields. An
electron-withdrawing group such as a nitro group on o-
hydroxycinnamate was well tolerated and afforded the
corresponding benzofuran derivative 3p in 74% yield.
Introduction of an α-substituent such as a methyl group on
the α,β-unsaturated ester part of 4 was also well tolerated and
produced the corresponding benzofuran derivative 3q in 85%
yield.
100
120
120
84
92
5
8
a
Reaction conditions: 4a (0.5 mmol), 5a (0.75 mmol), base (1.5
mmol), solvent (3 mL). Isolated yields.
b
an optimization study for this one-pot transformation by
varying the base, solvent, and reaction conditions in order to
find suitable conditions to obtain benzofuran 3a in high yields
(Table 1; also see Supporting Information for an extensive
optimization survey). Use of K3PO4 and DBU provided
moderate yields of 3a, while the formation of 1a′ was also
observed in low yields (Table 1, entries 2 and 3). However,
sodium hydride gave only O-allyl derivative 1a in 34% yield
(Table 1, entry 4). When we used NMP as a solvent, the
desired product 3a was obtained in good yield (Table 1, entry
5). Other solvents like acetonitrile and tert-butyl alcohol were
not effective in this transformation to provide the benzofuran
3a (Table 1, entries 6 and 7). To our delight, an increase in the
temperature provided an excellent yield of 3a (Table 1, entries
8 and 9). As expected, this transformation failed in the absence
of base (Table 1, entry 10).
We next sought to evaluate the scope of this transformation
using the optimized reaction conditions (Scheme 3). Initially,
o-hydroxycinnamates 4 and 4-bromocrotonates 5 containing
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DOI: 10.1021/acs.orglett.9b00414
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We next turned our focus to study the scope of the electron-
withdrawing groups on the alkene moieties of 4 and 5 (Scheme
4). Reaction of (E)-4-(2-hydroxyphenyl)but-3-en-2-one and
10% and 34% yields, respectively. After 2 h, the yield of 3a was
increased to 64%, and there was a decrease in the yields of 1a
and 1a′. As the time increased, the intermediate 1a was not
observed and yield of intermediate 1a′ dropped significantly.
At the end of 8 h, the yield of 3a reached 92%, and only traces
of intermediate 1a′ were observed. This study suggests that the
formation of benzofuran 3a occurred via the intermediates 1a
(or) 1a′.
a,b
Scheme 4. Synthesis of 2,3-Disubstituted Benzofurans
We have conducted some experiments to gain insights into
the reaction mechanism. Since we have observed both allylated
product 1a and its isomer 1a′ in the one-pot transformation
(Table 1) and also at different time intervals (Figure 1) in the
reaction of o-hydroxycinnamate 4a and 4-bromocrotonate 5a,
we thought 1a and 1a′ could be in equilibrium. We have
conducted a reaction of 1a in the presence of 1 equiv of base
and monitored the reaction to obtain 1a′ (Scheme 5, eq 1). It
Scheme 5. Mechanistic Studies
a
Reaction conditions: 4 (0.5 mmol), 5 (0.75 mmol), K2CO3 (1.5
b
mmol), NMP (3 mL). Isolated yields.
methyl 4-bromocrotonate 5a provided the corresponding
benzofuran derivative 3r in reasonable yield. Different
salicylaldehyde-derived chalcones proved to be good substrates
in the base-mediated sequential O-allylation−intra-VMA and
provided the corresponding benzofuran derivatives 3s−x in
moderate to high yields. The reaction of o-hydroxycinnamoni-
trile and 5a provided the corresponding benzofuran derivative
3y in moderate yield. However, o-hydroxy β-nitrostyrene was
found to be an unsuitable substrate, which decomposed under
the reaction conditions. Instead of an ester group on 5, we
have also used different electron-withdrawing group such as a
sulfone group on the allyl bromide partner 5. Accordingly, the
reaction of 4a and (E)-((3-bromoprop-1-en-1-yl)sulfonyl)-
benzene 5c was performed to obtain the corresponding
benzofuran derivative 3z in good yield.
was observed that either 1a or 1a′ lead to the formation of 3a
in excellent yields in the presence of base (Scheme 5, eq 2).
From this result, it is reasonable to think that 1a or 1a′ can be
the intermediates in the present transformation. The use of
cinnamyl bromide 5d, instead of 4-bromocrotonate, in the
one-pot reaction did not proceed to completion to provide the
corresponding benzofuran derivative, while only o-O-cinnamyl
product 6a was obtained. When we subjected the O-cinnamyl
cinnamate 6a to the optimized reaction conditions, however,
the reaction did not proceed. o-O-Cinnamyl cinnamate 6a did
not prove to be a substrate for the present transformation even
with the use of a strong base like n-butyllithium (Scheme 5, eq
3). These results suggest that there is a requirement of an
electron-withdrawing group on the allylic halide substrate to
direct the key intramolecular vinylogous Michael reaction.
On the basis of the control experiments and literature
reports,4 a plausible mechanism can be proposed for the
present one-pot transformation leading to 2,3-disubstituted
benzofurans (Scheme 6). Initially, O-allylation of o-hydrox-
ycinnamate 4a with 4-bromocrotonate 5a takes place to
provide intermediate 1a, which can be in equilibrium with its
tautomer 1a′. In the presence of base, 1a/1a′ would provide
anionic intermediate I that can undergo intramolecular
vinylogous Michael (conjugate) addition to provide the 2,3-
dihydrobenzofuran intermediate II. The intermediate II would
then undergo two consecutive [1,3]-H shifts leading to
aromatization to furnish 2,3-disubstituted benzofuran product
3a.
We have monitored the present sequential reaction at
different time intervals to follow the kinetics (Figure 1). After 1
h of reaction time, the benzofuran product 3a was isolated in
51% yield while the intermediates 1a and 1a′ were formed in
Figure 1. Kinetics of the reaction.
C
DOI: 10.1021/acs.orglett.9b00414
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Letter
Accession Codes
Scheme 6. Plausible Reaction Mechanism
CCDC 1887439 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: surisetti@iict.res.in, suresh.surisetti@yahoo.in.
ORCID
Surisetti Suresh: 0000-0003-0202-5781
Notes
To demonstrate the practicality and scalability of the present
one-pot transformation, a model reaction of 4a and 5a was
performed on a multigram scale to afford 3a in high yields
(Scheme 7, eq 1). We have subjected the benzofuran derivative
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Science & Engineering Research Board (SERB),
Department of Science and Technology (DST), India, for an
Extramural Research grant (EMR/2017/002601). O.O. and
B.H. thank CSIR and M.S. thanks SERB for financial support
in the form of fellowships. We thank Dr. N. Jagadeesh Babu,
CSIR-IICT, for single-crystal X-ray structure analysis. IICT
Communication No. IICT/Pubs./2019/034.
Scheme 7. Gram-Scale Synthesis of 3a and Hydrolysis of
Ester Groups of 3a
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