Unusual Reactivity of 4-Vinyl Isoxazoles in the Copper-Mediated Synthesis of Pyridines, Employing DMSO as a One-Carbon Surrogate

Article abstract of DOI:10.1021/acs.orglett.0c01935

An efficient protocol for the synthesis of nicotinate derivatives and tetrasubstituted pyridines through a copper-mediated cleavage of isoxazoles has been developed. The highlight of the work is the observation of an unusual reactivity of 4-vinyl isoxazoles under the reaction conditions. DMSO serves as a one-carbon surrogate generating an active methylene group during the reaction to form two C-C bonds. This protocol provides a facile and an expeditious approach for the assembly of densely substituted N-heterocyclic compounds.

Full text of DOI:10.1021/acs.orglett.0c01935

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Letter
Unusual Reactivity of 4‑Vinyl Isoxazoles in the Copper-Mediated
Synthesis of Pyridines, Employing DMSO as a One-Carbon Surrogate
Pravin Kumar and Manmohan Kapur*
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ABSTRACT: An efficient protocol for the synthesis of nicotinate
derivatives and tetrasubstituted pyridines through a copper-
mediated cleavage of isoxazoles has been developed. The highlight
of the work is the observation of an unusual reactivity of 4-vinyl
isoxazoles under the reaction conditions. DMSO serves as a one-
carbon surrogate generating an active methylene group during the
reaction to form two C−C bonds. This protocol provides a facile and an expeditious approach for the assembly of densely
substituted N-heterocyclic compounds.
Scheme 1. Synthesis of Nicotinate Derivatives and
Tetrasubstituted Pyridines (some previous reports and this
work)
yridines represent an important class of heterocyclic
scaffolds in biologically relevant molecules and serve as
P
versatile building blocks in the synthesis of many natural
products, bioactive compounds, and pharmaceutical agents.1−3
Pyridines and their derivatives are also useful ligands in various
metal-catalyzed organic transformations.4,5 Traditional ap-
proaches to their synthesis involve condensation and
aromatization of various carbonyl compounds or α,β-
unsaturated carbonyl compounds with ammonia or its
derivatives.6−8 In recent times, metal-catalyzed cyclization
reactions have proven to be efficient routes for the synthesis of
substituted pyridines and various efficient approaches have
been successfully developed by several research groups to
produce nicotinate skeletons by employing electron-deficient
β-enamino esters and their condensation with 1,3-dicarbonyl
compounds (Scheme 1).9−13 Despite these advances, the
development of newer methods for the efficient construction of
pyridines continues to attract considerable attention from
chemists.
Isoxazoles serve as versatile intermediates14−16 and have
been extensively employed in various catalytic transformations
to yield several synthetically useful heterocycles as well as
pharmaceutically active molecules.17,18 3,5-Diaryl isoxazoles
can serve as masked enaminones and also act as C,N-
dinucleophilic synthons to undergo reactions with various
coupling partners, resulting in a diverse array of heterocyclic
compounds.15c We report herein an unusual reactivity of 4-
vinyl isoxazoles in a copper-mediated synthesis of nicotinate
derivatives and the synthesis of tetrasubstituted pyridines using
DMSO as a one-carbon surrogate (Scheme 1).
Initially, we commenced our studies with 3,5-diaryl
isoxazoles. In this regard, studies were initiated with the
treatment of 3,5-diphenyl isoxazole with Cu(OTf)2 in DMSO
at 130 °C, which successfully led to the tetrasubstituted
pyridine in 78% yield. However, this reaction condition could
not be generalized; for example, the reaction of 5-phenyl-3-(p-
tolyl)isoxazole did not afford any product under this condition.
After a rigorous screening of various reaction conditions, we
found that upon addition of a protic source AcOH (2 equiv),
the reaction of 5-phenyl-3-(p-tolyl)isoxazole in the presence of
Cu(OTf)2 (2 equiv) in DMSO at 130 °C afforded the desired
product in 95% yield (see the Supporting Information for
Received: June 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01935
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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further details). To explore the substrate scope for the general
validity of the investigations presented here, a variety of
substituted isoxazoles were screened under this condition
(Scheme 2) and the reaction was found to be quite general.
diaryl isoxazole, under standard conditions, did not afford any
product [3r (Scheme 2)]. The reaction did not work with the
TMS-substituted isoxazole, and all starting material was
decomposed [3s (Scheme 2)]; on the contrary, in the case
of a monosubstituted isoxazole poor conversion was observed
with 40% yield [3t (Scheme 2)]. The reaction also worked well
with substrates containing substituents at the C5-aryl ring of
the isoxazoles and gave the corresponding products with good
to moderate yields [3u−3z (Scheme 2)].
a−c
Scheme 2. Synthesis of Tetrasubstituted Pyridines
After the successful synthesis of symmetrical tetrasubstituted
pyridines, we moved further to examine the reactivity of
various 4-vinyl isoxazoles under the optimized conditions.
Interestingly, we observed an unusual reactivity that led to the
formation of trisubstituted pyridine (Scheme 3). So far,
a,b
Scheme 3. Synthesis of Nicotinate Derivatives
a
Unless otherwise specified, all reactions were carried out using 1
(0.15 mmol), Cu(OTf)2 (2.0 equiv), and AcOH (2.0 equiv) at 130
b
°C for 6−26 h under N2. Values in parentheses indicate the 3:3′
c
ratio. Isolated yields after column chromatography purification.
a
Unless otherwise specified, all reactions were carried out using 4
(0.10 mmol), Cu(OTf)2 (2.0 equiv), and AcOH (2.0 equiv) at 130
°C for 8−24 h under N2. Isolated yields after column
chromatography purification.
Electronic factors did not seem to affect this transformation.
The reaction of 3,5-diaryl isoxazoles possessing electron-
donating substituents at the 3-aryl ring proceeded efficiently to
furnish the corresponding products in good to moderate yields
[3b−3d, 3h, 3i, 3v, and 3w (Scheme 2)].
b
cyclization of 4-vinyl isoxazoles was known to yield
pyrroles15c,19 rather than pyridines, and to the best of our
knowledge, this transformation has never been reported before.
To explore this further and to check the generality of this
reaction, a variety of C4-alkenylated isoxazoles were inves-
tigated under the optimum conditions (Scheme 3). The
reactivity was found to be quite similar to those in Scheme 2.
The reaction worked quite well with substrates containing
electron-donating, electron-withdrawing, and halogen substitu-
ents at the C3-aryl ring of C4 alkenyl-3,5-diaryl isoxazoles to
give nicotinate derivatives in moderate to good yields (Scheme
3). Interestingly, the reaction of 3,4-divinyl-5-phenyl isoxazoles
under standard conditions afforded 6-styryl nicotinates in good
yields [5o and 5p (Scheme 3)]. To check the substituent effect
However, the presence of electron-withdrawing substituents
in the C3-aryl ring of 3,5-diaryl isoxazole was found to be
detrimental, and the corresponding pyridines were obtained in
slightly reduced yields [3f, 3g, 3x, and 3y (Scheme 2)]. The
substrates possessing substituents at the meta position of the
C3-aryl ring of 3,5-diaryl isoxazoles furnished the desired
product in good to moderate yields [3h−3k (Scheme 2)]. In
each case, varying amounts of 3′ were also observed as the
minor product. Unfortunately for us, in some cases, 3 and 3′
were obtained as inseparable mixtures. Vinyl groups at the C3
position of the isoxazole were also compatible under these
conditions [3l and 3m (Scheme 2)]. However, the isoxazole
containing an o-fluorine substituent at the 3-aryl ring of 3,5-
B
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(other than a vinyl group at the C4 position of isoxazole ring),
a reaction of 4-methyl-3,5-diphenyl isoxazole was carried out
under standard conditions and resulted exclusively in the
cleaved product 5q (Scheme 3), which suggested that only
suitable substituents at the C4 position of isoxazole ring
facilitate the cyclization. This reaction condition was also
compatible with the substrates containing a substituent at the
C5-aryl ring of 4-vinyl isoxazoles, which upon cyclization gave
the corresponding products in moderate to good yields [5r−5x
(Scheme 3)].
To gain further insight into the plausible pathways for the
transformations, a variety of studies were carried out (Scheme
4). 3,5-Diphenyl isoxazole (1a) was treated under the standard
conditions in the presence of DMSO-d6, resulting in 3a′ with
complete deuteration at the C4 position, clearly indicating that
C4 of the tetrasubstituted pyridine was derived from DMSO
(Scheme 4a).
A similar observation was made in the case of 4u, which
resulted in the incorporation of D at the C2 position (Scheme
4a), which suggested that DMSO was acting as a one-carbon
surrogate in generating a methylene group during the reaction
to form the pyridine. Copper triflate was found to be necessary
to facilitate the reductive cleavage of 3,5-diphenyl isoxazole
that is also supported by the fact that when the reaction was
carried out with enaminone 1a′ as the substrate, in the absence
of copper triflate, the corresponding tetrasubstituted pyridine
was obtained in good yield (Scheme 4b), whereas in the case
of 3,5-diphenyl isoxazole, no product formation was observed
in the absence of copper triflate (Scheme 4b).
To check the possibility of the involvement of a single-
electron transfer pathway, experiments were carried out in the
presence of radical trap agents under standard conditions
(Scheme 4c). These resulted in the desired tetrasubstituted
pyridine product with almost no inhibition in rate or yield of
the product. This result indicated that a single-electron transfer
pathway may not be involved in the reaction. We also
performed crossover experiments to check if the reaction
depicted in Scheme 2 was intra- or intermolecular. When the
reaction was performed with an equimolar mixture of 1h and
1k, it resulted in the crossover product 3hk, along with the
tetrasubstituted pyridines 3b and 3f (Scheme 4d), which
indicated that the reaction was intermolecular. To check
whether 7 was an intermediate in the reaction, 6 was
synthesized20 and treated with 1a as well as 1h under the
standard conditions (Scheme 4e). In both cases, the product
arising from 6 was obtained, indicating that 7 was a likely
intermediate in this transformation (see the Supporting
Information for details).
Scheme 4. D Labeling Studies and Control Experiments
On the basis of these observations and literature reports,21
plausible mechanisms for the transformations are proposed in
Scheme 5. The isoxazole, in the presence of Cu(OTf)2, may
exist in equilibrium with its ring-opened nitrene form (Cu-
imido) at 130 °C, which in the presence of the protic
conditions may undergo a protodemetalation to give the
corresponding enaminone 1a′. At this moment, the exact
pathway for this first step is not very clear to us. It is quite
possible that a disproportionation process to give Cu(I) and
Cu(III) may be involved, and this Cu(I) species could be
responsible for the reductive cleavage of the N−O bond of the
isoxazole. However, during the optimization studies, we found
that Cu(I) salts were not very effective in carrying out this
transformation. Therefore, a much more detailed study is
necessary to delineate this first step. In addition, DMSO in the
presence of acetic acid generates a methyl(methylene)-
sulfonium intermediate that on reaction with enaminone 1a′
results in A (path II, Scheme 5), which upon α-elimination
yields B.22 This on further reaction with enaminone 1a′ gives
intermediate C, which in protic media is in equilibrium with
intermediate D. Intermediate C is converted into its
corresponding enamine (E) (path IIB, Scheme 5), followed
by intramolecular 1,4-addition to give cyclic intermediate F,
which on deamination gives the Hantzsch pyridine (H), and
subsequent oxidation by Cu(II) gives the corresponding
tetrasubstituted pyridine 3 as a major product.
Intermediate D can give rise to the corresponding
tetracarbonyl intermediate (I) (path IIA, Scheme 5), which
further in the presence of ammonia generated during the
course of reaction forms an ammonium ion intermediate J at
the more electrophilic carbonyl carbon, leading to L, and
C
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a
Scheme 5. Plausible Reaction Pathways
Experimental details and spectral characterization of all
new compounds (PDF)
Accession Codes
CCDC 1884316, 1941419, 1984052, and 1984061 contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Manmohan Kapur − Department of Chemistry, Indian Institute
of Science Education and Research Bhopal, Bhopal 462066,
MP, India; orcid.org/0000-0003-2592-6726; Email: mk@
iiserb.ac.in
Author
Pravin Kumar − Department of Chemistry, Indian Institute of
Science Education and Research Bhopal, Bhopal 462066, MP,
India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01935
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank SERB-India (EMR/2016/004298) and
CSIR-India (02(361)/19/EMR-II) for funding. P.K. thanks
UGC-India for a Research Fellowship. The authors thank the
CIF, IISERB, for the analytical data and the Director, IISERB,
for the funding and infrastructure facilities.
a
Counteranions (AcO− or TfO−) of the cationic species in the
mechanisms have been omitted for the sake of simplicity.
subsequent oxidation by Cu(II) yields the desired tetrasub-
stituted pyridine as a minor product 3′.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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