A heavy metal- and oxidant-free, one-pot synthesis of pyridines and fused pyridines based on a Lewis acid-catalyzed multicomponent reaction

Article abstract of DOI:10.1039/c4cc01791a

The InCl₃-catalyzed sequential multicomponent reaction between 2-furfurylamine, β-dicarbonyl compounds and α,β-unsaturated aldehydes in ethanol, followed by microwave irradiation in solvent-free conditions, afforded good to excellent yields of highly substituted pyridines, with loss of a 2-furylmethyl side chain. The method was also adapted to the synthesis of quinolones, isoquinolines, phenanthridines and more complex fused pyridine systems.

Full text of DOI:10.1039/c4cc01791a

Showcasing research from the laboratory of Prof. J. Carlos
Menéndez, Departamento de Química Orgánica y Farmacéutica,
Universidad Complutense, Madrid, Spain
As featured in:
A heavy metal- and oxidant-free, one-pot synthesis of
pyridines and fused pyridines based on a Lewis acid-catalyzed
multicomponent reaction
A sequential multicomponent reaction between 2-furfurylamine,
β-dicarbonyl compounds and α,β-unsaturated aldehydes
in ethanol in the presence of InCl3, followed by microwave
irradiation in solvent-free conditions, afforded good to excellent
yields of highly substituted pyridines, with loss of a 2-furylmethyl
side chain. The method was also useful for the synthesis of
more complex fused pyridine systems, including quinolines,
isoquinolines and phenanthridines.
See J. Carlos Menéndez et al.,
Chem. Commun., 2014, 50, 12270.
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A heavy metal- and oxidant-free, one-pot
synthesis of pyridines and fused pyridines based
on a Lewis acid-catalyzed multicomponent
reaction†
Cite this: Chem. Commun., 2014,
50, 12270
Received 10th March 2014,
Accepted 16th April 2014
V. P. Alex Raja,ab Giammarco Tenti,a Subbu Perumalb and J. Carlos Menendez*a
´
DOI: 10.1039/c4cc01791a
www.rsc.org/chemcomm
The InCl3-catalyzed sequential multicomponent reaction between regioselective multicomponent routes to functionalized pyri-
2-furfurylamine, b-dicarbonyl compounds and a,b-unsaturated alde- dines and their fused derivatives remains challenging.
hydes in ethanol, followed by microwave irradiation in solvent-free
Some multicomponent pyridine syntheses including, among
¨
conditions, afforded good to excellent yields of highly substituted others, the Bonnemann cyclization i.e. the [2+2+2] cycloaddition of
pyridines, with loss of a 2-furylmethyl side chain. The method alkynes with nitriles, require the use of transition metals.10 Besides
was also adapted to the synthesis of quinolones, isoquinolines, the need for expensive and toxic catalysts, these methods sometimes
phenanthridines and more complex fused pyridine systems.
suffer from a lack of regioselectivity. While many of the multi-
component methods leading to the pyridine ring that do not require
Pyridine is one of the best-studied nitrogen heterocycles due to the heavy metals are known,11 the ones most closely related to our
importance of its derivatives in many fields of academic and work start from b-dicarbonyl compounds and involve the
industrial research. Mono-, bi- and terpyridine scaffolds are widely intermediacy of b-enaminones, via a [3+3] mechanism. This is
employed in coordination chemistry, giving chelates that often have the case of the Hantzsch synthesis, which can be coupled with a
good catalytic properties.1 Pyridines are also important in supra- sequential or in situ oxidation to afford pyridines,12 the Bohlmann–
molecular chemistry2 and in the science of polymers,3 surfaces4 and Rahtz synthesis and related transformations.13 Recently, it has
materials.5 Pyridine substructures are also present in many natural been found that b-dicarbonyl compounds, a,b-unsaturated alde-
products6 and in a large number of bioactive compounds, and hydes or a,b-unsaturated a-ketoesters or amides and ammonia
hence pyridine can be regarded as a privileged structure in drug can give pyridines, in a Michael-initiated process that furnishes a
discovery.7 Furthermore, pyridine derivatives are also widely 1,5-dicarbonyl which then reacts with ammonia.14
employed in agricultural chemistry as herbicides, insecticides and
In this context, we have recently described a room-temperature,
antifungals, and they also are important synthetic intermediates. four-component reaction between b-dicarbonyl compounds,
Because of the immense importance of pyridines, synthetic a,b-unsaturated aldehydes, primary amines and alcohols in the
chemists have developed a large number of methods for their presence of Ce(IV) ammonium nitrate as a catalyst, which affords
preparation.8,9 Among these methods, those involving the use of excellent yields of 1-alkyl-6-alkoxy-1,4,5,6-tetrahydropyridines bear-
multicomponent reactions to create the pyridine ring are particularly ing alkyl groups at C-2 and an ester function at C-3.15 We became
efficient thanks to the generation of several bonds in a single interested in extending this methodology to the preparation of
operation. These methods are also preferable from the environ- pyridines, but found that the replacement of primary amines by
mental point of view, since avoiding workup and purification ammonia failed to give the desired products. Thus, the only
steps leads to a greatly diminished generation of waste from remaining option was to perform the multicomponent reaction
organic solvents and chromatographic stationary phases. with a primary amine whose substituent could act as a leaving
In spite of recent progress, the development of chemo- and group. Furthermore, in order to achieve a more general access to
pyridine derivatives, we also needed to increase the scope of our
reaction to include more varied substitution patterns and types of
a
´
´
´
Departamento de Quımica Organica y Farmaceutica, Facultad de Farmacia,
Universidad Complutense, 28040 Madrid, Spain. E-mail: josecm@farm.ucm.es;
Fax: +34-913941822
substituents, since the original process allows only simple alkyls at
C-2 and methyl groups at either C-4 or C-5, but not at both
positions. Regarding the first goal, we achieved limited success
by using dimethylhydrazine as the amino component, but the
scope of the reaction was very narrow, allowing substitution only
at C-2 and C-3, and the average yield was only 66%.16
b Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai - 625 021, Tamilnadu, India
† Electronic supplementary information (ESI) available: Copies of spectra of all
compounds. See DOI: 10.1039/c4cc01791a
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Scheme 1 Synthesis of polysubstituted pyridines.
We now report a satisfactory solution to both problems, which
has led to a one-pot synthesis of highly substituted pyridines and
several families of their fused derivatives from simple, readily
available starting materials. Our method is based on the sponta-
neous loss of the 2-furylmethyl substituent from an 1-(2-furylmethyl)-
6-ethoxy-1,4,5,6-tetrahydropyridine intermediate under microwave
irradiation. Benzyl leaving groups were also assayed, but led to
complex mixtures. As shown in Scheme 1, the sequential multi-
component reaction between b-ketoesters 1, 2-furylmethylamine 2
and unsaturated aldehydes 3 was performed under modified
conditions (0–5 1C, InCl3 as catalyst) and, without isolation of the
tetrahydropyridine product, the solvent was evaporated and the
residue was subjected to microwave irradiation (200 W, 100 1C)
to give pyridines 4 in a one-pot protocol.
Under these improved conditions the scope of the multi-
component reaction was considerably expanded in comparison to the
published method and hence a wide range of pyridines were
accessible, as summarized in Fig. 1. These include di-, tri- and
tetrasubstituted pyridines bearing alkyl or aryl substituents at C-4,5.
Furthermore, the C-2 position was readily amenable to the introduc-
tion of complex substituents containing a variety of functional groups,
including thioether and ester groups and alkene or diene fragments.
A rationalization of the pyridine synthesis is shown in Scheme 2.
As previously reported,15 the initial four-component reaction proceeds
via a sequence of b-enaminone formation, Michael addition,
intramolecular 6-exo-trig cyclization and hydroxy-alkoxy exchange
via an intermediate iminium intermediate, to give compound 5.
We propose that microwave irradiation of the latter induces its
SN1-type degradation to give an ethoxide anion and 6, a benzylic
cation stabilized by the furan oxygen, which then combine to
furnish 2-ethoxymethylfuran, detected in the crude reaction
mixtures. In the last step, air oxidation of 6 affords the final
products 4 without the need of addition of other oxidants.
This is relevant in view of the fact that redox reactions are
often difficult to scale up and are often undesirable from an
environmental point of view, which has led to the concept of
redox economy as a desirable feature of synthetic routes.17
In agreement with this proposal, starting compounds bearing
primary N-alkyl substituents, which cannot generate stable
carbocations, failed to give pyridine products. Interestingly,
Fig. 1 Scope of the pyridine synthesis.
Scheme 2 Mechanistic rationalization of the pyridine synthesis.
the microwave-assisted reactions showed a divergent behaviour unstable, but could nevertheless be identified by its NMR data
when carried out under conventional heating. Thus, the reaction (see the ESI†). This observation is consistent with the proposed
starting from ethyl 3-oxohept-6-enoate afforded compound 4d mechanism, since microwave irradiation is known to stabilize
under microwave conditions, while its reflux in toluene gave a polar transition states such as those involved in the transforma-
1-(2-furylmethyl)-1,4-dihydropyridine derivative that was rather tion of 5 into 6.18
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We thank MICINN, Spain, and the Department of Science
and Technology (India) for an Indo-Spanish collaborative grant
(ACI2009-0956 and DST/INT/SPAIN/P-11/09). JCM gratefully
acknowledges additional funding from MINECO (grant CTQ2012-
33272-BQU) and assistance from Padmakar A. Suryavanshi during
the preparation of this manuscript.
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12272 | Chem. Commun., 2014, 50, 12270--12272
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