De novo synthesis of 1,4-dihydropyridines and pyridines

Article abstract of DOI:10.1021/ja303002a

An efficient and general method for the synthesis of 1,4-dihydropyridines and pyridines based on a lithiation/isomerization/intramolecular carbolithiation sequence is reported. This procedure provides an efficient, divergent, and straightforward entry to a wide range of polysubstituted dihydropyridines and pyridines starting from readily available N-allyl-ynamides.

Full text of DOI:10.1021/ja303002a

Communication
pubs.acs.org/JACS
De Novo Synthesis of 1,4-Dihydropyridines and Pyridines
Wafa Gati,†,‡ Mohamed M. Rammah,‡ Mohamed B. Rammah,‡ Francois Couty,†
̧
and Gwilherm Evano*,†,§
†Institut Lavoisier de Versailles, UMR CNRS 8180, Universite
78035 Versailles Cedex, France
́
de Versailles Saint-Quentin en Yvelines, 45 avenue des Etats-Unis,
des Sciences de Monastir, Universite de
Libre de Bruxelles, Avenue F. D.
‡Laboratoire de Chimie Organique Het
́
er
́
ocyclique, Dep
́
artement de Chimie, Faculte
́
́
Monastir, avenue de l’environnement, 5019 Monastir, Tunisia
§Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite
Roosevelt 50, CP160/06, 1050 Brussels, Belgium
́
S
* Supporting Information
contrast, the synthesis of dihydropyridines has been far less
investigated and cannot yet be considered a trivial task. Indeed,
besides strategies based on nucleophilic addition to N-activated
pyridines, where the chemoselective generation of 1,4-
dihydropyridines over their 1,2-isomers is a frequent issue,5
most methods, including the classical Hantzsch synthesis6 and
related processes,3 are restricted to the synthesis of
dihydropyridines bearing a carbonyl group at the 3-position.7
Herein we report a general, efficient, single-step, and
divergent synthesis of 1,4-dihydropyridines 6 and pyridines 7
from readily available N-allyl-ynamides 1 (Scheme 1).8,9 On the
ABSTRACT: An efficient and general method for the
synthesis of 1,4-dihydropyridines and pyridines based on a
lithiation/isomerization/intramolecular carbolithiation se-
quence is reported. This procedure provides an efficient,
divergent, and straightforward entry to a wide range of
polysubstituted dihydropyridines and pyridines starting
from readily available N-allyl-ynamides.
itrogen-containing heterocycles are subunits found in
N
numerous natural products and many biologically active
pharmaceuticals. In 2010, 18 of the top 20 small-molecule
drugs contained at least one nitrogen heterocycle.1 Among
these, the pyridine2 and 1,4-dihydropyridine3 substructures are
among the most prevalent, the most famous ones certainly
being the proton-pump inhibitor esomeprazole, the tranquilizer
bromazepam, vitamin B6, the calcium agonists felodipine and
israpidine, and NADPH (Figure 1). In addition to being among
Scheme 1. New Approach to 1,4-Dihydropyridines and
Pyridines by Deprotonation/Carbolithiation from N-Allyl-
ynamides
basis of the work of Beak and co-workers on the α-lithiation of
Boc-protected amines,10 we anticipated that the N-alkynyl, Boc-
protected allylamines 1 would be readily deprotonated with a
suitable base, affording a chelation-stabilized allylic organo-
lithium intermediate 2 that might be in equilibrium with the
less-stable allyllithium species 3 and 4.11 The unique
combination of the electronic bias of the triple bond associated
with the chelating group of the ynamide moiety would then
allow for a highly regioselective 6-endo-dig intramolecular
carbolithiation from 4,12−14 which would afford the desired 1,4-
dihydropyridine 6 or pyridine 7 after simple hydrolysis or
oxidative workup, respectively.
Figure 1. Most representative biologically active pyridines and 1,4-
dihydropyridines.
the most prevalent heterocyclic structural units in pharmaceut-
ical and agrochemical targets, they are also especially versatile
building blocks, notably for the synthesis of piperidines. As a
result, pyridine synthesis has attracted significant efforts for
more than 130 years, and while there are many methods for
their preparation, mostly based on condensation of amines and
carbonyl compounds, cycloaddition reactions, or cross-coupling
chemistry, the search for new strategies that offer concise and
regiospecific access remains a topic of considerable interest.4 In
Received: March 28, 2012
Published: May 15, 2012
© 2012 American Chemical Society
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To test the feasibility of such a transformation, allylamine
1a9b was treated with 1 equiv of s-butyllithium and
tetramethylethylenediamine (TMEDA) in tetrahydrofuran
(THF) at −78 °C. To our delight, hydrolysis of the reaction
mixture after 1 h provided the desired highly sensitive
dihydropyridine 6a as a single product, while treatment with
acetic acid and o-chloranil7a afforded the corresponding
pyridine 7a in 81% isolated yield (Scheme 2).
ring, the cyclized products being obtained in all cases in good to
excellent yields from the corresponding N-Boc-N-alkynyl-
allylamine (Table 1, entries 1−6). Notably, no competitive
direct carbolithiation of the ynamide moiety, metalation of the
aromatic rings, 5-exo-dig carbolithiation, [1,2]-Boc migration,
or isomerization of the 1,4-dihydropyridine could be detected,
even in the presence of an additional phenyl substituent at the
C4 position (Table 1, entry 14).
The cyclization was also found to proceed smoothly starting
from a conjugated enynamine and efficiently produced the
corresponding alkenyl-substituted 1,4-dihydropyridine and
pyridine (Table 1, entry 7). However, the cyclization of an
alkyl-substituted ynamide was found to be more substrate-
dependent. Indeed, while a tert-butyl group on the starting
ynamide was perfectly tolerated (Table 1, entry 8), extensive
degradation was observed in the presence of a linear alkyl chain
such as an n-hexyl substituent (Table 1, entry 9), which is
certainly due to competitive lithiation at the propargylic
position.
Scheme 2. Optimized Conditions for the Divergent
Synthesis of 1,4-Dihydropyridines and Pyridines
With the appropriate conditions for the lithiation/cyclization
sequence and the workup leading to the selective formation of
either 1,4-dihydropyridines or pyridines, we next carefully
studied the scope of this procedure. The results from these
studies are collected in Table 1. A variety of electron-rich and
electron-deficient aromatic substituents could be successfully
introduced at the C3 position of the dihydropyridine/pyridine
The presence of additional substituents on the starting
allylamine had virtually no effect on the outcome of the
reaction, allowing for the preparation of various 3,5-
disubstituted (Table 1, entries 10−13) and 3,4- disubstituted
(Table 1, entries 14 and 15) 1,4-dihydropyridines and pyridines
a
Table 1. Scope of the Synthesis of 1,4-Dihydropyridines and Pyridines by Lithiation of N-Allyl-ynamides
a
b
Conditions: s-BuLi (1.2 equiv) was added to a solution of 1 (1.0 equiv) and TMEDA (1.1 equiv) in THF (0.5 mol. L−1) at −78 °C. The reaction
c
was quenched with a saturated aqueous solution of ammonium chloride. 1,4-Dihydropyridines are especially sensitive to trace acids and oxygen and
were obtained in virtually pure form after extraction. The reaction was quenched with acetic acid and o-chloranil (3,4,5,6-tetrachloro-1,2-
benzoquinone) and stirred at room temperature for 30 min. Yields of the pure, isolated products. Yield on a gram scale. The volatile product was
d
e
f
g
isolated as its hydrochloride salt.
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with similar efficiency. Interestingly, the reaction was not
limited to the small scale used for the reactions described above
(i.e., 1.0 mmol), as illustrated by the gram-scale synthesis of
dihydropyridine 6a and pyridine 7a (Table 1, entry 1).
This metalation/carbometalation strategy was finally also
found to be quite efficient for the synthesis of fused ring
systems when started from the corresponding cyclic allyl-
amines, as exemplified by the straightforward synthesis of hexa-
and tetrahydroisoquinoline derivatives 9 and 10, respectively,
from 8 (Scheme 3).
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and copies of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
gevano@ulb.ac.be
■
Notes
The authors declare no competing financial interest.
Scheme 3. Synthesis of Tetra- and Hexahydroisoquinoline
Derivatives
ACKNOWLEDGMENTS
■
The authors thank the CNRS, the Universities of Versailles and
Monastir, the ANR (Project DYNAMITE ANR-2010-BLAN-
704) and the CMCU/PHC Utique (Grant 10G1025) for
support. We are grateful to Ms. Estelle Galmiche and Mr.
Flavien Bourdreux (Lavoisier Institute) for their assistance with
high-resolution mass spectrometry and NMR analyses and to
In an effort to introduce an additional substituent at the C2
position of the dihydropyridine/pyridine ring, we next briefly
evaluated the possibility of trapping the final stabilized
vinyllithium intermediate by an electrophile. With this goal in
mind, N-allyl-ynamide 1a was metalated under our standard
conditions and treated with deuterated water or methyl iodide.
To our delight, the corresponding C2-substituted 1,4-
dihydropyridines 11 and 13, which are especially challenging
to prepare using alternative methods, were formed, albeit in
modest yields (Scheme 4). The reaction with methyl iodide was
́
Mr. Guillaume Boissonnat (Universite Libre de Bruxelles and
Ecole Polytechnique ParisTech) for technical assistance.
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