Use of β,γ-unsaturated α-ketocarbonyls for a totally regioselective oxidative multicomponent synthesis of polyfunctionalized pyridines

Article abstract of DOI:10.1002/chem.200902491

Versatile partners: α-Ketocarbonyls have been shown for the first time to be versatile partners in a Michael addition promoted oxidative domino threecomponent reaction under heterogeneous conditions. This multicomponent reaction sequence led to the development of a general synthesis of highly functionalized pyridines (see scheme), allowing selective and simultaneous incorporation of a substituent at the 4-position and a synthetically useful functionality at the strategic 2-position.

Full text of DOI:10.1002/chem.200902491

COMMUNICATION
DOI: 10.1002/chem.200902491
Use of b,g-Unsaturated a-Ketocarbonyls for a Totally Regioselective
Oxidative Multicomponent Synthesis of Polyfunctionalized Pyridines
Christophe Allais, Thierry Constantieux,* and Jean Rodriguez*[a]
Although pyridine is one of the most studied nitrogen
containing heterocycles with a large spectrum of fascinating
applications, the synthesis of highly substituted and specifi-
cally functionalized frameworks is a continuing challenge in
modern synthetic organic chemistry.[1] For example, 3-func-
tionalized pyridines, such as nicotinamides have strong bio-
logical interest,[2] and selective functionalizations at C2[3]
and C4[4] are of strategic importance in many areas including
coordination chemistry,[5] material sciences,[6] supramolecular
chemistry,[7] catalysis,[8] organocatalysis,[9] medicinal chemis-
try[10] and natural product synthesis.[11] For this purpose, met-
allo-pyridines generated from the corresponding halides[12]
are widely involved but frequently hampered by the unsta-
ble nature of the precursors, while directed synthetic routes
often lack of regioselectivity and offer only limited diversi-
ty.[13] Recently, we reported a metal-free Michael addition
initiated three-component substrate directed route to poly-
substituted pyridines 4 from 1,3-dicarbonyls 1 that could
solve part of the selectivity substitution problem
(Scheme 1).[14]
ever, this methodology was limited to the use of b-unsubsti-
tuted aldehydes and ketones 2 (R3, R4 =H, alkyl), probably
because of the reversibility of the Michael addition with hin-
dered substrates; this prevents any access to 4-substituted
pyridines and limits the functional diversity at the strategic
2-position. To circumvent these major drawbacks, we rea-
soned that the activation of the acceptor via the introduc-
tion of an electron-withdrawing group onto the carbonyl
moiety (R3 =EWG) could be a good solution. This prompt-
ed us to study the viability of a-ketocarbonyls as partners in
the multicomponent reaction which to the best of our
knowledge has never been reported before. Thus, we have
now designed an oxidative domino three-component reac-
tion under heterogeneous conditions involving the direct
condensation of 1,3-dicarbonyls 1 with ammonium acetate 3
and b,g-unsaturated-a-ketoesters 5 (R3 =CO2R),[18] -a-ke-
toamides 6 (R3 =CONR2),[19] or -a-ketophosphonates
7
(R3 =P(O)(OR)2,[20] leading regioselectively to diversely 2-
and 4-substituted pyridines.
A preliminary experiment confirmed our hypothesis and
the peculiar reactivity of such activated Michael acceptors.
As illustrated in Scheme 2, under standard conditions
(Table 1, entry 1), reaction of methylacetoacetate (1a) with
a-ketoester 5a and ammonium acetate (3) gave a mixture of
the expected pyridine 4a and the stable[21] dihydropyridine
4’a in a 3:5 ratio. The amount of 4a increased in the pres-
ence of Pd/C[22] as the catalyst using acetic acid as a co-sol-
vent (entry 2). However, as the selectivity of this sequence
was not satisfactory, we focused our efforts on the develop-
ment of a user friendly oxidative system capable to furnish
the expected pyridine as a unique product. After optimiza-
tion, it was found that addition of acetic acid as a co-solvent
and activated carbon[23] as heterogeneous catalyst under a
dioxygen atmosphere (entry 3) selectively afforded the pyri-
dine 4a in high yield.[24]
This simple and totally regioselective multicomponent re-
action (MCR) combines molecular complexity and diversi-
ty[15] with economic[16] and environmental aspects.[17] How-
Scheme 1. Three-component synthesis of polysubstituted pyridines 4.
[a] C. Allais, Prof. T. Constantieux, Prof. J. Rodriguez
UMR CNRS 6263 iSm2, Aix-Marseille Universitꢀ
Centre Saint Jꢀrꢁme, service 531
13397 Marseille Cedex 20 (France)
Fax : (+33)491-289-187
E-mail: Thierry.constantieux@univ-cezanne.fr
jean.rodriguez@univ-cezanne.fr
The scope of this multicomponent reaction under oxida-
tive conditions was examined using various easily available
starting materials (Figure 1).
Thus, a range of valuable new 2,3,4,6-tetrasubstituted pyr-
idines was synthesized in good to excellent yields (Figure 2).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902419.
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12945

Table 1. Optimization of the catalytic oxidative system.
tive
three-component
ap-
Entry
Solvent
Catalyst
Atm.[a]
t [h]
Yield 4a [%][b]
Yield 4’a [%][b]
proach, these scaffolds may be
accessed from a-ketoamides
6
1
2
3
toluene
toluene/acetic acid 5:1
toluene/acetic acid 4:1
none
air
air
O2
24
96
48
30
31
91
55
28
0
Pd/C[c]
[19] as depicted in Scheme 3.
The reaction proved to be
activated carbon[d]
[a] Reaction conducted under an air atmosphere or under an O2 atmosphere. [b] Isolated yield after flash chro-
matography. [c] 20% weight. [d] 50% weight.
general and gave reproducible
results under the heterogene-
Scheme 2. Preliminary experiments.
Figure 1. Starting materials for the three-component reaction.
Figure 2. 2,3,4,6-Tetrasubstituted pyridines from the MCR.
For example, the use of 5b in combination with either meth-
ylacetoacetate (1a) or acetoacetanilide (1d) led to the for-
mation of pyridines 4b and 4c, while 5a gave the nicotina-
mide derivatives 4d and 4e from b-ketoamides 1d and 1 f,
respectively. Alternatively, functional diversity may be intro-
duced in these biaryl compounds, as illustrated by the syn-
thesis of the 2-trifluorosubstituted pyridine 4 f from b-ke-
toester 1b and 5a, or by the synthesis of pyridines 4g–i
bearing electron-withdrawing or electron-donating groups
on the aryl moiety. Interestingly, the sequence allowed a
highly efficient access to 2,4-diaryl pyridines 4j and 4k, de-
rived either from b-ketoester 1c or b-ketoamide 1e. In all
cases, the formation of a single regioisomer illustrates the
remarkable selectivity of this metal free oxidative three-
component reaction.[25] Moreover, work-up of the reaction is
made easier by the combination of two heterogeneous cata-
lysts, molecular sieves and activated carbon being eliminated
by simple filtration through a short pad of Celite.
To further demonstrate the high synthetic potential of this
methodology and the generality of the reactivity of a-keto-
carbonyls, we prepared a series of pyridines bearing an
amide function in position 2, that is, picolinamide deriva-
tives. Pyridine-2-carboxamides are known not only as sub-
stances of great biological significance, but also as com-
pounds of widespread interest in coordination chemistry,[5b]
catalysis[8b] and organocatalysis.[9a,b] According to our oxida-
Scheme 3. Three-component synthesis of 2-amidopyridines 4.
ous oxidative conditions. The corresponding polyfunc-
tionalized pyridines were formed in yields ranging from 52
to 84% (Figure 3). For example, primary a-ketoamide 6a
reacted with methylacetoacetate (1a) affording the pyridine
4l in 73% yield. a-Ketoamides 6b–d were combined with
either methylacetoacetate (1a) or acetoacetanilide (1d) for
the preparation of pyridines 4m–o or nicotinamide deriva-
tives 4p and 4q, respectively. Alternatively, utilization of
the furane-substituted a-ketoamide 6e also led to the hetero
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Chem. Eur. J. 2009, 15, 12945 – 12948

Multicomponent Synthesis of Polyfunctionalized Pyridines
COMMUNICATION
biaryl compound 4r with comparable efficiency. In view of
some applications of these compounds as ligands, the intro-
duction of a chiral moiety on the amide function of com-
pound 4 s, derived from substrates 1a and 6 f in 54% yield,
is of primary interest. Finally, the sequence proved to be ef-
ficient for the synthesis of highly substituted 2-amido-4,6-
diaryl pyridines, such as products 4t and 4u.
Figure 4. Pyridinylphosphonates 4 from the MCR.
simultaneous incorporation of a substituent at the 4-position
and a synthetically useful functionality at the strategic 2-po-
sition. This approach offers an important breakthrough in
the construction of functionalized heterocycles of both bio-
logical and synthetic interest and should be a good alterna-
tive to other well-known methods.
Experimental Section
General procedure for the three-component synthesis of pyridines 4: To
a 50 mL two-necked round-bottom flask equipped with reflux condenser,
were introduced 1,3-dicarbonyl compound 1 (100 mg, 1 equiv), Michael
acceptor 5, 6 or 7 (1.0 equiv), ammonium acetate 3 (2 equiv), activated
carbon (50 mg, 50% w) and 4 ꢃ molecular sieves (3 g) in AcOH/toluene
1:4 (15 mL). The round-bottom flask was then placed under oxygen at-
mosphere. The mixture was stirred at reflux until complete consumption
of starting materials (monitored by TLC and MS). The heterogeneous so-
lution was then filtered on a short pad of Celite and thoroughly washed
with toluene. Sometimes, an acetate salt is formed after filtration on
Celite. In this case, a second filtration is needed. Solvent was then re-
moved by evaporation under reduced pressure to afford crude product
which was purified by chromatography on silica gel to afford pyridine 4.
Figure 3. 2-Amidopyridines 4 from the MCR.
Finally, we have successfully extended this multicompo-
nent sequence to the synthesis of 2-phosphorylated pyri-
dines 4. From a general point of view, amino-substituted
phosphonic acid derivatives are of interest with respect to
their biological properties, and some of them have been in-
volved in the preparation of DNA analogues.[26] Alternative-
ly, they may be considered as precursors of hybrid ligands
such as pyridinylphosphines.[7d,27] According to the general
Scheme 4, we have synthesized a series of pyridinylphospho-
nates 4v–y from a-ketophosphonate 7 and various 1,3-dicar-
bonyls (Figure 4). In particular, the method allows for a
direct access to the bi-aryl compound 4w in good yield with-
out any use of metal. The convenient preparation of these
compounds further highlights the synthetic potential of the
methodology. Notably, this sequence allowed the prepara-
tion of highly functionalized nicotinamide derivatives 4x
and 4y, which can serve as promising scaffolds for novel
hybrid ligands.
Complementary data are available in the Supporting Information.
Acknowledgements
C.A. thanks the French Research Ministry for a fellowship award. Uni-
versity Paul Cꢀzanne, CNRS (UMR 6263 iSm2 and RDR2 research net-
work) and French Research Ministry are acknowledged for financial sup-
port.
Keywords: ketones · Michael addition · multicomponent
reactions · pyridines · regioselectivity
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Received: September 9, 2009
Published online: November 5, 2009
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Chem. Eur. J. 2009, 15, 12945 – 12948