Metal-free Michael addition initiated multicomponent oxidative cyclodehydration route to polysubstituted pyridines from 1,3-dicarbonyls

Article abstract of DOI:10.1039/b805680c

A simple metal-free, step-economic and selective access to pyridines from readily available substrates is reported, involving a flexible 4 A molecular sieves promoted Michael addition initiated domino three-component reaction between a 1,3-dicarbonyl, a Michael acceptor and a synthetic equivalent of ammonia. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805680c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Metal-free Michael addition initiated multicomponent oxidative
cyclodehydration route to polysubstituted pyridines from 1,3-dicarbonylsw
´
Frederic Lieby-Muller, Christophe Allais, Thierry Constantieux* and
Jean Rodriguez*
´
´
Received (in Cambridge, UK) 3rd April 2008, Accepted 19th May 2008
First published as an Advance Article on the web 10th July 2008
DOI: 10.1039/b805680c
A simple metal-free, step-economic and selective access to pyr-
idines from readily available substrates is reported, involving a
˚
flexible 4 A molecular sieves promoted Michael addition initiated
domino three-component reaction between a 1,3-dicarbonyl, a
Michael acceptor and a synthetic equivalent of ammonia.
Scheme 1 MCR synthesis of polysubstituted pyridines 4.
providing after in situ oxidation the corresponding pyridine
derivatives 4 in a single operation (Scheme 1).19
Pyridines are one of the most important nitrogen heterocycles
found in numerous natural and synthetic pharmaceutical
agents.1 These scaffolds are also of widespread interest in
coordination and supramolecular chemistry, as well as for
materials science.2 The synthesis of these heterocycles has long
been an area of intense interest resulting in the development of
a wide range of synthetic methods.3 Among them, the direct
condensation of carbonyl compounds with a source of ammo-
nia is well documented,4 but still suffers from some limitations
in the substrates,5 or involves an oxidative agent6 or an
elimination step.7 Thereby, development of valuable synthetic
pathways still remains an industrial as well as an academic
challenge.8 In this context, the metal-catalysed [2+2+2]
cycloisomerisation of alkynes with nitriles largely leads the
way nowadays.9 However, despite recent spectacular ad-
vances,10 the low availability of some catalysts and substrates
associated with the lack of regioselectivity11 constitute major
drawbacks.
Due to the nature of the three partners, this strategy may be
viewed as a Michael addition initiated biomimetic approach
previously formulated by Baldwin and Marazano20 for natural
3-alkylpyridinium salts.
Preliminary experiments were conducted with easily avail-
able acyclic 1,3-dicarbonyls 1a–e and Michael acceptors 2a–c.
Under optimised conditions, NH4OAc proved to be the best
source of ammonia21 and the corresponding pyridines 4a–j
were obtained by simply heating a toluene solution of the three
partners in the presence of 4 A MS,22 acting both as dehydra-
ting agent and as heterogeneous catalyst as shown before.18a
The general applicability is clearly seen from the results
reported in Table 1. Acrolein (2a) (entries 1, 4, 8, 10) and
methacrolein (2b) (entries 2, 5, 7) may be used, as well as
methyl vinyl ketone (2c) (entries 3, 6, 9). Similarly, diversity
may be acceded through the use (Fig. 1) of either acetylacetone
(1a) (entries 1–3), methyl acetoacetate (1b) (entries 4–6) or
ethyl 4,4,4-trifluoroacetoacetate (1c) (entry 7). Interestingly
enough, b-ketoamide 1d led to the expected pyridines 4h and 4i
(entries 8 and 9), making this transformation a direct and user-
friendly one-pot access to nicotinamide derivatives. Finally,
In the course of our studies on the development of new
domino12 multicomponent reactions (MCRs)13 for creation of
molecular complexity and diversity14 whilst combining eco-
nomic aspects15 with environmental ones,16 we recently re-
ported molecular sieves-promoted transformations of various
1,3-dicarbonyls17 for the stereoselective synthesis of a series of
heterocycles.18 In this context, herein we wish to report on a
simple metal-free, step-economic and selective access to pyr-
idines from readily available substrates. Thus, we have now
designed a flexible domino three-component reaction invol-
ving the direct condensation of 1,3-dicarbonyls 1 with Michael
acceptors 2 and a synthetic equivalent of ammonia 3, under
heterogeneous catalysis by 4 A molecular sieves (MS),
this multicomponent reaction appears as a promising
new strategy for the direct metal-free synthesis of bi-aryl
Fig. 1 Acyclic 1,3-dicarbonyl substrates 1 for the MCR.
´
´
Aix-Marseille Universite, Institut des Sciences Moleculaires de
Marseille, iSm2 CNRS UMR 6263, Centre Saint Je´roˆme
service 531 13397, Marseille Cedex 20, France.
E-mail: jean.rodriguez@univ-cezanne.fr; thierry.constantieux@univ-
cezanne.fr; Fax: +33-(0)491-288-841; Tel: +33-(0)491-288-933
w Electronic supplementary information (ESI) available: Complete
experimental procedures and characterisations. See DOI: 10.1039/
b805680c
Fig. 2 Bi- and tricyclic pyridines from the MCR.
Chem. Commun., 2008, 4207–4209 | 4207
ꢀc
This journal is The Royal Society of Chemistry 2008

View Article Online
Table 1 Pyridine synthesis from acyclic 1,3-dicarbonyls
Entry
Substrate 1
R3
R4
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
10
a
1a
1a
1a
1b
1b
1b
1c
1d
1d
1e
H
Me
H
H
Me
H
Me
H
H
H
H
Me
H
H
Me
H
H
Me
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
52
65
62
56
44
65
70
61
42
65
H
4j
Isolated yield after flash chromatography.
may then react with ammonium acetate (3) leading to the
dihydropyridine 7 via an intramolecular dehydrative cyclisa-
tion sequence. As a validation of this first hypothesis, pyridine
4c was isolated by mixing the Michael adduct 5a28 with 3
under standard conditions (Scheme 2). Alternatively, a more
conventional mechanistic pathway could involve the prelimin-
ary formation of an enamino ketone intermediate 6, which
may lead to the final product via a Hantzsch-type reaction.29
Interestingly enough, when 6, independently prepared from
NH4OAc and acetylacetone (1a), was reacted with methyl
vinyl ketone (2c), pyridine 4c was not formed and starting
materials were recovered even after 24 hours (Scheme 2).
These preliminary results support our original mechanistic
proposal involving a 4 A MS initiated Michael addition30 as
the first step of the sequence.31
Fig. 3 Pyridines from sensitive Michael acceptors.
compounds from substrates such as 1e (entry 10), opening the
way to a flexible design of atropoisomers of bi-aryl ligands.23
To further demonstrate the versatility of the method, we
then examined the use of cyclic 1,3-dicarbonyls such as
dimedone (1f) or indane-1,3-dione (1g) in the sequence, and
some representative bi- and tricyclic pyridines are shown in
Fig. 2. In all cases, products are obtained with a total regio-
selectivity. Of particular interest is the one-pot synthesis of
4-azafluorenones 4m and 4n, which are common skeletons in
natural products and molecules of pharmacological interest,24
and generally accessed via multistep sequences.25
In conclusion, we have developed a regioselective, user-
friendly and mechanistically original three-component reac-
tion for the one-pot synthesis of polysubstituted pyridines
from readily accessible substrates. The biomimetic like se-
quence does not require any harmful reagents or metal-based
catalysts, and allows construction of highly functionalised
heterocycles of both biological and synthetic interest. This
pyridine approach should be a good and complementary
substrate directed synthetic alternative to other well known
methods.
The neutral heterogeneous reaction conditions are also
suitable with sensitive Michael acceptors such as a-exo-methy-
lene ketones 2d–f,26 leading to bi- and tricyclic pyridines 4o–q
in acceptable yields (Fig. 3).
From a mechanistic point of view, two multistep sequences
have been preliminarily explored. Both evolve through a
1,4-dihydropyridine intermediate 7 which suffers an in situ
oxidative aromatisation to the corresponding pyridine.27 We
initially postulated that the first step of the sequence may be
the molecular sieves promoted Michael addition between
substrates 1 and acceptors 2. The corresponding adduct 5
Notes and references
1 (a) H. J. Roth and A. Kleemann, Drug Synthesis, in Pharmaceu-
tical Chemistry, John Wiley and Sons, New York, 1988, vol. 1;
(b) J. P. Michael, Nat. Prod. Rep., 2005, 22, 627–646.
2 M. Balasubramanian and J. G. Keay, Comprehensive Heterocyclic
Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven,
Pergamon, Oxford, 1996, vol. 5, pp. 245–300.
3 D. Spitzner, in Science of Synthesis, ed. D. Black, StC., Georg
Thieme Verlag, Stuttgart, 2005, pp. 11–284.
4 (a) A. E. Chichibabin and O. A. Zeide, J. Russ. Phys. Chem., 1906,
37, 1229; (b) F. Bohlmann and D. Rahtz, Chem. Ber., 1957, 90,
2265–2272; (c) H. Nozaki, S. Fujita and T. Mori, Bull. Chem. Soc.
Jpn., 1969, 42, 1163.
5 (a) M. C. Bagley, C. Glover and E. A. Merritt, Synlett, 2007,
2459–2482, and references cited therein; (b) A.-L. Blayo, S.
´ ´
Le Meur, D. Gree and R. Gree, Adv. Synth. Catal., 2008, 350,
471–476.
6 See for example: (a) J. S. Yadav, B. V. S. Reddy, A. K. Basak, G.
Baishya and A. V. Narsaiah, Synthesis, 2006, 451–454; (b) T. R. K.
Reddy, R. Mutter, W. Heal, K. Guo, V. J. Gillet, S. Pratt and B.
Chen, J. Med. Chem., 2006, 49, 607–615.
Scheme 2 Mechanistic investigations.
ꢀc
This journal is The Royal Society of Chemistry 2008
4208 | Chem. Commun., 2008, 4207–4209

View Article Online
7 (a) F. Krohnke, Synthesis, 1976, 1–24; (b) G. J. Reddy, D. Latha,
¨
and B. C. Das, J. Am. Chem. Soc., 1998, 120, 8026–8034;
(c) J.-C. Wypych, T. M. Nguyen, M. Benechie and C. Marazano,
´ ´
J. Org. Chem., 2008, 73, 1169–1172.
C. Thirupathaiah and K. S. Rao, Tetrahedron Lett., 2005, 46,
301–302; (c) S. Kantevari, M. V. Chary and S. V. N. Vuppalapati,
Tetrahedron, 2007, 63, 13024–13031.
8 (a) F. Mongin and G. Queguiner, Tetrahedron, 2001, 57,
4059–4090; (b) G. D. Henry, Tetrahedron, 2004, 60, 6043–6061;
(c) A. R. Katritzky, Chem. Rev., 2004, 104, 2125–2126.
´
9 (a) J. A. Varela and C. Saa, Chem. Rev., 2003, 103, 3787–3802;
(b) I. Nakamura and Y. Yamamoto, Chem. Rev., 2004, 104,
2127–2198.
10 For recent examples with various metals, see: (a) Y. Zhou, J. A.
Porco, Jr and J. K. Snyder, Org. Lett., 2007, 9, 393–396; (b) H. T.
Chang, M. Jeganmohan and C.-H. Cheng, Org. Lett., 2007, 9,
505–508; (c) K. Kase, A. Goswami, K. Ohtaki, E. Tanabe, N.
Saino and S. Okamoto, Org. Lett., 2007, 9, 931–934; (d) A. Wada,
K. Nogushi, M. Hirano and K. Tanaka, Org. Lett., 2007, 9,
1295–1298.
21 (a) Sulfamic acid21b led also to the formation of pyridines, but with
lower yields. Hydroxylamine and ammonium chloride were tested
without any success; (b) C. Defieber, M. A. Ariger, P. Moriel and
E. M. Carreira, Angew. Chem., Int. Ed., 2007, 46, 3139–3143.
22 Crude products were easily obtained with acceptable chemical
purity by simple filtration through a short pad of Celite. It is
noteworthy that no reaction occurs in the absence of molecular
sieves.
23 G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser, J.
Garner and M. Breuning, Angew. Chem., Int. Ed., 2005, 44,
5384–5427.
24 K. J. Stauffer, P. D. Williams, H. G. Selnick, P. G. Nantermet, C.
L. Newton, C. F. Homnick, M. M. Zrada, S. D. Lewis, B. J. Lucas,
J. A. Krueger, B. L. Pietrak, E. A. Lyle, R. Singh, C. Miller-Stein,
R. B. White, B. Wong, A. A. Wallace, G. R. Sitko, J. J. Cook, M.
A. Holahan, M. Stranieri-Michener, Y. M. Leonard, J. J. Lynch,
D. R. McMasters and Y. Yan, J. Med. Chem., 2005, 48,
2282–2293.
25 See for example: (a) A.-S. Rebstock, F. Mongin, F. Trecourt and
G. Queguiner, Tetrahedron, 2003, 59, 4973–4977; (b) Multicompo-
nent approach: S. Tu, B. Jiang, H. Jiang, Y. Zhang, R. Jia, J.
Zhang, Q. Shao, C. Li, D. Zhou and L. Cao, Tetrahedron, 2007, 63,
5406–5414.
11 (a) C. Brandli and T. R. Ward, J. Comb. Chem., 2000, 2, 42–47;
¨
(b) K. Parthasarathy, M. Jeganmohan and C.-H. Cheng, Org.
Lett., 2008, 10, 325–328.
12 (a) Domino Reactions in Organic Synthesis, ed. L. F. Tietze, G.
Brasche and K. M. Gericke, Wiley-VCH, Weinheim, 2006; (b) A.
Padwa and S. K. Bur, Tetrahedron, 2007, 63, 5341–5378.
13 (a) Multicomponent Reactions, ed. J. Zhu and H. Bienayme, Wiley-
´
VCH, Weinheim, 2005; (b) A. Domling, Chem. Rev., 2006, 106,
17–89.
¨
14 (a) T. E. Nielsen and S. L. Schreiber, Angew. Chem., Int. Ed., 2008,
47, 48–56; (b) For a recent example of structurally-diversifying
domino reaction sequences yielding highly substituted pyridines,
26 (a) J.-L. Gras, Tetrahedron Lett., 1978, 24, 2111–2114; (b) J.-L.
Gras, Org. Synth., 1981, 60, 88.
27 The poor stability of dihydropyridines in acetic conditions is well
known and has been recently exemplified as a side reaction in the
use of Hantzsch ester as a reducing agent: G. Barbe and A. B.
Charette, J. Am. Chem. Soc., 2008, 130, 18–19.
28 5a was synthesised from acetylacetone (1a) and methyl vinyl
ketone (2c) with a catalytic amount of base-supported P-BEMP:
D. Bensa, T. Constantieux and J. Rodriguez, Synthesis, 2004,
923–927.
29 A. Hantzsch, Justus Liebigs Ann. Chem., 1882, 215–236.
30 After optimisation of the reaction conditions, we demonstrated
that 2 equiv. of NH4OAc (3) were necessary. However, it is
noteworthy that when only 1 equiv. of 3 was used, the expected
pyridine was obtained in admixture with a significant amount of 5,
which may confirm the preliminary formation of such Michael
adduct intermediates in the first step of the sequence.
31 The catalytic properties of 3 A MS activated with several neutral
Lewis bases were also recently reported for the promotion of
Michael addition of 1,3-dicarbonyl compounds: R. Villano and
A. Scettri, Synthesis, 2005, 757–760.
see: H. Waldmann, M. Kuhn, W. Liu and K. Kumar, Chem.
Commun., 2008, 1211–1213.
¨
15 (a) Step-economy: P. A. Wender, G. G. Gamber, R. D. Hubbard,
S. M. Pham and L. Zhang, J. Am. Chem. Soc., 2005, 127,
2836–2837; (b) Atom economy: B. M. Trost, Acc. Chem. Res.,
2002, 35, 695–705.
16 Special issue in green chemistry: Chem. Rev., 2007, 107, 2167–2820.
17 (a) C. Simon, T. Constantieux and J. Rodriguez, Eur. J. Org.
´
Chem., 2004, 4957–4980; (b) F. Lieby-Muller, C. Simon, T. Con-
stantieux and J. Rodriguez, QSAR Comb. Sci., 2006, 25, 432–438.
18 (a) C. Simon, J. F. Peyronel and J. Rodriguez, Org. Lett., 2001, 3,
2145–2148; (b) F. Lie
´
J. Am. Chem. Soc., 2005, 127, 17176–17177; (c) F. Lie
by-Muller, T. Constantieux and J. Rodriguez,
by-Muller, T.
´
Constantieux and J. Rodriguez, Synlett, 2007, 1323–1325.
19 For gas phase utilisation of zeolites as heterogeneous catalyst, see:
W. Hoelderich and N. Goetz, US Pat., 4960894, 1990.
20 (a) J. E. Baldwin and R. C. Whitehead, Tetrahedron Lett., 1992, 33,
2059–2062; (b) A. Kaiser, X. Billot, A. Gateau-Olesker, C. Marazano
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 4207–4209 | 4209