Michael addition of ethyl acetoacetate to α,β-unsaturated oximes in the presence of FeCl3: A novel synthetic route to substituted nicotinic acid derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01391-5

The FeCl₃-catalyzed reaction of α,β-unsaturated oximes with ethyl acetoacetate resulted in Michael addition followed by ring closure to produce substituted nicotinic acid derivatives in a very efficient way. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01391-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8011–8013
Michael addition of ethyl acetoacetate to a,b-unsaturated
oximes in the presence of FeCl3: a novel synthetic route to
substituted nicotinic acid derivatives
Andrey M. Chibiryaev,a Norbert De Kimpeb and Alexey V. Tkachevc,*
aDepartment of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia
bDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium
cNovosibirsk Institute of Organic Chemistry, Lavrentjev Ave. 9, Novosibirsk 630090, Russia
Received 10 July 2000; revised 11 August 2000; accepted 16 August 2000
Abstract
The FeCl3-catalyzed reaction of a,b-unsaturated oximes with ethyl acetoacetate resulted in Michael
addition followed by ring closure to produce substituted nicotinic acid derivatives in a very efficient way.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Michael addition; iron(III) chloride hexahydrate; unsaturated oxime; nicotinic acid.
The reaction of b-dicarbonyl compounds with a,b-unsaturated ketones (Michael addition) is
a very important and useful synthetic method for carbonꢀcarbon bond formation. In the case of
enimines the reaction leads to 1,4-dihydropyridines.1 The Michael type addition is usually a
base-catalyzed process. Recently it was found that iron(III) chloride is an extraordinarily
efficient catalyst for the Michael reaction: reaction conditions were very mild and gentle, and the
reaction procedure was reasonably easy.2
We have studied the reaction of a,b-unsaturated oximes with ethyl acetoacetate and pentane-
2,4-dione in the presence of FeCl3·6H2O and found in certain cases the formation of highly
substituted pyridines as the main products.
In contrast to the reported reactions of ethyl acetoacetate and b-diketones with a,b-unsatur-
ated ketones, neither pentane-2,4-dione nor ethyl acetoacetate reacted with enone oximes at
ambient temperature in the presence of FeCl3·6H2O. However, at higher temperature (about
150°C) a number of oximes of unsaturated acyclic ketones 1a–1e as well as monocyclic and
bicyclic oximes (1d and 1e, respectively) were easily transformed to the nicotinic acid ethyl esters
2a–2e in the reaction with ethyl acetoacetate (Scheme 1).3
* Corresponding author. Tel: +7 3832 344855; fax: +7 3832 344752; e-mail: atkachev@nioch.nsc.ru
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01391-5

8012
Scheme 1.
In the case of oxime 1e, derived from pinocarvone, we investigated the catalytic activity of
different transition metal chlorides, e.g. NiCl2·6H2O, CuCl2·2H2O, and CoCl2·6H2O. Although
all the chlorides showed catalytic activity and resulted in complete conversion of the starting
oxime, only FeCl3·6H2O provided a high yield of the pyridine 2e.
Substituted pyridines can be prepared from conjugated oximes under Vilsmeier conditions.4 In
this case the first stage of the multi-step process requires a Beckman rearrangement of the
starting oxime followed by ring closure, resulting in a substituted pyridine with the rearranged
(as compared with the starting oxime) carbon frame. In the case of oximes derived from cyclic
a,b-unsaturated ketones such a reaction is impossible. Addition of ethyl acetoacetate to oximes
of cyclic a,b-unsaturated ketones does not require the rearrangement stage and proceeds as an
addition ring closure sequence. The mechanism of the pyridine formation is not yet clear,
although a possible scheme might be formulated as follows (Scheme 2). Primary Michael
addition of ethyl acetoacetate to the enone oxime 1 gives the adduct 3, which undergoes a ring
closure accompanied by dehydration and subsequent migration of a proton to form the
N-hydroxy derivative 5. Alternatively, the cyclic N-hydroxy derivative 5 could arise from
intramolecular cyclization of N-hydroxy enamine 6. Elimination of an extra water molecule
from compound 5 provides the formation of the substituted pyridine 2.
The strength of this protocol for the synthesis of pyridines is its simplicity. The generality and
usefulness of this new pyridine synthesis is underlined by the use of complex oximes 1d,e. The
method allows the synthesis of tetra- and pentasubstituted pyridines. Thus, equimolar amounts
of ethyl acetoacetate and 5 mol% of FeCl3·6H2O were added to enone oximes 1a–1e, and the
reaction mixture was heated under vigorous stirring to 150–160°C and kept at this temperature
for 2–4 h. Unreacted acetoacetate was distilled off at reduced pressure. The residue was taken
up in tert-butyl methyl ether and the resulting mixture was extracted with 1 M HCl. The
combined acidic aqueous extracts were adjusted to pH 9 by means of aqueous ammonia and
extracted with CH2Cl2. The organic extract was dried and concentrated at reduced pressure to
afford the crude product, which was then purified by chromatography on a silica gel column to
give pyridines 2a–e as viscous oils.

8013
Scheme 2.
The synthetic route described can be considered as an alternative method to the well-known
pyridine synthesis from an amine or hydroxylamine and 1,5-diketones, which are usually
obtained by a Michael addition of 1,3-dicarbonyl compounds to enones.5
Acknowledgements
The authors thank the Russian Foundation for Basic Research (Grants 98-03-32910), the
International Association for the promotion of cooperation with scientists from the New
Independent States of the former Soviet Union (INTAS, Grant c 97-0217) and the Siberian
Division of RAS (Grant for young scientists 2000) for the financial support of this work.
References
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