A new one-pot three-component condensation reaction for the synthesis of 2,3,4,6-tetrasubstituted pyridines

Article abstract of DOI:10.1039/b203900a

The one-pot three-component condensation of a β-ketoester, ammonia and an alkynone in the presence of a Bronsted or Lewis acid or Amberlyst 15 ion exchange resin provided 2,3,6-trisubstituted or 2,3,4,6-tetrasubstituted pyridines directly in good yield and with total regiocontrol.

Full text of DOI:10.1039/b203900a

A new one-pot three-component condensation reaction for the synthesis
of 2,3,4,6-tetrasubstituted pyridines
Mark C. Bagley,*a James W. Dalea and Justin Bowerb
a Department of Chemistry, Cardiff University, PO Box 912, Cardiff, UK CF10 3TB.
E-mail: bagleymc@cf.ac.uk; Fax: 44 29 20874030; Tel: +44 29 20874029
b RiboTargets Ltd, Granta Park, Abington, Cambridge, UK CB1 6GB
Received (in Cambridge, UK) 23rd April 2002, Accepted 26th June 2002
First published as an Advance Article on the web 8th July 2002
The one-pot three-component condensation of a b-ketoester,
ammonia and an alkynone in the presence of a Brønsted or
Lewis acid or Amberlyst 15 ion exchange resin provided
2,3,6-trisubstituted or 2,3,4,6-tetrasubstituted pyridines di-
rectly in good yield and with total regiocontrol.
ammonia would provide a much more efficient approach
towards poly-substituted pyridine 4 (see Scheme 1). This new
tandem addition–elimination–Michael addition–cyclodehydra-
tion process would be related to the Hantzsch dihydropyridine
synthesis11 but with the advantage of total control of re-
giochemistry and access to the target heterocycle in the correct
oxidation state.
In order to test the validity of this proposal for a one-step
synthesis of poly-substituted pyridines, ethyl acetoacetate 1a
was reacted with either one or two equivalents of hex-3-yn-
2-one 5a and ammonium acetate in toluene, heated at reflux in
the presence of either acetic acid or zinc(II) bromide (Scheme 3),
catalysts employed to good effect in our previously reported
modified Bohlmann–Rahtz reactions.8,9 In all cases, pyridine 4a
was formed directly as the only reaction product, isolated in
good to excellent yield in a single preparative step (Scheme 3).
The reaction† proceeded with total regiocontrol, established by
comparing spectroscopic data of the product with an authentic
sample of 4a.8 The optimum reaction conditions used the Lewis
acid catalyst (0.2 equivalents) and an excess of hex-3-yn-2-one
5a to generate pyridine 4a in 96% yield after chromatographic
purification on silica (Table 1).
The synthesis, reactions and biological properties of pyridine-
containing derivatives constitutes a significant part of modern
heterocyclic chemistry. This heterocyclic motif may be found in
a large number of pharmaceutical agents,1 as a pharmacophore
of considerable historical importance, and so new and facile
methods for their synthesis are of great current interest.
Bohlmann and Rahtz first reported the preparation of a
trisubstituted pyridine 4 (R4 = H) from enamine 2 and alkynone
5 by Michael addition and subsequent cyclodehydration back in
1957.2 This two-step method requires harsh cyclodehydration
conditions (up to 200 °C) and isolation of the aminodienone
intermediate 3. The poor availability of enamine substrates has
also restricted the applicability of this reaction; typically
enamine 2 is prepared from b-ketoester 1 by reaction with
ammonium acetate under acidic conditions (benzene–acetic
acid) with azeotropic removal of water according to the
procedure of Baraldi et al. (Scheme 1).3 This long-winded and
somewhat laborious three-step process, nevertheless, displays
great potential for the synthesis of pyridine-containing hetero-
cycles of biological interest and has been put to a few notable
uses since its discovery.4–7
In order to investigate the scope of this reaction and establish
its tolerance of different substrates, a range of different b-
ketoesters 1a–d and alkynones 5a–d were heated at reflux in
toluene under acidic conditions in the presence of an excess of
ammonium acetate (Scheme 4). In all of the cases that were
In order to increase the scope and application of the
Bohlmann–Rahtz reaction, we have reported new facile proce-
dures using zinc(II) bromide, acetic acid or Amberlyst 15 ion
exchange resin as catalysts to affect Michael addition–
cyclodehydration in a single synthetic step and at a lower
reaction temperature (Scheme 2).8,9 However, in order to
overcome problems of poor substrate availability, to improve
the facility of the whole process and as part of our interest in the
discovery of new multiple-component condensation reactions
in heterocyclic chemistry,10 it was proposed that the three-
component condensation of a b-keto ester 1, alkynone 5 and
Scheme 2 The one-step Bohlmann–Rahtz reaction using acetic acid,
Amberlyst 15 ion exchange resin or zinc(II) bromide catalysis.
Scheme 3 Three-component condensation of ethyl acetoacetate 1a, hex-
3-yn-2-one 5a and ammonia under acidic conditions.
Table 1 Reaction conditions
Yielda of
Entry
5a equivalents
Acid catalyst
4a (%)
1
2
3
4
1
2
1
2
AcOH
AcOH
ZnBr2
ZnBr2
68
78
67
96
Scheme 1 The three-step heteroannulation procedure for the synthesis of
2,3,4,6-tetrasubstituted pyridine 4.
a Isolated yield after purification on silica.
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CHEM. COMMUN., 2002, 1682–1683
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Scheme 4 Three-component heteroannulation of b-ketoester 1, alkynone 5 and ammonia under acidic conditions.
Table 2 Examining the scope of the three-component heteroannulation reaction
Equivalents
of 5
Yielda
(%)
Entry
b-Ketoester 1
Alkynone 5
Acid catalyst
Conditions
Product
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1a
1a
1c
1c
1c
1c
1d
1d
5a
5b
5b
5b
5c
5c
5a
5b
5b
5a
5d
5d
2
2
2
2
2
2
3
2
3
3
3
3
ZnBr2
AcOH
AcOH
ZnBr2
ZnBr2
AcOH
ZnBr2
Amberlyst 15
Amberlyst 15
Amberlyst 15
AcOH
Toluene/reflux
Toluene/reflux
Toluene/reflux
Toluene/reflux
Toluene/reflux
Toluene/reflux
Toluene/reflux
Toluene/reflux
Toluene/reflux
Toluene/reflux
Toluene/reflux
Benzene/reflux
4a
4b
4c
4c
96
80
70
88
55
75
49
53
60
55
68b
71b
4d,4e (44+56)
4d
4f
4f
4f
4g
4h
4h
9
10
11
12
AcOH
a Yield of pure isolated product. b Formed in 78% ee (entry 11) or 98% ee (entry 12) by HPLC analysis [Chiralpak AD column, hexane-IPA (92+8)].
reflux for 20 h. The mixture was partitioned between aqueous saturated
sodium hydrogen carbonate solution (25 ml) and ethyl acetate (25 ml) and
the aqueous layer was further extracted with ethyl acetate (2 3 20 ml). The
combined organic layers were washed with brine (10 ml), dried (MgSO4)
and evaporated in vacuo. Purification by flash chromatography on silica,
eluting with light petroleum–ethyl acetate (3+1), gave pure pyridine 4a as a
pale yellow oil (0.36 g, 78%), with spectroscopic data that were identical
investigated (Table 2), pyridine 4 was isolated in good to
excellent yield (entries 1–4, 70–96% yield) as the only
regioisomeric reaction product. When 4-(trimethylsilyl)but-
3-yn-2-one 5c was reacted with ethyl acetoacetate 1a in the
presence of zinc(II) bromide, partial desilylation occurred to
give a mixture of pyridine 4d and 4e (entry 5). However, by
employing acetic acid as the catalyst, only a single pyridine 4d
was produced in 75% yield (entry 6). The use of tert-butyl
acetoacetate 1c (entries 7–10), caused a reduction in the
efficiency of the process but pyridine 4f was still isolated in
moderate yield under zinc(II) bromide or Amberlyst 15 ion
exchange resin catalysed conditions. In the synthesis of pyridine
4h a high degree of racemisation accompanied the reaction in
toluene, but by switching to benzene these problems were
avoided.12
In conclusion, this new three-component condensation
greatly simplifies and shortens the laborious traditional proce-
dure and proceeds with total control of regiochemistry and so
should offer considerable advantages over existing method-
ology.
with an authentic sample.
1 H. J. Roth and A. Kleemann, Pharmaceutical Chemistry. Volume 1:
Drug Synthesis, John Wiley & Sons, New York, 1988.
2 F. Bohlmann and D. Rahtz, Chem. Ber., 1957, 90, 2265.
3 P. G. Baraldi, D. Simoni and S. Manfredini, Synthesis, 1983, 902.
4 C. J. Moody and M. C. Bagley, Chem. Commun., 1998, 2049.
5 M. C. Bagley, K. E. Bashford, C. L. Hesketh and C. J. Moody, J. Am.
Chem. Soc., 2000, 122, 3301–3313.
6 R. M. Adlington, J. E. Baldwin, D. Catterick, G. J. Pritchard and L. T.
Tang, J. Chem. Soc., Perkin Trans. 1, 2000, 2311 and references
therein.
7 M. C. Bagley, D. D. Hughes, R. Lloyd and V. E. C. Powers, Tetrahedron
Lett., 2001, 42, 6585.
8 M. C. Bagley, J. W. Dale and J. Bower, Synlett, 2001, 1149.
9 M. C. Bagley, J. W. Dale, D. D. Hughes, M. Ohnesorge, N. G. Phillips
and J. Bower, Synlett, 2001, 1523.
Notes and references
10 M. C. Bagley and N. Singh, Chem. Commun., 2001, 2438.
11 A. Hantzsch, Ann. Chem., 1882, 215, 1; D. M. Stout and A. I. Meyers,
Chem. Rev., 1982, 82, 223; U. Eisner and J. Kuthan, Chem. Rev., 1972,
72, 1.
† General experimental procedure for the three-component cyclocondensa-
tion reaction catalysed by acetic acid: a solution of ethyl acetoacetate (0.28
ml, 2.2 mmol), hex-3-yn-2-one (0.50 ml, 4.5 mmol) and ammonium acetate
(1.7 g, 23 mmol) in toluene–glacial acetic acid (5+1) (12 ml) was heated at
12 The ee was established by chiral HPLC and reference to racemic 4h.
CHEM. COMMUN., 2002, 1682–1683
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