A new one-step synthesis of pyridines under microwave-assisted conditions

Article abstract of DOI:10.1016/S0040-4039(02)01975-5

Tri- or tetrasubstituted pyridines are prepared by microwave irradiation of ethyl β-aminocrotonate and various alkynones in a single synthetic step and with total control of regiochemistry. This new one-pot Bohlmann-Rahtz procedure conducted at 170°C in a

Full text of DOI:10.1016/S0040-4039(02)01975-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8331–8334
A new one-step synthesis of pyridines under microwave-assisted
conditions
Mark C. Bagley,* Rebecca Lunn and Xin Xiong
Department of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
Received 22 July 2002; accepted 13 September 2002
Abstract—Tri- or tetrasubstituted pyridines are prepared by microwave irradiation of ethyl b-aminocrotonate and various
alkynones in a single synthetic step and with total control of regiochemistry. This new one-pot Bohlmann–Rahtz procedure
conducted at 170°C in a self-tunable microwave synthesiser gives superior yields to similar experiments conducted using
conductive-heating techniques in a sealed tube and can be carried out in the presence of a Brønsted or Lewis acid catalyst. © 2002
Published by Elsevier Science Ltd.
In recent years, the use of microwave dielectric heating
in synthetic chemistry has emerged as a valuable alter-
native to conventional conductive heating methods.1
With no direct contact between the chemical reactants
and the energy source, microwave-assisted chemistry
has been heralded as being more efficient, in terms of
the energy used, capable of providing faster heating
rates and able to improve reaction rates and efficien-
cies. With many possible benefits and as a result of
improvements in instrumentation, with the advent of
dedicated ovens for synthesis that focus microwaves in
a monomodal cavity, the development of new repro-
ducible microwave-assisted procedures has been a pop-
ular area of chemistry of late.2
Brønsted or Lewis acid catalyst,10,11 and applied this
new methodology to the synthesis of heterocycles con-
taining the tetrasubstituted pyridine motif.12 We now
wish to report a new and extremely simple method to
facilitate this transformation in only 20 min using
microwave irradiation, which proceeds in good yield
and with total control of regiochemistry.
A solution of ethyl b-aminocrotonate 1 and an excess
of phenylpropynone 2a (R=Ph) (Scheme 2) was stirred
in toluene or DMSO, solvents that have been shown to
promote Michael addition in traditional Bohlmann–
Rahtz reactions in previous studies within the group,12
at 170°C by irradiating initially at 150 or 160 W using
a self-tunable microwave synthesiser (Table 1). The
reaction conducted in toluene was found to be sluggish
The Bohlmann–Rahtz synthesis of trisubstituted pyridi-
nes 4, from ethyl b-aminocrotonate 1 and an ethynyl
ketone 2, was first reported in 19573 and has since
found application in the preparation of the modified
oxazole–thiazole–pyridine core of the promothiocin
antibiotics,4–6 the synthesis of novel heterocyclic substi-
tuted a-amino acids7 and the transformation of 1,6-
diaminopyrimidin-4-one and uracil derivatives to
pyrido[2,3-d]pyrimidines.8,9 This high-yielding reaction
proceeds via dienone intermediate 3, formed by
Michael addition of enamine 1 and alkynone 2, that is
isolated and heated to high temperatures to effect
cyclodehydration to pyridine 4 in a two-step procedure
(Scheme 1). We have developed a number of methods
to effect this transformation in a single synthetic step,
and at a lower reaction temperature, using either a
* Corresponding author.
Scheme 1. The two-step Bohlmann–Rahtz pyridine synthesis.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01975-5

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M. C. Bagley et al. / Tetrahedron Letters 43 (2002) 8331–8334
Table 2. Reaction in a sealed tube using conventional
heating techniques
Entry
Solvent
Time (min)
Yield%a
1
2
3
Toluene
90
20
10
54
80
33
Dimethyl sulfoxide
Toluene–ZnBr2 (15
mol%)
Scheme 2. One-step Bohlmann–Rahtz synthesis of pyridine
4a.
4
5
Toluene–acetic acid (5:1) 10
Neat 20
95
93
Table 1. Reaction under microwave-assisted conditions
Entry
Solvent
Time (min)
Yield%a
a Isolated yield after purification by column chromatography on
silica.
1
2
3
Toluene
90
20
10
76
87
80
Dimethyl sulfoxide
Toluene–ZnBr2 (15
mol%)
Toluene–acetic acid (5:1) 10
Neat 20
presence of 15 mol% of zinc(II) bromide (entry 3),
although in many instances comparable yields were
obtained (entries 2, 4 and 5). Only the solventless
reaction (entry 5) gave superior results in a Carius tube,
making the microwave irradiation procedure the
method of choice for a rapid one-pot entry to trisubsti-
tuted pyridines.
4
5
98
84
a Isolated yield after purification by column chromatography on
silica.
With successful experimental procedures established for
the one-pot synthesis of pyridines, the heteroannulation
of ethyl b-aminocrotonate 1 and 4-(trimethylsilyl)but-3-
yn-2-one 6a was investigated under microwave-assisted
conditions and using conventional heating techniques
(Scheme 3). This alkynone has been shown to undergo
spontaneous desilylation under traditional Bohlmann–
Rahtz conditions,12 giving trisubstituted pyridine 4b in
preference to tetrasubstituted pyridine 5a, and so these
experiments would explore the scope of our new one-
pot reactions.
at best, providing pyridine 4a in 76% yield after 90 min
following purification by column chromatography on
silica (entry 1). The use of a more polar solvent, DMSO
that can couple more efficiently with the microwave
radiation, resulted in a more rapid reaction, Michael
addition and spontaneous cyclodehydration complete
after 20 min, to give pyridine 4a in 87% yield (entry
2).13 Reactions conducted in toluene were accelerated
dramatically by the presence of zinc(II) bromide (15
mol%) as a Lewis acid catalyst providing the product in
80% yield after 10 min at 170°C (entry 3). However, the
optimum conditions for this transformation employed
acetic acid as a Brønsted acid catalyst. After stirring for
10 min in a solution of toluene–acetic acid (5:1) at
170°C (160 W), pyridine 4a was isolated in 98% yield
following purification on silica; the highest ever yield
reported for a Bohlmann–Rahtz reaction to date (entry
4). Finally, in a bid to explore solventless reaction
conditions, a mixture of enamine 1 and alkynone 2a
was irradiated at 170°C (150 W) for 20 min to give the
product in 84% yield (entry 5). Although this final
experiment was not as efficient, the use of solventless
reaction conditions does have some intrinsic ecological
and chemical value.2c
When a mixture of ethyl b-aminocrotonate 1 and
(trimethylsilyl)butynone 6a was irradiated at 170°C in a
All of the microwave-assisted experiments facilitated
both Michael addition and cyclodehydration in a single
synthetic step and had generated the target pyridine 4a
as a single regioisomer. Although the use of microwave
irradiation had been successful, it was decided to inves-
tigate if traditional conductive heating methods could
facilitate a similar one-pot transformation. The reaction
of ethyl b-aminocrotonate 1 and phenylpropynone 2a
(Scheme 2) was repeated in a range of different solvents
in a sealed tube using an oil bath as an external heat
source (Table 2) and the results were compared with the
microwave-assisted reactions (Table 1). In almost all of
the experiments, the microwave-assisted conditions
gave the product in a higher yield, of particular rele-
vance for the reaction conducted in toluene in the
Scheme 3. One-pot heteroannulation of enamine
butynone 6a.
1 and
Scheme 4. One-pot heteroannulation of enamine
alkynones 6b–e.
1 and

M. C. Bagley et al. / Tetrahedron Letters 43 (2002) 8331–8334
8333
Table 3. Comparison of microwave-assisted conditions and conventional heating techniques for heteroannulation of enamine
1 and butynone 6a
Entry
Solvent
Time (min)
Carius tube product Carius tube yield%a Microwave product Microwave yield%a
1
DMSO
DMSO
Toluene–ZnBr2 (15
mol%)
20
20
10
4b
4b
5a
21
8
27
4b
4b
5a
62
69
60
2b
3
4
5
Neat
20
None
4b, 5a (1:2.8)
0
29
5a
10
25
Toluene–acetic acid (5:1) 10
4b, 5a (1:2.8)
a Isolated yield after purification by column chromatography on silica.
b A one-fold excess of enamine 1 was used.
tion of an enamine and alkynone in a single preparative
step and with total control of regiochemistry.
range of different solvents (Table 3) pyridine 5a or 4b
was formed, depending upon the solvent and catalyst
employed. These transformations proved to be less
efficient than the reactions of phenylpropynone 2a
(Table 1) and the experiment conducted under solvent-
less conditions (entry 4, Table 3) gave only a very
meagre yield of pyridine 5a. However, in comparison
with experiments conducted using conventional heating
techniques, which were extremely inefficient with
alkynone 6a, the microwave-assisted reactions were a
success—the optimum experimental conditions13
involving irradiation of reagents in DMSO for 20 min
to give trisubstituted pyridine 4b in 69% yield, desilyla-
tion occurring spontaneously throughout the course of
the reaction.
Acknowledgements
We are grateful to CEM (Microwave Technology) Ltd
for assistance, Dr. Justin Bower of RiboTargets Ltd for
valuable discussions and the EPSRC Mass Spectrome-
try Service, Swansea, for high resolution mass spectra.
References
1. Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.;
Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213.
2. Reviews on microwave chemistry include: (a) Kuhnert,
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4. Moody, C. J.; Bagley, M. C. Synlett 1998, 361.
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6. Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody,
C. J. J. Am. Chem. Soc. 2000, 122, 3301.
In order to test the microwave-assisted reaction that
had performed the best overall with the two alkynones,
2a and 6a,13 ethyl b-aminocrotonate 1 was reacted with
four other alkynyl ketones, 6b–e by irradiating a solu-
tion of the reagents in DMSO at 170°C for 20 min
(Scheme 4). In all of the experiments, a single regioiso-
meric pyridine was formed (Table 4). Although the
efficiency of the reaction of enamine 1 and phenylbu-
tynone 6b was low (entry 1), this alkynone has been
noted to be problematic in similar heteroannulation
reactions.10 The other microwave-assisted reactions
gave pyridine products 5c–e in good yields after purifi-
cation by column chromatography (entries 2–4), illus-
trating
that
the
one-pot
microwave-assisted
7. Adlington, R. M.; Baldwin, J. E.; Catterick, D.;
Pritchard, G. J.; Tang, L. T. J. Chem. Soc., Perkin Trans.
1 2000, 2311 and references cited therein.
Bohlmann–Rahtz reaction represents a simple and
highly-expedient route to tri- and tetrasubstituted
pyridines.
8. Bagley, M. C.; Hughes, D. D.; Lloyd, R.; Powers, V. E.
C. Tetrahedron Lett. 2001, 42, 6585.
In conclusion, we have explored two new methods for
the synthesis of pyridines using either microwave irradi-
ation or conductive heating techniques in a sealed tube
to facilitate the rapid Michael addition–cyclodehydra-
9. Hughes, D. D.; Bagley, M. C. Synlett 2002, 1332.
10. Bagley, M. C.; Dale, J. W.; Bower, J. Synlett 2001, 1149.
11. Bagley, M. C.; Dale, J. W.; Hughes, D. D.; Ohnesorge,
M.; Phillips, N. G.; Bower, J. Synlett 2001, 1523.
Table 4. Microwave-assisted synthesis of pyridines 5b–e
Entry
Alkynone
R4
R6
Product
Yield%a
1
2
3
4
6b
6c
6d
6e
Ph
Et
H
Me
Me
4%-C6H4Cl
4%-C6H4OMe
5b
5c
5d
5e
24
94
75
66
H
a Isolated yield after purification by column chromatography on silica.

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M. C. Bagley et al. / Tetrahedron Letters 43 (2002) 8331–8334
12. Bagley, M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.;
Phillips, N. G.; Xiong, X.; Bower, J. J. Chem. Soc.,
Perkin Trans. 1 2002, 1663.
poured into water (15 ml) and extracted with ethyl ace-
tate (8 ml). The aqueous layer was further extracted with
ethyl acetate (8 ml) and the organic extracts were com-
bined, washed successively with saturated aqueous
sodium hydrogen carbonate solution (10 ml) and brine
(10 ml), dried (Na2SO4) and evaporated in vacuo. Purifi-
cation by flash chromatography on silica, eluting with
dichloromethane-light petroleum (1:1), gave ethyl 2-
methyl-6-phenylpyridine-3-carboxylate 4a as a pale yellow
solid (0.21 g, 87%); spectroscopic properties agreed with
literature data according to Ref. 12.
13. In a typical procedure, a solution of ethyl b-aminocroto-
nate 1 (0.26 g, 2.0 mmol) and 1-phenylprop-2-yn-1-one 2a
(0.13 g, 1.0 mmol) in DMSO (3.0 ml) in a sealed pressure-
rated reaction tube (10 ml) was irradiated at 170°C
(initial power 150 W) for 20 min in a self tuning single
mode CEM Discover™ Focused Synthesiser. The mixture
was cooled rapidly to room temperature, by passing
compressed air through the microwave cavity for 5 min,