Synthesis of pyridine derivatives using aza Diels-Alder methodology

Article abstract of DOI:10.1016/S0040-4039(02)01215-7

Amidrazone 1 reacted with the unsymmetrical tricarbonyls 2a, 2c and 2d giving triazines 3a, 3c and 3d, respectively. These triazines were converted into their corresponding pyridine derivatives 6a, 6c and 6d in aza Diels-Alder reactions with 2,5-norbornad

Full text of DOI:10.1016/S0040-4039(02)01215-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6015–6017
Synthesis of pyridine derivatives using aza Diels–Alder
methodology
Stephen P. Stanforth,a,* Brian Tarbitb and Michael D. Watsona
aSchool of Applied and Molecular Sciences, University of Northumbria, Newcastle-upon-Tyne NE1 8ST, UK
bSeal Sands Chemicals Ltd., Seal Sands Road, Seal Sands, Middlesbrough TS2 1UB, UK
Received 21 May 2002; revised 20 June 2002; accepted 24 June 2002
Abstract—Amidrazone 1 reacted with the unsymmetrical tricarbonyls 2a, 2c and 2d giving triazines 3a, 3c and 3d, respectively.
These triazines were converted into their corresponding pyridine derivatives 6a, 6c and 6d in aza Diels–Alder reactions with
2,5-norbornadiene 5. Triazines 3c and 3d gave the pyridolactones 9c and 9d with 2,3-dihydrofuran. © 2002 Elsevier Science Ltd.
All rights reserved.
The aza Diels–Alder reaction as generalised in Scheme
1 has become an important synthetic route to pyridines
and several recent reviews discuss the scope and appli-
cation of this versatile methodology.1 In this reaction, a
2-azadiene reacts with a suitable dienophile to form a
dihydro or tetrahydropyridine derivative. A diverse
range of 2-azadienes and dienophiles have been utilised
in this reaction enabling the preparation of a wide
variety of pyridine derivatives. 1,2,4-Triazines2 have
been used on many occasions as 2-azadiene equivalents
and these heterocycles can react with suitable acetylene
equivalents yielding pyridines (Scheme 2).
We have been interested in preparing pyridine deriva-
tives 6 using the aza Diels–Alder reaction of 1,2,4-tri-
azines derivatives 3 with 2,5-norbornadiene 5 as an
acetylene equivalent (Scheme 3).3 The triazine deriva-
tives 3 which we required would be available from the
condensation2 of amidrazone 1 with the tricarbonyl
derivatives 2 (the central carbonyl groups of com-
pounds 2 are hydrated but their keto forms are shown
for simplicity). Interestingly, only a few examples of the
reaction of amidrazones with unsymmetrical tricarbonyl
compounds have been reported. Thus, the amidrazone
PhC(ꢀNH)NHNH2 and compound 2a gave only ethyl
3,5-diphenyl[1,2,4]triazine-6-carboxylate (70%)4 where-
as the same amidrazone and compound 2b gave a
mixture of triazines (which were derived from attack of
the hydrazine moiety of the amidrazone at each of the
keto-carbonyl groups of compound 2b) in unspecified
yields.5 The reaction of amidrazone 1 with tricarbonyl
2b was examined by Snyder and co-workers who
obtained a 10.5:1 mixture of triazines 3b and 4b in 46%
yield.6 Consequently, we envisaged that the reaction of
amidrazone 17 and unsymmetrical tricarbonyls 28 might
be developed as a useful method for the synthesis of
novel pyridine derivatives via triazine intermediates.
Scheme 1.
Amidrazone 1 and compound 2a reacted to give a
single triazine derivative, compound 3a (82%). When
compound 3a was heated in ethanol at reflux in the
presence of 2,5-norbornadiene 5, the pyridine derivative
6a was formed in 84% yield. The structure of com-
pound 6a was established by hydrolysis (EtOH/KOH/
reflux) of the less sterically crowded 6-ester substituent
and decarboxylation of the resulting carboxylic acid
yielding the known ethyl 2-phenylpyridine-3-carboxyl-
Scheme 2.
Keywords: aza Diels–Alder reaction; aza dienes; triazines; pyridines.
* Corresponding author. Tel.: 0191 2274784; fax: 0191 2273519;
e-mail: steven.stanforth@unn.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01215-7

6016
S. P. Stanforth et al. / Tetrahedron Letters 43 (2002) 6015–6017
Scheme 3.
ate.9 The condensation reaction of compounds 1 and 2a
must have therefore yielded triazine 3a and not the
isomeric triazine 4a. Pyridine 6a could also be prepared
in a ‘one-pot’ reaction in 59% without the isolation of
triazine 3a. Thus, after compounds 1 and 2a had been
heated in ethanol, 2,5-norbornadiene 5 was added and
heating was continued giving pyridine derivative 6a
directly.
reacted with 2,3-dihydrofuran in ethanol at reflux in a
‘one-pot’ reaction yielding the lactones 9c and 9d,
respectively, in moderate yields (both 44%) as shown in
Scheme 4. Only one product was isolated from these
reactions indicating the cycloaddition reactions giving
intermediates 7c and 7d were regioselective. Ring-open-
ing of the ether ring in compounds 7c and 7d then
yielded the pyridine intermediates 8c and 8d which
could not be isolated but underwent lactonisation giv-
ing the products 9c and 9d. The proposed regioselectiv-
ity depicted in formula 7 was confirmed by preparing
the mixed ester 3c (C5-ester=methyl ester). Reaction of
this compound with 2,3-dihydrofuran gave compound 9
(ester=methyl ester) indicating that the 2-ester sub-
stituent in triazine 3c is involved in lactonisation.
Amidrazone 1 and compound 2b gave a 7:3 mixture of
1
triazines 3b and 4b (95%) by H NMR spectroscopy
confirming Snyder’s observations.6 We therefore
decided to investigate the effect of larger alkyl sub-
stituents and the isomers 2c and 2d were chosen for
study. Pleasingly, both compounds 2c and 2d reacted
with amidrazone 1 giving the triazine derivatives 3c and
3d, respectively, in yields exceeding 90%. In view of the
simplicity of the ‘one-pot’ synthesis of pyridine 6a
noted above, pyridine derivatives 6c (78%) and 6d
(72%) were both prepared using similar reactions.
We have shown that amidrazone 1 reacts with unsym-
metrical tricarbonyl derivatives 2a, 2c and 2d giving
single triazine products 3a, 3c and 3d, respectively.
These triazines, can readily be converted into pyridine
derivatives by reaction with 2,5-norbornadiene 5 or
2,3-dihydrofuran under mild conditions. All new pyri-
dine derivatives gave satisfactory spectral and microan-
alytical data and/or high-resolution mass spectra.
2,3-Dihydrofuran has been used by Gilchrist and co-
workers10 as an acetylene equivalent in the aza Diels–
Alder reaction of triazines. Compounds 3c and 3d
Scheme 4.

S. P. Stanforth et al. / Tetrahedron Letters 43 (2002) 6015–6017
6017
Acknowledgements
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We thank Seal Sands Chemicals Ltd. for generous
financial support and the EPSRC mass spectrometry
service for high-resolution mass spectra.
6. (a) Benson, S. C.; Gross, J. L.; Snyder, J. K. J. Org.
Chem. 1990, 55, 3257–3269. Compound 6b has also been
obtained as a by-product of a Bohlmann–Rahtz reaction,
see: (b) Bagley, M. C.; Dale, J. W.; Hughes, D. D.;
Ohnesorge, M.; Phillips, N. G.; Bower, J. Synlett 2001,
1523–1526.
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