N-azinylpyridinium N-aminides: Tandem reactions with α-halocarbonyl derivatives and analogs

Article abstract of DOI:10.1016/S0040-4039(00)00839-X

Pyridinium-N-(2'-pyridyl)aminide was reacted with different α- halocarbonyl derivatives and related compounds. The method allows an easy preparation of several heterocyclic building blocks, all including the 2- aminopyridine moiety.

Full text of DOI:10.1016/S0040-4039(00)00839-X

Tetrahedron Letters 41 (2000) 5837±5840
N-Azinylpyridinium N-aminides: tandem reactions with
a-halocarbonyl derivatives and analogs
Rebeca de la Rosa, Valentõn Martõnez-Barrasa, Carolina Burgos
and Julio Alvarez-Builla*
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Departamento de Quõmica Organica, Universidad de Alcala, 28871 Alcala de Henares, Madrid, Spain
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Received 4 February 2000; accepted 23 May 2000
Abstract
Pyridinium-N-(20-pyridyl)aminide was reacted with di€erent a-halocarbonyl derivatives and related
compounds. The method allows an easy preparation of several heterocyclic building blocks, all including
the 2-aminopyridine moiety. # 2000 Published by Elsevier Science Ltd.
Keywords: alkylation; amidines; pyridinium salts; ylides.
Primary heterocyclic amidines 1 are 1,3-dinucleophiles bearing two di€erentially reactive centers:
The endocyclic sp2 nitrogen and the exocyclic amine. Usually, alkylation of 1 occurs regioselectively
on the endocyclic nitrogen, or leads to a mixture of both endo 2 and exo 3 substituted derivatives
(Scheme 1).1 The alkylation, however, can be preferentially directed to the exocyclic nitrogen using
di€erent methods, including deprotonation of the exocyclic amino group. We recently described
the use of pyridinium N-(azinyl)aminides 4 (Scheme 2), where the exocyclic nitrogen anion is
stabilized by the presence of a pyridinium moiety. Moreover, the endocyclic nitrogen is partially
blocked by an intramolecular hydrogen bond, making the alkylation highly regioselective, with no
signs of N-ring alkylations. Final ®ssion of N±N bond could allow the synthesis of 2-alkylamino
derivatives.2 4
Scheme 1.
* Corresponding author. Tel: 34-1-885-4606; fax: 34-1-885-4686; e-mail: jalvarez@quimor.alcala.es
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00839-X

5838
Scheme 2.
This communication discusses the nucleophilic properties of 4 in the presence of a-halocarbonyl
compounds and related esters and nitriles, and the use of 4 as precursors of di€erent heterocyclic
building blocks.
In the initial experiments, alkylation with a-haloesters was investigated. Reaction of 4 (Het=2-
pyridyl, Scheme 3) with alkyl bromoacetates under mild conditions (acetone, rt), produced a
mixture of pyridinium salts 5 and 6. Pyridinium salt 5 was formed along the expected reaction
pathway, and the formation of compound 6 could be explained through a process involving
elimination of pyridine, on the initially formed 5, followed by alkylation. When the process was
carried out in the presence of a base (potassium carbonate, acetone, rt, 24 h), the only compounds
isolated were 8 and 9. In addition, 8 was converted into 9 when attempted to separate them by
chromatography. To rationalise the process, it appears that the initially formed salt 6 was
deprotonated and reacted again with an additional molecule of electrophile, yielding the salt 7. In
Scheme 3.

5839
the presence of base, 7 may undergo elimination of the pyridine ring, yielding the enamine 8,
which cyclized to the pyrido[1,2-a]pyrimidin-4-one 9, either spontaneously or by the action of
silica gel. Varying the halide considerably altered the ®nal yield (for 9a, when Z=Cl, 25%, when
Z=I, 30%). The preparation of pyrido[1,2-a]pyrimidin-4-ones has been extensively studied by
Hermecz and Stanovnik.5 7
When alkylations were performed with a-haloketone derivatives under the same initial condi-
tions (potassium carbonate, acetone, rt, 24 h), either enamines 12 (X=Br, R=t-Bu, Ph) or
imidazo[1,2-a]pyridine 15b (X=Cl, R=Me) were isolated as the main products (Scheme 4).
Initially, the results suggested a reaction pathway similar to that shown in Scheme 3, where
enamine 12, by the intramolecular Michael addition and easy thermal dehydrogenation, may
yield the imidazopyridine 15 and where the ®nal product would be either 12 or 15 depending of
the steric hindrance of the R-substituent. When X=Br and R=Et, however, both 12a and 15a
were isolated, and attempts to convert 12a to 15a in acid or basic conditions failed. Consequently,
a competing alternative8 could be suggested, via the intermediate pyridinium ylide 13, explaining
the lack of conversion from 12 to 15. The dehydrogenation step from 14 to 15 has been previously
reported.9,10 This would mean that both mechanisms would compete, for all the subtrates, and
di€erences observed are related to the stability of the ®nal compounds, speci®cally in terms of the
steric hindrance of the R groups.
Scheme 4.
In recent years, biological properties of imidazo[1,2-a]pyridine derivatives, in particular of the
3-acyl derivatives have attracted much attention. Despite numerous applications of the most
common approach for this system, condensation of 2-aminopyridines with a-halocarbonyl com-
pounds, alternative methods are still required.9 12
Other electrophiles were reacted with 4. Thus, reaction with a-halomethylsulphones was not
successful, but with a-halocarbonitriles under the same conditions (potassium carbonate, acetone,
rt, 24 h), the substituted pyridine 16 was isolated, from a complex mixture, as the main product of
the process.13 The reaction course and results are summarized in Scheme 5.

5840
Scheme 5.
In conclusion, the use of heteroaryl-stabilized azinium aminides provides a simple approach for
producing di€erent heterocyclic fragments bearing the 2-aminopyridine moiety. Further experi-
ments are in progress to extend the process as a general methodology to other azine derivatives.
Acknowledgements
Author wish to thank C.I.C.Y.T. for ®nancial support (Project PM97-0074) and the Universidad
de Alcala for a grant to one of us (R.R.).
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