520
M. Menichincheri et al. / Tetrahedron Letters 44 (2003) 519–522
corresponding intermediate. By applying this method
compound 1 was obtained in 80% overall yield through
the double fluorine replacement with pyrrolidine at
90°C and subsequent hydrogenolysis of the dichloro
intermediate 4 (Scheme 3).4
Scheme 5. General reagents and conditions: (i) 1.3 equiv.
R1R2NH, NMP, 90°C, DIPEA, 18 h; (ii) 2.3 equiv. pyrro-
lidine, 90°C, NMP, DIPEA, 18 h; (iii) HCOONH4, Pd–C
10%, MeOH, 2 h.
substitution. Furthermore as compound 3 was more
reactive than the mono-substituted intermediate 5, we
considered the use of selected amines of unknown
reactivity in the first step followed by an excess of the
highly reactive pyrrolidine in the second step (Scheme
5).
Scheme 3. Reagents and conditions: (i) neat pyrrolidine,
reflux, 1 h, 80%; (ii) H2, Pd–C 10%, 30 psi, EtOH, 0.5 h, 80%.
When nucleophilic replacement reaction with pyrro-
lidine was carried out in toluene at room temperature,
the only isolated product was the monofluoro deriva-
tive 5, an intermediate useful for the synthesis of
unsymmetrical products. In fact when compound 5 was
reacted with piperidine and then hydrogenolyzed, the
unsymmetrically substituted compound 6 was achieved
in good yield (Scheme 4).
The dichloro intermediates 7 were purified over silica
gel by flash chromatography.5 At last parallel hydro-
genation of the intermediates 7 with NH4HCOO/Pd in
MeOH gave the final products of general formula 8
(Scheme 5).6,7 Unexpectedly we observed hydrogenoly-
sis of final compounds just for entry 4 and 15. The
investigated amines (R1R2NH) and the overall yields of
products 8 are reported in Table 1. Derivatives 8 were
analyzed by HPLC-MS and 1H NMR. Anilines and
carboline gave complex product mixtures; sterically hin-
dered as well as poorly reactive amines, like 1-
adamantyl amine and glycine derivatives, did not react
at all as inferred by the presence of only symmetrically
substituted compound 1 at the end of the synthetic
sequence. In conclusion our new method represents an
easy way for the preparation in solution phase of
4-amino-2,4-dialkylamino-pyridines both symmetrical
and unsymmetrical and it is applicable to combinatorial
synthetic purposes.
References
1. Cosstick, R.; Li, X.; Tuli, D. K.; Williams, D. M.; Con-
nolly, B. A.; Newman, C. Nucl. Acids Res. 1990, 18,
4771–4778.
2. (a) Jameson, D. L.; Goldsby, K. A. J. Org. Chem. 1990,
55, 4992–4994; (b) McCall, J. M.; Jacobsen, E. J.; Van
Doorick, F. J. European Patent 0263213 B1, 1986.
3. Ju¨nemann, W.; Opgenorth, H. J.; Scheuermann, H.
Angew. Chem., Int. Ed. Engl. 1980, 19, 388–389.
4. Chambers, R. D.; Hall, C. W.; Hutchinson, J.; Millar, R.
W. J. Chem. Soc., Perkin Trans. 1 1998, 1705–1713.
5. General procedure for preparation of intermediate 7: To a
solution of 2,6-difluoro-3,5-dichloro-4-amino-pyridine in
Scheme 4. Reagents and conditions: (i) pyrrolidine 1 equiv.,
toluene, rt, 18 h, 80%; (ii) piperidine, AcOEt, reflux, 8 h, 55%;
(iii) H2, Pd–C 10%, 30 psi, EtOH, 0.5 h, 80%.
The possibility to sequentially introduce different
amines onto position 2 and 6 proved to be crucial for
the preparation by parallel synthesis of a small library
of unsymmetrical compounds. In the final optimized
conditions, N-methyl-pyrrolidinone at 90°C turned out
to be the solvent of choice for the nucleophilic aromatic