Parallel synthesis of 4-amino-2,6-dialkylamino-pyridines

Article abstract of DOI:10.1016/S0040-4039(02)02585-6

In this letter a fast and useful parallel synthesis approach to 4-amino-2,6-dialkylamino-pyridines is described starting from commercially available 2,6-difluoro-3,5-dichloro-pyridine. Both symmetrical and unsymmetrical derivatives have been synthesized r

Full text of DOI:10.1016/S0040-4039(02)02585-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 519–522
Parallel synthesis of 4-amino-2,6-dialkylamino-pyridines
Maria Menichincheri, Domenico Fusar Bassini, Markus Gude† and Mauro Angiolini*
Department of Chemistry, Discovery Research Oncology, Pharmacia Corporation, Nerviano, Italy
Received 8 November 2002; accepted 14 November 2002
Abstract—In this letter a fast and useful parallel synthesis approach to 4-amino-2,6-dialkylamino-pyridines is described starting
from commercially available 2,6-difluoro-3,5-dichloro-pyridine. Both symmetrical and unsymmetrical derivatives have been
synthesized respectively in two or three steps in good yields. The method described is mild, adaptable to combinatorial purposes
and applicable to a variety of amines. © 2002 Elsevier Science Ltd. All rights reserved.
During the course of our work we became interested in
the synthesis of 4-aminopyridines bearing alkylamino
substituents onto positions 2 and 6, at least one of the
two being a pyrrolidinyl ring. One of the most represen-
tative examples of these compounds is 4-amino-2,6-
dipyrrolidinyl-pyridine 1 (Fig. 1).
Scheme 1. Reagents and conditions: neat pyrrolidine, reflux, 2
h, 70%.
dichloro-pyridine in a sealed tube2,3 (Scheme 2). This
behavior was in agreement with that of 2,6-dichloro-
pyridine in nucleophilic aromatic substitution reactions.
Figure 1.
These unsatisfactory results, due to the poor leaving
group properties of the chlorine atoms of the starting
material, prompted us to study a milder and more
efficient method suitable for the parallel synthesis of
both symmetrical and unsymmetrical 4-amino-2,6-
dialkylamino-pyridines. This effort allowed us to
develop a convenient two-step process comprising first
the nucleophilic substitution of the fluorine atoms of
the commercially available pyridine 3, and second the
hydrogenolytic removal of the chlorine atoms of the
A first attempt to synthesize compound 1 is reported in
Scheme 1 where 4-nitro-2,6-dichloro-pyridine, prepared
according to known procedure,1 has been subjected to
nucleophilic substitution in the presence of neat pyrro-
lidine at reflux temperature. Under these reaction con-
ditions we have only observed formation of product 2
confirming the good leaving group nature of the nitro
group.
On the other hand we could synthesize compound 1
only under harsh conditions and in low yield by heating
at 200°C the commercially available 4-amino-2,6-
Keywords: parallel synthesis; 4-amino-2,6-dialkylamino-pyridines;
aromatic substitution.
* Corresponding author. Tel. +39-02-48385343; fax: +39-02-
48383833; e-mail: mauro.angiolini@pharmacia.com
† Present address: Calbiochem-Novabiochem AG, La¨ufelfingen,
Switzerland.
Scheme 2. Reagents and conditions: neat pyrrolidine, sealed
tube, 200°C, 4 h, 20%.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02585-6

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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
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nolly, B. A.; Newman, C. Nucl. Acids Res. 1990, 18,
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2. (a) Jameson, D. L.; Goldsby, K. A. J. Org. Chem. 1990,
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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

M. Menichincheri et al. / Tetrahedron Letters 44 (2003) 519–522
Table 1. Investigated amines and overall yields
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N-methyl-pyrrolidinone (0.2 M) were added 3 equiv. of
7. General procedure for preparation of compound 8: Deriva-
tive of general formula 7 was dissolved in 2 ml of
methanol and 10 mg of Pd–C 10% catalyst and 150 mg
of ammonium formate were added. The mixture was
then stirred for 3 h at rt and solution was filtered over
Celite and the solvent evaporated. The residue was dis-
solved in DCM, washed with aqueous satured NaHCO3,
dried over Na2SO4 and evaporated to dryness. No fur-
the proper amine, 3 equiv. of N,N-diisopropylethylamine
and the mixture was heated to 90°C for 18 h. Then 6
equiv. of pyrrolidine were added and the mixture was
heated for 18 h. The solvent was evaporated to dryness
and the residue was purified by flash column chromatogra-
phy (eluant: n-hexane/ethyl acetate from 5/1 to 1/1). Rep-
resentative H NMR and MS data for Table 1, entry 1: H
NMR (400 MHz, DMSO-d6), ppm: 1.80 (m, 4H), 3.20 (m,
4H), 3.34 (m, 4H), 3.54 (m, 4H), 5.87 (sb, 2H), 6.77 (t,
1H), 6.96 (d, 2H), 7.21 (t, 2H); MS m/z: 392 (MH+); entry
2: 1H NMR (400 MHz, DMSO-d6), ppm: 1.78 (m, 4H),
3.22 (s, 3H), 3.30 (s, 3H), 3.38 (t, 2H), 3.42 (m, 4H), 4.56
(t, 1H), 5.62 (m, 3H); MS m/z: 335 (MH+).
1
1
1
ther purification was made. Representative H NMR and
MS data for Table 1, entry 6: 1H NMR (400 MHz,
CDCl3), ppm: 0.83 (s, 3H), 1.22 (s, 32H), 1.92 (m, 4H),
2.96 (s, 3H), 3.38–3.44 (m, 6H), 3.66 (sb, 2H), 5.04 (s,
1H), 5.17 (s, 1H); MS m/z: 445 (MH+); entry 17: 1H
NMR (400 MHz, CDCl3), ppm: 1.86 (m, 4H), 3.25–3.77
(m, 12H), 4.76 (sb, 2H), 5.15 (s, 1H), 5.30 (s, 1H); MS
m/z: 249 (MH+).
6. Miki, Y.; Fujita, R.; Matsushita, K. J. Chem. Soc., Perkin
Trans. 1 1998, 2533–2536.