achieve aryl substitution at C(7), C(8), or C(9) is demon-
strated.
Scheme 2. Synthesis of Pyridones 2a/b, 3a/b, and 4b
Our route to the 6,6-pyridone (1,2,3,4-tetrahydro-6H-
pyrido[1,2-a]pyrimidin-6-one) 2a began with 2,6-difluoro-
pyridine 5 which underwent nucleophilic substitution with
3-amino-1-propanol to provide 6 in 95% yield. Hydrolysis
of 6 (0.1 M HCl, 140 °C, microwave irradiation) gave 7 in
55% yield along with 15% of the final target 2a;4 the inter-
mediate pyridone 7 could be cyclized to 2a under Mitsunobu
cyclodehydration conditions5 in 83% yield (Scheme 1).
Scheme 1. Mitsunobu Route to Bicyclic Pyridone 2a
The N-benzyl variants 2b and 3b have also been prepared.
Reaction of 2,6-difluoropyridine 5 with N-benzyl ethanol-
amine and N-benzyl 3-aminopropan-1-ol gave the N-ben-
zylated adducts 9 and 10 in 81 and 87% yields, respectively.
Subsequent O-mesylation and cyclization gave 3b and 2b
in 86 and 90% overall yields, respectively. N-Benzyl pyri-
done 3b, the structure of which was confirmed by X-ray
crystallography (see Supporting Information), was more
stable than 3a under the reaction conditions used and in terms
of its “shelf stability”.
An entry to the 7,6-ring bicyclic pyridone (2,3,4,5-tetra-
hydro-1H-pyrido[1,2-a][1,3]diazepin-7-one) 4a/b has also
been evaluated. Mesylation of 11 (obtained in 83% yield
from 5 and 4-aminobutan-1-ol) led, after hydrolysis, to the
pyrrolidine adduct 156 as the only characterizable product
in 35% yield, and a similar outcome was observed with the
N-benzyl derivative 12.7 However, use of strongly acidic
conditions (conc HCl, heating) did convert 12 to a separable
mixture of 15 and the desired 4b in 22 and 5% yields,
respectively. Attempts to improve the yield of 4b have not
been successful,
The scale associated with the chemistry shown in Scheme
1 was limited by the necessity for microwave irradiation
(6f7) so a more efficient route was required. The key feature
here was incorporation of a suitable leaving group on the
aminoalcohol side arm to enable facile cyclization. After
screening a variety of leaving groups and conditions, a one-
pot procedure was identified (Scheme 2). This new meth-
odology was also applicable to the N-benzyl and correspond-
ing 5,6-variants 2b and 3a/b, respectively.
Aminoalcohol 6 was mesylated then cyclized (THF, reflux)
to give the pyridinium salt 13 (R ) H) as an isolable species.
1
This reaction was readily monitored by H NMR, and the
intermediacy of 13 was confirmed (see Supporting Informa-
tion). Mild basic hydrolysis gave 2a in 85% yield. Having
established a more efficient method for generation of 2a,
the scope of this chemistry has been extended to the related
5,6-ring system represented by 3a/b.
2,3-Dihydro-1H-imidazo[1,2-a]pyridin-5-one 3a was pre-
pared from 2,6-difluoropyridine 5 by nucleophilic substitution
with ethanolamine (to give 8) followed by mesylation and
cyclization as described for 2a. Mild hydrolysis (NaHCO3)
of 14 (R ) H) failed; however, aqueous NaOH (6 equiv, rt)
converted 14 (R ) H) to 3a in 88% overall yield. Pyridone
3a was unstable toward silica gel, but the efficiency of the
hydrolysis procedure allowed 3a to be isolated without
recourse to chromatography.
(5) Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J.
Tetrahedron Lett. 1998, 39, 7459-7462.
(6) Following mesylation of 12 and heating in THF, the formation of
the quaternary pyrrolidine salt shown in Scheme 2 was observed by 1H
NMR but was not fully characterized. Debenzylation of this intermediate
occurred on treatment with NaOH, and the apparently facile nature of this
step may be associated with the enhanced leaving group ability of a
2-aminopyridine. The structure of 15 was confirmed by an alternative
synthesis by reaction of 5 with pyrrolidine. See Supporting Information.
(7) Even under forcing conditions, we have not observed N-mesylation
of 11 which limits our ability to deactivate the exo-amino function.
(4) The primary chloride corresponding to 6 was isolated in 5% yield
using a shorter reaction time (15 min), and it was then shown that this
chloride cyclizes to give 2a under the microwave reaction conditions used.
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Org. Lett., Vol. 9, No. 25, 2007