nucleus was sought. The use of pyridinium salts as activated
electrophilic substrates for reduction via the use of organo-
metallic reagents and hydride donors has been well docu-
mented in the literature.3 It was believed that activation of
the nitrogen would afford substrates viable for reduction.
Initial investigation of this area showed promise with the
formation and reduction of 3 (Scheme 2). However, the
Scheme 3a
Scheme 2a
a Conditions: Na, NH3, then R-X.
yields of dihydropyridine 4 were poor; the product degraded
rapidly precluding effective purification. These observations
are consistent with other reports of the instability of 1,2-
dihydropyridines in the literature and our attempts to trap
the reduced product via a Diels Alder reaction met with
limited success.4 Therefore, a method of stabilizing the
dihydropyridine product was required.
At this point we were inspired by the work of Comins
regarding Grignard addition to C-4 methoxy-substituted
acylpyridinium salts.5 We undertook an efficient, one-pot,
synthesis of activated pyridine 5 from picolinic acid (Scheme
3).6 Subsequent N-alkylation was achieved in excellent yield
to furnish pyridinium salts 67 and 7. The rationale behind
the addition of a methoxy group at C-4 was to avoid the
generation of an unstable 1,2-dihydropyridine after reduc-
tion: acid-catalyzed hydrolysis in situ was predicted to
liberate a dihydropyridone that would be straightforward to
handle. As our strategy involved the use of an aqueous acid
quench to achieve the hydrolysis, this sequence was incom-
patible with ammonia solvent. Thus, we switched to a
reduction protocol developed over the past few years, using
lithium and di-tert-butylbiphenyl (DBB) or sodium and
naphthalene as a source of electrons (ammonia-free condi-
tions).8
a Conditions: [a] Na, naphthalene; [b] Li, DBB.
proved very effective, with isolation of the desired dihydro-
pyridone being achieved in an efficient manner (entry 1-3,
Scheme 3). The instability that had plagued the previous
products was completely absent. The reduction protocol was
then applied to pyridinium salt 7, so that more versatile
N-protecting groups could be taken through the reduction/
hydrolysis sequence. The dihydropyridones (11-14) were
furnished in good yield using a range of electrophiles. We
were pleased to find that the methodology was applicable
to electrophiles, such as methyl chloroformate, that cannot
be used under the standard Birch reduction conditions (entry
8, Scheme 3).7 Thus we have defined a highly versatile
method for introducing groups R to the nitrogen with great
potential for broader synthetic application.
Next, we progressed on to elaboration of the template
generated by this methodology, demonstrating that function-
ality can be introduced at any position around the dihydro-
pyridone ring (Scheme 4). The chemistry of dihydropyri-
dones is well documented in the literature9 and we aimed to
use a variety of precedented transformations to illustrate the
potential for derivatization.
Initial investigations focused on the reduction of the
N-methyl pyridinium salt 6. The reduction/hydrolysis strategy
(3) Thiessen, L. M.; Lepoivre, J. A.; Alderweireldt, F. C. Tetrahedron
Lett. 1974, 15, 59. Francis, R. F.; Davis, W.; Wiesner, J. T. J. Org. Chem.
1974, 39, 9, 59. O’Neill, B. T.; Yohannes, D.; Bundesmann, M. W.; Arnold,
E. P. Org. Lett. 2000, 2, 4201. Zhao, G.; Deo, U. C.; Ganem, B. Organic
Lett. 2001, 3, 201. For a general review see: Keay, J. G. In CompehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
p 579.
(4) Kunng, F.-A.; Gu, J.-M.; Chao, S.; Chen, Y.; Mariano, P. S. J. Org.
Chem. 1983, 48, 4262.
(5) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27, 4549. For
recent references, see: Comins, D. L.; Killpack, M. O.; Despagnet, E.;
Zeller, E. Heterocycles 2002, 58, 505. Kuethe, J. T.; Comins, D. L.; J.
Org. Chem. 2004, 69, 5219.
(6) Sundberg, R. J.; Jiang, S. Org. Prep. Proced. Int. 1997, 29, 117.
Acyl pyridinium salts of 5 were not suitable substrates for reduction.
(7) Essawi, M. Y.; Portoghese, P. S. J. Heterocycl. Chem. 1983, 20, 477.
(8) Donohoe, T. J.; Harji, R. R.; Cousins, R. P. C. Tetrahedron Lett.
2000, 41, 1327. Donohoe, T. J.; House, D. J. Org. Chem. 2002, 67, 5015.
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