pyridine part. Compound 5 can be regarded as a charged
analog of lophocladine A formed in a three-component
reaction. To examine if this three-component reaction also
could generate uncharged analogs, ammonium acetate was
used as the amine component. It was found that a larger
excess (3.5 equiv) of ammonium acetate was necessary to
efficiently give the dihydro naphthyridone. In addition, air
was not sufficient to oxidize this intermediate. Instead,
chloranil was added after generation of the dihydro
naphthyridone to ensure reliable oxidation. It was also
found that heating the three-component reaction could
significantly shorten the reaction time, and microwave
irradiation was used for convenience. This method yielded
the uncharged analog 8a in 42% yield (Table 1). The
reaction proceeded smoother with primary amines, and a
strategy using a primary amine followed by deprotection
was evaluated. The use of p-methoxybenzylamine followed
by acidic deprotection or β-alanine followed by thermal
deprotection, presumably by fragmentation to 8a and
acrylic acid,10 increased the yield of 8a compared to the
use of ammonium acetate.
Figure 2. Reaction of compound 3 with primary amines.
2.5 equiv of benzaldehyde and 1.5 equiv of ethanol amine
under an atmosphere of air, an acetate salt was formed.
After treatment with hydrochloric acid, naphthyridonium
salt 5 could be isolated in 42% yield (Scheme 1).
Scheme 1. Synthesis of Naphthyridonium Salt 6
Table 1. Evaluation of Different Ammonia Sources
Naphthyridoniumsalt5 containsa newcentral fragment
with similarities to the natural product lophocladine A.
Lophocladines are a group of compounds with diverse
biological activity. Lophocladine A (6) has δ-opioid re-
ceptor antagonist activity and lophocladine B (7) has
cytotoxic properties (Figure 3).6
entry
amine
deprotection
yield (%)
1
2
NH4OAc
PMBNH2
À
42
68
TFA/DCM/H2O 10:20:1
MWI 100 °C, 40 min
MeCN/AcOH 2:1
3
β-alanine
78
MWI 140 °C, 10 min
The most promising nitrogen source was β-alanine.
Although the deprotection step could be performed in
the acetonitrile/methanol solvent mixture from the pre-
vious steps in the one-pot procedure, changing the solvent
to an acetonitrile/acetic acid mixture increased the effi-
ciency of the deprotection. These conditions were then
used to examine the scope of aldehydes tolerated by
this transformation of 2-pyridones to naphthyridones
(Table 2). Both electron-rich and electron-poor benzalde-
hydes as well as both branched and unbranched alkyl
aldehydes were well tolerated. Different heteroaryls could
also be incorporated in good yields.
Figure 3. Structure of lophocladine A (6) and B (7).
2,7-Naphthyridine-1-ones are typically synthesized
from nicotinamides or nitriles,7 and both lophocladine A
and B8 and 4-substituted analogs9 have previously been
synthesized. However, these syntheses do not offer any
expedient access to libraries of analogs varied in the
To make closer analogs of lophocladine A and to
examine the reaction’s tolerance for different 2-pyridones,
compound 13 was prepared from 2-methoxypicoline 9
(Scheme 2). Compound 9 was dibrominated and then
selectively lithiated using conditions similar to those
(6) Gross, H.; Goeger, D. E.; Hills, P.; Mooberry, S. L.; Ballantine,
D. L.; Murray, T. F.; Valeriote, F. A.; Gerwick, W. H. J. Nat. Prod.
2006, 69, 640–644.
(7) (a) Wenkert, E.; Dave, K. G.; Lewis, R. G.; Sprague, P. W. J. Am.
Chem. Soc. 1967, 89, 6741–6745. (b) Baldwin, J. J.; Mensler, K.;
Ponticello, G. S. J. Org. Chem. 1978, 43, 4878–4880. (c) Sakamoto, T.;
Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1985, 33, 626–633.
(8) Lotter, M.; Schilling, J.; Reimann, E.; Bracher, F. Arch. Pharm.
2006, 339, 677–679.
(10) Bargar, T. M.; Dulworth, J. K.; Kenny, M. T.; Massad, R.;
Daniel, J. K.; Wilson, T.; Sargent, R. N. J. Med. Chem. 1986, 29, 1590–
1595.
(9) Zhang, A.; Ding, C. Y.; Cheng, C.; Yao, Q. Z. J. Comb. Chem.
2007, 9, 916–919.
Org. Lett., Vol. 13, No. 19, 2011
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