326
D. M. Hodgson et al.
LETTER
In attempting to apply the above chemistry towards new
epibatidine analogs, deoxygenation of the xanthate of 7-
azanortricyclanol 9 (R = 6-methoxypyridin-3-yl, 0.02
mol dm–3 in toluene) by addition of Bu3SnH (2 equiv) was
examined. However, none of the expected 2-azabicy-
clo[2.2.1]hept-5-ene 10 (R = 6-methoxypyridin-3-yl) was
detected, but rather the reaction proceeded cleanly to give
1,2-dihydropyridine 12 (R = 6-methoxypyridin-3-yl,
Scheme 4 (a) Zn/Ag, HOAc (80%); (b) MCPBA, NaHCO3 (44%);
(c) 4-MeOC6H4MgBr, THF (46%); (d) 1,1¢-thiocarbonyldiimidazole,
CH2Cl2 (quant.); (e) Bu3SnH, AIBN, toluene, reflux (41%).
1
78%, Scheme 3). All spectral data (including H–1H and
1H–13C correlation spectra) were fully in accord with the
structural assignment. Use of Bu3SnD instead of Bu3SnH
in the deoxygenation resulted in deuterium incorporation
in the methylene group of 1,2-dihydropyridine 12 (R = 6-
methoxypyridin-3-yl). This is what would be expected
from the fragmentation pathway suggested in intermedi-
ate 11. Further supporting evidence for the product of
deoxygenation was obtained by partial hydrogenation and
desulfonylation; the resulting tetrahydropyridines 13 and
14 both exhibited analytical data consistent with the
proposed structures.10
Dihydropyridines are important as biologically active
agents, and therefore new methods for their construction
are of significance.16 One common method to prepare di-
hydropyridines is by nucleophilic addition of organo-
metallics to N-acylpyridinium salts, although the
regioselectivity of addition (C-2/C-4) can sometimes be
problematic. For example, regioisomeric mixtures were
obtained in the addition of Grignard reagents to the N-
benzoylpyridinium salt of a pyridin-3-yl sulfonamide.17 In
the present study, reductive deoxygenation of 3-azatricy-
clo[2.2.1.02,6]heptan-5-ols 9 [bearing an aryl or methoxy
substituent in the 7-position and an electron withdrawing
group (sulfone or ester) at C-1] is shown to provide a re-
giospecific route to 2,5-disubstituted 1,2-dihydropy-
ridines 12. As the precursor to epoxide 8 (the cycloadduct
of N-Boc pyrrole and tosyl ethyne) is available as either
enantiomer,18 then the potential for accessing enantiopure
1,2-dihydropyridines 12 also exists.
Presuming that dihydropyridine formation might be
favoured by R in 9 being an electron donating and/or aryl
substituent, we examined additional 7-azanortricyclanols
9 bearing such functionality (Scheme 3). However, the
xanthate of 7-azanortricyclanol 9 (R = 4-MeOC6H4) ini-
tially gave a disappointing yield (31%) of the correspond-
ing dihydropyridine 12 (R = 4-MeOC6H4). This might be
due to stannyl radical attack on the product, since subject-
ing dihydropyridine 12 (R = 4-MeOC6H4) to the reaction
conditions resulted in 60% decomposition, whereas sim-
ply boiling dihydropyridine 12 (R = 4-MeOC6H4) in
toluene for two hours resulted in no discernible decompo-
sition (1H NMR analysis). With these observations in
Acknowledgment
We thank the EPSRC for a Research Grant (GR/M55541), and the
EPSRC, Evotec OAI and Syngenta for CASE awards (to M.L.J. and
mind, we reduced the quantity of Bu3SnH to 1.1 equiva- C.R.M.). We also thank the EPSRC National Mass Spectrometry
Service Center for mass spectra.
lents and increased the time over which it was added from
20 minutes to 2.25 hours. These latter conditions gave the
desired dihydropyridine 12 (R = 4-MeOC6H4) in satisfac-
References
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(1) (a) Beckwith, A. L. J.; Ingold, K. U. In Rearrangements in
2,3-dihydropyridines 12 were observed with phenyl and
pyridin-3-yl substituents. With a methoxy substituent the
yield was considerably reduced (25%), however, the 2,3-
dihydropyridine 12 (R = MeO) remained the only isolable
Ground and Excited States, Vol. 1; de Mayo, P., Ed.;
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Preliminary studies of the deoxygenation of xanthate of 7-
azanortricyclanol 9 (R = 4-MeOC6H4) but lacking the to-
syl substituent13 indicate that rearrangement only occurs
to a 2-azabicyclo[2.2.1]hept-5-ene 10 (R = 4-MeOC6H4,
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(Scheme 4). This alcohol was prepared by
debromination14 of the known diene 15,15 followed by ep-
oxidation and subsequent addition of 4-MeOC6H4MgBr.
Reaction of the corresponding thiocarbonylimidazole
with Bu3SnH gave 1,2-dihydropyridine 17 as the only
isolable product (41%).
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Synlett 2005, No. 2, 325–327 © Thieme Stuttgart · New York