J. A. Ripper et al. / Bioorg. Med. Chem. Lett. 11 (2001) 443±445
445
step. N-Acyl 14-hydroxycodones of this type have been
elaborated to the corresponding 14-hydroxymorphinan
pharmaceuticals in high yield.12 Unfortunately due to
the low yield of the photolysis step this approach does
not compare favorably with current syntheses where all
steps proceed in high yield.12,14
Work up A: The reaction mixture was extracted with water
(3Â50 mL), the aqueous phase washed with ether (50 mL) and
made acidic (pH ꢀ1±2) with concd HCl. The water was
removed in vacuo and the residue dissolved in a minimal
amount of ethanol. A large excess of ether was added, and
the mixture was left in the refrigerator overnight. Collection
of the precipitate gave a 79% yield of pure nortropine
hydrochloride.
In summary, a simple photochemical procedure invol-
ving an inexpensive catalyst and a sunlamp can be used
for the N-demethylation of certain alkaloids. This pro-
cedure works well for simple substrates, but the forma-
tion of byproducts lowers the yield in the case of more
complex structures. The reaction of 14-acyloxy-
codeinones gave rise to a tandem N-demethylation±acyl
transfer to yield the corresponding N-acyl 14-hydroxy
opiates. This process was accompanied by the forma-
tion of an interesting 1,2-dicarbonyl oxidation product.
Work up B: The reaction mixture was extracted with 1 M
HCl (3Â40 mL), the combined extracts were washed with di-
chloromethane (2Â10 mL) and then evaporated under reduced
pressure. The residual oil was taken up in saturated NaHCO3
and extracted with ethyl acetate (3Â50 mL). Ethyl acetate
portions were combined, dried (MgSO4) and evaporated to
aord a crude oil. Pure product was obtained (free base) after
column chromatography using an EtOAc/MeOH/NH3 gra-
dient (90:10:1 to 70:30:1).
Rose Bengal method: As above except Rose Bengal was used
instead of TPP in tert-butanol/water (80:20).
8. Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe, J. P. Tet-
rahedron Lett. 1977, 18, 1567.
References and Notes
9. Kraiss, G.; Nador, K. Tetrahedron Lett. 1971, 12, 57.
10. Montzka, T. A.; Matiskella, J. D.; Partyka, R. A. Tetra-
hedron Lett. 1974, 14, 1325.
11. Lee, L. Y. C.; Ci, X.; Giannotti, C.; Whitten, D. G. J. Am.
Chem. Soc. 1986, 108, 175.
1. von Braun, J. Chem. Ber. 1900, 33, 1438.
2. Cooley, J. H.; Evain, E. J. Synthesis 1989, 1.
3. Vinyl chloroformate was available in 5 and 10 mL pack
sizes from Sigma-Aldrich for >$A 3500 per mole at the time
this manuscript was written.
12. Olofson, R. A.; Pepe, J. P. Tetrahedron Lett. 1977, 18,
1575.
4. Lindner, J. H. E.; Kuhn, H. J.; Gollnick, K. Tetrahedron
Lett. 1972, 13, 1705.
5. Santamaria, J.; Ouchabane, R.; Rigaudy, J. Tetrahedron
Lett. 1989, 30, 2927.
6. Lopez, D.; Quinoa, E.; Riguera, R. Tetrahedron Lett. 1994,
35, 5727.
7. TPP method: Tropine (1.0 g, 7.1 mmol) and TPP (210 mg)
were dissolved in dichloromethane (100 mL) in a water jack-
eted reaction vessel. The mixture was irradiated with a 300 W
lamp (purchased from the local hardware store) while bub-
bling oxygen for 6 h.
13. Crystal data for C20H19NO7, M=385.4, orthorhombic,
a=7.345(7), b=7.673(4), c=30.537(8) A, T=173 K, space
group P212121, Z=4, m(Mo-Ka)=1.13 cmÀ1, 3638 re¯ections
measured on a Rigaku AFC7R diractometer, ymax 27.5ꢁ,
2868 unique (Rint=0.043), 1457 with I ꢂ3.0s(I) were used in
subsequent calculations: ®nal R=0.047 and Rw=0.038. The
absolute structure was determined from the chemistry. The
data has been deposited at the Cambridge Crystallographic
Data Centre (deposition number 148944).
14. Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.;
Malfoot, T. J. Org. Chem. 1984, 49, 2081.