4174
A. Denis, C. Renou / Tetrahedron Letters 43 (2002) 4171–4174
13. Smissian, E. E.; Makriyannis, A. J. Org. Chem. 1973, 38,
Acknowledgements
1652–1657.
14. Typical N-demethylation procedure: To a solution of I
(14 g, 18.8 mmol) in 260 ml of acetone, was added in 1 h
30 min 3.6 g (20.7 mmol) of diethyl azodicarboxylate
(DEAD) diluted in 20 ml of acetone. The reaction was
stirred at room temperature for 24 h and evaporated to
dryness. The brown residue was diluted in 40 ml of
MeOH and 40 ml of saturated NH4+Cl− and refluxed for
1 h. After evaporation to dryness, the residue was taken
up with 80 ml of water and the pH was adjusted to 8 with
aqueous ammonium hydroxide and finally extracted with
3×150 ml of ethyl acetate. Drying over MgSO4 and
evaporation of the solvent afforded 16 g of crude
product. The residue was purified by column chromato-
graphy over silica eluting with a 85/10/5 ethyl acetate/
MeOH/triethylamine mixture to afford 11.3 g (82%) of II
as a white foam. Spectral data for II: EI-MS=731+
We thank C. Lang and F. Maquin for the analytical
experiments.
References
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1
(MH+); H NMR (CDCl3): l 0.85 (t, 3H) CH3CH2, 1.02
(d, 3H) 10-CH3, 1.16 (d, 3H) 8-CH3, 1.23 (d, 3H) 5%-Me,
1.27 (d, 3H) 4-CH3, 1.33 (s, 3H) 6-CH3, 1.38 (d, 3H)
2-CH3, 1.47 (s, 3H) 12-CH3, 1.66 (m, 4H) CH6 2–CH6 2, 2.43
(s, 3H) NCH3, 2.48 (m, 1H) H3%, 2.60 (m, 1H) H8, 2.62 (t,
2H) CH2F, and 2.62 (s, 3H) 6-OCH3, 3.08 (dq, 1H) H4,
3.11 (q, 1H) H10, 3.59 (s, 1H) H11 and (m, 1H) H5%, 3.64
(m, 2H) CH6 2NCO, 3.86 (q, 1H) H2, 4.27 (d, 1H) H5, 4.29
(d, 1H) H%1, 4.97 (dd, 1H) H13, 7.1–7.25 (m, 5H) phenyl.
Anal. calcd (%) for C40H62N2O10: C, 65.73; H, 8.55; N,
3.83. Found: C, 65.4; H, 8.7; N, 3.7%.
4. Barman Balfour, J. A.; Figgitt, D. P. Drugs 2001, 61,
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16. Typical reductive amination experiment: A solution of II
(0.1 g, 0.14 mmol) and 4-chloro-3-hydroxy-benzaldehyde
(0.11 g, 0.7 mmol) in 3.5 ml of methanol and glacial
acetic acid (17 ml, 0.28 mmol) was stirred for 30 min at
room temperature. The borane–pyridine complex (0.28
ml, 0.28 mmol) was added and the reaction was stirred for
8 h. The reaction was diluted with 8 ml of a 9/1 MeOH/
AcOH mixture and poured over 2 ml (26 equiv.) of
Amberlyst 15® in a 20 ml solid phase extraction cartridge
fitted with the appropriate polyethylene frit (Supelco).
The cartridge was shaken for 30 min, filtered off, the
resin being finally washed with 15 ml of MeOH. Then 8
ml of a 88/12 MeOH/triethylamine mixture were added
and the cartridge was shaken for 30 min. The resin was
filtered off over a 45 m polypropylene filter (Millex) and
rinsed once with 10 ml of MeOH. The solution was then
evaporated to give 85 mg (70% yield) of compound 1.
Spectral data for compound 1 (Table 2, entry 1): MS=
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(c) Gayo, L. M.; Suto, M. J. Tetrahedron Lett. 1997, 38,
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871.5+ (MH+); 1H NMR (CDCl3):
l 0.86 (t, 3H)
CH3CH2, 1.01 (d, 3H) 10-CH3, 1.16 (d, 3H) 8-CH3, 1.27
(d, 3H) 5%-Me, 1.31 (d, 3H) 4-CH3, 1.34 (s, 3H) 6-CH3,
1.38 (d, 3H) 2-CH3, 1.47 (s, 3H) 12-CH3, 1.65 (m, 4H)
CH6 2–CH6 2, 2.17 (s, 3H) NCH3, 2.60 (m, 1H) H8 and (t,
2H) CH2F, 2.62 (s, 3H) 6-OCH3, 3.12 (m, 1H) H4 and
(m, 1H) H10, 3.30 (m, 1H) H3%, 3.59 (s, 1H) H11, 3.30–3.62
11. Stenmark, H. G.; Brazzale, A.; Ma, Z. J. Org. Chem.
2000, 65, 3875–3876.
(m, 2H) FCH6 2N, 3.65 (m, 2H) CH6 2NCO, 3.86 (q, 1H)
12. (a) Flynn, E. H.; Murphy, H. W.; McMahon, R. E. J.
Am. Chem. Soc. 1955, 77, 3103–3106; (b) Watanabe, Y.;
Adachi, T.; Asaka, T.; Kashimura, M.; Morimoto, S.
Heterocycles 1990, 31, 2121–2124; (c) Hengeveld, J. E.;
Gupta, A. K.; Kemp, A. H.; Thomas, A. V. Tetrahedron
Lett. 1999, 40, 2497–2500.
H2, 4.24 (d, 1H) H5, 4.30 (d, 1H) H%1, 4.97 (dd, 1H) H13,
5.59 (m, 1H) FOH, 7.1–7.30 (m, 6H) aromatics, 6.96 (d,
1H) and 7.06 (dd) aromatics. Anal. calcd (%) for
C47H67N2O11Cl: C, 64.77; H, 7.75; N, 3.21; Cl, 4.07.
Found: C, 63.9; H, 7.6; N, 3.2; Cl, 4.1%.