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M. Breznik et al. / Tetrahedron: Asymmetry 9 (1998) 1115–1116
to be solvent-dependent, and therefore this strategy can also be used for the synthesis of (S)-2-methyl-
3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acids on a preparative scale. The carboxylates 4
were efficiently transformed to amides (S)-56 using unexceptional chemistry by hydrolysis, subsequent
activation of the resulting carboxylic acids by a mixed anhydride method, and reaction with ammonia.
For the synthesis of (R)-5, the carboxy group of 2 was deactivated as a carboxamide. Compounds 3, thus
obtained from 2 by a mixed anhydride method,6 after reduction of the nitro group in methanol, underwent
a smooth in situ cyclization with exclusive participation of the ester group to afford (R)-5.6,7
In conclusion, both enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamides
5 with different substituents in the aromatic ring were efficiently prepared by selective reductive lac-
tamization of common precursors, (R)-monomethyl 2-methyl-2-(2-nitrophenoxy)malonates 2, employ-
ing a strategy of solvent- and derivatization-based reactivity manipulation of the carboxy group of 2.
Investigation of the full scope of this stereoselective synthesis is in progress and will be reported in due
course.
References
1. Kikelj, D.; Rutar, A.; Suhadolc, E.; Pecˇar, S.; Urleb, U.; Leskovšek, V.; Poncˇuh, A.; Krbavcˇicˇ, A.; Marc, G.; Sollner, M.;
Serša, G.; Novakovicˇ, S.; Povšicˇ, L.; Štalc, A. PCT Pat. Appl. WO 94/24152.
2. Kikelj, D.; Povšicˇ, L.; Pristovšek, P.; Štalc, A.; Kidricˇ, J. Med. Chem. Res. 1996, 6, 118–127.
3. Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry and Drug Discovery; Wolff, M. E., Ed.; John Wiley & Sons Inc.:
New York, 1995, pp. 803–861.
4. Rutar, A.; Žbontar, U.; Kikelj, D.; Leban. I. Chirality, in press.
5. Breznik, M.; Kikelj, D. Tetrahedron: Asymmetry 1997, 8, 425–434.
6. (R)- and (S)-2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide: white crystals; (R)-isomer: mp
292–293°C (from MeOH), [α]2D0=+87.4 (c=0.16, MeOH); (S)-isomer: mp 302–304°C (from MeOH), [α]2D0=−87.6
1
(c=0.16, MeOH); IR (KBr): ν 3376, 3154, 1699, 1609, 1520, 1495, 1361, 1237, 1151, 814 cm−1; H-NMR (300 MHz,
DMSO-d6): δ (ppm) 1.61 (s, 3H, 2-CH3), 2.20 (s, 3H, 6-CH3), 6.65 (d, 1H, J=1.8 Hz, H-5), 6.72 (dd, 1H, J=8.1 Hz, J=1.8
Hz, H-7), 6.94 (d, 1H, J=8.1 Hz, H-8), 7.32 and 7.51 (s br, 1H each, CONH2), 10.58 (s br, 1H, NH); MS (70 eV, EI):
m/z=220 (M+, 45%), 177 (100%). Anal. calcd for C11H12N2O3: C 59.99, H 5.49, N 12.72. Found: C 59.72, H 5.48, N 12.59.
7. The yields of (R)-5 were 70–75% based on 2.