Enantioselective synthesis of (R)- and (S)-2-methyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazine-2-carboxamides

Article abstract of DOI:10.1016/S0957-4166(98)00082-2

Enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2- carboxamides bearing different substituents in the aromatic ring are obtained by the cyclization of (R)-monomethyl2-methyl-2-(2-nitrophenoxy)malonates with the participation of the carboxy and methoxycarbonyl group, respectively.

Full text of DOI:10.1016/S0957-4166(98)00082-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1115–1116
Enantioselective synthesis of (R)- and (S)-2-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-2-carboxamides
Matej Breznik, Alenka Mrcina and Danijel Kikelj∗
University of Ljubljana, Faculty of Pharmacy, Aškercˇeva 7, 1000 Ljubljana, Slovenia
Received 13 February 1998; accepted 23 February 1998
Abstract
Enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamidesbearing different substituents
in the aromatic ring are obtained by the cyclization of (R)-monomethyl2-methyl-2-(2-nitrophenoxy)malonateswith
the participation of the carboxy and methoxycarbonyl group, respectively. © 1998 Elsevier Science Ltd. All rights
reserved.
Both enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamides 5 with differ-
ent substituents in the aromatic ring were required as key intermediates in the course of our ongoing
research programme1,2 directed towards the design and synthesis of peptidomimetics3 in order to study
the influence of chirality on biological activity within this class of compounds. Enantiomers of the parent
compound 5 (R=H) became available via (R)- and (S)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-
2-carboxylic acid which was obtained by resolution with (R)- and (S)-1-phenylethylamine. However, the
resolution method proved to be unsuccessful with compounds bearing a substituent bound to the aromatic
ring.4 Therefore, we sought for an efficient stereoselective synthesis of enantiomers of 5, possibly from
a common readily available chiral precursor.
Now we wish to report that hitherto unknown enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-
benzoxazine-2-carboxamides 5 are readily accessible via reductive cyclization of common chiral pre-
cursors (R)-monomethyl 2-methyl-2-(2-nitrophenoxy)malonates 2, with the participation of a carboxy
and methoxycarbonyl group, respectively. The preparation of malonates 2 by pig liver esterase cat-
alyzed hydrolysis of prochiral dialkyl 2-methyl-2-(2-nitrophenoxy)malonates has been reported by us
recently.5 Interestingly, contrary to our expectations based on the generally known reactivity of car-
boxylic acid derivatives, in situ cyclization of the aromatic amines obtained by hydrogenation of 2 in
chloroform afforded (R)-methyl 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates 4 in
60–80% yield accompanied by small amounts of the corresponding (S)-2-methyl-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-2-carboxylic acids which could be easily separated simply by extraction. The preference
of the carboxy or methoxycarbonyl group of 2 for cyclization after reduction of the nitro group was found
∗
Corresponding author. E-mail: danijel.kikelj@ffa.uni-lj.si
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00082-2

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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.