Stereoselective synthesis of (R)- and (S)-2-methyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazine-2-carboxylic acids, -carboxylates and -carboxamides

Article abstract of DOI:10.1016/S0957-4166(98)00485-6

(R)-Monomethyl 2-methyl-2-(2-nitrophenoxy)malonates obtained by PLE catalyzed hydrolysis of the corresponding dimethyl malonates undergo solvent- dependent enantioselective cyclization to afford (R)-methyl 2-methyl-3-oxo- 3,4-dihydro-2H-1,4-benzoxazine-2-

Full text of DOI:10.1016/S0957-4166(98)00485-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 153–167
Stereoselective synthesis of (R)- and (S)-2-methyl-3-oxo-3,4-
dihydro-2H-1,4-benzoxazine-2-carboxylic acids, -carboxylates
and -carboxamides
Matej Breznik, Valentina Hrast, Alenka Mrcina and Danijel Kikelj ∗
University of Ljubljana, Faculty of Pharmacy, Aškercˇeva 7, 1000 Ljubljana, Slovenia
Received 6 November 1998; accepted 26 November 1998
Abstract
(R)-Monomethyl 2-methyl-2-(2-nitrophenoxy)malonates obtained by PLE catalyzed hydrolysis of the
corresponding dimethyl malonates undergo solvent-dependent enantioselective cyclization to afford (R)-methyl
2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates and (S)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-
benzoxazine-2-carboxylic acids, respectively. These compounds are easily converted to enantiomerically and
diastereomerically pure carboxamides, which are used as peptidomimetic building blocks. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
In the course of our ongoing research programme directed towards the design and synthesis of mim-
etics of biologically active peptides,1,2 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic
acids 5 and derivatives thereof were envisaged as interesting peptidomimetic3,4 building blocks. In
order to investigate the influence of chirality on biological activity within the peptidomimetic class
of compounds under study, pure enantiomers of these key synthons were required. Enantiomers of
the parent compound, 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (5a) became
readily available by resolution of the racemic acid with (R)- and (S)-1-phenylethylamine. Unfortunately,
the resolution method proved to be unsuccessful with compounds bearing a substituent bound to the
aromatic ring.5 Therefore, we sought an efficient stereoselective synthesis of the enantiomers of 5,
possibly from a common readily available chiral precursor. Recently, we briefly communicated the enan-
tioselective synthesis of (R)- and (S)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamides
7 by cyclization of (R)-monomethyl 2-methyl-2-(2-nitrophenoxy)malonates 3.6 Now we report full
∗
Corresponding author. Fax: +386-61-125-80-31; e-mail: danijel.kikelj@ffa.uni-lj.si
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00485-6

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details of our studies on the stereoselective synthesis of (R)- and (S)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-
benzoxazine-2-carboxylic acids 5, -carboxylates 4 and -carboxamides 7 based on selective cyclization of
(R)-monomethyl 2-methyl-2-(2-nitrophenoxy)malonates 3 with the participation of the carboxy and the
methoxycarbonyl group, respectively.
2. Results and discussion
The enantiomers of the title compounds were prepared starting from common chiral precursors, (R)-
monomethyl 2-methyl-2-(2-nitrophenoxy)malonates 3, most of which were prepared by us previously in
a 69–81% enantiomeric excess by pig liver esterase (PLE) catalyzed hydrolysis of prochiral dimethyl
2-methyl-2-(2-nitrophenoxy)malonates 2 in a phosphate buffer (pH 7)/DMSO system.7 Interestingly,
we have found that if the enzymatic hydrolysis is performed in a phosphate buffer (pH 7):N,N-
dimethylformamide (8:2) mixture, the (R)-monomethyl malonates 3 are obtained in a higher (73–88%)
enantiomeric excess. The novel 3-methyl derivative 3b was prepared from 3-methyl-2-nitrophenol 1b
using the alkylation method described by us previously7 and PLE-catalyzed hydrolysis of the diester 2b
in the improved phosphate buffer/DMF system (Scheme 1).
Scheme 1. i: Br(CH3)C(COOMe)2, KF, DMF, 60°C, 6 h; ii: PLE, buffer (pH 7):DMF (8:2), room temp., 24 h
Initially, we anticipated that after reduction of the nitro group in (R)-3 the expected more reactive ester
moiety would participate in the cyclization to afford carboxylic acids (S)-5. However, the hydrogenolytic
reduction of the chiral intermediates (R)-3 in methanol, using palladium on charcoal as a catalyst after in
situ cyclization, unexpectedly consistently afforded almost equimolar mixtures of carboxylic acids (S)-
5 and esters (R)-4. Therefore, we reasoned that for the selective cyclization over the methoxycarbonyl
group, the carboxy group of (R)-3 should be deactivated and, consequently, we found that a straightfor-
ward transformation of the chiral intermediates (R)-3 to carboxamides (R)-7A is possible via conversion
of the carboxylic acids (R)-3 to carboxamides (R)-6 using the mixed anhydride method,8 reduction of the
nitro group, and subsequent in situ cyclization of the resulting amine with participation of the ester
group. For the synthesis of the opposite enantiomers, i.e. carboxamides (S)-7A, we tried to activate
the carboxy group of (R)-3 as mixed anhydride 8 and active ester with N-hydroxysuccinimide (9) or
pentafluorophenol (10) to achieve sufficient difference in reactivity between the methoxycarbonyl and the
activated carboxy group in the cyclization step. Unfortunately, in a very unclean reaction the 4-hydroxy
derivatives 11 were always formed as major by-products after reduction and following in situ cyclization
of the activated derivatives 8, 9 and 10. They were easily identified in the proton NMR spectra by the
presence of a broad signal (N–OH) at ca. 11.0 ppm, accompanying the signal of the 4-NH proton of (R)-4
at ca. 10.8 ppm.† The formation of these major by-products could be explained by the high reactivity of
the activated carboxy group which can trap the 2-hydroxyamino intermediate9 formed during reduction
of the nitro group (Scheme 2).
†
11a (R1_H): 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.75 (s, 3H, CH3), 3.65 (s, 3H, COOCH3), 7.00–7.10 (m, 3H, Ar–H),
7.22 (d, 1H, J=7.3 Hz, Ar–H), 11.03 (s broad, 1H, NOH); MS (70 eV, EI): m/z=237 (M+, 68%), 178 (100%).

M. Breznik et al. / Tetrahedron: Asymmetry 10 (1999) 153–167
155
Scheme 2. i: ClCOOEt, Et3N, CH2Cl2; ii: N-hydroxysuccinimide or pentafluorophenol, DCC; iii: H2, Pd/C (10%)
With the aim of obtaining the carboxamides (S)-7A our attention was focused on our earlier
observation that, contrary to expectations based on the generally known reactivity of carboxylic acid
derivatives, upon the reduction of (R)-3 in methanol, a mixture of the ester (R)-4 and carboxylic acid
(S)-5 was obtained. A systematic study of the catalytic hydrogenation of (R)-3 in different solvents
(chloroform, ethanol, methanol, isopropanol, acetic acid, tetrahydrofuran, water) was initiated with
the purpose of finding a solvent pair in which selective cyclization of (R)-monomethyl 2-methyl-2-(2-
aminophenoxy)malonates with the participation of the carboxy and methoxycarbonyl group, respectively,
would be possible. As a result of these efforts we found that in situ cyclization of the aromatic amines
obtained by hydrogenolytical reduction of (R)-3 in chloroform afforded (R)-methyl 2-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates 4 in a 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 5 which
could be easily separated simply by extraction. In contrast, when the reduction of (R)-3 and in situ
cyclization was performed in water in the presence of an equivalent amount of 0.1 N sodium hydroxide,
the methoxycarbonyl group selectively participated in the cyclization step and (S)-2-methyl-3-oxo-3,4-
dihydro-2H-1,4-benzoxazine-2-carboxylic acids 5 were obtained in good yields. The carboxylates (R)-4
were efficiently transformed to carboxamides (S)-7A using standard chemistry by hydrolysis, subsequent
activation of the resulting carboxylic acids (R)-5 and reaction with amines. Similarly, carboxamides (R)-
7A were obtained from carboxylic acids (S)-5 (Scheme 3).
Scheme 3.
The crude diastereomeric amides 7B obtained by coupling of the carboxylic acids (R)-4 and (S)-4
1
with D-phenylalanine benzyl ester displayed a single set of signals in their H NMR spectra, which, in

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M. Breznik et al. / Tetrahedron: Asymmetry 10 (1999) 153–167
addition to the specific rotation values, confirmed the high enantiomeric purity of the products of this
stereoselective synthesis.
In conclusion, the enantiomers of methyl 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-
carboxylates 4a–f, 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acids 5a–f and
2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamides 7aA–fA with different substituents
on the aromatic ring were efficiently prepared from common chiral precursors (R)-monomethyl
2-methyl-2-(2-nitrophenoxy)malonates 3, employing a strategy of solvent- and derivatization-based
reactivity manipulation of the carboxy group of 3. The application of these compounds as building
blocks for the construction of peptidomimetics will be reported elsewhere.
3. Experimental
Melting points were taken on a Reichert hot-stage microscope and are uncorrected. IR spectra were
recorded on a Perkin–Elmer 1600 Series FTIR spectrometer as KBr discs for solids and neat films for
oils. Optical rotations were measured on a Perkin–Elmer 1241 MC polarimeter. The reported values for
specific rotation are average values of 10 successive measurements using an integration time of 10 s.
Elemental analyses were performed at the Faculty of Chemistry and Chemical Engineering, University
of Ljubljana on a Perkin–Elmer C, H, N-Analyzer 240 C. Mass spectra were obtained on an Autospec Q,
VG-Analytical mass spectrometer using EI or FAB ionization. NMR spectra were obtained on a Bruker
Avance DPX 300 instrument operating at 300.13 MHz for protons with tetramethylsilane as an internal
standard. Pig liver esterase suspension in 3.2 M ammonium sulfate solution (activity 130 U/mg protein)
was obtained from Fluka. The enzyme used in all experiments was from the same Fluka lot, no. 46063.
1
Phosphate buffer (pH 7.00) was obtained from Merck. Enantiomeric excess determinations by the H
NMR method using (R)-1-methylbenzylamine as a chiral solvating agent were performed as described
previously.7 D-Phenylalanine benzyl ester p-toluenesulfonate10 was synthesized according to a published
procedure.
3.1. Dimethyl 2-methyl-2-(3-methyl-2-nitrophenoxy)malonate 2b
Dimethyl 2-bromo-2-methylmalonate7 (20.25 g, 90 mmol) was added to a stirred suspension of
potassium fluoride (13.07 g, 0.225 mol) in dry N,N-dimethylformamide (60 ml). After stirring for 15
min at room temperature, 3-methyl-2-nitrophenol (13.78 g, 90 mmol) was added. The resulting mixture
was stirred for 6 h at 60°C, cooled to room temperature and poured into crushed ice/water (250 g).
After dissolution of the ice, the aqueous solution was extracted with ether (3×200 ml), the ether phase
was washed successively with 0.1 N sodium hydroxide (3×50 ml) and 0.1 N hydrochloric acid (3×50
ml), dried over sodium sulfate, filtered and evaporated in vacuo to give 23.0 g (86%) of 2b as orange
crystals, mp 84–86°C; IR (film): ν 2960, 1771, 1745, 1618, 1582, 1532, 1473, 1375, 1283, 1140, 967,
1
852, 770 cm−1; H NMR (300 MHz, CDCl3): δ 1.77 (s, 3H, CH3), 2.33 (s, 3H, Ar–CH3), 3.84 (s, 6H,
2×COOCH3), 6.91 (d, 1H, J=9.0 Hz, Ar–H), 6.98 (d, 1H, J=7.2 Hz, Ar–H), 7.25 (dd, 1H, Ar–H) ppm;
MS (70 eV, EI): m/z=297 (M+, 7%), 113 (100%). Anal. calcd for C13H15NO7: C 52.56%, H 5.05%, N
4.71%. Found: C 52.58%, H 4.86%, N 4.62%.

M. Breznik et al. / Tetrahedron: Asymmetry 10 (1999) 153–167
157
3.2. (R)-(−)-Monomethyl 2-methyl-2-(3-methyl-2-nitrophenoxy)malonate (R)-3b. General procedure for
PLE-catalyzed hydrolysis of 2a–f in a phosphate buffer:DMF (80:20) mixture
A buffer solution (pH=7, 150 ml) containing 0.6 ml of PLE suspension was added to a solution of
dimethyl 2-methyl-2-(3-methyl-2-nitrophenoxy)malonate 2b (1.48 g, 5 mmol) in DMF (40 ml). The
mixture was stirred for 48 h at room temperature. During this time the pH remained constant. Then the
reaction mixture was made alkaline by the addition of a saturated aqueous NaHCO3 solution (25 ml) and
washed with ether (3×50 ml). The aqueous phase was acidified with 4 M hydrochloric acid to pH 2–3
and extracted with ether (2×40 ml), saturated with NaCl and extracted again with ether (2×30 ml). The
ether phase was washed with a saturated aqueous NaCl solution (2×25 ml), water (3×30 ml), dried over
MgSO4, filtered and evaporated in vacuo to afford 1.2 g (86%) of (R)-3b as a yellow oil; [α]20=−1.40
D
(c=0.63, methanol); IR (film): ν 3536, 2958, 1749, 1584, 1534, 1476, 1372, 1278, 1128 cm−1; 1H NMR
(300 MHz, CDCl3): δ 1.84 (s, 3H, CH3), 2.35 (s, 3H, Ar–CH3), 3.85 (s, 3H, COOCH3), 5.45 (s broad,
1H, COOH), 6.86 (d, 1H, J=8.3 Hz, Ar–H), 7.01 (d, 1H, J=7.9 Hz, Ar–H), 7.27 (dd, 1H, Ar–H) ppm;
MS (70 eV, EI): m/z=283 (M+, 6%), 146 (100%). Anal. calcd for C12H13NO7·0.25H2O: C 50.09%, H
4.69%, N 4.87%. Found: C 49.94%, H 4.35%, N 4.86%.
3.3. (R)-(−)-Methyl 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (R)-4a. General
procedure for the synthesis of carboxylates (R)-4a–f
(R)-Monomethyl 2-methyl-2-(2-nitrophenoxy)malonate (R)-3a (538 mg, 2 mmol) was dissolved in
ethanol free CHCl3 (200 ml) and hydrogenated over 10% Pd/C (54 mg) for 24 h at normal pressure and
room temperature. The catalyst was filtered off, the filtrate was extracted with saturated NaHCO3 solution
(3×50 ml), dried over MgSO4 and evaporated in vacuo. The crude product was recrystallized from MeOH
to constant specific rotation value;‡ yield: 0.36 g (81%), white crystals; mp 150–152°C (from MeOH),
[α]20 (crude product)=−41.5 (c=0.53, MeOH); [α]20 (recrystallized product)=−41.8 (c=0.40, MeOH),
D
D
Lit.:5 [α]20=−43.6 (c=0.50, MeOH); IR (KBr): ν 3248, 1750, 1710, 1613, 1506, 1429, 1380, 1239, 1153,
D
1124, 974, 767, 750, 578, 529 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.69 (s, 3H, CH3), 3.64
(s, 3H, COOCH3), 6.88–7.03 (m, 4H, Ar–H), 10.92 (s broad, 1H, NH); MS (70 eV, EI): m/z=221 (M+,
10%), 162 (100%). Anal. calcd for C11H11NO4: C 59.73%, H 5.01%, N 6.33%. Found: C 60.10%, H
4.96%, N 6.00%.
3.4. (R)-(−)-Methyl 2,5-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (R)-4b
Prepared from (R)-3b (566 mg, 2 mmol); yield: 0.22 g (47%), white crystals; mp 137–140°C (from
MeOH), [α]20 (crude product)=−71.7 (c=0.45, MeOH); [α]20 (recrystallized product)=−90.3 (c=0.39,
D
D
MeOH); IR (KBr): ν 3210, 1735, 1687, 1498, 1476, 1444, 1394, 1265, 1120, 779, 609 cm−1; 1H NMR
(300 MHz, DMSO-d6): δ (ppm) 1.68 (s, 3H, CH3), 2.22 (s, 3H, Ar–CH3), 3.62 (s, 3H, COOCH3),
6.80–6.88 (m, 3H, Ar–H), 10.41 (s broad, 1H, NH); MS (70 eV, EI): m/z=235 (M+, 53%), 176 (100%).
Anal. calcd for C12H13NO4: C 61.27%, H 5.57%, N 5.95%. Found: C 61.57%, H 5.52%, N 5.95%.
‡
During recrystallization from a minimal volume of methanol, a product of lower enantiomeric excess (containing the opposite
enantiomer) separated first from a saturated solution. After approximately 10% of the theoretical amount of the product
crystallized from a saturated solution, the crystals were filtered off and from the filtrate a product of higher enantiomeric
excess was slowly deposited. This process was repeated (usually 2–3 times) until a product of constant specific rotation value
was obtained.

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3.5. (R)-(−)-Methyl 2,6-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (R)-4c
Prepared from (R)-3c (566 mg, 2 mmol); yield: 0.37 g (78%), pale pink crystals; mp 135–138°C (from
MeOH), [α]20 (crude product)=−59.7 (c=0.49, MeOH); [α]20 (recrystallized product)=−66.4 (c=0.43,
D
D
MeOH); IR (KBr): ν 3236, 1760, 1693, 1608, 1518, 1485, 1374, 1247, 1121, 978, 819, 741, 538 cm−1; 1H
NMR (300 MHz, DMSO-d6): δ (ppm) 1.66 (s, 3H, CH3), 2.21 (s, 3H, Ar–CH3), 3.63 (s, 3H, COOCH3),
6.68 (d, 1H, J=1.9 Hz, Ar–H), 6.75 (ddd, 1H, J=8.3, 1.9, 0.8 Hz, Ar–H), 6.88 (d, 1H, J=8.3 Hz, Ar–H),
10.86 (s broad, 1H, NH); MS (70 eV, EI): m/z=235 (M+, 39%), 176 (100%). Anal. calcd for C12H13NO4:
C 61.27%, H 5.57%, N 5.95%. Found: C 61.55%, H 5.53%, N 6.17%.
3.6. (R)-(−)-Methyl 2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (R)-4d
Prepared from (R)-3d (566 mg, 2 mmol); yield: 0.34 g (73%), white crystals; mp 137–139°C (from
MeOH), [α]20 (crude product)=−12.3 (c=0.50, MeOH); [α]20 (recrystallized product)=−13.7 (c=0.46,
D
D
MeOH); IR (KBr): ν 3198, 3066, 1752, 1687, 1517, 1447, 1385, 1261, 1120, 987, 805, 579 cm−1; H
NMR (300 MHz, DMSO-d6): δ (ppm) 1.67 (s, 3H, CH3), 2.22 (s, 3H, Ar–CH3), 3.64 (s, 3H, COOCH3),
6.77 (s, 2H, Ar–H), 6.83 (s, 1H, Ar–H), 10.82 (s broad, 1H, NH); MS (70 eV, EI): m/z=235 (M+, 49%),
176 (100%). Anal. calcd for C12H13NO4: C 61.27%, H 5.57%, N 5.95%. Found: C 61.45%, H 5.60%, N
6.15%.
1
3.7. (R)-(−)-Methyl 7-fluoro-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (R)-4e
Prepared from (R)-3e (574 mg, 2 mmol); yield: 0.33 g (70%), pale pink crystals; mp 152–154°C (from
MeOH), [α]20 (crude product)=−22.1 (c=0.51, MeOH); [α]20 (recrystallized product)=−24.6 (c=0.55,
D
D
MeOH); IR (KBr): ν 3273, 2952, 1748, 1712, 1674, 1621, 1517, 1418, 1248, 1151, 1125, 995, 844, 752,
1
612, 526 cm−1; H NMR (300 MHz, DMSO-d6): δ (ppm) 1.70 (s, 3H, CH3), 3.66 (s, 3H, COOCH3),
6.81–6.99 (m, 3H, Ar–H), 10.97 (s broad, 1H, NH); MS (70 eV, EI): m/z=239 (M+, 57%), 180 (100%).
Anal. calcd for C11H10FNO4: C 55.23, H 4.21, N 5.86. Found: C 55.03%, H 4.16%, N 6.00%.
3.8. (R)-(−)-Methyl 6-methoxy-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (R)-4f
Prepared from (R)-3f (598 mg, 2 mmol); yield: 0.40 g (80%), white crystals; mp 124–127°C (from
MeOH), [α]20 (crude product)=−73.0 (c=0.51, MeOH); [α]20 (recrystallized product)=−88.0 (c=0.51,
D
D
MeOH); IR (KBr): ν 3266, 2959, 1753, 1702, 1623, 1518, 1485, 1373, 1314, 1266, 1228, 1157, 1120,
1035, 977, 866, 758, 646, 529 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.62 (s, 3H, CH3), 3.60
(s, 3H, COOCH3), 3.66 (s, 3H, OCH3), 6.42 (d, 1H, J=2.9 Hz, Ar–H), 6.49 (dd, 1H, J=8.6, 2.9 Hz,
Ar–H), 6.90 (d, 1H, J=8.6 Hz, Ar–H), 10.81 (s broad, 1H, NH); MS (70 eV, EI): m/z=251 (M+, 53%),
192 (100%). Anal. calcd for C12H13NO5: C 57.37%, H 5.22%, N 5.58%. Found: C 57.10%, H 5.20%, N
5.44%.
3.9. (S)-(+)-2-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (S)-5a. General proce-
dure for the synthesis of carboxylic acids (S)-5a–f
(R)-Monomethyl 2-methyl-2-(2-nitrophenoxy)malonate (R)-3a (538 mg, 2 mmol) was dissolved in
water (50 ml). An equivalent amount of 0.1 M NaOH (20.0 ml, 20 mmol) was added and the mixture was
hydrogenated over 10% Pd/C (54 mg) for 24 h at normal pressure and room temperature. The catalyst

M. Breznik et al. / Tetrahedron: Asymmetry 10 (1999) 153–167
159
was filtered off, the filtrate was acidified with 1 M HCl and extracted with ethyl acetate (4×30 ml), dried
over MgSO4 and evaporated in vacuo. The crude product was recrystallized from MeOH to constant
specific rotation value;‡ yield: 327 mg (79%), white crystals; mp 195–199°C (from MeOH), [α]20 (crude
D
product)=+65.4 (c=0.45, MeOH); [α]20 (recrystallized product)=+71.3 (c=0.34, MeOH); IR (KBr): ν
D
3186, 3063, 1759, 1661, 1608, 1502, 1406, 1233, 1145, 968, 768, 653, 584 cm−1; 1H NMR (300 MHz,
DMSO-d6): δ (ppm) 1.66 (s, 3H, CH3), 6.86–7.00 (m, 4H, Ar–H), 10.78 (s broad, 1H, NH), 13.5 (s
broad, 1H, COOH); MS (70 eV, EI): m/z=207 (M+, 29%), 163 (100%). Anal. calcd for C10H9NO4: C
58.00%, H 4.35%, N 6.76%. Found: C 57.98%, H 4.36%, N 6.73%.
3.10. (S)-(+)-2,5-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (S)-5b
Prepared from (R)-3b (566 mg, 2 mmol); yield: 358 mg (81%), white crystals; mp 197–200°C (from
MeOH), [α]20 (crude product)=+82.9 (c=0.56, MeOH); [α]20 (recrystallized product)=+112.5 (c=0.39,
D
D
MeOH); IR (KBr): ν 3219, 2496, 1730, 1654, 1481, 1440, 1372, 1264, 1225, 1152, 972, 778, 725, 605,
501 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.66 (s, 3H, CH3), 2.22 (s, 3H, Ar–CH3), 6.80–6.86
(m, 3H, Ar–H), 10.28 (s broad, 1H, NH), 13.45 (s broad, 1H, COOH); MS (70 eV, EI): m/z=221 (M+,
28%), 177 (100%). Anal. calcd for C11H11NO4: C 59.76% H 4.98% N 6.33%. Found: C 59.62%, H
5.07%, N 6.23%.
3.11. (S)-(+)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (S)-5c
Prepared from (R)-3c (566 mg, 2 mmol); yield: 371 mg (84%), white crystals; mp 181–183°C (from
MeOH), [α]20 (recrystallized product)=+85.1 (c=0.52, MeOH);§ IR (KBr): ν 3254, 1737, 1677, 1608,
D
1519, 1491, 1396, 1237, 1130, 865, 822, 740, 691, 533 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm)
1.64 (s, 3H, CH3), 2.21 (s, 3H, Ar–CH3), 6.68 (d, 1H, J=1.8 Hz, Ar–H), 6.73 (dd, 1H, J=7.9, 1.8 Hz,
Ar–H), 6.86 (d, 1H, J=7.9 Hz, Ar–H), 10.72 (s broad, 1H, NH), 13.4 (s broad, 1H, COOH); MS (70
eV, EI): m/z=221 (M+, 2.6%), 177 (100%). Anal. calcd for C11H11NO4: C 59.76%, H 4.98%, N 6.33%.
Found: C 59.64%, H 4.80%, N 6.45%.
3.12. (S)-(+)-2,7-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (S)-5d
Prepared from (R)-3d (566 mg, 2 mmol); yield: 407 mg (92%), white crystals; mp 180–183°C (from
MeOH), [α]20 (crude product)=+21.4 (c=0.51, MeOH); [α]20 (recrystallized product)=+28.2 (c=0.02,
D
D
MeOH);§ IR (KBr): ν 3237, 1739, 1669, 1518, 1383, 1302, 1241, 1210, 1139, 976, 814, 719 cm−1; 1H
NMR (300 MHz, DMSO-d6): δ (ppm) 1.64 (s, 3H, CH3), 2.22 (s, 3H, Ar–CH3), 6.76 (s, 1H, Ar–H),
6.77 (s, 1H, Ar–H), 6.81 (s, 1H, Ar–H), 10.68 (s broad, 1H, NH), 13.45 (s broad, 1H, COOH); MS (70
eV, EI): m/z=221 (M+, 28%), 177 (100%). Anal. calcd for C11H11NO4·0.25H2O: C 58.57%, H 5.10%,
N 6.21%. Found: C 58.91%, H 4.97%, N 6.22%.
3.13. (S)-(+)-7-Fluoro-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (S)-5e
Prepared from (R)-3e (574 mg, 2 mmol); yield: 396 mg (88%), white crystals; mp 168–170°C (from
MeOH); [α]20 (recrystallized product)=+34.9 (c=0.41, MeOH); IR (KBr): ν 3178, 1741, 1654, 1521,
D
§
Not recrystallized further due to a limited quantity of substance.

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1
1429, 1276, 1151, 956, 851, 806, 764 cm−1; H NMR (300 MHz, DMSO-d6): δ (ppm) 1.67 (s, 3H,
CH3), 6.78–6.90 (m, 2H, Ar–H), 6.94 (dd, 1H, J=2.6, 9.8 Hz, Ar–H), 10.83 (s broad, 1H, NH), 13.4 (s
broad, 1H, COOH). MS (70 eV, EI): m/z=225 (M+, 37%), 181 (100%). Anal. calcd for C10H8FNO4: C
53.37%, H 3.55%, N 6.22%. Found: C 53.15%, H 3.75%, N 6.11%.
3.14. (S)-(+)-6-Methoxy-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (S)-5f
Prepared from (R)-3f (598 mg, 2 mmol); yield: 388 mg (82%), white crystals; mp 175–182°C (from
MeOH); [α]20 (recrystallized product)=+82.0 (c=0.12, MeOH); IR (KBr): ν 3219, 2938, 1734, 1669,
D
1515, 1233, 1032 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.62 (s, 3H, CH3), 3.68 (s, 3H, OCH3),
6.45 (d, 1H, J=2.9 Hz, Ar–H), 6.50 (dd, 1H, J=8.7, 2.9 Hz, Ar–H), 6.91 (d, 1H, J=8.7 Hz, Ar–H), 10.70
(s broad, 1H, NH), 13.50 (s broad, 1H, COOH); MS (70 eV, EI): m/z=237 (M+, 25%), 193 (100%). Anal.
calcd for C11H11NO5: C 55.70%, H 4.67%, N 5.90%. Found: C 55.82%, H 5.03%, N 5.98%.
3.15. (R)-(−)-2-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (R)-5a. General pro-
cedure for hydrolysis of methyl esters (R)-4a–f
A solution of (R)-4a (221 mg, 1 mmol) and 1 M NaOH (1.2 ml, 1.2 mmol) in dioxane (5 ml) was
stirred at room temperature overnight and then evaporated in vacuo. The residue was dissolved in water
(6 ml), the solution was acidified to pH 1–2 with 1 M HCl and the precipitated product was isolated by
filtration; yield: 184 mg (89%); [α]20 (crude product)=−68.8 (c=0.50, MeOH). The product was in all
D
other respects identical to (S)-5a obtained by cyclization from (R)-3a.
3.16. (R)-(−)-2,5-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (R)-5b
Prepared from (R)-4b (235 mg, 1 mmol); yield: 210 mg (95%); [α]20 (crude product)=−109.8
D
(c=0.321, MeOH). The product was in all other respects identical to (S)-5b obtained by cyclization from
(R)-3b.
3.17. (R)-(−)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (R)-5c
Prepared from (R)-4c (235 mg, 1 mmol); yield: 206 mg (93%); [α]20 (crude product)=−79.6 (c=0.35,
D
MeOH); [α]20 (recrystallized product)=−93.5 (c=0.37, MeOH). The product was in all other respects
D
identical to (S)-5c obtained by cyclization from (R)-3c.
3.18. (R)-(−)-2,7-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (R)-5d
Prepared from (R)-4d (235 mg, 1 mmol); yield: 206 mg (93%); [α]20 (crude product)=−29.6 (c=0.40,
D
MeOH); [α]20 (recrystallized product)=−30.9 (c=0.44, MeOH). The product was in all other respects
D
identical to (S)-5d obtained by cyclization from (R)-3d.
3.19. (R)-(−)-7-Fluoro-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (R)-5e
Prepared from (R)-4e (239 mg, 1 mmol); yield: 211 mg (94%); [α]20 (crude product)=−30.2 (c=0.42,
D
MeOH). The product was in all other respects identical to (S)-5e obtained by cyclization from (R)-3e.

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161
3.20. (R)-(−)-6-Methoxy-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (R)-5f
Prepared from (R)-4f (251 mg, 1 mmol); yield: 215 mg (91%); [α]20 (recrystallized product)=−83.4
D
(c=1.0, MeOH). The product was in all other respects identical to (S)-5f obtained by cyclization from
(R)-3f.
3.21. General procedure for the synthesis of carboxamides 6 and 7 from carboxylic acids 3 and 5
To a stirred solution of a carboxylic acid 3 or 5 (1 mmol) in ethanol free CHCl3 (15 ml) cooled to −15°C
were added, successively, Et3N [0.172 ml (1.25 mmol) for the reaction with ammonia or 0.348 ml (2.50
mmol) for the reaction with phenylalanine benzyl ester p-toluenesulfonate)] and ethyl chloroformate
(0.109 ml, 1.15 mmol). After 0.5 h a slow stream of ammonia was passed through the mixture for 20 min,
whereby the temperature of the mixture was not allowed to exceed 10°C, and phenylalanine benzyl ester
p-toluenesulfonate (427 mg, 1 mmol) was added. The mixture was stirred for 1 h whereupon the solvent
was evaporated in vacuo and the residue dissolved in ethyl acetate (50 ml). The solution was washed
successively with 1 N HCl (3×20 ml), water (3×20 ml) and brine (20 ml), dried over MgSO4, filtered and
evaporated in vacuo. The crude product was used as such (6), recrystallized from methanol (unsubstituted
carboxamides 7A) or triturated with hexane and when necessary purified by column chromatography
(phenylalanine derivatives 7B).
3.22. (R)-(−)-Methyl 2-carbamoyl-2-(2-nitrophenoxy)propanoate (R)-6a
Prepared from (R)-3a (1.076 g, 4 mmol); yield: 0.804 g (75%), yellow oil; [α]20=−21.6 (c=0.82,
D
MeOH); IR (KBr): ν 3463, 1748, 1704, 1606, 1525, 1484, 1349, 1277, 1127, 746 cm−1; 1H NMR (300
MHz, DMSO-d6): δ (ppm) 1.69 (s, 3H, CH3), 3.73 (s, 3H, COOCH3), 7.02 (dd, 1H, J=8.5, 1.0 Hz,
Ar–H), 7.25–7.30 (ddd, 1H, J=8.1, 7.4, 1.0 Hz, Ar–H), 7.45 (s broad, 1H, CONH2), 7.67 (ddd, 1H,
J=8.5, 7.4, 1.7 Hz, Ar–H), 7.92 (s broad, 1H, CONH2), 7.99 (dd, 1H, J=8.1, 1.7 Hz, Ar–H); MS (70 eV,
EI): m/z=269 (MH+, 1%), 123 (100%). Anal. calcd for C11H12N2O6·0.25H2O: C 48.44%, H 4.58%, N
10.27%. Found: C 48.55%, H 4.44%, N 9.74%.
3.23. (R)-(−)-Methyl 2-carbamoyl-2-(4-methyl-2-nitrophenoxy)propanoate (R)-6c
Prepared from (R)-3c (1.132 g, 4 mmol); yield: 0.96 g (85%), white crystals, mp 115–117°C (from
MeOH); [α]20=−15.2 (c=0.44, MeOH); IR (KBr): ν 3442, 3246, 2957, 1749, 1677, 1533, 1393, 1342,
D
1277, 1248, 1120, 980, 828, 780 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.64, 3H, CH3), 2.33
(s, 3H, Ar–CH3), 3.72 (s, 3H, COOCH3), 6.92 (d, 1H, J=8.6 Hz, Ar–H), 7.43 (s broad, 1H, CONH2),
7.47 (dd, 1H, J=8.6, 2.2 Hz, Ar–H), 7.81 (d, 1H, J=2.2 Hz, Ar–H), 7.89 (s broad, 1H, CONH2). MS
(70 eV, EI): m/z=283 (MH+, 1.5%), 136 (100%). Anal. calcd for C12H14N2O6: C 51.06%, H 5.00%, N
9.93%. Found: C 50.76%, H 5.08%, N 9.98%.

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3.24. (R)-(+)-Methyl 2-carbamoyl-2-(5-methyl-2-nitrophenoxy)propanoate (R)-6d¶
Prepared from (R)-3d (1.128 g, 4 mmol); yield: 0.871 g (77%), white crystals, mp 141–144°C (from
MeOH); [α]20=+4.8 (c=0.36, MeOH); IR (KBr): ν 3420, 3161, 1751, 1701, 1590, 1508, 1388, 1273,
D
1121, 927, 817 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.69 (s, 3H, CH3), 2.37 (s, 3H, Ar–CH3),
3.73 (s, 3H, COOCH3), 6.76 (s, 1H, Ar–H), 7.07–7.10 (m, 1H, Ar–H), 7.45 (s broad, 1H, CONH2),
7.90–7.93 (m, 2H, Ar–H, CONH2); MS (70 eV, EI): m/z=283 (MH+, 1%), 236 (100%).
3.25. (R)-(−)-Methyl 2-carbamoyl-2-(5-fluoro-2-nitrophenoxy)propanoate (R)-6e
Prepared from (R)-3e (1.148 g, 4 mmol); yield: 0.938 g (82%), white crystals, mp 148–151°C (from
MeOH); [α]20=−22.8 (c=0.43, MeOH); IR (KBr): ν 3429, 3249, 1750, 1703, 1592, 1522, 1342, 1283,
D
1
1136, 988, 859, 608 cm−1; H NMR (300 MHz, DMSO-d6): δ (ppm) 1.76 (s, 3H, CH3), 3.76 (s, 3H,
COOCH3), 6.84 (dd, 1H, J=10.3, 2.5 Hz, Ar–H), 7.16 (ddd, 1H, J=9.2, 7.8, 2.5 Hz, Ar–H), 7.55 (s
broad, 1H, CONH2), 7.94 (s broad, 1H, CONH2), 8.13 (dd, 1H, J=9.2, 6.0 Hz, Ar–H); MS (70 eV, EI):
m/z=287 (MH+, 2%), 141 (100%). Anal. calcd for C11H11FN2O6: C 46.16%, H 3.87%, N 9.78%. Found:
C 46.58%, H 3.70%, N 10.17%.
3.26. (R)-(−)-Methyl 2-carbamoyl-2-(4-methoxy-2-nitrophenoxy)propanoate (R)-6f
Prepared from (R)-3f (1.196 g, 4 mmol); yield: 0.953 g (80%), white crystals, mp 114–115°C (from
MeOH); [α]20=−9.9 (c=0.42, MeOH); IR (KBr): ν 3377, 3210, 1700, 1618, 1509, 1336, 1158, 990, 808,
D
606 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.57 (s, 3H, CH3), 3.72 (s, 3H, COOCH3), 3.80 (s,
3H, OCH3), 7.01 (d, 1H, J=9.2 Hz, Ar–H), 7.25 (dd, 1H, J=9.2, 3.2 Hz, Ar–H), 7.46 (s, 1H, CONH2),
7.51 (d, 1H, J=3.2 Hz, Ar–H), 7.85 (s broad, 1H, CONH2); MS (70 eV, EI): m/z=298 (M+, 15%), 169
(100%). Anal. calcd for C12H14N2O7: C 48.32%, H 4.73%, N 9.39%. Found: C 48.16%, H 4.35%, N
9.55%.
3.27. (R)-(+)-2-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (R)-7aA
Prepared from (S)-5a (207 mg, 1 mmol); yield: 115 mg (56%), white crystals; mp 222–225°C (from
MeOH); [α]20 (recrystallized product)=+81.6 (c=0.13, MeOH); IR (KBr): ν 3374, 3222, 1701, 1613,
D
1
1503, 1356, 1235, 1153, 756 cm−1; H NMR (300 MHz, DMSO-d6): δ (ppm) 1.63 (s, 3H, CH3),
6.84–6.87 (m, 1H, Ar–H), 6.92–6.96 (m, 2H, Ar–H), 7.05–7.08 (m, 1H, Ar–H), 7.35 (s broad, 1H,
CONH2), 7.55 (s broad, 1H, CONH2), 10.65 (s broad, 1H, NH); MS (70 eV, EI): m/z=206 (M+, 10%),
162 (100%). Anal. calcd for C10H10N2O3: C 58.25%, H 4.89%, N 13.59%. Found: C 58.24%, H 4.94%,
N 13.47%.
Prepared from (R)-6a (268 mg, 1 mmol); yield: 144 mg (70%); [α]20 (recrystallized product)=+77.7
D
(c=0.11, MeOH). The product was in all other respects identical to (R)-7aA described earlier.
¶
Compound (R)-6d is the only compound in this carboxamide series which showed a positive specific rotation in methanol.
However, there are several instances where closely related substances with the same absolute configuration rotate the plane of
the plane-polarized light in different directions.7,11

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163
3.28. (S)-(−)-2-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (S)-7aA
Prepared from (R)-5a (207 mg, 1 mmol); yield: 146 mg (71%), white crystals; mp 224–226°C (from
MeOH); [α]20 (crude product)=−69.6 (c=0.09, MeOH).§ The product was in all other respects identical
D
to (R)-7aA.
3.29. (R)-(+)-2,5-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (R)-7bA
Prepared from (S)-5b (221 mg, 1 mmol); yield: 130 mg (59%), white crystals; mp 221–223°C (from
MeOH); [α]20 (recrystallized product)=+116.2 (c=0.07, MeOH). The product was in all other respects
D
identical to (S)-7bA described later.
3.30. (S)-(−)-2,5-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (S)-7bA
Prepared from (R)-5b (221 mg, 1 mmol); yield: 158 mg (72%), white crystals; mp 222–226°C (from
MeOH); [α]20 (recrystallized product)=−113.9 (c=0.09, MeOH); IR (KBr): ν 3458, 2924, 2854, 1702,
D
1475, 1360, 1135, 1034, 973, 782, 727, 603, 502 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.63
(s, 3H, CH3), 2.20 (s, 3H, Ar–CH3), 6.79–6.87 (m, 2H, Ar–H), 6.93 (dd, 1H, Ar–H, J=7.5, 1.9 Hz), 7.32
(s broad, 1H, CONH2), 7.52 (s broad, 1H, CONH2), 10.16 (s broad, 1H, NH); MS (70 eV, EI): m/z=220
(M+, 50%), 177 (100%); HRMS: calcd: 220.084792. Found: 220.085065.
3.31. (R)-(+)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (R)-7cA
Prepared from (R)-6c (282 mg, 1 mmol); yield: 185 mg (84%); white crystals, mp 292–293°C (from
MeOH); [α]20=+87.4 (c=0.16, MeOH). The product was in all other respects identical to (S)-7cA
D
described later.
3.32. (S)-(−)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (S)-7cA
Prepared from (R)-5c (221 mg, 1 mmol); yield: 154 mg (70%), white crystals; mp 302–304°C (from
MeOH), [α]20=−87.6 (c=0.16, MeOH); IR (KBr): ν 3376, 3154, 1699, 1609, 1520, 1495, 1361, 1237,
D
1
1151, 814 cm−1; H NMR (300 MHz, DMSO-d6): δ (ppm) 1.61 (s, 3H, CH3), 2.20 (s, 3H, Ar–CH3),
6.65 (d, 1H, J=1.8 Hz, Ar–H), 6.72 (dd, 1H, J=8.1, 1.8 Hz, Ar–H), 6.94 (d, 1H, J=8.1 Hz, Ar–H), 7.32 (s
broad, 1H, CONH2), 7.51 (s broad, 1H, CONH2) 10.58 (s broad, 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%.
3.33. (S)-(−)-2,7-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (S)-7dA
Prepared from (R)-5d (221 mg, 1 mmol); yield: 116 mg (53%), white crystals; mp 386–290°C (from
MeOH), [α]20=−39.0 (c=0.10, MeOH); IR (KBr): ν 3375 3199, 1699, 1698, 1518, 1157, 807 cm−1;
D
1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.62 (s, 3H, CH3), 2.22 (s, 3H, Ar–CH3), 6.72–6.88 (m, 2H,
Ar–H), 6.88 (s, 1H, Ar–H), 7.33 (s broad, 1H, CONH2), 7.50 (s broad, 1H, CONH2) 10.54 (s broad,
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 60.01%, H 5.39%, N 12.88%.

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3.34. (R)-(+)-7-Fluoro-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (R)-7eA
Prepared from (R)-6e (286 mg, 1 mmol); yield: 168 mg (75%), white crystals; mp 232–237°C (from
MeOH); [α]20 (recrystallized product)=+34.7 (c=0.12, MeOH);§ IR (KBr): ν 3377, 3210, 1700, 1509,
D
1336, 1158, 992, 860, 808 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.64 (s, 3H, CH3), 6.80–6.86
(m, 2H, Ar–H), 6.96 (dd, 1H, J=9.5, 2.3 Hz, Ar–H), 7.41 (s broad, 1H, CONH2), 7.58 (s broad, 1H,
CONH2), 10.69 (s broad, 1H, NH); MS (70 eV, EI): m/z=224 (M+, 35%), 181 (100%). Anal. calcd for
C10H9FN2O3: C 53.58%, H 4.05%, N 12.50%. Found: C 53.60%, H 4.06%, N 12.45%.
3.35. (S)-(−)-7-Fluoro-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (S)-7eA
Prepared from (R)-5e (225 mg, 1 mmol); yield: 128 mg (57%), white crystals; mp 236–240°C (from
MeOH); [α]20 (recrystallized product)=−36.9 (c=0.10, MeOH). The product was in all other respects
D
identical to (R)-7eA described earlier.
3.36. (R)-(+)-6-Methoxy-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (R)-7fA
Prepared from (R)-6f (299 mg, 1 mmol); yield: 217 mg (92%), white crystals; mp 252–255°C (from
MeOH); [α]20 (recrystallized product)=+81.3 (c=0.47, MeOH); IR (KBr): ν 3374, 3214, 1696, 1513,
D
643 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.60 (s, 3H, CH3), 3.67 (s, 3H, CH3), 6.42 (d, 1H,
J=2.9 Hz, Ar–H), 6.50 (dd, 1H, J=8.8, 2.9 Hz, Ar–H), 6.99 (d, 1H, J=8.8 Hz, Ar–H), 7.33 (s broad, 1H,
CONH2), 7.54 (s broad, 1H, CONH2), 10.56 (s broad, 1H, NH); MS (70 eV, EI): m/z=236 (M+, 65%),
192 (100%). Anal. calcd for C11H12N2O4: C 55.93%, H 5.12%, N 11.86%. Found: C 55.94%, H 5.02%,
N 11.90%.
3.37. (S)-(−)-6-Methoxy-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (S)-7fA
Prepared from (R)-5f (237 mg, 1 mmol); yield: 206 mg (85%), white crystals; mp 254–258°C (from
MeOH); [α]20 (recrystallized product)=−75.4 (c=0.29, MeOH).§ The product was in all other respects
D
identical to (R)-7fA described earlier.
3.38. N-{[(2S)-2,5-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-yl]carbonyl}-D-phenylalanine
benzyl ester (2S)-7bB
Prepared from (R)-5b (221 mg, 1 mmol); yield: 394 mg (86%), white solid foam; mp 46–48°C,
20
1
[α] =−31.3 (c=0.10, MeOH); IR (KBr): ν 3412, 1705, 1498, 1376, 1277, 1175, 699 cm−1; H NMR
D
(300 MHz, DMSO-d6): δ (ppm) 1.59 (s, 3H, CH3), 2.16 (s, 3H, Ar–CH3), 2.97 (ABX-system, 2H,
AB=13.9 Hz, JAX=9.8 Hz, JBX=4.1 Hz, CHCH2Ph), 4.32–4.40 (m, 1H, CH), 5.09 (AB-system, 2H,
J
J=12.4 Hz, COOCH2Ph), 6.80–6.82 (m, 2H, Ar–H), 6.84–6.93 (m, 3H, Ar–H), 7.05–7.14 (m, 3H, Ar–H),
7.28–7.42 (m, 5H, Ar–H), 8.45 (d broad, 1H, CONH, J=8.3 Hz), 10.16 (s broad, 1H, NH); MS (70 eV,
EI): m/z=458 (M+, 9%), 177 (100%); HRMS: calcd: 458.184172. Found: 458.184899. Anal. calcd for
C27H26N2O5·0.6H2O: C 69.14%, H 5.80%, N 5.97%. Found: C 68.88%, H 5.20%, N 6.04%.

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165
3.39. N-{[(2R)-2,5-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-yl]carbonyl}-D-phenylalanine
benzyl ester (2R)-7bB
Prepared from (S)-5b (221 mg, 1 mmol); yield: 417 mg (91%), white solid foam; mp 46–49°C,
[α]20=+85.6 (c=0.11, MeOH); IR (KBr): ν 3419, 1702, 1499, 1480, 1376, 1175, 1027, 749, 698 cm−1;
D
1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.47 (s, 3H, CH3), 2.16 (s, 3H, Ar–CH3), 3.03 (ABX-system,
2H, JAB=13.8 Hz, JAX=9.7 Hz, JBX=4.9 Hz, CHCH2Ph), 4.44–4.51 (m, 1H, CH), 4.93 (AB-system,
2H, J=12.3 Hz, COOCH2Ph), 6.76–6.86 (m, 3H, Ar–H), 7.10–7.13 (m, 2H, Ar–H), 7.18–7.23 (m, 5H,
Ar–H), 7.32–7.36 (m, 3H, Ar–H), 8.35 (d broad, 1H, J=8.3 Hz, CONH), 10.19 (s broad, 1H, NH); MS
(70 eV, EI): m/z=458 (M+, 5%), 177 (100%); HRMS: calcd: 458.184172. Found: 458.185100.
3.40. N-{[(2S)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-yl]carbonyl}-D-phenylalanine
benzyl ester (2S)-7cB
Prepared from (R)-5c (221 mg, 1 mmol); yield: 408 mg (89%), white solid foam; mp 29–30°C,
[α]20=−10.7 (c=0.10, MeOH); IR (KBr): ν 3410, 1705, 1519, 1453, 1377, 1231, 812, 744, 698 cm−1;
D
1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.57 (s, 3H, CH3), 2.20 (s, 3H, Ar–CH3), 2.98 (ABX-system,
2H, JAB=14.5 Hz, JAX=8.1 Hz, JBX=4.5 Hz, CHCH2Ph), 4.34–4.42 (m, 1H, CH), 5.08 (AB-system,
2H, J=12.8 Hz, COOCH2Ph), 6.59 (s, 1H, Ar–H), 6.87–6.95 (m, 3H, Ar–H), 7.09–7.14 (m, 3H, Ar–H),
7.31–7.38 (m, 7H, Ar–H), 8.44 (d broad, 1H, J=8.3 Hz, CONH), 10.59 (s broad, 1H, NH); MS (70 eV,
EI): m/z=458 (M+, 8%), 177 (100%); HRMS: calcd: 458.184172. Found: 458.183961. Anal. calcd for
C27H26N2O5·0.4H2O: C 69.67%, H 5.76%, N 6.02%. Found: C 69.98%, H 5.67%, N 5.51%.
3.41. N-{[(2R)-2,6-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-yl]carbonyl}-D-phenylalanine
benzyl ester (2R)-7cB
Prepared from (S)-5c (221 mg, 1 mmol); yield: 435 mg (95%), white solid foam; mp 44–48°C,
[α]20=+65.8 (c=0.11, MeOH); IR (KBr): ν 3256, 3032, 1702, 1609, 1518, 1454, 1379, 1231, 1168, 1026,
D
811, 741, 697 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.46 (s, 3H, CH3), 2.16 (s, 3H, Ar–CH3),
3.03 (ABX-system, 2H, JAB=13.7 Hz, JAX=9.8 Hz, JBX=5.3 Hz, CHCH2Ph), 4.44–4.51 (m, 1H, CH),
4.95 (AB-system, 2H, J=12.4 Hz, COOCH2Ph), 6.61–6.67 (m, 2H, Ar–H), 6.86 (d, 1H, J=8.3 Hz, Ar–H),
7.10–7.13 (m, 2H, Ar–H), 7.18–7.23 (m, 5H, Ar–H), 7.32–7.36 (m, 3H, Ar–H), 8.35 (d broad, 1H, J=8.3
Hz, CONH), 10.63 (s broad, 1H, NH); MS (70 eV, EI): m/z=458 (M+, 10%), 177 (100%); HRMS: calcd:
458.184172. Found: 458.185200. Anal. calcd for C27H26N2O5·0.5H2O: C 69.40%, H 5.78%, N 5.99%.
Found: C 69.61%, H 5.76%, N 5.86%.
3.42. N-{[(2R)-2,7-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-yl]carbonyl}-D-phenylalanine
benzyl ester (2R)-7dB
Prepared from (S)-5d (221 mg, 1 mmol); yield: 330 mg (72%), white solid foam; mp 43–45°C,
20
1
[α] =+29.0 (c=0.09, MeOH); IR (KBr): ν 3410, 1705, 1517, 1260, 1025, 799 cm−1; H NMR (300
D
MHz, DMSO-d6): δ (ppm) 1.47 (s, 3H, CH3), 2.15 (s, 3H, Ar–CH3), 3.03 (ABX-system, 2H, JAB=13.5
Hz, JAX=9.0 Hz, JBX=4.9 Hz, CHCH2Ph), 4.42–4.50 (m, 1H, CH), 4.92 (AB-system, 2H, J=12.6 Hz,
COOCH2Ph), 6.72–6.82 (m, 3H, Ar–H), 7.08–7.15 (m, 2H, Ar–H), 7.20–7.32 (m, 5H, Ar–H), 7.35–7.45
(m, 3H, Ar–H), 8.32 (d broad, 1H, J=8.3 Hz, CONH), 10.61 (s broad, 1H, NH); MS (70 eV, EI):

166
M. Breznik et al. / Tetrahedron: Asymmetry 10 (1999) 153–167
m/z=458 (M+, 10%), 177 (100%); HRMS: calcd: 458.184172. Found: 458.183074. Anal. calcd for
C27H26N2O5·0.9H2O: C 68.35%, H 5.86%, N 5.90%. Found: C 68.69%, H 5.60%, N 5.49%.
3.43. N-{[(2S)-6-Methoxy-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-yl]carbonyl}-D-phenyl-
alanine benzyl ester (2S)-7fB
Prepared from (R)-5f (237 mg, 1 mmol); yield: 0.380 mg (80%), white solid foam; mp 44–47°C,
[α]20=−10.3 (c=0.47, MeOH); IR (KBr): ν 3745, 1745, 1713, 1606, 1511, 1388, 1225, 1029, 800, 737
cm−D1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.56 (s, 3H, CH3), 3.00 (ABX-system, 2H, JAB=13.5 Hz,
J
AX=8.7 Hz, JBX=4.5 Hz, CHCH2Ph), 3.67 (s, 3H, OCH3), 4.35–4.42 (m, 1H, CH), 5.09 (AB-system,
2H, J=12.5 Hz, COOCH2Ph), 6.35 (d, 1H, J=2.9 Hz, Ar–H), 6.45 (dd, 1H, J=8.9 Hz, J=2.9 Hz, Ar–H),
6.92 (d, 1H, J=8.9 Hz, Ar–H), 6.93–6.97 (m, 2H, Ar–H), 7.07–7.13 (m, 3H, Ar–H), 7.29–7.41 (m, 5H,
Ar–H), 8.47 (d broad, 1H, J=8.1 Hz, CONH), 10.56 (s broad, 1H, NH); MS (70 eV, EI): m/z=474 (M+,
50%), 193 (100%). Anal. calcd for C27H26N2O6: C 68.35%, H 5.48%, N 5.90%. Found: C 68.08%, H
5.63%, N 6.06%.
3.44. N-{[(2R)-6-Methoxy-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-yl]carbonyl}-D-phenyl-
alanine benzyl ester (2R)-7fB
Prepared from (S)-5f (237 mg, 1 mmol); yield: 400 mg (84%), white crystals; mp 44–48°C (from
MeOH), [α]20=+58.9 (c=0.16, MeOH); IR (KBr): ν 3328, 2938, 1709, 1611, 1515, 1456, 1378, 1226,
D
1035, 741, 699 cm−1; 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.44 (s, 3H, CH3), 3.03 (ABX-system
2H, JAB=13.7 Hz, JAX=9.7 Hz, JBX=5.0 Hz, CHCH2Ph), 3.63 (s, 3H, OCH3), 4.52–4.44 (m, 1H, CH),
4.96 (AB-system, 2H, J=12.6 Hz, COOCH2Ph), 6.35–6.47 (m, 2H, Ar–H), 6.90 (d, 1H, J=8.7 Hz, Ar–H),
7.10–7.16 (m, 2H, Ar–H), 7.18–7.25 (m, 5H, Ar–H), 7.31–7.38 (m, 3H, Ar–H), 8.39 (d broad, 1H,
CONH, J=8.4 Hz), 10.60 (s broad, 1H, NH); HRMS: calcd: 474.180029. Found: 474.179087. Anal.
calcd for C27H26N2O6: C 68.35%, H 5.48%, N 5.90%. Found: C 67.85%, H 5.55%, N 5.39%.
3.45. General procedure for the synthesis of mixed anhydrides 8
Ethyl chloroformate (0.38 ml, 4 mmol) was added dropwise at −15°C to a stirred solution of (R)-
monomethyl 2-methyl-2-(2-nitrophenoxy)malonate (R)-3 (4 mmol) in ethanol free CHCl3 (20 ml). After
30 min, at which time thin layer chromatography (silica gel; CHCl3:MeOH, 9:1) indicated a complete
conversion of educt to the product 8, the reaction mixture was filtered and the filtrate was evaporated
in vacuo. The crude anhydride was almost pure on the basis of its proton NMR spectrum and was used
immediately in a further reaction.
8a (R1=H, R2=COOC2H5): 1H NMR (300 MHz, CDCl3): δ (ppm) 1.40 (t, 3H, J=7.1 Hz, CH2CH3),
1.88 (s, 3H, CH3), 3.88 (s, 3H, COOCH3), 4.38 (q, 2H, J=7.1 Hz, CH2CH3), 7.25 (ddd, 1H, J=8.4, 7.4,
0.9 Hz, Ar–H), 7.30 (dd, 1H, J=8.4, 0.9 Hz, Ar–H), 7.53 (ddd, 1H, J=8.1, 7.4, 1.7 Hz, Ar–H), 7.86 (dd,
1H, J=8.1, 1.7 Hz, Ar–H).
3.46. General procedure for the synthesis of N-hydroxysuccinimide esters 9
A solution of (R)-monomethyl 2-methyl-2-(2-nitrophenoxy)malonate (R)-3 (5 mmol) in dry tetrahy-
drofuran (50 ml) was cooled in an ice-water bath, then dicyclohexylcarbodiimide (1.03 g, 5 mmol) was
added with stirring and the mixture was kept at 0–5°C overnight. The separated N,N0-dicyclohexylurea

M. Breznik et al. / Tetrahedron: Asymmetry 10 (1999) 153–167
167
was removed by filtration and the solvent was evaporated in vacuo. The crude active ester was almost
pure on the basis of its proton NMR spectrum and was used immediately in a further reaction.
1
9a (R1=H, R2=succinimido): H NMR (300 MHz, DMSO-d6): δ (ppm) 1.86 (s, 3H, CH3), 2.84 (s,
4H, 2 CH2), 3.84 (s, 3H, COOCH3), 7.28 (d, 1H, J=8.4 Hz, Ar–H), 7.36 (ddd, 1H, J=8.1, 7.5, 1.0 Hz,
Ar–H), 7.68 (ddd, 1H, J=8.4, 7.5, 1.6 Hz, Ar–H), 7.96 (dd, 1H, J=8.1, 1.6 Hz, Ar–H).
3.47. General procedure for the synthesis of pentafluorophenyl esters 10
Pentafluorophenol (920 mg, 5 mmol) was added to an ice-cold solution of (R)-monomethyl 2-
methyl-2-(2-nitrophenoxy)malonate (R)-3 (5 mmol) in ethyl acetate (8 ml) followed by the addition of
dicyclohexylcarbodiimide (1.03 g, 5 mmol). The mixture was stirred for 6 h at −10°C and then kept at
0–5°C overnight. The separated N,N0-dicyclohexylurea was removed by filtration and the solvent was
evaporated in vacuo. The crude active ester was almost pure on the basis of its proton NMR spectrum
and was used immediately in a further reaction.
1
9a (R1=H, R2=C6F6): H NMR (300 MHz, CDCl3): δ (ppm) 1.98 (s, 3H, CH3), 3.92 (s, 3H,
COOCH3), 7.25–7.36 (m, 2H, Ar–H), 7.51–7.56 (m, 1H, Ar–H), 7.87–7.90 (dd, 1H, J=8.1, 1.7 Hz,
Ar–H).
Acknowledgements
This work was supported financially by the Ministry of Science and Technology of the Republic of
Slovenia. The authors thank the Faculty of Chemistry and Chemical Technology, University of Ljubljana
for microanalyses, and the J. Stefan Institute for mass spectra.
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