L. Banfi, A. Basso, L. Giardini, R. Riva, V. Rocca, G. Guanti
FULL PAPER
(2R,S)-N-Cyclohexyl-2-{(2R)-2-methyl-3-oxo-2H-benzo[b][1,4]-
oxazin-4(3H)-yl}-2-phenylacetamides (1n): The two diastereoiso-
mers (A/B, 72:28) could not be separated. Rf = 0.38 (PE/AcOEt,
1
Rf = 0.63 (PE/AcOEt, 50:50). H NMR (300 MHz, CDCl3, 50 °C,
only the signals for the major diastereoisomer are reported): δ =
0.86 (t, J = 7.2 Hz, CH3CH2), 1.15–1.48 (m, 4 H, CH2CH2CH3),
75:25). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 0.80–1.45 (m, 5 1.41 [s, 9 H, (CH3)3C], 2.07–2.21 (m, 2 H, OCH–CH2), 3.15–3.50
H), 1.57 (diast. A, d, J = 6.9 Hz, 2.16 H, CH3), 1.64 (diast. B, d,
J = 6.9 Hz, 0.84 H, CH3), 1.50–2.00 (m, 5 H), 3.75–3.94 (m, 1 H,
CHNH), 4.66 (diast. B, q, J = 6.8 Hz, 0.28 H, CHCH3), 4.76 (diast.
A, q, J = 6.8 Hz, 0.72 H, CHCH3), 5.90 (diast. B, br. d, J = 8.1 Hz,
0.28 H, NH), 5.95 (diast. A, br. d, J = 8.4 Hz, 0.72 H, NH), 6.11
(diast. A, s, 0.72 H, CHAr), 6.15 (diast. B, s, 0.28 H, CHAr), 6.80–
7.06 (m, 4 H, CH benzoxazinone), 7.28–7.38 (m, 5 H, CH phenyl)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 16.06 (A), 16.1 (B,
CH3), 24.6 (ϫ2), 25.4, 32.5 (A), 32.6 (B), 32.7 (cyclohexyl CH2),
48.5 (A), 48.6 (B, CHN), 61.3 (B), 61.6 (A, CHAr), 74.0 (A), 74.1
(m, 4 H, CH2NH), 4.72 (dd, J = 5.4, 6.9 Hz., 1 H, 2-H), 4.76 (br.
s, 1 H, NHBoc), 6.26 (s, 1 H, CHAr), 6.37 (br. t, J = 4.8 Hz, 1 H
NHCH2), 6.85–6.94 (m, 1 H), 6.95–7.05 (m, 3 H), 7.19 (t, J =
7.8 Hz, 1 H, 5Ј-H), 7.22–7.29 (m, 1 H, 6Ј-H), 7.42 (d, J = 7.8 Hz,
1 H, 4Ј-H), 7.53 (s, 1 H, 2Ј-H) ppm. 13C NMR (75 MHz, CDCl3,
50 °C, only the signals for the major diastereoisomer are reported):
δ = 13.6 (CH2CH3), 20.0 (CH2CH3), 28.4 [C(CH3)3], 30.6 (OCH-
CH2), 31.4 (NCH2CH2), 36.8 (br., CH2NHBoc), 39.8 (other
CH2NH), 60.2 (CHAr), 76.0 (2-C), 79.5 [very br., C(CH3)3], 117.4,
117.7, 123.0, 124.9 (C-5, C-6, C-7, C-8), 122.8 (C-Br), 126.3 (C-6Ј),
(B, CHCH3), 117.0 (A), 117.3 (B), 117.49 (B), 117.54 (A), 122.5 128.2 (C-4a), 130.1 (C-5Ј), 130.9 (C-2Ј), 131.3 (C-4Ј), 136.4 (C-1Ј),
(B), 122.7 (A), 124.4 (B), 124.5 (A, C-5, C-6, C-7, C-8), 127.6
(A+B, C-3Ј), 127.9 (A+B, C-4Ј), 128.19 (B), 128.21 (A, C-5a), 128.8
(B), 128.9 (A, C-2Ј), 134.1 (A+B, C-1Ј), 144.8 (A), 145.3 (B, C-8a),
166.75 (B), 166.80 (A), 168.5 (A), 168.6 (B, C=O) ppm. (C-5), 124.6
(C-4a or C-6a), 126.3 (C-7), 128.3 (C-2Ј or C-3Ј), 128.5 (C-4a or
C-6a), 128.8 (C-4Ј), 129.2 (C-2Ј or C-3Ј), 129.6 (C-2Ј or C-3Ј), 134.0
144.8 (C-8a), 155.9, 167.1, 167.8 (C=O) ppm. IR (CHCl ): ν
=
˜
3
max
3668, 3583, 3451, 2999, 2707, 1685, 1594, 1492, 1390, 1366, 1158,
1028, 922 cm–1 HRMS (ESI+): calcd. for C27H35BrN3O5 560.1760
.
[M + H]+; found 560.1756.
N-(4-Carboxyphenyl)-3-methyl-2-{3-oxo-2H-benzo[b][1,4]oxazin-
4(3H)-yl}butanamide (1q): Rf = 0.40 (PE/AcOEt, 1:1). 1H NMR
(300 MHz, CDCl3, 55 °C): δ = 0.79 (d, J = 6.6 Hz, 3 H, CH3), 1.14
(d, J = 6.6 Hz, 3 H, CH3), 2.99 [mc, 1 H, CH(CH3)2], 4.60 and 4.66
(AB system, J = 15.6 Hz, 2 H, CH2O), 4.50–4.75 (very br. signal,
1 H, CH–iPr), 4.90–5.50 (very br. signal, 1 H, CO2 H), 6.99–7.10
(m, 3 H), 7.52–7.61 (m, 1 H), 7.64 (d, J = 8.6 Hz, 2 H, H meta to
CO2 H), 8.05 (d, J = 8.6 Hz, 2 H, H ortho to CO2 H), 9.17 (br. s,
1 H, NH) ppm. 13C NMR (75 MHz, CDCl3, 55 °C): δ = 18.5, 20.2
(CH3), 25.9 [CH(CH3)2], 68.8 (CH2O), 117.4, 117.9, 119.3 (ϫ2),
123.5, 125.4, 131.5 (ϫ2, aromatic CH), 125.2, 128.9 (very br.),
142.7, 146.5 (aromatic quat.), 165.8, 168.1, 169.4 (C=O) ppm. Note:
As a result of restricted rotation, the signals of CH–iPr and of C-
4a are very broad, and the first of them could not be detected by
(C-1Ј), 149.6 (C-8a), 165.2, 166.0, 166.1 (C=O). IR (CHCl ): ν
˜
3
max
= 3670, 3418, 3006, 2854, 1675, 1601, 1493, 1448, 1378, 1210, 1110,
1028, 918, 821 cm–1 GC–MS: tR = 11.29 min. MS: m/z (%) = 378
.
(4.1) [M]+, 253 (100.0), 224 (5.8), 152 (5.2), 120 (63.1), 118 (5.0),
106 (6.6), 91 (75.0), 90 (9.8), 83 (5.4), 77 (8.5), 65 (7.9), 55 (19.5),
41 (13.5), 39 (5.2). HRMS (ESI+): calcd. for C23H26N2O3Na
401.1841 [M + Na]+; found 401.1822.
(2R,S)-N-Butyl-2-{(2R)-6-chloro-2-methyl-3-oxo-2H-benzo[b][1,4]-
oxazin-4(3H)-yl}-3-methylbutanamides (1o): The two diastereoiso-
mers (A/B, 64:36) could not be separated. Rf = 0.80 (PE/AcOEt,
50:50). 1H NMR (300 MHz, [D6]DMSO, 40 °C): δ = 0.58 (diast.
B, d, J = 6.6 Hz, 1.08 H, CH3CHCH3), 0.68 (diast. A, d, J =
6.6 Hz, 1.92 H, CH3CHCH3), 0.74 (diast. A, t, J = 7.2 Hz, 1.92 H,
CH3CH2), 0.80 (diast. B, t, J = 7.2 Hz, 1.08 H, CH3CH2), 1.046
(diast. A, d, J = 6.3 Hz, 1.92 H, CH3CHCH3), 1.051 (diast. B, d,
J = 6 . 3 Hz , 1 . 0 8 H , CH3 CHCH 3 ) , 1 . 1 0– 1. 37 (m , 4 H,
CH2CH2CH3), 1.44 (diast. A, d, J = 6.9 Hz, 1.92 H, CH3CH), 1.47
(diast. B, d, J = 6.9 Hz, 1.08 H, CH3CH), 2.42–2.56 [diast. B, m,
0.36 H, CH(CH3)2], 2.63 [diast. A, dsept, J = 6.6 (sept), 10.6 Hz
(d), 0.64 H, CH(CH3)2], 2.83–2.95 (diast. A, m, 0.64 H, CHHNH),
2.93–3.05 (diast. B, m, 0.36 H, CHHNH), 3.08–3.24 (diast. A + B,
m, 1 H, CHHNH), 4.74 (diast. B, q, J = 6.6 Hz, 0.36 H, CHCH3),
4.79 (diast. A, q, J = 6.6 Hz, 0.64 H, CHCH3), 4.88 (diast. A, d, J
= 10.6 Hz, 0.64 H, CH–iPr), 4.96 (diast. B, d, J = 10.6 Hz, 0.36 H,
CH–iPr), 7.01–7.12 (m, 2 H, 7-H and 8-H), 7.50 (diast. A, d, J =
1.8 Hz, 0.64 H, 5-H), 7.61 (diast. B, d, J = 1.8 Hz, 0.36 H, 5-H),
7.94 (diast. A, br. d, J = 5.7 Hz, 0.64 H, NH), 8.03 (diast. B, br. d,
J = 5.4 Hz, 0.36 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO,
40 °C): δ = 13.3 (A + B, CH2CH3), 15.5 (A), 15.9 (B, CH3CH),
17.8 (A + B, CH2CH3), 19.0 (A), 19.2 (B), 20.6 (B), 20.9 (A) [(CH3)2-
CH], 25.4 (B), 26.2 (A) [CH(CH3)2], 30.6 (A + B, NCH2CH2), 38.1
(A), 38.3 (B, CH2NH), 60.3 (B), 61.0 (A, CH–iPr), 72.8 (A), 73.1
(B, CHCH3), 116.5 (A), 117.0 (B, C-5), 118.1 (B), 118.2 (A), 123.3
(A), 123.5 (B, C-7 and C-8), 125.7 (B), 125.8 (A), 128.8 (A), 129.3
(B, C-4a and C-6), 143.3 (A), 143.9 (B, C-8a), 167.06 (A), 167.14
13C NMR spectroscopy. IR (CHCl ): ν
= 3674, 3510, 3261,
˜
3
max
2961, 2661, 1676, 1593, 1496, 1387, 1357, 1309, 1265, 1170, 1114,
1040, 918, 854 cm–1 HRMS (ESI–): calcd. for C20H19N2O5
.
367.1294 [M – H]+; found 367.1302.
N-[2-(4-Hydroxyphenyl)ethyl]-2-{3-oxo-2H-benzo[b][1,4]oxazin-
4(3H)-yl}-2-phenylacetamide (1r): Rf = 0.37 (PE/AcOEt, 1:1). 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 2.68 (t, J = 6.9 Hz, 2 H,
NHCH2CH2), 3.53 (q, J = 6.5 Hz, 2 H, NHCH2), 4.58 and 4.68
(AB system, J = 15.3 Hz, 2 H, CH2O), 5.97 (s, 1 H, CHPh), 6.10
(t, J = 5.7 Hz, 1 H, NH), 6.24 (br. s, 1 H, OH), 6.67 (d, J = 7.8 Hz,
2 H, H ortho to OH), 6.82–7.03 (m, 6 H), 7.24–7.35 (m, 5 H) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 34.3 (CH2CH2NH), 41.3
(CH2NH), 61.9 (CHPh), 68.1 (CH2O), 115.5 (ϫ2), 117.0, 117.2,
122.8, 124.6, 127.9 (ϫ2), 128.5, 129.0 (ϫ2), 129.7 (ϫ2, aromatic
CH), 128.7, 129.7, 133.7, 145.8, 154.7 (aromatic quat.), 166.5, 167.9
(C=O) ppm. IR (CHCl ): ν
= 3661, 3588, 3418, 3308, 3030,
˜
3
max
3004, 1672, 1604, 1490, 1400, 1338, 1202, 1052, 921 cm–1 HRMS
.
(ESI+): calcd. for C24H22N2O4Na 425.1477 [M + Na]+; found
425.1466.
2-(3-Furyl)-N-[2-(4-hydroxyphenyl)ethyl]-2-{3-oxo-2H-benzo[b][1,4]-
oxazin-4(3H)-yl}acetamide (1s): Rf = 0.37 (PE/AcOEt, 1:1). 1H
NMR (300 MHz, CDCl3 , 25 °C): δ = 2.60–2.77 (m, 2 H,
NHCH2CH2), 3.47 [dq, J = 6.6 Hz (q), 13.2 (d), 1 H, NHCHH],
3.56 [dq, J = 6.6 Hz (q), 13.2 (d), 1 H, NHCHH], 3.60 [dq, J =
6.6 Hz (q), 13.2 (d), 1 H, NHCHH], 4.52 and 4.67 (AB system, J
= 15.3 Hz, 2 H, CH2O), 6.04 (br. s, 1 H, OH), 6.19 (t, J = 5.6 Hz,
1 H, NH), 6.24–6.27 (m, 2 H, 4-H of furyl and CHAr), 6.67 (d, J
= 8.4 Hz, 2 H, H ortho to OH), 6.88 (d, J = 8.4 Hz, 2 H, H meta
to OH), 6.85–7.04 (m, 4 H), 7.33 (t, J = 1.8 Hz, 1 H, H furyl), 7.64
(B), 167.6 (A), 168.1 (B, C=O) ppm. IR (CHCl ): ν
= 3673,
˜
3
max
3599, 3403, 2997, 2872, 1670, 1602, 1489, 1435, 1370, 1231, 1111,
1029, 924 cm–1 HRMS (ESI+): calcd. for C18H25ClN2O3Na
.
375.1541 [M + Na]+; found 375.1457.
(2R,S)-2-(3-Bromophenyl)-2-{(2R)-2-[(2-tert-butoxycarbonylamino)-
ethyl]-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl}-N-butylacetamides
(1p): The two diastereoisomers (A/B, 84:16) could not be separated.
106
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Eur. J. Org. Chem. 2011, 100–109