Oxazepinones

A simple way to synthesis of [1,4]-oxazepine-7-ones started from Baylis-Hillman reaction.

(责嚆戾眚).

2-[(2-Hydroxymethyl-piperidin-1-ylmethyl)-3-(4-nitrophenyl)-acrylic acid methyl ester 3g.Yield 75%, (E:88%, Z:12%).

^{1H NMR (250 MHz, CDCl₃) d
1.17-1.70 (m, 6H, piperidine-CH_2,(E) and (Z)-isomeres), 1.79-1.89 (m, 1H, NCH₂, (E)-isomer), 1.97-2.04 (m, 1H, NCH₂, (Z)-isomer), 2.18-2.26 (m, 1H, NCH, (E)-isomer), 2.35-2.38 (m, 1H, NCH, (E)-isomer), 2.73-2.81 (m, 1H, NCH₂, (E)-isomer), 2.83-2.95 (m, 1H, NCH₂, (Z)-isomer), 3.03 (d, 1H, C-CH₂, J=13.3, (Z)-isomer), 3.15 (d, 1H, C-CH₂, J=13.0, (E)-isomer), 3.40 (dd, 1H, CH₂OH, J=3.5, J=11.8, (E)-isomer), 3.50 (dd, 1H, CH₂OH, J=3.9, J=13.5, (Z)-isomer), 3.67 (s, 3H, COOMe, (Z)-isomer), 3.68-3.74, 3.87-4.06 (two m, 1H+1H, C-CH₂ and CH₂OH, (E) and (Z)-isomeres), 3.85 (s, 3H, COOMe, (E)-isomer), 6.80 (s, 1H, CH=C, (Z)-isomer), 7.37-7.40 (m, 2H, Ar-CH, (Z)-isomer), 7.49-7.54 (m, 2H, Ar-CH, (E)-isomer), 7.76 (s, 1H, CH=C, (E)-isomer), 8.14-8.21 (m, 2H, Ar-CH, (Z)-isomer), 8.22-8.27 (m, 2H, Ar-CH, (E)-isomer).

^{13C NMR (63 MHz, CDCl₃) d
23.56, 24.33 (-, piperidin-C, (Z)-isomer), 23.63, 24.25, 27.38 (-, piperidine-C, (E)-isomer), 48.05 (-, NCH₂, (E)-isomer), 51.17 (-, CCH₂, (E)-isomer), 51.55 (-, NCH₂, (Z)-isomer), 52.09 (+, OMe, (Z)-isomer), 52.55 (+, OMe, (E)-isomer), 57.50 (-, CCH₂, (Z)-isomer), 61.54 (+, NCH, (Z)-isomer), 62.16 (+, NCH, (E)-isomer), 62.64 (-, CH₂OH, (E)-isomer), 123.52 (+, 2C, Ar-CH, (Z)-isomer), 123.66 (+, 2C, Ar-CH, (E)-isomer), 129.03 (+, 2C, Ar-CH, (Z)-isomer), 130.08 (+, 2C, Ar-CH, (E)-isomer), 131.84 (+, CH=C (Z)-isomer), 134.57 (C_quat, CH=C, (E)-isomer), 137.06 (C_quat, CH=C, (Z)-isomer), 138.48 (+, CH=C (E)-isomer), 141.85, 147.51 (C_quat, Ar-C, (E)-isomer), 142.21, 147.23 (C_quat, Ar-C, (Z)-isomer), 168.28 (C_quat, C=O, (E)-isomer), 169.00 (C_quat, C=O, (Z)-isomer).
MS m/e 335.3 [MH⁺], 305.3, 303.3 [M⁺-OMe], 273.2, 116.1.}HRMS m/e calculated for C₁₇H₂₂N₂O₅: 334.15287, found 334.15263.

2-{[(2-Hydroxyethyl)-methylamino]-methyl}-3-(4-methylphenyl)-acrylic acid methyl ester 3j. Yield 97%, (pure E-isomer).

1H NMR (250MHz, CDCl₃) d
2.13 (s, 3H, NMe), 2.33 (s, 3H, Ar-Me), 2.49-2.53 (m, 2H, NCH₂), 2.96 (bs, 1H, OH), 3.46 (s, 2H, C-CH₂), 3.56-3.60 (m, 2H, CH₂OH), 3.79 (s, 3H, OMe), 7.15-7.18, 7.31-7.35 (two m, 2H+2H, Ar-CH), 7.77 (s, 1H, CH=C).

^{13C NMR (63 MHz, CDCl₃) d
21.32 (+, Ar-Me), 41.64 (+, NMe), 52.09 (+, COOMe), 52.20 (-, NCH₂), 58.65 (-, C-CH₂), 58.66 (-, CH₂OH), 129.21 (+, 2C, Ar-CH), 129.59 (C_quart, CH=C), 129.82 (+, 2C, Ar-CH), 132.23 (C_quart, Ar-C), 139.01 (C_quat, Ar-C), 142.48 (+, CH=C), 169.02 (C_quat, C=O).}MS m/e 264.2 [MH⁺], 232.1 [M⁺-OMe], 208.2.
Anal. calcd. for C₁₅H₂₁NO₃: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.07; H, 8.26; N, 5.64.

3,4-Tetramethylene-6-(2-(4-nitrophenyl)-1-ylmethyl)-[1,4]-oxazepine-7-one 2e. Yield 60%, mp 110-115^OC, (pure (E)-isomer).

^{1H NMR (250 MHz, CDCl₃) d
1.12-1.89 (m, 6H, piperidine-CH₂), 2.23-2.38 (m, 1H+1H, NCH and NCH₂), 2.92 (d, 1H, J=11.1 Hz, NCH), 3.19 (bd, 1H, J=14.1, CCH₂), 3.38-3.48 (m, 1H, CCH₂), 4.04-4.16 (m, 1H, CH₂O), 4.19-4.24 (m, 1H, CH₂O), 7.25 (s, 1H, CH=C), 7.66 (d, 2H, J=8.7 Hz, Ar-CH), 8.22-8.32 (m, 2H, Ar-CH).
^{13C NMR (63 MHz, CDCl₃) d
24.00, 25.68, 28.84 (-, piperidine-C), 55.09 (-, NCH₂), 55.50 (-, NCH₂), 63.71 (+, NCH), 72.33 (-, CH₂O), 123.82, 130.41 (+, 2C+2C, Ar-CH), 135.22 (+, CH=C), 137.62 (C_quat, CH=C), 141.03, 147.54 (C_quat, Ar-C), 172.25 (C_quat, C=O).}}MS m/e 303.2 [MH⁺], 273.2, 168.1, 98.0.

Anal. calcd. for C₁₆H₁₈N₂O₄: C, 63.45; H, 6.00; N, 9.27. Found: C, 63.45; H, 6.22; N, 9.07.

3,4-Tetramethylene-6-(2-(4-methylphenyl)-1-ylmethyl)-[1,4]-oxazepine-7-one 2f. Yield 75%, mp 118-120^OC, (pure (E)-isomer).

1H NMR (250MHz, CDCl₃) d
1.23-1.86 (m, 6H, piperidine-CH₂), 2.22-2.34 (m, 1H+1H, NCH and NCH₂), 2.38 (s, 3H, Ar-Me), 2.92 (d, 1H, J=10.9 Hz, NCH), 3.19 (bd, 1H, J=13.3, CCH₂), 3.53 (dd, 1H, J=0.7, J=14.6, CCH₂), 3.99-4.06 (m, 1H, CH₂O), 4.20 (d, 1H, J=13.0, CH₂O), 7.21 (d, 2H, J=7.8 Hz, Ar-CH), 7.26 (s, 1H, CH=C), 7.37 (d, 2H, J=8.0, Ar-CH).

13C NMR (63 MHz, CDCl₃) d
21.38 (+, Ar-Me), 24.15, 25.72, 28.96 (-, piperidine-C), 55.39 (-, NCH₂), 55.55 (-, NCH₂), 63.79 (+, NCH), 71.83 (-, CH₂O), 129.35, 129.84 (+, 2C+2C, Ar-CH), 131.99 (C_quat, CH=C), 132.74, 139.04 (C_quat, Ar-C), 137.94 (+, CH=C), 173.36 (C_quat, C=O).

MS m/e 272.3 [MH⁺].
Anal. calcd. for C₁₇H₂₁NO₂: C, 75.24; H, 7.80; N, 5.16. Found: C, 75.17; H, 7.76; N, 5.17.

3,4-Tetramethylene-6-benzyl-[1,4]-oxazepine-7-one 10a. Yield 52%, m.p. 96-98^OC.
1H NMR (250 MHz, CDCl₃) d
1.09-1.78 (m, 6H, piperidine-CH₂), 2.03 (dt, 1H, J=3.3, 11.6 Hz, PhCH₂CH ), 2.21 (t, 1H, J=8.6 Hz, NCH), 2.34 (dd, 1H, J=9.5, 12.8 Hz, PhCH₂), 2.58 (dd, 1H, J=10.2, 16.0 Hz, PhCH₂), 2.73 (t, 2H, J=10.7 Hz, NCH₂CH₂), 3.25 (dd, 2H, J=5.7, 16.1 Hz, NCH₂CH), 3.90 (d, 1H, J=13.2 Hz, OCH₂), 4.25 (dd, 1H, J=8.6, 13.3, OCH₂), 7.18-7.33 (m, 5H, Ph).

^{13C NMR (63 MHz, CDCl₃) d
23.82, 25.37, 28.85 (-, piperidine-C), 36.25 (-, CH₂Ph), 44.99 (+, PhCH₂CH), 56.05 (-, NCH₂), 58.14 (-, NCH₂), 63.31 (+, NCH), 72.79 (-, CH₂O), 126.47 (+, 1C, Ph-CH), 128.51, 129.39 (+, 2C, Ph-CH), 138.92 (C_quat, Ar-C), 176.16 (C_quat, C=O).

MS m/e 260.2 [MH⁺].
HRMS calcd for C₁₆H₂₁NO₂259.15723 Found 259.15741}}