Domino Ring-Closing Enyne-Metathesis-Cross-Metathesis Approach to 1-Phosphonylated Benzazepines

Abstract

A short approach was developed towards phosphon­ylated benzazepines. Aminophosphonates containing an ‘yne’ and an ‘ene’ moiety were synthesised via phosphonylation of the ­corresponding imines. The key step in the reaction sequence is a domino enyne-metathesis-cross-metathesis.

Key words

domino reactions - enynes - fused-ring systems - meta­thesis - phosphorus

References and Notes

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18

Synthesis of Derivatives 3 from 4; General Procedure
To a solution of 4 (1 equiv) in anhyd CH₂Cl₂ (15 mL) was added the alkene (5 equiv). This mixture was refluxed under N₂ atmosphere and the second-generation Grubbs’ catalyst 2 (10 mol%) was added. The resulting solution was refluxed for 4 h. The residue was adsorbed onto silica gel and purified by flash chromatography. Synthesis of Derivatives 3 from 5; General Procedure
To a solution of 5 (1 equiv) in anhyd CH₂Cl₂ (15 mL) was added the alkene (5 equiv). This mixture was refluxed under N₂ atmosphere and the second-generation Grubbs’ catalyst 2 (10 mol%) was added. An additional amount of alkene (5 equiv) was added after 2 h and refluxing was continued for an additional 4 h. The residue was adsorbed onto silica gel and purified by flash chromatography. Dimethyl 2-Benzyl-5-[( E )-2-phenylvinyl]-2,3-dihydro-1 H -2-benzazepin-1-ylphosphonate: R _f = 0.27 (EtOAc-MeCN, 8:2). IR: 1031 (PO), 1057 (PO), 1247 (P=O), 1600 (C=C) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.79 (dd, J = 7.2 Hz, J = 11.6 Hz, 1 H, NCH _AH_BCH), 3.04 (dd, J = 7.2 Hz, J = 11.6 Hz, 1 H, NCH_A H _BCH), 3.50 (d, J = 10.5 Hz, 3 H, OCH₃), 3.62 (d, J = 12.6 Hz, 1 H, NCH _AH_BPh), 3.62 (d, J = 10.7 Hz, 3 H, OCH₃), 4.06 (d, J = 12.6 Hz, 1 H, NCH_A H _BPh), 4.35 (d, J = 25.0 Hz, 1 H, CHP), 6.30 (t, J = 7.2 Hz, 1 H, NCH₂CH), 6.67 (d, J = 16.2 Hz, 1 H, HC=CHPh), 7.00 (d, J = 16.2 Hz, 1 H, HC=CHPh), 7.16-7.47 (m, 13 H, 13 × ArCH), 7.53 (d, J = 7.2 Hz, 1 H, ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 50.14 (d, J = 5.8 Hz), 53.04 (d, J = 10.4 Hz), 61.48 (d, J = 11.5 Hz), 64.71 (d, J = 171.9 Hz), 126.58, 127.42, 127.96, 128.05, 128.32, 128.43, 128.69, 129.42, 129.50, 129.76, 131.44, 131.61 (d, J = 10.4 Hz), 133.13, 137.45, 138.14 (d, J = 6.9 Hz), 138.63, 143.58. ³¹P NMR (121.5 MHz, CDCl₃): δ = 26.30. MS (ESI): m/z (%) = 446.3 (M + H⁺, 100), 336.2 [M⁺ - P(O)(OMe)₂, 50].
Dimethyl 2-Benzyl-5-(3-trimethylsilanyl-propenyl)-2,3-dihydro-1 H -2-benzazepin-1-ylphosphonate: E/Z, 66:34. R _f = 0.47 (hexane-EtOAc, 2:8). IR: 1033 (PO), 1059 (PO), 1248 (P=O), 1636 (C=C) cm^-1. ¹³C NMR (75 MHz, CDCl₃): δ = 127.28, 127.45, 127.67, 127.80, 127.93, 128.35, 129.21, 129.30, 129.39, 129.45, 129.91, 130.86; where it was possible to assign the chemical shift to a specific isomer, the assignments are given below. ³¹P NMR (121.5 MHz, CDCl₃): δ = 26.33, 26.36. MS (ESI): m/z (%) = 456.2 (M + H⁺, 100), 346.3 [M⁺ - P(O)(OMe)₂, 53]. E-Isomer: ¹H NMR (300 MHz, CDCl₃): δ = 0.03 [s, 9 H, Si(CH₃)₃], 1.59 (d, J = 8.3 Hz, 2 H, CH₂Si), 2.75 (dd, J = 7.0 Hz, J = 11.7 Hz, 1 H, NCH _AH_BCH), 2.86 (dd, J = 7.0 Hz, J = 11.7 Hz, 1 H, NCH_A H _BCH), 3.49 (d, J = 10.5 Hz, 3 H, OCH₃), 3.54 (d, J = 13.2 Hz, 1 H, NCH _AH_BPh), 3.63 (d, J = 10.7 Hz, 3 H, OCH₃), 4.08 (d, J = 13.2 Hz, 1 H, NCH_A H _BPh), 4.29 (d, J = 25.0 Hz, 1 H, CHP), 5.81 (dt, J = 8.3 Hz, J = 15.5 Hz, 1 H, HC=CHCH₂), 5.99 (t, J = 7.0 Hz, 1 H, NCH₂CH), 6.09 (d, J = 15.5 Hz, 1 H, HC=CHCH₂), 7.25-7.46 (m, 18 H, 18 × ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = -1.67, 24.03, 50.12 (d, J = 6.9 Hz), 53.00 (d, J = 5.8 Hz), 53.07 (d, J = 5.8 Hz), 61.19 (d, J = 9.2 Hz), 64.41 (d, J = 168.4 Hz), 123.97, 131.04, 131.30 (d, J = 9.2 Hz), 132.92 (d, J = 2.3 Hz), 133.09 (d, J = 2.3 Hz), 138.83, 139.11 (d, J = 8.1 Hz), 139.79, 144.03. Z-Isomer: ¹H NMR (300 MHz, CDCl₃): δ = 0.02 [s, 9 H, Si(CH₃)₃], 1.64 (d, J = 9.0 Hz, 2 H, CH₂Si), 3.07 (dd, J = 6.4 Hz, J = 13.9 Hz, 1 H, NCH _AH_BCH), 3.17 (dd, J = 6.4 Hz, J = 13.9 Hz, 1 H, NCH_A H _BCH), 3.54 (d, J = 13.4 Hz, 1 H, NCH _AH_BPh), 3.54 (d, J = 10.4 Hz, 3 H, OCH₃), 3.69 (d, J = 10.5 Hz, 3 H, OCH₃), 4.04 (d, J = 13.4 Hz, 1 H, NCH_A H _BPh), 4.36 (d, J = 24.8 Hz, 1 H, CHP), 5.74 (dt, J = 9.0 Hz, J = 12.2 Hz, 1 H, HC=CHCH₂), 6.01 (t, J = 6.4 Hz, 1 H, NCH₂CH), 6.01 (d, J = 12.2 Hz, 1 H, HC=CHCH₂), 7.25-7.46 (m, 18 H, 18 × ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = -1.40, 19.67, 51.27 (d, J = 8.1 Hz), 52.96 (d, J = 6.9 Hz), 53.34 (d, J = 6.9 Hz), 60.30 (d, J = 8.1 Hz), 64.84 (d, J = 166.1 Hz), 130.91 (d, J = 8.1 Hz), 138.87, 139.95 (d, J = 8.1 Hz). Dimethyl 2-Benzyl-5-[(1 E )-5-oxohex-1-enyl]-2,3-dihydro-1 H -2-benzazepin-1-ylphosphonate: R _f = 0.27 (EtOAc-MeCN, 8:2). IR: 1031 (PO), 1057 (PO), 1249 (P=O), 1713 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.15 (s, 3 H, C=OCH₃), 2.42 (dt, J = 6.8 Hz, J = 6.8 Hz, 2 H, CH ₂CH₂C=O), 2.56 (t, J = 6.8 Hz, 2 H, CH₂CH ₂C=O), 2.73 (dd, J = 7.1 Hz, J = 11.9 Hz, 1 H, NCH _AH_BCH), 2.98 (dd, J = 7.1 Hz, J = 11.9 Hz, 1 H, NCH_A H _BCH), 3.47 (d, J = 10.5 Hz, 3 H, OCH₃), 3.59 (d, J = 13.1 Hz, 1 H, NCH _AH_BPh), 3.66 (d, J = 10.5 Hz, 3 H, OCH₃), 4.01 (d, J = 13.1 Hz, 1 H, NCH_A H _BPh), 4.29 (d, J = 25.0 Hz, 1 H, CHP), 5.79 (dt, J = 6.8 Hz, J = 15.5 Hz, 1 H, HC=CHCH₂), 6.08 (t, J = 7.1 Hz, 1 H, NCH₂CH), 6.26 (d, J = 15.5 Hz, 1 H, HC=CHCH₂), 7.23-7.41 (m, 9 H, 9 × ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 27.16, 30.06, 43.17, 50.07 (d, J = 5.8 Hz), 52.92 (d, J = 6.9 Hz), 53.07 (d, J = 8.1 Hz), 61.41 (d, J = 10.4 Hz), 64.91 (d, J = 171.9 Hz), 126.38, 127.35, 127.82, 128.37, 129.16, 129.45, 131.47, 131.53 (d, J = 9.2 Hz), 131.76, 132.98, 138.49 (d, J = 6.9 Hz), 138.69, 143.06, 208.13. ³¹P NMR (121.5 MHz, CDCl₃): δ = 26.22. MS (ESI): m/z (%) = 439.7 (M + H⁺, 10), 330 [M⁺ - P(O)(OMe)₂, 100].
Dimethyl 2-Benzyl-5-[(1 Z )-5-oxohex-1-enyl]-2,3-dihydro-1 H -2-benzazepin-1-ylphosphonate:
R _f = 0.27 (EtOAc-MeCN, 8:2). IR: 1030 (PO), 1058 (PO), 1252 (P=O), 1714 (C=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.10 (s, 3 H, C=OCH₃), 2.34-2.53 (m, 4 H, CH₂CH₂C=O), 3.01 (dd, J = 6.1 Hz, J = 13.8 Hz, 1 H, NCH _AH_BCH), 3.29 (dd, J = 6.1 Hz, J = 13.8 Hz, 1 H, NCH_A H _BCH), 3.53 (d, J = 10.5 Hz, 3 H, OCH₃), 3.66 (d, J = 13.2 Hz, 1 H, NCH _AH_BPh), 3.71 (d, J = 10.4 Hz, 3 H, OCH₃), 3.94 (d, J = 13.2 Hz, 1 H, NCH_A H _BPh), 4.36 (d, J = 24.8 Hz, 1 H, CHP), 5.61 (dt, J = 7.0 Hz, J = 11.4 Hz, 1 H, HC=CHCH₂), 6.00 (t, J = 6.1 Hz, 1 H, NCH₂CH), 6.13 (d, J = 11.4 Hz, 1 H, HC=CHCH₂), 7.26-7.38 (m, 9 H, 9 × ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 23.28, 29.90, 43.68, 50.87 (d, J = 6.9 Hz, 52.97 (d, J = 6.9 Hz, 53.29 (d, J = 8.1 Hz), 61.02 (d, J = 9.2 Hz), 65.75 (d, J = 167.3 Hz), 127.33, 127.70, 128.02, 128.37, 128.81, 129.16, 129.39, 131.16, 131.41 (d, J = 9.2 Hz), 131.59, 133.10, 138.74, 139.22 (d, J = 8.1 Hz), 139.53, 208.25. ³¹P NMR (121.5 MHz, CDCl₃): δ = 25.89. MS (ESI): m/z (%) = 439.7 (M + H⁺, 13), 330 [M⁺ - P(O)(OMe)₂, 100].
Dimethyl 2-(4-Bromobenzyl)-4-[(1 E )-4-fenylvinyl]-2,3-dihydro-1 H -2-benzazepin-1-ylphosphonate: R _f = 0.20 (hexane-EtOAc, 4:6). IR: 1031 (PO), 1057 (PO), 1250 (P=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.52 (d, J = 13.6 Hz, 1 H, NCH _AH_BPh), 3.65 (d, J = 10.7 Hz, 3 H, OCH₃), 3.68 (d, J = 11.0 Hz, 3 H, OCH₃), 3.75 (d, J = 13.5 Hz, 1 H, NCH_A H _BPh), 3.95 (d, J = 18.4 Hz, 1 H, NCH _AH_BC), 4.37 (d, J = 18.4 Hz, 1 H, NCH_A H _BC), 4.47 (d, J = 27.5 Hz, 1 H, CHP), 6.46 (d, J = 16.4 Hz, 1 H, HC=CHPh), 6.68 (s, 1 H, C=CHC), 6.89 (d, J = 16.4 Hz, 1 H, HC=CHPh), 7.10-7.42 (m, 13 H, 13 × ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 53.08 (d, J = 6.9 Hz), 53.65 (d, J = 4.6 Hz), 53.72 (d, J = 6.9 Hz), 57.07, 64.14 (d, J = 155.8 Hz), 121.25, 126.46, 127.33, 127.68, 128.06, 128.09, 128.92, 130.55, 130.92, 131.54, 132.31 (d, J = 4.6 Hz), 132.52, 132.83, 133.74, 136.28 (d, J = 8.1 Hz), 136.57, 137.33, 137.71, 139.27. ³¹P NMR (121.5 MHz, CDCl₃): δ = 25.29. MS (ESI): m/z (%) = 524.03/526.3 (M + H⁺, 60), 414.2/416.2 [M⁺ - P(O)(OMe)₂, 100].
Dimethyl 2-(4-Bromobenzyl)-4-[(1 E )-4-bromobut-1-enyl]-2,3-dihydro-1 H -2-benzazepin-1-ylphosphonate: R _f = 0.29 (hexane-EtOAc, 4:6). IR: 1031 (PO), 1058 (PO), 1252 (P=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.67 (q, J = 7.0 Hz, 2 H, CH ₂CH₂Br), 3.40 (t, J = 7.0 Hz, 2 H, CH₂Br), 3.46 (d, J = 13.5 Hz, 1 H, NCH _AH_BPh), 3.63 (d, J = 10.7 Hz, 3 H, OCH₃), 3.68 (d, J = 10.8 Hz, 3 H, OCH₃), 3.71 (d, J = 13.5 Hz, 1 H, NCH_A H _BPh), 3.79 (d, J = 18.6 Hz, 1 H, NCH _AH_BC), 4.22 (d, J = 18.6 Hz, 1 H, NCH_A H _BC), 4.38 (d, J = 27.8 Hz, 1 H, CHP), 5.54 (dt, J = 7.0 Hz, J = 15.8 Hz, 1 H, HC=CHCH₂), 6.23 (d, J = 15.8 Hz, 1 H, HC=CHCH₂), 6.49 (s, 1 H, C=CHC), 7.10-7.46 (m, 8 H, 8 × ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 32.39, 36.61, 53.07 (d, J = 6.9 Hz), 53.68 (d, J = 5.8 Hz), 53.68, 57.01, 63.98 (d, J = 154.6 Hz), 121.19, 125.74, 127.21, 128.02, 130.48, 130.89, 131.50, 132.67, 133.62 (d, J = 2.3 Hz), 136.20 (d, J = 6.9 Hz), 136.57, 137.68, 138.67. ³¹P NMR (121.5 MHz, CDCl₃): δ = 25.24. MS (ESI): m/z (%) = 554.0/556.0/558.0 (M + H⁺, 35), 444.0/446.0/448.0 [M⁺ - P(O)(OMe)₂, 100].
Dimethyl 2-(4-Bromobenzyl)-4-[(1 E )-hex-1-enyl]-2,3-dihydro-1 H -2-benzazepin-1-ylphosphonate: R _f = 0.27 (hexane-EtOAc, 4:6). IR: 1031 (PO), 1058 (PO), 1253 (P=O) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.90 (t, J = 7.0 Hz, 3 H, CH₃), 1.25-1.43 (m, 4 H, CH₂CH₂CH₃), 2.11 (q, J = 6.9 Hz, 2 H, HC=CHCH ₂), 3.46 (d, J = 12.4 Hz, 1 H, NCH _AH_BPh), 3.64 (d, J = 10.7 Hz, 3 H, OCH₃), 3.68 (d, J = 12.1 Hz, 3 H, OCH₃), 3.72 (d, J = 12.4 Hz, 1 H, NCH_A H _BPh), 3.80 (d, J = 18.4 Hz, 1 H, NCH _AH_BC), 4.19 (d, J = 18.4 Hz, 1 H, NCH_A H _BC), 4.39 (d, J = 27.5 Hz, 1 H, CHP), 5.60 (dt, J = 6.9 Hz, J = 16.0 Hz, 1 H, HC=CHCH₂), 6.13 (d, J = 16.0 Hz, 1 H, HC=CHCH₂), 6.44 (s, 1 H, C=CHC), 7.11-7.40 (m, 8 H, 8 × ArCH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.06, 22.35, 31.63, 33.08, 53.00 (d, J = 6.9 Hz), 53.73 (d, J = 8.1 Hz), 53.83 (d, J = 6.9 Hz), 56.80, 63.97 (d, J = 155.8 Hz), 121.18, 126.83, 127.97, 129.85, 130.52, 130.98, 131.45, 133.22, 132.38, 133.64, 136.54 (d, J = 6.9 Hz), 137.76, 139.32. ³¹P NMR (121.5 MHz, CDCl₃): δ = 25.29. MS (ESI): m/z (%) =504.6/506.2 (M + H⁺, 60), 394.2/396.3 [M⁺ - P(O)(OMe)₂, 100].