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

Nicolai Dieltiens; Christian V. Stevens

doi:10.1055/s-2006-950262

LETTER

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

Nicolai Dieltiens, Christian V. Stevens*
Research Group SynBioc, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: chris.stevens@UGent.be;

Abstract

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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

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References

References and Notes

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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].