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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Referenzen

References and Notes

1 Horton DA. Bourne GT. Smythe ML. Chem. Rev. 2003, 103: 893

2a Arany A. Groundwater PW. Nyerges M. Tetrahedron Lett. 1998, 39: 3267

2b Arany A. Bendell D. Groundwater PW. Garnett I. Nyerges M. J. Chem. Soc., Perkin Trans. 1 1999, 2605

2c Gerdes K. Sagar P. Fröhlich R. Wibbeling B. Würthwein E.-U. Eur. J. Org. Chem. 2004, 3465

2d Sajitz M. Fröhlich R. Salorinne K. Würthwein E.-U. Synthesis 2006, 2183

3a Van Otterlo WAL. Pathak R. de Koning CB. Synlett 2003, 1859

3b Toda N. Tago K. Marumoto S. Takami K. Ori M. Yamada N. Koyama K. Naruto S. Abe K. Yamazaki R. Hara T. Aoyagi A. Abe Y. Kaneko T. Kogen H. Bioorg. Med. Chem. 2003, 11: 4389

For recent reviews on ring-closing metathesis, see:

4a Schrock RR. Hoveyda AH. Angew. Chem. Int. Ed. 2003, 42: 4592

4b Grubbs RH. Tetrahedron 2004, 60: 7117

4c Deiters A. Martin F. Chem. Rev. 2004, 104: 2199

4d Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed. 2005, 44: 4490

4e Dragutan I. Dragutan V. Filip P. Arkivoc 2005, (x): 105

5 For a review on the use of Fisher carbene complexes for heterocyclisation, see: Barluenga J. Martinez S. Arkivoc 2006, (vii): 129

6 Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett. 1999, 1: 953

7 Moonen K. Laureyn I. Stevens CV. Chem. Rev. 2004, 104: 6177

8 Gaffar A. inventors; US 5753633. ; Chem. Abstr. 1998, 129, 8161

9 Danikiewicz W. Makosza M. J. Org. Chem. 1991, 56: 1283

10a Dieltiens N. Stevens CV. De Vos D. Allaert B. Drozdzak R. Verpoort F. Tetrahedron Lett. 2004, 45: 8995

10b Dieltiens N. Stevens CV. Allaert B. Verpoort F. Arkivoc 2005, (i): 92

10c Moonen K. Dieltiens N. Stevens CV. J. Org. Chem. 2006, 71: 4006

10d Dieltiens N. Moonen K. Stevens CV. Chem. Eur. J. 2006, in press

For recent reviews on enyne metathesis, see:

11a Poulson CS. Madson R. Synthesis 2003, 1

11b Diver ST. Giessert AJ. Chem. Rev. 2004, 104: 1317

11c Maifeld SV. Lee D. Chem. Eur. J. 2005, 11: 6118

12a Royer F. Vilain C. Elkaïm L. Grimaud L. Org. Lett. 2003, 5: 2007

12b Lee H.-Y. Kim HY. Tae H. Kim BG. Lee J. Org. Lett. 2003, 5: 3439

12c Imhof S. Blechert S. Synlett 2003, 609

12d Kitamura T. Sato Y. Mori M. Tetrahedron 2004, 60: 9649

13 Van Meenen E. Moonen K. Acke D. Stevens CV. Arkivoc 2006, (i): 31

14 Azizi N. Saidi MR. Tetrahedron 2003, 59: 5329

15 Mori M. Sakakibara N. Kinoshita A. J. Org. Chem. 1998, 63: 6082

16 Lloyd-Jones GC. Margue RG. de Vries JG. Angew. Chem. Int. Ed. 2005, 44: 7442

17 For a general model for selectivity in cross-metathesis, see: Chatterjee AK. Choi TL. Sanders DP. Grubbs RH. J. Am. Chem. Soc. 2003, 125: 11360

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].