Synthesis of Indolo[2,1-a][2]benzazepine and Indolo[2,1-a][2]-benzazocine

Abstract

The synthesis of functionalised 6,7-dihydro-5H-indolo[2,1-a][2]benzazepine and 5,6,7,8-tetrahydroindolo[2,1-a][2]benz­azocine from methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxy­late, involving RCM as the key step to generate the tetracyclic indolo[2,1-a][2]benzazepine and indolo[2,1-a][2]benzazocine core structure, is outlined.

Key words

hepatitis C - HCV NS5B polymerase inhibitor - ­5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine - 6,7-dihydro-5H-­indolo[2,1-a]­benzazepine - ring-closing metathesis

References and Notes

• 1a Stansfield I. Ercolani C. Mackay A. Conte I. Pompei M. Koch U. Gennari N. Giuliano C. Rowley M. Narjes F. Bioorg. Med. Chem. Lett.  2009,  19:  627 
• 1b Hirashima S. Oka T. Ikegashira K. Noji S. Yamanaka H. Hara Y. Goto H. Mizojiri R. Nima Y. Noguchi T. Ando I. Ikeda S. Hashimoto H. Bioorg. Med. Chem. Lett.  2007,  17:  3181 
• 1c Ikegashira K. Oka T. Hirashima S. Noji S. Yamahaka H. Hara Y. Adachi T. Tsuruha J.-I. Doi S. Hase Y. Noguchi T. Ando I. Ogura N. Ikeda S. Hashimoto H. J. Med. Chem.  2006,  49:  6950 
• 2 Kozikowski AP. Me D. Tetrahedron Lett.  1991,  32:  3317 
• 3 Kozikowski AP. Me D. Brewer J. Sun S. Costa E. Romeo E. Guidotti A. J. Med. Chem.  1993,  36:  2908 
• 4 Fiumana A. Jones K. Tetrahedron Lett.  2000,  41:  4209 
• 5 Vincze Z. Biro AB. Csekei M. Timari G. Kotschy A. Synthesis  2006,  1375 
• 6 Ikegashira K. Oka T. Hirashima S. Noji S. Yamanaka H. Hara Y. Adachi T. Tsuruha J. Doi S. Hase Y. Noguchi T. Ando I. Ogura N. Ikeda S. Hashimoto H. J. Med. Chem.  2006,  49:  6950 
• 7 Lautens M. J. Org. Chem.  2008,  73:  1888 
• 8 Suzuki A. Pure Appl. Chem.  1991,  63:  419 
• 9a Ettari R. Micale N. J. Organomet. Chem.  2007,  692:  3574 
• 9b Zhan Z.-Y. inventors; WO 2007003135  A1. The catalyst was purchased from Zhannan Pharma Ltd., Shanghai, China:
• 10 Raghavan S. Rajender A. Tetrahedron  2004,  60:  5059 
• 11 Brown HC. J. Org. Chem.  1986,  51:  439 
• 12 Corey EJ. Org. Lett.  2003,  5:  2465 

13

Typical Procedure for Compounds 3a-d, 4b,c
Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (7) and (2-vinylphenyl)boronic acid (1.5 equiv) were dissolved in dioxane (0.07 M) and 2 M aq Na₂CO₃ (6 equiv) was added. The soln was degassed by bubbling argon, Pd(PPh₃)₂Cl₂ (0.2 equiv) was added, and the reaction mixture was refluxed for 1 h; after cooling, EtOAc was added, and the solution washed with H₂O and brine,
dried over Na₂SO₄ and concentrated in vacuo. Methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (8) was isolated by chromatography (PE-EtOAc); yield 91%. To a 0.3 M soln of methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (8) in dry DMF, 60% NaH (1.5 equiv) in mineral oil was added at 0 ˚C, after 1 h allyl bromide (1.5 equiv) or 4-bromo-1-butene (2 equiv) were added, and the suspension was stirred at r.t. for 2 h or at 40 ˚C for 5 h. The mixture was diluted with EtOAc, washed with 1 N HCl, H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo to give methyl 1-allyl-3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (9b, 98%) or methyl 1-buten-3-en-1-yl-3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (9a, 60%). Methyl 1-allyl-3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (9b) or methyl 1-buten-3-en-1-yl-3-cyclohexyl-2-(2-vinyl-phenyl)-1H-indole-6-carboxylate (9a) were dissolved in CH₂Cl₂ (0.02 M) and treated with Zhannan catalyst I (0.3 equiv) at 35 ˚C for 1 h. After removal of solvent the residue was purified by chromatography (PE-EtOAc) to afford methyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (10b) or methyl 14-cyclohexyl-7,8-dihydro-indolo[2,1-a][2]benzazocine-11-carboxylate (10a) in 84% and 80% yield. BH₃˙SMe₂ (1.6 equiv, 2 M soln in THF) was added to a 0.2 M solution of methyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (10b) in THF or methyl 14-cyclohexyl-7,8-dihydroindolo[2,1-a][2]benz-azocine-11-carboxylate (10a), and the mixture was stirred for 2 h at r.t.; 3 M aq NaOH (3 equiv) and 35% H₂O₂ (3 equiv) were added at 0 ˚C, and stirring was continued overnight at r.t. After dilution with sat. NaHCO₃ the aqueous phase was extracted with EtOAc, the organic phase was washed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo to give a 4:1 mixture of methyl 13-cyclohexyl-5-hydroxy-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (11b) and methyl 13-cyclohexyl-6-hydroxy-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (12b) or methyl 14-cyclohexyl-5-hydroxy-5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine-11-carboxylate (11a). The foregoing crude was dissolved in toluene (20 mL/mmol), 40% aq NaOH (15 equiv) and TBAB (0.25 equiv) were added, and the mixture was stirred for 30 min. Selected dialkylamino-ethyl chloride (3 equiv) was then added and the resulting mixture heated at 70 ˚C for 1 d; evaporation to dryness gave a residue which was purified by RP-HPLC to give products 3a-d, 4b,c.
Selected Data for 3a
^¹H NMR (TFA salt, 400 MHz, DMSO-d ₆, 300 K): δ = 1.16-2.30 (20 H, m), 2.61-2.72 (1 H, m), 2.93-3.05 (2 H, m), 3.15-3.30 (3 H, m), 3.41-3.52 (2 H, m), 3.78 (1 H, d, J = 9.0 Hz), 4.40-4.45 (1 H, m), 7.38 (1 H, d, J = 7.4 Hz), 7.47-7.50 (1 H, m), 7.62-7.71 (3 H, m), 7.85 (1 H, d, J = 8.3 Hz), 8.07 (1 H, s), 9.31 (1 H, br s), 12.59 (1 H, br s). MS (ES⁺): m/z = 487 [M + H]⁺.
Selected Data for 3d ^¹H NMR (TFA salt, 400 MHz, DMSO-d ₆, 300 K): δ = 0.58-0.67 (1 H, m), 0.79-0.82 (1 H, m), 1.16-1.23 (6 H, m), 1.38-1.49 (2 H, m), 1.58-2.06 (8 H, m), 2.62-2.90 (3 H, m), 3.05-3.80 (7 H, m), 4.23-4.28 (1 H, m), 4.58-4.71 (1 H, m), 7.43-7.64 (5 H, m), 7.83-7.87 (1 H, d, J = 8.4 Hz), 8.13 (1 H, s). MS (ES⁺): m/z = 475 [M + H]⁺.

14

Typical Procedure for Compounds 5a-d
Phosphorus tribromide (0.5 equiv) was added at 0 ˚C to a 0.2 M soln of methyl 13-cyclohexyl-5-hydroxy-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (11b) or methyl 14-cyclohexyl-5-hydroxy-5,6,7,8-tetrahydroindolo-[2,1-a][2]benzazocine-11-carboxylate (11a) in CH₂Cl₂, and the mixture was stirred at r.t. for 2 h. The reaction mixture was diluted with EtOAc, washed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo to give methyl 5-bromo-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (15b) or methyl 5-bromo-14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2]benzazocine-11-carboxylate (15a) that were dissolved in MeCN and treated with the selected N,N-dialkylethylenediamine (8 equiv) at 55 ˚C for 3 h; evaporation in vacuo to dryness gave crude products 16a,b, an amount of which was dissolved in CH₂Cl₂ and pH adjusted to 6 with AcOH; 37% aq HCHO and NaCNBH₃ (3 equiv, after 30 min) were added, and the mixture was stirred at r.t. overnight. The reaction mixture was diluted with EtOAc and washed with 1 N NaOH and brine, dried, and evaporated affording compounds 16c,d. Hydrolysis of the foregoing methyl esters was done with 1 M aq KOH (6 equiv) in dioxane (0.1 M) at 60 ˚C; the reaction was complete in 2 h, and the title compounds 5a-d were obtained after RP-HPLC purification.
Selected Data for 5b
^¹H NMR (TFA salt, 400 MHz, DMSO-d ₆, 300 K): δ = 1.15-1.77 (7 H, m), 1.90-2.17 (10 H, m), 2.78-2.91 (2 H, m), 3.40-3.59 (7 H, m), 4.11-4.16 (1 H, m), 4.75-4.81 (1 H, m), 7.51-7.66 (5 H, m), 7.92 (1 H, d, J = 8.5 Hz), 8.20 (1 H, s). MS (ES⁺): m/z = 472 [M + H]⁺.
Selected Data for 5d ^¹H NMR (TFA salt, 400 MHz, DMSO-d ₆, 300 K): δ = 1.16-1.77 (8 H, m), 1.80-2.11 (8 H, m), 2.19-2.31 (2 H, m), 2.61-2.87 (5 H, m), 2.98-3.41 (7 H, m), 4.54-4.66 (1 H, m), 7.42 (1 H, d, J = 8.1 Hz), 7.47-7.54 (2 H, m), 7.63 (1 H, d, J = 8.3 Hz), 7.69-7.75 (1 H, m), 7.86 (1 H, d, J = 8.3 Hz), 8.12 (1 H, s). MS (ES⁺): m/z = 486 [M + H]⁺.

15

Typical Procedure for Compounds 6b A soln (0.11 M) of methyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (10b) in acetone-THF-H₂O (1:1:1) was treated with N-methylmorpholine-N-oxide (1.2 equiv), followed by OsO₄ (4% wt in H₂O; 0.1 equiv) and left stirring at r.t. overnight. The clear soln was then treated with 10% wt Na₂SO₃ and left stirring for 30 min, then diluted with H₂O, and extracted with EtOAc. The organic phase was washed with brine, dried over Na₂SO₄, and evaporated in vacuo to give methyl 13-cyclohexyl-5,6-dihydroxy-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (17b). A soln (0.05 M) of methyl 13-cyclohexyl-5,6-dihydroxy-6,7-dihydro-5H-indole[2,1-a][2]benzazepine-10-carboxylate (17b) in CH₂Cl₂ was treated with Et₃N (4 equiv), and cooled to -50 ˚C. Triphosgene (0.4 equiv) was added, and the soln was allowed to warm to r.t. over 30 min. After 2 h at r.t., sat. NaHCO₃ was added and the solution extracted with EtOAc. The organic phase was washed with H₂O, brine, dried over Na₂SO₄, and evaporated in vacuo to leave methyl 10-cyclohexyl-2-oxo-3a,14b-dihydro-4H-[1,3]dioxolo[4,5-d]indolo[2,1-a][2]benzazepine-7-carboxylate (18b). A solution (0.02 M) of methyl 10-cyclohexyl-2-oxo-3a,14b-dihydro-4H-[1,3]dioxolo[4,5-d]indolo[2,1-a][2] benzazepine-7-carboxylate (18b) in acetone-MeOH (3:1) was treated with Raney-Ni (slurry in H₂O), and the vigorously stirred reaction mixture was hydrogenated at 1 atm H₂. After 48 h the solid was filtered and the filtrates evaporated in vacuo to leave the clean methyl 13-cyclohexyl-6-hydroxy-6,7-dihydro-5H-indolo[2,1-a] [2]benzazepine-10-carboxylate (12b). A solution (0.05 M) of methyl 13-cyclohexyl-6-hydroxy-6,7-dihydro-5H-indolo[2,1-a][2] benzazepine-10-carboxylate (12b) in CH₂Cl₂ was treated with DMP (1.3 equiv) at 0 ˚C and left warming to r.t. and then stirred for 2 h under nitrogen. The solution was then diluted with EtOAc and washed with sat. NaHCO₃, H₂O, brine, dried over Na₂SO₄, and evaporated in vacuo to afford methyl 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (19). The crude material was dissolved in DCE (0.05 M), 2-dimethylaminoethylamine was added, the pH adjusted to 6 with AcOH, and the soln left stirring for 30 min. NaBH(OAc)₃ was added, and the soln was left stirring at r.t. overnight. After diluting with EtOAc, the organic phase was washed with NaOH (1 N), H₂O, brine, dried over Na₂SO₄, and evaporated in vacuo to afford methyl 13-cyclohexyl-6-{[2-(dimethylamino)ethyl]amino}-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (20). Hydrolysis of the foregoing methyl ester was done with 1 M aq KOH (6 equiv) in dioxane (0.1 M) at 60 ˚C; the reaction was complete in 2 h, and the title compound was obtained after RP-HPLC purification.
Selected Data for 6b
^¹H NMR (TFA salt, 400 MHz, DMSO-d ₆, 300 K): δ = 1.16-1.59 (4 H, m), 1.61-2.12 (6 H, m), 2.74-2.98 (8 H, m), 3.12-3.43 (7 H, m), 4.69-4.73 (1 H, m), 7.49-7.58 (4 H, m), 7.67-7.73 (1 H, m), 7.90-7.93 (1 H, m), 8.24 (1 H, br s).
MS (ES⁺): m/z = 446.4 [M + H]⁺.

16

Typical Procedure for Compounds 4a
Methyl 14-cyclohexyl-6-hydroxy-5,6,7,8-tetrahydro-indolo[2,1-a][2]benzazocine-11-carboxylate (12a), prepared as its seven-membered ring analogue as reported above, was dissolved in toluene (20 mL/mmol), 40% aq NaOH (15 equiv), and TBAB (0.25 equiv) were added, and the mixture was stirred for 30 min. 1-(2-chloroethyl)-pyrrolidine (3 equiv) was then added and the resulting mixture heated at 70 ˚C for 1 d; evaporation to dryness gave a residue which was purified by RP-HPLC to give product 4a; yield 23% from the alkene 10a.
Selected Data for 4a
^¹H NMR (TFA salt, 400 MHz, DMSO-d ₆, 300 K): δ =
1.16-1.39 (3 H, m), 1.43-1.58 (2 H, m), 1.64-1.75 (2 H, m), 1.82-2.18 (9 H, m), 2.18-2.34 (1 H, m), 2.57-2.68 (1 H, m), 2.99-3.11 (3 H, m), 3.12-3.29 (2 H, m), 3.50-3.65 (4 H, m), 3.73-3.94 (2 H, m), 4.26-4.45 (1 H, m), 7.31-7.56 (4 H, m), 7.66-7.68 (1 H, d, J = 8.4 Hz), 7.86-7.88 (1 H, d, J = 8.4 Hz), 8.08 (1 H, s). MS (ES⁺): m/z = 487 [M + H]⁺.