Synlett 2013; 24(3): 389-393
DOI: 10.1055/s-0032-1318099
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the Reverse Transcriptase Inhibitor L-737,126 and the CB2 Cannabinoid Receptor Agonist Pravadoline by a Copper-Catalyzed Intramolecular Cross-Coupling

Detian Gao
Department of Chemistry, University of Calgary, Calgary, Alberta, T2N 1N4, Canada   Fax: +1(403)2899488   Email: tgback@ucalgary.ca
,
Thomas G. Back*
Department of Chemistry, University of Calgary, Calgary, Alberta, T2N 1N4, Canada   Fax: +1(403)2899488   Email: tgback@ucalgary.ca
› Author Affiliations
Further Information

Publication History

Received: 12 November 2012

Accepted after revision: 20 December 2012

Publication Date:
16 January 2013 (online)


Abstract

The conjugate additions of N-formyl-o-haloanilines to acetylenes activated by electron-withdrawing groups afford products which undergo subsequent intramolecular C-arylations mediated by copper(II) acetate in DMF to produce the corresponding indoles. These processes require no external ligands and can be carried out without protection from air or moisture. This procedure was applied to the concise syntheses of two pharmacologically interesting indoles: the anti-HIV agent L-737,126 and the antinociceptive CB2 cannabinoid agonist pravadoline.

 
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  • 12 Attempts to debenzylate 7 were made with CrO3, PCC, KMnO4, Pd-catalyzed hydrogenolysis, LiAlH4, and TMSI under a variety of conditions, but afforded poor or no yields of the desired alcohol. Alternative protecting groups that were studied included various silyl, acetyl, benzoyl, and PMB groups. These failed because of difficulties in preparing the precursor acetylenic sulfones or during the cyclization step.
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  • 14 Imine 9 was obtained as a mixture of E/Z isomers, accompanied by small amounts of the corresponding enamine isomers. The unseparated mixture was employed directly in the next step. The imine structure was consistent with signals in its 1H NMR spectrum at δ = 4.29 (s, 2 H) and 1.96 (s, 3 H) ppm for the major isomer (see ref. 16 for the complete characterization of this compound).
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  • 16 Preparation of L-737,126 (1) N-Formylaniline 3 19 was prepared by the general procedure we described previously.10 Acetylenic sulfones 5 11 and 8 13 were obtained by literature procedures. (E)-N-[1-(Benzyloxy)-3-(phenylsulfonyl)prop-1-en-2-yl]-N-(4-chloro-2-iodophenyl)formamide (6) Acetylenic sulfone 5 (430 mg, 1.50 mmol) was added to aniline 3 (281 mg, 1.00 mmol) and K2CO3 (138 mg, 1.00 mmol) in DMF–H2O (9:1, 5 mL), and the mixture was stirred at r.t. for 16 h. It was then diluted with H2O (50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and evaporated under vacuum. Flash chromatography on silica gel (hexanes–EtOAc = 8:1 to 4:1) afforded 511 mg (90%) of sulfonyl enamine 6 as a brown oil consisting of a mixture of rotamers. IR (film): 1569, 1306, 1154 cm–1. 1H NMR (400 MHz, CDCl3): δ (major rotamer) = 8.28 (s, 1 H), 8.02–7.00 (m, 13 H), 6.87 (s, 1 H), 4.65 (s, 2 H), 3.95 (br s, 2 H); δ (minor rotamer) = 8.20, 6.78, 4.48. 13C NMR (101 MHz, CDCl3): δ (both rotamers) = 162.6, 162.4, 153.4, 152.3, 139.9, 139.8, 139.1, 138.8, 137.4, 135.6, 135.4, 135.3, 135.0, 134.0, 133.7, 132.1, 131.9, 130.1, 129.7, 129.2, 128.8, 128.6, 128.5, 128.4, 128.0, 127.7, 108.7, 106.1, 99.7, 98.6, 75.2, 74.9, 52.9, 52.7. MS (EI): m/z (%) = 567 (0.5) [M+], 426 (60), 91 (100). HRMS (EI): m/z calcd for C23H19 35ClINO4S: 566.9768; found: 566.9750. 2-(Benzyloxymethyl)-5-chloro-3-(phenylsulfonyl)-1H-indole (7) A mixture of sulfonyl enamine 6 (1.65 g, 2.90 mmol), Cu(OAc)2 (162 mg, 0.87 mmol), and Cs2CO3 (2.08 g, 6.38 mmol) in DMF (35 mL) was stirred at 125 °C for 3 h. The solvent was removed under reduced pressure, and the residue was triturated with CH2Cl2. The solid was filtered, the filtrate was concentrated, and the resulting residue was purified by flash chromatography on silica gel (hexanes–EtOAc = 3:1) to afford 1.00 g (84%) of indole 7 as a yellow oil, which solidified upon standing. IR (film): 3280, 1585, 1285, 1183 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.35 (s, 1 H), 7.99 (d, J = 1.9 Hz, 1 H), 7.95–7.90 (m, 2 H), 7.55–7.49 (m, 1 H), 7.48–7.42 (m, 2 H), 7.40–7.34 (m, 5 H), 7.27 (d, J = 8.6 Hz, 1 H), 7.17 (dd, J = 8.7, 2.0 Hz, 1 H), 5.14 (s, 2 H), 4.68 (s, 2 H). 13C NMR (101 MHz, CDCl3): δ = 143.3, 142.6, 136.9, 132.8, 132.7, 129.2, 128.7, 128.40, 128.35, 128.1, 126.3, 126.2, 124.0, 119.0, 112.8, 110.1, 73.8, 64.3. MS (EI): m/z (%) = 411 (20) [M+], 320 (57), 305 (100), 91 (85). HRMS (EI): m/z calcd for C22H18 35ClNO3S: 411.0696; found: 411.0694. 4-Chloro-2-iodo-N-[1-(phenylsulfonyl)propan-2-ylidene]aniline (9) Imine 9 was obtained from aniline 3 (2.00 g, 7.10 mmol) and acetylenic sulfone 8 (1.90 g, 10.5 mmol) under the same conditions used for the preparation of enamine 6. The product 9 (2.60 g, 84%) was a crude E/Z mixture that was obtained as a yellow oil. IR (film): 1657, 1607, 1325, 1157 cm–1. 1H NMR (400 MHz, CDCl3): δ (major isomer) = 7.99–7.91 (m, 2 H), 7.70 (d, J = 2.2 Hz, 1 H), 7.70–7.51 (m, 3 H), 7.18 (dd, J = 8.3, 2.2 Hz, 1 H), 6.23 (d, J = 8.2 Hz, 1 H), 4.29 (s, 2 H), 1.96 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 163.9, 149.9, 138.8, 138.1, 134.2, 129.51, 129.45, 129.1, 128.3, 119.2, 88.4, 66.6, 21.4. MS (EI): m/z (%) = 433 (16) [M+], 368 (41), 278 (75), 242 (100). HRMS (EI): m/z calcd for C15H13 35ClINO2S: 432.9400; found: 432.9415. The crude product was used directly in the preparation of 10. 5-Chloro-2-methyl-3-(phenylsulfonyl)-1H-indole (10) Indole 10 was obtained from imine 9 (1.40 g, 3.23 mmol) under the same conditions used for the preparation of indole 7. The product 10 (0.81 g, 82%) was obtained as pale yellow crystals, mp 184–185 °C (from CHCl3). IR (film) 3299, 1578, 1303, 1154 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 12.37 (s, 1 H), 7.95 – 7.90 (m, 2 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.63 – 7.51 (m, 3 H), 7.41 (d, J = 8.6 Hz, 1 H), 7.19 (dd, J = 8.6, 2.1 Hz, 1 H), 2.67 (s, 3 H). 13C NMR (101 MHz, DMSO-d 6): δ = 144.3, 144.2, 133.5, 133.3, 130.0, 126.7, 126.5, 126.1, 123.1, 118.0, 113.9, 110.2, 13.0. MS (EI): m/z (%) = 305 (100) [M+], 241 (12). MS (EI): m/z (%) = 305 (100) [M+], 241 (12). HRMS (EI): m/z calcd for C15H12 35ClNO2S: 305.0277; found: 305.0279. 5-Chloro-3-(phenylsulfonyl)-2-(trichloromethyl)-1H-indole (11) A mixture of indole 10 (612 mg, 2.00 mmol), NCS (801 mg, 6.00 mmol), and AIBN (41 mg, 0.25 mmol) in benzene (40 mL) was refluxed for 10 h. Two additional portions of NCS (267 mg, 2.00 mmol) and AIBN (21 mg, 0.13 mmol) were added, and refluxing was continued for 3 h each time. The reaction mixture was cooled to r.t. and the succinimide was removed by filtration. The filtrate was evaporated, and the residue was purified by flash chromatography on silica gel (hexanes–EtOAc = 8:1) to afford 622 mg (76%) of the trichlorinated indole 11 as a yellow oil. IR (film): 3276, 1735, 1320, 1154 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 13.28 (s, 1 H), 8.05 (d, J = 1.7 Hz, 1 H), 7.95 (d, J = 7.5 Hz, 2 H), 7.73 (d, J = 8.6 Hz, 1 H), 7.67–7.53 (m, 3 H), 7.43 (dd, J = 8.8, 1.8 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 143.4, 140.6, 133.8, 131.9, 129.9, 128.7, 127.9, 126.8, 126.2, 120.1, 116.3, 111.2, 87.9. MS: (EI): m/z (%) = 247 (34), 211 (100). 5-Chloro-3-(phenylsulfonyl)-1H-indole-2-carboxylic acid (12)2d Indole 11 (409 mg, 1.00 mmol) was refluxed in 20% NaOH solution (10 mL) for 16 h. The reaction mixture was washed with EtOAC, acidified with 35% aq HCl and extracted with EtOAc. The organic layer was washed with brine, dried, and filtered. The filtrate was evaporated under vacuum to afford 255 mg (76%) of the carboxylic acid 12 as a white solid, mp 265 °C (dec.; from EtOAc–hexanes). IR (film): 3239 (br), 1712, 1303, 1151 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 14.18 (br s, 1 H), 13.17 (s, 1 H), 8.22 (d, J = 1.7 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 2 H), 7.65–7.53 (m, 4 H), 7.41 (dd, J = 8.8, 2.0 Hz, 1 H). 13C NMR (101 MHz, DMSO-d 6): δ = 160.6, 143.3, 133.5, 132.7, 129.4, 128.1, 127.3, 126.5, 126.0, 120.3, 115.9, 115.7. MS (EI): m/z (%) = 335 (10) [M+], 317 (5), 69 (100). HRMS (EI): m/z calcd for C15H10 35ClNO4S: 335.0019; found: 335.0006. 5-Chloro-3-(phenylsulfonyl)-1H-indole-2-carboxamide (L-737,126) (1) SOCl2 (143 mg, 1.21 mmol) was added dropwise to a solution of indole-2-carboxylic acid 12 (201 mg, 0.600 mmol) in THF at 0 °C, and the reaction mixture was then stirred at 40 °C for 4 h. Volatile material was evaporated under reduced pressure, and the resulting acid chloride was used without further purification. NH3 in THF (5 mL, ca. 2 M) was added to a solution of the acid chloride in THF (5 mL) at 0 °C. The reaction mixture was stirred at r.t. for 16 h, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (EtOAc–hexanes = 1:2) to afford 180 mg (90%) of amide 1. Recrystallization from CH2Cl2 afforded needle-like white crystals, mp 255–257 °C; lit.2f mp 255–257 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 13.00 (s, 1 H), 8.45 (s, 1 H), 8.21 (s, 1 H), 8.05–7.97 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 7.64–7.52 (m, 3 H), 7.50 (d, J = 8.8 Hz, 1 H), 7.31 (dd, J = 8.8, 2.1 Hz, 1 H). 13C NMR (101 MHz, DMSO-d 6): δ = 161.1, 143.2, 137.7, 133.8, 133.3, 129.9, 127.8, 126.7, 125.9, 125.3, 119.4, 115.4, 111.6. MS (EI): m/z (%) = 334 (100) [M+], 317 (40), 190 (45). HRMS (EI): m/z calcd for C15H11 35ClN2O3S: 334.0179; found: 334.0174.
  • 17 Herrero MT, Tellitu I, Domínguez E, Hernández S, Moreno I, SanMartín R. Tetrahedron 2002; 58: 8581
  • 18 Preparation of Pravadoline (2) 1-(4-Methoxyphenyl)but-2-yn-1-one (14).20 A solution of EtMgBr in THF (3.0 M, 12 mL, 36 mmol) was added to 1-propyne (1.2 g, 30 mmol) in 50 mL of THF at –78 °C. The mixture was warmed to r.t. and stirred for 3 h. The resulting solution of 1-propynylmagnesium bromide in THF was cooled to –78 °C and was then added to a solution of anisaldehyde (4.10 g, 30.0 mmol) in THF at –78 °C. The reaction mixture was warmed to 0 °C, stirred for 3 h, and quenched with sat. NH4Cl solution. The solution was extracted with Et2O, and the organic layer was dried and filtered. The filtrate was evaporated under reduced pressure, and the resulting alcohol was used without further purification. MnO2 (22 g, 0.25 mol) was added in portions to a solution of the alcohol in CH2Cl2 (200 mL) at 0 °C, and the reaction mixture was stirred at r.t. for 2 d. It was then filtered through a pad of Celite, the filtrate was evaporated, and the resulting white solid was purified by chromatography on silica gel (hexane–EtOAc = 20:1 to 8:1) to afford 4.4 g (84%) of ynone 14 as colorless crystals, mp 107.0–107.5 °C (from EtOAc). 1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 8.8 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 3.85 (s, 3 H), 2.11 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 176.9, 164.3, 131.9, 130.2, 113.7, 91.6, 79.0, 55.6, 4.3. MS (EI): m/z (%) = 174 (100) [M+], 146 (24), 131 (29), 103 (30). HRMS (EI): m/z calcd for C11H10O2: 174.0681; found: 174.0677. (Z)-3-(2-Iodophenylamino)-1-(4-methoxyphenyl)but-2-en-1-one (15) Ynone 14 (0.69 g, 4.0 mmol) and N-formylaniline 13 (0.69 g, 2.9 mmol) were heated with K2CO3 (0.76 g, 5.5 mmol) in of DMF–H2O (9:1, 25 mL) at 80 °C for 16 h. The solvent was removed under reduced pressure, the resulting residue was triturated with CH2Cl2, and filtered, and the filtrate was concentrated and purified by silica gel chromatography (EtOAc–hexanes = 1:5) to afford 0.87 g (75%) of enaminone 15 as a grey powder; mp 110.5–111.5 °C (from EtOAc). IR (KBr): 3399, 1592, 1569 cm–1. 1H NMR (400 MHz, CDCl3): δ = 12.77 (s, 1 H), 7.92 (d, J = 8.7 Hz, 2 H), 7.88 (d, J = 7.9 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 6.98–6.87 (m, 3 H), 5.90 (s, 1 H), 3.83 (s, 3 H), 1.96 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 188.3, 162.1, 161.0, 141.3, 139.6, 132.5, 129.2, 128.8, 127.9, 127.2, 113.5, 97.7, 93.9, 55.4, 20.4. MS (EI): m/z (%) = 393 (60) [M+], 392 (65), 266 (100), 135 (41). HRMS (EI): m/z calcd for C17H16INO2: 393.0226; found: 393.0231. Pravadoline (2) Enaminone 15 (0.79 g, 2.0 mmol), Cu(OAc)2 (54 mg, 0.30 mmol), and Cs2CO3 (0.65 g, 2.0 mmol) were heated in DMF (50 mL) at 125 °C for 3 h. The solvent was removed under reduced pressure, the resulting residue was triturated with CH2Cl2, and filtered, and the filtrate was concentrated and purified by flash chromatography on silica gel (EtOAc–hexanes = 1:5) to afford 0.44 g (83%) of 3-methoxybenzoyl-2-methyl-1H-indole (16) as a grey powder; mp 214.5–215.5 °C (from EtOAc); lit.4c mp 215–217 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 11.84 (s, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), 7.40–7.30 (m, 2 H), 7.10 (t, J = 7.4, 1 H), 7.06–6.95 (m, 3 H), 3.84 (s, 3 H), 2.41 (s, 3 H). 13C NMR (101 MHz, DMSO-d 6): δ = 191.0, 162.3, 143.8, 135.4, 134.1, 131.2, 127.8, 122.1, 121.1, 120.4, 114.0, 113.2, 111.7, 55.8, 14.5. The conversion of 16 to pravadoline (2) was carried out in 72% yield by a literature procedure.4c Alternative One-Pot Procedure A mixture of enaminone 15 (59 mg, 0.15 mmol), Cs2CO3 (59 mg, 0.18 mmol), and Cu(OAc)2 (4.0 mg, 0.02 mmol) in DMF (10 mL) was stirred at 125 °C for 3 h. Cs2CO3 (123 mg, 0.38 mmol) and 17 (21 mg, 0.11 mmol) were added and stirred at 120 °C for 8 h. A second portion of 17 (13 mg, 0.070 mmol) was added, and the resulting mixture was stirred for another 8 h at 120 °C, and worked up as previously to afford 37 mg (65%) of pravadoline (2); mp 100–102 °C; lit.4c mp 104–105 °C. 1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.6 Hz, 2 H), 7.42–7.31 (m, 2 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 2 H), 4.29 (t, J = 7.1 Hz, 2 H), 3.90 (s, 3 H), 3.76–3.71 (m, 4 H), 2.73 (t, J = 7.1 Hz, 2 H), 2.64 (s, 3 H), 2.57–2.52 (m, 4 H). 13C NMR (101 MHz, CDCl3): δ = 191.7, 162.6, 143.4, 135.7, 133.7, 131.6, 127.4, 121.9, 121.2, 121.1, 114.1, 113.4, 109.2, 66.9, 57.5, 55.4, 54.1, 41.2, 12.4.
  • 20 Yamamoto Y, Okinaka T, Nakatani M, Akiba K. Nippon Kagaku Kaishi 1987; 128 ; Chem. Abstr. 1987, 109, 22614