Synthesis of Pentafluorosulfanyl-Containing Indoles and Oxindoles

Abstract

Vicarious nucleophilic substitution (VNS) of 3- and 4-nitro(pentafluorosulfanyl)benzenes with phenoxyacetonitrile followed by catalytic hydrogenation provided a two-step, atom-economical synthetic route to 6- and 5-(pentafluoro-sulfanyl)­1H­indoles. The VNS reaction with chloromethyl phenyl sulfone, nitro group reduction, imine formation, and base-induced cyclization gave efficient access to 2-aryl substituted 6- and 5-(pentafluorosulfanyl)-1H-indoles. Finally, the VNS reaction with ethyl chloroacetate and nitro group reduction followed by thermal cyclization (lactam formation) furnished SF₅-containing oxindoles. Their transformation into 2-halo-substituted SF₅-indoles was demonstrated.

Key words

indoles - fluorine - sulfur - heterocycles - vicarious ­nucleophilic substitution

• References and Notes

• 1a Eicher T, Hauptmann S In The Chemistry of Heterocycles . 2nd ed. Wiley-VCH; Weinheim: 2003: 99
• 1b In Chemistry of Heterocyclic Compounds: Heterocyclic Compounds with Indole and Carbazole Systems. Vol. 8. Sumpter WG, Miller FM. John Wiley & Sons, Inc; Hoboken: 2008
• 1c Cacchi S, Fabrizi G. Chem. Rev. 2005; 105: 2873
• 1d Humphrey GR, Kuethe JT. Chem. Rev. 2006; 106: 2875
• 1e Bandini M, Eichholzer A. Angew. Chem. Int. Ed. 2009; 48: 9608
• 1f Sharma V, Kumar P, Pathak D. J. Heterocycl. Chem. 2010; 47: 491
• 1g Kawasaki T, Higuchi K. Nat. Prod. Rep. 2005; 22: 761
• 2a Kirsch P In Modern Fluoroorganic Chemistry . Wiley-VCH; Weinheim: 2004: 146
• 2b Winter RW, Dodean RA, Gard GL. Fluorine-Containing Synthons . In ACS Symposium Series 911 . Soloshonok VA. American Chemical Society; Washington DC: 2005: 87
• 2c Kirsch P, Röschenthaler GV. Current Fluoroorganic Chemistry, In ACS Symposium Series 949 . Soloshonok VA, Mikami K, Yamazaki T, Welch JT, Honek FJ. American Chemical Society; Washington DC: 2007: 221
• 3a Aït-Mohand S, Dolbier WR. Jr. Org. Lett. 2002; 4: 3013
• 3b Dolbier WR. Jr, Aït-Mohand S, Schertz TD, Sergeeva TA, Cradlebaugh JA, Mitani A, Gard GL, Winter RW, Thrasher JS. J. Fluorine Chem. 2006; 127: 1302
• 4 Umemoto T, Garrick LM, Saito N. Beilstein J. Org. Chem. 2012; 8: 461
• 5a Bowden RD, Greenhall MP, Moilliet JS, Thomson J. WO 9705106, 1997 ; Chem. Abstr. 1997, 126, 199340
• 5b Bowden RD, Comina PJ, Greenhall MP, Kariuki BM, Loveday A, Philp D. Tetrahedron 2000; 56: 3399
• 5c Chambers RD, Spink RC. H. Chem. Commun. 1999; 883
• 6 Beier P, Pastýříková T, Vida N, Iakobson G. Org. Lett. 2011; 13: 1466
• 7a Beier P, Pastýříková T, Iakobson G. J. Org. Chem. 2011; 76: 4781
• 7b Iakobson G, Beier P. Beilstein J. Org. Chem. 2012; 8: 1185
• 8 Beier P, Pastýříková T. Tetrahedron Lett. 2011; 52: 4392
• 9 Pastýříková T, Iakobson G, Vida N, Pohl R, Beier P. Eur. J. Org. Chem. 2012; 2123
• 10 Vida N, Beier P. J. Fluorine Chem. 2012; 143: 130
• 11 Beier P, Pastýříková T. Beilstein J. Org. Chem. 2013; 9: 411
• 12 Frischmuth A, Unsinn A, Groll K, Stadtmüller H, Knochel P. Chem. Eur. J. 2012; 18: 10234
• 13 Makosza M, Danikiewicz W, Wojciechowski K. Liebigs Ann. Chem. 1988; 203
• 14 6-(Pentafluorosulfanyl)­1H­indole (3): ¹² 10% Pd/C (360 mg) was added to a solution of 5a ^7a (466 mg, 1.62 mmol) and acetic acid (277 μL, 4.85 mmol, 3 equiv) in EtOAc (5 mL) and the mixture was hydrogenated in an autoclave (10 bar) at room temperature for 24 h. The catalyst was filtered off, the filter was washed with EtOAc (3 × 10 mL), and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane–EtOAc) to give 3 as a white solid (194 mg, 50%); mp 97.1–98.4 °C; R_f  = 0.46 (hexane–EtOAc, 85:15). ¹H NMR (600 MHz, CDCl₃): δ = 6.62 (ddd, J = 3.2, 2.0, 1.0 Hz, 1 H), 7.40 (dd, J = 3.2, 2.5 Hz, 1 H), 7.53 (dd, J = 8.8, 2.0 Hz, 1 H), 7.66 (dquint., J = 8.8, 0.6 Hz, 1 H), 7.86 (ddd, J = 2.0, 1.0, 0.5 Hz, 1 H), 8.43 (br s, 1 H). ¹³C (150 MHz, CDCl₃): δ = 102.9, 109.8 (quint, J = 4.9 Hz), 117.3 (quint, J = 4.5 Hz), 120.1, 127.9, 129.7, 133.8, 148.8 (quint, J = 16.6 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = 65.1 (d, J = 149.9 Hz, 4 F), 85.8–87.4 (m, 1 F). MS (EI): m/z (%) = 243 (100) [M]⁺, 135 (42), 116 (40), 108 (21), 89 (28). HRMS (EI): m/z [M]⁺ calcd for C₈H₆F₅NS: 243.0141; found: 243.0135.
• 15 5-(Pentafluorosulfanyl)­1H­indole (4): Prepared as described for 3 from 10% Pd/C (600 mg), 6 ^7a (623 mg, 2.16 mmol) and acetic acid (370 μL, 6.49 mmol, 3 equiv) in EtOH (6 mL) in 20 h, giving 4 as a white solid (362 mg, 69%) after purification by column chromatography (silica gel, hexane–EtOAc); mp 85.2–87.0 °C; R_f  = 0.22 (hexane–EtOAc, 85:15). IR (film): 3493, 3122, 1615, 1512, 1419, 1331, 1257, 1096, 1072, 897, 835, 819, 808 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.64 (ddd, J = 3.2, 2.1, 0.9 Hz, 1 H), 7.30 (dd, J = 3.2, 2.3 Hz, 1 H), 7.35 (dquint., J = 9.0, 0.9 Hz, 1 H), 7.58 (dd, J = 9.0, 2.2 Hz, 1 H), 8.09 (dt, J = 2.2, 0.9 Hz, 1 H), 8.33 (br s, 1 H). ¹³C (125.7 MHz, CDCl₃): δ = 104.1, 110.4, 119.3 (quint, J = 4.7 Hz), 119.4 (quint, J = 4.7 Hz), 126.5, 126.7, 136.2, 147.1 (quint, J = 16.1 Hz). ¹⁹F NMR (470 MHz, CDCl₃): δ = 65.4 (d, J = 149.7 Hz, 4 F), 86.7–87.8 (m, 1 F). MS (EI): m/z (%) = 243 (100) [M]⁺, 135 (38), 116 (44), 108 (19), 89 (24). HRMS (EI): m/z [M]⁺ calcd for C₈H₆F₅NS: 243.0141; found: 243.0150.
• 16 Wojciechowski K, Makosza M. Bull. Soc. Chim. Belg. 1986; 95: 671
• 17 Kraus GA, Guo H, Kumar G, Pollock GIII, Carruthers H, Chaudhary D, Beasley J. Synthesis 2010; 1386
• 18 [2-Benzenesulfonylmethyl-5-(pentafluorosulfanyl)phenyl]-(4-chlorobenzylinene)amine (9a): A mixture of 8 ^7a (100 mg, 0.27 mmol), p-chlorobenzaldehyde (41 mg, 0.30 mmol, 1.1 equiv), TsOH (cat.) and benzene (15 mL) was heated to reflux for 4 h using a Dean–Stark apparatus, followed by removal of the solvent under reduced pressure. The residue was dissolved in cold CH₂Cl₂ (10 mL), saturated Na₂CO₃ was added, and the mixture was vigorously stirred. The aqueous layer was extracted with CH₂Cl₂ (2 × 5 mL), the combined organic phase was dried, and the solvent was removed under reduced pressure followed by the purification by column chromatography (silica gel, hexane–CH₂Cl₂–EtOAc, 65:32.5:2.5) to give 9a (110 mg, 83%) as a white solid; mp 194.5–195.5 °C (EtOH); R_f  = 0.26 (hexane–acetone, 80:20). IR (film): 3070, 1635, 1591, 1305, 1146, 1115, 1015, 857, 848, 840, 829, 818 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 4.68 (s, 2 H), 7.19–7.24 (m, 3 H), 7.40–7.51 (m, 5 H), 7.59–7.68 (m, 4 H), 7.77 (s, 1 H). ¹³C (100 MHz, CDCl₃): δ = 57.5, 115.5 (quint, J = 4.8 Hz), 123.4 (quint, J = 4.8 Hz), 126.7, 128.5, 128.8, 129.2, 130.3, 132.3, 133.7, 138.3, 138.5, 150.6, 154.9 (quint, J = 17.6 Hz), 160.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = 62.4 (d, J = 150.3 Hz, 4 F), 82.2–83.9 (m, 1 F). MS (EI): m/z (%) = 495 (4) [M]⁺, 356 (38), 355 (17), 354 (100), 229 (9), 227 (26), 109 (12), 89 (15), 77 (8). HRMS (EI): m/z [M]⁺ calcd. for C₂₀H₁₅ClF₅NO₂S₂: 495.0153; found: 495.0166.
• 19 2-(4-Chlorophenyl)-6-(pentafluorosulfanyl)-1H-indole (10a): To a stirred suspension KOH (113 mg, 2.02 mmol, 10 equiv) in DMSO (3 mL), a suspension of 9a (100 mg, 0.202 mmol) in DMSO (3 mL) was added and the mixture was stirred at r.t. for 30 min. Aqueous NH₄Cl (10 mL) was added and the product was extracted into Et₂O (3 × 5 mL). The organic phase was washed with water (2 × 5 mL), dried, and solvent was removed under reduced pressure. Purification by column chromatography (silica gel, hexane–EtOAc) gave 10a (49 mg, 68%) as a white solid; mp 161–164 °C; R_f  = 0.45 (hexane–CH₂Cl₂, 60:40). IR (film): 3474, 1483, 1073, 1010, 935, 837, 828, 815, 812 cm^–1. ¹H NMR (400 MHz, acetone-d ₆): δ = 7.03 (dd, J = 2.1, 0.9 Hz, 1 H), 7.49–7.54 (m, 3 H), 7.69–7.73 (m, 1 H), 7.86–7.90 (m, 2 H), 7.94–7.95 (m, 1 H), 11.14–11.30 (m, 1 H). ¹³C (100 MHz, acetone-d ₆): δ = 100.5, 100.6, 110.7 (quint, J = 5.1 Hz), 117.9 (quint, J = 4.6 Hz), 120.9, 128.0, 130.0, 131.3, 132.1, 134.6, 136.4, 142.0, 149.3 (quint, J = 16.1 Hz). ¹⁹F NMR (376 MHz, acetone-d ₆): δ = 66.1 (d, J = 148.0 Hz, 4 F), 87.8–89.5 (m, 1 F). MS (EI): m/z (%) = 355 (37) [M]⁺, 354 (17) [M]⁺, 353 (100) [M]⁺, 247 (10), 245 (29), 226 (10), 191 (15), 190 (15), 123 (10), 105 (7). HRMS (EI): m/z [M]⁺ calcd for C₁₄H₉ClF₅NS: 353.0064; found: 353.0074
• 20 Brown GD, Wong H. Tetrahedron 2004; 60: 5439
• 21a Lu S, Wang R, Yang Y, Li Y, Shi Z, Zhang W, Tu Z. J. Org. Chem. 2011; 76: 5661
• 21b Lu S, Wei S, Wang W, Zhang W, Tu Z. Eur. J. Org. Chem. 2011; 5905
• 22 Kenda B, Quesnel Y, Ates A, Michel P, Turet L, Mercier J. WO 128692 A2, 2006 , (compound x160) Chem. Abstr. 2006, 146, 45393.