Double Palladium-Catalyzed Synthesis of Azepines

Abstract

The synthesis of new 5H-pyridobenzazepine and 5H-dipyridoazepine compounds using as key step a palladium-catalyzed amination–cyclization reaction is reported. By choosing an appropriate combination of ligands and reactants under standardized reaction conditions, N- and S-tricyclic products can be prepared in one step from the appropriate stilbenes.

Key words

azepines - thiepines - palladium - double N- and S-arylation - fused heterocycles

• References and Notes

• 1 LeDuc B, Foye's Principles of Medicinal Chemistry . 6th ed. Lemke TL, Williams DA. Williams and Williams; Philadelphia, PA: 2002: 521-546
• 2 Miles KC. Emergency Medicine: A Comprehensive Study Guide . 6th ed.. Tintinalli JE, Kelen GD, Stapczynski JS. McGraw-Hill; New York: 2004: 1025-1033
• 3a Möller HJ, Voltz HP, Reimann IW, Stoll KD. J. Clin. Psychopharmacol. 2001; 21: 59
• 3b Müller WE, Siebert B, Holoubek G, Gentsch C. Pharmacopsychiatry 2004; 37: 189
• 4 Kricka LJ, Ledwith A. Chem. Rev. 1974; 74: 101 ; and references cited therein
• 5 Knell A, Monti D, Maciejewski M, Baiker A. Appl.Catal., A 1995; 121: 139
• 6 Elliott E.-C, Bowkett ER, Maggs JL, Bacsa J, Park BK, Regan SL, O’Neill PM, Stachulski AV. Org. Lett. 2011; 13: 5592
• 7 Tokmakov GP, Grandberg II. Tetrahedron 1995; 51: 2091
• 8 Tsvelikhovsky D, Buchwald SL. J. Am. Chem. Soc. 2010; 132: 14048
• 9 Della Ca’ N, Maestri G, Malacria M, Derat E, Catellani M. Angew. Chem. Int. Ed. 2011; 50: 12257
• 10a Nozaki K, Takahashi K, Nakano K, Hiyama T, Tang H.-Z, Fujiki M, Yamaguchi S, Tamao K. Angew. Chem. Int. Ed. 2003; 42: 2051
• 10b Nakano K, Hidehira Y, Takahashi K, Hiyama T, Nozaki K. Angew. Chem. Int. Ed. 2005; 44: 7136
• 10c Kitawaki T, Hayashi Y, Chida N. Heterocycles 2005; 65: 1561
• 10d Kitawaki T, Hayashi Y, Ueno A, Chida N. Tetrahedron 2006; 62: 6792
• 10e Kawaguchi K, Nakano K, Nozaki K. J. Org. Chem. 2007; 72: 5119
• 10f Kawaguchi K, Nakano K, Nozaki K. Org. Lett. 2008; 10: 1199
• 10g Ueno A, Kitawaki T, Chida N. Org. Lett. 2008; 10: 1999
• 10h Zhou YB, Verkade JG. Adv. Synth. Catal. 2010; 352: 616
• 10i Abboud M, Aubert E, Mamane V. Beilstein J. Org. Chem. 2012; 8: 253
• 11a Koeckelberghs G, De Cremer L, Vanormelingen W, Dehaen W, Verbiest T, Persoons A, Samyn C. Tetrahedron 2005; 61: 687
• 11b Balaji G, Valiyaveettil S. Org. Lett. 2009; 11: 3358
• 11c Mitsudo K, Shimohara S, Mizoguchi J, Mandai H, Suga S. Org. Lett. 2012; 14: 2702
• 12a Loones KT. J, Maes BU. W, Dommisse RA, Lemière GL. F. Chem. Commun. 2004; 2466
• 12b Willis MC, Brace GN, Findlay TJ. K, Holmes IP. Adv. Synth. Catal. 2006; 348: 851
• 12c Hodgkinson RC, Schulz J, Willis MC. Tetrahedron 2009; 65: 8940
• 12d Henderson LC, Lindon MJ, Willis MC. Tetrahedron 2010; 66: 6632
• 12e Dong S.-X, Zhang X.-G, Liu Q, Tang R.-Y, Zhong P, Li J.-H. Synthesis 2010; 1521
• 13 Winkler JD, Twenter BM, Gendrineau T. Heterocycles 2012; 84: 1345
• 14 Song C, Walker DB, Swager TM. Macromolecules 2010; 43: 5233
• 15a Sinning S, Musgaard M, Jensen M, Severinsen K, Celik L, Koldsø H, Meyer T, Bols M, Jensen HH, Schiøtt B, Wiborg O. J. Biol. Chem. 2010; 285: 8363
• 15b Christensen H, Schjøth-Eskesen C, Jensen M, Sinning S, Jensen HH. Chem.–Eur. J. 2011; 17: 10618
• 16 Biscoe MR, Fors BR, Buchwald SL. J. Am. Chem. Soc. 2008; 130: 6686
• 17 Dunne EC, Coyne J, Crowley PB, Gilheany DG. Tetrahedron Lett. 2002; 43: 2449
• 18 Takano Y, Shiga F, Asano J, Ando N, Uchiki H, Fukuchi K, Anraku T. Bioorg. Med. Chem. 2005; 13: 5841
• 19a Surry DS, Buchwald SL. Angew. Chem. Int. Ed. 2008; 47: 6338
• 19b Surry DS, Buchwald SL. Chem. Sci. 2011; 2: 27
• 20a Bergmann ED, Rabinovitz M. J. Org. Chem. 1960; 25: 828
• 20b Protiva M, Šedivý Z, Pomykáček J, Svátek E, Holubek J. Collect. Czech. Chem. Commun. 1981; 46: 1199
• 20c Jílek J, Pomykáček J, Holubek J, Svátek E, Ryska M, Protiva J, Protiva M. Collect. Czech. Chem. Commun. 1984; 49: 603
• 20d Shirani H, Janosik T. J. Org. Chem. 2007; 72: 8984
• 20e Shirani H, Bergman J, Janosik T. Tetrahedron 2009; 65: 8350
• 20f Saito M, Yamamoto T, Osaka I, Miyazaki E, Takimiya K, Kuwabara H, Ikeda M. Tetrahedron Lett. 2010; 51: 5277
• 21 Jepsen TH, Larsen M, Joergensen M, Nielsen MB. Synlett 2012; 23: 418
• 22 Park N, Park K, Jang M, Lee S. J. Org. Chem. 2011; 76: 4371
• 23 General Procedure for Pd-Catalyzed Synthesis of Azepines A reaction tube containing a stirrer bar was evacuated and backfilled with argon. The tube was then charged with Pd(OAc)₂ (5 mol%), JohnPhos (10 mol%), and NaOt-Bu (2.8 equiv) under argon. Toluene was added. After stirring at r.t. for 5 min, aryl halide (1 equiv) and amine (3 equiv) were added, the tube was returned under argon and capped. The reaction mixture was heated with stirring to 100 °C for the appropriate time. Products were purified by preparative column chromatography. N,N-Dimethyl-3-{(5H-pyrido[4,3-b][1]benzazepin-5-yl}propan-1-amine (10) Yield 81%; yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 8.35 (d, J = 5.5 Hz, 1 H), 8.17 (s, 1 H), 7.30–7.22 (m, 1 H), 7.05–6.98 (m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 6.81 (d, J = 5.5 Hz, 1 H), 6.74 (d, J = 11.5 Hz, 1 H), 6.60 (d, J = 11.5 Hz, 1 H), 3.80–3.73 (m, 2 H), 2.39–2.33 (m, 2 H), 2.15 (s, 6 H), 1.82–1.70 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 158.8, 150.5, 150.1, 149.1, 134.1, 133.6, 129.5, 129.3, 129.2, 129.1, 124.1, 121.1, 114.7, 57.1, 48.2, 45.5, 25.4. IR (ATR): 3413, 3023, 2944, 2858, 2817, 2767, 1635, 1578, 1481, 1419, 1392, 1332, 1244, 1184, 1123, 1060, 919, 831, 794, 766 cm^–1. ESI-HRMS (+): m/z = 280.18125 [M + H]⁺ (error: 1.51 ppm).
• 24 Procedure for the Microwave Pd-Catalyzed Synthesis of Thiepines 18 and 19 A reaction tube containing a stirring bar was evacuated and backfilled with argon. The tube was charged with Pd(OAc)₂ (5 mol%), dppf (10 mol%), NaOt-Bu (1.2 equiv), aryl halide (1 equiv), and KSAc (1.2 equiv) under argon. The flask was capped with a rubber septum, and toluene was added. The reaction mixture was heated in a Biotage Initiator 2.5 microwave at 175 °C for 90 min. After completion, the reaction mixture was cooled to r.t., and the products were purified by preparative column chromatography. [1]Benzothiepino[3,2-c]pyridine (18) Yield 51%; white solid; mp 80–82 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.48–8.44 (m, 2 H), 7.48–7.44 (m, 1 H), 7.36–7.28 (m, 3 H), 7.28–7.24 (m, 1 H), 7.13 (d, J = 12.5 Hz, 1 H), 6.99 (d, J = 12.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 149.9, 149.8, 144.7, 139.7, 136.1, 135.4, 133.0, 132.7, 130.4, 129.9, 129.7, 128.7, 126.3. IR (ATR): 3056, 3025, 2927, 2855, 1738, 1629, 1563, 1538, 1471, 1442, 1416, 1389, 1306, 1275, 1174, 1056, 885, 836 cm^–1. ESI-HRMS (+): m/z = 212.05209 [M + H]⁺ (error: –3.58 ppm).