Synlett, Inhaltsverzeichnis Synlett 2016; 27(01): 146-150DOI: 10.1055/s-0035-1560519 letter © Georg Thieme Verlag Stuttgart · New York Synthetic Studies on Psychotrimine: Palladium-Catalysed Arylation of 2-(N-Indolyl) Amides Emma L. Watson a Institute of Process Research and Development and School of Chemistry, University of Leeds, Leeds LS2 9JT, UK eMail: s.p.marsden@leeds.ac.uk , Anthony Ball a Institute of Process Research and Development and School of Chemistry, University of Leeds, Leeds LS2 9JT, UK eMail: s.p.marsden@leeds.ac.uk , Steven A. Raw b AstraZeneca, Chemical Development, Charter Way, Silk Road Business Park, Macclesfield SK10 2NA, UK , Stephen P. Marsden* a Institute of Process Research and Development and School of Chemistry, University of Leeds, Leeds LS2 9JT, UK eMail: s.p.marsden@leeds.ac.uk › Institutsangaben Artikel empfehlen Abstract Artikel einzeln kaufen Alle Artikel dieser Rubrik Dedicated to Professor Steve Ley FRS on the occasion of his 70th birthday Abstract Through careful choice of conditions, 2-(N-indolyl) amides can be directed to undergo selectively either enolate arylation to give oxindoles or direct arylation to give indolo-fused benzodiazepines. The former chemistry facilitates the synthesis of the hexahydropyrrolindole core of psychotrimine. Key words Key wordsalkaloids - arylation - cyclisation - polycycles - total synthesis Volltext Referenzen References and Notes 1 Takayama H, Mori I, Kitajima M, Aimi N, Lajis NH. Org. Lett. 2004; 6: 2945 2a Anthoni U, Christophersen C, Nielsen PH In Alkaloids: Chemical and Biological Perspectives . Vol. 13. Pelletier SW. Pergamon Press; Oxford: 1999: 163 2b Steven A, Overman LE. Angew. Chem. Int. Ed. 2007; 46: 5488 2c Schmidt MA, Movassaghi M. Synlett 2008; 313 2d Ruiz-Sanchis P, Savina SA, Albericio F, Alvarez M. Chem. Eur. J. 2011; 17: 1388 3 Foo K, Newhouse T, Mori I, Takayama H, Baran PS. Angew. Chem. Int. Ed. 2011; 50: 2716 4 Schallenberger MA, Newhouse T, Baran PS, Romesberg FE. J. Antibiot. 2010; 63: 685 5 Matsuda Y, Kitajima M, Takayama H. Org. Lett. 2008; 10: 125 6 Takahashi N, Ito Y, Matsuda Y, Kogure N, Kitajima M, Takayama H. Chem. Commun. 2010; 46: 2501 7a Newhouse T, Baran PS. J. Am. Chem. Soc. 2008; 130: 10866 7b Newhouse T, Lewis CA, Eastman KJ, Baran PS. J. Am. Chem. Soc. 2010; 132: 7119 8a Araki T, Ozawa T, Yokoe H, Kanematsu M, Yoshida M, Shishido K. Org. Lett. 2013; 15: 200 8b Zhang H, Kang H, Hong L, Dong W, Li G, Zheng X, Wang R. Org. Lett. 2014; 16: 2394 9a Marsden SP, Watson EL, Raw SA. Org. Lett. 2008; 10: 2905 9b Jia Y.-X, Hillgren JM, Watson EL, Marsden SP, Kundig EP. Chem. Commun. 2008; 4040 9c Watson EL, Raw SA. Tetrahedron Lett. 2009; 50: 3318 10 Hillgren JM, Marsden SP. J. Org. Chem. 2008; 73: 6459 11a Marsden SP. Cross-Coupling and Heck-Type Reactions . In Science of Synthesis . Vol. 2. Wolfe JP. Thieme; Stuttgart: 2013: 565 11b Bellina F, Rossi R. Chem. Rev. 2010; 110: 1082 11c Johansson CC. C, Colacot TJ. Angew. Chem. Int. Ed. 2010; 49: 676 11d Culkin DA, Hartwig JF. Acc. Chem. Res. 2003; 36: 234 12 Lebsack AD, Link JT, Overman LE, Stearns BA. J. Am. Chem. Soc. 2002; 124: 9008 13a Sames D, Brown MA, Lane BS. J. Am. Chem. Soc. 2005; 127: 8050 13b Bressy C, Alberico D, Lautens M. J. Am. Chem. Soc. 2005; 127: 13148 14 For a related synthesis of medium-ring-fused indoles by direct oxidative C–H coupling, see: Pintori DG, Greaney MF. J. Am. Chem. Soc. 2011; 133: 1209 15 Gentles RG, Ding M, Bender JA, Bergstrom CP, Grant-Young K, Hewawasam P, Hudyma T, Martin S, Nickel A, Reguiero-Ren A, Tu Y, Yang Z, Yeung K.-S, Zheng X, Chao S, Sun J.-H, Beno BR, Camac DM, Chang C.-H, Gao M, Morin PE, Sheriff S, Tredup J, Wan J, Witmer MR, Xie D, Hanumegowda U, Knipe J, Mosure K, Santone KS, Parker DD, Zhuo X, Lemm J, Liu M, Pelosi L, Rigat K, Voss S, Wang Y, Wang Y.-K, Colonno RJ, Gao M, Roberts SB, Gao Q, Ng A, Meanwell NA, Kadow JF. J. Med. Chem. 2014; 57: 1855 16 General Procedure for the Synthesis of Indolo-Fused Benzodiazepinones 8 To a mixture of Pd(OAc)2 (0.1 equiv), Ph3P (0.1 equiv), TBAB (1 equiv), and KOAc (2 equiv) in a microwave vial was added toluene (1 mL) and the mixture stirred at r.t. for 30 min. A solution of the substrate (0.5 mmol) dissolved in toluene (1 mL) was added, the vial sealed under nitrogen, and the mixture subjected to microwave irradiation [CEM Discover, variable power mode (max 300 W), constant temperature of 120 °C] for 15 min. The reaction mixture was cooled and filtered. The filtrate was diluted with EtOAc and H2O. The layers were separated and the organic layer dried (MgSO4) and concentrated under reduced pressure to give the crude product, which was purified by chromatography. By this general procedure, compound 6a (200 mg, 0.54 mmol) gave the known product 8a (134 mg, 87% yield), whose spectral data were identical to those reported in ref. 9a. 17 General Procedure for the Synthesis of Oxindoles 14 To a mixture of Pd2(dba)3 (0.05 equiv), 1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride (0.01 equiv), and NaOt-Bu (3.0 equiv) was added toluene (ca. 0.10 M). A solution of the substrate (1.0 equiv) in the minimum volume of toluene was added, and the mixture was stirred and heated to 80 °C for 8 h. After cooling to r.t., the reaction mixture was concentrated under reduced pressure to leave a dark brown powdery residue. This was dry-loaded onto a silica gel column and purified by chromatography. By this procedure, amide 13a (0.10 g, 0.14 mmol) gave, after chromatography (eluent EtOAc–PE, 1:5), oxindole 14a (66.8 mg, 73%) as a yellow oil; Rf = 0.31 (solvent Et2O–PE, 1:1). IR (film): νmax = 2928, 1730, 1693, 1612, 1459, 1364, 1171, 1098 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.58–7.24 (9 H, m, ArH), 7.10 (1 H, d, J = 7.2 Hz, ArH), 7.00 (1 H, t, J = 7.5 Hz, ArH), 6.91 (1 H, d, J = 7.8 Hz, ArH), 6.77 (1 H, t, J = 7.7 Hz, ArH), 6.29 (1 H, d, J = 8.4 Hz, ArH), 5.04 (1 H, d, J = 15.4 Hz, NCH AHBPh), 4.87 (1 H, d, J = 15.4 Hz, NCHA H BPH), 3.74–3.46 (4 H, m, OCH2, NCH2), 3.18–2.66 (7 H, m, NCH3, CqCH2, ArCH2), 1.43 [9 H, br s, OC(CH3)3], 0.82 [9 H, s, SiC(CH3)3], –0.01 (3 H, s, SiCH3), –0.06 (3 H, s, SiCH3). 13C NMR (75 MHz, CDCl3): δ = 174.9 (oxindole C=O), 155.8 (Boc C=O), 142.4 (ArCq), 135.6 (ArCq), 129.8 (ArCH), 129.5 (ArCq), 128.9 (2 × ArCH), 128.7 (ArCq), 128.4 (ArCq), 128.3 (ArCH), 128.0 (ArCH), 127.5 (ArCH), 124.4 (ArCH), 123.4 (ArCH), 121.8 (ArCH), 119.5 (ArCH), 118.9 (ArCH), 113.1 (ArCq), 111.5 (ArCH), 109.7 (ArCH), 79.3 [OC(CH3)3], 64.9 (Cq), 58.2 (OCH2), 49.8 (NCH2), 44.4 (NCH2Ph), 40.1 (CqCH2), 34.4 (NCH3), 28.5 [OC(CH3)3], 25.9 [SiC(CH3)3], 23.8 (ArCH2), 18.2 [SiC(CH3)3], –5.4 [Si(CH3)2]. HRMS: m/z calcd for C39H52N3O4Si [MH+]: 654.3722; found: 654.3720. 18 Nandra GS, Porter MJ, Elliott JM. Synlett 2005; 475 19a Seo JH, Artman GD, Weinreb SM. J. Org. Chem. 2006; 71: 8891 19b Inoue M, Furuyama H, Sakazaki H, Hirama M. Org. Lett. 2001; 3: 2863 19c Lin S, Danishefsky SJ. Angew. Chem. Int. Ed. 2001; 40: 1967
