Synlett, Inhaltsverzeichnis Synlett 2017; 28(20): 2859-2864DOI: 10.1055/s-0036-1589105 letter © Georg Thieme Verlag Stuttgart · New York One-Pot Michael Addition/Radical Cyclization Reaction of N-Acryloyl Indoles Lauren C. Irwin Department of Chemistry, The University of Western Ontario, London, ON, N6A 5B7, Canada eMail: makerr@uwo.ca , Michael A. Kerr* Department of Chemistry, The University of Western Ontario, London, ON, N6A 5B7, Canada eMail: makerr@uwo.ca › Institutsangaben Artikel empfehlen Abstract Artikel einzeln kaufen Alle Artikel dieser Rubrik Abstract From N-acryloyl indoles, ten examples of 1,2-annulated indole products were generated in a one-pot procedure via a Michael addition and radical cyclization mediated by Mn(OAc)3. Key words Key wordsindoles - radical reaction - heterocycles - alkaloids - Michael addition Volltext Referenzen References and Notes 1a Samala S. Arigela RK. Kant R. Kundu B. J. Org. Chem. 2014; 79: 2491 1b Sessler JL. Cho D.-G. Lynch V. J. Am. Chem. Soc. 2006; 128: 16518 1c Zhang M.-Z. Chen Q. Yang G.-F. Eur. J. Med. Chem. 2015; 89: 421 1d Hamann MT. Waseem G. Life. Sci. 2005; 78: 442 1e Gul W. Hamann MT. Life Sci. 2005; 78: 442 Tronocarpine: 2a Sim K.-M. Lim T.-M. Kam T.-S. Tetrahedron Lett. 2000; 41: 2733 2b Sapeta K. Kerr MA. Org. Lett. 2009; 11: 2081 2c Torres-Ochoa RO. Reyes-Gutierrez PE. Martinez R. Eur. J. Org. Chem. 2014; 48 3a Ervataine: Jin Y.-S. Du J.-L. Chen H.-S. Jin L. Liang S. Fitoterapia 2010; 81: 63 3b Chippiinne: Van Beek TA. Verpoorte R. Baerheim Svendsen A. Fokkens R. J. Nat. Prod. 1985; 48: 400 4a Abubakar IB. Lim K.-H. Kam TS. Loh H.-S. Phytochemistry 2017; 30: 74 4b Raja VJ. Lim K.-H. Leong C.-O. Kam T.-S. Bradshaw TD. Invest. New Drugs 2014; 32: 838 4c Low Y.-Y. Lim K.-H. Choo Y.-M. Pang H.-S. Etoh T. Hayashi M. Komiyama K. Kam T.-S. Tetrahedron Lett. 2010; 51: 269 For other examples of radical chemistry to functionalize indoles, see: 5a Chuang C.-P. Wang S.-F. Tetrahedron Lett. 1994; 35: 1283 5b Bhat V. Mackay JA. Rawal VH. Org. Lett. 2011; 13: 3214 5c Tsai A.-I. Lin C.-H. Chuang C.-P. Heterocycles 2005; 65: 2381 5d Lopchuk JM. Montgomery WL. Jasinski JP. Gorifard S. Gribble GW. Tetrahedron Lett. 2013; 54: 6142 5e Baciocchi E. Muraglia E. J. Org. Chem. 1993; 58: 7610 For reviews on Mn(OAc)3 chemistry, see: 6a Mondal M. Bora U. RCS Adv. 2013; 3: 18716 6b Snider BB. Chem. Rev. 1996; 96: 339 6c Snider BB. Cole BM. J. Org. Chem. 1995; 60: 5376 6d Snider BB. Tetrahedron 2009; 65: 10735 6e Mohan R. Kates SA. Domroski MA. Snider BB. Tetrahedron Lett. 1987; 28: 854 7a Artis DR. Cho I.-S. Muchowski JM. Can. J. Chem. 1992; 70: 1838 7b Artis DR. Cho I.-S. Jaime-Figueroa S. Muchowski JM. J. Org. Chem. 1994; 59: 2456 8 Magolan J. Kerr MA. Org. Lett. 2006; 8: 4561 9 Magolan J. Carson CA. Kerr MA. Org. Lett. 2008; 10: 1437 10 Kandukuri SR. Schiffner JA. Oestreich M. Angew. Chem. Int. Ed. 2012; 51: 1265 11a Michael A. J. Prakt. Chem. 1887; 35: 349 11b Liu X. Chen X. Mohr JT. Chem. Eur. J. 2016; 22: 2274 11c Alcaide B. Almendros P. Aragoncillo C. J. Org. Chem. 2001; 66: 1612 11d Wu B. Gao X. Yan Z. Chen M.-W. Zhou Y.-G. Org. Lett. 2015; 17: 6134 12 General Experimental Procedure: One-Pot Michael Addition, Radical Cyclization (15a–j, 16) To an argon-flushed round-bottom flask was added half of the total volume of THF (0.15 M) required followed by NaH (60% dispersed in mineral oil, 1.5 equiv). The 1,3-dicarbonyl species (1.5 equiv) was added dropwise via syringe with stirring under argon. The resultant mixture was stirred for 15 min at which point the desired indole (1 equiv), dissolved in the other half-volume of THF, was added via syringe or cannula. The Michael addition was monitored by TLC. Once TLC confirmed complete consumption of starting indole, Mn(OAc)3(7 equiv) was added to the round-bottom flask followed by AcOH (0.12 M). The flask was equipped with a reflux condenser and put back under an argon atmosphere. The reaction was brought to 110 °C and refluxed until the mixture changed color from a dark brown to now containing obvious white solid in a yellow/orange solution. At this point, TLC analysis always indicated complete consumption of starting materials. The crude reaction mixture was allowed to cool to r.t. and then diluted with a large excess of EtOAc. The solution was vacuum filtered through a thick pad of Celite and then flushed with even more EtOAc. The solvent was removed under reduced pressure with added toluene to aid in the removal of AcOH. The obtained dried crude product was purified with flash column chromatography (EtOAc in hexanes). The desired fractions of the column were collected to a separatory funnel and washed twice with 1 M NaOH solution and then followed with a brine wash. The organic layer was collected, dried with MgSO4, and concentrated in vacuo to yield product. Product 15a Following the general experimental procedure, 15a was synthesized from acyl-indole 14a (0.30 g, 1.51 mmol), NaH (0.091g, 2.27 mmol), dimethyl malonate (0.30 g, 2.27 mmol, 0.26 mL) in 10 mL of THF then Mn(OAc)3 (2.80 g, 10.6 mmol) in AcOH (13 mL). Compound 15a was isolated as a yellow solid (0.33 g, 65%); Rf = 0.40 (20% EtOAc in hexanes); mp 126–129 °C. 1H NMR (400 MHz, CDCl3): δ = 8.50 (d, J = 8.2 Hz, 1 H), 7.50 (d, = 7.7 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 2.90 (ddq, J = 12.6, 6.5, 6.3 Hz, 1 H), 2.84 (dd, J = 13.0, 4.4 Hz, 1 H), 2.39 (t, J = 13.0 Hz, 1 H), 2.16 (s, 3 H), 1.42 (d, J = 6.8 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.9, 170.4, 169.0, 134.5, 131.1, 128.2, 125.7, 124.0, 118.6, 117.9, 116.8, 55.7, 53.6, 37.5, 35.4, 15.7, 9.2 IR 3027, 2954, 1785, 1702, 1456, 1386, 1385, 1308, 1245, 751. HRMS: m/z calcd for C18H19NO5: 329.1263; found [M+]: 329.12682. Product 15d Following the general experimental procedure, 15d was synthesized from acryloyl indole 14d (0.25 g, 1.35 mmol), dimethyl malonate (0.27 g, 2.02 mmol, 0.23 mL), NaH (0.081 g, 2.02 mmol) in 9 mL of THF. Following completion of the Michael addition was then added Mn(OAc)3 (2.53 g, 9.40 mmol) and AcOH (11 mL). Compound 15d was isolated as a pale orange solid (0.18 g, 45%); Rf = 0.27 (20% EtOAc in hexanes); mp 109–113 °C. 1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 8.2 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.39–7.31 (m, 1 H), 7.28 (m, 1 H), 6.68 (s, 1 H), 3.89 (s, 3 H), 3.77 (s, 3 H), 2.80 (ddd, J = 13.3, 6.7, 4.5 Hz, 1 H), 2.72 (dd, J = 13.6, 4.5 Hz, 1 H), 2.51 (t, J = 13.5 Hz, 1 H), 1.43 (d, J = 6.8 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 171.0, 169.6, 168.8, 135.4, 133.0, 129.3, 125.5, 124.3, 120.8, 116.8, 109.2, 55.7, 53.7, 42.0, 36.4, 35.3, 15.9. IR: 2956, 2923, 2852, 1746, 1708, 1437, 1300, 1144, 1063, 836 cm–1. HRMS: m/z calcd for C17H17NO5: 315.11067; found [M+]: 315.11120. 13 Cai G.-X. Wen J. Lai T.-T. Xie D. Zhou C.-H. Org. Biomol. Chem. 2016; 14: 2390 For other indoline to indole oxidations involving Mn, see: 14a Ketcha DM. Tetrahedron Lett. 1988; 29: 2151 14b Gourdoupis CG. Stamos IK. Synth. Commun. 1993; 23: 2241 Zusatzmaterial Zusatzmaterial Supporting Information
