Synlett 2016; 27(05): 754-758
DOI: 10.1055/s-0035-1561320
cluster
© Georg Thieme Verlag Stuttgart · New York

Intermolecular Photocatalytic C–H Functionalization of Electron-Rich Heterocycles with Tertiary Alkyl Halides

Elizabeth C. Swift
Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, MI 48109, USA   Email: crjsteph@umich.edu
,
Theresa M. Williams
Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, MI 48109, USA   Email: crjsteph@umich.edu
,
Corey R. J. Stephenson*
Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, MI 48109, USA   Email: crjsteph@umich.edu
› Author Affiliations
Further Information

Publication History

Received: 29 October 2015

Accepted after revision: 16 December 2015

Publication Date:
08 January 2016 (online)

Abstract

The coupling of tertiary alkyl halides with electron-rich arenes is promoted by visible-light photoredox catalysis. Tris[2-phenylpyridinato-C 2,N]iridium(III) [Ir(ppy)3] was the optimal catalyst, enabling direct reduction of the halide from the excited state, and thereby eliminating the requirement for a stoichiometric electron donor. High yields were obtained when the aromatic component was used in excess, although equimolar amounts afforded only slightly diminished yields. The reaction tolerates a number of functional groups, including allyl, ester, amide, or carbamate. The efficiency of this reaction has been improved through demonstration of scale-up in flow, and a new substituted Ir(ppy)3 derivative was isolated and characterized.

Supporting Information

 
  • References and Notes

    • 1a Narayanam JM. R, Stephenson CR. J. Chem. Soc. Rev. 2011; 40: 102
    • 1b Tucker JW, Stephenson CR. J. J. Org. Chem. 2012; 77: 1617
    • 1c Prier CK, Rankic DA, MacMillan DW. C. Chem. Rev. 2013; 113: 5322
    • 1d Peña-López M, Rosas-Hernández A, Beller M. Angew. Chem. Int. Ed. 2015; 54: 5006
    • 2a Quasdorf KW, Overman LE. Nature 2014; 516: 181
    • 2b Corey EJ, Guzman-Perez A. Angew. Chem. Int. Ed. 1998; 37: 388

      For comparison of rates of addition, see:
    • 3a Giese B. Angew. Chem. Int. Ed. 1983; 22: 753
    • 3b Beckwith AL. J, Poole JS. J. Am. Chem. Soc. 2002; 124: 9489

    • For an insightful review, see:
    • 3c Rowlands GJ. Tetrahedron 2009; 65: 8603
    • 4a Lackner GL, Quasdorf KW, Pratsch G, Overman LE. J. Org. Chem. 2015; 80: 6012
    • 4b Pratsch G, Lackner GL, Overman LE. J. Org. Chem. 2015; 80: 6025
    • 4c Lackner GL, Quasdorf KW, Overman LE. J. Am. Chem. Soc. 2013; 135: 15342
    • 4d Chu L, Ohta C, Zuo Z, MacMillan DW. C. J. Am. Chem. Soc. 2014; 136: 10886
    • 4e Lo JC, Gui J, Yabe Y, Pan C.-M, Baran PS. Nature 2014; 516: 343
  • 5 Fischer H, Radom L. Angew. Chem. Int. Ed. 2001; 40: 1340

    • For additions to enamines and olefins, see:
    • 6a Silvi M, Arceo E, Jurberg ID, Cassani C, Melchiorre P. J. Am. Chem. Soc. 2015; 137: 6120
    • 6b Lin R, Sun H, Yang C, Shen W, Xia W. Chem. Commun. 2015; 51: 399
    • 6c Arceo E, Montroni E, Melchiorre P. Angew Chem Int. Ed. 2014; 53: 12064
    • 6d Wei X.-J, Yang D.-T, Wang L, Song T, Wu L.-Z, Liu Q. Org. Lett. 2013; 15: 6054
    • 6e Nishikata T, Noda Y, Fujimoto R, Sakashita T. J. Am. Chem. Soc. 2013; 135: 16372
    • 6f Gu X, Li X, Qu Y, Yang Q, Li P, Yao Y. Chem. Eur. J. 2013; 19: 11878
    • 6g Nicewicz DA, MacMillan DW. C. Science 2008; 322: 77
    • 7a Furst L, Narayanam JM. R, Stephenson CR. J. Angew. Chem. Int. Ed. 2011; 50: 9655

    • For manganese-catalyzed addition of malonates to pyrrole, thiophene, or furan, see:
    • 7b Hattori K, Ziadi A, Itami K, Yamaguchi J. Chem. Commun. 2014; 50: 4105

    • These conditions are not compatible with indole. For Ni-catalyzed addition of a tertiary radical to benzofuran, see:
    • 7c Nakatani A, Hirano K, Satoh T, Miura M. Chem. Eur. J. 2013; 19: 7691
    • 7d Zhou S, Zhang D, Sun Y, Li R, Zhang W, Li A. Adv. Synth. Catal. 2014; 356: 2867

      For radical addition to electron-rich aromatic heterocycles, see:
    • 8a Baciocchi E, Muraglia E. J. Org. Chem. 1993; 58: 7610
    • 8b Baciocchi E, Muraglia E, Sleiter G. J. Org. Chem. 1992; 57: 6817
    • 8c Baciocchi E, Muraglia E. IT MI921405, 1993
    • 8d Baciocchi E, Muraglia E. Tetrahedron Lett. 1993; 34: 5015
    • 8e Byers JH, DeWitt A, Nasveschuk CG, Swigor JE. Tetrahedron Lett. 2004; 45: 6587
    • 8f Guadarrama-Morales O, Méndez F, Miranda LD. Tetrahedron Lett. 2007; 48: 4515
    • 8g Lindsay KB, Ferrando F, Christensen KL, Overgaard J, Roca T, Bennasar M, Skrydstrup T. J. Org. Chem. 2007; 72: 4181
    • 8h Reyes-Gutiérrez PE, Torres-Ochoa RO, Martínez R, Miranda LD. Org. Biomol. Chem. 2009; 7: 1388
    • 9a Furst L, Matsuura BS, Narayanam JM. R, Tucker JW, Stephenson CR. J. Org. Lett. 2010; 12: 3104
    • 9b Tucker JW, Narayanam JM. R, Krabbe SW, Stephenson CR. J. Org. Lett. 2010; 12: 368
    • 10a Kaburagi Y, Tokuyama H, Fukuyama T. J. Am. Chem. Soc. 2004; 126: 10246
    • 10b Martin CL, Overman LE, Rohde JM. J. Am. Chem. Soc. 2010; 132: 4894
    • 10c Martin CL, Nakamura S, Otte R, Overman LE. Org. Lett. 2011; 13: 138
    • 10d Kuehne ME, Roland DM, Hafter R. J. Org. Chem. 1978; 43: 3705
    • 10e Magolan J, Kerr MA. Org. Lett. 2006; 8: 4561

      For selected recent examples of malonates in the synthesis of pharmaceutically relevant molecules, see:
    • 11a Yamakawa N, Suemasu S, Okamoto Y, Tanaka K.-i, Ishihara T, Asano T, Miyata K, Otsuka M, Mizushima T. J. Med. Chem. 2012; 55: 5143
    • 11b Roth GJ, Heckel A, Colbatzky F, Handschuh S, Kley J, Lehmann-Lintz T, Lotz R, Tontsch-Grunt U, Walter R, Hilberg F. J. Med. Chem. 2009; 52: 4466
    • 11c Duan JJ.-W, Chen L, Lu Z, Jiang B, Asakawa N, Sheppeck JE. II, Liu R.-Q, Covington MB, Pitts W, Kim S.-H, Decicco CP. Bioorg. Med. Chem. Lett. 2007; 17: 266
  • 12 Mahboobi S, Kuhr S, Meindl W. Arch. Pharm. (Weinheim, Ger.) 1994; 327: 611
    • 13a Beyer J, Jensen BS, Strøbaek D, Christophersen P, Teuber L. WO 037422, 2000
    • 13b Ledoux J, Werner ME, Brayden JE, Nelson MT. Physiology (Bethesda) 2006; 21: 69
    • 13c Dolga AM, Culmsee C. Front. Pharmacol. 2012; 3: 196
  • 14 Devery JJ. III, Douglas JJ, Nguyen JD, Cole KP, Flowers RA. II, Stephenson CR. J. Chem. Sci. 2015; 6: 537
    • 15a Kalyanasundaram K. Coord. Chem. Rev. 1982; 46: 159
    • 15b Juris A, Balzani V, Belser P, von Zelewsky A. Helv. Chim. Acta 1981; 64: 2175
  • 16 Lowry MS, Goldsmith JI, Slinker JD, Rohl R, Pascal RA, Malliaras GG, Bernhard S. Chem. Mater. 2005; 17: 5712
  • 17 Slinker JD, Gorodetsky AA, Lowry MS, Wang J, Parker S, Rohl R, Bernhard S, Malliaras GG. J. Am. Chem. Soc. 2004; 126: 2763
  • 18 Flamigni L, Barbieri A, Sabatini C, Ventura B, Barigelletti F. Top. Curr. Chem. 2007; 281: 143
  • 19 The reaction was found to proceed in a number of solvents; see Supporting Information for details.
  • 20 Nguyen JD, D’Amato EM, Narayanam JM. R, Stephenson CR. J. Nat. Chem. 2012; 4: 854
  • 21 Nguyen JD, Tucker JW. Konieczynska M. D, Stephenson CR. J. J. Am. Chem. Soc. 2011; 133: 4160
  • 22 Fors BP, Hawker CJ. Angew. Chem. Int. Ed. 2012; 51: 8850
  • 23 Diethyl 1H-Indol-2-yl(methyl)malonate (7); Typical Procedure A 7 mL vial equipped with magnetic stirrer bar was charged with diethyl-2-bromo-2-methylmalonate (1.0 equiv, 0.40 mmol, 0.10g), 2,6-lutidine (1.0 equiv, 0.40 mmol, 43 mg), Ir(ppy)3 (1 mol%, 4.0 µmol, 2.6 mg), and indole (5.0 equiv, 2.0 mmol, 0.23 g). Anhyd MeCN (0.5 mL, 0.8 M) was added, and the mixture was sparged with N2 for 15 min. It was then surrounded by a string of 1 W blue LEDs and stirred under N2 at r.t. for 24 h. The resulting mixture was diluted with EtOAc and extracted with H2O. The aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0–5% EtOAc–hexane) to give a white solid; yield: 97 mg (83%); Rf  = 0.36 (10% EtOAc–hexane). IR (neat): 3372, 2972, 1732, 1707, 1454, 1263 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.08 (s, 1 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.18 (t, J = 7.1 Hz, 1 H), 7.09 (t, J = 7.1 Hz, 1 H), 6.47 (s, 1 H), 4.27–4.23 (m, 4 H), 1.95 (s, 3 H), 1.28 (t, J = 7.1 Hz, 6 H). 13C NMR (176 MHz, CDCl3): δ = 170.4, 136.2, 134.7, 127.5, 122.2, 120.5, 119.7, 111.0, 101.4, 62.2, 54.3, 21.2, 14.0. HRMS (ESI): m/z [M + H]+ calcd for C16H20NO4: 290.1387; found: 290.1386. Dimethyl (4-{[tert-Butyl(dimethyl)silyl]oxy}butyl)(1H-indol-2-yl)malonate (14) Yellow oil; yield: 0.15 g (89%); Rf = 0.6 (20% EtOAc–hexane). IR (neat): 3426, 2951, 2356, 1729, 1456, 1254 cm–1. 1H NMR (700 MHz, CDCl3): δ = 9.60 (s, 1 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.11 (t, J = 7.5 Hz, 1 H), 6.44 (s, 1 H), 3.78 (s, 6 H), 3.57 (t, J = 6.3 Hz, 2 H), 2.45–2.43 (m, 2 H), 1.54 (quintet, J = 7.1 Hz, 2 H), 1.29–1.25 (m, 2 H), 0.87 (s, 9 H), 0.02 (s, 6 H). 13C NMR (176 MHz, CDCl3): δ = 170.6, 135.8, 133.9, 127.7, 122.1, 120.5, 119.9, 111.3, 101.3, 62.6, 58.5, 53.2, 36.5, 32.8, 26.0, 21.1, 18.3, –5.2. HRMS (ESI): m/z [M + H]+ calcd for C23H36NO5Si: 434.2357; found: 434.2355. Methyl 3-(1H-Indol-2-yl)-2-oxooxepane-3-carboxylate (24) Purple oil; yield: 40 mg (35%); Rf = 0.25 (30% EtOAc–hexane). IR (neat): 3317, 2943, 2360, 1738, 1696, 1454, 1224 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.72 (s, 1 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.38 (dd, J = 8.2, 0.7 Hz, 1 H), 7.20 (td, J = 7.6, 1.1 Hz, 1 H), 7.11 (td, J = 7.5, 0.8 Hz, 1 H), 6.50 (d, J = 1.3 Hz, 1 H), 4.19 (ddd, J = 12.7, 7.6, 1.9 Hz, 1 H), 4.08 (ddd, J = 12.7, 8.1, 1.8 Hz, 1 H), 3.78 (s, 3 H), 2.72 (dt, J = 14.7, 5.8 Hz, 1 H), 2.38 (dt, J = 14.7, 6.6 Hz, 1 H), 2.06 (quintet, J = 6.1 Hz, 2 H), 1.94–1.88 (m, 1 H), 1.85–1.80 (m, 1 H). 13C NMR (176 MHz, CDCl3): δ = 171.6, 169.6, 136.7, 133.6, 127.7, 122.8, 120.8, 120.2, 111.4, 102.3, 69.5, 59.8, 53.5, 31.3, 28.1, 24.1. HRMS (ESI): m/z [M + H]+ calcd for C16H18NO4: 288.1230; found: 288.1299. Diethyl Methyl(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)malonate (29) Brown oil; yield: 0.11 g (80%); Rf = 0.5 (20% EtOAc–hexane). IR (neat): 2982, 1724, 1648, 1597, 1558, 1228 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.24–7.21 (m, 2 H), 6.08 (t, J = 6.9 Hz, 1 H), 4.24–4.13 (m, 4 H), 3.47 (s, 3 H), 1.74 (s, 3 H), 1.20 (t, J = 7.1 Hz, 6 H). 13C NMR (176 MHz, CDCl3): δ = 170.7, 161.2, 137.5, 135.4, 131.7, 105.0, 61.6, 57.4, 37.8, 20.8, 14.0. HRMS (ESI): m/z [M + Na]+ calcd for C14H19NNaO5: 304.1155; found: 304.1155.
  • 24 Smith FX, Evans GG. Tetrahedron Lett. 1972; 13: 1237
    • 25a For a recent review, see: Su Y, Straathof NJ. W, Hessel V, Noël T. Chem. Eur. J. 2014; 20: 10562. For selected examples, see
    • 25b Bou-Hamdan FR, Seeberger PH. Chem. Sci. 2012; 3: 1612
    • 25c Andrews RS, Becker JJ, Gagné MR. Angew. Chem. Int. Ed. 2012; 51: 4140
    • 25d Tucker JW, Zhang Y, Jamison TF, Stephenson CR. J. Angew. Chem. Int. Ed. 2012; 51: 4144
    • 25e Beatty J, Stephenson CR. J. J. Am. Chem. Soc. 2014; 136: 10270