Synlett 2017; 28(17): 2335-2339
DOI: 10.1055/s-0036-1588491
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3,3′-Disubstituted Indolenines Utilizing the Lewis Acid Catalyzed Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates

Arijit A. Adhikari, Léa Radal, John D. Chisholm*
  • Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, NY 13244-4100, USA   Email: jdchisho@syr.edu
Acknowledgement is made to the Donors of the American Chemical Society Petroleum Research Fund for a New Directions award in support of this research (54823-ND1). The National Institute of General Medical Sciences (R15-GM116054) also provided financial support. NMR spectra were obtained at Syracuse University using instrumentation acquired with the assistance of the National Science Foundation (CHE-1229345). L. R. thanks the Laboratoire d’Excellence Multiscale Integrative Chemistry (LabEx MiChem) for a travel grant to facilitate study in the USA.
Further Information

Publication History

Received: 09 May 2017

Accepted after revision: 13 June 2017

Publication Date:
11 July 2017 (eFirst)

Abstract

Trichloroacetimidates function as effective electrophiles for the selective C3-alkylation of 2,3-disubstituted indoles to provide 3,3′-disubstituted indolenines. These indolenines are common synthetic intermediates that are often utilized in the synthesis of complex molecules. Effective reaction conditions utilizing Lewis acid catalysts have been determined, and the scope of the reaction with respect to indole and imidate reaction partner has been investigated. This chemistry provides an alternative to base promoted and transition-metal-catalyzed methods that are more commonly utilized to access similar indolenines.

Supporting Information

 
  • References and Notes

    • 1a James MJ. O'Brien P. Taylor RJ. K. Unsworth WP. Chem. Eur. J. 2016; 22: 2856
    • 1b Roche SP. Youte Tendoung J.-J. Treguier B. Tetrahedron 2015; 71: 3549
    • 1c Zhou C.-X. Zhang W. You S.-L. Angew. Chem. Int. Ed. 2012; 51: 12662
    • 1d Roche SP. Porco JA. Jr. Angew. Chem. Int. Ed. 2011; 50: 4068
    • 1e Bandini M. Eichholzer A. Angew. Chem. Int. Ed. 2009; 48: 9608
  • 2 Ahmad Y. Fatima K. Atta urR. Occolowitz JL. Solheim BA. Clardy J. Garnick RL. Le Quesne PW. J. Am. Chem. Soc. 1977; 99: 1943
  • 3 Liu C.-T. Wang Q.-W. Wang C.-H. J. Am. Chem. Soc. 1981; 103: 4634
  • 4 Kump WG. Patel MB. Rowson JM. Schmid H. Helv. Chim. Acta 1964; 47: 1497
  • 5 Subramaniam G. Hiraku O. Hayashi M. Koyano T. Komiyama K. Kam T.-S. J. Nat. Prod. 2007; 70: 1783
  • 6 Numata A. Takahashi C. Ito Y. Takada T. Kawai K. Usami Y. Matsumura E. Imachi M. Ito T. Hasegawa T. Tetrahedron Lett. 1993; 34: 2355
    • 7a Nakazaki M. Bull. Chem. Soc. Jpn. 1959; 32: 838
    • 7b Nakazaki M. Bull. Chem. Soc. Jpn. 1961; 34: 334
    • 7c Jackson AH. Lynch PP. J. Chem. Soc., Perkin Trans. 2 1987; 1215
    • 7d Fishwick CW. G. Jones AD. Mitchell MB. Heterocycles 1991; 32: 685
    • 7e Solovjova J. Martynaitis V. Mangelinckx S. Holzer W. De Kimpe N. Sackus A. Synlett 2009; 3119
    • 7f Lin A. Yang J. Hashim M. Org. Lett. 2013; 15: 1950

    • A combination of photochemistry and a weak amine base has also been employed, see:
    • 7g Kandukuri SR. Bahamonde A. Chatterjee I. Jurberg ID. Escudero-Adan EC. Melchiorre P. Angew. Chem. Int. Ed. 2015; 54: 1485
    • 8a Kimura M. Futamata M. Mukai R. Tamaru Y. J. Am. Chem. Soc. 2005; 127: 4592
    • 8b Trost BM. Quancard J. J. Am. Chem. Soc. 2006; 128: 6314
    • 8c Zhu Y. Rawal VH. J. Am. Chem. Soc. 2012; 134: 111
    • 8d Montgomery TD. Zhu Y. Kagawa N. Rawal VH. Org. Lett. 2013; 15: 1140
    • 8e Kagawa N. Malerich JP. Rawal VH. Org. Lett. 2008; 10: 2381
    • 8f Chen J. Cook MJ. Org. Lett. 2013; 15: 1088
    • 8g Rocchigiani L. Jia M. Bandini M. Macchioni A. ACS Catal. 2015; 5: 3911
    • 8h Nibbs AE. Montgomery TD. Zhu Y. Rawal VH. J. Org. Chem. 2015; 80: 4928
    • 9a Cai Q. Liu C. Liang X.-W. You S.-L. Org. Lett. 2012; 14: 4588
    • 9b Romano C. Jia M. Monari M. Manoni E. Bandini M. Angew. Chem., Int. Ed. 2014; 53: 13854
    • 9c Zhang Y.-C. Zhao J.-J. Jiang F. Sun S.-B. Shi F. Angew. Chem. Int. Ed. 2014; 53: 13912
    • 9d Yeung CS. Ziegler RE. Porco JA. Jacobsen EN. J. Am. Chem. Soc. 2014; 136: 13614
    • 10a Duffy BC. Howard KT. Chisholm JD. Tetrahedron Lett. 2015; 56: 3301
    • 10b Wallach DR. Stege PC. Shah JP. Chisholm JD. J. Org. Chem. 2015; 80: 1993
    • 10c Wallach DR. Chisholm JD. J. Org. Chem. 2016; 81: 8035
    • 10d Adhikari AA. Chisholm JD. Org. Lett. 2016; 18: 4100
    • 10e Adhikari AA. Suzuki T. Gilbert RT. Linaburg MR. Chisholm JD. J. Org. Chem. 2017; 82: 3982
    • 11a Schmidt RR. Hoffmann M. Tetrahedron Lett. 1982; 23: 409
    • 11b Schmidt RR. Effenberger G. Carbohydr. Res. 1987; 171: 59
    • 11c Mahling JA. Schmidt RR. Synthesis 1993; 325
    • 11d Ali IA. I. El Ashry ES. H. Schmidt RR. Tetrahedron 2004; 60: 4773
    • 11e Zhang J. Schmidt RR. Synlett 2006; 1729
    • 11f Li C. Wang J. J. Org. Chem. 2007; 72: 7431
    • 11g Devineau A. Pousse G. Taillier C. Blanchet J. Rouden J. Dalla V. Adv. Synth. Catal. 2010; 352: 2881
    • 11h Piemontesi C. Wang Q. Zhu J. Org. Biomol. Chem. 2013; 11: 1533
    • 12a Schmidt RR. Effenberger G. Liebigs Ann. Chem. 1987; 825
    • 12b El-Desoky ES. I. Abdel Rahman HA. R. Schmidt RR. Liebigs Ann. Chem. 1990; 877
    • 12c Schnabel M. Römpp B. Ruckdeschel D. Unverzagt C. Tetrahedron Lett. 2004; 45: 295
    • 12d Tokuyama H. Okano K. Fujiwara H. Noji T. Fukuyama T. Chem. Asian J. 2011; 6: 560
    • 12e Wiebe C. Schlemmer C. Weck S. Opatz T. Chem. Commun. 2011; 47: 9212
    • 12f Wiebe C. Fuste de la Sotilla S. Opatz T. Synthesis 2012; 44: 1385
    • 13a Anderson AG. Stang PJ. J. Org. Chem. 1976; 41: 3034
    • 13b Brown HC. Kanner B. J. Am. Chem. Soc. 1966; 88: 986
    • 14a Schmidt RR. Michel J. J. Carbohydr. Chem. 1985; 4: 141
    • 14b Thierry J. Yue C. Potier P. Tetrahedron Lett. 1998; 39: 1557
    • 14c Respondek T. Cueny E. Kodanko JJ. Org. Lett. 2012; 14: 150
    • 14d Adhikari AA. Shah JP. Howard KT. Russo CM. Wallach DR. Linaburg MR. Chisholm JD. Synlett 2014; 25: 283
    • 14e Shah JP. Russo CM. Howard KT. Chisholm JD. Tetrahedron Lett. 2014; 55: 1740
    • 14f Howard KT. Duffy BC. Linaburg MR. Chisholm JD. Org. Biomol. Chem. 2016; 14: 1623
  • 15 For a review on synthetic routes to communensin, see: Trost BM. Osipov M. Chem. Eur. J. 2015; 21: 16318

    • For other routes to similar communensin core structures, see ref. 8b and:
    • 16a May JA. Zeidan RK. Stoltz BM. Tetrahedron Lett. 2003; 44: 1203
    • 16b Boal BW. Schammel AW. Garg NK. Org. Lett. 2009; 11: 3458
    • 16c Robertson FJ. Kenimer BD. Wu J. Tetrahedron 2011; 67: 4327
  • 17 Representative Procedure for C3-Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates In a flame-dried flask allyl trichloroacetimidate 7 (121 mg, 0.60 mmol) was dissolved in 4 mL of anhydrous DCE. 2,3-Dimethylindole (6, 130 mg, 0.90 mmol) was then added followed by freshly distilled TMSOTf (20 mol%, 27 μL, 0.12 mmol). After 3 h at rt the reaction mixture was quenched with the addition of 10 mL of 1 M NaOH. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30% EtOAc/70% hexanes) to provide 2,3-dimethyl-3-(prop-2-en-1-yl)-3H-indole (8) as a yellow oil (82.0 mg, 74%). TLC Rf = 0.11 (10% EtOAc/90% hexanes). IR (neat): 3079, 3009, 2966, 2827, 2869, 1579 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.0 Hz, 1 H), 7.33–7.21 (m, 2 H), 7.19 (td, J = 7.2, 0.8 Hz, 1 H), 5.21–5.11 (m, 1 H), 4.98–4.85 (m, 2 H), 2.66–2.60 (m, 1 H), 2.42 (dd, J = 14.0, 8.0 Hz, 1 H), 2.26 (s, 3 H), 1.31 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 186.6, 154.2, 143.4, 132.5, 127.7, 125.0, 121.8, 119.8, 118.0, 57.5, 41.2, 21.8, 15.9. This compound has been reported previously.8f