Further Investigations into the Regioselectivity of 6,7-Indole Aryne Cyclo­additions with 2-Substituted Furans: Remarkable Contrasteric Preference Depends­ on Pyrrole and Benzene Ring Substitution

This paper is warmly dedicated to Professor Scott Denmark on the occasion of his 60^th birthday.

Abstract

A series of related 6,7-dibromoindole compounds were prepared to study the effects of pyrrole and benzene ring substitution patterns on the regioselectivity of 6,7-indole aryne cycloadditions with 2-tert-butylfuran. The arynes were generated by our metal–halogen exchange/elimination protocol. The results of this investigation reveal that substitution at the 3-position on the indole ring in particular results in remarkable regiocontrol that favored the contrasteric products. Aromatic conjugation at this site significantly enhanced this effect. However, the presence of most 4- or 5-substituents generally resulted in markedly reduced selectivity. Exceptions in this latter series included the 4-ethyl and 4-iodo cases both of which also gave predominantly contrasteric products even in the absence of a beneficial C-3 substituent.

Key words

alkaloids - arynes - cycloaddition - indoles - regioselectivity

• References


For reviews of arynes, see:
• 1a Gampe CM, Carreira EM. Angew. Chem. Int. Ed. 2012; 51: 3766
• 1b Hoffmann RW. Dehydrobenzene and Cycloalkynes . Academic; New York: 1967
• 1c Pellissier H, Santelli M. Tetrahedron 2003; 59: 701
• 1d Wenk HH, Winkler M, Sander W. Angew. Chem. Int. Ed. 2003; 42: 502
• 1e Reinecke MG. Tetrahedron 1982; 38: 427
• 2a Buszek KR, Luo D, Kondrashov M, Brown N, VanderVelde D. Org. Lett. 2007; 9: 4135
• 2b Buszek KR, Brown N, Luo D. Org. Lett. 2009; 11: 201
• 2c Brown N, Luo D, VanderVelde D, Yang S, Brassfield A, Buszek KR. Tetrahedron Lett. 2009; 50: 63
• 2d Brown N, Luo D, Decapo JA, Buszek KR. Tetrahedron Lett. 2009; 50: 7113
• 2e Garr AN, Luo D, Brown N, Cramer CJ, Buszek KR, VanderVelde D. Org. Lett. 2010; 12: 96
• 2f Chandrasoma N, Brown N, Brassfield A, Nerurkar A, Suarez S, Buszek KR. Tetrahedron Lett. 2013; 54: 913
• 3 Brown N, Buszek KR. Tetrahedron Lett. 2012; 53: 4022
• 4 Buszek, K. R. Heterocycles 2013, in press.
• 5a Thornton PD, Brown N, Hill D, Neuenswander B, Lushington GH, Santini C, Buszek KR. ACS Comb. Sci. 2011; 13: 443
• 5b Perchellet J.-PH, Waters AM, Perchellet EM, Thornton PD, Brown N, Hill D, Neuenswander B, Lushington GH, Santini C, Chandrasoma N, Buszek KR. Anticancer Res. 2012; 32: 4671
• 6a Bronner SM, Bahnck KB, Garg NK. Org. Lett. 2009; 11: 1007
• 6b Tian X, Huters AD, Douglas CJ, Garg NK. Org. Lett. 2009; 11: 2349
• 6c Bronner SM, Garg NK. J. Org. Chem. 2009; 74: 8842
• 6d Cheong PH.-Y, Paton RS, Bronner SM, Im G.-TJ, Garg NK, Houk KN. J. Am. Chem. Soc. 2010; 132: 1267
• 6e Im G-YJ, Bronner SM, Goetz AE, Paton RS, Cheong PH.-Y, Houk KN, Garg NK. J. Am. Chem. Soc. 2010; 132: 17933
• 6f Bronner SM, Goetz AE, Garg NK. J. Am. Chem. Soc. 2011; 133: 3832
• 6g Huters AD, Quasdorf KW, Styduhar ED, Garg NK. J. Am. Chem. Soc. 2011; 133: 15797
• 6h Goetz AE, Bronner SM, Cisneros JD, Melamed JM, Paton RS, Houk KN, Garg NK. Angew. Chem. Int. Ed. 2012; 51: 2758
• 6i Quasdorf KW, Huters AD, Lodewyk MW, Tantillo DJ, Garg NK. J. Am. Chem. Soc. 2012; 134: 1396
• 7a Nguyen TD, Webster R, Lautens M. Org. Lett. 2011; 13: 1370
• 7b Candito DA, Dobrovolsky D, Lautens M. J. Am. Chem. Soc. 2012; 134: 15572

Bartoli indole synthesis:
• 8a Bartoli G, Palmieri G, Bosco M, Dalpozzo R. Tetrahedron Lett. 1989; 30: 2129
• 8b Bartoli G, Bosco M, Dalpozzo R, Palmieri G, Marcantoni E. J. Chem. Soc., Perkin Trans. 1 1991; 2757
• 8c Bosco M, Dalpozzo R, Bartoli G, Palmieri G, Petrini M. J. Chem. Soc., Perkin Trans. 2 1991; 657
• 8d Dalpozzo R, Bartoli G. Curr. Org. Chem. 2005; 9: 163

Leimgruber–Batcho indole synthesis:
• 9a Lloyd DH, Nichols DE. J. Org. Chem. 1986; 51: 4294
• 9b Mayer JP, Cassady JM, Nichols DE. Heterocycles 1990; 31: 1035
• 9c Leze M.-P, Palusczak A, Hartmann RW, Le Borgne M. Bioorg. Med. Chem. Lett. 2008; 18: 4713
• 10 No solvent dependence on regiochemical selectivity was observed with Et₂O, THF, or toluene. The chemical yields are somewhat higher in toluene, as side reactions tend to be fewer. Toluene is a more practical solvent and is known to promote metal–halogen exchange over any competing acid-base processes: Coe JW, Wirtz MC, Bashore CG, Candler J. Org. Lett. 2004; 6: 1589

This conclusion is supported, for example, by the many different and creative strategies from various laboratories involved with the total synthesis of the family of trikentrins, some members of which feature a conjugated trans-butenyl appendage at C-5. See for example:
• 11a MacLeod JK, Monahan LC. Tetrahedron Lett. 1988; 29: 391
• 11b Huntley RJ, Funk RL. Org. Lett. 2006; 8: 3403
• 11c Jackson SK, Kerr MA. J. Org. Chem. 2007; 72: 1405
• 11d Silva LF, Craveiro MV. Org. Lett. 2008; 10: 5417
• 11e Liu W, Lim HJ, RajanBabu TV. J. Am. Chem. Soc. 2012; 134: 5496