Mechanistic considerations in the synthesis of 2-aryl-indole analogues under Bischler–Mohlau conditions

Abstract

Mechanistic insight into the pathway of the Bischler-Mohlau indole formation reaction is provided by isotopic labeling utilizing judicious incorporation of a 13C atom within the α-bromoacetophenone analogue reactant. The resulting rearranged 2-aryl indole, isolated as the major product, located the 13C isotope label at the methine carbon of the fused five-membered heterocyclic ring, which suggested that the mechanistic pathway of cyclization, in this specific example, required two equivalents of the aniline analogue reactant partner and proceeded through an imine intermediate rather than by direct formation of the corresponding 3-aryl indole accompanied by a concomitant 1,2-aryl shift rearrangement.

Synthesis of dihydronaphthalene analogues inspired by combretastatin A-4 and their biological evaluation as anticancer agents

“…1 Experimental procedures for intermediates in Scheme 5 4.1.1.21. Dibenzyl (2-methoxy-5-(3,4,5-trimethoxyphenyl)-7,8dihydronaphthalen-1-yl) phosphate (15). 47,49 To a well-stirred solution of 13 (1.40 g, 4.09 mmol) in CH 3 CN (25 mL) at −25°C , CCl 4 (25 mL) was added, and the reaction mixture was stirred for approximately 15 min.…”

“…[4][5][6][7][8][9] Key structural features of the combretastatins include the trimethoxy phenyl ring, the p-methoxyphenyl moiety, cis-configuration of the aromatic rings and a distance of approximately 4-5 Å between the aryl rings. 5,9,10 Our long-standing research agenda in this area has contributed a variety of functionalized molecular scaffolds including benzo[b]thiophene, [11][12][13] indole, 12,[14][15][16][17][18] benzofuran, 12,15,19 stilbenoid, 5,9,[20][21][22] and benzosuberene analogues [23][24][25][26] that bear structural analogy to colchicine and CA4. Our original molecular design motif recognized salient aspects of structural similarity between non-steroidal, 11 anti-estrogen agents (such as nafoxidine and LY117018) 27,28 and CA4, which led us to the discovery of a collection of highly potent inhibitors of tubulin polymerization that function through a direct binding interaction at the colchicine site on the tubulin heterodimer.…”

HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation

“…The classical name reactions, such as Bischler indole synthesis [11,12], Fischer indole synthesis [13,14], Bartoli indole synthesis [15,16], have been widely used for indole synthesis. In recent years, efforts have been devoted to improve the Bischler indole synthesis [17,18,19,20,21,22,23]. Metal catalysts, including Rh [17], Ir [18], Ru [19], and Zn [20], have been applied to such transformations.…”