Synthesis of Heteroarenes via Radical Cyclisation onto Nitriles

Abstract

A new protocol for the synthesis of tetracyclic nitrogen heteroarenes using cascade radical cyclisation has been developed.The key steps involve 5-exo vinyl radical cyclisation onto nitriles to yield intermediate iminyl radicals which cyclise onto an arene rings. Rings A-D of the anticancer alkaloids camptothecin, mappicine and nothapodytines A and B have been synthesised using this protocol.

Cascade cyclization of 1-(2-yl-3-phenylprop-2-enyl)-6-oxo-1,6-dihydropyridine-2-carbonitrile radical: Mechanistic insights from DFT study

“…Thereby, the regiochemistry of the first step in the cascade radical cyclization becomes apparent, i.e., it should be a carbon-philic cyclization, not a nitrogen-philic cyclization. The favored carbonphilic 5-exo cyclization of carbon-centered radicals onto nitrile group has been frequently observed in previous investigations [42,43,[107][108][109]. The thermodynamical preponderance of the 5-exo cycloadduct 4 relative to the 6-endo cycloadduct 9 mainly comes from the low-strained in-plane structure of the singly occupied molecular orbital (SOMO) of the exocyclic iminyl radical in 4 and the high-lying endocyclic carbon-centered radical in 9.…”

“…In previous experimental works, radical addition/cyclization methods were frequently used by Curran [39][40][41], Bennasar [32,38], and Bowman [42,43] because of the unique advantages of radical reactions. In particular, Bowman performed his pioneering study of constructing B and C rings by an intramolecular cascade radical cyclization method [43], and the proposed reaction pathways are depicted in Scheme 2.…”

Interplay of ortho- with spiro-cyclisation during iminyl radical closures onto arenes and heteroarenes

“…This research initiated spiralling interest by synthetic chemists in iminyl radical-mediated preparations. Recently iminyls have been generated from quite a variety of precursors [10–15], and their cyclisations onto arenes [16–21] and heteroarenes [22–24] have attracted attention. Iminyl cyclisations have also been utilised in natural-product syntheses [10,16,25–26].…”

Light-Induced Iminyl Radicals: Generation and Synthetic Applications

“…The intermolecular addition of the sulfanyl radical to isonitriles gave an imidoyl radical, which was able to add to a nitrile to provide an iminyl radical that cyclizes to complete the cascade reaction (Camaggi et al, 1998;Nanni et al, 2000). The preparation of rings A-D of the alkaloids camptothecin and mappicine has been achieved in good yield using this protocol (Bowman et al, 2001;. After light-induced cleavage of hexamethylditin and abstraction of the iodine atom to give a vinyl radical, subsequent 5-exo cyclization onto the nitrile and 6-exo cyclization of iminyl radical followed by aromatisation led to the four ring skeleton (Scheme 24).…”