W. Russell Bowman

Synthesis using aromatic homolytic substitution—recent advances

This critical review aims at presenting recent developments in intramolecular aromatic homolytic substitution which has become one of the common methodologies in modern synthesis. The application of Bu3SnH-mediated cyclisations have proved especially useful. The critical review illustrates the mechanistic considerations required for planning synthetic applications and a wide range of synthetic protocols and natural product syntheses are shown. The latest evidence for the mechanisms involved in aromatic homolytic substitution are presented. (152 references).

Oxidation during reductive cyclisations using Bu3SnH

Abstract Reductive cyclisations using Bu 3 SnH include an “oxidation” step if the removal of an acidic proton from the intermediate cyclised radical, by Bu 3 SnH acting as a base, is favourable. A “pseudo” S RN 1 mechanism is proposed.

Copper(1) catalysed aromatic nucleophilic substitution: A mechanistic and synthetic comparison with the SRN1 reaction

Evidence is provided to support a mechanism for Cu(1) catalysed aromatic nucleophilic substitution via inner-sphere electron-transfer and a Cu(111) intermediate, and to show the synthetic potential for Cu(1) catalysis relative to the SRN1 reaction.

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone , mackinazolinone , tryptanthrin , luotonin A and rutaecarpine were synthesised by radical cyclisation onto 3H-quinazolin-4-one.

Bu3SnH mediated oxidative radical cyclisation onto imidazoles and pyrroles

Abstract A new protocol using radical cyclisation has been developed for the synthesis of [1,2-c]-fused imidazoles and [1,2-a]-fused pyrroles. The intermediate nucleophilic N-alkyl radicals, generated using Bu3SnH from N-(ω-bromoalkyl) or N-[ω-(phenylselanyl)alkyl] imidazoles and pyrroles, undergo regio-selective radical cyclisation onto the azole rings followed by oxidative re-aromatisation.

OXIDATIVE RADICAL CYCLISATIONS ONTO IMIDAZOLES AND PYRROLES USING BU3SNH

Oxidative radical cyclisation using Bu3SnH has been used for the synthesis of [1,2-c]-fused imidazoles and [1,2-a]-fused pyrroles from imidazolecarbaldehydes and acylpyrroles respectively. The intermediate nucleophilic N-alkyl radicals cyclise onto imidazole and pyrrole rings followed by oxidative re-aromatisation.

Generation of aminyl radicals using sulfenamides as synthetic precursors

Abstract Sulfenamides are synthesised from reaction between amines and N -(benzenesulfenyl)-phthalimide or benzenesulfenyl chloride. The sulfenamides undergo reaction with tributyltin hydride to yield aminyl radicals which can be cyclised onto suitable alkenes.

A facile method for the N-alkylation of α-amino esters

Abstract Monoalkylation of the α-amino group of α-amino acid derivatives can be facilitated using 2- and 4-nitrophenylsulfonamide intermediates. The nitrophenylsulfonamides of α-amino esters can be alkylated using an equimolar amount of carbonate base and a variety of alkyl bromides. Ready removal of the nitrophenylsulfonyl group is facilitated by S N Ar reaction between the N -alkylated sulfonamide and phenylthiolate to give the N -alkylated α-amino esters in good yield without racemisation of the chiral α-centres.

Synthesis of oxindoles by radical cyclisation

Abstract Oxindoles are readily synthesised by intramolecular addition of aryl radicals to the α-position of α,β-unsaturated N -alkylamides.

Radical cyclisation onto pyrazoles: synthesis of withasomnine

Abstract A novel synthetic protocol for the synthesis of [1,2- b ]-fused bicyclic pyrazoles has been developed using radical cyclisation. The protocol uses cyclisation of pyrazole-1-(ω-alkyl) radicals generated from 1-[ω-(phenylselenyl)alkyl]-pyrazole precursors. The pyrazole natural product, withasomnine (3-phenyl-5,6-dihydro-4 H -pyrrolo[1,2- b ]pyrazole), and larger ring analogues have been synthesised in good yield using the protocol. A Bu 3 SnH-mediated oxidative cyclisation mechanism is facilitated by azo or Et 3 B radical initiators acting as oxidants of the intermediate π-radicals.