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).

Synthesis using aromatic homolytic substitution—recent advances

Xanthates and related derivatives have proved to be extremely useful for both inter- and intramolecular radical additions. The broad applicability of the intermolecular addition to un-activated olefins opens tremendous opportunities for synthesis, since various functional groups can be brought together under mild conditions and complex structures can be rapidly assembled. The presence of the xanthate in the product is also a powerful asset for further modifications, by both radical and non-radical pathways. Of special importance is the access to highly substituted aromatic and heteroaromatic derivatives and the synthesis of block polymers through a controlled radical polymerisation mediated by various thiocarbonylthio group containing agents (RAFT and MADIX processes).

Powerful carbon - Carbon bond forming reactions based on a novel radical exchange process

The reactivity of the N-Boc protecting group: an underrated feature

Formation of five- and six-membered heterocyclic rings under radical cyclisation conditions

Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues: a novel DYRK1A inhibitor class.

Synthesis of 3-Aminochroman Derivatives by Radical Cyclization

Enantiomerically pure (3‘R)- and (3‘S)-3‘,4‘-dihydrospiro[piperidine-2,3‘(2‘H)-benzopyran]s (R)-10 and (S)-10 were successfully synthesized according to the CN(R,S) methodology with the aim of serving as a pattern for the generation of related spirocyclic compounds. Two different synthetic pathways were studied starting from 2-cyano-6-phenyloxazolopiperidine (−)-2. One of them was selected and used for the preparation of amines (R)-17 and (S)-17 starting from (−)-2 and (+)-2, respectively. The enantiomeric purity of all final aminochroman derivatives was determinated by capillary electrophoresis using β-cyclodextrin as the chiral selector.

Enantioselective synthesis of spirocyclic aminochroman derivatives according to the CN(R,S) strategy.

Enantiomerically pure (3R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran was successfully synthesised in nine steps starting from l -serine. The same synthetic pathway was used to prepare the (3S)-aminochroman derivative starting from d -serine. The enantiomeric purity of the final aminochroman derivatives was determined by capillary electrophoresis using β-cyclodextrin as the chiral selector.

Synthesis of enantiomerically pure 3-aminochroman derivatives

Synthesis of hexahydrochromeno[4,3- b ]azepine derivatives

A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives were prepared and evaluated to determine their affinity for the 5-HT7 receptor. Various substitutions on piperazine were explored as well as replacement of the piperazine by other amines.

/pdf/synthesis-of-aminopyrrolo-1-2-a-thieno-3-2-e-pyrazine-31kwtg4v62.pdf

Gregoire Pave

Papers

Synthesis of 3-Aminochroman Derivatives by Radical Cyclization

Enantioselective synthesis of spirocyclic aminochroman derivatives according to the CN(R,S) strategy.

Synthesis of enantiomerically pure 3-aminochroman derivatives

Synthesis of hexahydrochromeno[4,3- b ]azepine derivatives

Synthesis of aminopyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives as serotoninergic 5-HT7 ligands