Iodine/palladium approaches to the synthesis of polyheterocyclic compounds

Abstract

A simple, straightforward strategy for the synthesis of polyheterocyclic compounds (PHCs) is reported, which involves iterative cycles of palladium-catalyzed Sonogashira coupling, followed by iodocyclization using I(2) or ICl. A variety of heterocyclic units, including benzofurans, benzothiophenes, indoles, and isocoumarins, can be efficiently incorporated under mild reaction conditions. In addition, variations of this strategy afford a variety of linked and fused PHCs.

SCHEME 1. Iodocyclization Reaction

SCHEME 2. Generation of Polyheterocyclic Compounds by the General Strategy^a

Conditions: ^aAll Sonogashira reactions were carried out on a 0.25–5.0 mmol scale and the iodocyclization reactions were carried out on a 0.10–4.0 mmol scale using I₂ or ICl (see the Supporting Information). ^bThis compound was prepared from 4c by desilylation.

SCHEME 3. Simultaneous and Stepwise Diiodination

SCHEME 4. Click Chemistry Followed by Iodo-desilylation

SCHEME 5. Double Sonogashira Coupling, Followed by Double Iodocyclization

SCHEME 6. Palladium-catalyzed Ullmann Reaction

SCHEME 7. Previously Reported Examples of 1,3-Diyne Cyclization

SCHEME 8. Preparation of 1,3-Diynes

SCHEME 9. Iodocyclization of Homo- and Hetero-1,3-diynes

SCHEME 10. Tuning of Reaction Conditions for Single or Double Cyclization

SCHEME 11. Elaboration of the Iodine-containing Products

SCHEME 12. Cyclocarbonylation Attempt

SCHEME 13. Alkyne Annulation Reaction Leading to a Fused PHC