Medium-sized heterocycles (with 8 to 11 atoms) constitute important structural components of several biologically active natural compounds and represent promising scaffolds in medicinal chemistry. However, they are under-represented in the screening of chemical libraries as a consequence of being difficult to access. In particular, methods involving intramolecular bond formation are challenging due to unfavorable enthalpic and entropic factors, such as transannular interactions and conformational constraints. The present review focuses on the synthesis of medium-sized heterocycles by transition-metal-catalyzed intramolecular cyclization, which despite its drawbacks remains a straightforward and attractive synthesis strategy. The obtained heterocycles differ in their nature, number of heteroatoms, and ring size. The methods are classified according to the metal used (palladium, copper, gold, silver), then subdivided according to the type of bond formed, namely carbon–carbon or carbon–heteroatom.

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A new structural family of benzothiazocines bearing two or three carbon stereogenic centers on the 8-membered ring was synthesized by intramolecular Cu-catalyzed N-arylation. The chiral racemic 1,3-aminothioethers precursors have been prepared from easily available starting materials. An ionic organic base was used for the first time in an intramolecular CÀ N coupling, in medium-ring series, leading to higher yields than those obtained with an inorganic base, and a partial epimerization in some cases. The synthetic sequence was successfully performed on one example in asymmetric version, demonstrating the accessibility of enantioenriched benzothiazocines.

A series of 1,4-thiazepanes were synthesized using gold-catalysis from 1,3-aminothioethers having two or three carbon stereocenters. The process consists in a 7-exo-dig cyclization with CÀ S bond formation and concomitant allyl S-to-C migration, which occurs intramolecularly as demonstrated by a cross-over experiment. X-ray crystal-structure analysis of one product confirmed the expected stereochemistry. Two examples of reactions, azide-alkyne cycloaddition (CuAAC) and N-alkylation, illustrate the potential postfunctionalization of the synthesized 1,4-thiazepanes. Finally, the N-propargyl 1,4-thiazepanes underwent a sulfur-assisted 1,6-enyne cycloisomerization, which led through a 6-exo-dig cyclization to N,Sheterobicyclo[4.3.1] systems with a bridgehead double bond.

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