Pd‐Catalyzed Dihalogenative <i>Endo</i> Cyclization of 1,6‐Enynes

Comprehensive Summary Described here is an unusual palladium‐catalyzed dihalogenative endo cyclization of unactivated 1,6‐enynes. In sharp contrast to previous related studies, which have long been restricted to activated electron‐deficient enynes and/or exclusively resulted in exo cyclization, the present process for the first time enables unactivated 1,6‐enynes to overcome the inherent kinetic tendency toward 5‐exo‐trig cyclization and lead to the kinetically disfavored 6‐endo‐trig pathway. This distinctive cyclization mode is inconsistent with classical Baldwin's rules, which typically favor the formation of five‐membered rings through exo‐trig cyclization due to kinetic advantages and lower energy barriers. Both dibromination and dichlorination transformations are successfully achieved under optimized reaction conditions, employing a palladium catalyst in combination with a copper halide salt, an appropriate base and solvent system to ensure high reactivity, excellent regioselectivity, and outstanding stereoselectivity. This synthetic strategy facilitates the rapid and efficient construction of highly functionalized six‐membered heterocycles, including piperidines and tetrahydropyrans, as well as carbocycles, all of which exhibit satisfactory overall performance across a broad substrate scope encompassing aryl, heteroaryl, and alkyl substituents on the enyne scaffold. The resulting products possess two versatile carbon‐halogen bonds, including C(sp 2 )‐X and C(sp 3 )‐X type, and a stereodefined olefin with excellent &gt;20 : 1 E / Z selectivity, rendering them valuable building blocks for subsequent organic transformations. Control experiments further confirm the essential roles of both palladium and copper salts in promoting the reaction, while preliminary DFT calculations shed light on the origin of reaction selectivity and the cyclization mechanism. Collectively, all these features underscore the significant synthetic utility of this newly developed cyclization protocol in modern organic synthesis.