Addition of Metalated 3‐Alkyl‐Substituted Alkoxyallenes to Imines: Preparation of Tetrasubstituted 2,5‐Dihydropyrroles, Pyrrolidin‐3‐ones, and Pyrroles

Metalated 3‐alkyl‐substituted methoxyallenes were either generated by lithiation of the corresponding methoxyallenes or, according to a procedure of Brandsma, from 3‐alkyl‐substituted propargyl methyl ethers. Additions of these axially chiral intermediates to various imines afforded the expected allenylamines in good yields, but low diastereoselectivity. The products were cyclized either under basic conditions or with silver nitrate as catalyst to furnish the desired 1,2,3,5‐tetrasubstituted 2,5‐dihydropyrrole derivatives. Under basic conditions the cyclization is stereospecific whereas the presence of silver nitrate can induce partial crossover. The mechanisms of the two cyclization modes are discussed. Two of the N‐tosyl‐substituted dihydropyrroles were subjected to an excess of potassium tert‐butoxide giving the expected aromatized 3‐methoxypyrrole derivatives by elimination of p‐tolyl sulfinate. Acid‐promoted hydrolysis of the enol ether moiety of 2,5‐dihydropyrroles furnished the corresponding pyrrolidin‐3‐ones in good yields. The sodium borohydride reduction of these intermediates gave the corresponding 3‐hydroxypyrrolidine derivatives with high diastereoselectivity that strongly depends on the substitution pattern of the precursor. This study reveals that 3‐alkyl‐substituted methoxyallenes and their propargylic ether equivalents allow an efficient and flexible approach to 1,2,3,5‐substituted pyrrole derivatives that are useful intermediates for subsequent stereoselective elaboration and promising candidates for natural product syntheses. Metalated axially chiral alkoxyallenes can be generated from alkoxyallenes or from propargyl ethers. They add with low diastereoselectivity to imines and the resulting allenylamines cyclize under base or silver nitrate catalysis to give cis‐ and trans‐substituted 2,5‐dihydropyrrole derivatives. These cyclizations proceed in part stereospecifically. Subsequent reactions such as hydrolysis are also studied.