Efficient Syntheses of 2,5‐Dihydropyrroles, Pyrrolidin‐3‐ones, and Electron‐Rich Pyrroles from N‐Tosylimines and Lithiated Alkoxyallenes

Abstract

N‐Tosylimines and lithiated alkoxyallenes afforded the corresponding allenyl N‐tosylamines in good to excellent yields. The 5‐endo‐trig cyclizations of these intermediates to 2,5‐dihydropyrrole derivatives were achieved under strongly basic conditions with potassium tert‐butoxide or under milder conditions with either silver(I) or gold(I) catalysis. In general, gold chloride catalyzed reactions occurred with the lowest catalyst loadings and delivered the best yields. With phenyl‐substituted 2,5‐dihydropyrrole, we investigated typical reactions such as oxidative and reductive transformations. The acid‐promoted hydrolysis of the enol ether moieties of three 2,5‐dihydropyrroles furnished the corresponding pyrrolidin‐3‐ones, which were reduced to give 3‐hydroxypyrrolidine derivatives in good yields. The aromatization of 2,5‐dihydropyrroles to 3‐methoxypyrrole derivatives was accomplished by base treatment, which caused the elimination of p‐tolyl sulfinate. Electron‐rich pyrrole derivatives were synthesized in good yields even on a large scale. All of the experiments illustrate the efficacy and flexibility of the alkoxyallene approach to pyrrole derivatives.

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

“…The substituent at the nitrogen seems to be of minor influence, but N ‐benzyl‐substituted imines gave dramatically lower yields. This behavior compares well to that of the parent compound methoxyallene , . Since the distance of the relatively small 3‐alkyl substituents of the nucleophile and the prochiral carbon of the electrophile is large in the C–C bond forming event, there is only little influence of the arrangement of the two components and hence the diastereoselectivity of the addition is generally very low.…”

“…This recovered diastereomerically pure allenylamine was again subjected to the reaction conditions and after 12 h pure 2,5‐dihydropyrrole trans ‐ 14 was obtained in 71 % yield (entry 2). The two experiments reveal that 3‐alkyl‐substituted allenylamines such as 9 cyclize considerably more slowly than the corresponding compounds without the 3‐alkyl group, whose cyclization is complete after one hour . Also, the pro‐ cis ‐precursor cyclizes faster than the pro‐ trans ‐isomer.…”

“…The 5‐ endo ‐ trig cyclizations of the prepared allenylamines were first examined under strongly basic conditions that were successfully applied to the reactions of related allenyl alcohols, amines and hydrazines , . Treatment of N ‐tosyl allenylamine 9 (as a mixture of diastereomers) with potassium tert ‐butoxide (0.15 equiv.)…”

“…We recently reported that lithiated alkoxyallenes and imines provide allenylamines that could be cyclized under different conditions to furnish a series of 3‐alkoxy‐2,5‐dihydropyrroles in good overall yields . These were converted into pyrrolidin‐3‐ones or into electron‐rich pyrroles which were employed as starting material for the synthesis of new dipyrrins and the corresponding boron dipyrrins.…”

A Convenient Synthesis of 1,2‐Disubstituted‐cis‐3,4‐Dihydroxypyrrolidines via an Ugi‐Four‐Component‐Reaction/Cycloisomerization/Dihydroxylation Protocol

“…[13] On the other hand, Murruzzu and coworkers reported the synthesis of compound 10 by an OsO 4 -catalyzed dihydroxylation of 3-pyrrolines. [5,[15][16][17] However, although several different synthetic approaches to the 3-pyrroline core have been reported to date, including metal-mediated reactions (Ru, [18][19][20][21] Pd, [22,23] Au, [24] Cu, [25][26][27] Ag, [28][29][30] Cr [31] ), cycloaddition reactions, [32][33][34][35] carbene-insertion reactions, [36] dehydration reactions, [37] organocatalytic processes, [38] and other miscellaneous reactions, [39][40][41] no MCRs, and specifically Ugi four-component-reactions, have been reported. [5,[15][16][17] However, although several different synthetic approaches to the 3-pyrroline core have been reported to date, including metal-mediated reactions (Ru, [18][19][20][21] Pd, [22,23] Au, [24] Cu, [25][26][27] Ag, [28]…”