Molecular Iodine-Mediated α-C–H Oxidation of Pyrrolidines to N,O-Acetals: Synthesis of (±)-Preussin by Late-Stage 2,5-Difunctionalizations of Pyrrolidine

Abstract

We previously reported an iterative synthesis of unsymmetrical 2,5-disubstituted pyrrolidines from pyrrolidine by two rounds of redox-triggered α-C-H functionalization. Although this approach can be used to introduce substituents at the 2- and 5-positions, it is lengthy because the redox auxiliary must be removed and then reinstalled. Therefore, we sought to develop a method to oxidize 2-functionalized pyrrolidine to cyclic N,O-acetal which could then react with a nucleophile for introduction of the 5-substituent. In this work, we found that molecular iodine can mediate the preferential oxidation of secondary over tertiary α-C-H bonds of α-substituted pyrrolidines to form cyclic N,O-acetals, improving the step economy of our previously reported method. With this strategy, (±)-preussin and its C(3) epimer were synthesized from (±)-pyrrolidin-3-ol.

Metal‐Free Cross‐Dehydrogenative Coupling (CDC): Molecular Iodine as a Versatile Catalyst/Reagent for CDC Reactions

“…The regio-and diastereoselective oxidation of pyrrolidinest o form trans-N,O-acetals by C(sp 3 )ÀHf unctionalization has been accomplished (Scheme 64). [76] b-Dicarbonylated sulfones have been prepared by C(sp 3 )ÀH functionalization by treating b-dicarbonyls with sodium sulfonates (Scheme 66). [78] Various b-dicarbonyl compounds (b-keto esters and 1,3-diketones) react with sodiuma rene-and alkanesulfinates to give the corresponding products in good to excellent yields.…”

“…The regio‐ and diastereoselective oxidation of pyrrolidines to form trans ‐N,O‐acetals by C(sp 3 )−H functionalization has been accomplished (Scheme ) . I 2 reacts with the phenolic oxygen atom of 363 to form O ‐iodo species 364 , which undergoes oxidation to generate iminium ion 365 .…”

α,α′-C–H Bond Difunctionalization of Unprotected Alicyclic Amines

“…The introduction of ring substituents via the C–H bond functionalization of the parent heterocycles is a particularly attractive strategy for accessing complex amines, and is continuing to inspire the development of diverse synthetic strategies. , While numerous methods for the α-C–H bond functionalization of amines have emerged, procedures that achieve an α,α′-C–H bond difunctionalization in a single operation remain rare (Scheme ). − Selected examples include the rhodium-catalyzed metal carbenoid insertion involving carbamates (Scheme b) , and the ruthenium-catalyzed hydroalkylation of N -2-pyridylamines (Scheme c) . A rare method enabling the introduction of two different substituents is the palladium-catalyzed diarylation of thioamides with boronic acids (Scheme d) .…”

Research Progress in C(sp3)—H Functionalization Reaction via Molecular Iodine-Catalyzed Oxidation

“…本, 这也是分子碘作为催化剂的特别之处. 分子碘催化 的 C(sp 3 )-H 功能化反应应用于各种含杂原子化合物的 合成, 实现了精准转化, 这其中包括许多具有生物活性 的复杂杂环化合物, 例如尼古丁衍生物 [45] 、β-氨基醇生 物 [27] 、生物碱衍生物 [102,162,173] 、喹喔啉衍生物 [75][76] 以及 三唑衍生物 [74,114]…”