Umpolung Asymmetric 1,5‐Conjugate Addition via Palladium Hydride Catalysis

Abstract

Electronically matched nucleophilic 1,6-conjugate addition has been well studied and widely applied in synthetic areas. In contrast, nucleophilic 1,5-conjugate addition represents an electronically forbidden process and is considered unfeasible. Here, we describe modular protocols for 1,5-conjugate addition reactions via palladium hydride catalysis. Both palladium and synergistic Pd/organocatalyst systems are developed to catalyze 1,5conjugate reaction, followed by inter-or intramolecular [3+2] cyclization. A migratory 1,5-addition protocol is established to corroborate the feasibility of this umpolung concept. The 1,5-addition products are conveniently transformed into a series of privileged enantioenriched motifs, including polysubstituted tetrahydrofuran, dihydrofuran, cyclopropane, cyclobutane, azetidine, oxetane, thietane, spirocycle and bridged rings. Preliminary mechanistic studies corroborate the involvement of palladium hydride catalysis.

Catalytic Asymmetric Hydroalkoxylation and Formal Hydration and Hydroaminoxylation of Conjugated Dienes

“…Similarly, deuteration appeared exclusively at the terminal carbon of d - 3b and recovered d - 1a . Generally, if a PdH catalysis was involved, deuteration might appear at multiple sites of products and the recovered diene substrates, ,, inconsistent with present observation. The kinetic isotope effect (KIE) via two separate reactions using 2b and d - 2b was determined to be 8.7 (Scheme d), reflecting that the hydrogen transfer from alcohol to the diene is likely the turnover-limiting step.…”

“…As unprotected allyl alcohols , and allyl hydroxylamines , are ubiquitous skeletons and building blocks in medicinal, material, and agrochemistry, asymmetric hydration and hydroaminoxylation of conjugated dienes are highly valuable routes for furnishing motifs with corresponding free hydroxyl or aminoxyl units. Although transition-metal-catalyzed asymmetric hydrofunctionalizations of conjugated dienes have received considerable attention , and a group of transition metals, including Pd, − Ni, − Rh, − Co, − and Cu, have been demonstrated to stereoselectively catalyze the formation of allylic C–C, C–N, C–S, C–P, C–Si, and C–B bonds, the catalytic system for the construction of C–O bonds has not been elucidated (Scheme a), that is, all types of O-based nucleophiles, including abundant alcohols, − phenols, carboxylic acids, water, hydroxylamine, oxime, and so forth, are not suitable for this enantioselective hydrofunctionalization process. Only the use of allenes and alkynes, which are significantly more reactive electrophilic substrates, has received a few successes. − …”

“…As a part of our group’s ongoing efforts in asymmetric hydrofunctionalizations, ,, we envisioned that novel ligands would need to be designed to resolve the aforementioned challenges that have persisted for half a century (Scheme c). Most recently, an elegant Ni-catalyzed enantioselective hydroalkoxylation of conjugated dienes was published by Dong and Yang (Scheme b) .…”

Accessing indole–isoindole derivatives via palladium-catalyzed [3+2] cyclization of isocyanides with alkynyl imines

“…We recently communicated a palladium-catalyzed [4+1] cyclization/reductive isocyanide insertion cascade for efficient access to pyrroles (Schemes 1B, 1). 15 In this process, a palladium catalyst converts into a palladium-hydride species 15,16 in situ , which is employed as a hydride ion donor to trigger the aromatization. As a continuation of this project and our continuous interest in isocyanide chemistry, herein we report a novel palladium-catalyzed [3+2] cyclization of isocyanides with alkynyl imines.…”

Palladium-Catalyzed Asymmetric Hydrofunctionalization of 1,3-Dienes for Construction of C—O Bonds

“…何智涛课题组起初采用 Josiphos 型配体, 检测到少 资伟伟课题组 [4] 在 1,3-二烯烃的氢砜化反应中提出 了钯催化的配体-配体氢转移(LLHT)机制, 该机理随后 在 Dong 课题组 [5] 的氢胺化反应中进一步得到了验证. 在何智涛课题组的机理研究中, 作者同样发现氢-氧官能 团化反应的 π-烯丙基钯中间体可能经过配体-配体氢转 移 过 程 , 而 不 是 传 统 的 钯 氢 化 物 迁 移 插 入 过 程 [6][7][8][9][10] (Scheme 3). 肟与钯配位能力比醇强, 这对于关键的 LLHT 步骤是有利的, 这也解释了氢烷氧基化过程需要 10 equiv.的醇, 而水合化和氢胺羟化过程只需要 1 equiv.…”