One‐Pot Synthesis of Primary and Secondary Aliphatic Amines via Mild and Selective sp³ C−H Imination

Abstract

The direct replacement of sp3 C−H bonds with simple amine units (−NH2) remains synthetically challenging, although primary aliphatic amines are ubiquitous in medicinal chemistry and natural product synthesis. We report a mild and selective protocol for preparing primary and secondary aliphatic amines in a single pot, based on intermolecular sp3 C−H imination. The first C−H imination of diverse alkanes, this method shows useful site‐selectivity within substrates bearing multiple sp3 C−H bonds. Furthermore, this reaction tolerates polar functional groups relevant for complex molecule synthesis, highlighted in the synthesis of amine pharmaceuticals and amination of natural products. We characterize a unique C−H imination mechanism based on radical rebound to an iminyl radical, supported by kinetic isotope effects, stereoablation, resubmission, and computational modeling. This work constitutes a selective method for complex amine synthesis and a new mechanistic platform for C−H amination.

Recent Progress in Synthetic Applications of Cyclic Hypervalent Iodine(III) Reagents

“…Cyclic hypervalent iodine reagents with alkoxy groups as ligands are well known as the reagents for transferring alkoxy groups to suitable substrates, [148][149][150][151] and are also utilized as the one-electron oxidizing reagents. [152][153][154][155][156] In addition, alkoxybenziodoxoles are commonly used as starting compounds that can be converted to various cyclic hypervalent iodine reagents by ligand exchange reactions with suitable nucleophiles. [155,[157][158][159][160][161][162] On the other hand, alkoxybenziodoxoles can be synthesized by the reaction of another substituted benziodoxole with alcohols.…”

“…[152][153][154][155][156] In addition, alkoxybenziodoxoles are commonly used as starting compounds that can be converted to various cyclic hypervalent iodine reagents by ligand exchange reactions with suitable nucleophiles. [155,[157][158][159][160][161][162] On the other hand, alkoxybenziodoxoles can be synthesized by the reaction of another substituted benziodoxole with alcohols. [151,[153][154]163] Examples of recently reported reactions using alkoxybenziodoxoles as reagents are presented below.…”

“…Comito's group reported that methoxybenziodoxole 95 reacts with imine 94 and excess amounts of alkanes 93 under heat or blue LED irradiation, followed by appropriate treatment to give the corresponding primary or secondary amines 96 or 97 (Scheme 36). [155] The authors performed additional experiments to verify the reaction mechanism, including measuring first‐order kinetic isotope effects and examining stereoisomer ratios. They also synthesized a hypervalent iodine reagent with an imine ligand and confirmed that its reaction hardly proceeds.…”

Additive-Free Copper-Catalyzed Benzylic C(sp3)–H Carbamation: Simple Preparation of Primary Benzylic Amines

“…31 Most recently, the Comito group reported a versatile hyper-valent iodine(III)-mediated C-H imination under blue LED light and heating (75 °C) conditions to form primary and secondary amines after a mild deprotection (Figure 2C). 32 While practical for both benzylic and non-benzylic substrates, the biggest drawback of the method was the use of large excess of the substrates (60-120 equiv) that makes the methodology less atom-economical and energy efficient (use of both light and heat) as shown in Figure 2C. In light of the above considerations, we sought a C-N coupling protocol that combines operational simplicity with use of earth-abundant catalyst to access primary amines with using only 1 equiv of R-H substrate.…”

Radical aminoalkylation of maleimides with alkylamines and alkanes

“…[ 5b ] We envisioned that if this relay catalysis could be extended to the radical alkylation fashion using various simple alkanes, a significant number of 3‐carbo‐4‐amino maleimides could be easily viable from three‐component coupling. However, the involved three‐component reactions are full of challenges, mainly because the radical amination of alkane with organic amines and hydroalkylation of maleimide with saturated aliphatic hydrocarbon easily occur in the reaction process, [ 6 ] which inhibits the formation of the target product. Herein, we disclose a novel copper‐catalyzed oxidative carboamination of malemides using unactivated alkanes as alkylating reagent, in which the formation of 3‐amino maleimides and alkyl radical were identified as indispensableelementary reactions during the transformation process (Scheme 1B).…”