Enantioselective hydroamination of unactivated terminal alkenes

The amide is one of the most prevalent functional groups in all of pharmaceuticals, and for this reason, reactions that introduce the amide moiety are of particular value. Intermolecular hydroamidation of alkenes remains an underexplored method for the synthesis of amide-containing compounds. The majority of hydroamidation procedures exhibit Markovnikov regioselectivity, while current methods for anti-Markovnikov hydroamidation are somewhat limited to activated alkene substrates or radical processes. Herein, we report a general method for the intermolecular anti-Markovnikov hydroamidation of unactivated alkenes under mild conditions, utilizing Rh(III) catalysis in conjunction with dioxazolone amidating reagents and isopropanol as an environmentally friendly hydride source. The reaction tolerates a wide range of functional groups and efficiently converts electrondeficient alkenes, styrenes, and 1,1-disubstituted alkenes, in addition to unactivated alkenes, to their corresponding linear amides. Mechanistic studies reveal a reversible rhodium hydride migratory insertion step, leading to exquisite selectivity for the anti-Markovnikov product.

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confidence: 99%

Rhodium(III)-Catalyzed Anti-Markovnikov Hydroamidation of Unactivated Alkenes Using Dioxazolones as Amidating Reagents

Wagner-Carlberg

Rovis

2022

“…The process also meets the requirements of green chemistry and sustainable development . Over the past decades, transition-metal-catalyzed hydroamination of unsaturated hydrocarbons, such as alkenes, allenes, 1,3-dienes, alkynes, and enynes, has been a valuable strategy to access various functionalized alkylamines and allylamines via the formation of a C–N bond. This approach has been applied to the synthesis of numerous pharmaceuticals and natural products …”

Section: Introductionmentioning

confidence: 99%

Palladium-Catalyzed Asymmetric Sequential Hydroamination of 1,3-Enynes: Enantioselective Syntheses of Chiral Imidazolidinones

Fang

Pan

et al. 2022

Pd-catalyzed sequential hydroamination of readily available 1,3-enynes is reported. The redox-neutral process provides an efficient route to synthesize a broad scope of imidazolidinones, thiadiazolidines, and imidazolidines. Asymmetric sequential hydroamination generates a series of synthetically valuable, enantioenriched imidazolidinones. Mechanistic studies revealed that the transformation occurred via an intermolecular enyne hydroamination pathway to give an allene intermediate. Subsequent intramolecular hydroamination of the allene intermediate proceeded under the Curtin–Hammett principle to provide enantioenriched imidazolidinone products.

“…To achieve remote hydroamination of internal alkenes, we first sought to identify an aminopyridine that would change the selectivity from the hydroamination we reported previously. To do so, we conducted the reactions of a model alkene, cis -4-octene ( 1a ) with a series of 2-aminopyridines in combination with our previously developed cationic iridium catalyst. , The reaction with the electron-rich 6-methyl-2-aminopyridine ( 2a ) led to slow isomerization of cis -4-octene, the formation of the 2-aminoalkane ( 3aa ) with low selectivity (30%), and the 4-aminoalkane from direct addition of the N–H bond to the internal alkene as the major product (Scheme A, entry 1).…”

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confidence: 99%

“…While synthetically appealing, this reaction could generate a mixture of products with the amino group at multiple internal sites . Our group recently reported catalytic hydroamination of internal and terminal alkenes with a 2-aminopyridine (Scheme C) − that suppressed isomerization and led to direct hydroamination. We envisioned that appropriate modifications to the amine and catalyst could increase the rate of isomerization over that of hydroamination at internal sites thereby creating a remote hydroamination of internal alkenes by selective N–H addition to the terminal alkene (Scheme D).…”

mentioning

confidence: 99%

Remote Hydroamination of Disubstituted Alkenes by a Combination of Isomerization and Regioselective N–H Addition

Fan

Day

et al. 2023

Self Cite

Remote hydrofunctionalizations of alkenes incorporate functional groups distal to existing carbon−carbon double bonds. While remote carbonylations are well-known, remote hydrofunctionalizations are most common for addition of relatively nonpolar B−H, Si−H, and C−H bonds with alkenes. We report a system for the remote hydroamination of disubstituted alkenes to functionalize an alkyl chain selectively at the subterminal, unactivated, methylene position. Critical to the high regioselectivity and reaction rates are the electronic properties of the substituent on the amine and the development of the ligand DIP-Ad-SEGPHOS by evaluating the steric and electronic effects of ligand modules on reactivity and selectivity. The remote hydroamination is compatible with a broad scope of alkenes and aminopyridines and enables the regioconvergent synthesis of amines from an isomeric mixture of alkenes. The products can be derivatized by nucleophilic aromatic substitution on the amino substituent with a variety of nucleophiles.