Borrowing hydrogen amine alkylation

Madsen and co-workers have reported an important extension to the amine alkylation chemistry, in which oxidation takes place to give the amide product [13]. A ruthenium NHC complex is formed in situ by the reaction of [RuCl Ccod)] with a phosphine and an imidazolium salt in the presence of base. Rather than returning the borrowed hydrogen, the catalyst expels two equivalents of H. For example, alcohol 31 and benzylamine 27 undergo an oxidative coupling to give amide 32 in good isolated yield (Scheme 11.7). 

Scheme 26 Alkylation of amines with alcohols by borrowing hydrogen...

Saidi O, Blacker AJ, Lamb GW et al (2010) Borrowing hydrogen in water and ionic liquids iridium-catalyzed alkylation of amines with alcohols. Org Process Res Dev 14(4) 1046-1049... 

Hamid MHSA, Allen CL, Williams JMJ et al (2009) Ruthenium-catalyzed V-alkylation of amines and sulfonamides using borrowing hydrogen methodology. J Am Chem Soc 131(5) 1766-1774... 

Enyong AB, Moasser B (2014) Ruthenium-catalyzed Al-alkylation of amines with alcohols under mild conditions using the borrowing hydrogen methodology. J Org Chem 79(16) 7553-7563... 

Liu H, Chuah G-K, Jaenicke S (2012) A-alkylation of amines with alcohols over alumina-entrapped Ag catalysts using the borrowing hydrogen methodology. J Catal 292 130-137... 

A-Alkylation of amides and amines and dehydrative -alkylation of secondary alcohols and a-alkylation of methyl ketones " have been carried out by an activation of alcohols by aerobic oxidation to aldehydes, with copper(II) acetate as the only catalyst. A relay race process rather than the conventional borrowing hydrogen-type mechanisms has been proposed for the aerobic C-alkylation reactions, based on results of mechanistic studies. A Winterfeldt oxidation of substituted 1,2,3,4-tetrahydro-y-carboline derivatives provides a convenient and efiflcient method for the synthesis of the corresponding dihydropyrrolo[3,2-fc]quinolone derivatives in moderate to excellent yields. The generality and substrate scope of this aerobic oxidation have been explored and a possible reaction mechanism has been proposed. Direct oxidative synthesis of amides from acetylenes and secondary amines by using oxygen as an oxidant has been developed in which l,8-diazabicyclo[5.4.0]undec-7-ene was used as the key additive and copper(I) bromide as the catalyst. It has been postulated that initially formed copper(I) acetylide plays an important role in the oxidative process. Furthermore, it has been postulated that an ct-aminovinylcopper(I) complex, the anti-Markovnikov hydroamination product of copper acetylide, is involved in the reported reaction system. Copper(I) bromide... 

Santoro E, Psaro R, Ravasio N et al (2014) iV-Alkylation of amines through hydrogen borrowing over a heterogeneous Cu catalyst. RSC Adv 4(6) 2596-2600... 

Hydrogen borrowing will likely become competitive with alkyl halide and reductive amination approaches as the method of choice for N-alkylation. Its broad functional group tolerance, continuously increasing scope, and facile scalability point toward a major impact in drug discovery in the coming years. 

Hydrogen borrowing and dehydrogenative condensations provide new opportunities for the preparation of both saturated and aromatic heterocycles respectively. The ability to directly access azacycles from stable species such as alcohols and amines allows chemists to circumvent the preparation and use of relatively unstable carbonyls and alkyl halides that conventional methods require. Pyridines, pyrazines, pyrroles, as well as fused bicyclic heteroaromatics, may all be prepared by dehydrogenative condensation this reactivity will likely be extended to pyrimidines, imidazoles, pyrazoles, and triazoles in the near future. Continuous advances in scope and scalability will expand the role of hydrogen transfer in the discovery and production of small molecule therapeutics. 

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