Mechanisms aerobic oxidative amination

The CDC between A-f-butyl nitrones and terminal alkynes to form alkynylated nitrones in good to excellent yields, catalysed by zinc trifiate, was achieved using 3,3, 5,5 -tetra-tertbutyldipheno-quinone and O2 as oxidants. The alkynylated nitrones were transformed to regioisomerically pure 3,5-disubstituted isoxazoles. Experimental and DFT computational studies of Pd(OAc)2/pyridine-catalysed intramolecular aerobic oxidative amination of alkenes supported a stepwise mechanism that involved (i) the formation of a Pd(ll)-amidate-alkene chelate with release of 1 equiv. of pyridine and AcOH from the catalyst centre, (ii) insertion of alkene into a Pd—N bond. 

Another argument against the oxo-transfer mechanism in our catalytic aerobic oxidation protocol is the lack of formation of sulfoxides from sulfides, N-oxydes from amines and phosphine oxydes from phosphines. Alkenes also proved to be inert towards oxidation no epoxide formation could be detected under our reaction conditions. 

Copper amine oxidase (CAO) enzymes carry out the aerobic oxidation of primary amines to aldehydes (Scheme 14.8a). While copper is present in the active site, substrate oxidation proceeds by an organocatalytic pathway involving an o-quinone cofactor via a transamination mechanism (Scheme 14.8b). 

Through subtle modification of the reaction mechanism, the scope of o-quinone-catalyzed aerobic oxidations has been expanded to secondary amines and JV-heterocyclic compounds as well [45-47]. For example, aerobic oxidation of secondary amines and iV-heterocycles has been achieved by using 10-phenanthroline-5,6-dione (phd) as a catalyst (Scheme 14.10a). Using phd and cocatalytic Znl2, a diverse range of iV-heterocyclic compounds undergo... 

The mechanism proposed for Cu(02CCF3)2-catalysed aerobic oxidative intramolecular alkene C—H amination of (130), leading to formation of A-heterocycles in good to excellent yields, is summarized in Scheme 14. ... 

The mechanism of Gutknecht pyrazine synthesis has been studied and is well understood. Reduction of the a-oximino ketone affords an a-amino ketone. If the reduction is carried out under acidic conditions, the a-amino ketone may be isolated as an acid salt. These acid addition salts are entirely stable. In these salts the ketone carbonyl may be hydrated, and this is particularly true for a-amino aldehydes. However, as soon as the free base of the amine is generated, either from the salt or during reduction of the oxime if this is carried out under neutral or basic conditions, rapid bimolecular imine formation occurs, which is then followed by rapid intramolecular formation of a second imine to afford a dihydropyrazine. Oxidation to the pyrazine may occur spontaneously upon exposure to air, particularly in the presence of transition metals, and it is this facile aerobic oxidation that doubtless accounts for the isolation of pyrazines by early workers in the field. 

Scheme 12.11 Mechanism of Pd-catalyzed aerobic Waeker cyclization (Nu = 0)/ oxidative amination (Nu = NTs) of alkenes.

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... 

Simple palladium(II) salts such as chloride and acetate efficiently catalyse aerobic oxidative A-alkylation of amines and amides with alcohols. This method is suitable for a variety of sulfonamides, amides, aromatic and heteroaromatic amines as well as benzylic and heterobenzylic alcohols with a low loadings of the catalyst (0.5-1 mol%) and the alcohols. A selective carbon-carbon double bond assisted o-C-H olefination is catalysed by palladium(II) acetate. The terminal oxidant is oxygen. Addition of TFA is essential for any meaningful yield. (PdOCOCF3)+ has been proposed as the active catalyst. The observed large difference in the inter- and intra-molecular KIE values implied that the coordination of the C=C bond occurs before C-H palladation in the catalytic cycle consequently, a mechanism involving the initial coordination of allylic C=C bond to (PdOCOCF3)+ followed by selective o-C-H bond metalation has... 

Scheme 14.10 (a) Aerobic phd-catalyzed oxidation of diverse classes of secondary amines through (b) an "addition-elimination" mechanism, (c) Improved reaction efficiency is obtained by replacing Zn + with and I" cocatalyst with Co(salophen). 

In 2015, Yao, Zhao, and co-workers reported a base-catalyzed IV-alkylation of anilines and heteroarylamines with benzylic, heterobenzylic, aliphatic alcohols using catalytic amounts of O2 as the initiator (Eq. 69) [208]. They found air or O2 play important roles in the reactions because the reactions under O2 or in open air led to formation of imines in high ratios. The authors further optimized the reaction conditions and found that adding 2-5 mol% O2 to the reaction vessel was the best, giving high yields and selectivies of the product amines. Therefore, they proposed a mechanism for the N-alkylation reaction that was initiated by base-catalyzed aerobic alcohol oxidation by O2 to the aldehydes (Scheme 48). 

---