Copper hydroamination with

The proposed reaction mechanism involves intermolecular nucleophilic addition of the amido ligand to the olefin to produce a zwitterionic intermediate, followed by proton transfer to form a new copper amido complex. Reaction with additional amine (presnmably via coordination to Cn) yields the hydroamination prodnct and regenerates the original copper catalyst (Scheme 2.15). In addition to the NHC complexes 94 and 95, copper amido complexes with the chelating diphosphine l,2-bis-(di-tert-bntylphosphino)-ethane also catalyse the reaction [81, 82]. 

Anfj-Markovnikov products are only observed. The postulated mechanism for these reactions is analogous to the previously discussed for the copper-catalysed hydroamination (Scheme 2.15) with the coordinated thiolate (rather than the amide) acting as nucleophile [82, 85]. 

The first example of a heterogeneously catalyzed hydroamination of an alkene appeared in a 1929 patent in which it is claimed that NHj reacts with ethylene (450°C, 20 bar) over a reduced ammonium molybdate to give EtNH2 [24]. An intriguing reaction was also reported by Bersworth, who reacted oleic acid with NH3 in the presence of catalysts like palladium or platinum black or copper chromite to give the hydroamination product in quantitative yields [25]. However, this result could not be reproduced [26]. 

The aziridination of olefins, which forms a three-membered nitrogen heterocycle, is one important nitrene transfer reaction. Aziridination shows an advantage over the more classic olefin hydroamination reaction in some syntheses because the three-membered ring that is formed can be further modified. More recently, intramolecular amidation and intermolecular amination of C-H bonds into new C-N bonds has been developed with various metal catalysts. When compared with conventional substitution or nucleophilic addition routes, the direct formation of C-N bonds from C-H bonds reduces the number of synthetic steps and improves overall efficiency.2 After early work on iron, manganese, and copper,6 Muller, Dauban, Dodd, Du Bois, and others developed different dirhodium carboxylate catalyst systems that catalyze C-N bond formation starting from nitrene precursors,7 while Che studied a ruthenium porphyrin catalyst system extensively.8 The rhodium and ruthenium systems are... 

Finally, though not strictly a hydroamination reaction, the asymmetric addition of alkynes to imines with a copper-bis(oxazoline) complex is worth briefly mentioning.[144] The nature of the ionic liquid cation has a strong effect on the enantioselectivity of the reaction and it appears that a good balance between hydrophobicity and acidity play an important role with best results obtained with [C4Ciim][Tf2N]. 

This section focuses on hydroamination catalyzed by transition metal complexes, but many studies on hydroamination catalyzed by acid, base, - main group metals such as mercury and copper, and heterogeneous catalysts have been reported. Because the elementary steps of the mechanisms of these reactions lie outside the scope of this text, this chapter does not present details of the hydroaminations conducted with these t5q>es of catalysts. This material has been presented in many reviews. - ... 

In 2008, Li et al. reported a copper-catalyzed amine-alkyne-alkyne addition reaction as an efficient method for the synthesis of Y,5-alkynyl-p-amino acid derivatives 102 (Scheme 3.52) [137]. In this case, the first step of the reaction is proposed to be the hydroamination of the electron-deficient alkyne 100, which plays the role of the aldehyde component. Subsequent reaction of the resultant intermediate XXX with alkyne 101 would afford intermediate XXXI, which would be then protonated to give an iminium intermediate XXXII. Finally, an intramolecular transfer of the alkyne moiety to the iminium ion would yield the 7,8-alkynyl-p-amino ester 102 and regenerate the catalyst. The reaction was later extended using chiral prolinol derivatives as the amine component, which afforded the corresponding Y,5-alkynyl-p-amino acid derivatives with excellent diaste-reoselectivities (up to >99 1) [138]. 

The copper-catalyzed C—H activation reactions of 2-alkynylbromobenzene with pyrazoles, to afford pyrazolo[5,l-fl]isoquinolines, have been reported by Wu and coworkers as part of their efforts to synthesize drug-like small moleculesd Several ligands were screened under different base/solvent combinations. The reaction was found to proceed well with 10 mol% of ligand A, in the presence of 10 mol% 2,6-diethylaniline, whose role in the catalytic cycle remains unclear (Scheme 7.6). The reader is referred to the reference for a discussion of the mechanistic cycle for this tandem copper-catalyzed hydroamination and C—H activation reaction. 

During the course of the author s efforts directed toward the development of useful transformations of allenic compounds [66-77], the author found that the reaction of A -tosylated 2-ethynylaniline 1 with paraformaldehyde 2 and diisopropylamine 3 in dioxane in the presence of copper(l) bromide (Crabbe conditions) [78] afforded a 2-(aminomethyl)indole derivative 7 in 92% yield (Scheme 2) without forming the expected [2-(A -tosylamino)phenyl]allene. This reaction can be rationalized by Mannich-type MCR followed by indole formation through intramolecular hydroamination toward the activated alkyne moiety of a plausible intermediate 6. This is the first example of three-component indole formation without producing stoichiometric amount of salts as byproducts. 

Both copper- and silver-catalyzed three-component reactions between an aldehyde, terminal alkyne, and secondary amine have been used to generate propargylamines [17, 18] The copper-catalyzed hydroamination between hydroxylamine esters and unactivated aUcenes generates amines with the desired regiochemistry for a wide range of diverse substrates [20]... 

When one of the N—H bonds of primary amines is used for arene formation, the other N—H bond can serve as another reaction site for further elaboration. For example, IV-unsubstituted 2-alkynylaniline derivatives 309 undergo a copper-catalyzed direct C—H/N—H coupling with azoles 310 followed by cycloisomerization to form A -azoylindoles 311 in good yields (Scheme 19.83) [153]. Oxadiazoles, benzoxa-zoles, and benzothiazoles can be used as the azole 310 for the reaction. Double hydroamination reaction of the anilines of type 309 with terminal alkynes leading to A -vinylindoles was reported by Zhang et al. [154]. 

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... 

---