Copper mechanistic considerations

In the improved synthesis of Ifetroban described above, environmental concerns due to special handling of copper bromide waste and hazards associated with hexa-methylene tetramine (HMT) on manufacturing scale led to further perfection of the synthesis. Mechanistic considerations suggested that an oxidized form of aminoamide B (Scheme 4) would eliminate the necessity for a late-stage copper-mediated oxidation. This was indeed accomplished. The cyclization-elimination sequence was initiated by a Lewis acid and completed by base-mediated elimination to afford the Ifetroban penultimate. In addition to eliminating the need for copper bromide and HMT, this modification helped to reduce the cost of the product by an additional 15%. 

As for many other nucleophiles, the nitrite anion undergoes addition to the iodonium ion generated by the reaction of alkenes and 1,3-alkadienes with electrophilic iodine reagents. Two procedures have been described bis(pyridine)iodine(I) tetrafluoroborate136,137 [prepared from mcrcury(II) oxide and tctrafluoroboric acid supported on silica gel and pyridine on dichloromethane] and copper(II) tetrafluoroborate [prepared from copper(II) oxide and te-trafluoroboric acid] and iodine138 139. trans Addition would be expected for all products from mechanistic considerations, however, only the cyclohexene adduct 1 has been shown to have trans configuration ( H-NMR spectroscopy)139. 

Martmez-Asencio A, Ramon DJ, Yus M (2011) W-alkylation of poor nucleophiUc amines and derivatives with alcohols by a hydrogen autotransfer process catalyzed by copper(ll) acetate scope and mechanistic considerations. Tetrahedron 67(17) 3140-3149... 

Reactions in Water.— Tanaka has developed his idea of using mechanistic considerations as the basis for predictions of the stability constants of mixed-ligand ternary complexes to copper(n). 

ATRP, other factors, such as solvent and temperature, must also be taken into consideration. Typical monomers and alkyl halide initiators that are used in ATRP are shown in Scheme 5 [47], The copper complex is perhaps the most important component of this catalytic system because it regulates the dynamic equilibrium between dormant and active species. In this article, structural and mechanistic aspects of copper-catalyzed ATRP are discussed. 

Nucleophilic displacement of halogen by amines is an important method of introducing amino groups into the anthraquinone ring system. In the Ullmann reaction the displacement is catalysed by metallic copper or by copper ions so that relatively mild conditions can be used. Mechanistic studies suggest that copper(I) ions exert a catalytic effect via complex formation. Derivatives of 1,4-diaminoanthraquinone are of considerable industrial significance. Many compounds are prepared from the reduced form of quinizarin (6.6). 

Julian, R. R., May, J. A., Stoltz, B. M., Beauchamp, J. L. Gas-Phase Synthesis of Charged Copper and Silver Fischer Carbenes from DIazomalonates Mechanistic and Conformational Considerations In Metal-Mediated Wolff Rearrangements. J. Am. Chem. Soc. 2003, 125, 4478 486. 

Mechanistic interpretations of the copper-catalyzed aromatic nucleophilic substitution reactions remain unsettled even after half-a-century of debate [19, 20]. Possible pathways involve an S Ar reaction mediated by copper complexation to the pi-system (Scheme 4a), an electron transfer reaction followed by halide dissociation (Scheme 4b), four-centered c-bond metathesis reaction (Scheme 4c) and Cu(l) oxidative addition to the Ar-X bond, followed by the nucleophile exchange and reductive elimination in the resulting Cu(lll) system (Scheme 4d). There is presently a considerable body of experimental and theoretical data for and against each of the proposed mechanisms [21]. While the mechanistic studies were mostly related to the formation of C-C, C-O and C-N bonds, it is likely that the copper-catalyzed halogen exchange reactions follow a similar trend. 

Fokin et al. [38] reported that the dinuclear alkynyl complexes exhibit superior reactivity toward organic azides compared to their monomeric analogues. Based on the previous reports and density functional theory (DPT) calculation data, a plausible mechanistic pathway is shown in Scheme 21. Initially the Cu(ll) acetylide complex is formed and the second nearby Cu atom accelerates the activation of azide. Very fast ring contraction from intermediafe 13 or 14 to 15 in acetonitrile followed by the protonation of the triazole-copper derivative gives the product with regeneration of catalyst. The catalyst was recovered by centrifugation and reused up to five cycles without considerable loss of activity. 

The careful mechanistic studies that have been documented by Evans are a highly attractive aspect associated with these catalyst systems, and the work is well worth consulting for the practical and mechanistic insight it provides [152, 154, 155]. The investigations have permitted an understanding of the structural and coordination chemistry of the metal complexes, which is sure to have a positive impact on the evolution of enantioselective catalysts. For example, Evans has noted that the general addition of TMSOTf can lead to considerable acceleration in the aldol reaction. Thus, the addition reaction of pyruvate and trimethylsilyl tert-butyl thioketene acetal mediated by 2 mol % of copper(bisoxazoline) affords product in 97 % ee over the course of 14 hours when the same reaction is conducted with one equivalent of TMSOTf and Cu catalyst under otherwise identical conditions, reaction is observed to reach completion in 35 minutes, with no deterioration in enan-... 

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