Copper catalyzed reactions addition Atom

The first example for the use of a diphosphine bearing stereogenic phosphorus atoms as a ligand in copper-catalyzed Michael additions has been reported by Inamoto and co-workers,265,265a who showed that the reaction of cyclohex-2-enone and the corresponding seven-membered enone with diethylzinc in the presence of Cu(OTf)2 and 307 (abbreviated as MiniPHOS) gave rise to the formation of the addition products with 70% and 97% ee, respectively (Scheme 84). The corresponding transformation of chalcone proceeded with 71% ee. Other simple diphosphines, however, displayed only moderate enantioselectivities in copper-catalyzed Michael additions.226... 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

Oxidation of C—bonds by copper ion catalyzed reaction with an organic peroxy ester (the Kha-rasch-Sosnovsky reaction) was at one time very popular for allylic oxidation and has been thoroughly reviewed. The reaction is usually carried out by dropwise addition of peroxy ester (conunonly r-butyl peracetate or r-butyl perbenzoate) to a stirred mixture of substrate and copper salt (0.1 mol % commonly copper(I) chloride or bromide) in an inert solvent at mildly elevated temperature (60-120 C). The mechanism involves three steps (i) generation of an alkoxy radical (ii) hyttogen atom abstractitm and (iii) radical oxidation and reaction with carboxylate anion (Scheme 11). 

Greening of Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions... 

DFT computations showed that the intramolecular addition of the aryllithium generated from 425 occurs on the central carbon atom of the allenic moiety to yield the intermediate 427 from which lithium ethoxide is eliminated to furnish the benzofuran product 426. Both cyclization processes were found to pass through low-lying transition states, as it would be expected for fast reactions at low temperatures [123]. Further explorations on the anti selectivity in the intramolecular carbolithi-ation by DFT computations revealed additional details regarding the mechanism of this carbocyclization and led the authors to conclude that such a transformation is controlled by the appropriate molecular editing [123]. The synthesis of functionalized heterocycles can be relatively easy to achieve by intramolecular carbometallation reactions. For example, Kunz and Knochel [124] recently reported the preparation of benzothiophene scaffolds 429 by copper-catalyzed carbomagnesiation ofalkynyl thioethers 428 (Scheme 10.148). 

It should also be noted that copper-catalyzed Ullmann-type coupling of aryl halides with amines yields substituted products [206], and reaction with diphenylamine has been used to form triaryl-amines [207], Triarylamines may also be formed in a variation of the Meyers reaction [47] by displacement by lithium amides of fluoro- or methoxy-substituents activated by an ort/io-ester function [208], The oxidation of a-adducts is discussed in Chapter 11, but it should also be mentioned that aminated products may also be produced by the oxidation of adducts formed by the addition of amide or alkylamide ions at ring carbon atoms carrying hydrogen [209]. 

The Li catalytic system of CuBr and peroxide behaves differently, with a lesser role for copper in line with the Doyle analysis above. The nucleophile 2-naphthol is found to be reactive in this catalyst system while it is ineffective in the CuCl2-catalyzed reaction. Analysis of the reaction mixture by NMR spectroscopy did not reveal the presence of any iminium ion but rather the formation of appreciable quantities of the perojqr adduct 27c. Formation of this compound was found to be relatively insensitive to the addition of methanesulfonic acid, suggesting a radical pathway for its formation. This conclusion was supported by a slowing of the formation of the peroxy adduct in the presence of BHT, though these experiments are another cautionaiy example of the use of BHT since the additive by no means completely suppressed this reaction pathway. It was postulated that while the formation of the perojqr adduct was radical based (a rate-limiting abstraction of a hydrogen atom was proposed that was supported by a primaiy KIE of 3.4... 

Eckenhoff WT, Pintauer T. Copper catalyzed atom transfer radical addition (ATRA) and cyclization (ATRC) reactions in the presence of reducing agents. Catal. Rev. 2010 52 (l) l-59. 

A significant part of the examples of transition metal catalyzed formation of five membered heterocycles utilizes a carbon-heteroatom bond forming reaction as the concluding step. The palladium or copper promoted addition of amines or alcohols onto unsaturated bonds (acetylene, olefin, allene or allyl moieties) is a prime example. This chapter summarises all those catalytic transformations, where the five membered ring is formed in the intramolecular connection of a carbon atom and a heteroatom, except for annulation reactions, involving the formation of a carbon-heteroatom bond, which are discussed in Chapter 3.4. 

Several examples of intramolecular addition of (5-unsaturated sulfonyl radicals have also been reported [36], In agreement with Baldwin s rule and notwithstanding the reversibility of the cyclization step, the 5-exo mode is preferred when the reaction is catalyzed by copper salts, since in this case the carbon-centered radical is trapped through a fast atom transfer reaction [36b],... 

The hydroxylation of DPQ (steps F-H in Figure 7) is mimicked by the copper(II)-catalyzed aqueous autooxidation of 4-alkylcatechols to 2-alkyl-5-hydroxybenzoquinones (Figure 10). The role of the catalyst here is to promote oxidation of the catechol precursor the subsequent hydrolysis step is promoted by base, but not by copper. Interestingly, the hydrolysis is in fact a result of 1,4-addition of H2O2 to C5 of the catechol, rather than H2O (Figure 10) " H2O2 is produced in the reaction mixture as a by-product of catechol oxidation. Hence, this apparently simple synthetic reaction does not accurately model the biogenesis of TPQ, in which the C2 O atom in the final product is derived from water. 

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