Copper nucleophilic aliphatic

Although the mechanism is not understood, evidence strongly suggests this much the alkyl group R is transferred from copper, taking a pair of electrons with it, and attaches itself to the alkyl group R by pushing out halide ion (nucleophilic aliphatic substitution. Sec. 14.9). 

This chemistry was extended to a catalytic enantioselective alkenylation and phenylation of aldehydes and a-ketoesters. Using CuF-DTBM-SEGPHOS complex, products were obtained with excellent enantioselectivity from a wide range of aldehydes including aromatic and aliphatic aldehdyes, [Eq. (13.26)]. Previously catalytic enantioselective vinylation and phenylation are restricted using the corresponding zinc reagents. The active nucleophile is proposed to be an alkenyl or phenyl copper, based on NMR studies. The chiral CuF catalyst can also be applied to a catalytic enantioselective aldol reaction to ketones... 

In addition to aliphatic and aromatic amines, amides275 and sulfonamides285 have also been used as nitrogen nucleophiles for copper-mediated coupling with arylboronic acids, and these reactions provide protected anilines. 

Air oxygen can also play the role of oxidant in the amination reactions. It is well known that 1,4-benzoquinone reacts with aliphatic amines in the presence of copper acetate to give 2,5-bis(dialkylamino)-l,4-benzoquinones in good yields [64]. The reaction mechanism involves nucleophilic 1,4-addition followed by oxidation of intermediate aminohydroquinones with air oxygen. The reactions of this type, which are also inherent to ort/io-quinones, have been reviewed earlier [65, 66]. It is interesting that amination is also possible in case of some heterocyclic phenols, which are first converted in situ into the corresponding ort/io-quinones. This approach has successfully been exploited to aminate ort/io-quinones generated from quinolines, indoles, acridines, isoquinolines, quinoxalines, benzofurans, and benzothiazoles (Scheme 15) (for review, see [65, 66]). 

Aryl glyoxals, ArCOCHO, or their hydrates, ARCOCH(OH)2, as well as their aliphatic analogues, typically react with nucleophiles at the aldehyde carbon, but a chiral copper(II)-iminopyridine catalyst switches the reactivity, allowing Henry reaction at the ketone, and with high ee, giving a quaternary stereocentre in the product, without any specific protection of the aldehyde. ... 

The low ionic character of the aluminium-silicon bond has been cleverly utilized to develop a very mild, general and effective synthesis of acyl silanes, successful for aliphatic, aromatic, heteroaromatic, a-aUcoxy, a-amino and even a-chiral and a-cyclopropyl acyl sUanes. Acyl chlorides are treated with lithium tetrakis(trimethylsilyl)aluminium or lithium methyl tris(trimethylsilyl) aluminium in the presence of copper(I) cyanide as catalyst to give the acyl silanes in excellent yields after work-up. Later improvements include the use of 2-pyridinethiolesters in place of acyl halides, allowing preparation of acyl silanes in just a few minutes in very high yields indeed (Scheme 9) °, and the use of bis(dimethylphenylsilyl) copper lithium and a dimethylphenylsilyl zinc cuprate species as nucleophiles. 

A sophisticated chemoselective 1,4-addition of silicon nucleophiles to a.P Unsaturated aldehydes (1,2- versus 1,4-addition) was disclosed by the groups of Ibrahem and Cordova, merging copper(I)-catalyzed silicon-boron bond activation with iminium ion catalysis (Scheme 13) [40]. Proline derivative (S)-68 induced good to high levels of enantiocontrol in reactions of enals with either aromatic [22a-c —> (S)-67a-c] or aliphatic substituents [22d —> (/ )-67d] in the p-position. The chemoselectivity was excellent throughout. Moreover, p,p-disubstituted substrates were also converted chemoselectively with acceptable 76% ee [(S)-69],... 

Baylis-Flillman acetates 87 and 89 were involved in the nucleophilic substitution with sodium azide followed by the copper(I) catalyzed 1,3-dipolar cydoaddition of the generated azide to terminal alk5mes (Scheme 51) [80]. The geometry of the products was found to depend on the type of substituents at the Baylis-Hillman acetates. In case of methoxycarbonyl substituent, E-isomers 88 were isolated, while cyano-substituted substrates 89 afforded Z-isomers 90. The reaction of aliphatic alkynes with long chain gave lower yields (e.g., 88, R=hexyl, 58% R=octyl, 42%). It should also be noted that with respect to other solvents, PEG 400 allowed performing the reaction in the absence of... 

More recently, we demonstrated the first alkynylation of benzylic C-H bonds not adjacent to a heteroatom with 1 mol% of a CuOTf-toluene complex in the presence of 1.5 equiv. of DDQ. Various allq nes were successfully coupled with diphenylmethane derivatives (Scheme 1.8). Aromatic allq nes were smoothly converted and the use of electron-rich derivatives resulted in a slightly improved jdeld, rationalized by the nucleophilicity of the substrates. However, aliphatic allq nes [i.e., n-heiq ne) did not give the corresponding CDC product under standard conditions. The mechanism was proposed to proceed via the generation of radical intermediates, which were converted into a benzylic cation in the presence of DDQ through two successive SET steps. The resulting hydroquinone subsequently then abstracted the acidic proton from the allq ne to form the copper acetylide, which added to the benzylic cation to afford the desired product. 

The aryl ether formation was, until the late 1990s, the domain of copper-catalyzed processes, namely the Ullmann reaction. Around 15 years ago, Hartwig and Buchwald independently discovered the palladium-catalyzed alkoxylation of aryl halides with phenols. Later, these reactions were extended to aliphatic alcohols and to hydroxide as nucleophiles (vide infra. Scheme 5-159). The mechanism of the reductive elimination has been elucidated on isolated complexes. ... 

While palladium-catalyzed alkenylation reactions involving amines as nucleophiles have been extensively explored, the related copper-catalyzed processes are rare and only few examples have been reported in the literature. The first example was described in 2001 and implied the particular use of l,3-dibenzyl-5-iodouracil as electrophilic counterpart for the access of enamine-type products with potential pharmacological activity (Scheme 20) [87]. The authors demonstrated that the conditions previously reported by Buchwald for the arylation of imidazoles [88] were suitable for the vinylation of numerous amines (including primary heteroaromatic substrates and both primary and secondary aliphatic ones) to yield thus the corresponding 5-aminouracil derivatives in yields up to 78%. 

In 2008, Miyaura et al. discovered novel cyclic potassium triolborates of high nucleophilicity, both stable in air and water. These compounds were able to provide various coupling products with aliphatic amines, anilines, amides and imidazole derivatives, in the presence of copper catalysts. Depending on the N-nucleophUe, the reaction was performed under oxygen atmosphere with or without a trimethylamine N-oxide as an additional oxidant (Scheme 28) [283, 284]. These triolborates were found to be more reactive than their potassium aryl triliuoroborate analogs or than traditional arylboronic acids, as illustrated in the N-aiylation of piperidine. 

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