Quinoline copper coupling

Scheme 73 Copper coupling of quinoline A/-oxides with amides and amines.

The most useful approaches to the synthesis of di- and poly-ynes from terminal alkynes are undoubtedly the copper-catalyzed couplings discovered by Glaser (CuCl, NH4OH, EtOH, 02)," Eglinton [Cu(OAc)2, hot pyridine or quinoline, 02], and Hay [Cu(I), tmed, 02]. Some of the many applications of these reactions are discussed in the following. 

Although aryl chlorides are not usually reactive enough to couple efficiently with alkyl-coppers, heteroaryl chlorides often couple quite well. For example, the most efficient way of alkylating chlorinated phenanthrolines and quinolines, and both 2- and 3-substitued pyridines involves the use of Grignard reagents and copper salts (equation 51)73. 

An organocopper intermediate was detected by Lewin and Cohen in the reaction of / -iodotoluene with copper in a good complexing solvent (184). Analysis of protonated aliquots from a reaction performed in quinoline indicated an accumulation of />-tolylcopper to a maximum of 43% after 95 hours, at which point the iodide was consumed, and then a slow decrease to by dimerization. Other experiments also indicate the formation of an arylcopper compound in Ullmann reactions (127,141, 210). The isolation of deuterated products, presumably from the decomposition of an intermediate organocopper species in deuterated benzene and cyclohexane, suggested decomposition to free radicals (127). Decompositions of certain o-haloarylcopper intermediates by a benzyne mechanism cannot be totally excluded. The formation of a dichlorobenzene and by-products such as dibenzofuran and triphenylene from only the ortho isomer of the chloroiodobenzenes in Ullmann coupling reactions (210)... 

The reactions between i-dinitrobenzene or 1,3,5-trinitrobenzene, aryl halides, and copper(I) oxide in quinoline 17-19, 21) provide a simple synthesis of nitrobiphenyls uncontaminated by symmetrical biphenyls. These couplings may be related to the Ullmann reaction, the decarboxylative coupling of benzoic acids with aryl halides, and the preparation of ethers from phenols 165). Although no intermediates... 

The preparation and reaction of zincated quinolines offers an effective means for substitution <97T7237>. The copper-mediated coupling of l,2-dihydroquinolin-2-ones with phenyllead triacetate was studied. Depending on the sub.stitution of the ring the regiochemistry varies between the 1- and 3-positions or both <97JCS(P1)229>. 

In respect to the Suzuki and the Negishi couplings, quinoline stannanes provide an easy entry to highly substituted derivatives. As a highlighted example, 2-trimethylstannyl-5,8-dimethoxyquinoline reacts with appropriately substituted pyridyltriflate in the presence of palladium tetrakis-(triphenylphospine), lithium chloride, and copper bromide to produce 2-pyridylquinoline, an advance intermediate for the total syntheses of antitumor compounds streptonigrin and lavendamycin. ... 

Similar to the C-H/C-H coupling mentioned in Section 2, some A A -bidentate coordinating groups also work well in the C-H/N-H coupling. Benzamides bearing the quinoline moiety are directly aminated under the copper/silver bimetallic catalyst system, although the exact role of the silver salt is not clear (Eq. 31)... 

Quinoline N-oxides were shown to couple with amides and cyclic amines in the presence of copper, expanding the possibilities for dehydro-genative coupling of quinoline N-oxides (Scheme 73) (130L5198). The quinoline-N-oxide could have various substituents such as halides, methoxys, and alkyl groups. Neither sterics nor electronics appear to hinder the reaction. The reaction also tolerated a number of lactams and cyclic amines (13 examples, 52-93%). Finally, the products were cleanly reduced to provide 2-aminoquinohne derivatives in good yields. 

While other more costly catalysts such as a variety of palladium salts also enabled direct 2-sulfonylation of the quinoline A/-oxides, the copper salts are more flexible and inexpensive. While a number of aryl sulfonyl chlorides coupled with quinoline N-oxides and isoquiniohne-AT-oxide, related compounds (N-oxides of pyridine and pyrazines) failed to react under these conditions. 

NHC (IMS HCl) as the ligand or even under ligand-free conditions. Copper salts were applied in these transformations as well. In 2003, a nickel-catalyzed system was also developed. With Ni(0) generated in situ as the catalyst and 2,2 -hipyridine or N,A/ -his(2,6-diisopropylphenyl)dihy-droimidazol-2-ylidene (SIPr) as the ligand, the intramolecular coupling of aiyl chlorides with amines was achieved with NaOfBu as the base. Indoles, quinolines, benzazepines, benzoxazines, and benzoxazepines were produced in good yields from the corresponding substrates. 

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