Copper catalyzed amidations

Scheme 9.16 Copper-catalyzed amidation of vinyl halides.

Parco et al. described a copper-catalyzed amidation of vinyl iodide 115 to give 116 (Scheme 20).28e Enhanced conversions were attained using copper(i) thiophenecarboxylate (GuTG) in a polar aprotic solvent such as NMP. The total synthesis of the antitumor natural product, lobatamide G, has been accomplished by using this reaction.28f Buchwald et al. developed a general and efficient copper-catalyzed method using N,N -dimethyl ethylenediamine L8. The double-bond geometry of the alkenyl halides was retained under the reaction conditions. 

Copper-catalyzed amidation has also been achieved, and an example is the amidation of 5-bromopyrimidine 130 with cyclohexanecarboxamide 142 which went in 86% yield in the presence of catalytic copper iodide and a diamine ligand <2001JA7727, 2002JA7421>. 

Novel imidazolidinone tetrahydropyrroloindole. During the attempted total synthesis of roquefortine C, a fungal metabolite of Penicillium roqueforti, an essential fungus in the production of Roquefort cheese, the copper catalyzed amidation of the vinyl bromide 34 in Scheme 1 was envisioned to lead to the requisite diketopiperazine ring contained in 35. " Preliminary spectroscopic data, however, suggested that the amidation had not gone as anticipated and that an unknown cyclization product had instead formed. 

Copper Catalysts Copper is an excellent catalyst for nitrogen transfer reactions via copper-nitrene intermediates. Benzylic hydrocarbons are selectively converted to the corresponding sulfonamides [40]. The intermolecular amidation of saturated C—H bonds of cyclic ethers has been reported using TsNH2-PhI(OAc)2 or PhI=NTs as the nitrene source [41]. The copper-catalyzed amidation of unactivated sp3 C—H bonds adjacent to a nitrogen atom has also been achieved using tert-butyl hydroperoxide or... 

Overman and Tomasi applied the copper-catalyzed amidation of compound 658 (Scheme 3.262) in the key step of the enantioselective total synthesis of the natural tetracyclic spermidine alkaloid (-)-hispidospermidin [805],... 

Scheme 63 Copper-catalyzed amidation of quinoline W-oxides.

Wang and coworkers report a practical method for the copper-catalyzed amidation of aldehydes in the presence of NBS. The method is operationally simple, requiring no additional ligands or catalysts, and is found to proceed in the presence of a range of functional groups. Examples are shown here (Table 7.9). 

Scheme 4.50 Copper-catalyzed amidative cross-coupling of alkynes...

Another route to 4-quinolones, which also exploits the use of o-haloarylketone substrates is illustrated in Scheme 24.22. Zhao and Xu reported a strategy employing a tandem C—N bond formation to construct the quinolone framework [96]. Mechanistic studies suggested that the reaction proceeded via conjugate addition product 47, which could then undergo intramolecular C—N bond formation under the action of palladium catalysis. A variety of 2-substituted 4-quinolones could be accessed with this methodoiogy, as shown in Scheme 24.22. Jones et al. have also reported a related process based on copper-catalyzed amidation [97]. 

Scheme 32 Copper-catalyzed amidations of allenyl halides...

A series of chiral phosphinous amides bearing pendant oxazoline rings (50, Ri=H,Tr R2=H,Tr, 51, Ri=H,Tr R2=H,Tr and 54, Ri=H,Tr R2=H,Tr in Scheme 41) have been used as ligands in the copper-catalyzed 1,4-addition of diethylzinc to enones. Two model substrates have been investigated, the cyclic 2-cyclohexenone and the acyclic trans-chalcone. The addition products are obtained quantitatively in up to 67% ee [171]. 

Some other examples of metal-catalyzed substitutions are given in Scheme 11.10. Entries 1 to 3 are copper-catalyzed reactions. Entry 1 is an example of arylation of imidazole. Both dibenzylideneacetone and 1,10-phenanthroline were included as ligands and Cs2C03 was used as the base. Entry 2 is an example of amination by a primary amine. The ligand used in this case was (V,(V-diethyl sal icyl amide. These conditions proved effective for a variety of primary amines and aryl bromides with both ERG and EWG substituents. Entry 3 is an example of more classical conditions. The target structure is a phosphodiesterase inhibitor of a type used in treatment of asthma. Copper powder was used as the catalyst. 

In recent years, cross-coupling methodology has emerged as a viable tool for enamide synthesis, and, indeed, there are a number of published protocols which employ palladium- or copper-catalyzed stereospecific amidations of vinyl halides [17]. For example, Buchwald and coworkers had recently shown that a copper-catalyzed cross-coupling of vinyl bromides or iodides proceeded with retention of stereochemistry (Scheme 9.16), though the only example using a tetrasubstituted vinyl halide, 23, lacked the need for any stereochemical control in the halide portion [18]. Based on this it seemed feasible that the desired enamide 22 could potentially be assembled via a comparable coupling between amide 24 and a stere-odefined vinyl halide such as 25. 

On the other hand, thermolysis of ferrocenylsulpkonyl azide (14) in aliphatic solvents may lead to the predominant formation of the amide (16) 17>. A 48.4% yield of (16) was obtained from the thermolysis in cyclohexane while an 85.45% yield of 16 was formed in cyclohexene. Photolysis of 14 in these solvents led to lower yields of sulphonamide 32.2% in cyclohexane, 28.2% in cyclohexene. This suggests again that a metal-nitrene complex is an intermediate in the thermolysis of 14 since hydrogen-abstraction appears to be an important made of reaction for such sulphonyl nitrene-metal complexes. Thus, benzenesulphonamide was the main product (37%) in the copper-catalyzed decomposition of the azide in cyclohexane, and the yield was not decreased (in fact, it increased to 49%) in the presence of hydroquinone 34>. On the other hand, no toluene-sulphonamide was reported from the reaction of dichloramine-T and zinc in cyclohexane. 

Tandem azidination- and hydroazidination-Hiiisgen [3 +2] cycloadditions of ynamides are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted 1,2,3-triazoles <06OBC2679>. A series of diversely l-substituted-4-amino-l,2,3-triazoles 132 were synthesized by the copper-catalyzed [3+2] cycloaddition between azides 130 and ynamides 131 <06T3837>. 

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

The utility of the method was demonstrated with a variety of electron-rich and electron-poor aryl aldehydes, but the method was not suitable for aliphatic aldehydes. No racemization was observed in the copper-catalyzed oxidative amidation reaction when an optically active amine, (S)-valine methyl ester, was employed. 

The copper-catalyzed addition of amines and amides Goldberg Reaction) are placed in this section ... 

Elimination-addition reactions of aryl halides with alkali-metal amides are discussed in Section 14-6C high-temperature copper-catalyzed amination, also effective, usually does not lead to rearrangement. 

Itoh reports that copper-catalyzed Grignard additions to N-tosyl-N-alkyl-a.p-unsaturated amides and N-tosyl-a,(3-unsaturated lactams proceed efficiently while deprotonation occurs exclusively with the corresponding A/-alkyl-a,(3-unsaturated lactams (Scheme 45).94... 

A new copper-catalyzed reaction involving imines, acid chlorides, and alkynes has been applied to the synthesis of propargyl amides 160 in a single operation by Arndtsen and co-workers. The same method allows the synthesis of N-carbamate-protected propargylamines [149]. a-Substituted amides 161 may also be prepared under palladium catalysis by substituting alkynes for vinyltin (Scheme 8.71) [150]. 

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