Amidation copper-catalyzed

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. 

Scheme 9.16 Copper-catalyzed amidation of vinyl halides.

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. 

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>. 

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]. 

The hydration of nitriles to form amides is promoted by metallic catalysts such as nickel and copper,9 and the copper catalyzed hydration has been utilized in an industrial process for the production of acrylamide from acrylonitrile.10 The hydration of... 

Llewellyn DB, Arndtsen BA (2005) Synthesis of a library of chiral a-amino acid-based borate counteranions and their application to copper catalyzed olefin cyclopropanation. Tetrahedron Asymmetry 16 1789-1799 Makino T, Baba N, Oda J, Inouye Y (1977) Asymmetric reduction of alpha, beta-unsaturated iminuum salt with A-glucopyranosyl-l,4-dihydronicotin-amides. Chemlnd 1977 277-278... 

The stereoselective allylation of aldehydes was reported to proceed with allyltrifluorosilanes in the presence of (S)-proline. The reaction involves pentacoordinate silicate intermediates. Optical yields up to 30% are achieved in the copper-catalyzed ally lie ace-toxylation of cyclohexene with (S)-proline as a chiral ligand. The intramolecular asymmetric palladium-catalyzed allylation of aldehydes, including allylating functionality in the molecules, via chiral enamines prepared from (5)-proline esters has been reported (eq 15). The most promising result was reached with the (S)-proline allyl ester derivative (36). Upon treatment with Tetrakis(triphenylphosphine)palladium(0) and PPh3 in THF, the chiral enamine (36) undergoes an intramolecular allylation to afford an a-allyl hemiacetal (37). After an oxidation step the optically active lactones (38) with up to 84% ee were isolated in high chemical yields. The same authors have also reported sucessful palladium-catalyzed asymmetric allylations of chiral allylic (S)-proline ester enamines" and amides with enantiomeric excesses up to 100%. 

Benzoxazoles are found in a variety of natural products and routinely find use in pharmaceutical research. They are generally made by condensation of a 2-aminophenol with a carboxylic acid or oxidative cylization of an imine intermediate. A mild copper-catalyzed cyclization of o/t/ o-haloanilides to give benzoxazoles 209 has been reported (Scheme 62) <2006JOC1802>. This route is conceptually different to the aforementioned methods in that the starting material is a 2-haloaniline rather than a 2-aminophenol. The reaction conditions tolerate various functional groups in the amide portion of the molecule. 

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