Amines copper-catalyzed

Reaction of Alkyl Amines Copper-catalyzed cross-coupling of aliphatic amines with aryl halides has made considerable progress. Several methods have used Ctil with p-amino alcohols L58 [42], amino acids L59, L60 [43], Al,Al-diethyl saUcylaldehyde L61 [44], or p-diketones L62-L65 [45] (Fig. 20.3). Among these, the protocol using p-diketones exhibited the superior results catalyzing the reaction even at room temperature (Scheme 20.19). 

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. 

Next, reductive amination (step 4 in scheme 1) was exchanged with copper catalyzed palladium coupling (step 2 in scheme 1). Atomic absorption analysis for palladium in RWJ-26240 samples prepared by scheme 2 indicated that the level of palladium was reduced to an acceptable level. This improvement may be due to the two reduction steps subsequent to the use of palladium in scheme 2.177 The final major modification to the reaction scheme was the substitution of NaBH4 for NaBH3CN. The yield of product (60%) was determined by HPLC (Method 2). Reductive alkylation with formalin/NaBH4 afforded a pharmaceutically acceptable drug substance. 

Recently, a new method for synthesis of tertiary amines 326 from iV,iV-dialkyl O-benzoyl hydroxylamines 325 was proposed.425 The protocol is based on the copper-catalyzed reaction of hydroxylamines 325 with dialkyl- and diarylzinc reagents (Scheme 166). It is noteworthy that alkyl- and phenylzinc halides also reacted with compounds 325, however, yields were significantly lower than those for ZnR2 (18-29% vs. 69-98%). 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

Many other kinds of nucleophiles can be arylated by copper-catalyzed substitution.132 Among the reactive nucleophiles are carboxylate ions,133 alkoxide ions,134 amines,135... 

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 ... 

The results show that a number of ruthenium carbonyl complexes are effective for the catalytic carbonylation of secondary cyclic amines at mild conditions. Exclusive formation of N-formylamines occurs, and no isocyanates or coupling products such as ureas or oxamides have been detected. Noncyclic secondary and primary amines and pyridine (a tertiary amine) are not effectively carbonylated. There appears to be a general increase in the reactivity of the amines with increasing basicity (20) pyrrolidine (pKa at 25°C = 11.27 > piperidine (11.12) > hexa-methyleneimine (11.07) > morpholine (8.39). Brackman (13) has stressed the importance of high basicity and the stereochemistry of the amines showing high reactivity in copper-catalyzed systems. The latter factor manifests itself in the reluctance of the amines to occupy more than two coordination sites on the cupric ion. In some of the hydridocar-bonyl systems, low activity must also result in part from the low catalyst solubility (Table I). 

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