Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates

3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates 

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Palladium-catalyzed carbonylation of aryl halides with nucleophiles such as alcohols, amines, and water can be performed in ionic liquid media. Several systems have been designed so that the ionic phase can be isolated and recycled. Once carbonylation substrates/products form homogeneous mixtures with ionic liquids, the experimental protocols for catalyst/ionic liquid mixture recycling involve separation of the product by either distillation or extraction procedures using organic solvents or supercritical CO2. 

Indoles, pyrroles and carbazoles themselves are suitable substrates for palladium-catalyzed amination. An initial study of this reaction using DPPF-ligated palladium as catalyst showed that these reactions occurred readily with electron-poor aryl halides. With unactivated aryl bromides, the reaction with pyrrole or indole resulted in good yield, but reaction times were long and the temperature was 120 °C. Thus, an improved catalyst system was necessary for reactions to occur in a more general fashion and with temperature- or base-sensitive substrates. 

The amination of aryl halides and triflates catalyzed by palladium complexes is suitable for use in complex synthetic problems. Many substrates will produce high yields of mixed arylamines with one of the existing catalyst systems. Nevertheless, there are many combinations of substrates for which the amination chemistry may be substantially improved. For the most part, these reactions involve nitrogen centers, such as those in pyrroles, indoles, amides, imidazoles and other heterocyclic groups that are less basic than those in standard alkylamines. Although mild reaction conditions have been developed for many substrates, the harsh conditions used in many of the applications indicate that continued studies on developing mild condi-... 

The use of a strong base in the palladium-catalyzed amination of aryl halides precludes the use of many substrates, such as those with aromatic nitro groups or enolizable hydrogens, esters other than tert-butyl esters, and many substrates with base-sensitive stereochemistry such as some protected amino acids and heterocyclic substrates [191]. Thus, conditions that employ milder bases are required. A solution that involves reaction temperatures as low as those used for reactions conducted with sodium tert-butoxide has not been developed. However, carbonate and phosphate bases can be used with certain catalysts at reaction temperatures comparable to those of reactions involving the first- and second-generation catalysts. 

Although the substrate scope for the palladium-catalyzed aminations of aryl halides was improved by the use of weaker bases, these procedures still had limitations. First, the reactions were typically slower and required higher levels of catalyst than those with f-BuONa as base. Second, reactions of substrates containing alcohol, phenol or amide functional groups have been difficult to accomplish. Recently, Buchwald and coworkers... 

C.iii.c. Preparation of Small Molecules for Materials Science. Pd-catalyzed amination has also been used to prepare small molecules that are useful as hole-transport materials, selective metal-cation detection systems, and dyestuffs. As mentioned briefly in the section on reacting diarylamines with aryl halides, Marder and co-workers used palladium chemistry to form triarylamines, which are useful as hole-transport layers. Reactions of primary arylamines with aryl halides using DPPF-hgated palladium as catalyst allows for the selective addition of one aryl halide, followed by the addition of a second aryl halide to form mixed triarylamines, as shown in Eq. 42. This procedure has been used to generate unsymmetrical triarylamines that are analogs of TPD, as shown in Eq. 43. hi addition, they have used aminoferrocene as a substrate to conduct diarylations to form N, A-diarylaminoferrocenes. ... 

All substrates mentioned in the previous chapter easily undergo palladium-catalyzed aminocarbonylation also. It should be mentioned that even allylic carbonates instead of halides could be converted into carboxamides by this method, as it vas demonstrated during the total synthesis of antillatoxin [94]. The use of aryl chlorides is somewhat restricted owing to the low reactivity ofthese type of substrates in oxidative addition to palladium(O), as well as the competitive amination observed, for example, in the reaction of 1-chloroisoquinoline [95]. Functionalization of a great number of pharmaceutically important skeletons, for example, steroids [96-99], tropenes [100], benzodiazepines [101], indoles [102], benzo[c[quinolizine derivatives [103], and quinolones [104], have been carried out. 

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