C-N Cross-coupling

Halogen-substituted 2-pyridones are key intermediates for further metal-catalyzed coupling reactions and the halogenation of these scaffolds has already been described in previous sections. In the following section, a variety of C - C and C - N cross-coupling reactions under microwave-assisted conditions are described with some illustrative examples. 

N-Arylated heterocycles are an important class of compounds often associated with biological activity. It has been shown that yields and reaction rates in copper(II)-mediated C-N cross coupling reactions on a solid support could be dramatically im-... 

Denmark, S. E. Sweis, R. F. Organosilicon Compounds in Cross-Coupling Reactions In Metal-Catalyzed C-C and C-N Cross-Coupling Reactions F. Diederich, A. deMei-jere, Eds. Wiley-VCH, 2004 Vol. 1 Chapt. 4. 

Combs, A.P., Saubern, S., Rafalski, M. and Lam, P.Y.S., Solid supported aryl/heteroaryl C—N cross-coupling reactions, Tetrahedron Lett., 1999, 40, 1623-1626. 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

C-C/C-N Cross-Coupling Reactions with Organometallic Reagents... 

Metal-catalyzed C-C and C—N cross-coupling reactions in the synthesis of pyridine-containing drugs ... 

Collman and Zhong reported the first catalytic, oxidative C-N cross coupling between an arylboronic acid and a substrate containing an N-H bond. " In the presence of 10 mol % of commercially available [Cu(OH)TMEDA]jClj in dichloromethane, imidazole coupled with phenylboronic acid at room temperature. Lam and co-workers and Antilla and Buchwald expanded the scope of this type of catalytic coupling to encompass the reactions of amines. Lam and co-workers reported the first catalytic version of the reactions of aiylboronic acids with phenols to yield aryl ethers in good yields. The highest yields were obtained when Oj was used as co-oxidant. After these early discoveries, several reports on... 

Reddy, K. H. V., Satish, G., Ramesh, K., Kamakar, K., and Nageswar, Y. V. D. 2012. An efficient synthesis of N-substituted indoles from indoline/indoline carboxylic acid via aromatization followed by C-N cross-coupling reaction by using nano copper oxide as a recyclable catalyst. Tetrahedron Lett. 53(24) 3061-3065. 

Scheme 13.4 Product distribution for the C-N cross-coupling with amines in the presence of a base and preformed lithium amides [23].

The realization that metal-arene interactions enhance the stability of the catalyst led to the development of phosphines bearing substituents in ortho position to the phosphorus atom. Such ligands in combination with appropriate Pd sources are among the most active and versatile catalysts for the Hartwig-Buchwald C-N cross-coupling reaction to date. 

Table 13.1 Advantages and disadvantages of selected bases in the C-N cross-coupling.

Scheme 13.48 Synthesis of rocaglamide analogs by C-N cross-coupling [103].

Scheme 13.59 C-N cross-coupling of anilines with BINAP (1) as supporting ligand [38cj.

Scheme 13.69 Synthesis of cyclophanes by Pd-catalyzed C-N cross-coupling [118].

Buchwald s biarylphosphines also have found wide application in the synthesis of materials. Ward and Meyer [119] obtained the copolymer 56 by Pd-catalyzed C-N cross-coupling of 57 and 58 employing JohnPhos (36) as a ligand (Scheme 13.71). The obtained copolymer 56 revealed electrochemical properties comparable to those of polyaniline. 

Scheme 13.84 Trifold C-N cross-coupling of N-heterocycles with aryl bromides [130],...

Scheme 13.91 Intramolecular C-N cross-coupling to access indoline scaffolds [137].

Scheme 13.93 Synthesis of aminobenzimidazoles by intramolecular C-N cross-coupling [139].

Benzo- as well as heteroaromatic systems were obtained allowing for a variable substitution pattern in the benzoazepine frameworks. To access the dibenzo-diazepine or dibenzoxazepinone frameworks according to C-N cross-coupling methodology, a different strategy had to be pursued. The introduction of the nitrogen atom or the amide functionaHty was accompHshed by the condensation of ammonia with keto- or ester-carbonyl frmctionaHties (Scheme 13.96 and Scheme 13.97) [142],... 

This section addresses typical problems encountered in Pd-catalyzed C-N crosscoupling reactions. By-products of the attempted C-N cross-coupling are often symptomatic and help identify the problematic steps in the catalytic reaction. Thus, even if the catalytic transformation does not proceed with the expected efficiency, an analysis of the reaction products is highly recommended. 

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