C-N cross-coupling reactions

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 ... 

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. 

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. 

In 2013, AbbVie reported the scalable synthesis of a cis-substituted cydobutyl-benzothiazole pyri-dazinone, which is a potent and selective competitive antagonist for human and rat histamine H3 receptors, and thus important in attention-deficit hyperactivity disorder (ADHD), Alzheimer s disease, and in cognitive deficits of schizophrenia [84], The key step in the synthesis of this API was a C-N cross-coupling reaction on a bromothioindole—acetal intermediate (Scheme 2.18). 

Scheme 2.18 Process development of an efficient copper-catalyzed C-N cross-coupling reaction by a team at AbbVie [84].

Breitler S, Oldenhuis NJ, Fors BP, Buchwald SL (2011) Synthesis of unsymmetrical diarylureas via Pd-catalyzed C-N cross-coupling reactions. Org Lett 13(12) 3262-3265 Hooker JM, Reibel AT, Hill SM, Schueller MJ, Fowler JS (2009) One-Pot, Direct Incorporation of [ C]C02 into Carbamates. Angew Chem Int Ed 48(I9) 3482-3485 Peterson SL, Stucka SM, Dinsmore CJ (2010) Parallel synthesis of ureas and carbamates from amines and CO2 under mild conditions. Org Lett 12(6) 1340-1343 Wei Y, Liu J, Lin S, Ding H, Liang F, Zhao B (2010) Acetoacetanilides as masked isocyanates facile and efficient synthesis of unsymmetrically substituted ureas. Org Lett 12 (19) 4220 223... 

Combs et al. [73] reported the first examples of polymer-supported aryl-heteroaryl C-N cross-coupling reactions and dramatically decreased reaction times upon microwave irradiation. The methodology provides easy access to N-arylated heterocycles from heterocycles bearing an N-H bond and readily available arylboronic acids in the presence of copper(II) acetate and pyridine. 

Figure 1. Overview of metal-catalyzed C-C and C-N/C-0 cross-coupling reactions of halopyridines or C-metallated pyridines...

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... 

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. 

Transition metal catalysed cross-coupling reactions of organometalUc reagents containing Zn, Si, Mg, Sn or B with organic electrophiles in the presence of group 8-10 metals, notably Ni and Pd, are routinely the method of choice, both in academia and industry, for the preparation of C-0, C-S, C-H, C-N and C-C bonds [1]. 

---