C-metalated pyridines

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. 

Among all the methods of introducing a pyridine moiety into a drug-like molecule, metal-catalyzed carbon-carbon or carbon-nitrogen bond formation reactions of C-metallated pyridines or pyridine halides are the most important and widely used. 

The widely available halogen pyridines can be used as starting materials for the preparation of C-metallated pyridines. For example, 2,6-dibromopyridine can be desymmetrized by mono-lithiation with nBuLi, followed by trapping the resultant anion 64 with an electrophile to afford compounds 65. ... 

The C-metallated pyridines can undergo the following types of reactions ... 

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

A completely similar reaction occurs when Ru2(CO)6(R-Pyca R R2 ) (R-Pyca R R2 = 6-R NC5H3-2-C(R2) = NR with R = alkyl or aryl Rl = H, Me and R2 = H, Me) is reacted with excess pyridinimine.164 The facile reaction leads to the formation of Ru2(CO)5(APM) (APM — bis(/i-t-butylamino)(2-pyridyl)methane-N) (ref. 162, footnote). (The crystal structure of this compound shows two C—C-coupled pyridin-2-imines which bridge a non-bonding Ru2 metal pair. The... 

The presence of the nitrogen atom presumably gives rise to an (relatively small) increase of the acidity of the ring protons, compared to benzene. The pK-values of the pyridine protons are not known, but it may be assumed that these are a few units lower than those of benzene (pK 43) but higher than 36, the value of diisopropylamine. Attempts to metallate pyridine did not result in any accumulation of metallated intermediates [146]. The isolation of 2,2 -bipyridyl from this reaction was considered as evidence for the intermediate occurrence of 2-pyridyl-lithium. Even pyridinecarboxamides Py—C(=0)NR2 are incompletely metallated by LDA [147]. 

In 2011, Woo and collaborators prepared ORR catalysts from the pyrolysis at 700, 800, and 900 °C of a mixture of iron oxide supported on Vulcan and dicyandiamide (C2H4N4 a dimer of cyanamide) [111]. TEM of the catalysts revealed that at 700 °C metal particles were encapsulated with a carbon layer, while they were mostly in carbon tubes at 900 °C. The total N content was 2.2,3.5, and 6.6 at.% for the catalysts heat treated at 700,800, and 900 °C, respectively. This N content was broken down as 54 % pyridinic and 0 % graphitic nitrogen atoms at 700 °C, while it was 61.4 % pyridinic and 10.7 % graphitic at 900 C. The Fe content was also measured in these catalysts and also for the catalyst iron... 

Empirical quantum-chemical predictions summarized above from classic inorganic chemistry and ligand field theory are correlated wifli macroscopic enhancements in the glass-transition temperature for Ni(II) complexes wifli poly(4-vinylpyridine). The 102°C enhancement in Tg of P4VP occurs when flie metal/pyridine-ligand concentration ratio is approximately 1 2 on a molar basis. It is postulated that thermal... 

Scandium hydrides [(Me5C5)2ScH] and (Me5C5)2ScH(THF) react with pyridine like the Lu-analog to give the product of C-metallation ... 

Heteroatom-directed C(sp )-H bond fimctionalizalion with stoichiometric transition metals was first disclosed in 1984 [1]. In 2002, Sames and coworkers developed an efficient route to constmct the teleocidin B4 core via the activation of C(sp )-H bond to prepare two diastereomeric paUadacycle key intermediates [2]. As a follow-up work, Ru3(CO)i2-catalyzed arylation of various C(sp )-H bonds with arylboronate esters using pyridine, pyrimidine, and amidine as directing groups was reported (Scheme 1.1) [3]. The use of ketones as solvent was necessary for a successfid arylation, mainly due to the trapping effect of the ruthenium hydride species. Despite of its efficiency, this transformation needs elevated temperatures (150 °C). Further, pyridine-directed a-C(sp )-H arylation of piperidines with arylboronate esters was developed with alcohols as solvent [4]. 

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