Direct Ring C-H Metallation

Regioselective metallation at an a-position of a pyridine can be achieved with the mixed base prodnced from two mole equivalents of n-butyllithium with one of dimethylaminoethanol i.e. it is a 1 1 mixtnre of n-BuLi and Me2N(CH2)20Li (BuLi-LiDMAE). The regioselectivity is ascribed to intramolecular delivery 

2- methoxy-, 2-methylthio- and 2-dimethylamino-pyridines all lithiate efficiently at C-6 3-chloro- and 

3- methoxypyridines are lithiated at C-2 4-chloro-, 4-dimethylamino- and 4-methoxypyridines, again lithiate at an a-carbon 2-, 3- or 4-phenylpyridines are metallated only at an a position it is even possible to lithiate 4-picoline at C-2, ° despite potential loss of a side-chain proton (cf. 8.10). An extrapolation of this idea is the use of McsSiCHaLi-LiDMAE, which is less nuclophilic and so is a lesser problem with respect to a subseqnently added electrophile.  

A nice example of the use of a-lithiated pyridines is their nucleophilic addition to azines, oxidation during work-np then producing bihetaryls.  

There are many example of direct hthiation with the assistance of ortfto-directing groups. Halo-, particularly chloro-, or better, fluoro-pyridines, but even bromo-pyridines undergo hthiation ortho to the halogen, nsing lithinm di-wo-propylamide. 3-Halopyridines react mainly at C-4, and 2- and 4-halo-pyridines necessarily hthiate at a P-position. In the hthiation of methoxy-pyridines, using mesityllithium the 3-isomer metahates at C-2, whereas 3-methoxymethoxypyridine, 3-di-/xo-propylaminocarbonyl-  

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The aziridination of olefins, which forms a three-membered nitrogen heterocycle, is one important nitrene transfer reaction. Aziridination shows an advantage over the more classic olefin hydroamination reaction in some syntheses because the three-membered ring that is formed can be further modified. More recently, intramolecular amidation and intermolecular amination of C-H bonds into new C-N bonds has been developed with various metal catalysts. When compared with conventional substitution or nucleophilic addition routes, the direct formation of C-N bonds from C-H bonds reduces the number of synthetic steps and improves overall efficiency.2 After early work on iron, manganese, and copper,6 Muller, Dauban, Dodd, Du Bois, and others developed different dirhodium carboxylate catalyst systems that catalyze C-N bond formation starting from nitrene precursors,7 while Che studied a ruthenium porphyrin catalyst system extensively.8 The rhodium and ruthenium systems are... 

Binding of metals directly to the carbon skeleton of the thiophene ring is a common binding scheme, especially at the activated C-2 position. Attack at this C-H bond is usually regarded as a possible first step in the activation of the carbon-sulfur bond important for the HDS process <20010M1259, 2003CL14, 2006POL499>. 

Cyclometalation is one of the most reliable and versatile methods for the synthesis of stable Pd-C a-bonds. In this reaction, a palladium (or other metal) complex is reacted with a ligand possessing a donor atom. The metal is directed by the donor atom to insert into a C-H bond, forming a chelate ring. This donor is usually the nitrogen of a tertiary amine, heterocyclic amine, or imine, or a phosphorus in a tertiary phosphine or phosphite. Other donor atoms, such as O and S, are occasionally encountered. The chelate ring size is normally five. ... 

An immediate issue in the chemisorption of aromatic compounds is whether the phenyl ring is oriented parallel or perpendicular to the plane of the metal surface. In this regard, the intensity of the out-of-plane C-H bend (yen) relative to the in-plane C-H stretch (vch) provides a direct diagnostic indicator of adsorbed aromatic orientation. At specular... 

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