2- Chloropyrazine lithiation

The lithio derivatives 63 are converted into deuteriopyrazines 64, and their yields can be equivalent to those of the hydrogen/lithium exchange (Scheme 15). As a result, the lithiation of chloropyrazines and pyrazinethiocarboxamide is optimized at —70 to —75°C, whereas that of methoxy- or acylamino-pyrazines at 0°C. Conversely,... 

S235). Examples of halogen directed metallation include the lithiation of 5-bromopyrimidine (345) or chloropyrazine (346) by LDA. 3-Halopyridines are also lithiated regiospecifically at C-4, but pyridyne formation is then rapid. 

A convenient synthetic method was described to introduce reactive functionalities as well as heterocyclic moieties at the C(2) position of 4-(A,2V-dimethylamino)pyridine (4-DMAP) via an unprecedented direct lithiation with BuLi-LiDMAE reagent [23]. Stille coupling of 2-chloropyrazine with 2-tributyltin-4-(2V,2V-dimethylamino)pyridine in the presence of PdCl2(PPh3)4 afforded 2-pyrazinyl-(4-A,2V-dimethylamino)pyridine (30) [23]. New useful 4-DMAP-containing synthons as polyhetero-cycles have been efficiently prepared. 

Pyrazinyl ketones have been prepared by treatment of pyrazinecarboxylic esters with an organo-metallic (alkyllithium or Grignard) reagent <84MI 603-01 >. Homolytic acylation of pyrazines and quinoxalines with a-keto acids is an important method for preparation of the acyl compounds (Section 6.03.5.6.1), but the procedure for monosubstitution needs care because the electron-withdrawing effect of the first-formed monoacyl compounds facilitates further substitution. An additional synthesis of pyrazinyl ketones is the lithiation of halogenopyrazines followed by treatment with carboxylic esters or carboxamides (Equation (8) and Scheme 24). Reaction of 2-chloropyrazine... 

Metallation of 2-chloropyrazine occurs ortho to the chlorine atom as this gives the most-stabilized organolithium intermediate C. The second lithiation occurs at C-6, to give the 6-iodopyrazine 7. The regioselectivity of this reaction can be explained if one takes into account the fact that the species in solution is not the alcohol but the lithium alkoxide, which can chelate to the pyrazine nitrogen atom, N-4. This leaves the other pyrazine nitrogen atom (N-1) free and hence results only in the C-6 lithiated intermediate D. 

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