Pyridine-hexafluoroacetone complexes

Af-Activation by BF3 to form complex 230 can be used to promote ortholithiation of pyridine itself , though not quinoline and isoquinoline (Scheme 112). Temporary formation of a pyridine-hexafluoroacetone adduct 231 achieves the same result. ... 

At -107°C, reaction of hexafluoroacetone-complexed pyridine with LiTMP followed by MeOD as the electrophile gave 90% C-2 deuteriation, whereas at -78°C, C-2 (48%) and C-4 (28%) deuterium incorporation was observed. 

When pyridine is heated to 165 °C in MeONa-MeOD, H-D exchange occurs at all positions via small concentrations of deprotonated species, at the relative rates a (3 7, 1 9.3 12. However, using the combination n-butyllithium/potassium t-butoxide, efficient formation of 2-pyridylpotassium or 4-pyridylpotassium has been achieved." Some pyridines have been selectively lithiated at C-2 via complexes with hexafluoroacetone " complexation removes the lone pair (cf. section 5.5.1) and additionally provides inductive and chelation effects to assist the regioselective metallation. In practice, simple lithiopyridines are generally prepared by metal-halogen exchange, however the presence of chlorine or fluorine, or other substituents which direct ortho metallation, allows direct lithiation (section 5.5.1). 

A behavior similar to that of pyridine and pyrazine N-oxides is exhibited by complexes of pyridines with hexafluoroacetone. Such complexes are expected to enhance the acidity of the pyridine hydrogens by oxygen-lithium chelating effects and therefore direct 2-deprotonation. In fact, treatment of f-butylpyridine (495) with LiTMP/THF-Et20/- 107°C generated, via the known complex 507, the stable 2-lithio species 508 which, upon reaction with electrophiles, furnished 2-substituted pyridines 509 (Scheme 154) (83JOC4156). 

The metaiation of heterocycles is possible without the aid of a directing group. This type of reaction is most common in the ir-excessive heterocycles, and is most important for thiophenes. For nitrogen heterocycles, examples of unactivated lithiation of ir-excessive azoles have been reported, and are summarized below. ir-Deficient heterocycles such as pyridine are resistant to unactivated lithiation, although pyridine can be metalated with low regioselectivity using butylsodium. Pyridines also form weak complexes with fluoro ketones the complex of 4-r-butylpyridine and hexafluoroacetone can be lithiated and added to benzaldehyde in 60% yield. ... 

BF3 Et20 complex),or BuLi-LiDMAE." For example, lithiation of adduct 58 was obtained from the reaction of pyridine with the highly polarized carbonyl group of hexafluoroacetone with LiTMP to give 2-lithio species 59. Compound 59 was then trapped with electrophiles such as I2 or Br2 to produce the desired 2-halopyridines 60 and 61, respectively." ... 

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