Pyridines, 3-lithio-4-substituted

The synthesis of the four monocarboxylic acids of dibenzothiophene has been recorded in the previous review. However, several modified preparations have since been described. Ethyl 1-dibenzothiophene-carboxylate has been synthesized from 2-allylbenzo[6]thiophene (Section IV,B, 1) hydrolysis afforded the 1-acid (57% overall). In a similar manner, 3-methyl-1-dibenzothiophenecarboxylic acid was obtained from the appropriately substituted allyl compound. This method is now the preferred way of introducing a carbon-containing substituent into the 1-position of dibenzothiophene. 2-Dibenzothiophenecarboxylic acid has been prepared by oxidation of the corresponding aldehyde or by sodium hypoiodite oxidation of the corresponding acetyl compound. Reaction of 2-acetyldibenzothiophene with anhydrous pyridine and iodine yields the acetyl pyridinium salt (132) (92%), hydrolysis of which yields the 2-acid (85%). The same sequence has been carried out on 2-acetyldibenzothiophene 5,5-dioxide. The most efficient method of preparing the 2-acid is via carbonation of 2-lithio-... 

Several extensions of these reactions are possible with respect to the electrophilic reagent as well as to the structure of the adduct. Thus functionalized alkyl groups, such as 2-hydroxyethyl and 2-hydroxy-2-phenylethyl, can be introduced into the pyridine ring at the position by treating l-lithio-2-phenyI-l,2-dihydropyridine with ethylene epoxide and styrene epoxide, respectively.144 When polyhalides such as CF3I are used, bis-(substituted-pyridyl)methanes and the dimeric substituted dipyridyls are obtained along with other products.144... 

In an interesting study with potential for the synthesis of 3-substituted pyridines, Katritzky has shown that LDA metalation of the benzothiazol-2-yl thioether 479 gives the highly coordinated lithio species 480, as demonstrated by quench with several electrophiles to give products 481 (Scheme 144) [87H(26)427]. 

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). 

Ring metallation generally succeeds with /V-oxides. a-Lithio derivatives (348) can be generated in non-protic conditions by treating pyridine 1-oxides with n-butyllithium. These may be intercepted by various electrophiles such as cyclohexanone (Scheme 35). Reaction of substituted lithio /V-oxides with carbon dioxide gives carboxylic acids with elementary 02 and S8 (347, X = 0, S) are produced. 

The cyano group has been used as an ortho -directing group for lithiation in the pyridine series.79 Lithiation of 4-cyanopyridine using LiTMP and trapping the lithio intermediate with electrophiles have provided an efficient and straightforward access to ortho -substituted-4-cyanopyridines. 

Reaction with alkyl- or aryl-lithiums proceeds in two discrete steps addition to give a dihydro-pyridine iV-lithio-salt which can then be converted into the substituted aromatic pyridine by oxidation (e.g. by air), disproportionation or elimination of lithium hydride. The N-lithio-salts can be observed spectroscopically and in some cases isolated as solids. Attack is nearly always at an a-position reaction with 3-substituted-pyridines usually takes place at both available a-positions, but predominantly at C-2 this regioselectivity may be associated with relief of strain when C-2 rehybridises to sp during addition. 

An earlier application of 1,4-conjugate additions employing azaallyllithium reagents formed from ketone dimethylhydrazones is Kelly s hydrazone version of the classical Knoevenagel route to substituted pyridine derivatives.71 In this chemistry, a mixed cuprate derived from a dimethylhydrazone lithio anion and copper thiophenoxide was first allowed to react with an a,p-unsaturated ketone. The product enolate can then be acylated or protonated to yield either a diketo hydrazone or a keto hydrazone. Addition of... 

Aqueous titanium (III) chloride reductively removes cyano and halo groups from substituted pyridines by a two-electron process and promotes reduction of pyridyl ketones and aldehydes to glycols by a one-electron-transfer process.49 a useful review of the reactions of halopyridines with lithiating reagents is now available.50 Choice of reaction conditions can be critical thus, depending on the conditions, 3-fluoropyridine can be converted into either 2- or 4-lithio-3-fluoropyridine and therefore be used as a precursor of both 2,3- and 3,4- disubstituted pyridines. 

In contrast, 2-lithio-l,3-dithiane gives with pyridine the product of 4-substitution 32. 

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