Pyridine 1-oxide, lithiation

Fluoropyridines form valuable starting materials for a range of disubstituted pyridines because, after lithiation, nucleophilic substitution of fluoride (sometimes via the N-oxide) can be used to introduce, say, N or O substituents as in 191 and 192 (Scheme 96). Subsequent annelations can allow complex polycyclic heteroaromatics to be constructed. ... 

Closely related are the pyridine-A-oxides, which are readily lithiated in the 2-position , even in examples such as 228 where there is a powerful competing directing group (Scheme 111). Lithiation of the bipyridine-Af-oxide 229 was used in a synthesis of the caerulomycins and collismycins. ... 

An excellent example of the application of pyridine lithiation is the synthesis of the fully substituted pyridine atpenin B 255, an antibiotic produced by Penicillium. Its first synthesis, in 1994, was achieved by a series of directed metallations (Scheme 126) which started with 2-chloropyridine 256 and introduced the substituents stepwise around the ring. 2-Chloropyridine can be lithiated ortho-directed by the chlorine) by either LDA or by PhLi, and the organolithium 257 was oxidized to 258 with trimethylborate and then peracetic acid. 0-Methylation and substitution of chloride by methoxide gave 2,3-dimethoxypyridine 259 (Scheme 127). 

If the lithiated dihydropyridine contains a removable substituent on the nitrogen and if subsequent removal of the substituent is accompanied by oxidation then substituted pyridines can be obtained [88AHC(44)-199]. Thus, pyridine can be converted to a l-(t< r/-butoxycarbonyl)-... 

In pyridine-A-oxide, 2-proton acidity is considerably enhanced by the inductive effect of the oxide and by the complexing capability of the lone pair on oxygen with lithium. Hence, 2-lithiation and sometimes 2,6-dilithiation with alkyllithium and lithium dialkylamide bases is feasible. In the case of ring substituted pyridine-A-oxides 498, fair to good yields of... 

Lithiation of thiazolo[5,4-b]pyridine-N-oxides (503) by n-butyllithium at -65°C is selectively directed by the pyridine N-oxide moiety, whereas lithiation of the parent heterocycle by LDA at -78°C exclusively occurs at the C-4 position (89TL183). Interestingly, no metalation of the furan ring occurred (Scheme 152). 

Pyridine A-oxide can be a-lithiated in a reaction which is essentially an ortholithiation.29 The reaction works in the saturated series too - quinuclidine-A-oxide 105 may be lithiated and functionalised as shown below.72... 

Pyridine A-oxides are readily deprotonated at C(2) using LDA or -butyllithium as base in THF and the reagents thus produced react in the usual way in high yields with a variety of electrophiles including iodine, alkyl halides, aldehydes, and ketones < 1995J(P 1 )2503>. For example, -lithio derivative 361 can be generated and intercepted by various electrophiles, e.g., carbon dioxide, elementary sulfur, or cyclohexanone giving 362 note that the lithiation prefers the carbon to the oxide rather than that ortho to the chlorine. 

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