Pyridine, 3-methoxy-, lithiation

When the 4-position is substituted, Grignard addition occurs at the 2-position, to eventually give a 2,4,6-trisubstituted pyridine via the 6-lithiated species (Scheme 145) (88TL1751). Alternatively, if the 4-substituent is a chloro (88TL1751) or methoxy group (89TL5053), the initial product can be hydrolyzed to an enone rather than being aromatized to a pyridine. 

The lithiation of anisylpyridines has been studied.80 Whereas usual reagents did not react or gave addition products on the pyridine ring, the BuLi-LiDMAE superbase has induced exclusive pyridino-directed metallation. The latter selectivity has been attributed to an internal cooperating lithium complexation by both the pyridine nitrogen and methoxy group. 

A palladium-catalyzed reaction has been reported to C-6 alkylate 6-bromoimidazo[4,5-h]pyridine (109) <87EUP290153>. In this reaction, 2-methoxy-6-bromo-8-methylquinoline (110) was treated with butyllithium to give the 6-lithiated derivative (111). To this compound (111) was added zinc chloride, followed by 6-bromoimidazo[4,5-/>]pyridine (109) and tetrakis(triphenylphosphine)palladium(0)... 

Nitrosation at the 5-position of 3-methoxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine (237) has been used as a method to block this basic nitrogen in the synthesis of compound (242) (Scheme 23), a conformationally restricted 7V-methyl-(/ )-aspartic acid analogue, for evaluation as a potential excitor of neurotransmitters in the mammalian central nervous system <82Mi 708-02, 86ACS(B)92>. Lithiation of the derivative (238) with n-butyllithium regiospecifically at the 4-position followed by C-alkylation with the addition of methyl chloroformate gave the 4-methoxycarbonyl derivative (239), albeit in a low 16% yield. The remainder of the synthetic sequence involves a stepwise deprotection sequence (239)-(242). 

In the metalation reaction of pyridine 5 with tBuLi the methoxy substituent exhibits a directing effect. Solvated (tBuLi)4 aggregate 19 coordinates to the oxygen of the methoxy group to give 20. Successive deprotonation yields the ortljo-lithiated species 21, which is stabilized by 0-Li coordination. 

A practical six-step synthesis of (S)-camptothecin was developed by D.L. Comins and co-workers." In order to prepare the DE ring fragment, 2-methoxypyridine was Iithiated at C3 with mesityllithium and treated with A/-formyl-A/,A/, A/ -trimethyl ethylenediamine to form an -amino alkoxide in situ. In the same pot, the addition of n-BuLi brought about a directed lithiation at C4 to afford a dianion, which was trapped with iodine and treated with NaBHVCeCIs to give the desired 4-iodo-2-methoxy-3-hydroxymethyl pyridine in 46% yield. 

Pivaloylamino-5-methoxypyridine has been selectively acylated and alkylated in the 4-position by successive reaction with n-butyl-lithium and an electrophile. The activating effect of a A -pivaloylamino- (NHCOBu ) or a methoxy-group alone failed to give orf/to-lithiation. A new general route to nitroso-substituted heterocycles, particularly useful when direct nitrosation is inapphcable, as in the case of pyridine, is illustrated in Scheme 16. 

Oxazolines (4) are easily prepared from benzoic acids and behave as activating groups in nucleophilic aromatic substitution. Thus, o-methoxy- or o-fluoro-substituents are replaced by the alkyl group of RLi. " The same oxazoline group in the 4-position of pyridine promotes 3-lithiation, whereas in the 3-position it induces nucleophilic alkylation to give 1,4-dihydropyridine derivatives. Benzyl alcohol is lithiated in the 2-position of the benzene nucleus. Solvent effects are suggested to be responsible for the quantitative syn selectivity in the alkylation of lithiated ketimines (5). ... 

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