Pyridines directed lithiation

Pyridines are yet more susceptible to nucleophilic attack, but may just about direct lithiation if ring addition can be avoided. Organolithium 135 is unstable and slowly isomerizes to 136 (Scheme 63). ... 

The direct metalation of 5-methylpyrimidine and 5,5 -bipyrimidinyl in the 4-position has been reported with LDA in low yield [74TL2373 75AG(E)713], but apart from that there are few other reports on the direct metalation of unactivated diazines. However, as with pyridine and quinoline, directed metalation can readily be achieved with all three of the diazine systems when the appropriate substituent groups are present [91AHC(52)187]. Thus, the direct lithiation of pyridazine in the 4-position has now been achieved with both the 3,6-dichloro and the... 

The reactivity of pyridine organometallic nucleophiles is of course the same whether they are prepared by direct lithiation or by halogenmetal exchange from pyridine halides. Accordingly, the reactions of these organometallic intermediates are discussed partly here but mainly in Section 3.2.3.11, Reactions of substituents Metals and Metalloid Derivatives. 

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. 

Direct lithiation of pyridine is a common method of generating the precursors required for the organopalladium cross-coupling reactions. However, if one is not carefiil, the pyridine ring is susceptible to direct addition of the alkyllithium reagent (Chichibabin reaction) as opposed to deprotonation of the ring. 

Direct lithiation at the 2-position of the pyridine ring could be accomplished using... 

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. 

Direct lithiation of l,2,3-triazolo[l,5-a]pyridines occurs with ease, at C-7, subsequent reaction with electrophiles being unexceptional, for example conversion into the 7-bromo derivative then allows nucleophiles to be introduced via displacement of bromide, thus providing, overall, a route to 2,6-disubstituted pyridines. ... 

Interring-directed lithiation With LTMP at -40° or -70°, 2,4 -bipjiridyl is Uthiated at the C-3 of the 4-substituted pyridine ring, owing to the directing effect of the second nitrogen atom. Thus, selective functionalization (such as by stannylation and Heck reaction) at that position is readily achieved. 

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). 

Regioselective metalation of a wide variety of trifluoromethylated pyridines and quinolines was exhaustively studied by the Schlosser research group." " It was demonstrated that regioselectivity of direct lithiation of fluorinated heterocycles depends signihcantly on reagents, reaction conditions and type of solvent. For example, the lithiation of 2-CF3-pyridine using lithium 2,2,6,6-tetramethylpiperidine (LiTMP) in THF at —75°C results in exclusive formation of acid 109, while the reaction with BuLi in the presence of Et2NCH2CH20Li in less polar ether leads to selective formation of isomeric acid 110 (Fig. 7.39). ... 

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