Lithiation nitrogen-directed

Whereas the repeated lithiation-trimethylsilylation sequence of trimethyl-silylbicyclopropylidene 43 a yielded predominantly the cyclopropene derivative 51 [54], bicyclopropylidenecarboxylates 42-Me, 42-fBu after repeated deprotonation and carboxylation retain the bicyclopropylidene moiety and give 2,2-disubstituted products 52-R only (Scheme 9) [55]. So far, alkylbicyclopropyl-idenes 43 e, f, g have not been induced to undergo deprotonation and a second substitution [56a]. The urethane 53 with a nitrogen directly attached to the skeleton, more easily than any other bicyclopropylidene derivative, rearranges to... 

Bipyridines can be lithiated with LiTMP (if only in moderate yield), with one nitrogen atom directing the lithiation of the other ring (Scheme 89) . Both 2,2 - and 2,4-bipyridines 177 and 178 can be lithiated in this way. 

The a-metalation of azoles (aromatic nitrogen-containing five-mem-bered rings) is a much more facile process than that for the analogous saturated systems, and a small number of heterocycles containing free NH groups can undergo some direct lithiation, despite the ionization of the... 

Examples of the direct 5-metalation of nonfused compounds containing heterocyclic sp3-nitrogen are quite limited, often because of competing side-reactions such as benzylic deprotonation. However, with the appropriate substitution pattern 8-metalation can occur even in those cases where benzylic deprotonation is a possibility. Examples of successful 8-lithiation include the imidazolidine 172 and 2-methyloxazolidine 173 (91G249), as well as the tetrahydroisoquinoline derivative 174 [69CI(L)621], although in this latter case subsequent steps resulted in only a 10% yield of the desired product 175. 

A variety of heterocyclic systems containing unsaturated nitrogen can partake in directed aromatic or heteroaromatic lithiations. Pyrazole (II,D), tetrazole (II,G,2), imidazoline (V,B,2), and pyridine (IV,A,4) derivatives were discussed in the sections indicated. In addition, lithio derivatives of 2-oxazoline 178 (76LA183), 4,4-dimethyl-2-oxazoline 179 (790R1 85T837),... 

Examples of the direct lithiation of sites more remote from heterocyclic 5/ 2-nitrogen are much less common, although evidence for direct 8-lithiation has been seen with 2-phenylthio-4,4-dimethyloxazoline, where migration of the oxazoline ring occurred as a result of nucleophilic attack by the initially formed 8-carbanion (Scheme 143) (83JOC2610). 

The antihypertensive agent 278 has been 14C-labelled by carbonation of the 2-lithiated indole, 279 (R = Li), with 14CC>2 and subsequent combination with a preformed peptide side chain. In 279 (R = H) the indole nitrogen has been converted into its benzenesulphonyl derivative to direct properly the lithiation while the 2-hydroxy-3-isopropylaminopropoxy side chain has been protected as oxazolidin-2-one290. 

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