Lithiation five-membered heterocycles

Silicon protection is also commonly used to direct lithiation chemistry in five-membered heterocycles. For example, oxazoles , thiazoles and Ai-alkylimidazoles ° ° lithiate preferentially at C-2, where the inductive effect of the heteroatoms is greatest. If C-2 is blocked, lithiation occurs at C-5, where there is no adjacent lone pair to destabilize the organolithium. Functionalization of these heterocycles at C-5 can therefore be achieved by first silylating C-2, reacting at C-5 and then removing the silyl group. The synthesis of 666 illustrates this sort of sequence (Scheme 258) °. ... 

There are several bicyclic compounds with five-membered heterocycles fused to pyridine rings, where metalation occurs in the smaller ring due to activation by the heteroatom. The ring-A lithiation of imidazopyridines and pyrimidines was discussed in Section II,E,6, but in addition, the a-lithio derivatives of thieno[2,3-6]pyridine 119 (74JHC355), thieno[3,2-... 

The inductive effect of the heteroatom, which withdraws electrons to a greater extent from an adjacent carbon atom (a-positions), allows direct a-lithiation of practically all five-membered heterocycles. The relative acidities of a-hydrogens in some different classes are illustrated in the table below. 

Directing groups can overcome the normal tendency for a-lithiation in five-membered heterocycles, as shown in the thiophene example below, however the use of lithium diisopropylamide does allow normal a-lithiation in this case. ... 

Discovery that the N-substituted carboxamide group could direct metalation(46) led to the eventual establishment of synthetic routes to a number of heterocycles, including substituted lactones, phthalimidines, and isocarbostyrils (47). Cyclization of the products of condensation of the lithio intermediates of N-methylbenzamide yielded five-membered heterocycles (Reaction 38) (48). o-Methyl-N-methylbenzamide, in which the methyl group was lithiated, gave six-membered ring heterocycles (Reaction 39) (49). The mechanism of the cyclization step in the latter procedure has been dealt with in some depth in the literature (50) an independent reinvestigation, however, has cast doubt on the validity of the dihydroisocarbostyril structures proposed (51). 

Five-membered heterocycles Nitrogen heterocycles. Aminomethylenemalononitrile was transformed to azafulvene by lithiation Cyclohexylidenemalononitrile 188 yielded spiro pyrroline 194 by reaction with trimethylsilyl cyanide. The reaction was catalyzed by KCN/18-crown-6262. 

In many ways, the electron-rich five-membered aromatic heterocycles behave very much like carbocyclic aromatic compounds when it comes to lithiation. Lithiation a to O or S of furan and thiophene is straightforward (Scheme 130) . The usual selection of orf/io-directing groups allows lithiation at other positions and some examples... 

Six-membered heterocycles are more resistant to an arene catalyzed lithiation than the corresponding five-membered ones. For instance, tetrahydropyran can not be cleaved under the reaction condition employed to open tetrahydrofuran (activation by BF3) ... 

Lithiation of the methyl derivatives of such five-membered heteroaromatics as pyrrole , thiophene , l,3-thiazole ° , 1,3-oxazole , isoxazole , 1,3,4-thiadiazole , 1,3,4-oxadiazole and imidazole also occurs. For the sulfur heterocyclics, ring metallations and ring opening after lithiation are complications. 

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