Lithiation ortho-type

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaUy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphorus [7723-14-0]y produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-lithiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has litde commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

The isocoumarin and the dihydroisocoumarin ring systems occur widely in nature Their synthesis by lithiation method is according to type C and involves ortho metalation of N-methyl arylcarboxamides. The organometallic compounds on treatment with electrophilic reagents such as an epoxide or allylbromide followed by hydrolysis and cyclisation furnish the dihydroisocoumarins. Bromination at benzylic position followed by dehydrobromination then gives the isocoumarins themselves. 

Condensed furans hke coumarins belong to type 13 mentioned in page 8. As in the case of the synthesis of coumarins, the ortho disubstituted starting compounds are obtained by lithiation of phenol or its methyl or methoxymethyl derivatives (Type B synthesis). These are reacted with electrophilic reagents such as DMF, Br... 

The synthesis of isoquinoline by lithiation route is according to type C. Thus aromatic benzylamines or P-phenylethylamines are lithiated at ortho position. The organo-metallic compounds on treatment with epoxide or an aldehyde furnish ortho substituted compounds which are converted to isoquinolines... 

The directed metalation reaction—lithiation with n-butyl-lithium of a position ortho to a substituent on an aromatic ring—is described. Aromatic systems in which the reaction has been studied are benzene, thiophene, naphthalene, and ferrocene. A systematic listing of the bond types that can be formed at the site of metalation is provided. Also of interest is the assessment of the relative directing abilities of directing substituents and comments and observations on the mechanism of the reaction. Utility of the reaction is indicated by the results from asymmetric-directed lithiation and the synthesis of heterocycles. 

A route in which a synthon for such a dialdehyde is central depends on ortho lithiation of an aryl bromide for conversion to ortho bromoaryl aldehyde, then palladium-catalysed replacement of the halide with an alkyne, subsequent reaction with ammonia producing the isoquinoline. The sequence below shows how this type of approach can be used to produce naphthyridine mono-A-oxides by reaction of the alkynyl-aldehyde with hydroxylamine instead of ammonia. 

Clayden s group has reported pioneering studies on asymmetric ortho-lithiation reactions. They have shown that treatment of lithiated hindered tertiary amides such as 19 with chiral sulfinate esters of type 20 gives the... 

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