Phenothiazines lithiation

Directed metalation by the N-anion of phenothiazines is not confined to /3-lithiation, and it is even more facile when a y-proton is involved. Thus,... 

The metalation of phenoxazine has also been investigated, but in contrast to phenothiazine, direct lithiation at C-l can only be achieved in very low yield (58JA2195 68JMC807). Fortunately, however, the carboxylate protection method is just as efficient as that with phenothiazine, and the... 

Halogen-metal exchange reactions provide the main route to 3-lithiated derivatives of phenothiazine and phenoxazine and examples of metalated compounds formed by the use of such exchange reactions include the... 

When lithiated phenothiazine is treated with methyl sulfate, acetyl chloride, and ethylene oxide 10-substituted derivatives are obtained. Lithium salts of carboxylic acids, however, lead to 1-phenothiazinyl ketones Scheme 14 presents the evidence for the structures assigned to these substances. 

The preparative value of metalation reactions consists primarily in the possibility of obtaining 1- and 4-substituted phenothiazines, which are difficult to prepare by other methods. Also lithiation at position 3 by halogen-metal exchange using triphenylsilyllithium presents interesting possibilities. 

Lithiation of both A/-phenyl- and 0-phenyl-urethanes has been reported. The ortho lithiadon of /V-r-bu-toxycaibonylaniline and subsequent addition to carbonyls, nitriles and several other electrophiles was first reported by Muchowski in 1980. In some cases the adduct cyclized by attacking the urethane carbonyl. Typical examples are shown in Scheme 17. Lithiation of an /V-r-butoxycarbonylaniline derivative served as one of two directed lithiation steps in Snieckus synthesis of anthramycin (17 Scheme 18). Treatment of phenothiazines with 2 equiv. of butyllithium affords an A(,o-dilithium species, but reaction with electrophiles occurs at both sites. Katritzky has shown that the sequence of N-lithiadon, car-bonation and o-lithiation protects the nitrogen from alkylation (Scheme 19). ... 

The DTBB-catalyzed lithiation of 4-hetero-substituted dibenzothiins (68), such as phenoxathiin (68a), phenothiazine (68b) and thianthrene (68c), at low temperature gives the corresponding functionalized organolithium intermediates (69), which by reaction with different electrophiles afford, after hydrolysis, the expected functionalized... 

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