Thiazole-5-tertiary-amide

The directed metalation of aromatic systems that was discussed in Section 2.1.3.3 has one ramification that was not mentioned there the directed lithiation of an o-methyl group. Although the resultant species is formally a resonance-stabilized anion, and therefore covered in Volume 2 of this series, we mention it here for consistency with the other topics covered. In particular, the examples that have appeared in recent years involve substrates having a methyl ortho to a tertiary amide. Intentional use of such a directed lithiation has been used in the synthesis of the isocoumarin natural products hydrangenol and pyllodul-cin.137,138 Interestingly, the directed metalation of 5-methyl-oxazoles and -thiazoles occurs in preference to deprotonation at a 2-methyl group (azaenolate) (Scheme 33). ... 

Protons on alkyl groups at the 1,3-azole 2-positions are sufficiently acidic for strong base deprotonation,and are more acidic than methyl groups at other positions even the assistance of an or/Ao-related carboxylate is usually insufficient to overcome the intrinsic tendency for 2-methyl-lithiation, though an adjacent tertiary amide can do this. The side-chain metallated derivatives can be utilised in reactions with electrophiles. The presence of a 5-nitro group allows much milder, base-catalysed condensations to occur. The condensation at the 2-methyl of thiazoles proceeds in organic acid solution. ... 

The reaction outlined in eq 3, was conducted photolyticaUy in benzene solution, with the benzene presumably scavenging the trifluoromethyl radical, as it is scavenged in eq 2. A dozen examples of iodides were successful in yields generally over 60% and with retention of configuration. These room-temperature examples show the reaction to be compatible with such diverse functionality as free hydroxyl, ester, amide, thiazole, and potential -elimination substrates, and succeeded with primary, secondary, and tertiary iodides. 

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