Carbamates ortholithiation

Af,Af-Dimethylcarbamates are unstable once ortholithiated, and rearrange rapidly by a carbamoyl transfer mechanism known as the anionic ortfio-Fries rearrangement . With Af,Af-diethylcarbamates, this rearrangement can be controlled the ortholithiated carbamate 64 is stable at —78°C but, on warming to room temperamre, rearranges to give a 2-hydroxybenzamide 65 (Scheme 33) °. ... 

BuLi-TMEDA , are similarly powerful directors (Scheme 54). By contrast, the related amides, carbamates and ureas (125, R = COAr, CONR2, CO2R) usually undergo ben-zylic a-lithiation (see Section II.B). The bias can be shifted towards ortholithiation by additional electron-withdrawing substituents on the ring . 

This chemistry can be very powerful, since the amide product itself offers further possibilities for functionalisation by lithiation. The synthesis of the natural product ochratoxin A (section 9.1) illustrates this point. Two successive ortholithiations of carbamate 210 are used first to introduce one amide group and then a second, by anionic ortho-Fries rearrangement. The symmetrical diamide 211 can be allylated and then cyclised in acid, with concomitant hydrolysis of the second amide and deprotection of the phenol to yield a known intermediate... 

The starting point for the metallation sequence was /7-chlorophenol, whose directing power was first maximised by conversion to the carbamate 3. Ortholithiation and reaction with N,N-diethylcarbamoyl chloride gave the amide 4. The second ortho carbonyl substituent was then introduced simply by allowing the lithiated carbamate 5 to undergo an anionic ortho-Fries rearrangement to the bis-amide 6. The phenol was protected as its methyl ether 7. 

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