Directed ortho Metalation ether

Snieckus, V. The directed ortho metalation— Ullmann connection. A new Cu(I (-catalyzed 231 variant for the synthesis of substituted diaryl ethers. J. Org. Chem. 1999, 64, 2986—2987. 

For conversion of functionalized diorganozincs into tertiary amines, aromatic compounds which contain a directed metallation group, such as Af,Af-dialkylbenzamides, methoxymethyl phenyl ether, phenyl oxazolines and phenyl Af,Af-dialkylcarbamates, were ortho-lithiated, transmetallated and then aminated with 2a in good yields, but with a slower reaction rate (Scheme 19). 

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. 

Ether groups exert their ortho-directing action in the metallation of aromatic rings mainly via their electron-withdrawing inductive effect. Methoxybenzene has been lithiated with BuLi in Et20 or THF. The metallation in the latter solvent can be carried out in a reasonable time (2-3 h at 20 °C), but part of the butyllithium is consumed by reaction with the solvent, unless a considerable excess of anisole is used. The activating influence of two methoxy groups in 1,3-dimethoxybenzene renders the metallation easier. 

Electrophilic substitution is difficult with electron-deficient heteroatomic compounds such as pyridine and quinoline. However, an electrophile can be readily introduced when the heterocycles have an effective ortho-directing group such as a sulfamoyl moiety. Lithiation of the 2-pyridinesulfonamide (51) was performed at low temperature by using 2 equivalents of LDA in ether at —78 °C for 1.5 h (equation 27). Addition of benzophenone to the solution of 52 gave the adduct in high yield38. Metallation of the 4-pyr-idinesulfonamide 53 with 3 equivalents of LDA, followed by reaction with benzaldehyde, afforded the 3,5-disubstituted pyridine 54 (equation 28). 

The Cr(CO)3 unit also activates the ring protons towards removal. Ring deprotonation can be made easier and be directed if a substituent with lone pairs is present on the ring. A lone pair can coordinate to the lithium of the incoming base and direct deprotonation to the ortho position. In many cases this reaction -orfAo-metallation - is already possible without metal complexation, but complexation makes it easier. Not all substituents show this behavior equally.A fluorine substituent is particularly effective, even more effective than a methoxy substituent in a competition experiment (Scheme 10.57), while, amongst ethers, the methoxymethoxy substituent proved best. ... 

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