Orthodirecting groups

The usually very powerfully orthodirecting groups such as secondary carboxamide surprisingly do not always lead to ortholithiation on pyrazine and pyridazine rings lithiation of 386 and 387, for example, takes place principally (at least kinetically) at the meta and para positions.339 340... 

Blocking either the 2- or 4-position allows lithiation at the other LDA or BuLi can be used to 4-lithiate the 2-blocked 3-fluoropyridines 319,284 320285 and 321,286 287 and BuLi 2-lithiates the 4-blocked 3-fluoropyridine 322.284 288 289 Note the selectivity for removal of the acidified pyridine protons in 321 and 322 over the coordination-activated ones adjacent to the pivalanilide group. A double orthodirecting effect ensures 4-lithiation of 323.290... 

The alkoxysulfonyl group has recently been demonstrated to be an efficient orthodirecting substituent. The metallation of 19 can be accomplished in good yields with 1.1 equivalents of BuLi at — 78 °C in THF for 5 hours (equation 13). The choice of the appropriate esters is important in this reaction, since with the methyl ester the yield of the product is low due to the competing facile displacement of the methyl group27. The results of the ortho derivatizations are shown in Table 2. These products can be readily isolated, unlike the acidic products obtained by ortho-lithiation of arenesulfonic acids21. 

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