Pyridines auxiliary directed

Scheme 6.8 The auxiliary directed asymmetric hydrogenation of pyridines.

Several approaches have been followed for the generation of optically active heteroarenes by homogeneous asymmetric hydrogenation. One approach involves direct asymmetric hydrogenation of the unactivated heteroarene. This approach has been most successful for heteroarenes that are polycyclic, like quinolines, isoquinolines, or quinoxa-lines (benzopyrazines). Less success has been achieved on the direct asymmetric hydrogenation of pyridines. To address this limitation, the hydrogenation of modified pyridines has been conducted. In one set of examples, pyridines and related benzo-fused heteroarenes were modified at tfie nitrogen by acylation or the installation of another auxiliary to make the pyridine more electron poor and to dock the catalyst. In a second set of examples, a chiral auxiliary was placed on the pyridine, and the product was formed diastereoselectively by an achiral catalyst. 

By using 8-aminoquinoline benzamide substrates and picolinic acid auxiliaries as the directing groups, the Daugulis group reported a novel method for selective mono- or di-fluorination of arene and heteroarene C—H bonds. AgF was used as fluoride source and DMF, pyridine, or DMPU as solvent. This Cu-promoted C—H activation method shows excellent functional group tolerance and provides a straightforward way for the preparation of ortto-fluorinated benzoic acids (Scheme 9.14). ... 

The implications of the data of Table 5.37 for orientation and for activation should be considered separately. For electrophilic substitution in both pyridine and pyridinium (the situation in which is represented by giving An a high value), C(3) is always indicated to be the most reactive position. The relative order of C(2) and C(4> (for which there is no direct evidence) depends upon the assumptions made, in particular as to whether the auxiliary inductive effect operates at C(2) when that is the position of localization. For pyridine 1-oxide C(2) is always the most reactive position, and with the preferred parameters, the complete sequence is C(2) > C(4) > C(3). In contrast, for the protonated oxide, C(3) is the favoured position, and these results led Barnes 20 correctly to conclude that in electrophilic substitutions of pyridine 1-oxide which proceeded at C(4) the free base was involved, as against the conjugate acid in those which proceeded at C(3). In the former case, C(4) rather than C(2) was attacked because of a steric factor. 

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