Oxygen reaction with organolithium reagents

Reaction with (172) and other aldoximes may require oxime activation, which can be achieved with the addition of 1 equiv. of BF3-OEt2." " Yields in the addition of organometallic reagents to substituted aldoximes are modest and are a function of the isomeric composition of the oxime ethers, as the (Z)-oxime isomers are reported to preferentially react with organolithium reagents (entries 1 and 2, Table 13). ° The reaction has been employed for the preparation of 6-aminoalkyl-substituted pencillins (entry 3, Table 13)."° Cyclic oxime ether additions have also been evaluated (entries 4 and 5, Table 13). ° With the lability of the nitrogen-oxygen bond, addition to S-substituted isoxazolines provides a potential avenue for stereospecific synthesis of substituted 3-aminoalcohols (entry 5, Table 13). 

Pyridine is an aromatic 6n electron heterocycle, which is isoelectronic with benzene, but electron deficient. Nucleophiles thus add almost invariably to carbon C2 of the imine-like C=N double bond. Perhaps the best known nucleophilic addition is the Chichibabin reaction with sodium amide in liquid ammonia, giving 2-aminopyr-idine. Reactions of the quinoline moiety of cinchona alkaloids can be more complex. Although expected 2 -addition can be achieved easily with organolithium reagents to yield 13 (Scheme 12.6) [9], LiAlH4, for example, has been shown to attack C4 en route to quincorine and quincoridine (Schemes 12.4 and 12.5). C4 selectivity is due to chelation of aluminum by the C9 OH oxygen. 

Few detailed mechanistic studies of reactions of organolithium reagents are known, apparently because of the high specific rate constants exhibited by most of these processes, coupled with the sensitivity of these organometallic compounds toward oxygen and water. Nevertheless the last several years have afforded much data which indicate the direction that research in reaction mechanisms in this area, as well as in others, is taking or should take. Specifically, they first involve the problems of structure and the effect of solvent on structure 1-14). This area has been reviewed by Brown (i). 

The chelative ability of the oxygen atoms in the MEM group results in an ideal environment for the addition of organolithium reagents to the ester group of 372. If the reaction is performed at —100 °C in ether/pentane (1 1) for a maximum of 10 min, protected a-hydroxyketones 374 are produced, with only minor amounts of alcohol 375 appearing [5]. At temperatures below — 80 °C the intermediate 373 is sufficiently stable to prevent in situ formation of 374, which upon further addition of RLi is responsible for production of the undesired alcohol 375. 

---