Lithiation lithium diethylamide

The existence of a metalated epoxide was first proposed by Cope and Tiffany, to explain the rearrangement of cyclooctatetraene oxide (8) to cydoocta-l,3,5-trien-7-one (11) on treatment with lithium diethylamide. They suggested that lithiated epoxide 9 rearranged to enolate 10, which gave ketone 11 on protic workup (Scheme 5.4) [4],... 

The effect of substrate structure on product profile is further illustrated by the reactions of cis- and trons-stilbene oxides 79 and 83 with lithium diethylamide (Scheme 5.17) [32]. Lithiated cis-stilbene oxide 80 rearranges to enolate 81, which gives ketone 82 after protic workup, whereas with lithiated trans-stilbene oxide 84, phenyl group migration results in enolate 85 and hence aldehyde 86 on workup. Triphenylethylene oxide 87 underwent efficient isomerization to ketone 90 [32]. 

On the contrary, a-lithiated epoxides have found wide application in syntheses . The existence of this type of intermediate as well as its carbenoid character became obvious from a transannular reaction of cyclooctene oxide 89 observed by Cope and coworkers. Thus, deuterium-labeling studies revealed that the lithiated epoxide 90 is formed upon treatment of the oxirane 89 with bases like lithium diethylamide. Then, a transannular C—H insertion occurs and the bicyclic carbinol 92 forms after protonation (equation 51). This result can be interpreted as a C—H insertion reaction of the lithium carbenoid 90 itself. On the other hand, this transformation could proceed via the a-alkoxy carbene 91. In both cases, the release of strain due to the opening of the oxirane ring is a significant driving force of the reaction. 

Lithiated nitrites. This base is somewhat more effective than LDA or lithium diethylamide for deprotonation of the allylic nitrile 1, used in a synthesis of 2, which has the ferulol skeleton.1... 

Corey, Enders and Bock were among the first to describe the utility of lithium dimethylhydrazone anions for crossed aldol reactions. In the reaction shown in equation (14), an azaallyllithium reagent derived from an aldehyde dimethylhydrazone was first silylated with trimethylsilyl chloride to yield a silyl aldehyde dimethylhydrazone. Subsequent lithiation using lithium diethylamide at -20 C for 1 h generated the silylated azaallyllithium reagent (29). Subsequent addition of one equivalent of an aldehyde or ketone at -78 C and warming to -20 C then yielded the product a,p-unsaturated aldehyde dimethylhydrazone in yields of 85-95%. Hydrolysis produced the unsaturated aldehyde in 75% overall yield. 

Analogous condensations using lithium enolates of /V,/V-diethyl-o-toluamide (149) have been described by Clark and Jahangir for the synthesis of 3,4-dihydro-l(2//)-isoquinolones123,124 (151 Scheme 31). It is fortunate that the enolate-imine addition-cyclization process occurs at low temperature, since warming the reaction mixture to room temperature, a common practice in many enolate-imine additions, leads to side reactions due to the instability of the 4-lithiated derivative (150) formed by release of lithium diethylamide. The authors have exploited the in situ formation of (150) for the synthesis of 4-sub-stituted isoquinolones by trapping it with electrophiles. A cycloaddition mechanism via an... 

Evans and co-workers developed a regioselective lithiation protocol of 2-methyl-4-substituted oxazoles 945 during their synthesis of phorboxazoles. In particular, the authors required a general method to generate regioselectively a 2-(lithiomethyl)oxazole and to functionalize the intermediate without competitive lithiation and reaction at C(5). Among the bases investigated, lithium diethylamide was particularly effective and selective for the required transformation (Scheme 1.253, p. 206). 

Snieckus and co-workers reported the directed lithiation of 3-furanecarboxylic acid diethylamide (6.21.), which proceeded selectively in the 2-position, and the subsequent zinc-lithium exchange. The so formed fiiranylzinc reagent underwent Negishi-coupling with 2-bromotoluene in the presence of a palladium-triphenylphosphine catalyst to give 2-(o-tolyl)furane in good yield.26... 

Two groups report the addition of metalated benzamides to aldehyde carbonyls. The methods differ in the metal. Lithiated diethylamides must be transmetalated with MgBr2 before addition to the aldehyde, but p-aminoamides react similarly as the lithium derivative. Following addition, the hydroxyamide is hydrolyzed to afford phthalides in moderate overall yield (Scheme 11). 

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