A-Lithiated oxirane

The tin-lithium exchange is also suitable for the generation of a-lithiated oxiranes 53245-247 jjyg jQ jjjg enhanced acidity of a carbon atom incorporated into a three-membered ring, the metalation of epoxides by treatment with various alkyllithium reagents of lithium amide bases also permits one to obtain carbenoids 53 in situ (equation 35) °. 

An overview of oxiranyllithiums as chiral synthons for asymmetric synthesis discussed the generation of a-lithiated oxirane derivatives by various synthetic methods." The mechanism and stereochemical features in asymmetric deprotonafion... 

The intermediacy of an a-lithiated oxirane was postulated for the first time by Cope in the 1950s while studying the reaction of cyclooctatetraene oxide with hthium diethylamide (1951JA4158, 1960JA6370). Since then, and particularly over the last 10 years, many synthetic methodologies have... 

Finally, metalated epoxides undergo isomerization processes characteristic of traditional carbenoids (Scheme 5.2, Path C). The structure of a metalated epoxide is intermediate in nature between the structures 2a and 2b (Scheme 5.2). The existence of this intermediacy is supported by computational studies, which have shown that the a-C-O bond of oxirane elongates by -12% on a-lithiation [2], Furthermore, experimentally, the a-lithiooxycarbene 4a (Scheme 5.3) returned cydo-pentene oxide 7 among its decomposition products indeed, computational studies of singlet 4a suggest it possesses a structure in the gas phase that is intennediate in nature between an a-lithiocarbene and the lithiated epoxide 4b [3],... 

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. 

Finally, a reaction that clearly shows the electrophihc carbenoid-type character of a-lithiated epoxides is the reductive alkylation discovered by CrandaU and Apparu. The transformation is illustrated by the treatment of f-butyl ethylene oxide with t-butyllithium to yield ii-di-f-butylethene (equation 55). The overall reaction results in a conversion of an oxirane into an aUcene under simultaneous substitution of an a-hydrogen atom by the alkyllithium reagent ... 

Some reports concerning the reaction of lithiated thioallylethers with oxiranes have been published. A slow reaction was observed with a terminal oxirane. However, with cyclopentadiene oxide, the reaction occured smoothly with an excellent regioselectivity in favor of the Sjv2 displacement in the ally lie position. Other examples involving sulfur, selenium and silicon stabilized organolithium reagents have been reported . 

Oxiranes are converted into 4,5-dihydrooxazoles by treatment with cyanides in the presence of sulfuric acid (equation 171). a-Lithiated isocyanides react with aromatic aldehydes to furnish 2-lithiodihydrooxazoles (equation 172) (79JCS(P1)652). 

Lithiation of a-heterosubstituted oxiranes 129 has been investigated and favorable reaction conditions have been established with the aim of preparing nucleophilic oxirane molecules that can be employed in organic syntheses." ... 

In the second half of this chapter the enantioselective generation and reactivity of a-lithiated epoxides 53 (also named oxiranyl anions) is reviewed such orga-noUthiiuns are reactive intermediates in which the anion is carried by the ox-irane,as shown in Fig. 1. After a short introduction the different reactivities that such intermediates can exhibit, which depend on the other substituents of the oxirane and, of course, on the reaction conditions, will be discussed [29,30]. 

Finally, Seebach has used the cyclic urea (69), DMPU, as a co-solvent in double lithiations, oxirane ring-opening, Wittig reactions, Michael additions of lithiated dithianes to cycloalkenones, and the selective generation of enolates." The interesting point here is that DMPU exhibits the same solvent effect as the carcinogen HMPA and might therefore be a safe substitute. 

Metalation of dimethylhydrazone derivatives of aldehydes and ketones occurs cleanly. Unsymmetrical ketones suffer proton abstraction from the lesser-alkylated a-carbon atom specifically, and the a-lithiated dimethylhydrazones react more vigorously than the corresponding enolates with halides (Scheme 23), oxirans, and carbonyl compounds (Scheme 23). Cuprate derivatives can be obtained from the lithiated species in the usual manner and the cuprates undergo Michael addition to ajS-unsaturated ketones. 

Computational studies of the carbenoid cyclopropanation reactions of methoxymethyl-lithium and intra- and intermolecular carbenoid reactions of lithiated oxiranes have been reported. Computations suggest that methoxymethyllithium reacts with ethylene exclusively by a stepwise carbolithiation mechanism. The intramolecular reaction of lithiated l,2-epoxy-5-hexene was found to proceed by both the carbohthiation and the methylene transfer pathways, but the former is expected to dominate at room and low temperatures because the free energy of activation is less than half that of the latter pathway. 

In addition to asymmetric deprotonation. Cope observed that cyclic epoxides in the presence of base give rise to products derived from transannular reactions [110], Boeckman carried out a study of oxiranes fused to medium-size rings and noted that the more commonly observed deprotonation of oxiranes can be suppressed at low temperature, permitting the formation of bi-cyclic structures [118]. In such cases, a-lithiation of an epoxide followed by 1,1-elimination generates a carbene that participates in a subsequent CH-insertion process (cf. 131). An enantioselective version of this reaction was investigated by Hodgson (Scheme 9.15) [119]. Thus, in the presence of sparteine (130), treatment of cyclooctene oxide 129 with i-PrLi affords bicyclic alcohol 132 in 84% ee. 

Alkenylbenzotriazoles 865 are readily prepared by isomerization of the corresponding allyl derivatives catalyzed by Bu OK. Lithiated compounds 865 are treated with electrophiles to provide a-substituted derivatives 866. Epoxidation of the double bond with ///-chloroperbenzoic acid converts intermediates 866 into oxiranes 867 that can be hydrolyzed to furnish a-hydroxyketones 868 in good yields (Scheme 140) <1996SC2657>. 

In general, addition of lithiated dialkoxydihydropyrazines occurs at the less hindered site of the oxirane. However, with phenyloxirane, ring opening does not take place regioselectively, and a complex product mixture is formed29. 

Reductive lithiation [74] of epoxides (110) or oxiranes (107) is a good method for the preparation of highly reactive carbohydrate anions (111 or 108). Such species may also be obtained in a two-step procedure involving the opening of the epoxide ring with a tin nucleophile (to 109), which is replaced finally with lithium (O Scheme 30) [75]. 

The three-component reaction of lithiated [bis(phenylsulfanyl)methyl]trimethylsilane, phenyloxirane, and an alkene takes an interesting reaction pathway. Obviously the oxirane serves as a trapping reagent for lithium benzenethiolate, which results from a-elimination of the initially formed organolithium compound. The generated phenylsulfanyl(trimethylsilyl) carbene (4) adds stereoselectively to various alkenes. In all cases the sterically less crowded Z-isomer cyclopropane 5 is formed. 

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