Intermolecular carbolithiation

There is one example, unique for several reasons, of the formation of a four-membered ring by anionic cyclisation onto an oxazoline. Attempted oxazoline-directed lithiation of the styrene 122 gave, instead, the cyclobutane 124 via addition of the alkyllithium to give a benzylic organolithium 123 which cyclises stereoselectively.63 The initial intermolecular carbolithiation proceeds remarkably easily - no additives (such as TMEDA) are required, even with MeLi. 

Cyclisation of the organolithium 247 formed from the selenide 246 is unfavourable because it would generate a three-membered ring. But in the presence of ethylene, an intermolecular carbolithiation provides an unusual route to a primary organolithium, giving the cyclopentane 248.128... 

It is presumed that the initial step for the intermolecular as well as intramolecular carbolithiation is an energetically favorable coordination of the lithium atom with the n-system, which serves to establish the geometry of the system prior to addition. The chiral benzylic organolithium compound 45, obtained after the carbolithiation step, reacted diastereoselectively with a number of electrophiles, yielding a formal inversion of the configuration. 

Major advances have been made in the intermolecular carbolithiation of unactivated alkenes (such as 128) and alkynes in recent years. Wei and Taylor designed a tandem intermolecular-intramolecular carbolithiation sequence, giving rise to cyclic products, 129 (Scheme 42), using organolithium reagents as difunctional reagents106. 

The carbolithiation of unactivated alkenes has also proven very successful for the synthesis of complex polycyclic systems. This has typically been achieved by reaction sequences utilizing an intramolecular carbolithiation process to generate a variety of carbocycles185 and heterocycles186. To achieve the intermolecular carbolithiation reaction required to initiate a controlled cascade reaction sequence for the generation of indole ring scaffold, Kessler and coworkers44 have expanded the synthetic utility of the styrene... 

Very few non-arylated alkenes xmdergo intermolecular carbolithiation. This is the case for diallylamines once they have been converted to a dianionic intermediate which promotes the desired addition of n-butyllithium [36] (Scheme 13), and of 2-azaallylHthiums which react with vinylsilanes [37] by an anionic [3-1-2] -cycloaddition process followed by elimination (Scheme 14). 

Scheme 103 Intermolecular carbolithiation of styrenes results in living polymerization [5].

Scheme 10.4 The first example of an asymmetric intermolecular carbolithiation of cinnamyl alcohol [7].

Such a principle was effectively employed in the synthesis of both achiral and chiral heterocyclic compounds. For instance, O Shea et al. [8] have demonstrated the benefit of intermolecular carbolithiations of o-substituted styrenes 9a in a one-pot synthesis of substituted indoles 11a and have extended this principle to the carbolithiation of 3-vinylpyridin-2-ylamines 9b eventually resulting in 7-azaindoles 11b (Scheme 10.5). 

Scheme 10.5 Intermolecular carbolithiation of functionalized styrenes and vinylpyridines in the preparation of indoles and 7-azaindoles [8].

Scheme 10.7 Intermolecular diastereoselective carbolithiation of unsymmetrical stilbenes [10].

Scheme 10.16 Synthesis of enantioenriched allenes by intermolecular carbolithiation of enynes 48 [13].

Scheme 10.19 Deuterium-labeling experiments in the intermolecular carbolithiation of unactivated alkenes with lithium dianions of polycyclic arenes [18b].

The reactivity of carbenes/carbenoids towards C=C bonds continues to attract much attention from theoretical and synthetic chemists alike. Calculations using different levels of theory have thus been conducted to better understand the reactivity of cyclo-propenylidene towards C=C bonds. This DFT study has suggested that the reaction involves two pathways from a common intermediate to give products featuring three-and four-membered rings, respectively. Computational methods applied for the first time to intra- and inter-molecular cyclopropanations involving oxiranyllithiums have provided mechanistic rationale for such carbenoid reactions. " While the intramolecular cyclopropanation of oxiranyllithiums equipped with an olefinic moiety (i.e., 1,2-epoxyhexene used as model substrate) proved to follow either a two-step carbolithiation pathway or a concerted methylene transfer, the latter route predominates for intermolecular cyclopropanation. 

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. 

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