Intramolecular carbolithiation reactions

Inter- and intramolecular enantioselective carbolithiation reactions in the presence of a chiral ligand for lithium, such as (—)-sparteine 13BJ0313. New application progress of chiral bis(oxazoline) ligands in asymmetric catalysis 13CJ02283. 

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. 

The intramolecular carbolithiation of 6-lithio-l-hexene (9) was studied after lithiation of 6-chloro-l-hexene (8) in the presence of a catalytic amount of DTBB (5%). At —78 °C the corresponding organolithium compound 9 is stable, giving the expected products 10 by reaction with different electrophiles. However, when the lithiation step was carried out at — 30 °C a cyclization reaction took place, so that a new organolithium intermediate 11 was formed, which reacted with the same electrophiles to give cyclic products 12 (Scheme 5). ... 

Due to its high ionic character, the carbon-lithium bond is very reactive and adds under mild conditions to ethylene or dienes and under more severe conditions to other alkenes. Some functionalized alkenes can be used, and high regio- and stereo-selectivity is usually observed in these carbolithiation reactions, especially if a precoordination of the lithium organometallic with the alkene is possible. Intramolecular carbolithiations of alkenes proceed under mild conditions and allow the preparation of several stereochemically well defined mono- and bi-cyclic compounds. Alkynes are too reactive, and can lead, with organolithium derivatives, to several side reactions, and seldom afford the desired carbolithiated product in good yield. 

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

An effective and general method for the synthesis of 2,3-dihydrobenzofuran derivatives has been developed via an intramolecular carbolithiation reaction of o-lithioaryl ethers (Scheme 16).89 This process was the first example in which the carbolithiation reaction has been stopped at the 2,3-dihydrobenzofuran stage by appropriate selection of the ether moiety. 

The addition of organolithiums to polarised C=X bonds is one of the most widely used ways of making C-C bonds, and (excepting some unusual intramolecular cases) will not be discussed in this book other than to say it is a reliable and successful reaction. With a few exceptions,1 3 stereoselectivity is not a general feature of organolithium addition reactions to C=0 n bonds. Much of this chapter will concern controlled addition of organolithiums to C=C 7i bonds after an overview of carbolithiation, we shall review the development of intramolecular carbolithiation, or anionic cyclisation. 

The carbolithiation of alkenes and alkynes is a useful transformation for the generation of a new carbon—carbon bond, specially when the alkenes and alkynes are activated by conjugation to carbonyl and related electron-withdrawing groups. Similarly to the intramolecular carbolithiation, it is possible to carry out this reaction with high diastere-o selectivity. 

The enantioselective metalation at the a-position of a carbamate in the presence of (—)-sparteine followed by a diastereoselective intramolecular carbolithiation onto a double120 or triple bond121 was recently studied. The precursor 185 was deprotonated with s-BuLi/(—(-sparteine in Et20 at — 78 °C, the reaction mixture was stirred for 20 to 30 h at this temperature and the electrophilic reagent was subsequently added (Scheme 57)60. 

For 6-chloro-2-phenylhex-l-ene, 197, the DTBB-catalyzed lithiation, even at — 78 °C, gives the cyclic intermediate 198 (probably formed by an intramolecular carbolithiation), which by reaction with some electrophiles afforded, after hydrolysis, the corresponding products 199 (Scheme 59). The conversion is total after about 1 h the rest of the starting material is transformed into a mixture of compounds, among them the reduced product... 

Carbon—carbon bond formation by an intramolecular carbolithiation (anionic cycliza-tion) reaction to give heterocyclic systems has been gaining increasing use in organic... 

On the other hand, alkenyl aryllithiums can undergo diastereoselective cyclizations in very good yields. Pedrosa and coworkers163 reported that chiral 2-(o-bromophenyl)-substitutedperhydro-l,3-benzooxazines 281, initially transformed to the aryllithium derivative, gave the intramolecular 6-exo carbolithiation reaction with unactivated double bonds attached to the nitrogen substituent of the heterocycle (Scheme 87). By adding 2 equivalents of TMEDA to the aryllithium derivative 1,3-benzooxazines 281 prepared at —90 °C,... 

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... 

One general aspect to consider about intramolecular carbolithiation reactions is the fact that the isomerizations of unsaturated organolithiums could, in principle, proceed via... 

Control of absolute stereoselectivity in the intramolecular carbolithiation reactions is not a completely solved subject and several approaches have been used ... 

Without careful design of the starting material it is not usually possible to form three-and four-membered rings by intramolecular carbolithiation reaction onto carbon-carbon... 

Krief and coworkers have also shown that vinyl sulphides are useful traps for the intramolecular carbolithiation reactions. Interestingly, as the sulphide substituent can be reductively removed, the cyclization reactions of benzyllithiums derived from 73 and 75 are synthetically equivalents to cyclizations onto disubstituted double bonds, giving rise by complementary routes to compound 74 (Scheme 20)46. Like the corresponding carbolithiation reactions onto monosubstituted alkenes they are highly stereoselective but dependent on the solvent used, i.e. the derivatives in which the methyl- and the phenylthio groups are cis (THF) or trans (pentane) one to the other are selectively formed. 

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