Organolithium intermediate

Several groups have developed procedures for Pd-mediated coupling based on this general chemistry. The variety of such procedures and the range of compounds for which they are applicable suggest that Pd-calalysed coupling is currently the most versatile method for introduction of 2-substituents which cannot be prepared directly from organolithium intermediates. 

As shown in Table 4, the same ratio of diastcreomeric sulfinylalkcnols was obtained from both (R)-(E)- and (/ )-(Z)-l-sulfinylalkenes (vinyl sulfoxides). This is explained by the fast cisjtrans isomerization of the organolithium intermediates in a strongly basic medium. Thus, EjZ mixtures of vinyl sulfoxides can be used without prior separation. 

Arylboronic acids have traditionally been prepared via the addition of an organomagnesium or organolithium intermediate to a trialkyl borate. Subsequent acidic hydrolysis produces the free arylboronic acid. This limits the type of arylboronic acids one can access via this method, as many functional groups are not compatible with the conditions necessary to generate the required organometallic species, or these species may not be stable intermediates. 

A more recent application of this chemistry was reported by Oestreich and Hoppe [74] and involved the enantioselective deprotonation of the enyne carbamate ester 125 with sec-butyllithium in the presence of (-)-sparteine (Scheme 2.41). Removal of the pro-S hydrogen atom led to the corresponding organolithium intermediate, which then underwent a highly enantioselective intramolecular 1,4-addition to the enyne. Protonation of the resulting allenyllithium species 126 provided a 70 30 mixture of the two diastereomeric allenes 127. 

Halogen-lithium exchange of iodide 71 and subsequent addition of 2-acetyl-furan (72) to the resultant organolithium intermediate yielded two diastereomeric tertiary alcohols (dr=l l), which were converted to (E)-olefin 73 with complete diastereoselectivity upon brief exposure to catalytic amounts of concentrated aqueous hydrogen chloride (Scheme 11) [18]. Diastereoselective hydroboration/oxidation of 73 gave largely the desired stereoisomer 74 due to... 

The application of mixed enolates/homoenolates of type 14 for the racemic synthesis of y-butyrolactones has been already discussed (cf. Scheme 1). An ingenious way to render this strategy asymmetric was demonstrated with the regio- and stereoselective carbolithiation of 114, generating the organolithium intermediate 115, which could be reacted with the appro-... 

In this section are presented a few instances of the application of XRD crystallography for structural elucidation. Additional examples appear in Section V, dealing with association of organolithium compounds in the solid state, and in Section VI, when dealing with solid products of reactions involving organolithium intermediate stages. 

Various organolithium intermediates may be posmlated for the synthesis of functionalized indoles and other heterocyclic compounds, from substituted Af-allylanilines (331a-c) or the cychc analog 332, on treatment with f-BuLi. For example, in equation 81 intermediate 333, derived from 331a, was quenched with deuterium oxide. Participation of benzyne metallated intermediates, such as 334, derived from 332, is surmised in equation 82 and other processes. The products of equations 81 and 82 can be characterized by H and NMR spectra . 

Functionalized organolithium intermediates 412-417, can be used as synthones for addition to various substrates containing the C=C—C=0 moiety or for dimerization via the C—Li bonds, all catalyzed by Cu(I) and Cu(II) salts . They may also be exposed to various electrophiles for example, intermediate 412 reacts with carbon dioxide as shown in equation 115, to yield a lactone (418) as the only product after workup. ... 

Using 10% of DTBB as electron carrier, 2,5-disubstituted chlorocyclopentanes 6 were lithiated, the corresponding organolithium intermediates having being employed for the preparation of boronic esters 7, after reaction with triethyl borate and the corresponding 1,3-diol (Scheme 4). ... 

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). ... 

However, either for aliphatic or aromatic amines, the corresponding S-phenylthio derivatives are adequate precursors in order to generate /i-amido organoUthium intermediates. Starting materials 157 were successively treated with n-butyllithium and lithinm in the presence of a catalytic amount of DTBB (15%) in THF at —78 °C giving the expected functionalized organolithium intermediates 158, which reacted with different electrophiles to afford, after hydrolysis, the corresponding products 159 (Scheme 56) " ". 

By a DTBB-catalyzed (5%) lithiation of chlorinated unsaturated amines 191 in the presence of a carbonyl compound as electrophile, the final hydrolysis afforded 192 as a Z/E mixture of diastereomers (Scheme 66). In this process, the corresponding sp -hybridized functionalized organolithium intermediate is probably involved. 

A particular case for the generation of a y-substimted organolithium compound, derived from an imine, was used for the synthesis of 2-substituted pyrrolidines. DTBB-catalyzed (5%) lithiation of y-chloro imines 196 yielded, after hydrolysis, 2-substituted pyrrolidines 198, including nomicotine (R = H, R = 3-pyridyl). The corresponding y-nitrogenated organolithium intermediate 197 was probably involved (Scheme 68). ... 

In the case of unsaturated chloramines 209, the DTBB-catalyzed lithiation had to be carried out in the presence of the electrophile in THF at —78 °C in order to avoid decomposition of the corresponding functionalized organolithium intermediate through elimination reactions. Final hydrolysis yielded a mixture (variable ratios 11.5/1 to 1/19 depending on the electrophile) of the a- and y-products 210 (Scheme 72) . ... 

Starting from different chiral epoxides, such as 255 or 256, and following the same protocol as for the epoxide 252, the expected primary organolithium intermediates 257 and 258 were generated, and then the final compounds 259 and 260, respectively, by reaction with different electrophiles and final hydrolysis in 69-80% and 70-90%, respectively. 

Other chiral oxetanes used to generate chiral y-oxido functionalized organolithium intermediates are 306-309, which gave the expected enantiopure products by reaction with non-prochiral electrophiles"" °. In all cases, when prochiral electrophilic reagents were used, a mixture of the corresponding diastereomers was obtained in variable proportions depending on the electrophile, which could be easily separated by column chromatography. 

The ring opening of five-membered rings allows one of the easiest entries to S-functionalized organolithium intermediates (rf" -reagents). 

When 2,2-diphenyl-l,3-dioxolane (410, R = Ph) was lithiated with lithium and a catalytic amount of naphthalene (4%) in THF at —40°C (see Section VI.F.l) and then reacted with an aldehyde as electrophile, intermediates 437 were generated. The further lithiation of these compounds at the same temperature cleaved the second benzylic carbon-oxygen bond giving new organolithium intermediates 438, and a second electrophile could be introduced to give 439, after hydrolysis. In these products, two different electrophilic fragments have been incorporated, so the starting material behaves as the 1,1-diphenylmethane dianion synthon (Scheme 122) °. 

The only way to introduce two different electrophilic fragments in compounds such as 508 is to have a starting material with different halogens. This is the case with 510, which could be lithiated (bromide-lithium exchange) with t-butyllithium in THF at — 100°C giving intermediates 511, which reacted with a carbonyl compound R R CO and, after naphthalene-catalyzed lithiation, gave the new functionalized organolithium intermediate 512. Final reaction with 3-pentanone followed by hydrolysis yielded mixed products 513 (Scheme 142) °. 

The utility of -phenyl camphor-derived oxazolidinones as chiral formyl anion syn-thons has been demonstrated by Gawley and coworkers (Scheme 42). Deprotonation yields a dipole-stabihzed organolithium intermediate and the absolute configuration of the lithium-bearing carbon is presumed to be R. Additions to benzaldehyde and cyclohexane carboxaldehyde are 86% and 76% diastereoselective, respectively, but recrystallization affords a single diastereomer in the yields shown. Addition is postulated to proceed via the pre-complex shown in the inset, in which the aldehyde is coordinated to the R epimer... 

The chiral base i-BuLi/(—)-sparteine enantioselectively deprotonates the benzylic position of Ai-Boc-3-chloropropyl carbamates, which then cyclize to yield 2-substituted pyrrolidines with enantiomeric ratios greater than 90 10 (Scheme 63). Beak and coworkers showed that enantioselectivity is achieved through an asymmetric deprotonation to give an enantioenriched organolithium intermediate, which undergoes cyclization faster than epimerization. 

The most effective and widely established method today is the tin-lithium transmetala-tion, especially of a-stannylated oxygen compounds, but reductive processes to generate the organolithium intermediates also seem to be promising. 

To facilitate the deprotonation conditions the diethoxymethyl- group, an acid labile protective group, was introduced. This group not only protected the NH function but also stabilised the organolithium intermediate. 

The precise nature of the carbon-lithium bond is beyond the scope of this book. Organolithium intermediates are here represented as carbanion and cation to emphasise differences in properties and reactivities as compared with full covalent bonds. 

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