Lithium carbon-hydrogen bonds

A widely exploited procedure for bringing about carbenoid reactions of organic mono- and fifem-dihalides is by use of lithium alkyls. Examples are given in equations (11) and (12). Dimeric olefin formation, stereospecific cyclopropane formation from olefins, and insertion into carbon-hydrogen bonds have all been observed in suitable cases, together with further reactions of these products with excess of the lithium alkyl. 

Alkane Carbon-Hydrogen Bond Activation), such behavior might not be expected of a monophosphine. However, in the reaction of [Rh(/u.-Cl)(COE)2]2 with four equivalents of PhCH2CH2PBu 2, this is observed as the product in (18) and conversion to (19) occurs on chloride abstraction (see also (174), Section 42). " A related situation is obtained when [Rh(/x-Cl)(Bu 2PCH2PBu 2)]2 is treated with neopentyl lithium where the highly unsaturated, 14-electron metal in the product, (20), is stabilized by an agostic interaction. ... 

Because carbon-hydrogen bonds exhibit very low acidity (see Chapter 7), very strong bases are required for such reactions. However, C—H bonds adjacent to substituents such as carbonyl or cyano groups are more acidic. Nitrogen bases have been used effectively in these reactions to minimize the nucleophilic addition that can compete with proton removal when an orga-nometallic compoimd such as n-butyllithium is used as the base. For example, methyl ketones react with lithium diisopropylamide (LDA) to form the enolate ion (equation 5.64), " ... 

Metal-catalysed biaryl formation continues to be of interest, and there has been a theoretical study of reactivity and regioselectivity in biaryl formation involving the cleavage of carbon-hydrogen bonds by a concerted metalation-deprotonation pathway. Various combinations of metal/ligand/base have been evaluated for the arylation of benzene with aryl bromides at high temperatures and pressures. The combination of cobalt(III) acetylacetonate and lithium bis(trimethylsilyl)amide proved to be effective. ... 

The metalation reaction, that is, the conversion of a relatively unuseful carbon-hydrogen bond to a synthetically advantageous carbon-metal bond, is one of the most important and widespread chemical transformations practiced today. A key intermediary tool for the preparation of pharmaceuticals, agrochemicals, perfumes/ cosmetics and fine chemicals, amongst other everyday commodities, the metalation reaction has typically been the domain of the highly polar alkali metals, nearly always lithium. Indeed, Collum emphasized this domination in 1993 stating that it would appear that well over 95% of natural products syntheses rely upon lithium based reagents in one form or another [1]. 

Although catalytic hydrogenation is the method most often used, double bonds can be reduced by other reagents, as well. Among these are sodium in ethanol, sodium and rerr-butyl alcohol in HMPA, lithium and aliphatic amines (see also 15-14), " zinc and acids, sodium hypophosphate and Pd-C, (EtO)3SiH—Pd(OAc)2, trifluoroacetic acid and triethylsilane (EtsSiH), and hydroxylamine and ethyl acetate.However, metallic hydrides, such as lithium aluminum hydride and sodium borohydride, do not in general reduce carbon-carbon double bonds, although this can be done in special cases where the double bond is polar, as in 1,1-diarylethenes and in enamines. " °... 

The details of the mechanism are poorly understood, though the oxygen of the alcohol is certainly attacking the carbon of the isocyanate. Hydrogen bonding complicates the kinetic picture. The addition of ROH to isocyanates can also be catalyzed by metallic compounds, by light, or, for tertiary ROH, by lithium alkoxides ° or n-butyllithium. ° ... 

Hydrogenation of the carbon-carbon double bond occurs without alteration of the ester function when citronellyl acetate is treated with 2.5 equivalents of trifluoroacetic acid and two equivalents of triethylsilane in 2-nitropropane.205 The reduced product is obtained in 90% yield after 22 hours at room temperature in the presence of one equivalent of added lithium perchlorate (Eq. 82). The yields are lower in the absence of this added salt. Similar reduction of an unsaturated phenolic chroman derivative occurs to give an 85% yield of product with only the carbon-carbon double bond reduced (Eq. 83).205... 

A quite consistent relationship is found in these and related data. Conditions of kinetic control usually favor the less substituted enolate. The principal reason for this result is that removal of the less hindered hydrogen is faster, for steric reasons, than removal of more hindered protons. Removal of the less hindered proton leads to the less substituted enolate. Steric factors in ketone deprotonation can be accentuated by using more highly hindered bases. The most widely used base is the hexamethyldisilylamide ion, as a lithium or sodium salt. Even more hindered disilylamides such as hexaethyldisilylamide7 and bis(dimethylphenylsilyl)amide8 may be useful for specific cases. On the other hand, at equilibrium the more substituted enolate is usually the dominant species. The stability of carbon-carbon double bonds increases with increasing substitution, and this effect leads to the greater stability of the more substituted enolate. 

Iodine at the N-alkylcarbazole 3-position has been reductively removed with lithium aluminium hydride - and hydrogen-Raney nickel, and bromine at the same position has been removed with lithium-tcrt-butanol. Hydrogen-nickel at 600 psi has also been used to hydrogenolyze carbazole carbon-bromine bonds, and hydrogen-palladium/charcoal at 200°C to remove a 1-chlorine. ... 

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