Metalation with lithium amides

As may be concluded from the high yields of some alkylation reactions performed in liquid ammonia, the interaction between aldimines and sodamide or potassium amide gives rise to predominant or complete metallation. With lithium amide the ionization equilibrium is probably strongly on the side of the reactants. 

Due to the high interest in metalation reactions with lithium amide or alkyllithiums, an indicator scale of lithium ion pairs in THF has been developed119. Aggregation studies have indicated that organolithium species exist predominantly, if not exclusively, as monomers in the 10-3-10-4 M concentration range. Particular attention has been devoted to the lithium and caesium ion-pair acidities of diphenylamine in THF120 that, at 25 °C, have been found to be 19.05 and 24.20, respectively. 

There have been several reviews on alkali metal amide structural chemistry. Most of these deal with lithium amides but there is also significant coverage of the heavier elements and other topics such as derivatives of primary amides and hydrazides. " Two comprehensive reviews for lithium amides and related salts published in 1991 and 1995 include extensive tables of structural data. There have also been reviews of the of lithium amides as well as of the extensive use of alkah metal... 

As shown by the last reaction in Scheme 5.23, the metalation of benzamides is complicated by several potential side reactions (Scheme 5.24). Thus, benzamides can also undergo ortho-metalation [181, 217-222] or metalation at benzylic positions [223-225], Ortho-metalation seems to be promoted by additives such as TMEDA, and benzylic metalation can be performed selectively with lithium amide bases [217,224], which are often not sufficiently basic to mediate ortho- or a-amino metalation. If deprotonation of the CH-N group succeeds, the resulting product might also undergo cydization by intramolecular attack at the arene [214, 216] (see also Ref. [226] and Scheme 5.27) instead of reacting intermolecularly with an electrophile. That this cydization occurs, despite the loss of aromatidty, shows how reactive these intermediates are. 

Several Lewis acid-base interactions between alkali metal cations and heteroatom-containing molecules are indispensable in the promotion of reactions involved in critically important and fundamental transformations—deprotonation with lithium amides at the a-hydrogens of carbonyl or imino compounds and the addition of organolithium compounds to such electrophilic substrates. Because it is impossible to cover the multitude of these and other closely related subjects, this chapter describes only briefly general aspects of current interest. 

Metallated orthothioformates and their seleno analogs (available by metallation of orthothio- and orthoseleno-formate " with lithium amides or on S/Li or Se/Li exchange between orthothio- and orthoseleno-carbonates react efficiently with methyl iodide > as well as with reactive electrophiles such as benzyl chloride and n-butyl iodide (Scheme 84, entry a). ... 

In the procedure described in this experiment, o- and p-tolunitrile are metallated with alkali amides in liquid ammonia and with KDA in THF and the intermediary anions alkylated with butyl bromide. Side-reactions such as selfcondensation or addition of the base across the C=N function only take place during the reactions with lithium amide, but to a lesser extent than with LDA in THF. 

As far as the basic system is concerned, KDA in THF-4iexane (a 1 1 mixture of lithium diisoprq>yl-amide (LDA) and potassium t-butoxide) > is by far more efficient than lithium tetramethylpiperidide (LiTMP) (in THF-HMPA or THF-hexane 72) which is in fact at least a power of 10 more reac-tive -56 than lithium amides (in HMPA- or THF-bexane3W6-- i 3< -W - 2- W 2 3.95.97.99,ioi-J03). Thus, although bis(phenylseleno)methane and its bis(m-trifluoromethyl) analogs are almost quantitatively metallated with lithium diisobutyramide or LDA in THF, respectively (Scheme 21, b and c ... 

Synthesis by high-dilution techniques requires slow admixture of reagents ( 8-24 hrs) or very large volumes of solvents 100 1/mmol). Fast reactions can also be carried out in suitable flow cells (J.L. Dye, 1973). High dilution conditions have been used in the dilactam formation from l,8-diamino-3,6-dioxaoctane and 3,6-dioxaoctanedioyl dichloride in benzene. The amide groups were reduced with lithium aluminum hydride, and a second cyclization with the same dichloride was then carried out. The new bicyclic compound was reduced with diborane. This ligand envelops metal ions completely and is therefore called a cryptand (B. Dietrich, 1969). 

AletalHydrides. Metal hydrides can sometimes be used to prepare amines by reduction of various functional groups, but they are seldom the preferred method. Most metal hydrides do not reduce nitro compounds at all (64), although aUphatic nitro compounds can be reduced to amines with lithium aluminum hydride. When aromatic amines are reduced with this reagent, a2o compounds are produced. Nitriles, on the other hand, can be reduced to amines with lithium aluminum hydride or sodium borohydride under certain conditions. Other functional groups which can be reduced to amines using metal hydrides include amides, oximes, isocyanates, isothiocyanates, and a2ides (64). 

A number of compounds of the types RSbY2 and R2SbY, where Y is an anionic group other than halogen, have been prepared by the reaction of dihalo- or halostibines with lithium, sodium, or ammonium alkoxides (118,119), amides (120), azides (121), carboxylates (122), dithiocarbamates (123), mercaptides (124,125), or phenoxides (118). Dihalo- and halostibines can also be converted to compounds in which an antimony is linked to a main group (126) or transition metal (127). 

An isolated acetoxyl function would be expected to be converted into the alkoxide of the corresponding steroidal alcohol in the course of a metal-ammonia reduction. Curiously, this conversion is not complete, even in the presence of excess metal. When a completely deacetylated product is desired, the crude reduction product is commonly hydrolyzed with alkali. This incomplete reduction of an acetoxyl function does not appear to interfere with a desired reduction elsewhere in a molecule, but the amount of metal to be consumed by the ester must be known in order to calculate the quantity of reducing agent to be used. In several cases, an isolated acetoxyl group appears to consume approximately 2 g-atoms of lithium, even though a portion of the acetate remains unreduced. Presumably, the unchanged acetate escapes reduction because of precipitation of the steroid from solution or because of conversion of the acetate function to its lithium enolate by lithium amide. 

Metalation of nonenolizable carbonyl groups.1 This lithium amide, which lacks -hydrogens, cannot reduce nonenolizable aldehydes or ketones but can metalate these substrates. Thus reaction of LTMP with trimethylacetaldehyde (1) evidently results in an acyllithium (a) as shown by formation of an acyloin (2, equation I). 

Considering the importance of alkali metal phosphanides it is not surprising that numerous review articles have dealt with this subject [34-36]. The solid state and solution structures vary from dimers with central M2 P2 cycles to larger rings and from chain to ladder structures as described for the lithium amides (see Sections 3.6.1 and 3.6.2). Cage compounds in the field of lithium phosphanides are unusual... 

At the outset of our studies of the reactivity of I and II, it was necessary to investigate claims that tertiary henzamides were inappropriate substrates for the Birch reduction. It had been reported that reduction of A,A-dimethylbenzamide with sodium in NH3 in the presence of tert-butyl alcohol gave benzaldehyde and a benzaldehyde-ammonia adduct. We formd that the competition between reduction of the amide group and the aromatic ring was strongly dependent on reaction variables, such as the alkali metal (type and quantity), the availability of a proton source more acidic than NH3, and reaction temperature. Reduction with potassium in NH3-THF solution at —78 °C in the presence of 1 equiv. of tert-butyl alcohol gave the cyclohexa-1,4-diene 2 in 92% isolated yield (Scheme 3). At the other extreme, reduction with lithium in NH3-THF at —33 °C in the absence of tert-butyl alcohol gave benzaldehyde and benzyl alcohol as major reaction products. ... 

Ruthenium(III) catalyses the oxidative decarboxylation of butanoic and 2-methylpropanoic acid in aqueous sulfuric acid. ° Studies of alkaline earth (Ba, Sr) metal alkoxides in amide ethanolysis and of alkali metal alkoxide clusters as highly effective transesterification catalysts were covered earlier. Kinetic studies of the ethanolysis of 5-nitroquinol-8-yl benzoate (228) in the presence of lithium, sodium, or potassium ethoxide revealed that the highest catalytic activity is observed with Na+.iio... 

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