Lithium alkyl amides

The unique feature of the alkyllithium compounds that makes them useful as diene initiators is their character as exceedingly powerful bases yet they are soluble in organic solvents and quite thermally stable. Alkyllithium compounds are sufficiently basic to add to hydrocarbon monomers. However, lithium salts of stabilized anions, such as acetylide and fluorenyl anions, are too weakly basic to add to such double bonds. Similarly, alkoxides and mercaptides fail to react with hydrocarbon monomers, but lithium alkyl amides react analogously to alkyllithium compounds. 

The utility of carbonylation of lithium amides for the synthesis of complex molecules has been also demonstrated. V.V.V V -Tetrasubstituted ureas 5 were obtained in good yields by reaction of lithium alkyl amides in THF solution with carbon monoxide under mild conditions (0°C, 1013 mbar), followed by treatment with oxygen prior to work-up... 

Lithium Alkyl Amide as Initiator for Polymerizations of Isoprene and 1,4-Divinylbenzene... 

Another approach to make homo- or copolymers which contain primary amino functions was developed by Maeda and coworkers.A lithium alkyl-amide catalyzed addition of mono N-alkyl-substituted ethylene diamines [34] to 1,4-divinylbenzene [33] yielded a styrene derivative [35] containing both tertiary and primary amino groups (Scheme 4). 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

I he diaryImethanes (105). The protons on the methylene group of lliese compounds are sufficiently acidic to be removed by strong b.ises such as sodium amide or butyl lithium. Alkylation of the resulting carbanion with w-C2-chloroethyl)dimethylamine affords,... 

The stereochemistry of the silyl ketene acetal can be controlled by the conditions of preparation. The base that is usually used for enolate formation is lithium diisopropyl-amide (LDA). If the enolate is prepared in pure THF, the F-enolate is generated and this stereochemistry is maintained in the silyl derivative. The preferential formation of the F-enolate can be explained in terms of a cyclic TS in which the proton is abstracted from the stereoelectronically preferred orientation perpendicular to the carbonyl plane. The carboxy substituent is oriented away from the alkyl groups on the amide base. 

Due to the small size of this data set no reliance can be placed on these results. We have carried out the correlation only to illustrate the method. In an earlier paper Arnett and Moe reported AH prin for the deprotonation of i-PrOH by lithium A-alkyl and N,N-diaUcyl amides, and by lithium alkyls (sets CR3 and CR4, Table 9). As the electrical effects of alkyl groups are constant within experimental error, only the number of alkyl groups, their steric effects and their polarizabilities can be variables. Values of AH pm for the amides were correlated with equation 28 ... 

Apparently a substantial spacer is also allowable between the aromatic ring and the carboxy group. Gemfibrozi 1 (52), a iiypotriglyceridemic agent which decreases the influx of steroid into the liver, is a clofibrate homologue. It is made readily by lithium diisopropyl amide-promoted alkylation of sodium iso-propionate with alkyl bromide 51. ... 

This section deals with the alkylation reactions of such enolates. In the presence of strong bases, amides carrying at least one a-hydrogen 1 can be deprotonated to form enolate ions which, on subsequent alkylation, give alkylated amides. Further reaction, e g., hydrolysis or reduction, furnishes the corresponding acids or primary alcohols, respectively. The pKa values for deprotonation are typically around 35 (extrapolated value DMSO3 7) unless electron-withdrawing substituents are present in the a-position. Thus, deprotonation usually requires non-nucleophilic bases such as lithium diisopropylamide (extrapolated 8 pKa for the amine in DMSO is around 44) or sodium hexamethyldisilazanide. 

The regio- and stereoselective alkylations of a number of bicyclic racemic dioxopiperazines have been reported3. For example, dioxopiperazine 9 is deprotonated by lithium diisopropyl-amide in tetrahydrofuran at — 78 °C to yield a monoanion. Alkylation with iodomethane in the presence of hexamethylphosphoric triamide gives products 10 and 11 in a 81 19 ratio and 75 % yield based on recovered starting material3. 

The chiral, nonracemic, 6-monosubstituted bicyclic lactams 1 are deprotonated by a strong base (usually lithium diisopropyl amide) and then alkylated with an iodoalkane or an allylic or benzylic bromide. Alkylation preferentially takes place from the side opposite to that of the substituent R1, which is usually an alkyl or an aryl group. While the diastereomeric ratios may be as low as 75 25, they are most often >90 10 (see Table 9). The minor diastereomer can in most cases be easily removed by liquid chromatography and/or recrystallization to yield the pure major diastereomer. 

S)-2-Amino-3-methylbutanol [(S)-valinol] derived oxazolidinones, i.e., (S)-3-acyl-4-iso-propyl-2-oxazolidinones 1, have been used extensively for the preparation of a-alkylated acids, aldehydes and alcohols. The enolates are formed by deprotonation with lithium diisopropyl-amide or sodium hexamethyldisilazanide at low temperature in tetrahydrofuran. Subsequent addition of a haloalkane gives alkylation, which occurs from the Si-face2. The diastereoselectivities are usually good (>90 10), and the products are usually purified by flash chromatography and/or recrystallization (see Table 10). Additional examples of alkylation of 1 have been published5 l0 12- 20 22-29 39.44.-47,49.57.70-78... 

Formation of a-Sulfinyl carbanions has been widely investigated17. Several bases were found to be suitable for the generation of these species, e.g., methyllithium and lithium diisopropyl-amide. Butyllithium and rm-butyllithium, however, must be used with caution since they can cause cleavage of the carbon sulfur bond, resulting in an exchange of the ligand at sulfur by a nucleophilic displacement28-29. This method has been used for the preparation of optically active alkyl methyl sulfoxides 28. 

The ladder structures formed by lithium amides and their heavier group 15 analogues stand in contrast to those formed by the related lithium alkyls which generally prefer aggregates with three-dimensional or one-dimensional polymeric structures. 

Although of relatively weak acidity, amines will react with either carbanionic metal alkyls or hydridic metal hydrides to form amides with the elimination of alkane or hydrogen, respectively. The easiest and most exploited method for the synthesis of lithium and magnesium amides is to treat lithium alkyls or Grignard reagents (normally commercially available) with the corresponding amine (equations 25,47 264 and 2749). 

When generating the ylide from the corresponding phosphonium salt, the choice of the method of formation is important for the stereochemistry of the reaction. With the original application of lithium alkyls as bases one equivalent of lithium halogenide is always formed this lowers the stereoselectivity. Not before the development of methods for the preparation of salt-free ylide solutions, such as the sodium amide... 

Alkyl carbonyl substrates turn out to be more reactive when stabilized in the cnolic form cither as silyl enolethcrs 4, obtained by reaction with (CH.O.iSiCl,- or as metal enolatcs 5, usually produced by lithium alkyls, lithium amides, or hydrides starting, for instance, from cnolcthers <>i... 

Aminopyrazine was alkylated with ethyl methyl ketone and sodium in liquid ammonia (in the absence of a catalyst) to 2-amino-6-butylpyrazine, and a similar reaction occurred with isobutyraldehyde (614) and 2-cyano-3-(A, A -dimethylamino-methyleneamino)-5-methylpyrazine was deprotonated with lithium diisopropyl-amide (from butyllithium and diisopropylamine) and alkylated with ethyl iodide followed by removal of the protecting group by acid hydrolysis to give 3-amino-2-cyano-5-propylpyrazine (1031). 

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