Lithium amides nucleophilic addition reactions

The reactions of ketone dilithio ,/i-dianions with imines and hydrazones have been investigated.77 The nucleophilic addition reaction to C—N double bonds took place selectively at the -position of dianions to form lithium (Z)-enolates containing a lithium amide portion, which is then transformed into y-amino ketones and related compounds by the subsequent reaction with electrophiles. 

Carboxylic acid derivatives can also undergo nucleophilic addition reactions. By a combination of nucleophilic acyl substitution and nucleophilic addition, all of the acid derivatives except amides can be reduced to primary alcohols using lithium aluminum hydride. The first hydride ion displaces the leaving group the resulting aldehyde is reduced to the primary alcohol. Reduction of amides produces amines. 

Figure 3 shows the typical synthetic route to prepare the TFSA anion based phosphonium RTILs. We have chosen triethylphosphine (P(C2Hs)3) and tii(n-bulyl)phosphine (P( -C4H9)3) as commercially available starting materials since these two phosphines can afford relatively small quaternary phosphonium cations. The preparation process of the phosphonium RTCLs includes two steps nucleophilic addition reactions of trialkylphosphines to alkyl halides to form precursor phosphonium halides and then aqueous ion exchange reactions of the precursor phosphonium halides with lithium bis(trifluoromethylsulfonyl)amide (Li-TFSA) to obtain TFSA anion based phosphonium RTBLs. 

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. 

The sensitivity of position 2 in 4-chloroquinazoline for nucleophilic addition was also demonstrated in the reaction with lithium piperidide (73RTC460). Whereas in the amination with potassium amide/liquid ammonia no open-chain intermediate could be isolated, with lithium piperi-dide/piperidine the open-chain compound ort/z6>-(piperidinomethy-leneamino)benzonitrile (78,60%) was obtained, in addition to 4-piperidino-quinazoline (80,19%) (Scheme 11.35). The formation of 80 from 78 involves... 

Meyers and Shimano further expanded the scope of this methodology to include lithium amides as the nucleophile. The authors meticulously optimized the reaction conditions and determined the scope of the amide addition. Selected examples are listed in Table 8.32 (Scheme 8.163). The best results were obtained when THF was used as the solvent together with a stoichiometric amount of HMPA, relative to the lithium amide. The reaction was quite sensitive to the steric demand of the amide. Thus, lithium diethylamide give no product whereas lithium methyl n-pentylamide and lithium piperidide gave efficient reaction. Primary amides also failed to react. 

Unlike analogous reactions with a carbon nucleophile, the initial attack of the lithium amide was reversible. A strong piece of supporting evidence was the exclusive formation of the butyl addition product 504 when w-butyllithium was added after initial formation of the aza enolate 505 (Scheme 8.164). The reaction outcome is therefore heavily dependent on the secondary reaction with the... 

General methods for the preparation of a.jS-unsaturated iron-acyl complexes are deferred to Section D 1.3.4.2.5.1.1. examples of the alkylation of enolates prepared via Michael additions to ii-0 ,/ -unsaturated complexes prepared in situ are included here. Typical reaction conditions for these one-pot processes involve the presence of an excess of alkyllithium or lithium amide which first acts as base to promote elimination of alkoxide from a /f-alkoxy complex to generate the -a,)S-unsaturated complex which then suffers 1,4-nucleophilic addition by another molecule of alkyllithium or lithium amide. The resulting enolate species is then quenched with an electrophile in the usual fashion. The following table details the use of butyllithium and lithium benzylamide for these processes44,46. 

QUINAPHOS ligands are usually synthesized in a one-pot-procedure from readily available 8-substituted quinolines [8] via nucleophilic addition of a lithium reagent [9] to the azomethinic double bond and direct quenching of the resulting 1,2-dihydroquinoline amide 1 with a phosphorochloridite derived from enantio-merically pure binaphthol (1) or from 3,3 -di-t-butyl-5,5 -dimethoxybiphenyl-2,2 -diol (m) [10] (Scheme 2.1.5.1, Method A). Alternatively, the anion 1 can be reacted with an excess (in order to avoid multiple substitution) of phosphorous trichloride to obtain the corresponding phosphorous dichloridite 2, which can be isolated (Scheme 2.1.5.1, Method B). In a second step, 2 is converted into 4 by reaction with the desired diol in the presence of triethylamine. 

Additions to l,3-dienes6 (12, 367-368 14, 249-250 15, 245). This reaction can be used to effect intramolecular cyclization of cyclic 1,3-dienes substituted by a suitable nitrogen nucleophile. Thus reaction of the amido diene 1 with lithium acetate catalyzed by Pd(OAc)2 (with benzoquinone as reoxidant) provides the ds-fused heterocycle cis-2, in which the acetoxy group is cis to the ring fusion, formed by an overall trans-1,4-oxyamidation of the diene system. Addition of a trace of LiCl improves the yield and results in an overall cis- 1,4-oxyamidation (equation I). Acetamides and carbamates can also be used in place of amides. 1,4-Chloroamidation can also be effected by use of 2 equiv. of LiCl. 

Rapopoit found that 5-(2-pyridyl) thioates such as (28) did not function as selective acylating agents, and substantial amounts of tertiary alcohol were formed through overaddition (equation 16). Presumably, the tetrahedral intermediate, derived from nucleophilic addition to the S-(2-pyridyl) thioate, was not a stable entity in the reaction mixture. As will be discussed shortly, the lability of these intermediates had been recognized previously. The novel dimethylpyrazolide moiety of substrate (29) also did not confer any additional stability to the tetrahedral intermediate and tertiary alcohol was the major product (equation 16). Tertiary amides, such as those derived from pyrrolidine or dimethylamine, were reactive towards lithium adkynides in the presence of BF3, but analysis of the product indicated that it had undergone substantial racemization. ... 

The successive reaction of (dibromomethyl)silanes with LDA (hthium diisopropyl-amide) and two equivalents of benzaldehyde gives 1,3-diol monosilyl ethers in good yield (Scheme 10.221) [574]. This tandem reaction would proceed via anionic 1,3-silyl migration of /l-lithioxyalkylsilane intermediate 152 and addition of the resulting lithium carbenoid to benzaldehyde. Thus, internal activation of the silicon-lithium alkoxide promotes nucleophilic addition of a-haloalkylsilanes. Similar tandem reactions of 2-trimethylsilyl-l,3-dithiane with aldehydes [575] and epoxides [576] have been reported. 

Another auxiliary that became well known in enolate chemistry is chiral acyl iron complexes for alkylation, aldol reactions, and conjugate additions indeed, so-called Davies-Liebeskind enolates [60] can be generated either by deprotonation of alkanoyl complexes 124a or conjugate addition of strong nucleophiles like alkyllithium compounds or lithium amides to alkenoyl complexes 127. 

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