Imine salts from aldehydes

CuOTf/PyBox System The first direct asymmetric addition of alkynes to imines, generated from aldehydes and amines in situ, was reported by using copper salts in the presence of chiral PyBox ligand (Scheme 5.2). The products were obtained in good yields and excellent enantioselectivities in most cases. When toluene was used as solvent, up to 93% yield and 99% ee were obtained. Up to 99.5% ee was obtained when the reaction was carried out in 1,2-dichloroethane. The reaction can also be performed in water smoothly, and good enantioselectivities (78-91% ee) were obtained. 

The reaction has been used to synthesize libraries of benzonaphthyridines 196, in high diastereoselectivity, from the cycloaddition of 1,4-dihydrop3Tidines with imines formed from aldehydes and anilines. When cyclic enol ethers were used as dienophUes, mixtures of diastereomers 197 were obtained. These compounds were oxidized to the corresponding quinolines 198 and were further transformed to the quinolinium salts 199 as shown in Scheme 36 [76]. Compounds 196 and 198 were tested for their ability to inhibit human propyl oligopeptidase (POP) and were found to have modest potencies. Much better results were obtained when the quinoline nitrogen was methylated to provide adducts 199. The cationic center improved the inhibitory activity of these compounds (Fig. 23). 

Via intermediates 3-Ammosydnone imine salts from hydrazines and aldehydes via a-cyanohydrazines... 

Primary and secondary halides do not perform well, mostly because N-alkylation becomes important, particularly with enamines derived from aldehydes. An alternative method, which gives good yields of alkylation with primary and secondary halides, is alkylation of enamine salts, which are prepared by treating an imine with ethylmagnesium bromide in THF ... 

The imines are prepared by 16-12. The enamine salt method has also been used to give good yields of mono a alkylation of a,P-unsaturated ketones. Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields. N-alkylation in this case is presumably prevented by steric hindrance. 

The tetrachloroferrate or tetralluoroborate salts of alkylated alkyl- or aryl-nitriles (nitrilium ions) are reduced to imines with triethylsilane. Subsequent hydrolysis of the intermediate imines leads to aldehydes in good yields, thus providing an excellent overall route to aldehydes from nitriles (Eq. 338).28,562... 

C(R)=NR group with a nitrilium salt RCssNR .222 The acylation of the enamine can take place by the same mechanism as alkylation, but another mechanism is also possible, if the acyl halide has an a hydrogen and if a tertiary amine is present, as it often is (it is added to neutralize the HX given off). In this mechanism, the acyl halide is dehydrohalogenated by the tertiary amine, producing a ketene (7-14) which adds to the enamine to give a cyclobutanone (5-49). This compound can be cleaved in the solution to form the same acylated imine salt (27) that would form by the more direct mechanism, or it can be isolated (in the case of enamines derived from aldehydes), or it may cleave in other ways.223... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

These are the most favourable of all and the precursors, such as the hydroxy acids, e.g. 15, cannot usually be isolated, though the carboxylate salts are stable. The only important thing is to get the oxidation level of the precursor right. Using cyclic amines as examples, a fully saturated ring 45 would come from an alkylation reaction on 46 X = a leaving group. Imines 47 or enamines 49 would come from aldehydes or ketones 48. 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of y -amino ketones and esters [46]. Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have improved the process. Some of these materials are, however, unstable and difficult to isolate, and deaminations of the products that occur under the reaction conditions still remain as problems. The direct synthesis of /5-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view [47, 48]. Our working hypothesis is that aldehydes could react with amines in the hydrophobic micellar system in the presence of a catalytic amount of lanthanide triflate and a surfactant to produce imines, which could react with hydrophobic silyl enolates [49]. 

The assumption that the azomethine 34 is formed by an intermolecular hydride transfer from aldehyde 30 to the nitrilium salt 31 is not confirmed because the different Schiff bases 34 obtained carry the group R which are originated from the aldehyde 30. In this way, the process described in equation 14 can be reversed and applied as an enamide synthesis by acylation of imines . However, the A -ethylbenzonitrilium salt 35 reacts with benzaldehyde to give the more stable Af-benzoyl-A -ethyliminium ions 36 which add to trimethylethylene to form 5,6-dihydro-4/f-l,3-oxazinium salt 37. On the other hand, the reaction of ions 36 with phenylacetylene leads to another type of 1,3-oxazinium heterocycle, namely to 47/-l,3-oxazinium hexachloroantimonate 38 (equation 15). 

Dai and coworkers have investigated the addition of ylides derived from allylic sulfonium salts to IV-sulfonyl imines derived from aromatic aldehydes to produce 2-vinyl aziridines [98]. The general reaction studied is shown in Eq. (69), where a sulfonium salt 285 can be converted to its ylide in situ under either phase transfer conditions, or by use of a strong amides base, and then combined with an N-sulfonyl imine to provide a 2-vinyl aziridine 286. In gene-... 

Another approach to the synthesis of p hydroxy-a-amino acids is by aldol reaction of imines derived from amino adds. The benzophenone imine of glycine (7.102) undergoes highly enantioselective aldol addition with a range of aliphatic aldehydes, including (7.71) xmder phase-transfer conditions in the presence of the bromide salt of phase-transfer catalyst (7.103). A similar transformation is catalysed, in low to moderate ee, by the bimetallic catalysts developed by Shibasaki and CO workers. ... 

An intriguing example of a structurally very simple self-replicating systems utilizes amidinium carboxylate salt bridges to enhance the catalytic condensation of an aniline structure with a benzaldehyde derivative (Figure IS). " Several structures with various substituents in para-position to the recognition sites have been investigated. For instance, autocatalysis was established in the formation of imine 14 from aniline 12 and aldehyde 13. Adding preformed template to the reaction mixture increased the initial rate of product formation, and the obtained experimental data was in accordance with the square root model. 

Aldehydes and ketones serve as useful precursors to amino acids when they are converted to a Schiff base (from aldehydes) or an imine (from ketones). Reduction of the imino C=N moiety, usually in situ, generates the amine. When 1.83 (m = 1, 2) was treated with ammonia, for example, the resulting iminium salt (1,84) was hydrogenated to give either 8-aminooctanoic acid (7.[Pg.18]

The aza-Diels-Alder reaction of imines with diene of Danishefsky is an important route to 2,3-dihydro-4-pyridones. A number of Lewis acids have been used to catalyze the reaction in organic solvents. In water the reaction was realized by acid catalysis via iminium salts or by Bronsted acids. The montmorillonite K-10 catalyzed this cycloaddition in water or in aqueous acetonitrile in excellent yield. Recently Kobayashi has performed the reaction in water at room temperature under neutral conditions in two (imine - - diene) or three (aldehyde -b amine -b diene) component versions by using sodium triflate as catalyst. Imine intermediates from the indium-mediated reaction, in aqueous medium at 50° C, between aromatic nitro compounds and 2,3-dihydrofuran undergo aza-Diels-Alder cycloadditions to give tetrahydroquinoline derivatives in good overall yields. ... 

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