Aldehydes Betti reaction

Betti reaction. The reaction of aromatic aldehydes, primary aromatic or heterocylic amines, and phenols leading to a-aminobenzylphenols. 

In this reaction, the course of condensation and the type of products formed depend on several factors, such as the nature of hydroxyaromatic compounds, amines, aldehydes, and the actual ratio of the components in the reaction system. For examples, besides the initial ammonia, this reaction has been extended successfully to both primary amines and secondary amines and among the secondary amines, the reaction particularly works for dimethylamine, diethylamine, and piperidine. In addition, when one of the secondary amines exists in large excess or when dimethylamine or ammonia is removed from the reaction system via vaporization, good yields of pure products are often achievable. Besides the commonly used -naphthol, many other hydroxyaromatic compounds are suitable for this reaction as well, such as phenols, and quinolinols. " It is found that among kojic acid, 8-quinolinol, and 8-hydroxquinaldine, kojic acid is the most reactive compound for the Betti reaction, which reacts with benzylideneaniline in less than 1 day... 

It is agreed that Betti reaction involves the initial reaction between aldehyde and amine, followed by the second condensation of naphthol (or phenol or other active methylenes), as shown by the reaction among -naphthol, benzaldehyde, and methylamine. 

On the basis of Betti s initial work, the Betti reaction has been extended to both primary amines and secondary amines. The resulting Betti amines have been applied as ligands or chiral auxiliaries in asymmetric synthesis. In addition, the Betti reaction has also been extended to the reaction among aldehydes, secondary amines, and compounds of active methylene moiety, such as dibenzyl ketones which can tautomerize to enols and mimic naphthol. Moreover, the reaction of aromatic aldoximes and 0-keto esters to afford isoxazolones should also be considered as an extension of the Betti reaction. 

The multicomponent reaction between 2-naphthol (1), aryl aldehydes and amines is known as the Betti reaction. ... 

Although detailed mechanistic studies on the Betti reaction have not been carried out, it is widely assumed the reaction follows a similar course to the Mannich reaction. This principally involves the condensation of the aldehyde and amine constituents to form the active iminium electrophile 7. 2-Naphthol (1) functions as a nucleophile, giving the intermediate represented by the resonance structures 8 and 9, which subsequently loses a proton to yield the product. It is easy to appreciate from this mechanism why acid catalysis may facilitate the reaction, and indeed increased rates have been observed using such catalysis. ... 

Early work by Littman and Erode established that it was possible to vary the amino constituent of the Betti reaction. It has subsequently been shown that a wide variety of amines are suitable, depending on the reaction conditions. Indeed, primary and secondary aliphatic amines, aromatic amines and heteroaromatic amines have been used. For example, morpholine (17) was a suitable substrate for a Betti reaction when the reaction constituents were neat in the presence of a catalytic amount of p-toluenesulfonic acid under microwave irradiation. This reaction protocol is especially notable for its fast reaction rates, with the products obtained after only one minute of irradiation. Other useful reaction procedures to form diverse Betti bases have also been reported including the use of water as a solvent,and the addition of nonionic surfactants to the reaction mixture. In addition to variation of the amine component, a number of alternative aromatic and heteroaromatic aldehydes are suitable substrates. Finally, although most of the examples in the literature focus on 2-naphthol, a few alternatives have been reported, including the use of 8-quinolinol. ... 

The multicomponent reaction between 2-naphthol, aryl aldehydes and ammonia or amines yields aminobenzylnaphthols in a process known as the Betti reaction, which was first uncovered at the beginning of the 20th century. The aminobenzylnaphthols could be easily resolved into their enantiomers. After a long silenee, the results of our research a decade ago on this useful reaction and on the chiral materials produced has stimulated further work in a number of other laboratories. As a result, novel applications of the Betti reaction to produce new chiral aminobenzylnaphthols were reported together with the evaluation of these chiral bases in asymmetric s5mthesis. 

Either ammonia or a variety of amine substrates can be used to prepare the product 2, widely called a Betti base. Various substitution patterns are tolerated on both the naphthol and aryl aldehyde component. While the reaction was classically performed in ethanol, a variety of solvents, and using the substrates neat are also possible. Increased rates have been observed using acid catalysis. The reaction results in a product 2 with a benzylic chiral center, which as such can be resolved into its enantiomers. Alternatively, chiral amines can be used to control the stereoselectivity of the process. Enantiomerically pure Betti bases have shown potential as chiral auxiliaries and as ligands in asymmetric reactions. ... 

A number of studies have also been reported using enantiopure Betti base derivatives as chiral ligands in asymmetric reactions. For example, Chan et al. reported that Betti base 33 was a useful ligand for the additional of diethyl zinc to aryl aldehydes, with excellent enantiomeric excesses... 

Readily available chiral amines related to the Betti base [phenyl(2-hydroxy-l-naphthyl)methanamine] catalyse enantioselective addition of diethylzinc to aldehydes in moderate to excellent ee Observed enantioselectivities in addition of diethylzinc to aldehydes catalysed by a series of (5)-proline-derived pyrrolidines have been explained in terms of steric effects. New 2,5-diazabicyclo[2.2.1]heptanes have been applied to enantioselective addition of diethylzinc to benzaldehyde. (S)-2-(3-Methyl-2-pyridyl)-3,5-di-r-butylphenol (76) has been used as an enantioselective catalyst of diethylzinc addition to benzaldehydes. Reaction in toluene shows a significant variation in % ee with temperature, including observation of an inversion temperature with maximum ee. This value varies with the nature of the para-substituent in the aldehyde, and the overall behaviour may be due to a shift in the rate-determining step of the reaction. Other reports of zinc reagents include enantioselective addition of diethylzinc to aldehydes addition of diphenylzinc to aldehydes using a chiral ferrocene-based hydroxyoxazoline catalyst in up to 96% ee and 3-exo-morpholinoisoborneol has been proposed as a more convenient and efficient enantioselective catalyst of alkylzincs than Noyori s original 3-exo-dimethylamino catalyst. ... 

The marked temperature dependence of the enantioselective addition of diethylz-inc to aryl aldehydes catalysed by (S)-2-(3-methyl-2-pyridyl)-3,5-di-r-butylphenol displays an inversion temperature which is affected by the para-substituent of the aldehyde. Enantioselectivities of up to 78% ee for addition of diethylzinc to ben-zaldehyde have been achieved using (15, 45)-2,5-diazabicyclo[2.2.1]heptane derivatives as catalysts however, a study of chiral compounds related to the Betti base (51a) has identified r-aminonaphthol (51b) as a much more effective catalyst (99% ee) for this reaction. The catalytic efficiency of chiral pyrrolidine derivatives and (25)-3-eJt -(dimethylamino)isobomeol have also been explored. 

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