Primary amines azomethine derivatives

Asymmetric 1, 3-dipolar cycloaddition is a powerful tool for synthesizing chiral heterocyclopentane compounds. Chen group demonstrated that primary amine 143 derived from cinchona-alkaloid was an effective catalyst for the 1,3-dipolar cycloaddition of a,p-enones and azomethine imines (Schane 5.38) [67], It was proposed that multi-hydrogen-bonding, particularly those between the free OH and the substrate are critical for stereocontrol (Scheme 5.38). The reaction went smoothly with a wide range of substrates with up to 99% yield, 99 1 dr and 95% ee. 

The alkylation of caclohexanone has been studied as a model reaction in detail. Generally, enamino compounds (126) are allowed to react with alkyl halides or a, 3-unsaturated carbonyl compounds. The enamine (126a) is prepared directly from the ketone and a chiral secondary amine (route A). A metalloenamine (126b) can be synthesized from chiral azomethine, derived from the model ketone and a primary chiral amine (route B). The primary amine used for the formation of (126b) must possess an oxygen function. This oxygen function plays a key role in the coordination of the lithium ion in the complex (126b). 

Several pharmacological studies were earned out to substantiate the proposed prodrug concept for (/< )-a-methylhistamine (12). The parent compound of this series of azomethines is the 2-hydroxybenzophenone derivative of (ft)-a-methylhistamine which is designated BP 2.94 (36). To evaluate the desired protection against HMT metabolization, BP 2.94 (36) was tested as a possible substrate in the presence of S-adenosylmethionine in comparison to histamine and ( )-a-methylhistamine (12). As a result no methylation of the prodrug 36 was observed, whereas both primary amines displayed similar Km- and Fmax-values [6],... 

The iV-alkyl and iV-aryl derivatives (Schiff bases, azomethines, anils) that can be obtained from aldehydes and ketones by use of primary amines are considerably more important than the unsubstituted imines. 

Although considerable improvements have been made for endo-selective cycloadditions of azomethine imines, methods for exo and enantioselective cycloaddition of azomethine imines were relatively scarce. By employing novel, multifunctional primary amine catalysts 145 derived from cinchona alkaloids in the presence of triisopropylbenzene sulfonic acid (TIPBA) 146 as cocatalyst, Chen and coworkers developed the first organocatalytic, highly exo-selective, and enantioselective 1,3-DC reaction of cyclic enones 142 and azomethine imines 143 in 2007 [53]. The additional and synergistic hydrogen-bonding interaction of catalyst and 1,3-dipole is essential for enantiocontrol, and excellent stereoselectivities were achieved for a broad scope of substrates (dr > 99 1, up to 95% ee) (Scheme 2.37). 

Aldehydes and ketones react with primary amines to form azomethines which are usually known as Schiff bases, or sometimes, if the amine is aromatic, as anils. Stable Schiff bases are formed with aromatic aldehydes and with aliphatic and aromatic ketones, those formed from ahphatic aldehydes are often subject to aldol-type polymerization and are not suitable for group protection. The Schiff bases formed from aliphatic ketones are potentially tautomeric with the corresponding enamines, but they exist as azomethines unless there is some other structural feature present to stabilize the enamine form (section 2.1.3.2). The condensation reaction by which these derivatives are formed is acid-catalyzed and easily reversible, thus this method of oup protection is only applicable under neutral or alkaline conditions. The condensation using aromatic aldehydes or aliphatic ketones take place readily without solvent or in refluxing ethanol, those with aryl-alkyl or diaryl ketones may require catalysis or azeotropic removal of the water formed in the reaction. 

A stereoselective [3+2] dipolar cycloaddition of azomethine imines 141 with ot,P-unsaturated aldehydes catalyzed by ot,a-diarylprolinol salts was also reported by Chen et al. [88]. More important, they extended the strategy to cyclic enones by employing a Cinchona alkaloid-derived bifunctional primary amine catalyst 142 (Scheme 1.52) [89]. The synergistic hydrogen-bonding interaction of the catalyst and 1,3-dipoles 141 plays a critical role in high enantiocontrol (dr >99 1, up to 95% ee). 

Alkylation of 2,1-benzisothiazoles (102) with trialkyl orthoformates in the presence of Lewis acids such as boron trifluoride etherate affords the quaternary salts (103). Their treatment with secondary amines produces the expected 1 -alky 1-3-aryl-3-dialkylamino-2,1 -benzisothiazoline derivatives (104). In contrast, the presumed intermediates (105) arising from primary amines (including glycine methyl ester) are cleaved, with extrusion of sulphur, to the azomethines (106). ... 

Aromatic nitro compounds are often strongly colored. They frequently produce characteristic, colored, quinoid derivatives on reaction with alkali or compounds with reactive methylene groups. Reduction to primary aryl amines followed by diazotization and coupling with phenols yields azo dyestuffs. Aryl amines can also react with aldehydes with formation of Schiff s bases to yield azomethines. 

---