Aldehydes passerini-type reaction

In a related study Denmark and Fan [22] investigated chiral Lewis base-catalyzed enantioselective a-additions of isocyanides to aldehydes in a Passerini-type reaction (Scheme 9.14). The development of the reaction was based on the concept of Lewis base activation of a weak Lewis acid such as SiCl4 forming a trichlorosilyl-Lewis base adduct which is capable of activating aldehydes towards nucleophilic attack. 

Aqueous mineral acids have been shown to be capable of promoting Passerini-type reactions, producing a-hydroxyamides in good yields. Both aldehydes and unencumbered ketones function well as appropriate substrates. 

Denmark has described several chiral bis-phosphoramides as Lewis base activators of weak Lewis acid SiCL and demonstrated their ability to mediate an enantioselective Passerini-type reaction. Catalytic bis-phosphoramide 36 and stoichiometric SiCU, in the presence of a proton scavenger (Htinig s base), promoted the formation of a-hydroxyamides with remarkably good enantioselectivity and yield. A variety of aromatic and unsaturated aldehydes and aryl, alkyl, and functionalized alkyl isocyanides proved to be useful and effective starting materials. High yields of Passerini products were attributed to the production of imidoyl chloride 37, which reduced the prevalence of the nitrilium intermediate and prevented the addition of a second equivalent of isonitrile. 

Almost simultaneously, the same research group disclosed a [(salen)Al "Me] 43-catalyzed enantioselective Passerini-type reaction of aldehydes, isocyanides, and hydrazoic acid 42, affording a great scope of tetrazole derivatives 44 with good to excellent enantioselectivities (51-95%) (Scheme 8.16) [39]. 

In 2008, Wang and Zhu s group reported the catalytic asymmetric Passerini-type reaction of aldehydes, isocyanides and hydrazoic acid with... 

Lewis acid catalysis serves for the Passerini-type reaction of aldehydes with isocyanides forming a-hydroxyamides. The catalytic system consisting of SiCU and (107) provides high yield and good to excellent enantioselectivity for the addition of t-butyl isocyanide to a wide range of aldehydes [167]. The amide product is formed from the imidoyl chloride intermediate (110) by hydrolysis (Scheme 9.78). Treatment of the intermediate product with methanol followed by hydrolysis gives a-hydroxyesters with the retention of enantioselectivity. 

Ganem and co-workers have developed the use of a Zn(OTf)2/TMSCl system to promote a variety of Passerini-type processes. The combination is active even for a,P-unsaturated aldehydes and usually problematic ketones. The promoter system was developed around a strategy of tethering nucleophilic functional groups to the isonitrile component to intercept the transient nitrilium species internally. Depending on the attached functionality either the a-hydroxy amide or a substituted oxazole could be obtained in high yield. For 1-isocyano-(2-morphilino)ethane (28), the reaction with... 

In one of the initial such examples, Domling and coworkers have reported both Ugi and Passerini-type MCR in concert with RCM. The general approach is outlined in Scheme 11.25, with the linear precursor (186) obtained from the MCR then subjected to standard RCM to give the macrocyclic products 187 or 188. In this manner, the representative 22-membered macrocycle (189) is produced from the Ugi four-component coupling reaction (4CR) of an acid, amine, isonitrile and paraformaldehyde. In a similar way, the exemplary 17-membered macrocycle (190) was prepared from the Passerini SCR of an acid, aldehyde and isonitrile. Methods for the synthesis of the starting materials also needed to be developed to ensure sufficient... 

Finally, other reactions can be performed directly using water as a solvent. Ugi s four components reaction, for example, provides an expedient access to peptidic scaffolds starting from an isocyanide, an amine, an aldehyde and a carboxylic acid. However, in competition to Ugi s reaction, Passerini ester formation often pollutes the reaction mixture and it is of great interest to perform this type of highly complex transformation in supported versions. Indeed, when an ammonium chloride supported aldehyde, similar to those used in Grieco s multicomponent reactions, are dissolved in water in the presence of an amine, the imine formation occurs within 15 min and isocyanide and acid can subsequently be added to the mixture. After 24 h at room temperature, amides were isolated in high yield with no other purification than washing with diethyl ether [135] (Fig. 44). 

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