Passerini reaction amide synthesis

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

Hagedorn, I., Eholzer, U. Isonitrfles. VII. Single-step synthesis of a-hydroxy acid amides by a modification of the Passerini reaction. Chem. 

Titanium chelates of semi-salen 59 and salen 60 are used in asymmetric synthesis of a-cyanoalkyl ethyl carbonates from aldehydes and ethyl cyanoformate. By changing the metal atom to aluminum for complexing 60 a catalyst for elaborating a-acetoxy amides (Passerini reaction) is obtained (but enantioselectivity varies)/ ... 

The synthesis of hydrastine (61) by Falck and Manna demonstrate that the amide product of the Passerini reaction could be used in a subsequent Bischler-Napieralski reaction as a method to produce isoquinolines. In their report, carboxybenzaldehyde derivative 62 was condensed with isonitrile 63 in 71% yield to provide amide 64. Cyclization (POCI3/CH3CN), reduction of the dihydroisoquinoline (Adam s catalyst/H2), and reductive alkylation with formaldehyde gave a diastereomeric mixture of a- and p-hydrastines in 58% overall yield from Passerini product 64. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

The power of the Passerini and Ugi reactions in constructing polyfunctional molecules has been well appreciated since the early studies. The classical Passerini and Ugi reactions afford a-acyloxy carboxamides and a-acylamino amides respectively, that can be easily manipulated by post-condensation reactions, generating molecular diversity for drug discovery and natural product synthesis [22], This strategy has been widely applied to the synthesis of natural peptides and open-chain peptide mimetics covered in this section. 

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