A-acyloxy-carboxamide

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. 

In the classic Passerini reaction (P-3CR), an a-acyloxy carboxamide is formed from the reaction of an isocyanide, an aldehyde (or ketone), and a carboxylic acid. The... 

Originally described in 1921 by the Italian chemist Mario Passerini [23], this reaction facilitates the synthesis of a-acyloxy-carboxamides 16 in one step. The postulated mechanism is shown in Scheme 11.3. 

The Passerini reaction, also called the 3-CC reaction, which consists of the reaction of a carboxylic acid, a carbonyl compound, and an isocyanide providing an a-(acyloxy)carboxamide in a single step, was carried out for the first time in [bmim] [BFJ (Fig. 12.1) [1]. 

This reaction was done with a variety of substituted aromatic and aUphalic carboxylic acids and aldehydes. Unlike the aromatic aldehydes that produced the corresponding products in high purity and good yields, reactions with aliphatic aldehydes produced several unidentified substances together with the desired a-(acyloxy)carboxamide products. In the case of ketones, cyclohexanone was successfully included into this 3-CC process and gave the corresponding products in reasonable yield, but attempts to use acetophenone as the carbonyl substrate failed. The inactivity of the acetophenone in this reaction may be due to the steric effect of the relatively bulky phenyl group. 

The IBX-mediated oxidative Ugi-type multicomponent reaction of tetrahydroisoquinoUne with isocyanides and carboxylic acids affords the nitrogen- and carbon-functionalized tetrahydroisoquinolines 867 in good to excellent yields [1184]. Likewise, the three-component Passerini reaction of an alcohol, carboxylic acid and an isonitrile in the presence of IBX affords the corresponding a-acyloxy carboxamides 868 in generally high yields (Scheme 3.347) [1185]. 

The Passerini three-component reaction, discovered in 1921, involves the condensation of carbonyl compounds, carboxylic acids, and isocyanides to afford the corresponding a-acyloxy carboxamides [22]. Among several advantages are the... 

Aminoacridine carboxamide derivatives binding with DNA, 194, 195 Anomeric amides, 37, see also A-acyloxy-A-alkoxyamides... 

The Passerini reaction between a-chloroketones, isocyanides, and carboxylic acids afforded a-acyloxy-jS-chlorocarboxamides 52, which, on treatment with an excess of powdered KOH in tetrahydrofuran, underwent O-deacylation followed by a Darzens-type O-alkylation to give the functionalized oxiranes 53. When carboxamides 52 were treated with an excess of CsF, with or without a phase-transfer catalyst, a different ring closure took place to afford 3-acyloxy-2-azetidinones 54 in high yields (Scheme 2.21) [46]. 

Davidson s synthesis consists of the cydization of a-acyloxyketones with ammonia or ammonium acetate to give 2,4,5-trisubstituted oxazoles. The Passerini reaction between arylglyoxals, carboxylic acids, and isocyanides afforded N-substituted 2-acyloxy-3-aryl-3-oxopropionamides 83 in high yields. Upon heating with an excess of ammonium acetate in acetic acid, compounds 83 were cydized to N,2,4-trisubstituted oxazole-5-carboxamides 84 in fair yields [59]. A large number of a-acyloxy-jS-ketoamides can be prepared by changing the reaction components, so the method provides straightforward access to a variety of oxazole-5-carboxamides (Scheme 2.30). 

According to route II, FGA d (addition of H2O at C-4) gives rise to hydroxyoxazoHne 26, which by disconnection e leads to the iminoester 28 and FGI f to the (a-acyloxy)carbonyl compound 29 and two sets of components, namely 31/33 (via disconnection h) and 34/carboxylate (via disconnection i). Alternatively, 28 can be disconnected according to g leading to components (a-halogeno)carbonyl compound 32/carboxamide. Thus, retrosynthesis proposes systems 27-29 to be suitable educts for approaches to oxazole synthesis [262]. 

A-acetoxy-lV-/e//-butoxybenzamide, 55 /V-acyloxy- /V-alkoxyalky lam ides, 55 /V- acy I o x y- /V-a I k o x y u re as, 56 /V-chlorohydroxamic esters, 56 N, /V-dialkoxyamidcs, 56 Intercalative guest molecules, binding dynamics of DNA with, 186-201 acridine derivatives, 190-194 9-aminoacridine carboxamide derivatives, 194, 195... 

Similar to [bis(acyloxy)iodo]arenes, HTIB can serve as an efficient oxidant in Hofmann-type degradation of carboxamides to the respective amines [495 99], In a representative example, HTIB has been used for the preparation of cubyl ammonium salt 407 from the respective carboxamide derivative 406 under mild reaction conditions (Scheme 3.163) [504],... 

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