Multicomponent reaction oxazoles

Keywords Isocyanide Macrocycle Macrocyclization Macrocylopeptide Multicomponent reaction Multicomponent reaction Oxazole Passerin-3CR Staudinger reaction Ugi 4CR... 

Because of the retained isocyano functionality, the dihydropyridone MCR product 85 can be used in various follow-up (multicomponent) reactions. For example, the Passerini reaction between 85, a carboxylic acid, and an aldehyde or ketone produces a series of dihydropyridone-based conformationally constrained depsipeptides 86 [171]. The subsequent Passerini reaction could also be performed in the same pot, resulting in a novel 6CR toward these complex products containing up to seven points of variation. Reaction of 85 with an aldehyde or ketone and amine component resulted in the isolation of dihydrooxazolopyridines (DHOPs, 87) [172] via a similar approach as the 2,4,5-trisubstituted oxazole variant toward 42 reported by Tron and Zhu (Fig. 15) [155]. The corresponding DHOPs (87), which... 

Multicomponent reactions (MCR) were also highlighted in the literature. The reaction of dimethyl butynedioate 160 and benzyhdenemalononitrile 161 in anhydrous THF with isoquinoline at room temperature gave a mixture of two diastereomers 162 and 163 (2 1) in 81% yield (Scheme 46) <05TL5333>. Isoquinohne was also used in a MCR that included methyl chloroformate and morpholinyl-a-isocyano-P-phenylpropionamide resulting in the synthesis of (l,3-oxazol-2-yl)-l,2-dihydro(iso)quinoline derivatives in moderate yields <05SL532>. 

Multicomponent reactions in alkaloid-based drug discovery 12KGS38. Muscarine, imidazole, oxazole, and thiazole alkaloids 13NPR869. Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids 12CRV3193. 

An impressive and more current multicomponent reaction by Masson and Zhu [11] orchestrates the same strategy as a key step in another furanoid synthesis (Scheme 6.3). Again, a triple bond, unactivated in this example, undergoes a Diels-Alder reaction with a more electron-deficient oxazole moiety. A consecutive... 

For selected examples, see (a) G. Zhao, X. Sun, H. Bienayme, J. Zhu, J. Am. Chem. Soc. 2001, 123, 6700-6701. Activation of a terminal carboxylic acid by an internal oxazole a novel synthesis of macrocyclodepsipeptide. (b) P. Janvier, M. Bois-Choussy, H. Bienayme, J. Zhu, Angew. Chem. Int. Ed. 2003, 42, 811-814. A one-pot four-component (ABC ) synthesis of macrocycles, (c) L. A. Wessjohann, E. Ruijter, Mol. Divers 2005, 9, 159-169. Macrocycles rapidly produced by multiple multicomponent reactions including bifunctional building blocks (MiBs). (d) C. Bughin, G. Zhao, H. Bienayme, J. Zhu, Chem.-Eur. J. 2006, 12, 1174-1184. 5-Aminooxazole as an internal traceless activator of C-terminal carboxylic acid rapid access to diversely functionalized cyclodepsipeptides. (e) T. Pirali, G. C. Iron, J. Zhu, Org. Lett. 2006,8,4145 148. One-pot synthesis of macrocycles by a tandem three-component reaction and intramolecular [3 +2] cycloaddition. 

In 2007, Tron and Zhu reported the multicomponent synthesis of 5-iminoox-azolines (42) starting from a,a-disubstituted secondary isocyano amides (41), amines, and carbonyl components (see Fig. 15) [155]. The reaction presumably follows a similar mechanism as in the 2,4,5-trisubstituted oxazole MCR (described in Fig. 11) however, because of the absence of a-protons at the isocyano amide 41, the nonaromatized product is obtained. As in the 2,4,5-trisubstituted oxazole MCR, toluene was found to be the optimal solvent in combination with a weak Brpnsted acid. The reaction was studied for a range of aldehydes and secondary amines. In addition, a variety of functionalities such as acetate, free hydroxyl group, carbamate, and esters are tolerated. Clean conversions were observed for this MCR as indicated by NMR analysis of the crude products (isolated yield 50-68%). The... 

Some multicomponent syntheses of trisubstituted oxazoles were described. a-Isocyano-a-alkyl(aryl)acetamides, as 131 <05S161>, was demonstrated to be a useful starting material for a three-component reaction involving isoquinoline 129 <05SL532>. A four-component synthesis was also published starting from an aldehyde, a silylamide, an acyl chloride and a terminal acetylene derivative. The overall process is a modification of a four-component synthesis of a propargylic amide 134 which can be eventually isolated <05T 11317>. 

Annulated pyridines have also been synthesized via a (4+2) cycloaddition strategy involving oxazole 6, which is made via a multicomponent coupling reaction in a single step <01OL877>. Acylation of 6 with a a,P-unsaturated acyl chloride is the first step in a domino reaction where an intramolecular Diels-Alder reaction is followed by a retro-Michael reaction (7-+8). 

In a number of multicomponent condensation reactions, TMSCl has also been utilized to improve the yield or efficacy of the desired product, or is directly incorporated into the final molecules. Examples include the synthesis of Al-aryl-3-arylamino acids from a three-coir onent reaction of phenols, glyoxylates, and anilines, preparation of 2,4,5-trisubstituted oxazoles, or 4-cyanooxazoles, and the three-component BigmeUi reaction... 

Although there is no general mechanism for this reaction in the cited literature, it is plausible that ammonia (or primary amine) reacts with an of-dicarbonyl compound to form Qf-diimine, which then condenses with an aldehyde, as displayed here. In the meantime, it is also possible to form an oxazole by-product from this multicomponent condensation. 

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