MCRs isonitrile-based

As for any organic reactions, appropriate experimental conditions are of paramount importance. In Scheme 15.6 are depicted two most important isonitrile-based MCRs the Passerini-3CR (P-3CR, (Eq. (1), Scheme 15.6) and the Ugi-4CR (U-4CR, Eq. (2), Scheme 15.6). While the P-3CR is generally performed in nonpolar aprotic solvents (e.g., CH2CI2), the U-4CR prefers polar protic solvents (e.g., MeOH). Indeed, if one carries out the U-4CR in CH2CI2, then the P-3CR... 

If in Chapter 7 different aspects about Ugi reaction have been discussed, in this chapter, we are going to disclose to the reader a vision about the new contributions regarding other crucial isonitrile-based multicomponent reaction (MCR) the Passerini reaction (P-3CR) discovered in 1921 [1], The traditional multicomponent Passerini reaction [2] is another isonitrile-based MCR that provides easy access to a-acyloxycarboxamides 4 in a one-pot synthesis involving an aldehyde 1, a carboxylic acid 2, and an isonitrile 3 (Scheme 8.1), which has been subject of intensive studies in the last decade [3], The importance of using isocyanides lays in its dual role as nucleophile and electrophile, and moreover, if R R, a new stereocenter could be created under asymmetric conditions. 

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. 

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... 

Kennedy and cowoikers repOTted Ihe use of resin-bound isonitriles in the Ugi MCR to afford valuable 2,5-diketq)iperazines and l,4-benzodiazepine-2-5-diones [89]. They developed a resin-bound carbonate convertible isonitrile based on a hydroxymethyl polystyrene resin. As shown in Scheme 11.38, the Ugi reaction with these resin-bound convertible isonitiiles afforded, after several derivatizations, the desired 2,5-diketopiperazines in good yields 178. 

The first MCR involving the explicit use of a-acidic isonitriles was reported in 1998 by Sisko [131]. The reaction involves the cycloaddition of aTosMIC derivative (8) to an (in situ-generated) imine (10) followed by the elimination of p-toluenesulfinic acid (TsH) as described in 1977 by van Leusen for preformed imines (Fig. 5, scaffold P) [119]. Although several potential pitfalls for the conversion of the traditional van Leusen [3 + 2] cycloaddition to the so-called van Leusen three-component reaction (vL-3CR) of imidazoles were expected by the author, simply stirring the aldehyde and amine for 20 min followed by addition of the TosMIC derivative and base resulted in the isolation of the corresponding imidazole (9) in high yield [131]. 

In 2006, our research group reported a novel MCR based on the reactivity of a-acidic isocyano esters (1) toward 1-azadienes (84) generated by the 3CR between phosphonates, nitriles, and aldehydes [169]. Remarkably, the dihydropyridone products (85) for this 4CR contained the intact isonitrile function at C3. The exceptional formation of the 3-isocyano dihydropyridone scaffold can be explained by the Michael-attack of the a-deprotonated isonitrile (1) to the (protonated) 1-azadiene (84), followed by lactamization via attack of the ester function by the intermediate enamine. Although in principle the isocyano functionality is not required for the formation of the dihydropyridone (85) scaffold, all attempts using differently functionalized esters (e.g., malonates, ot-nitro, and a-cyano esters) gave lower yields of the dihydropyridone analogs [170] (Fig. 26). 

One of the pioneer works in the synthesis of DKPs through MCRs was reported by Hulme and coworkers in a three-step solution phase protocol based on UDC [33, 34]. They have obtained a series of different DKPs by reacting Armstrong s convertible isocyanide with aldehydes, M-Boc-protected amino acids as bifunctional acid component containing a protected internal amino nucleophile, and amines in methanol at room temperature. After Ugi-reaction, the isonitrile-derived amide is activated with acid (UAC) and allows cyclization to the DKP with the... 

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