MCRs isonitrile

In case of macrocyclization through two or more MCRs, the resulting macrocycle may be uni- or bidirectional, i.e., the resulting dipeptide moieties (N- to C-terminal direction) run in the same (parallel) or in opposite (counter) direction, respectively. Figure 16 shows an example of a unidirectional MiB (the isonitrile and amine function are too far apart for intramolecular reaction, and thus, a double U4CR results). 

In addition, we should note that data of H, NMR spectroscopy, mass-spectra, and elemental analysis given in [138] did not contradict the structure of compound 98, being regioisomer of 97. The similar situation had already been shown in the synthesis of 3-aminoimidazo[l,2-a]pyrimidines [139]. Mandair et al. carried out the model MCRs of 2-aminopyrimidine with several aldehydes and isonitrile components in the methanol under the ambient temperamre with the various catalysts. As a result, 3-aminoimidazo[l,2-a]pyrimidine and position isomeric 2-aminoimidazo[l,2-a]pyrimidines were isolated from the reaction mixture in different ratio (Scheme 45). The stmctures of the isomers obtained in this case were confirmed by the X-ray diffraction analysis, as well as the structures of the side-products isolated. 

Besides numerous applications of a-acidic isocyanides in classical IMCRs, such as the Ugi and Passerini reaction, the presence of an a-acidic proton enables other reaction paths and, subsequently, the development of novel MCRs. Here we focus on novel MCRs involving a-acidic isonitriles that have been described in literature since 1998. 

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 2009, the MCR between o-phenylenediamines (13), aldehydes, and TosMIC (8a) which yields 2,6,7-trisubstituted quinozalines (14) has been described [135]. The mechanism probably proceeds via the initial attack of deprotonated TosMIC at the in situ-generated imine affording intermediate 16 (Fig. 8). Apparently, attack of the secondary amine in 16 at the terminal isonitrile C-atom that yields the... 

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 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. 

Fig. 3 The three most common modes to activate linear Ugi-products for cyclization, especially if the cyclization involves Ugi-reactive groups (e.g., acid, oxo-compound, or amine). Activation is mostly achieved with convertible isonitriles, i.e., activated amides (see text). Other MCRs follow similar concepts. With orthogonal second functionalities for cyclizations such deprotection and/or activation is not required (see below, e.g., RCM or cycloadditions)...

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... 

This chapter contains a survey of free-radical-mediated multicomponent reactions (MCRs), which permit the coupling of three or more components. Even though they are not technically classified as MCRs, remarkable intramolecular radical cascade processes have been developed. Some examples, such as those shown in Scheme 6.3, use an isonitrile or acrylonitrile as the intermolecular component for each reaction [6]. These examples demonstrate the tremendous power of the combination of inter- and intramolecular radical cascade processes in organic synthesis. Readers are advised to be aware of remarkable intramolecular aspects of modem radical chemistry through excellent review articles published elsewhere [1, 7]. It should also be noted that there has also been remarkable progress in the area of living radical polymerizations, but this will not be covered here. 

Among the most widely used components for MCRs involving amines and carbonyls are the isocyanides (isonitriles) 26, which were initially used in the Pass-erini reaction [21] and more extensively in a series of MCRs introduced by Ugi (Scheme 7.4) [1, 5, 22], The great effectiveness of isocyanides in MCRs is apparently a result of their remarkable balance between nucleophilic and electrophilic reactivity that enables them to be relatively unreactive towards carbonyl compounds but quite reactive with activated derivatives such as the corresponding imi-nium species. Numerous applications of isocyanides in MCRs leading to a variety of novel multifunctional derivatives and heterocyclic systems have appeared in recent years [5-9]. 

In a recent example, Mironov used the rational replacement of starting materials for oligomerization reactions to discover new MCRs in a systematic way [31]. A reaction library of six alkenes/alkynes, two isonitriles, two nitriles and isoquinoline was set up, giving (n1 — n)/2 different reactions products. A minimum peak height of 30% of the total reaction product was used as a criterion for identifying an efficient MCR. In this way, a novel MCR that yields pyrrolo[2,l-a]isoquinolin-1-ones from electron-deficient olefins, isonitriles and isoquinoline was found (Scheme 10.6). 

On the basis of the same principle, we developed a three-component synthesis of macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-mide (48) (the cx-isocyanoacetamides are easily available, see [84—86]) bearing a terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole 52 (selected examples [88-94]). The oxazole 52, although isolable, was in situ converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition of Cul and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne functions were not directly involved in the three-component construction of oxazole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was built up. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole and one triazole (Scheme 15). 

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... 

It is clear from the Hst of reactants presented above that the bottleneck for potential combinatorial expansions of this reaction arises from the limited commercial availabihty of isonitriles, along with the intrinsic difficulty in handling these chemicals because of their toxicity and malodor. These are the reasons why the great majority of Ugi MCRs on the soHd phase were performed by anchoring the isonitrile component on the resin. 

Different novel resin-bound isonitriles have been prepared in order to perform Ugi multicomponent reactions on the solid phase. Thus, Kennedy et al. [346] prepared a novel resin-bound carbonate convertible isonitrile (CCI) that was applied in the preparation of constrained 2,5-diketopiperazine and l,4-benzodiazepine-2,5-dione libraries in parallel 80-well format The first step of the synthetic strategy was a Ugi reaction with a wide variety of amines, aldehydes, and carboxylic acids. Further manipulations of the Ugi MCR products were achieved after basic cleavage from the resin. 

Diketopiperazines and benzodiazepin-2,5-diones represent the same target obtained by performing a Ugi MCR on the universal Rink-isonitrile resin [347]. The final product could be cleaved from the resin with HOAc/1,2 dichloroethane 1 9 (v/v). Wang resin-bound isonitrile (419) has been employed in a Ugi MCR-N-acyli-minium ion cyclization [348]. Using aminoacetaldehyde diethyl acetal (420) and then exposing the Ugi products to a 20% dichloromethane solution of TFA, the desired A -2-oxopiperazines (422) were obtained with simultaneous release from the resin (Scheme 86). 

Polymer-bound isonitrile (423), obtained from TentaGel-NH2 through treatment of the resin with formic acid and acetic anhydride, followed by dehydration of the resulting formamide with tosyl chloride and pyridine, has been employed in the preparation of N-substituted amino add ester [349]. Thus, Ugi MCR, performed in the presence of an alcohol instead of the carboxylic component, gave rise to an imino-ether spedes (426). Several Lewis acids were tested in searching for optimal reaction conditions. Boron trifluoride etherate displayed the better yields in term of desired product of the Ugi-type reaction. Amino acid methyl esters (427) were thus obtained when using methanol as the alcohol component, after deavage from the resin of the intermediate imino-ethers by an acetone/water mixture (Scheme 87). 

Good yields and purities were obtained for the two examples shown. Ugi reaction using solid-supported benzenesulfonamide, prepared by coupHng 4-carbox-ybenzenesulfonamide onto Rink resin, has also been described. The sulfonamide took the place of the amino component in the classical Ugi MCR. An extension of this Ugi reaction involving a support-bound amine, furfural, and an isonitrile and an acrylic acid was used by Schreiber [307] to generate support-bound dipeptides capable of performing intramolecular Diels-Alder reactions (see Section 4.5.9). 

The same authors who employed solid-supported benzenesulfonamide as a replacement for the amino component in the Ugi reaction also used solid-supported carboxylic acid (433) (carboxypolystyrene) and performed the MCR in the presence of an aldehyde, an isonitrile, and a benzenesulfonamide to obtain (437) (Scheme 89) [352]. 

Universal Rink-isonitrile resin (450) has been applied to the synthesis of imi-dazo[l,2-a]pyridines (452) [356], a novel [357] MCR consisting of a condensation among 2-aminopyridines, aldehydes, and isonitriles. During the course of the reaction, the isonitrile component becomes an enamine. The reaction was performed in the presence of a catalytic amount of para-toluenesulfonic add in a desiccating mixture of CHCU/MeOH/trimethylorthoformate (TMOF) (Scheme 92). 

Multicomponent reactions (MCRs) were applied to the synthesis of substituted isoxazolines. For example, 64 was obtained by addition of nitro-alkene 60 and acrylate 61 to a solution of isonitrile 59 generated in situ by reaction of trimethylsilyl cyanide and isobutene oxide in the presence of Pd(CN)2 <05OL3179>. This cascade MCR is believed to occur through [1+4] cycloaddition of 59 with 60, subsequent fragmentation of 62 and 1,3-DC of nitrile oxide 63 with 61. Under microwave irradiation, reaction times could be reduced from several hours to 15 min, with comparable yields. 

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... 

In the second communication, Passerini also determined that the addition of hydrogen peroxide was unnecessary and, to an extent, deleterious as it mediated the decomposition of /7-isonitrileazobenzene. The formation of a-acyloxyamides from isonitriles, carboxylic acids and ketones or aldehydes subsequently became known as the Passerini reaction or the Passerini multicomponent reaction. The process is sometimes denoted as P-3CR according to Ugi s classification of multicomponent reactions (MCR). ... 

With these two intermediates on hand, the authors proposed the combination of the isonitrile intermediate 77 (from a U-3CR) and the acid intermediate 74 (from a U-3CR) to carry out the Ugi reaction by addition of the corresponding aldehyde and amine, obtaining in this manner the 8-MCR product 79 (Scheme 7.32). 

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. 

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. 

One could argue that this synthesis actually employs protective groups in the Passerini reaction by use of the formamide in 123. However, the formamide also allows dehydration to the desired isonitrile 126. This dual role offers considerable advantages in terms of both atom and step economy. The observed yields and selec-tivities of the MCR sequence were more than satisfactory and therefore allowed industrial application. 

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