MCRs reactions

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

Fig. 10.2. Four different chemical scaffolds available through the Doebner MCR reaction.

However, the validity of such computer-proposed MCR reactions has always to be verified by experiment. Since such examples are scarce it cannot be judged how efficient this approach will be in suggesting useful MCRs. 

The utility of TOSMIC in MCR reactions has also received recent interest in the pharmaceutical arena as an approach to the preparation of imidazoles 91. Originally reported by van Leusen in 1977 [76], and involving cycloaddition of tosyl-methyl isocyanides to carbon-nitrogen double bonds, recent elegant work by Sisko et al. has heightened its profile with the description of a one-pot synthesis of imidazole 92, a potent inhibitor of p38 MAP kinase, implicated with the release of the pro-inflammatory cytokine TNF-a (Scheme 11.19) [77]. In this particular example a fluorinated analogue of TOSMIC 90, is employed. 

Nucleophiles with high tendency to migrate preferentially undergo the tandem MCR reaction, providing a useful route for the synthesis of substituted 1-alkynes. Examples of the MCR reaction with little or no tendency to compete with the MCI pathway are summarized in Eq. (113) Nu = thiocyanate [200,201], thiotosylate [202], thiolate [203], phosphorodithioate [204], tosylate [205], car-boxylate [206], phosphate [206], lithium diphenylamine [207], and halide [171]. It appears likely that, because of the electron-deficient nature of the carbenic... 

When migratory aptitudes of a-substituents of alkylidene carbenes are relatively poor, the MCI pathway competes with the MCR reaction. Reaction of the alkynyliodane with benzenesulfinate anion in water leads to a mixture of the MCI and the MCR products, because of a moderate migratory aptitude of aryl-sulfonylgroups [Eq. (114)] [170]. 

Privileged building blocks in chemo-differentiating ABB MCRs (reactions introducing into the final product one molecule of component A and two molecules of component B) 07CSR484. 

Contemporaneously, the use of microwave as promoter chemical reactions has become increasingly popular in organic synthesis [68]. This tool has been demonstrated to be efficient for increasing the rate of MCR reactions reducing the reaction times and improving the yields [69, 70], However, the first example of MW-assisted Passerini reaction has been only recently disclosed (Scheme 8.28) [71]. 

Shaabani and coworkers simply used 1,2-DAB or 1,2-DACH instead of heterocyclic systems containing a H2N-C = N fragment in the known Groehke-Blackbum-Bienayme MCR reaction (Groebke et al. 1998 Blackburn et al. 1998 Bienayme and Bouzid 1998) (Ugi-type MCR reaction). 

The Biginelli reaction involves an one-pot reaction between aldehyde 1, 1,3-dicarbonyl 2, and urea 3a or thiourea 3b in the presence of an acidic catalyst to afford 3,4-dihydropyrimidin-2(l//)-one (DHPM) 4. This reaction is also referred to as the Biginelli condensation and Biginelli dihydropyrimidine synthesis. It belongs to a class of transformations called multi-component reactions (MCRs). 

Scheme 9 Fluorous MCR and subsequent cross-coupling reactions...

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

The inverse electron demand Diels-Alder reaction has also been used to provide expedient access to unnatural 6-carboline alkaloids from 1,2,4-triazines, prepared by microwave-assisted MCR [92]. One-pot reaction of an acyl hydrazide-tethered indole 73, 1,2-diketone and ammonium acetate in acetic acid provided triazines 74 (see Sect. 3.2, Scheme 22), bearing an electron-rich dienophilic indole moiety (Scheme 31). By carrying out the... 

Macrocycles 260 Mannich Reaction 19 MCR, pyrimidines/pyrazoles/isoxazoles 46... 

Ugi, I. (1998) MCR. XXIII. The Highly Variable Multidisciplinary Preparative and Theoretical PossibUities of the Ugi Multicomponent Reactions in the Past, Now, and in the Future. Proceedings of the Estonian Academy of Science Chemistry, 47, 107-127. 

Type I MCRs are usually reactions of amines, carbonyl compounds, and weak acids. Since all steps of the reaction are in equilibrium, the products are generally obtained in low purity and low yields. However, if one of the substrates is a bi-funchonal compound the primarily formed products can subsequently be transformed into, for example, heterocycles in an irreversible manner (type II MCRs). Because of this final irreversible step, the equilibrium is forced towards the product side. Such MCRs often give pure products in almost quantitative yields. Similarly, in MCRs employing isocyanides there is also an irreversible step, as the carbon of the isocyanide moiety is formally oxidized to CIV. In the case of type III MCRs, only a few examples are known in preparative organic chemistry, whereas in Nature the majority of biochemical compounds are formed by such transformations [3]. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The first MCR involving isocyanides (IMCR) was reported in 1921 with the Passerini reaction (P-3CR) [8], and over the years these reactions have become increasingly important and have been highlighted in several publications (for discussions, see below). Another older MCR which leads to (non-natural) a-amino acids is the Bucherer-Bergs reaction (BB-4CR), which was first reported in 1929 [9]. This type of transformation is closely related to the Strecker reaction, with C02 employed as a fourth component. 

Modern MCRs that involve isocyanides as starting materials are by far the most versatile reactions in terms of available scaffolds and numbers of accessible compounds. The oldest among these, the three-component Passerini MCR (P-3CR), involves the reaction between an aldehyde 9-1, an acid 9-2, and an isocyanide 9-3 to yield a-acyloxycarboxamides 9-6 in one step [8], The reaction mechanism has long been a point of debate, but a present-day generally accepted rational assumption for the observed products and byproducts is presented in Scheme 9.1. The reaction starts with the formation of adduct 9-4 by interaction of the carbonyl compound 9-1 and the acid 9-2. This is immediately followed by an addition of the oxygen of the carboxylic acid moiety to the carbon of the isocyanide 9-3 and addition of this carbon to the aldehyde group, as depicted in TS 9-5 to give 9-5. The final product 9-6 is... 

The diversity of the Ugi-MCR mainly arises from the large number of available acids and amines, which can be used in this transformation. A special case is the reaction of an aldehyde 9-26 and an isocyanide 9-28 with an a-amino acid 9-25 in a nucleophilic solvent HX 9-30 (Scheme 9.5). Again, initially an iminium ion 9-27 is formed, which leads to the a-adduct 9-29. This does not undergo a rearrangement as usual, but the solvent HX 9-30 attacks the lactone moiety. Such a process can be used for the synthesis of aminodicarboxylic acid derivatives such as 9-31 [3, 30],... 

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