Multicomponent approaches

Another recent development in the field of palladium-catalyzed reactions with alkynes is a novel multicomponent approach devised by the Lee group. Starting from a-bromovinyl arenes and propargyl bromides, the assembly ofeight-membered car-bocycles can be realized via a cross-coupling/[4+4] cycloaddition reaction. The authors also presented the combination of a cross-coupling and homo [4+2], hetero [4+2], hetero [4+4] or [4+4+1] annulation leading to various cyclic products [147]. 

A comparison of Tables 1 and 5 reveals the novelty of our multicomponent approach to capsule formation and permeability control. Of the existing chemistries in Table 5 only capsules 3,4, and 5 conform to our recipe (technol-... 

The third multicomponent approach to tetrahydrotetrazolo[l,5-zz]pyrazines elaborated by a German team is also reminiscent of the previously discussed two procedures <2004TL3725>. The specific feature of this method is the use of 2-tosyl-oxyethylisocyanide instead the isocyano derivatives described above. This transformation was also carried out in methanolic solution, and simple stirring at room temperature for 24 h led to the tetrahydro products 122 in medium to good yields (42-75%). 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

Fig. 27 Application of 3-isocyano dihydropyridones (85) in the multicomponent approaches toward conformationally constrained depsipeptides (86), dihydrooxazolopyridmes (87), and conformationally constrained peptidomimetics (88)...

The combination of the benefits from the two approaches clearly presents an attractive reaction design, and this chapter presents an overview of the reported examples in which the microreactor technology and the multicomponent approach are combined, usually with dramatically improved results compared to those previously reported. 

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

Pyridine and its partially or totally unsaturated derivatives such as tetrahydropy-ridines, DHPs, and piperidines are ubiquitous cores found in numerous natural product skeletons and in synthetic compounds of primary interest for synthetic chemistry, agrochemistry, or pharmacology. Among the various methodologies available for the synthesis of these compounds, multicomponent approaches have attracted much attention in the last few years. Most of these sequences are initiated by a Michael addition. 

Coquerel Y, Eilippini MH, Bensa D, Rodriguez J (2008) The MARDi cascade a Michael-initiated domino-multicomponent approach for the stereoselective synthesis of seven-membered rings. Chem Eur J 14 3078-3092... 

A multicomponent approach for synthesizing ionic fullerene compounds Di Dn (fuUerene) is very effective in developing various functional and structural fullerene CT solids, including a- and re-type dimers of fullerenes and an ry-type... 

However, the key disadvantage of the reaction described in [199] is observed in the first step—synthesis of unsaturated ketoacids 236 with very low yields (20-30%) [200]. The same authors [201] proposed a multicomponent approach to azolopyr-imidinecarboxylic acids. The reactions of pyruvic acid 239 and aromatic aldehydes 240 with 2-aminobenzimidazole, 5-aminotetrazole 156 and 3-amino-1,2,4-triazole 147 in alcohols, DMF and acetic acid were studied (Scheme 3.67). 

MUller reports a four component, one-pot synthesis of pyridines <02TL6907>. For example, aryl halide 15 and propargylic alcohol 16 were combined in the presence of copper and palladium to afford enone 17. The addition of cyclic enamine 18 led to Michael addition and the subsequent cyclocondensation was achieved by adding ammonium chloride and acetic acid (19—>20). Other multicomponent approaches to substituted pyridines have been reports by Litvinov <02RCBIE362>, Elkholy <02SC3493> and Veronese <02T9709>. 

Alkynones are potent Michael acceptors in heterocyclic chemistry and many five-, six-, and seven-membered heterocycles can be synthesized from reactive, bifunctional three-carbon building blocks such as alkynones by classical heterocyclic chemistry [32]. Taking into account the mild, catalytic access to alkynones the coupling-addition-cyclocondensation sequence for multicomponent approaches to five-, six-, and seven-ring heterocycles lies at hand (Scheme 19). 

Braun RU, Muller TJJ (2004) Coupling-isomerization-stetter and coupling-isomerization-stetter-paal-knorr sequences - a multicomponent approach to furans and pyrroles. Synthesis 2391-2406... 

Dediu OG, Yehia NAM, Oeser T, Polbom K, Muller TJJ (2005) Coupling-isomerization-enamine-addition-cyclocondensation sequences - a multicomponent approach to substituted and annealed pyridines. Eur J Org Chem 1834-1858... 

The librariesPPl of U-4CR products already mentioned in 1961,were not prepared until 1995. Since then, this approach has found widespread application in industrial chemical research. It is expected that this one-pot, multicomponent approach will play an essential role in synthetic organic strategies in the future.P 1... 

There are several excellent reviews of multicomponent solubility parameters, including those by Hansen (1967), Karger et al. (1973), Barton (1975), and Snyder (1978). Barton s review provides all the information necessary to familiarize the reader with the subject, and it contains a comprehensive reference list to the original work that developed the theory and techniques on which the multicomponent approach is founded. 

Abstract. Temporary engineering materials became gradually more and more complex in their composition and structure. The multiple functions required today in our machine parts and other applications demand this complex structure, consisting of different components, all contributing with their best features. This multicomponent approach is dominant in the polymer engineering field in systems such as... 

It was our aim to extract from the literature and from our own work the prototypical reactive building blocks that are especially well suited for such a multigeneration/multicomponent approach. We have classified the reactophores into three categories ... 

The general mathematical multicomponent approach, based on matrix notation, can be advantageous from the practical point of view for the modeling of this kind of systems [138, 139]. Consider the application of the terminal model to a general multicomponent copolymerization of c comonomers. A general propagation step can be written as follows ... 

Stryker recently reported a metal-catalyzed [3+2+2] cycloaddition leading to a seven-membered ring (Eq. 51)7 This is a fundamentally new development in this area and suggests that multicomponent approaches to seven-membered rings akin to those developed for five-and six-membered rings (e.g., Pauson-Khand, [2+2+2]) are on the horizon. 

Scheme 5 An iron-catalyzed multicomponent approach to pyridines.

Multicomponent approaches toward the formation of more complex phthalazine-containing compounds were reported in 2014. A four-component one-pot condensation reaction was employed by Dabiri and coworkers to generate (1,2,3-triazol-4-yl)methyl-3-amino-5,10-dihydro-5,10-dioxo-lH-pyrazolo[l,2-f)]phthalazine-2-carboxylates 26 (Scheme 18) (14SC2037). Catalyzed by Cu(OAc)2 (10mol%) and sodium ascorbate (20mol%), the reaction of benzaldehyde derivatives (1 equivalent), azides (1 equivalent), prop-2-ynyl-2-cyanoacetate (27) (1 equivalent), and phthalhydrazide (28) (1... 

Scheme 2.7 Multicomponent approaches to lactones from alkynes and CO [16, 17].

Scheme 2.41 Multicomponent approach to lactones from alkynes and formaldehyde [87].

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