Multicomponent reactions agents

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

Multicomponent reactions (MCRs) have high efficiency in the construction of complex molecules [39,40]. In general practice, more than one reagent is used in excess to push the reaction to go to completion. The unreacted components left in the reaction mixture may complicate the product purification. The employment of a fluorous component as the limiting agent for the MCRs is a good way to simplify the purification. 

In recent years multicomponent reactions have been extensively utilized to produce libraries of heterocyclic molecules with biological activity against a variety of targets. The majority of these compounds were tested for their anticancer, antioxidant and antimicrobial properties and numerous promising compounds were identified and were further evaluated. With the continuous development of new multicomponent reactions and combinations of MCRs with subsequent transformations, this area of research holds great promise for the discovery of novel therapeutic agents. 

Depending on the length of the tether of the sulfone used, mono and di car-bonylation products could be obtained through a multicomponent reaction. Benzenethiosulfonate thus constitutes a very efficient radical-trapping agent for acyl radicals. 

Synthesis and biological evaluation as microtubule-active agents of several tetrahydrofiiran and spiroacetal derivatives 13CMD1173. Tandem multicomponent reactions toward the des p and synthesis of novel polysubstituted imidazopyridines and imidazopyrazines as antibacterial and cytotoxic motifs 13CMD1445. 

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. 

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. 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

Different types of activating agents have been employed in Reissert-related reactions (Scheme 6). In many cases, it is mandatory to generate, or even isolate, the corresponding azinium salt intermediate, and sequentially proceed with the nucleophilic addition. Moreover, since the former step often takes place selectively and at a fast rate, the transformation can be performed in a multicomponent manner without any functional group interference. 

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