Multicomponent reactions illustration

As summarized recently [61], a large scope of Brpnsted and Lewis acids catalyze this multicomponent reaction to promote the DHPM formation. The heterocyclic Biginelli scaffold has also been obtained under eco-Mendly conditions, as illustrated... 

Heterocycles with a l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine core are also available through this multicomponent reaction. Compounds with a related structure are of high interest either for synthetic applications or for biological purposes. For the first time we were able to propose a one-pot access to pyrrolopiperazine and azasteroide-type scaffolds, illustrating the potential of this ecocompatible sequence to create molecular complexity and diversity from simple and readily available substrates (Scheme 60) [164]. In this case, the primary amine partner bears a pyrrole nucleophile, which neutralizes the transient iminium intermediate to form a new C-C bond via an intramolecular Pictet-Spengler-type cyclization. 

Many of the recent advances in synthetic applications of allylic boron reagents have focused on the use of these reagents as key components of tandem reactions and one-pot sequential processes, including multicomponent reactions. The following examples briefly illustrate the range of possibilities. Most cases involve masked allylboronates as substrates, and the tandem process is usually terminated by the allylboration step. 

This work is not meant to be an exhaustive review of the literature but rather illustrates innovative strategies that give priority to diversity (maximum amount of variation). The less common multicomponent reactions directed toward target synthesis will also be discussed. 

This simple sketch illustrates clearly that convergent multicomponent reactions performed with a limited set of reactive building blocks (reactophores) in a multigeneration format offer a tremendous potential to produce diverse small-molecule compound collections, depending on the reaction sequence used (the combinatorics of reactive building blocks ). The concept of combinatorics of reactive building blocks should ultimately lead to novel multicomponent reactions. In Section III we will focus on reactophores such as a-alkynyl ketones, which allow the construction of a wide variety of core structures. 

Another example of transient formation of a palladacycle is the Pd-mediated ortho-alkylation and ipso-vinylation of aryl iodides depicted in Scheme 8.23. In this multicomponent reaction the ability of norbomene to undergo reversible arylation and palladacycle formation is exploited. This reaction also illustrates that aryl halides undergo oxidative addition to Pd faster than do alkyl halides, and that aryl-alkyl bond-formation by reductive elimination also proceeds faster than alkyl-alkyl bond-formation. The large excess of alkyl iodide used in these reactions prevents the formation of biaryls. Benzocyclobutenes can also be formed in this reaction, in particular when the alkyl group on the aryl iodide is sterically demanding or when a secondary alkyl iodide is used [161]. 

The same group reported on a library synthesis of 3-aminoimidazo[l,2-a]-pyridines/pyrazines by fluorous multicomponent reactions. Here the overall yields, as well as the yields for the separate Suzuki-Miyaura reactions that were a part of the synthesis, were relatively low due to competing reactions and the poor reactivities of the substrates, but the speed of the microwave-mediated syntheses and ease of separation underlined the usefulness of fluorous reagents [140]. A recent paper further illustrated the use of Suzuki-Miyaura couplings of aryl perfluorooctylsulfonates in the decoration of products derived from 1,3-dipolar cycloadditions [141]. 

In term of diversity-oriented strategies, multicomponent reactions (MCR) represent an attractive and rapid access to libraries of macrocycles inspired by biologically active natural products. Combined with Passerini and Ugi reactions, M-RCM has already shown promising synthetic potential, as illustrated by the pioneering work of Domling and coworkers [46]. Condensation of isocyanide 69 with carboxylic acid 70 in the presence of paraformaldehyde leads to bis-olefin 71, which is subsequently submitted to RCM in the presence of G1 and titanium isopropoxide to give the 22-membered macrocycle 72 (Scheme 2.27). 

The above example illustrates how an approximate hand calculation can be carried out to obtain the effectiveness factor for a single reaction in a multicomponent reaction mixture. It has of course been necessary to make a number of assumptions. One... 

Fig. 3 Schematic illustration of a multicomponent reaction toward a complex product...

Chapter 12 illustrates the apphcability of ionic hquids in multicomponent reactions and confirms the usefulness of ionic liquids as substituents of traditional organic solvents in certain synthetic transformations. 

Employing a stacked-plate micro reactor (channel dimensions = 100 pm, volume = 2 ml), Acke and Stevens [21] investigated the continuous flow synthesis of a series of pharmaceutically relevant chromen-l-ones via the multicomponent route illustrated in Scheme 6.4. To ensure that HCN was formed within the confines of the micro reaction channel, solutions of acetic acid (12) (2 equiv.)-2-formylbenzoic acid (13) (1 equiv.) and aniline (8) (2 equiv.(-potassium cyanide (14) (1.2 equiv.) were introduced into the reactor from separate inlets. A maximum concentration of0.15 M was selected for 13 as this prevented precipitation of the reaction products and intermediates within the micro reactor. Employing a reactant residence time of 40 min, the authors obtained 3-diamino-lff-isochromen-l-one (15) in 66% yield ... 

The reactions that have been illustrated should give an idea of the potential of a methodology which combines the criterion of multicomponent reactions with that of selectivity, usually difficult to reconcile. One key feature is the use of an olefin as a scaffold for the construction of a palladacycle that is able to direct aromatic functionalization selectively and can be easily removed at the end of the process. Another important feature is the use of different oxidation states of palladium to control reactivity. The combination of an inorganic catalyst (palladium) with an organic one (norbornene) leads to a variety of syntheses in one-pot reactions, which represent only the beginning of what may be expected to be a very fruitful development. Needless to say, any advancement in this area requires a thorough study of the reactivity of the organometallic species involved. 

Multicomponent reactions are an increasingly important class of reactions because they combine simplicity, atom economy and efficiency in terms of both yields and the introduction of molecular diversity [52]. These reactions have been described on both solid and soluble supports, as well as giving an easy entry into libraries of compounds. BTSILs are appropriate soluble supports for such reactions. This is illustrated by the tetrahydroquinoline synthesis developed in solution and on solid supports [52]. The reaction of an aniline supported on an ammonium salt in solution of [BuMe3N][NTf2] with benzaldehydes and electron-rich olefins such as styrene, cyclopentadiene and indene in the presence of a trace of TEA, led quantitatively and rapidly (20 to 60 min) to the corresponding tetrahydroquinolines at room temperature according to (Scheme 5.5-36) [21,51]. 

The use of multicomponent reactions (MCRs) constitutes an attractive synthetic strategy for rapid and efficient library generation because diverse products are formed in a single step. Usually, MCR transformations do not involve the simultaneous reaction of all components. Instead, they are undertaken in a sequence of steps that are determined by the synthetic design. A drawback of many MCR processes is that they can be slow and inefficient, but microwave heating can be used as a tool to overcome these problems, as illustrated here with selected examples. 

As illustrated in Scheme 6.13, a range of other R-X substrates can be coupled with heterocycle formation, as can carbon monoxide insertion to form keto-substituted products (Scheme 6.13b) [22]. These are typically postulated to proceed in an analogous fashion to the reactions above. In addition to these, several mechanistic variants have also been developed. For example, Zhang has reported that allyl-substituted furans can be synthesized in a multicomponent reaction of ketone 11, allylic halides and various nucleophiles (Scheme 6.16) [23]. This reaction utilizes the... 

Synthetic highlights The synthesis of 1,2-DQs exemplifies asymmetric organo-catalysis in which enantioselective synthetic reactions are catalyzed by small organic molecules. To generate 1,2-DQs, achiral thiourea and axially chiral biphenols are used as catalysts for the enantioselective Petasis reaction. This is an illustration of a multicomponent reaction (MCR), for which the general concept and examples are also described. 

Multicomponent reactions represent a flexible tool for the synthesis of a large number of target molecules from three or more starting molecules. They are one-step, one-pot reactions, economic regarding resotrrces and today considered to be close to what is defined as ideal synthesis [1]. Their general synthetic value was recognized when I. Ugi and collaborators reported on some important variants of four-component reactions [2] and their application in the production of known drugs an illustrative example is presented in the next section. 

As illustrated in Scheme 1.40, in addition to the amphiphilic reactants bearing nucleophilic and electrophilic sites, compatible separated nucleophiles and electrophiles can also be employed in iminium-activated cascades in multicomponent reactions. 

Though illustrated here by the Scott and Dullien flux relations, this is an example of a general principle which is often overlooked namely, an isobaric set of flux relations cannot, in general, be used to represent diffusion in the presence of chemical reactions. The reason for this is the existence of a relation between the species fluxes in isobaric systems (the Graham relation in the case of a binary mixture, or its extension (6.2) for multicomponent mixtures) which is inconsistent with the demands of stoichiometry. If the fluxes are to meet the constraints of stoichiometry, the pressure gradient must be left free to adjust itself accordingly. We shall return to this point in more detail in Chapter 11. 

The material in this section is divided into three parts. The first subsection deals with the general characteristics of chemical substances. The second subsection is concerned with the chemistry of petroleum it contains a brief review of the nature, composition, and chemical constituents of crude oil and natural gases. The final subsection touches upon selected topics in physical chemistry, including ideal gas behavior, the phase rule and its applications, physical properties of pure substances, ideal solution behavior in binary and multicomponent systems, standard heats of reaction, and combustion of fuels. Examples are provided to illustrate fundamental ideas and principles. Nevertheless, the reader is urged to refer to the recommended bibliography [47-52] or other standard textbooks to obtain a clearer understanding of the subject material. Topics not covered here owing to limitations of space may be readily found in appropriate technical literature. 

The same system was used by Frechet s group of to achieve a multicomponent one-pot cascade reaction with mutually interfering acid and proline-derived pyrrolidine catalysts [31]. The concept is illustrated in Figure 5.1. The protonation of imidazo-lidone (3) by the immobilized PSTA (5) gives the desired iminium catalyst (6), while... 

This sequence has been successfully extended to the regioselective multicomponent construction of bis- pyrano-l,4-benzoquinone derivatives when unsubstituted 2,5-dihydroxy-l,4-benzoquinone is used (Scheme 39) [130], Depending on the alkene moiety, the reaction yielded only the linear tri-, penta-, or heptacyclic product in a 1 1 diasteromeric ratio, as illustrated with indene. 

The interpretation of the C.E. by a superimposition of reactions occurring at different active surface centers is compatible with the fact that many multicomponent catalysts exhibit a C.E. but no C.E. is found when very pure substances have been subjected to different thermal pretreatments (17). This implies the possibility that many active centers are due to impurities and that their numbers may change with the pretreatment of the catalyst, e.g., by means of aggregation, volatilization, etc. As an illustration, data for the decomposition of N2O on MgO, prepared from synthetic and from natural magnesites, and data for the para-ortho hydrogen conversion on pure metals and on alloys are presented in Tables II and III. 

In particular, it is useful to define the critical point through F(nc) = 0 (the stationary state). Since multicomponent chemical systems often reveal quite complicated types of motion, we restrict ourselves in this preliminary treatment to the stable stationary states, which are approached by the system without oscillations in time. To illustrate this point, we mention the simplest reversible and irreversible bimolecular reactions like A+A —> B, A+B -y B, A + B —> C. The difference of densities rj t) = n(t) — nc can be used as the redefined order parameter 77 (Fig. 1.6). For the bimolecular processes the... 

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