Multicomponent three-component

Rigorous tray-by-tray computations for multicomponent mixtures of more than three components can be very tedious, even when made omitting a heat balance. Computers are quite adaptable to this detail and several computation methods are in use. 

Various multicomponent systems have also been described. Three component systems in which a second reducing agent (eg. sulfite) acts to recycle the transition metal salt, have the advantage that less metal is used (Scheme 3.43). 

The use of microwave-assisted multicomponent cycloaddition reactions allows unique heterocyclic scaffolds to be assembled rapidly from readily accessible starting materials. The three-component reaction of M-alkyl-l,4-DHP... 

In emulsion and foam technology much is known concerning the properties and behavior of systems which involve only two or three components. Given a particular system and data concerning concentration, temperature, and manner of mixing, we can today predict fairly well the properties of the comparatively simple emulsion or foam. However, most emulsions and foams of importance are multicomponent systems and in these systems the predictability of the action or the properties of the emulsion or foam on a theoretical basis often becomes small. 

In a further example of a multicomponent synthesis, dihydrobenz[/] 1,4 oxazepin-5-ones were prepared in good yields in two steps by combining an initial three-component Ugi condensation with a subsequent Mitsunobu cyclisation to give (124 e.g. R1 = H, R2 = i-Pr, R3 = cyclohexyl, 65%) <06OBC4236>. 

A further neat example of multicomponent reactions in heterocyclic synthesis was reported by Ma et al. <06AG(E)7793>. They prepared the furan-fused 1,4-thiazepine 140 in good yield using the three components 137, 138, and 139 in the one reaction. A range of other furan-fused analogues with different substituent groups in the thiazepine ring were also synthesised. 

Another frequently used multicomponent reaction is the Kindler thioamide synthesis (the condensation of an aldehyde, an amine, and sulfur). The Kappe group has described a microwave-assisted protocol utilizing a diverse selection of 13 aldehyde and 12 amine precursors in the construction of a representative 34-member library of substituted thioamides (Scheme 6.114) [226]. The three-component con-... 

A different multicomponent route to imidazoles has been described by the group of O Shea, involving the diversity-tolerant three-component condensation of an aldehyde, a 2-oxo-thioacetamide, and an alkyl bromide (5 equivalents) in the presence of ammonium acetate (Scheme 6.201) [364]. This allowed the preparation of a 24-membered 4(5)-alkylthio-lH-imidazole demonstration library from 21 different aldehydes, 12 alkyl bromides, and two 2-oxo-thioacetamides. The library was synthesized in a parallel format using a custom-built reaction vessel. Alkylthioimidazoles... 

The palladium-catalyzed multicomponent coupling reactions have attracted considerable interest.12,12a 12e A reaction using allylstannane 39 and allyl chloride 40 was applied to the three-component diallylation of benzylidenema-lonitrile and its congeners by Yamamoto et al 2 Analogous diallylation of isocyanate 41 was studied by Szabo et al. (Scheme 7).12a The reaction mechanism can be explained by formation of an amphoteric bis-allylpalladium intermediate 43 which undergoes an initial electrophilic attack on one of the allyl moieties followed by a nucleophilic attack on the other. 

Multicomponent reaction systems are highly valued in solid-phase organic synthesis because several elements of diversity can be introduced in a single transformation.1 The Mannich reaction is a classic example of a three-component system in which an active hydrogen component, such as a terminal alkyne, undergoes condensation with the putative imine species formed from the condensation of an amine with an aldehyde.2 The resultant Mannich adducts contain at least three potential sites for diversification specifically, each individual component—the amine, aldehyde, and alkyne—can be varied in structure and thus provide an element of diversity. 

Covalently bonded substructures having compositions distinguishable from their surroundings are formed in multicomponent systems they are called chemical clusters. The adjective chemical defines covalency of bonds between units in the cluster. To be a part of a cluster, the units must have a common property. For example, hard clusters are composed of units yielding Tg domains. Hard chemical clusters are formed in three-component polyurethane systems composed of a macromolecular diol (soft component), a low-molecular-weight triol (hard component) and diisocyanate (hard component). Hard clusters consist of two hard... 

Zdanovskii, A. B. Solov eva, E. F. Lyakhovskaya, E. I. "Three Component Systems. Books 1 and 2" in "Handbook of Experimental Data on Solubility of Multicomponent Water-Salt Systems" Vol. 1, Khimiya, Leningrad Otd., Leningrad, USSR, 1973. 

A general approach to the analysis of multicomponent analytes bearing chromophores was demonstrated with a mixture of nitrophenylhydrazines (250). In a FLA system the mixture was preconcentrated by SPE on Q x bonded silica, followed by desorption with a buffer and detection by UW on a diode array. The spectrum, resolved for three components, had RSD 1.43% for 11 samples containing 2 x 10 5 M of 250c. The method allowed up to 40 samplings per hour527. 

In extending this concept to transformations that formally deliver Diels-Alder products, a one-pot three-component Mannich/Michael reaction pathway was developed in which simple cyclic enones, formaldehyde, and aryl amines were treated with catalytic amounts of proline (2) to provide regio-, diastereo-, and enantioselective bicyclic compounds in high yields (Scheme ll.lOb). Multicomponent domino... 

The basic problem in determining phase equilibria in multicomponent systems is the existence of a large number of variables, necessitating extensive experimental work. If ten measurements are considered satisfactory for acceptable characterization of the solubility in a two-component system in a particular temperature range, then the attainment of the same reliability with a three-component system requires as many as one hundred measurements. Therefore, a reliable correlation method permitting a decrease in the number of measurements would be extremely useful. Two different methods - the first of them based on geometrical considerations, and the second on thermodynamic condition of phase equilibria - are presented and their use is demonstrated on worked examples. 

The adjustable interaction constants Q can be evaluated from the experimental data for three-component systems these constants can then be employed for concentration of temperature interpolations and also for calculation of phase equilibria in multicomponent systems. Moreover, the constants Q usually depend very little on temperature, as the relative molalities, related to the solubility of the substance in the pure solvent, are employed hence calculations of other isotherms can be carried out easily. 

It should be noted that carbonyl compounds, more often aldehydes, are usual second reagent in both the groups. Other building-blocks in these multicomponent processes, leading to the formation of five-, six-, and seven-membered heterocycles, can be numerous acids and their derivatives, p-dicarbonyl compounds or other CH-acids, isocyanides, etc. At this, three-component reactions of ABC and ABB types [32] are the most typical for aminoazole, although some four-component ABCC processes were also published. 

In several subsequent publications, this promising multicomponent synthetic approach was used for the synthesis of certain types of biologically active heterocyclic compounds. For instance. Boros and co-authors [35] reported application of the three-component heterocyclization between bicyclic aminoazole 2, acetoacetic acid derivatives 3, and aldehyde 4 to obtain compound 5 being aza-analog of known [36] agonist of the calcetonine receptor (Scheme 4). 

As CH-acids in the MCRs with aldehydes and aminoazoles, other classes of organic compounds were used as well. Cyanoacetic acid derivatives, acetoyl(aroyl) acetonitriles, ketosulfones, acetophenones, and other reagents were successfully introduced into these three-component heterocyclizations. For example, synthesis of pyrazolo[3,4-b]pyridine-5-carbonitriles 40 was carried out as the multicomponent treatment of 5-aminopyrazole, aldehyde, and benzoylacetonitriles solvent-free by fusion either in ammonium acetate at 120°C or in boiling ethanol with EtsN (Scheme 17) [69]. The second approach gave the worst results from the viewpoint of yields and purity of the target compounds. 

Quiroga and co-authors [101] also reported eco-friendly solvent-free approach to the synthesis of fused benzo[fjpyrazolo[3,4-b]quinolines 72 by three-component reaction of 5-aminopyrazoles, aldehydes, and p-tetralone accomplished by fusion procedure (Scheme 32). However, this method was found inapplicable for the similar reaction of a-tetralone - multicomponent procedure allowed obtaining only bispyrazolopyridines 74 instead of benzo[h]pyrazolo[3,4-b]quinolines 73. According to these experimental results, the latter were generated via preliminary synthesis of arylidentetralones 75. 

The manufacturer of the commercially available Syrris Africa system [14] reports on the optimization of several multicomponent reactions Passerini, Biginelli and Ugi reaction. However, only the details of the three-component Passerini reaction were available [15]. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

Utilization of Multicomponent Propellants. One approach to the utilization of a metallized system such as that involving hydrazine, aluminum, and oxygen is to inject the three components separately into the combustion chamber (tripropellant system). This avoids the problems associated with the suspension of the metal in the fuel or oxidizer (and is therefore not a heterogeneous propellant), but it imposes other prob-... 

For a two-component mixture the multicomponent diffusion coefficients D, become the ordinary binary diffusion coefficients Sh,. For these quantities 2D,-, = 2D,- and 2D = 0. For a three-component system the multicomponent diffusion coefficients are not equal to the ordinary binary diffusion coefficients. For example, it has been shown by Curtiss and Hirschfelder (C12) in their development of the kinetic theory of multicomponent gas mixtures that... 

The multicomponent FID observed in the amine-hardened diglycidyl ether of di-phenylpropane is believed to be a consequence of nonuniformity in the kinetic behaviour of the various network fragments in the case of three components, protons are ascribed to the following groups ends (molecules attached with with one end to a nodal fragment), spacers (chains between crosslinks) and nodal fragments, respectively 104). 

Groebke, K., Weber, L. and Mehlin, E, Synthesis ofimidazo[l,2-a] annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation, Synlett, 1998, 661 Blackburn, C., Guan, B., Shiosaki, K. and Tsai, S., Parallel synthesis of 3-aminoimidazo[l,2-a] pyridines and pyrazines by a new three-component condensation, Tetrahedron, 1998, 3635-3638 Bienayme, H. and Bouzid, K., A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles, Angew. Chem., Int. Ed. Engl, 1998, 37, 2234-2237. 

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