Multicomponent condensations

In this section we review the experimental studies that have been carried out with a view to testing models of multicomponent condensation. There is a great shortage of experimental data on mass transfer in multicomponent vapor (plus inert gas)-liquid systems. Most published works deal with absorption (or condensation or evaporation) of a single species in the presence of a nontransferring component. Thus, this review is necessarily brief. 

Numerical simulations of Sardesai s experiments are discussed by Webb and Sardesai (1981) and Webb (1982) (who used the Krishna-Standart (1976), Toor-Stewart-Prober (1964) and effective diffusivity methods to calculate the condensation rates), McNaught (1983a, b) (who used the equilibrium model of Silver, 1947), and Furno et al. (1986) (who used the turbulent diffusion models of Chapter 10 in addition to methods based on film theory). It is the results of the last named that are presented here. 

Webb and Sardesai (1981) used a fourth-order Runge-Kutta method to integrate the differential equations modeling the condenser. Furno (1986) divided the condenser tube into 40 sections. Both investigators used the same method to calculate physical properties. The Fanning friction was calculated from a correlation obtained by Webb and Sardesai 

We see from these figures that the mass transfer models that take diffusional interactions into account are quite a lot better than the effective diffusivity model, which underpredicts the rate of condensation of 2-propanol in every case. However, the effective diffusivity methods give good predictions of the overall temperature drops (Fig. 15.19) although there is little to distinguish any of the models here on this basis. 

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For multicomponent condensation, the condensation will not be isothermal, leading to a nonlinear temperature-enthalpy profile for the condensation. If this is the case, then the exchanger can be divided into a number of zones with the temperature-enthalpy profiles linearized in each zone. Each zone is then modeled separately and zones summed to obtain the overall area requirement1. 

Recently, a new multicomponent condensation strategy for the stereocontrolled synthesis of polysubstituted tetrahydropyran derivatives was re-published by the Marko group, employing an ene reaction combined with an intramolecular Sakurai cyclization (IMSC) (Scheme 1.14) [14]. The initial step is an Et2AlCl-promoted ene reaction between allylsilane 1-50 and an aldehyde to afford the (Z)-homoallylic alcohol 1-51, with good control of the geometry of the double bond. Subsequent Lewis acid-media ted condensation of 1-51 with another equivalent of an aldehyde provided the polysubstituted exo-methylene tetrahydropyran 1-53 stereoselectively and... 

R = CN, C02Et, CONH2 Scheme 6.245 Multicomponent condensation in the synthesis of tetrahydrobenzo[b]pyrans. 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

In a related example involving the use of the same instrument (Fig. 12.6) in the Hantzsch multicomponent condensation, the serial synthesis of 24 dihydropyridine... 

A. Studer, P. Jeger, P. Wipf, D. P. Curran, Fluorous Synthesis Fluorous Protocols for the Ugi and Biginelli Multicomponent Condensations ,/. Org. Chem. 1997,62,2917. 

Multicomponent condensations have also been described in these an isonitrile, a carbonyl compound and a suitable transition metal complex are combined in one step to afford heterocycloalkylidene complexes. Examples of the use of isolated or intermediate isonitrile complexes for the preparation of aminocarbene complexes are given in Table 2.4. 

For example, the formation of mixtures of 4,5- and 4,7-dihydroisomers 45 and 46 was observed by Werman and Hartman [79] in the reaction of 3-amino-l,2,4-triazole with two equivalents of methylarylketone in the presence of ZnCl2 as a catalyst (Scheme 20). The ratios between two position isomers were from 50 50 to 74 26. However, Desenko et al. [80] established that treatment of the same starting compounds under acidic catalysis (acetic or mineral acids) yielded only 4,5-dihy-droderivatives 46 and heterocycles 47 [81]. In the latter case, the third component of the multicomponent condensation was the solvent - DMF. It is worth noting that heterocychc compounds 46 were also the products of the reaction between 3-amino-1,2,4-triazole with a,p-unsaturated ketones 48 (Scheme 20). 

Muravyova EA, Shishkina SV, Musatov VI, Knyazeva IV, Shishkin OV, Desenko SM, Chebanov VA (2009) Chemoselectivity of multicomponent condensations of barbituric acids, 5-aminopyrazoles, and aldehydes. Synthesis 1375-1385... 

Chebanov VA, Saraev VE, Desenko SM, Chernenko VN, Knyazeva IV, Groth U, Glasnov TN, Kappe CO (2008) Tuning of chemo- and regioselectivities in multicomponent condensations of 5-aminopyrazoles, dimedone, and aldehydes. J Org Chem 73 5110-5118... 

A further method for preparing hydantoins is the N-alkylation of other hydantoins with reactive alkyl halides in the presence of strong bases [154]. Hydantoinimines have been synthesized from polystyrene-bound isonitriles by an Ugi-type multicomponent condensation (Entry 15, Table 15.13). 

Stadler, A. and Kappe, C.O., Automated library generation using sequential microwave-assisted chemistry. Application toward the Biginelli multicomponent condensation, /. Comb. Chem., 2001, 3,624-630. 

All the approaches discussed in Sections 13.16.9 and 13.16.10 were widely applied to the synthesis of 1,3,5-triazepine heterocyclic ring. For the monocyclic and fused compounds, the [1+6] and [3+4] cyclization reaction and the azine ring expansion are the most popular routes (for additional information on the early reports, see CHEC-II(1996)). The bridged derivatives, such as hexaazaisowurtzitanes 5 (Figure 1), are available by multicomponent condensation. 

Several groups have pioneered the use of such multicomponent condensation reaction (MCR) technologies, including those led by Ugi, Bienayme, Domling, and Weber, spawning new chemically driven companies that have rapidly built up their own internal corporate collections. One particular branch of MCR methodologies, namely postcondensation modifications (or secondary reactions) of IMCRs (isocyanide - based multicomponent reactions), forms the basis of this chapter. 

The three-component reaction of pyruvic acid, aldehydes and anilines can also yield pyrrolidine-2,3-dione [198], but in most cases the products of such multicomponent condensations are quinoline carboxylic acids identical to compounds obtained via the reaction of arylidenepyruvic acids [217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228]. 

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-... 

For instance, condensation of ethyl acetoacetate, formaldehyde, and ammonia gives dihydropyridine 5.12 which is readily oxidised with nitric acid to give pyridine 5.13. Although the precise details of this multicomponent condensation are not known, a reasonable pathway is shown below. 

This simple and versatile combinatorial one-pot method will surely provide, in future, many diverse libraries, and its use in combination with solution purification techniques (see the next sections) will help in automating the experimental procedures. A thorough search for new multicomponent condensations should even increase their applications in combinatorial library synthesis. 

Studer A, Jeger P, Wipf P, Curran DP, Fluorous synthesis Fluorous protocols for the Ugi and Biginelli multicomponent condensations, J. Org. Chem., 62 2917-2924, 1997. 

The Gewald reaction can be conveniently performed via a multicomponent condensation between sulfur, an -methylene carbonyl compound, and an -cyanoester. The use of ionic liquids as solvents <2004SC3801>, or performing this condensation under microwave irradiation without solvent (Scheme 84) <2005SC1351>, leads to generally better yields of 2-aminothiophenes . 

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