Multi-component Condensation Reactions

Merocyanine dyes 50-55 (Fig. 5.18) possess an electronic structure at the meso-meric center between neutral and zwitterionic electron distribution and have high polarizabilities and dipole moments and exhibit absorption spectra with sharp bands that give rise to exceptionally brilliant magenta hues [60], 

From the set of products, two members, 62a and 62b (Fig. 5.20), with the most intense fluorescence were selected for photophysical evaluation. Inspection of the maximum emission wavelengths and fluorescence quantum yields in solvents with different polarities (CH2C12, MeOH and THF) reveals a significant solvochro-micity of the emission maxima that influence the corresponding fluorescent quantum yields to only a minimal extent. 

Additionally, this methodology was transposed to liquid-phase synthesis of 2,6-dicyanoanilines using polyethylene glycol) (PEG) as support, starting with a 

Physical and chemical stimuli such as temperature, solvent polarity and addition of various cations induce conformational changes in the nonconjugated polysquaraines, leading to either preferential folding to, or unfolding from, chromo-phore H-dimers. The binding event is translated into a shift in the monomer to H-dimer equilibrium of the squaraine chromophores and can be conveniently visualized by UV-Vis and fluorescence spectroscopy and, therefore, can successfully be exploited for cation sensing. 

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Multi-component condensation reactions offer tremendous scope for increasing diversity in combinatorial chemistry programs since, in a single reaction, structurally advanced compounds can be realized from very simple starting materials. In... 

Scheme 2.50 A novel multi-component condensation reaction catalyzed by scandium triflate.

Heterocyclic chemistry has been a major beneficiary of MW-expedited solvent-lfee chemistry utilizing mineral supported reagents. It has been exploited for parallel synthesis, a strategy that is adaptable for multicomponent reactions, such as Ugi " and Biginelli reactions " , for rapid assembly of a library of compoimds. A representative multi-component condensation reaction to create a small-molecule library of imidazo[l,2-a]pyridines, imidazo[l,2-a] pyrazines, and imidazo[l,2-a]pyrimidines is depicted in Scheme 3. 

Broad biological potential of enantiopure 1,2-dihydroquinolines prompted the recently reported organocatalytic, asymmetric Petasis reaction, catalyzed by chiral biphenols [31]. Since it was observed that chiral biphenol derivatives XXVI-XX-VIII serve as proficient catalysts for asymmetric reactions involving boronates [32, 33], the authors postulated that they could be used as ligands in multi-component condensation reactions, and the Petasis reaction in particular. 

Several multi-component domino reactions for the preparation of libraries have been developed in the last years.141 One of the first examples in solution is a four-component reaction described by Ugi et al. in which a carbocyclic acid 5, an aldehyde 6 and an isocyanide 7 are condensed in presence of methanol to give amino acids 8 (scheme 2).151... 

The Gewald Reaction is a synthesis of 2-aminothiophenes via a multi-component condensation between sulfur, an a-methylene carbonyl compound and an a-cyanoester. 

This multi-component condensation of a nonenolizable aldehyde, a primary or secondary amine and an enolizable carbonyl compound affords aminomethylated products. The iminium derivative of the aldehyde is the acceptor in the reaction. 

Multi-component condensation of ketones (or aldehydes), a-aclivc methylene nitriles and elementary sulfur (the Gewald reaction) is an efficient methodol-... 

More significant results are the multi-component condensation by way of Michael-aldol and Michael-Michael-aldol reaction sequences and the Michael-Baylis-Hillman tandem, each leading to cyclohexenes bearing multiple functional groups and stereogenic centers. 

Based on a multi-component condensation approach related to the Doebner reaction,Gopalsamy et developed a solid-phase synthesis for this clinically useful pharmacophore. Thus, starting from Rink resin 65, acylation with the required N-Fmoc-amino acid 232 and deprotection with piperidine gave the polymer-supported amine 233 (90% yield) which was acylated with pyruvyl chloride (234). Immobilised pymvic amide 235 was refluxed with excess of preformed benzyUdene aniline 239 or alternatively condensed with an excess of an equimolecular mixture of aldehyde 236 and anilines 237. Cleavage of 238 with 45% TFA afforded compounds 240 in good yields and with high purities (>90%) (Scheme 4.3.5). 

Heavily substituted fused-ring derivatives of 1,3-diazocine (37 R = Pr, Bu, -pentyl, allyl) are reportedly formed in low (10-19%) yield, together with several other products, upon the multi-component condensation of xanthines with dimethyl acetylenedicarboxylate in DMF the same reactions in methanol do not afford (37) (Equation (14)) <91CPB270>. 

A multi component condensation of substituted phenylthiourea/urea, aqueous formaldehyde and substituted aromatic/heterocyclic amines leads to 2-thioxohexa-hydro-l,3,5-triazines in aqueous medium under microwave irradiation in 30-60 sec in quantitative yield with reasonable purity. Furdier, triazolo[4,3-a]triazines were also prepared by a one pot reaction of in situ synthesized triazinyl hydrazine with... 

The Biginelli reaction involves an one-pot reaction between aldehyde 1, 1,3-dicarbonyl 2, and urea 3a or thiourea 3b in the presence of an acidic catalyst to afford 3,4-dihydropyrimidin-2(l//)-one (DHPM) 4. This reaction is also referred to as the Biginelli condensation and Biginelli dihydropyrimidine synthesis. It belongs to a class of transformations called multi-component reactions (MCRs). 

Although the condensation of phenol with formaldehyde has been known for more than 100 years, it is only recently that the reaction could be studied in detail. Recent developments in analytical instrumentation like GC, GPC, HPLC, IR spectroscopy and NMR spectroscopy have made it possible for the intermediates involved in such reactions to be characterized and determined (1.-6). In addition, high speed computers can now be used to simulate the complicated multi-component, multi-path kinetic schemes involved in phenol-formaldehyde reactions (6-27) and optimization routines can be used in conjunction with computer-based models for phenol-formaldehyde reactions to estimate, from experimental data, reaction rates for the various processes involved. The combined use of precise analytical data and of computer-based techniques to analyze such data has been very fruitful. 

Keywords 1,3-Dicarbonyls, Biginelh reaction, Hantzsch reaction, Heterocyclic chemistry, Knoevenagel condensation, Mannich reaction, Michael addition, Multi-component reactions... 

Domling, A., The discovery of new isocyanide-based multi-component reactions, Curr. Opin. Chem. Biol, 2000, 4, 318-323 Domling A., and Ugi I.K., A new 5,6-dihydro 211 1,3-oxazine synthesis via Asigner-type condensation, Tetrahedron, 1993, 49, 9495-9500. 

Multi-component reactions where three or more components build a single product have received considerable interest for several years. Since most of these reactions tolerate a wide range of building block combinations, these types of reactions are frequently applied for combinatorial purposes. A solid-phase application towards the Ugi four component condensation (Ugi-4CC) generating a 18-member acylamino amide library appeared in 199939. The acylamino amide library was synthesised using amino-functionalised PEG-polystyrene (TentaGel S RAM) as the solid support. (Scheme 7.22). 

The formation of macrocyclic ligands by template reactions frequently involves the reaction of two difunctionalised precursors, and we have tacitly assumed that they react in a 1 1 stoichiometry to form cyclic products, or other stoichiometries to yield polymeric open-chain products. This is certainly the case in the reactions that we have presented in Figs 6-8, 6-9, 6-10, 6-12 and 6-13. However, it is also possible for the difunctionalised species to react in other stoichiometries to yield discrete cyclic products, and it is not necessary to limit the cyclisation to the formal reaction of just one or two components. This is represented schematically in Fig. 6-19 and we have already observed chemical examples in Figs 6-4, 6-11 and 6-18. We have already noted the condensation of two molecules of 1,2-diaminoethane with four molecules of acetone in the presence of nickel(n) to give a tetraaza-macrocycle. Why does this particular combination of reagents work Again, why are cyclic products obtained in relatively good yield from these multi-component reactions, rather than the (perhaps) expected acyclic complexes We will try to answer these questions shortly. 

A series of tetrasubstituted thiazole derivatives 28 has been prepared via a multi-component tandem protocol <07T10054>. Reaction of bis(aroylmethyl)sulfides 23 with aryl aldehydes and ammonium acetate in 1 2 1 ratio under solvent-free microwave irradiation affords 28 in good yields. This reaction presumably starts with Knoevenagel condensation of sulfide with 2 equiv. of aryl aldehydes to give 24. Michael addition with ammonia and concomitant cyclocondensation lead to 26. Base-catalyzed ring opening of 26 to 27 and ring... 

In an exploration of multi-component reactions for the synthesis of a diverse array of heterocyclic scaffolds Martin et al. demonstrated a cascade reaction involving the imine, formed from the condensation of 2-azidobenzaldehyde 97 with propargylamine, acetyl chloride and ketene acetal 98 to furnish the triazolo-fused benzodiazepine 99 via an intramolecular [3+2] cycloaddition <07OL4223>. 

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