Three component condensation, synthesis

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

The condensation of activated thiols onto adjacent nitriles is a common method for the preparation of amine-substituted thiophenes. A three component condensation was utilized to prepare a-aminothiophene 11 <00TL1597>. An alternate method for preparing amino-substituted thiophenes involved the treatment of ketene S,JV-acetal 12 with an activated carbonyl compound 13 which gave thiophene 14 <00JOC3690>. This type of reaction has also been utilized to prepare building blocks for the synthesis of fused thiophenes <00JHC363>. 

MCRs of aminoazoles and aldehydes with acetoacetamides are also known. For example, combinatorial-oriented synthesis of potentially pharmacologically active dihydrotriazolopyrimidines 13 was described in [38].The authors considered that carrying out S-alkylation at the last step of pathway a (Scheme 6) was more convenient for the combinatorial procedure however, aU attempts to realize three-component condensation of 3-amino-l, 2,4-triazolo-5-thione 8 with aldehydes 9 and... 

In 2008, Lhommet and co-workers, by extrapolation of a previously described polycyclic version [144], proposed the three-component condensation of acrolein, (5)-2-phenylglycinol, and various acyclic 1,3-dicarbonyls in toluene in the presence of 4 A molecular sieves for the preparation of chiral, bicyclic functionalized tetrahydropyridines (Scheme 50) [145]. These heterocycles may be used as chiral building blocks for the synthesis of alkaloids, as illustrated by the total enantiose-lective synthesis of (—)-lupinine in five steps and 29% overall yield. 

Another example of a MCR-based strategy for the synthesis of pyridines was reported by Kantevari et al. in 2007. Thus, the three-component condensation of enaminones, 1,3-dicarbonyls, and ammonium acetate in the presence of a catalytic amount of a tangstocobaltate salt as heterogeneous catalyst, either in refluxing solvent or under solvent-free conditions, allowed the regioselective formation of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones (Scheme 55) [155]. This methodology combines shorter reaction times and... 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

Finally, a one-pot, three-component condensation reaction in water provides an efficient procedure for the synthesis of furo[2,3-r/ pyrimidine-2,4(1/7,3//)-diones 303 (Scheme 26). A, A -Dimethylbarbituric acid 301 and 4-nitrobenzaldehyde 302 are reacted with a series of isocyanides to give good yields of the 6-amino products 303 <2002TL9151, 2005SC535>. 

Blackburn, C. Guan, B. Fleming, P. Shiosaki, K. Tsai, S. Parallel Synthesis of 3-Aminoimidazo[l,2-a]pyridines and Pyrazines by a New Three-Component Condensation, Tetrahedron Lett. 1998, 39, 3635. 

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. 

Varma, R.S. and Kumar, D., Microwave-accelerated three-component condensation reaction on day solvent-free synthesis ofimidazo[l,2-fl] annulated pyridines, pyrazines and pyrimidines, Tetrahedron Lett., 1999, 40, 7665-7669. 

In 1893 the Italian chemist Pietro Biginelli [2] reported the one-pot synthesis of 4-aryl-3, 4-dihydropyrimidin-2(lff)-ones (DHPMs 1) by a three-component condensation reaction of aromatic aldehydes, urea and ethylacetoacetate (Scheme 11.1). 

A three-component condensation of 5-aminotetrazole with pyruvic acid and aromatic aldehydes was developed as a procedure for the synthesis of 5-aryl-5,8-dihydrotetrazolo[l,5- ]pyrimidine-7-carboxylic acids 414 (Equation 75) <2005S2597>. 

Microwave reaction conditions have been reported for the synthesis of 2-pyridones in a modern version of the traditional three-component condensation reaction (Scheme 108) <2004T8633>. A library of 18 3,5,6-trisubstituted pyridines was generated and includes aryl, alkyl, and fused derivatives. 

Three component condensation reactions (Gewald reaction) between an activated nitrile, ketone or aldehyde, and sulfur has been utilized to prepare a variety of a-aminothiophenes. Recent examples utilizing this condensation reaction include the synthesis of 4,5-dialkyl-2-... 

Very recently, Maiti and coworkers150 developed a new methodology for the synthesis of dihydropyrimidones, 246, by a one-pot three-component condensation using a catalytic amount of LiBr, under very mild reaction conditions (Scheme 76). 

A recent paper by Kiselyov et al. (91) reported the synthesis of two small SP discrete libraries of tetrahydroquinolines LI and L2 inspired by a three-component condensation reaction in solution (92-94) as depicted in Eig. 6.8. The scope of this condensation had been expanded by other groups (95-97), and the use of polymer-supjxMted metal catalysts had also been reported (98, 99) however, an SP route with a broad tolerance for different amines, aldehydes, and olefins had still not been defined prior to this work. 

Figure 6.8 Synthesis of tetrahydroquinolines via a three-component condensation.

Tu S, Zhou D, Cao L et al (2009) A simple three-component condensation highly efficient microwave-assisted one-pot synthesis of polyfunctional pyridine derivatives. J Heterocycl Chem 46 54-57... 

Legeay JC, Eynde JJV, Toupet L et al (2007) A three-component condensation protocol based on ionic liquid phase bound acetoacetate for the synthesis of Biginelli 3,4-dihydropyr-imidine-2(l//)-ones. Arkivoc (iii) 13-28... 

Groebke K, Weber L, Mehlin F (1998) Synthesis of imidazo[l,2-a]annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation. Synlett 661-663... 

Recently, Holmes et al. reported the solution and polymer-supported synthesis of 4-thiazolidinones and 4-metathiaznones derived from amino acids (Scheme 7) [29]. A three-component condensation of an amino ester or resin-bound amino acid (glycine, alanine, /1-alanine, phenylalanine, and valine). 

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