Three Component Condensation

The 2(3//)-oxazolones may be synthesized by the direct condensation of three components. Thus, a mixmre of a-halo ketones 123, carbon dioxide, and primary amines can be heated at 80-100 °C under gas pressure of 50 kg/cm to result in the direct formation of 3-substituted 2-oxazolones 124 in 4-25% yield (Fig. 5.30).  

Direct condensation of propargyl alcohols 125 (Fig. 5.31), carbon dioxide, and propylamine can be realized by Ru3(CO)i2 catalysis at 80 °C under CO2 pressure of 50 kg/cm. The reaction mechanism is rationalized as shown below. When diethylamine is used in place of a primary amine, 2-oxoalkyl WA -diethylcarba-mates are isolated in moderate yields. 

3-dipolar cycloaddition of a-keto carbenoids to the polar double bond of heterocumulenes provides a direct access to five-membered heterocycles. The reaction of a-diazo ketones 132 with phenyl isocyanate in the presence of a Rh2(OAc)4 catalyst affords the 1,3-cycloadduct, 3-phenyl-2(3//)-oxazolones 133 (Fig. 5.32).  

Heating a-hydroxy amides 135 in xylene with the cumulated phosphoms ylide 134 gives the 2(3//)-oxazolones 140. The reaction proceeds via an addition-cyclization-intermolecular-Wittig olefination sequence, which imphes three different types of phosphorus ylides, 134,136, and 137, respectively, of increasing ylide activity (Fig. 5.33 Table 5.7, Figs. 5.34, 5.35). 

TABLE 5.7. 2(3//)-OXAZOLONES FROM a-HYDROXY AMIDES AND PHOSPHORUS YLIDE 134  

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This method is especially useful as part of a three-component condensation of optically active y-alkoxycyclopentenones leading to prostaglandin and compactin precursors268. 

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 Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

Another method for preparing pyrrole rings is by Ugi-type three-component condensation (Scheme 6.184). In the protocol published by Tye and Whittaker [345], levulinic acid was reacted with two different isonitriles and four amine building blocks (1.5 equivalents) to provide a set of eight pyrrole derivatives. While the previously published protocol at room temperature required a reaction time of up to 48 h and provided only moderate product yields, the microwave method (100 °C, 30 min) optimized by a Design of Experiments (DoE) approach (see Section 5.3.4), led to high yields of the desired lactams for most of the examples studied. 

Scheme 6.184 Ugi-type three-component condensation reactions.

Scheme 6.195 Three-component condensation leading to fused pyrazoles.

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... 

Scheme 6.201 Three-component condensation reactions leading to 4-alkylthioimidazoles.

To demonstrate the feasibility of this method for library generation, the isocyanides produced were subjected to an Ugi three-component condensation with various primary amines and carboxybenzaldehyde. The resulting 2-isoindolinone derivatives were obtained in high to excellent yields. 

Using a similar format, dihydropyrimidines were obtained in a microwave-expedited version of the classical Biginelli three-component condensation (Scheme 12.24) [73]. Neat mixtures of /i-kctocstcrs, aryl aldehydes and (thio)ureas with polyphosphate ester (PPE) as reaction mediator were irradiated in a domestic microwave oven for 1.5 min. The desired dihydropyrimidines were obtained in 61-95% yield after aqu-... 

The three component condensations of aldehydes, amines and elemental sulfur using 1-methyl-2-pyrrolidone as solvent employing microwave flash heating 100-180 °C for 2-20 min give the corresponding primary, secondary and tertiary thioamides (Scheme 6).23... 

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>. 

Arylbenzoxazoles were prepared by Pd-catalyzed three-component condensation of aryl halides with o-aminophenols and carbon monoxide followed by dehydrative cyclization [24], A variant of such methodology using o-fluorophenylamines in place of o-aminophenols was used to synthesize arylbenzoxazoles [25]. 

A highly efficient access to diversely substituted indolizines using a new three-component condensation of activated methylene compounds, aldehydes, and isonitriles is described <2006QSAR504>. 

Biginelli reactions, using microwave irradiation, 16 579-580 Biginelli three-component condensation products, 16 550... 

Scheme 2.57 Three component condensation reaction using polymer supported scavenger purification alternatively the trisamine resin could be substituted for purification in this step.

The Grieco reaction is a three component condensation of anihnes, aldehydes and electron rich alkenes to form six-membered nitrogen-containing heterocycles. Ki-seljov et al. for example synthesized a library of tetrahydroquinohnes using this synthetic pathway (Scheme 3.24) [282]. 

Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford a-acyloxycarboxamides. Cf. Ugi reaction. 

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... 

This new three-component condensation was performed in the presence of either Brpnsted (e.g., perchloric [127] or glacial acetic acid [125]) or Lewis acids [126] in methanol at room temperature giving the desired fused imidazoles in good yields and was defined as Ugi-type 3-CR or Groebke reaction [128]. 

Scheme 15 A three-component condensation including a radical carbonylation [36]...

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... 

Shaabani A, Rahmati A, Rezayan AH, Darvishi M, Badri Z, Sarvari A (2007) Clean s)mthesis in water Uncatalyzed three-component condensation reaction of 3-amino-l,2,4-triazole or 2-aminobenzimidazole with aldehyde in the presence of activated CH-Acids. QSAR Comb Sci 26 973-979... 

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... 

Condensation products of 4(5//)-oxazolonium salts with aldehydes and orthoesters are the subject of a series of papers by Kosulina and co-workers Reaction of 2-methyl-4(5//)-oxazolonium perchlorates 44 with an ortho ester gives rise to an enol ether, which reacts with furanamides to afford the frani-eneamides 45 (Scheme 6.14). " Using electron deficient anilines in a three component condensation affords either 46 or 47 in 64-80% and 78-84% yields, respectively, depending on whether the reaction is performed in acetic acid or acetic anhydride. Electron-rich anilines are unreactive since they are merely protonated by the perchloric acid present in the reaction medium. ... 

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