Three-component cyclocondensation

In a facile and rapid stereoselective, three-component, one-pot reaction, a series of cis-isoquinolonic acids 132 were synthesized using silica supported sulfuric acid to catalyze the reaction between homophthalic anhydride 133 with different aldehydes 134 and amines 135. This three-component cyclocondensation offers a variety of advantages including high yields, easy experimental work-up, and the use an inexpensive, non-toxic, readily available, and recyclable catalyst <06JHC187>. 

The sodium bromide catalyzed three-component cyclocondensation of aryl aldehydes, CH-acidic nitriles, and dimedone under solvent-free conditions has been studied by Devi and Bhuyan (Scheme 6.245) [429]. Utilizing equimolar amounts of the building blocks and 20 mol% of sodium bromide as catalyst, microwave irradia-... 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

Kappe et al. reported the microwave-assisted synthesis of pyrido[2,3-ri ]pyrimidines via a one-pot three component cyclocondensation of a,(3-unsaturated esters, amidines and malonitrile (or ethyl cyanoacetate) (Scheme 3.45)71. Quiroga et al. reported a similar three component cyclocondensation to synthesise regiospecif-ically 5,8-dihydropyrido[2,3-ri ]pyrimidines under solvent-free conditions, starting from a combination of aminopyrimidin-4-ones, benzoylacetonitrile and benzaldehyde (Scheme 3.45)72. 

In 1998, Rad-Moghadam and Khajavi47 developed a microwave-assisted three-component cyclocondensation for the synthesis of quinazolin-4(3//)-ones. 

Three-component cyclocondensation of keto sulfone 172 (n — 1), enamino ester 169 (R = C02Me), and 2-nitrobenzaldehyde unexpectedly afforded hexahydrothieno [3,2-Z>]pyridine 173 (n — 1) instead of the 1,4-dihydropyridine derivative. Heating the latter led to its dehydration to thienopyridine 174 (n — 1), which serves as a calcium channel blocker with a broad spectrum of biological activities (2000Mil). 

Scheme 11 Microwave-mediated synthesis of indolizines via a three-component cyclocondensation...

Rapid access to an array of fused 3-aminoimidazoles was conveniently achieved by a Sc(OTf)3 catalyzed three-component cyclocondensation of heterocyclic amidines (such as 2-aminopyridine) and aldehydes with isocyanides (Ugi MCR) [52] or, alternatively, with trimethylsilylcyanide (TMS-CN) [53]. AT-Unsubstituted 3-aminoimidazo[ l,2-a]pyridincs 28 were formed in the latter case (Scheme 19). Microwave dielectric heating of the methanolic... 

Pyrido[2,3-d]pyrimidines 70 were synthesized in a one-pot three-component cyclocondensation of os/i-unsalurated esters 67, CH-active nitriles 68 and amidines 69 [122], While reflux in THF or MeOH for 24 hours was required... 

Liang B, Wang X, Wang JX et al (2007) New three component cyclocondensation micro-wave assisted one-pot synthesis of 5-unsubistutited-3,4-dihydropyrimidin-2(lH)-ones under solvent-free conditions. Tetrahedron 63 1981-1986... 

A mixture of the iminochlorosulfide (145), pyrazine, and an isocyanide (R—NC) underwent a three-component cyclocondensation to give the salt (146). Initial reaction gave a A -imidoyl-pyrazinium salt, which was then trapped by the nucleophilic isocyanide to form the desired product <93TL2319>. 

In a one-pot three-component cyclocondensation, but-2-en-l-yl ethyl ketone, -butylamine and nitromethane form a product A in 47% 3deld in THF at 60°C in the presence of Sml2 as catalyst. 

Deaza-5,8-dihydropterins were prepared from 2,6-diaminopyrimidin-4-one, 1,3-dicarbonyl compounds, or benzoylacetonitrile, and aromatic or aliphatic aldehydes [115]. This three-component cyclocondensation proceeds under microwave-assisted conditions in good yield using Zn(II) bromide as a Lewis acid catalyst, and with total control of regiochemistry. 

Another way of forming more complex, nonsymmetrical DHPs was introduced by Bagley et al. [36]. The authors developed a one-pot three-component cyclocondensation reaction for preparation of 5-deaza-5,8 dihydropterin 6 (Scheme 17.7) which proceeded with total control of regiochemistry [37]. The three-component reaction was originally conducted under thermal conditions and was catalyzed by zinc(II) bromide but required long reaction times and quite high temperatures to obtain a good yield of the cyclized product 6. 

Pyrido[2,3-d]pyrimidines are annelated uracils which have received substantial attention in recent years because of their biological activity [51, 52]. Several reports have appeared in the literature describing the preparation of these molecules starting from uracils and build-up of the pyridine moiety. These methods usually require long reaction times and complex synthetic pathways, however [53, 54]. Devi et al. developed a one-pot three-component cyclocondensation reaction under solvent-free MW-assisted conditions (Scheme 17.17) [55]. In this procedure, N,N-dimethyl-6-aminouracil 22 reacts with equimolar amounts of triethylorthofor-... 

One-pot three-component cyclocondensation of l-(3-aryl-l,2,4-oxadia-zol-5-yl)acetone 229, thiourea, and aromatic aldehydes formed 5-(l,2,4-oxadiazol-5-yl) DHPM 230 (Scheme 88) (09MI8). 

A simple highly versatile and efficient synthesis of 2,4,5-triarylimid-azoles 78 was achieved by three-component cyclocondensation of benzil 77, aromatic aldehydes, and ammonium acetate under various conditions and is shown in the table below... 

Matveeva developed a three-component cyclocondensation of tetrazo-lopyrimidines (Scheme 29) (13CHC1877). 

Knoevenagel/cyclocondensationreaction [111] the synthesis of tri- and tetrasubstituted imidazoles by three-component cyclocondensation of 1,2-dicarbonyl compounds, aldehydes, and ammonium acetate using (5)-proline (1) [112] the preparation of functionalized CM-decahydroquinolines (framework widespread in biologically active alkaloids) by means... 

Safari J, Gandomi-Ravandi S (2013) Microwave-accelerated three components cyclocondensation in the synthesis of 2,3-dihydroquinazolin-4(l H)-ones promoted by Cu-CNTs. J Mol Catal A Chem 371 135-140... 

Pasha et al. [120] developed an efficient, solvent-free, one-pot, three-component cyclocondensation reaction between aldehyde, ketone, and urea to synthesize 4,6-diarylpyrimidin-2(lH)-ones (DAPMs) 76 irsing iodine as a catalyst This protocol provides a simple and enviromnentally benign route along with the associated advantages of good to excellent yield of the products (90-96 %) and shorter reaction times (5-15 min) at 80 °C (Scheme 10.56). 

In a three-component cyclocondensation, a-halocarbonyl compounds react with P-ketoesters (or P-diketones) and ammonia or primary amines to give pyrrole-3-carboxylates (or 3-acyIpyrroIes), which are substituted either in 1,2,4- or in 1,2,5-position, for example, 43/45 (Hantzsch synthesis) ... 

Three-component cyclocondensation of 1,2-diketones, reactive a-methylene esters, and hydrazines lead (often as a one-pot procedure) to pyridazin-3(2H)-ones 11 (Schmidt-Druey synthesis) ... 

Kobayashi et al. were the first to report the use of lanthanide triflates as catalysts in imino Diels-Alder reactions [9], The successful three-component cyclocondensation of an aldehyde, amine and diene in acetonitrile was realized in the presence of lanthanide triflates as the Lewis-acid catalyst. This process is reminiscent of the protonated iminium-ion-based methodologies whereby the coordinated imine formation and [4+2] cycloaddition occur in one pot. 

In their report, Khurana and his group [81] also showed that DBU (10mol%) can effectively catalyze the three-component cyclocondensation reaction between aromatic aldehydes, malononitrile or ethyl 2-cyanoacetate, and 2-hydroxynaphthalene-l,4-dione in aqueous medium under reflux to afford 2-amino-4H-benzo[ ] chromenes (10). A series of diversely substituted 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4ff-benzo[g]chromene-3-carbonitriles and ethyl-2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[j]chromene-3-carboxylates were synthesized using this protocol in excellent yields (Scheme 5). The reactions were claimed to be remarkably clean, and no chromatographic purification was required. 

The research group of Bazgir [112,113] also reported the S5mthesis of a series of diverse spiro[indole-3,8 -phenaleno[l,2-l ]pyran]-9 -carbonitriles 25 in good yields from the one-pot, three-component cyclocondensation reaction of 3-hydroxy-IH-phenalen-l-one (24), malononitrile (3), and substituted isatins (20) in refluxing aqueous media using the same catalysts (Scheme 13). 

One-pot, three-component cyclocondensation reaction of isatins (20), malonotrile or ethyl 2-cyanoacetate (3), and 4-hydroxycoumarin (13) catalyzed by L-proline (10mol%) or sodium stearate (10mol%) in aqueous medium yielded a variety of spirooxindole derivatives (28) (Scheme 15) [114,115], The protocols are efficient and good yielding. 

A series of densely substituted spiroindole derivatives 35 were synthesized from the one-pot, three-component cyclocondensation reactions involving substituted isatins, active methylenic compounds, and varying 1,3-dicarbonyls... 

Abstract The Biginelli reaction, a three-component cyclocondensation reaction, is an important member of the multicomponent reaction (MCR) family. The Biginelli reaction is so efficient and shares many similar properties as the recent click reactions. In this chapter, we summarised the current applications of the Biginelli reaction in polymer chemistry including polymer coupling, post polymer modification, and new functional polymer synthesis. We expect this old reaction (>120 years) can draw attention from polymer chemists and play new roles in the polymer science. 

---