Domino condensation catalyst

Scheme 5.131 Domino hydroformylation-cross aldol addition with a chiral rhodium catalyst and a chiral aldol condensation catalyst.

Another intramolecular ene-yne metathesis followed by an intermolecular metathesis with an alkene to give a butadiene which is intercepted by a Diels-Alder reaction was used for the synthesis of condensed tricyclic compounds, as described by Lee and coworkers [266]. However, as mentioned above, the dienophile had to be added after the domino metathesis reaction was completed otherwise, the main product was the cycloadduct from the primarily formed diene. Keeping this in mind, the three-component one-pot reaction of ene-yne 6/3-94, alkene 6/3-95 and N-phenylmaleimide 6/3-96 in the presence of the Grubbs II catalyst 6/3-15 gave the tricyclic products 6/3-97 in high yield (Scheme 6/3.28). 

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

The N-alkylation of amines with alcohols [63] can also be carried out with Ir catalysts through a similar domino sequence reaction. In this case, the aldehyde/ketone resulting from oxidation is condensed with an amine to the corresponding imine, which is hydrogenated to the alkylated amine [63]. By way of example, the reaction of benzyl alcohol with aniline in toluene afforded benzylaniline in a 88% isolated yield by using catalytic amounts of [ lr(/z-Cl)Cp Cl 2]/K2C03. 

This three-component reaction as the key step of this synthesis is called a domino-Knoevenagel-hetero-Diels-Alder reaction. Domino reactions are defined as processes of two or more bond forming reactions in which a subsequent transformation takes place by virtue of the functionalities introduced in a former transformation.2,16 The tetrahydrocarbolinaldehyde 11 first reacts in a Knoevenagel type condensation with Meldrum s acid 14 and ethyleneammonium diacetate 41 as the catalyst to oxabutadiene 44 which then undergoes a Diels-Alder reaction with enol ether 13. 

An organocatalytic (j0rgensen-Hayashi catalyst 1) domino Micliael/Michael/aldol condensation was used to prepare a hexahydronaphtlialenone (+)-121 m route to the natural product (+)-galbulin (Scheme 7.22). In this case, it was proposed that an iminium salt 118 (activated from the re face) and an enamine species 117 were preformed. Following a kinetic asymmetric transformation (KAT) of the racemic precursor 115, the intermediate 119 is first formed through an intermolecular Michael reaction. A second intramolecular Michael reaction occurs and the intermediate 120 forms, and finally an acid-initiated aldol condensation... 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

Latterly, Reddy et al. reported a novel three-component assembly of 2//-indazoles catalyzed by Cu(II)-HT (Prasad et al., 2013). Through consecutive condensation, and C-N and N-N bond formation processes, the domino reactions of 2-bromobenzal-dehydes, primary amines, and sodium azide smoothly gave the desired 2//-indazole derivatives (Scheme 4.59). The heterogeneous catalyst could be readily recovered and reused several times without significant loss of activity. 

Researchers at the University of Tokyo prepared a small (2 X 2) library in a chip microreactor by reacting 3-nitroben-zoyl chloride and 3,5-dinitrobenzoyl chloride, each with dl-1-phenylethylamine and 4-amino-1-benzylpiperidine using a phase-transfer catalyst. GlaxoSmithKline (GSK) generated a 2 x 2 library for a domino reaction, which consisted of a Knoevenagel condensation that gave an intermediate that immediately underwent an intramolecular hetero-Diels-Alder reaction with inverse electron demand. GSK published the synthesis of a 3 x 7 library using... 

Relying, as in the previous studies, on the capability of secondary amine catalysts to activate both nucleophile and electrophile, Enders assembled a quadruple domino Friedel-Crafts-type/Michael/Michael/aldol condensation sequence, affording an efficient and direct asymmetric synthesis of polyfunctionalized 3-(cyclohexenylmethyl)-indoles 172 with moderate to high yields (Scheme 2.55) [82]. 

For other example of the use of same type of catalyst, in the obtainment of indole derivatives, see D. Enders, C. Wang, M. Mukanova, A. Greb, Chem. Commun. 2010, 46, 2447-2449. Organocatalytic asymmetric synthesis of polyfunctionalized 3-(cyclohexenyhnethyl)-indoles via a quadruple domino Friedel-Crafts-type/Michael/Michael/aldol condensation reaction. 

Z. N. Tisseh, M. Dabiri, M. Nobahar, H. R. Khavasi, A. Bazgir, Tetrahedron 2012, 68,1769-1773. Catalyst-free, aqueous and highly diastereoselective synthesis of new 5-substituted H-tetrazoles via a multi-component domino Knoevenagel condensation/l,3-dipolar cycloaddition reaction. 

Dabiri has developed a catalyst-free three-component synthesis of a series of stmc-turally diverse 5-substituted tetrazoles 24 and 25 in good yields under mild conditions from caiboityl compounds (including benzaldehydes, isatin and ninhydrin), malononitrile and sodium azide in water [19], This process can be assumed to proceed through a domino Knoevenagel condensation/l,3-dipolar cycloaddition sequence (Scheme 1.13). 

Scheme 5.133 Domino hydroformylation-(aldol condensation)-hydrogenation reaction with a rhodium catalyst based on NAPHOS for both hydroformylation and hydrogenation.

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