Knoevenagel efficiency

The domino Knoevenagel/hetero-Diels-Alder reaction is a prominent example of the great advantage of domino processes as it not only allows the efficient synthesis of complex compounds such as natural products starting from simple substrates, but also permits the preparation of highly diversified molecules. Due to the vast number of reports that have been made, only a few recent publications can be discussed here, although several excellent reviews on this topic have been produced that provide a more detailed insight into this useful method [372]. 

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... 

Microwave activation and solvent-free PTC have been shown to be of prime efficiency for the synthesis of new benzylidene cineole derivatives (UV sunscreens) by the Knoevenagel reaction. When performed classically by use of KOH in ethanol at room temperature for 12 h (Eqs. 43 and 44) the yield was 30%. This was improved to 90-94% within 2-6 min under PTC + MW conditions (Tabs 5.17 and 5.18) [27, 28],... 

An efficient solventless synthesis of imidazolones via the Knoevenagel reaction using microwave irradiation has appeared recently in Green Chemistry [76] (Scheme 8.52). 

An efficient and also elegant synthesis of the active anti-influenza A virus indole alkaloid hirsu-tine 67 is performed by an inter-intermolecular anionic-pericyclic three- component domino reaction followed by solvolysis and hydrogenation (scheme 13).[261 The synthetic sequence developed by us contains first a Knoevenagel condensation of enantiopure 61 and 62 with the formation of the... 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

Tellurium tetrachloride is an efficient catalyst in the Knoevenagel reaction of non-enoUz-able aldehydes with active methylene compounds. ... 

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... 

More recently, Tietze s group adapted the well-known domino Knoevenagel-Hetero-Diels-Alder MCR to the efficient synthesis of the deoxyaminosugar (-l-)-D-Forosamine starting from nitroacetone, aqueous formaline, and ethyl vinyl ether (Scheme 65) [169]. The expected racemic dihydropyran was obtained in 37% yield and further transformed to the optically pure product in eight steps in chiral resolution with chiral HPLC. 

Jimenez-Alonso S, Chavez H, Estevez-Braun A, Ravelo AG, Feresin G, Tapia A (2008) An efficient synthesis of embelin derivatives through domino Knoevenagel hetero Diels-Alder reactions under microwave irradiation. Tetrahedron 64 8938-8942... 

Ito and Hayashi noticed that Au(I)-chiral fenocenylphosphine complexes are remarkably efficient in the Knoevenagel reaction between aldehydes and isocyanoacetic esters to form 5-alkyl-2-oxazoline-4-car-boxylates with high enantio- and diasteieoselectivity (Scheme 116)... 

The domino-Knoevenagel-hetero Diels-Alder reaction is furthermore suitable for the efficient preparation of D-homosteroids [492]. Another effective use of this method is the synthesis of heterosteroids, which are interesting due to their potential pharmacological properties [493],... 

Novel supported guanidine catalysts, based on 1,1,3,3-tetramethylguanidine have been prepared using a variety of synthetic routes. The catalysts have been shown to be efficient catalysts for the base-catalysed epoxidation of electron-deficient alkenes, and show promise in the Linstead variation of the Knoevenagel condensation. 

Cai, Y., Peng, Y, and Song, G. 2006. Amino-functionalized ionic liquid as an efficient and recyclable catalyst for Knoevenagel reactions in water. Catalysis letters, 109 61-64. 

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