Knoevenagel/Diels-Alder

Recently, a first example of an organocatalytic asymmetric domino Knoevenagel/ Diels-Alder reaction was reported by Barbas and coworkers (Scheme 2.182) [409]. Spiro[5,5]undecane-l,5,9-triones of type 2-818/2-819 were obtained from comma-daily available 4-substituted-3-butene-2-ones 2-813, aldehydes 2-814, and Mel-drum s acid (2-801) in the presence of 20 mol% of the amino acid 2-815 with 80-95% ee and diastereoselectivity of dr> 12 1. 

Scheme 2.182. Amino acid-catalyzed asymmetric three-component Knoevenagel/Diels-Alder reactions.

Scheme 5.48. Domino-Knoevenagel-Diels-Alder process catalyzed by proline 245 or pyrrolidine 246.

Scheme 9.21. DMTC-catalyzed asymmetric three-component domino-Knoevenagel-Diels—Alder reaction.

A domino Knoevenagel/Diels-Alder epimerization sequence followed by Suzuki coupling provided a library of biphenyl and terphenyl spirocychc triones (Scheme 24) [58]. The initial Knoevenagel adducts 103 were formed from either 1,3-indandione or Meldrum s acid 101 and various bromosubstituted benzalde-hydes in the presence of catalytic (l)-5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) in high yields. Diels-Alder cycloaddition of 103 with 104, formed in sim from 102 and (l)-DMTC, provided exclusively the cA-spiro compounds 105 due to epimerization of the minor trans isomer to the thermodynamically more stable cis. Subsequent Suzuki couplings of 105 with various boronic acids afforded the final compounds 106. 

Pizzirani D, Robert M, Recanatini M (2007) Domino Knoevenagel/Diels-Alder sequence coupled to Suzuki reaction a valuable synthetic platform for chemical biology. Tetrahedron Lett 48 7120-7124... 

The corresponding enantiopure spirocyclic ketones were remarkably obtained in high yields, as shown in Scheme 10.31. These products constitute attractive starting materials for the synthesis of natural and biologically active products. Later, these authors extended the scope of this reaction by performing hetero-domino Knoevenagel/Diels-Alder/epimerization reactions which provided access to highly... 

Scheme 10.31 Three-component domino Knoevenagel/Diels-Alder reaction.

The same group reported an organocatalytic diastereo-specific and enantioselective domino Knoevenagel/Diels-Alder procedure to obtain highly substituted spiro[5,5]... 

The combination of the three-component domino Knoevenagel/Diels-Alder/epimerization allowed the construction of structures that with suitable modification gave the natural product-like cores as reported in a work of 2007 [87]. Hence, 1,3-dicarbonyl compounds 182 with benzaldehydes 4 and ( )-4-phenyl-3-buten-2-one 183 in the presence of a catalytic amount of (5)-5,5-dimethyl thiazoli-dinium-4-carboxylate 184 produced corresponding spiro compounds 185 in good yields (50-80%) and high diastere-oselectivity [dr (cis/trans) >99 1] (Scheme 2.61). 

SCHEME 2.60 Synthesis of spiro[5,5]undecane-l,5,9-triones 181 via domino Knoevenagel/Diels-Alder. 

D. B. Ramachary, N. S. Chowdari, C. F. Barhas IB, Angew. Chem. Int. Ed. Engl. 2003, 42, 4233 237. Organocatalytic asymmetric domino Knoevenagel/Diels-Alder reactions a hioorganic approach to the diastereospecific and enanti-oselective construction of highly suhstituted spiro[5,5] undecane-1,5,9-triones. 

A. Palasz, Synthesis 2010, 4021—4032. A green approach to the synthesis of fused uracils pyrano[2,3-[Pg.483]

A. Palasz, Monatsh. Chem. 2012,143,1175—1185. Synthesis of fused uracils pyrano[2,3-<3f]pyrimidines and l,4-his(pyrano[2,3-(7]pyrimidinyl)benzenes by domino Knoevenagel/Diels-Alder... 

A number of tandem transformations taking advantage of the reactivity of the Knoevenagel products have been described, including tandem Knoevenagel-Michael, Knoevenagel-ene, Knoevenagel-Diels-Alder, and... 

The tandem Knoevenagel-Diels-Alder sequence is well known, and has been extensively studied by Tietze and others. The Knoevenagel products have been shown to be active as dienophiles in normal-electron-demand Diels-Alder reactions, as well as heterodienes in inverse-electron-demand hetero-Diels-Alder reactions. One of the most elegant examples of a tandem Knoevenagel-hetero-Diels—Alder sequence is Tietze s synthesis of hirsutine 76. In this sequence, a mixture of aldehyde 70, Meldrum s acid 71, enol ether 73 (a mixture of isomers) and a catalytic amount of ethylenediamine diacetate were sonicated in Benzene for 12 h at 60 °C. This effected a cascade sequence that began with Knoevenagel condensation to form the heterodiene 72, followed by intermolecular hetero-Diels-Alder reaction with enol ether 73 to lead to 74, which underwent in situ hydrolysis and decarboxylation to yield intermediate 75 in 84% yield. 

Tandem sequences involving Knoevenagel condensation followed by electrocyclization have not been employed as extensively as other tandem reactions (such as the tandem Knoevenagel-Diels-Alder reaction), but have been used in a few cases with great success, rapidly constructing complex polycyclic cores. 

On another occasion, Barbas s group developed the first organocatalytic diastereospecific and enantioselective direct asymmettic domino Knoevenagel/ Diels-Alder reactions that produce highly substituted spiro[5,5]undecane-l,5,9-triones 57 from commercially available 54, aldehydes 55, and 2,2-dimethyl-l,3-dioxane-4,6-dione 56 (Scheme 1.16) [18]. Among the catalysts screened, 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield, and provided 57 in 88% yield and 86% ee. Up to 93% yield and 99% ee were observed when the reaction was extended to other substrates. It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58. 

The asymmetric domino three-component Knoevenagel/Diels-Alder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported. Various pharmacological multisubstituted spiro[5,5]undecane-1,5,9-triones were obtained in moderate to good yields (up to 81%) with excellent diastereo-(>99 1 dr) and enantioselectivities (up to 97% ee) [19]. The enamine-mediated Diels-Alder reactions of a,P-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefmic oxindoles [21]. 

Inspired by the unexpected formation of symmetric 58, Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldol/Knoevenagel/Diels-Alder reaction sequence in one pot (Scheme 1.18) [22]. The Diels-Alder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products. 

SCHEME 1.18 Pyrrolidine-catalyzed stereospecific multicomponent aldol/Knoevenagel/ Diels-Alder reaction. 

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