Dimedone, Michael addition

Keywords arylidene malodinitril, dimedone, Michael addition, cyclization, pyrane... 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

Electron-poor alkenes are suitable starting points for Michael additions. For example, the arylidene malononitrile 363 adds quantitatively to solid dimedone (255) upon milling at 80 °C followed by heating of the yellow powder to 100 °C. The initial Michael adduct 364 is not isolated, as it cyclizes in the solid state to give the pyrone 365 with 100% yield [107] (Scheme 58). The potentials for waste-free solid-state chemistry are manifold indeed and deserve further exploration. 

Keywords dimedone, aromatic aldehyde, Knoevenagel condensation, Michael addition, uncatalyzed... 

Dimedon, 5,5-dimethylcyclohexane-l,3-dione, is prepared by an interesting process discovered by Vorlander. The reaction of 1 mole each of diethyl malonate, mesityl oxide, and sodium ethoxide in absolute ethanol probably involves a Michael addition followed by an intramolecular ester condensation to close the ring to give the diketo ester formulated (procedure of Shriner and Todd. Aqueous potassium... 

The synthesis of alicyclic 1,3-diketones from 7- or 6-keto esters is a well-established reaction. Over SO examples are tabulated in the 1954 chapter in Organic Reactions, and a similar number are tabulated as involving a Michael addition of a diester or keto ester to an unsaturated ketone followed by a Claisen condensation. These latter reactions involve such well-known syntheses as that of dimedone (S,S-di-methylcyclohexane-l,3-dione Scheme 75). 

Michael addition of 1 to dimethyl acetylene dicarboxylate in the presence of sodium methoxide, potassium fluoride, or aluminum trioxide gave 435 (R = Me) via an intermolecular cyclocondensation (89MI87). Regioselective cycloaddition of propargylic alcohol and dimedone in the presence of thiolate-bridged diruthenium complex afforded the tetrahydrobenzo[fr]pyran 451 (04JOC3408). 

It is of interest to note that the preparation of dimethyldihydroresorcinol also named dimedone and methone Section VII,15) involves an initial Michael addition to mesityl oxide, followed by an internal Claisen condensation. 

When aldoximes 309 reacted with dimedone 58 in the presence of ammonium acetate under MWI, they gave acridines 308 in 80 92% yields within 5 min. These reactions may occur through a Michael addition of dimedone 58 to 309 to give the intermediate 310, which on elimination of hydroxylamine gave 313. Then Michael addition between 311 and 312, resulting from dimedone 58 and ammonium acetate, produced 313, which isomerized and cyclodehydrated to give 308 (Scheme 63) (04SC1289). 

The stoichiometric reaction of aromatic aldehydes with Meldrum s acid at 50°C gave an intermediate melt from which products 139 crystallized quantitatively at the reaction temperature (Scheme 2.47). These Knoevenagel condensations were termed melt reactions with direct crystallization. Similar condensation with dimedone 140 afforded a cascade reaction starting with Knoevenagel condensation, which was followed by elimination and subsequent Michael addition (Scheme 2.48). Unlike the solution synthesis, yields are superior and no wastes was produced. 

Cascade Knoevenagel condensation/Michael addition of dimedone and aromatic aldehydes. 

The products could be easily isolated by filtration, and recrystallizafion from elhanol led to the pure desired compounds. The authors suggested an iminium ion-catalyzed Knoevenagel condensation mechanism, followed by enamine-Michael addition and intramolecular cyclization. One year later, the same group reported the diammonium hydrogenphosphate-catalyzed synthesis of various pyrano-pyrimidinones by exchanging dimedone by barbituric and thiobarbituric add in aqueous ethanol at ambient temperature [13]. The desired compounds could be afforded in good yields. 

The reaction of dimedone-derived enamines 110, methyl (2-cyano)acetate 109, and formaldehyde 72 mediated by lithium perchlorate led to the formation of a Knoevenagel/ enamine-Michael addition product (Scheme 13.33) [52], This could be cyclized in a one-pot procedure with substoi-chiometric amounts of triphenyl phosphine to provide... 

Michael addition of thioacetic acid to a series of a-substituted (V-acryloyloxazolidin-2-ones, followed by enantioselective protonation, catalysed by the cinchonidine-derived thiourea (288a), has been reported to proceed with <97% ee The pseudo-enantiomeric, cinchonine-derived thiourea (289a) can catalyse the Michael addition of dimedone to enone RCH=CHCO( -Py) with <98% ee The isosteviol-derived thiourea (290) represents yet another variation this organocatalyst has been reported to facilitate the Michael addition of a-substituted cyanoacetates NCCH(Ar)C02R and maleimides in toluene at -30 °C (with <93% ee and <98 2 dr) as a method for the construction of quaternary chiral centres " ... 

The bifunctional squaramide (343) has been found to catalyse Michael addition of cyclic -diketones (e.g. dimedone) to / ,y-unsaturated a-keto esters with <99% ee at 2.5 mol% catalyst loading. The reaction model (344) has been proposed to rationalize the enantioselectivity. i... 

The Knoevenagel condensation with 1,3-dicaibonyls followed by a Michael reaction of a second molecule of the methylene compound, with or without addition of an amine or ammonia, may be used for the qualitative and quantitative determination of aldehydes even in the presence of ketones. Thus, cyclic 3-diketones such as dimedone (59) react with aldehydes but not with ketones in the absence of a catalyst. For the characterization the bis(2,6-dioxo-4,4-dimethylcyclohexyl)methanes (67) or the 4,6-dioxo-2,2,8,8-tetramethyl-l,2,3,4,5,6,7,8-octahydro-9F/-xanthene (68) may used. ... 

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