Dimedone synthesis

Amines, thiols, eOH (p. 226), etc., will also add to the 0-carbon atom of 0-unsaturated carbonyl compounds and esters, but the most important reactions of C=C—C=0 systems are in Michael reactions with carbanions reactions in which carbon-carbon bonds are formed. A good example is the synthesis of l,l-dimethylcyclohexan-3,5-dione (dimedone, 100) starting from 2-methylpent-2-ene-4-one (mesityl oxide, 101) and the carbanion 0CH(CO2Et)2 ... 

Lipson VV, Shirobokova MG, Shishkin OV et al (2006) Synthesis of partially hydrogenated pyrazolo[3, 4-b]quinolinones by condensation of 3-amino-5-methylpyrazole with aromatic aldehydes and dimedone. Russ J Org Chem 42(7) 1015-1021... 

Cyclic 1,3-diketones can also participate in this MCR. Thus, utilization of two equivalents of 1,3-cyclohexanedione or dimedone instead of (3-ketoesters led to hydrogenated acridine derivatives. However, when only one equivalent of cyclic 1,3-dicarbonyl is used in combination with one equivalent of (3-ketoester, unsym-metric 1,4-DHPs may be obtained (Scheme 3). For example, this reaction was applied to the synthesis of ZD0947, a potassium chaimel opener [20]. 

This approach has been extended to cyclic 1,3-dicarbonyls for the synthesis of tetrahydrobenzopyrane derivatives, also known as tetrahydrochromenes, which have attracted much attention due to their wide range of biological properties. Thus, a mixture of an aromatic aldehyde, dimedone, and malonitrile in aqueous media catalyzed either by (5)-proline [123] or tetramethylammoniura hydroxide (TMAH) [124] gave the bicyclic heterocycle in excellent yields (Scheme 35). 

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. 

Benzylthiocrellidone (605) was isolated from Crella spinulata and the structure was confirmed by synthesis [479]. It is the first reported example of a natural product containing a dimedone unit [22]. 

Frequently the basic conditions used cause the initial Michael adduct to undergo intramolecular transformations, as for example in the synthesis of dimedone (Expt 7.11). This involves a Michael reaction between mesityl oxide and diethyl malonate followed by an internal Claisen ester condensation. 

The synthesis using malonate is a one-step process with NaOEt in EtOH followed by hydrolysis and decarboxylation in the usual way to give dimedone 83 in 67-85% yield.16... 

A more dramatic example is the synthesis of cA-chrysanthemic acid 11, the basis of most modern insecticides, from dimedone 8, whose synthesis we discussed in chapter 21. Methylation between the two carbonyl groups gives 9, with the complete skeleton of 11—a little reorganisation of the atoms is needed. Treatment with bromine and base gives the inevitably cis-fused bicyclic dione 10 and a further three simple steps produce chrysanthemic acid.3... 

Approaches that represent a type (ii) synthesis of 277-pyran-2-ones include the self-condensation of 1,3-dicarbonyl compounds, the reaction of cyclopropanones with pyridinium enolbetaines and the reaction of activated methylene groups with acetylenic esters <1984CHEC, 1996CHEC-II>. 4-Perfluoroalkyl-6-aryl-pyran-2-ones are formed by the reaction of the phosphonium salts 631 with 2-perfluoroalkynoates (Equation 254) <1999JFC(95)135, 1998JFC(91)99>. Dimedone reacts with dimethyl acetylenedicarboxylate to afford the pyran-2-one 632 in excellent yield (Equation 255) <2003PS2627>. 

The precise nature of the carbonyl groups determines what happens next. If R is a leaving group (OR, Cl, etc.), the tetrahedral intermediate collapses to form a ketone and the product is a 1,3-di-ketone. The synthesis of dimedone (later in this chapter) is an example of this process where an alkoxy group is the leaving group. Alternatively, if R is an alkyl or aryl group, loss of R is not an option and the cyclization is an intramolecular aldol reaction, Dehydration produces an a,P-unsaturated ketone, which is a stable final product. 

The whole operation is conducted in one flask, just as for the Robinson annelation, and dimedone is isolated as the crystalline enol in 84% yield. This reaction has not enjoyed such wide application as the Robinson annelation but it has been used to make an aromatic compound that is a starting material for the synthesis of maytensine, which we discussed at the end of Chapter 22. 

The clue to the synthesis of this compound using a dimedone-style condensation is the 1,3,5-relationship between OMe, N, and Me around the ring. If we carry out the conjugate addition on an enone with only one methyl group at the end of the double bond, this is what we will get. 

Interception of the ji-allyl palladium intermediate with soft nucleophiles such as morpholine and dimedone is attractive on the grounds of efficacy, economy, safety and scope. Deprotection of a phenol allyl ether in a synthesis of the antibiotic Vancomycin demonstrates that aryl iodides and chlorides remain intact [Scheme 4.227],429... 

A synthesis of (-)-Chlorothricolide was impeded by problems deprotecting the spirotetronate unit in 63 1 [Scheme 6.63].159 Early attempts to deploy 2-(tri-methylsilyl)ethoxymethyl or p-methoxy benzyl ethers failed because the product was unstable to the conditions of the deprotection. After much experimentation, a solution to the problem was found simultaneous deprotection of the spirotetronate and the carboxyl group was achieved with Pd(0) and dimedone in 94% yield. 

A new series of polyhydroquinolines 64 has been prepared by Shingare and co-workers [111] using nanosized Ni as a heterogeneous catalyst in a one-pot synthesis via Hantzsch condensation by reacting an aldehyde, dimedone, ethyl aceto-acetate and ammonium acetate in a domestic microwave oven. Ni (80 0.5 nm), having a higher surface to volume ratio, has given the best results in terms of short reaction times and excellent product yields. This method has demonstrated that Ni, in the form of nanoparticles, is a potential alternative catalyst for the Hantzsch... 

Ferrocene derivatives coupled with heterocyclic systems have attracted special attention in recent years because of their interesting organic and inorganic properties. Recently, an efficient and rapid route for the synthesis of 4-aryl-2-ferrocenyl-quinolines 70 has been described by Tu and co-workers [116] through a microwave-assisted MCR of acetylferrocene with an aromatic aldehyde and dimedone in the presence of ammonium acetate in DMF. This novel procedure provides the target hetero-metallic compounds in excellent yields without the need of any purification (Scheme 54). 

Organ and co-workers [120] described a unique approach to MCRs using a microwave-assisted, continuous flow process for the synthesis of new series of tetrahydro-pyrazolo[3,4-6]quinolin-5(6//)-ones 79. An aldehyde, dimedone, and 5-amino-3-methyl-l//-pyrazole were reacted, yielding the desired compound 79 in moderate to excellent yields. It was proved that the electronic properties of the substituted benzaldehydes have an important impact on the conversions as with electron-donating groups rather low yields were obtained (Scheme 60). 

Cyclohexadienes. The last steps in a recent novel synthesis of /3-damascenone (3) from dimedone by way of 1 required oxidation of an allylic hydroxyl group and 1,4-elimination of acetic acid. Activated Mn02 proved to be superior to pyridinium chlorochromate (40% yield) and to NCS-S(CH3)2 (4,87-89), which caused elimination of the hydroxyl group. The last step was effected by DBU at reflux for 20 seconds in 79% yield. ... 

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