Reaction with cyclic 1,3-diketones

Interesting reagents for such MCRs from the viewpoint of selectivity tuning are 5-aminopyrazoles containing carboxamide substituent. In the first article concerning the behavior of these aminozoles in the reactions with cyclic 1,3-diketone and aldehydes, it was found that only one direction of the treatment leads to tricyclic Biginelli-like heterocycles 61 (Scheme 30) [96]. 

Reaction with cyclic diketones. Cyclohexane-1,3-dione (also dimedone) reacts with 1 eq. each of Meerwein s reagent and ethyldiisopropylamine to give the monoenol ether in quantitative yield. When excess reagent is used, 1,3-diethoxycyclohexadiene-1,3 is obtained in essentially quantitative yield. These... 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

Recently, reactions of cyclic diketones 103 with UNs were carried out via solvent-free ball-milling of starting materials at 100-130°C (03T3753) or at room temperature in the presence of TEBAC (06SC2363) with nearly quantitative yields. 

For 3-aryl-5-aminopyrazoles 222 the direction of the multicomponent reaction with cyclic P-diketones and aromatic aldehydes is not so unequivocal. Quiroga et al. [190] found that during refluxing of these starting materials in ethanol, the reaction products were only derivatives of pyrazoloquinoline 227,... 

It was of interest to extend the reactions of tetrols with cyclic diketones to produce a variety of spiro polymers with less oxygen in the base chain and with other functional groups present... 

Thioketals are readily formed by acid-catalyzed reaction with ethane-dithiol. Selective thioketal formation is achieved at C-3 in the presence of a 6-ketone by carrying out the boron trifluoride catalyzed reaction in diluted medium. Selective protection of the 3-carbonyl group as a thioketal has been effected in high yield with A" -3,17-diketones, A" -3,20-diketones and A" -3,l 1,17-triones in acetic acid at room temperature in the presence of p-toluenesulfonic acid. In the case of thioketals the double bond remains in the 4,5-position. This result is attributed to the greater nucleophilicity of sulfur as compared to oxygen, which promotes closure of intermediate (66) to the protonated cyclic mercaptal (67) rather than elimination to the 3,5-diene [cf. ketal (70) via intermediates (68) and (69)]." " ... 

Cyclic 1,3-diacetoxy-l,3-dienes can be generated in situ from cyclic 1,3-diketones under the influence of isopropenyl acetate. The dienes then undergo Diels-Alder reactions with maleic anhydride giving as products 1-acetoxybicycloalkane dicarboxylic anhydride derivatives (10). The procedure is also successful with cyclic 1,2- and 1,4-diketones as well as cyclic a,j3-unsaturated ketones. The products, after hydrolysis to... 

The net effect of the Stork reaction is the Michael addition of a ketone to an cn/3-unsaturated carbonyl compound. For example, cyclohexanone reacts with the. cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 23.8). 

Barbituric acid can be considered as a cyclized malonic acid diamide (malonyl-urea). It is therefore a cyclic diketone that may be classified, in the sense of the compounds discussed in Section 12.6, as a coupling component with a methylene group activated by two carbonyl groups in the a- and a -positions. The reaction with arenediazonium salts was studied by Nesynov and Besprozvannaya (1971). These authors obtained coupling products (in good yield) that they considered to be arylhydrazones. Coupling with 4-(phenylazo)benzenediazonium chloride was studied by Chandra and Thosh (1991). The lH NMR spectra of these compounds are consistent with the arylhydrazone structure 12.68. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

Aside from alcohols, other oxygen nucleophiles have also participated in hydroalkoxylation reactions with alkynes. The most common of these are 1,3-dicarbonyl compounds, whose enol oxygens are readily available to add to alkynes. Cyclization reactions of this type have been carried out under Pd(0) catalysis with various aryl or vinyl iodides or triflates, often in the presence of CO, affording the corresponding furan derivatives (Equation (95)).337-340 A similar approach employing cyclic 1,3-diketones has also been reported to prepare THFs and dihydropyrans under Pd, Pt, or W catalysis.341 Simple l-alkyn-5-ones have also been isomerized to furans under the influence of Hg(OTf)2.342... 

It was reported [59] that temperature in combination with the choice of catalyst is, indeed, the main factor in controlling the direction of this MCR. Under ambient and neutral conditions, the reaction between 5-amino-3-phenylpyrazole, cyclic diketones, and aromatic aldehydes yielded Biginelh-type dihydropyrimidines 54 (Scheme 24). Increase in the reaction temperature with simultaneous addition of triethylamine allowed the reaction to proceed along the thermodynamically controlled pathway with formation of dihydropyrazolopyridines 53. 

An interesting synthetic approach to cyclic enamine ketones is provided by waste-free and quantitative solid-state reaction of the anilines 236 with cyclic 1,3-diketones such as 332 or enolized 334 (Scheme 52). The enamine ketones 333c-h are quantitatively obtained in the solid state by milling at room temperature. The melt reaction (80 °C) for 333a is not quantitative, but 333b arises with 100% yield from the melt reaction [10]. All of the solid-state reactions give 100% yield, as usual. 

Aldol reactions are often used to close five- and six-membered rings. Because of the favorable entropy (p. 211), such ring closures generally take place with ease, even where a ketone condenses with a ketone. An important example is the Robinson annulation reaction which has often been used in the synthesis of steroids and terpenes. In this reaction a cyclic ketone is converted to another cyclic ketone, with one additional six-membered ring containing a double bond. The substrate is treated with methyl vinyl ketone (or a simple derivative of methyl vinyl ketone) and a base.551 The enolate ion of the substrate adds to the methyl vinyl ketone in a Michael reaction (5-17) to give a diketone that undergoes or... 

---