1.5- Dicarbonyl compounds from unsaturated ketones

Analysis Another lactone FGl reveals the true TM (A). Our normal discormection a of an a,p-unsaturated carbonyl compound gives us the 1,5-dicarbonyl compound (B) and the ketone (C) clearly derived from phenol. Alternatively we could disconnect bond b to the keto-ester (D) with the further discormection shown ... 

The procedure described illustrates a general method for the preparation of o ,j3-unsaturated aldehydes and ketones from the enol ethers of 3-dicarbonyl compounds. 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

A mixture of 1,4-dioxane and water is often used as the solvent for the conversion of aldehydes and ketones by H2Se03 to a-dicarbonyl compounds in one step (Eq. 8.117).331 Dehydrogenation of carbonyl compounds with selenium dioxide generates the a, (i-unsaturated carbonyl compounds in aqueous acetic acid.332 Using water as the reaction medium, ketones can be transformed into a-iodo ketones upon treatment with sodium iodide, hydrogen peroxide, and an acid.333 Interestingly, a-iodo ketones can be also obtained from secondary alcohol through a metal-free tandem oxidation-iodination approach. 

The Michael addition of nitroalkanes to a,P-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a h Various natural products have been prepared via this route.157 For example, r/.v-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f... 

Keto amides (see Dicarbonyl compounds) Keto esters (see Dicarbonyl compounds) Ketones (see also Dicarbonyl compounds, Unsaturated carbonyl compounds) From alcohols by oxidation... 

We have already seen (chapter 19) the synthesis of cyclopentanone itself 24 via the useful (3-ketoester 23 from adipate esters 22. In the same way unsaturated ketones 25 disconnect with an aldol in mind to the 1,6-dicarbonyl compound 26. There may again be regioselectivity questions in the cyclisation. 

An enamine is formed from a ketone when it is necessary to synthesize a 1,5-diketone or a 1,5-dicarbonyl compound containing an aldehyde or ketone. The ketone starting material is converted to an enamine in order to increase the reactivity of the ketone and to direct the regiochemistry of addition. The process, as described in Section 23.11, is (1) conversion of a ketone to its enamine (2) Michael addition to an a,P-unsaturated carbonyl compound (3) hydrolysis of the enamine to the starting ketone. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

Michael reactions of silyl enolates or ketene silyl acetals with a, -unsaturated carbonyl compounds are among the most important carbon-carbon bond-forming processes in organic synthesis. Sc(OTf)3 was found to be effective [4], and the reactions proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, under extremely mild conditions, to give the corresponding 1,5-dicarbonyl compounds in high yields after acid work-up (Eq. 2). Silyl enolates derived from ketones, thioesters, and esters were applicable, and no 1,2-addition products were obtained. The products could, furthermore, be isolated as synthetically valuable silyl enol ethers (I) when acid-free work-up was performed. The catalyst could be recovered almost quantitatively and could be re-used. 

Whereas a stoichiometric amount of TiCU was used in the original liquid-phase reactions [87], it was found that a catalytic amount of Sc(OTf)3 was effective in solid-phase Michael reactions of PSSEEs with a,/3-unsaturated ketones [88], Whereas the 1,5-dicarbonyl compound was obtained in 38 % yield in the model reaction of PSSEE 5 with chalcone and a stoichiometric amount of TiCU, the yield was improved to 93 % by use of 20 mol % Sc(OTf)3 as a catalyst in the same reaction. In addition to improvement of the yield, it should be noted that after the reaction Sc(OTf)3 was readily removed from the product resins by filtration because it is soluble in water the insoluble titanium residue which appeared after quenching the reaction by addition of water in the TiCU-mediated reaction was often difficult to remove and would contaminate the product resins. 

Catalytic multicomponent synthesis of highly substituted pyrroles has been described. A one-pot reaction uses DBU with the commercially available thiazolium salt 513 to produce the necessary nucleophilic zwitterionic catalyst in situ, which promotes a conjugate addition of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. Subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired polysubstituted pyrrole compounds in a one-pot process in moderate to high yields (Scheme 129) <2004OL2465>. Microwave heating dramatically reduced the reaction time (from 16 h to 30 min), but offered no improvement in yields. 

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an a,/3-unsaturated carbonyl acceptor in a Vlichael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyl compound. The overall reaction is thus a three-step sequence of (1) enamine formation from a ketone, (2) Michael addition to an o ,j8-unsaturatcd carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

Other synthons for 1,3-dicarbonyl compounds that have been successfully applied include p-chloro-a,P-unsaturated ketones and aldehydes, P-dimethylamino-a,P-unsaturated ketones (easily obtained from ketones by reaction with DMFDMA), P-alkoxy-enones"" and vinyl-amidinium salts."" Alkynyl-ketones react with 5-alkyl-isothioureas, giving 2-alkylthio-pyrimidines" and propiolic acid reacts with urea to give uracil directly in about 50% yield. "" 1,3-Keto-esters with formamidine produce 4-pyrimidinones"" and C-substituted formamidines with ethyl cyanoacetate give 2-substituted-6-amino -pyrimidinones. In analogy, pyrimidines fused to other rings, for example as in quinazolines, can be made from ortho-aminonitriles " and in general, from P-enamino esters. ... 

The Knoevenagel condensation is the method of choice for the preparation of a,p-unsaturated dicarbonyl compounds and related compounds and only a few alternative methods have been developed. However, with the traditional Knoevenagel condensation there are problems with the reactivity of ketones, with the competitive Michael addition occuring in the reaction of some active methylene compounds. There is also a problem with steieocontrol in the synthesis of Knoevenagel products from unsymmetrical 1,3-dicarbonyl compounds. An alternative method is the addition of Grignard reagents to vinylogous carbamates (see Section 11.2.6). Another possibility is the reaction of a metal ketimate with malonodini-trile to yield ylidenemalonodinitriles (see Section 11.3.1.7). ... 

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