Unsaturated dicarbonyl compound

This ring system has been covered in several reviews <1984CHEC(5)305, 1984CHEC(5)607, 1987AHC(41)319, 1996CHEC-II(8)345, B-2002SOS(12)613>. The methods used for synthesis are quite diverse, and include the reactions of thiosemicarbazide with 1,3,5-tricarbonyl compounds and unsaturated dicarbonyl compounds, or their equivalents. 

Oxidation of 2,5-dialkylfurans with pyridinium chlorochromate results in high yields of, -unsaturated -dicarbonyl compounds. Similar results are obtained by peracid oxidation of furans, most frequently CPBA. It is assumed that the first step involves epoxidation as shown in Scheme 67. Mono-, di-, and trisubstituted furans are oxidized to (Z)-enediones by methyltrioxorheniumureaH202 <1998TL5651>. Mo(CO)6-catalyzed oxidation of 2,5-dialkyl furans by cumyl hydroperoxide provides (A)-enediones selectively. In the presence of Na2C03, the corresponding (Z)-isomers are obtained <2003TL835>. 

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). ... 

These data show that under atmospheric conditions the adducts will react predominantly with O2 to form hydroxycyclohexadienylperoxy radicals. The subsequent reactions of these peroxy radicals leading to ring-opening are still unclear. Several possible reaction pathways which result in formation of dicarbonyl and unsaturated dicarbonyl compounds are outlined in Fig. 10. Experiments on radical cycling (Zetzsch) indicate that the reaction of the aromatic-OH adducts with O2 produce HO2 radicals with high yield on a short timescale. The mechanism leading to this so-called "prompt HO2" formation in the aromatic compound oxidation systems is presently unclear. 

As one would expect, oximes and nitroso-compounds are frequently encountered starting materials throughout the chemistry of this group of heterocycles. Further examples of their reactions have appeared. Reaction with enol ethers produces dihydro-oxazines (260), which may be converted to pyridine N-oxides upon treatment with HCl. Dihydro-oxazines are also obtained upon treatment of 7,6-unsaturated dicarbonyl compounds with nitrous acid. Thermolysis of these products leads to nitrones (261). 

Probably the most popular carbon-carbon double-bond-forming reaction involving sulphur proceeds via the elimination of a sulphur-oxygen species. This is illustrated by a synthesis of 1,5-unsaturated dicarbonyl compounds (236) which proceeds by phenylthioalkylation of enolates (236a), using the phenyl-thioalkene (237), followed by ozonolysis and elimination of the sulphoxide moiety to provide the double bond. An alternative method for double-bond formation is shown in the preparation of alkenes R CH=CHR by reductive cleavage of the sulphide (238) with titanium salts, and demonstrates the versatility of sulphur in such double-bond formations. In the latter example... 

Dicarbonyl compounds condense with aldehydes and ketones that do not undergo self-aldol reaction. The products are afi-unsaturated dicarbonyl compounds, and the process goes by the colorful name of Knoevenagel condensation, (a) An example of a Knoevenagel condensation is given below. Propose a mechanism. 

The Knoevenagel reaction is the condensation of an active methylene compound with an aldehyde or ketone, to give an a,p-unsaturated dicarbonyl compound.(l + 2 —> 3). ... 

Indeed, when the pre-formed aminal 12 was treated with ethyl acetoacetate in ethanol, the bis-adduct 7 was isolated in good yield. Knoevenagel s proposal for the mechanism of this reaction therefore was first, condensation of the amine and aldehyde to give the aminal 12, followed by attack of this by the acetoacetate to produce a presumed 3-amino dicarbonyl intermediate 13, which would then eliminate piperidine to give the a,p-unsaturated dicarbonyl compound 14, which in this case underwent a final Michael addition with an additional equivalent of ethyl acetoacetate to provide the bis-adduct 7. 

Both A and B are 1,5-dicarbonyl compounds, but only B can be discormected in the usual way. The result is two molecules of an a,p-unsaturated ketone and we can continue the analysis ... 

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 ... 

Butyl vinyl ether reacts with aroyl chlorides using Pd(OAc)2 without a ligand to give the unsaturated ketone 839, which is a precursor of a 1-aryl-1,3-dicarbonyl compound. The reaction is regioselective /3-attack. Addition of PhjP inhibits the reaction[718]. 

Vinyl ethers and a,P unsaturated carbonyl compounds cyclize in a hetero-Diels-Alder reaction when heated together in an autoclave with small amounts of hydroquinone added to inhibit polymerisation. Acrolein gives 3,4-dihydro-2-methoxy-2JT-pyran (234,235), which can easily be hydrolysed to glutaraldehyde (236) or hydrogenated to 1,5-pentanediol (237). With 2-meth5lene-l,3-dicarbonyl compounds the reaction is nearly quantitative (238). 

The cyclization of 6-aminouracils with three-carbon fragments such as a,B- unsaturated carbonyl compounds, /3-dicarbonyl compounds, acetylenic esters, etc., is dealt with as a [3+3] reaction (see Section 2.15.5.7.2). Reactions with alkoxymethylenemalonates and related compounds are regarded as proceeding through [6 + 0 (y)] cyclizations (see Section 2.15.5.4.2). 

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. 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

The enolate anion 1 may in principle be generated from any enolizable carbonyl compound 4 by treatment with base the reaction works especially well with /3-dicarbonyl compounds. The enolate 1 adds to the a ,/3-unsaturated compound 2 to give an intermediate new enolate 5, which yields the 1,5-dicarbonyl compound 3 upon hydrolytic workup ... 

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. 

Strategy The overall result of an enamine reaction is the Michael addition of a ketone as donor to an cr,/3-unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product. The C—C bond made in the Michael addition step is the one between the a- carbon of the ketone donor and the /3 carbon of the unsaturated acceptor. 

Conjugate addition of enolate anions to a, jS-unsaturated sulphoxides followed by a sulphoxide- ketone transformation were used for the preparation of 1,4-dicarbonyl compounds and cyclopentenone derivatives (equation 355)648. 

Aldehydes (see also Dicarbonyl Compounds, Unsaturated Carbonyl Compounds, etc.)... 

The enolized form of 2-acetyl-2-cyclohexen-l-one has been synthesized in low yield by dehydrochlorination of 2-acetyl-2-chlorocyclohexanone in collidine at 180° and by elimination of acetamide from 3-acetamido-2-acetylcyclohexanone at 120-140°. The preparation of other a,/3-unsaturated /3-dicarbonyl compounds has been attempted with varying degrees of success. The... 

In a similar way, lipases catalyze Michael addition of amines, thiols [110], and even 1,3-dicarbonyl derivatives [111, 112] to a,/ -unsaturated carbonyl compounds (Scheme 5.21). 

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