A,/3-unsaturated carbonyl compound

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

Considerable attention has been devoted to the preparation and chemistry of a,/3-unsaturated carbonyl compounds, which are valuable intermediates in organic synthesis [125]. Acid-promoted hydrolysis of alkoxyallenes has therefore frequently been employed to prepare a variety of functionalized a,/8-unsaturated carbonyl compounds [12b, 41, 44, 60, 126]. A recent example is illustrated in Scheme 8.54with C-l-silylated alkoxyallene 218 as a convenient starting material for the synthesis of bicyclo[5.4.0]undec-4-en-2-one 221. Sequential deprotonation and silylation at the terminal C=C bond efficiently transformed 218 into a 1,3-disilylated allene which was converted into the acryloylsilane 219 under acidic conditions. A [3 + 4] annula-tion of intermediate 219 with lithium dienolate 220 furnished bicydic compound 221 in good yield [127]. 

Dialkoxy-3,4-dihydropyrans are produced under mild conditions from the zinc chloride-catalyzed cycloaddition of a,/8-unsaturated carbonyl compounds with ketene acetals (Scheme 47) (81RTC13). At lower temperatures a [2 + 2]-cycloaddition leads to oxetanes, but on warming these compounds revert to starting materials and thence to the thermodynamically favoured dihydropyrans. 

Isoprene can be polymerized in the laboratory by a radical chain mechanism. As shown in the following equations, the odd electron of the initially produced radical is delocalized onto both C-2 and C-4 by resonance. Either of these carbons may add to another isoprene monomer to continue the chain reaction. If C-2 adds, the process is called 1,2-addition if C-4 adds, the process is called 1,4-addition. (This is similar to the addition of electrophiles to conjugated dienes discussed in Section 11.13 and the addition of nucleophiles to a,/8-unsaturated carbonyl compounds described in Section 18.10.)... 

The reaction of a,/8-unsaturated carbonyl compounds with enamines also leads to dihydropyrans, although it is not always possible to isolate these since they react further to give either ring-opened by-products or bicyclic derivatives arising from a Stork annelation. There has been considerable discussion on the mechanism of this reaction, although the initial nucleophilic attack of the enamine on the /3-carbon of the diene is not in doubt (63JA207). It is possible that a zwitterionic species is involved, either as an intermediate or merely in equilibrium with the dihydropyran (67JCS(C)226). 

Although reaction of a,/3-unsaturated carbonyl compounds with diazo compounds generally gives cyclopropyl compounds in low yields, in the presence of SbFs, the cyclopropanation of a,)8-unsaturated carbonyl compounds with diazocarbonyl compounds proceeds very well to produce the desired products in good yields (Eq. 22) [41]. 

The strong Lewis acids HC(py)3M (NO)2 (M = Mo, W) (see also Section 14.3.1), with Lewis acidities comparable with that of BF3, were shown by Faller et al. to coordinate and activate a,/8-unsaturated carbonyl compounds via formation of an M-O a-bond. These complexes, in nitromethane, catalyze Diels-Alder reactions with dienes (e.g. butadiene). They also readily polymerize butadiene when a less basic dienophile com-... 

Instead of relying on ionic reactions to execute the crucial assembling of two glycosidic units, one may profitably consider radical reactions [12,16]. An anomeric radical, being an alkoxyalkyl radical, will behave as a nucleophile, and its high-lying SOMO will better interact with the LUMO of an electron-poor alkene, typically a, 8-unsaturated carbonyl compounds or similar derivatives. In other words, in intermolecular reactions, the radical acceptor should be activated enough to compete efficiently with an H-donor. 

Addition to a,]8-unsaturated carbonyl compounds. Michael addition. Discussed in Sec. 27.7. 

AU considered condensation reactions have some anomalies for the a,j8-unsaturated carbonyl compounds. Most reagents with active hydrogen atoms can react not only with carbonyl groups but also with polarized conjugated double bonds C = C. As a result of this regularity, three products, instead of the estimated one target derivative, are formed in the reactions of a,)8-unsaturated carbonyl compounds with O-alkyl hydroxylamines ... 

The net effect of the Stork reaction is the Michael addition of a ketone to an a,)8-unsaturated carbonyl compound. For example, cyclohexanone reacts w ith the cyclic amine pyrrolidine to yield an enamine further reaction w ith 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). 

Organozinc carbenoids generated from aryl and a,)8-unsaturated carbonyl compounds by treatment with zinc and l,2-bis(chlorodimethylsilyl)ethane have been trapped with alkenes to give cyclopropanes. The reaction is limited as it cannot be applied to all carbonyl compounds in general examples are the formation of 25 and 26. ... 

The 2,3-dihydro-l//-pyrazole obtained from the reaction of hydrazine with an a-)8-unsaturated carbonyl compound will sometimes give a sufficient proportion of the 4,5-dihydro-3i/-pyrazole tautomer at equilibrium so that it is possible just to heat the 1//-tautomer to eliminate nitrogen and form a cyclopropane. In other cases, it is necessary to reduce the 1//-tautomer and oxidize back to the 3 -form. It is also possible to use the conversion of the H- to the 3//-tautomer to introduce substituents at C3 of the 4,5-dihydro-3//-pyrazole and hence into the cyclopropane. The reaction of 4-methylpent-3-en-2-one with hydrazine gave 2,2,4-trimethyl-2,3-dihydro-lH-pyrazole (1). Treatment with lead tetraacetate gave the 3-acetoxy derivative 2 and on thermolysis, l-acetoxy-l,2,2-trimethylcyclopropane (3). Alternatively, tosylation and reaction with methyllithium gave 3,3,5,5-tetramethyl-4,5-dihydro-3//-pyrazole (4) which on thermolysis or photolysis gave 1,1,2,2-tetramethylcyclopropane route to tetramethylcy-... 

Kelly and colleagues explored the use of bisphenylenediol 103 as a catalyst in Diels-Alder reactions of a,)8-unsaturated carbonyl compounds. Activation of the dieno-phile occurred through double hydrogen bonding of the two hydroxyl functions on 103 to the carbonyl group on the dienophile. The reaction of cyclopentadiene with methyl vinyl ketone (equation 31) at ambient temperature showed, after a reaction time of 10 minutes, 3% of product formation in the absence of 103 against 90% of product formation in the presence of 0.4 equivalents of 103. 

Two kinds of selective asymmetric hydrosiiyiation of a,)8-unsaturated carbonyl compounds have been performed. The 1,4-addition induces asymmetry on a /3-carbon to give optically active saturated carbonyl compounds ... 

Azran, J., 0. Buchman, I. Amer, and J. Blum, Selective Hydrogenation of a, 8-Unsaturated Carbonyl Compounds by Rhodium Trichloride and Aliquat 336 in a Two-Phase Liquid System,7. MoL CataL, 34, 229 (1986). 

Perhaps the most successful approach for promoting the 47r participation of 1-oxabutadiene systems in intermolecular Diels-Alder reactions employs a,/8-unsaturated carbonyl compounds substituted with an additional C-3 (a) electron-withdrawing group. The addition of the C-3 electron-withdrawing substituent increases the electron-deficient character of the oxabutadiene system, decreases the LUM0oxabutadiene, and as expected, enhances the observed [4 + 2] cycloaddition rate and regioselec-... 

Ethynylnickel compounds, prepared from aluminum acetylides and nickel acetylace-tonate pretreated with diisobutylaluminum hydride, also undergo insertions with a, 8-unsaturated carbonyl compounds to form enolates which hydrolyze to 4-ynones . Similarly, vinylnickel derivatives from vinylzirconium compounds and nickel acetylace-tonate add to a, 8-unsaturated ketones to give enolates ... 

Several reactions in biological systems involve addition to a,)8-unsaturated carbonyl compounds. The following are examples of conjugate addition reactions that occur in biological systems. Notice that the carbonyl groups are either unreactive (COO ) or have low reactivity (the CoA ester) toward the nucleophile, so conjugate addition occurs in each case. The last reaction is an important step in the biosynthesis of fatty acids (Section 19.21). 

All these reactions take place by the same mechanism A base removes a proton from the a-carbon of the carbon acid, the enolate adds to the 8-carbon of an a, 8-unsaturated carbonyl compound, and the a-carbon obtains a proton from the solvent. 

By analyzing a Robinson annulation, we will be able to determine which part of the molecule comes from which reactant. This, then, will allow us to choose appropriate reactants for any other Robinson annulation. Analysis shows that the keto group of the cyclo-hexenone comes from the a, 8-unsaturated carbonyl compound and the double bond results from attack of the enolate of the a,j8-unsaturated carbonyl compound on the carbonyl group of the other reactant. Thus, we can arrive at the appropriate reactants by cutting through the double bond and cutting between the p- and y-carbons on the other side of the carbonyl group. 

Enols are particularly reactive toward carbonyl compounds and toward electrophilic alkenes such as a, 8-unsaturated carbonyl compounds. For example, the Robinson annulation proceeds under acidic conditions as well as under basic conditions, as shown in the next example. Under acidic conditions, the electrophilic carbonyl compound is protonated to make a carbocation before it is attacked by the enol. 

Enantioselective conjugate addition to a,8-unsaturated carbonyl compounds has been performed using two alternative strategies. The possibility of achieving useful... 

Condensation of iV-amino derivative (504) with various a,)8-unsaturated carbonyl compounds and )8-dicarbonyl compounds leads to the bicyclic derivatives (505) and (506), respectively <88MI 831-01,90MI 83i-0i>. Similarly, amino derivative (507) treated with diethyl ethynedicarboxylate provides (508) (Scheme 109) <85MI 83l-oi>. 

The Diels-Alder reaction of simple a,/3-unsaturated carbonyl compounds generally proceed only under vigorous thermal reaction conditions (150-250°C), " ° even when electron-rich dienophiles are employed. Under vigorous thermal conditions, dimerization and polymerization of the a,jS-unsaturated carbonyl compounds or thermally sensitive electron-rich dienophiles will compete effectively with the desired [4 + 2] cycloaddition. Two experimental methods have been employed to facilitate the 47t participation of simple a,/8-unsaturated carbonyl compounds in Diels-Alder reactions. Lewis acid catalysis has proved effective in accelerating the rate of [4 + 2] cycloadditions of simple a,/3-unsaturated carbonyl compounds with electron-rich olefins [Eqs. (3)-(5)], and it is surprising that this technique has not been... 

In studies extending the thermal and Lewis acid-catalyzed [2 + 2] cycloadditions of electron-rich olefins with carbonyl groups and electron-deficient olefins, the reactions of ketene acetals with extended ir systems including )8,/3-dicyano a,/8-unsaturated carbonyl compounds have been investigated." The reaction of 6 with ketene acetals and tetramethox-yethylene provided the regiospecific [4 + 2] cycloadducts with no apparent competing [2 + 2] cycloaddition [Eq. (29)]. "... 

In a second part, the reactivity of a-phenylselanyl enolates, derived from ketones, esters, lactones and a, 8-unsaturated carbonyl compounds, is discussed. Alkylation, aldolisation and Michael reactions are considered as the use of selenium-stabiUzed carbanions in the natural product synthesis. Others a-fimctionalyzed species are also presented. 

The often difficult conjugate addition of alkynyl organometallic reagents to enones is greatly facilitated by TMSOTf. In particular, alkynyl zinc reagents (normally unreactive with a, 8-unsaturated carbonyl compounds) add in good yield (eq 22). The proportion of 1,4-addition depends on the substitution pattern of the substrate. 

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