P-Unsaturated Carbonyl Compounds

Problem 20.35 What epoxide is needed to convert CH3CH2MgBr to each of the following alcohols, after quenching with water  

Because the two it bonds are conjugated, the electron density in an oc,P-unsaturated carbonyl compound is delocalized over four atoms. Three resonance structures show that the carbonyl carbon and the P carbon bear a partial positive charge. This means that a,P-unsaturated carbonyl compounds can react with nucleophiles at two different sites. 

Addition of a nucleophile to the carbonyl carbon, called 1,2-addition, adds the eiements of H and Nu across the C=0, forming an allylic alcohol. 

Chapter 20 Introduction to Carbonyl Chemistry Organometallic Reagents Oxidation and Reduction 

Both 1,2- and 1,4-addition result in nucleophilic addition of the elements of H and Nu. 

The opening of epoxide rings with negatively charged nucleophiles was discussed in Section 9.15A. 

The reaction follows the same two-step process as the opening of epoxide rings with other negatively charged nucleophiles— that is, nucleophilic attack from the back side of the epoxide ring, followed by protonation of the resulting alkoxide. In unsymmetrical epoxides, nucleophilic attack occurs at the less substituted carbon atom. 

Both functional groups of a, 3-unsaturated carbonyl compounds have Jt bonds, but individually, they react with very different kinds of reagents. Carbon-carbon double bonds react with electrophiles (Chapter 10) and carbonyl groups react with nucleophiles (Section 20.2). What happens, then, when these two functional groups having opposite reactivity are in close proximity  

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So far in this section we have combined enolate anions with other carbonyl compounds by direct attack at the carbonyl group. We can expand the scope of this reaction by using a,p-unsaturated carbonyl compounds as the electrophiles. This is the Michael reaction. Remind yourself of tliis by writing out the mechanism of a Michael reaction such as ... 

The Michael reaction plays a part in some more extended synthetic sequences of great importance. Analyse TM 116 as an a,p-unsaturated carbonyl compound and continue your analysis by the Michael reaction. 

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 carbonyl group withdraws rr electron density from the double bond and both the carbonyl carbon and the p carbon are positively polarized Their greater degree of charge separation makes the dipole moments of a p unsaturated carbonyl compounds signifi cantly larger than those of comparable aldehydes and ketones... 

The diminished rr electron density m the double bond makes a p unsaturated aide hydes and ketones less reactive than alkenes toward electrophilic addition Electrophilic reagents—bromine and peroxy acids for example—react more slowly with the carbon-carbon double bond of a p unsaturated carbonyl compounds than with simple alkenes... 

Ordinarily nucleophilic addition to the carbon-carbon double bond of an alkene is very rare It occurs with a p unsaturated carbonyl compounds because the carbanion that results IS an enolate which is more stable than a simple alkyl anion... 

CONJUGATE ADDITION OF ORGANOCOPPER REAGENTS TO a,p-UNSATURATED CARBONYL COMPOUNDS... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Ethyl acetoacetate behaves similarly to diethyl malonate in its reactivity toward a p unsaturated carbonyl compounds Give the structure of the product of the following reaction sequence... 

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). 

A particularly useful reaction has been the selective 1,2-reduction of a, P-unsaturated carbonyl compounds to aHyUc alcohols, accompHshed by NaBH ia the presence of lanthanide haUdes, especially cerium chloride. Initially appHed to ketones (33), it has been broadened to aldehydes (34) and acid chlorides (35). NaBH by itself gives mixtures of the saturated and unsaturated alcohols. 

AldolRea.ctlons, In the same way, hydroxybenzaldehydes react readily with aldehydes and ketones to form a,P-unsaturated carbonyl compounds in the Claisen-Schmidt or crossed-aldol condensation (60). 

Mesityl Oxide. Mesityl oxide (MSO) (4-metliyl-3-penten-2-one) is an oily colorless liquid with an unpleasant odor. It exhibits the versatiUty and unusual reactivity associated with conjugated a,P unsaturated carbonyl compounds (172). On standing ia air, mesityl oxide slowly forms bis(3,5,5-trimethyl-l,2-dioxolanyl)-3-peroxide (173). 

The highly ionic thaHic nitrate, which is soluble in alcohols, ethers, and carboxyhc acids, is also a very useful synthetic reagent. Oxidation of olefins, a,P-unsaturated carbonyl compounds, P-carbonyl sulfides, and a-nitrato ketones can aH be conveniently carried out in good yields (31,34—36). 

A significant advance in the synthesis of monoorganotin trihaHdes was the preparation of P-substituted ethyl tin trihaHdes in good yield from the reaction of stannous chloride, hydrogen haHdes, and a,P-unsaturated carbonyl compounds, eg, acryHc esters, in common solvents at room temperature and atmospheric pressure (153,154). The reaction is beHeved to proceed through a solvated trichlorostannane intermediate (155) ... 

Subsbtuting vinylic hydrogen in a,P-unsaturated carbonyl compounds with vinylic fluonne does not affect their dienophilic character negatively Indeed, 3,3-difluoroacrylic acid is more reactive toward furan than its nonfluonnated counterpart [95] (equation 81) Consistent with this observation is the fact that tctrafluorobenzoquinone forms only a bis-Diels-Alder adduct m 68% yield in its reaction with cyclopentadiene at room temperature [96, 97 ... 

On the other hand, the polarization of electron density in a,p-unsaturated carbonyl compounds makes their p-carbon atoms rather electrophilic. Some chemical consequences of this enhanced electrophilicity are described in the following section. 

Epoxidation of aldehydes and ketones is the most profound utility of the Corey-Chaykovsky reaction. As noted in section 1.1.1, for an a,P-unsaturated carbonyl compound, 1 adds preferentially to the olefin to provide the cyclopropane derivative. On the other hand, the more reactive 2 generally undergoes the methylene transfer to the carbonyl, giving rise to the corresponding epoxide. For instance, treatment of P-ionone (26) with 2, derived from trimethylsulfonium chloride and NaOH in the presence of a phase-transfer catalyst Et4BnNCl, gave rise to vinyl epoxide 27 exclusively. ... 

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 arylation of alkenes by treatment with a diazonium chloride (or bromide) solution and cupric chloride (or bromide) is called the Meerwein arylation reaction, after its discoverer (Meerwein et al., 1939). Originally, it was discovered using a,P-unsaturated carbonyl compounds, namely coumarin (Scheme 10-43) and cinnamic derivatives (Schemes 10-44 and 10-45). As Scheme 10-45 shows, the Meerwein reac-... 

Aminodienylesters. I the cycloaddition reactions of ferf-aminodienylester with a,p-unsaturated carbonyl compounds, styrenes and quinones [148]... 

The a-seleno and a-sulfenyl carbonyl compounds prepared by this reaction can be converted to a,P-unsaturated carbonyl compounds (17-11). The sulfenylation reaction has also been used as a key step in a sequence for moving the position of a carbonyl group to an adjacent carbon. ... 

For a review of reductions of a,p-unsaturated carbonyl compounds with metals in liquid NH3, see Caine, D. Org. React., 1976, 23, 1. 

Under the principle of vinylogy, the active hydrogen can be one in the y position of an a,P-unsaturated carbonyl compound ... 

The enantioselective 1,4-addition addition of organometaUic reagents to a,p-unsaturated carbonyl compounds, the so-called Michael reaction, provides a powerful method for the synthesis of optically active compounds by carbon-carbon bond formation [129]. Therefore, symmetrical and unsymmetrical MiniPHOS phosphines were used for in situ preparation of copper-catalysts, and employed in an optimization study on Cu(I)-catalyzed Michael reactions of di-ethylzinc to a, -unsaturated ketones (Scheme 31) [29,30]. In most cases, complete conversion and good enantioselectivity were obtained and no 1,2-addition product was detected, showing complete regioselectivity. Of interest, the enantioselectivity observed using Cu(I) directly in place of Cu(II) allowed enhanced enantioselectivity, implying that the chiral environment of the Cu(I) complex produced by in situ reduction of Cu(II) may be less selective than the one with preformed Cu(I). 

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