Ketones, catalytic conjugated compounds

Conjugate Reduction. The carbon-carbon double bonds of various a, 8-unsaturated ketones and related compounds can be selectively reduced with a heterogeneous palladium catalyst. When nonpolar solvents such as toluene were employed, 1,4-reduction products of a,/8-unsaturated ketones, esters, amides, and nitriles were obtained in high yields (87-100%) with high chemoselectivities in the presence of a catalytic amount of Pd/C(2.5-5 mol %) and acetic acid. Highly-polar solvents enhanced 1,2-reduction to afford alcohols as a result of overreduction. 

Recall aldol 33 from Section 22.3 and envision a reaction in which it is heated in benzene with a catalytic amount ofp-toluenesulfonic acid (p-TsOH). The product under these conditions is 56, where loss of water generates a carbon-carbon double bond (an alkene). Aldehyde 5 is called a conjugated ketone (also called an a,(3-unsaturated ketone see Chapter 23, Section 23.2) because the carbonyl is attached directly to one of the sp carbon atoms of the alkene unit. The major product is drawn as the J-isomer, which is usually more stable than the Z-isomer. Note that the phenyl group is also attached to an sp carbon of the alkene, making 56 even more conjugated. When such extended conjugation occurs, dehydration is very easy and it is sometimes difficult to isolate the aldol. Many examples of conjugated compounds are known and some of their unique chemistry is discussed in Chapter 23. 

The nitro-Mannich reaction has been reviewed (266 references), covering a variety of its manifestations simple nitroalkane versus more functionalized nitro compounds, non-catalytic, metal ion- and organo-catalytic, conjugate and cycloadditions and so on. 0 New chiral modular bifimctional iminophosphorane superbase organocatalysts allow 0 metal-free enantioselective addition of nitromethane to otherwise unreactive ketone-derived imines. The readily scalable reaction yields -nitroamines (20) with a fully 0 substituted carbon atom, in up to 95% ee. 

Electrocatalytic hydrogenation has the advantage of milder reaction conditions compared to catalytic hydrogenation. The development of various electrode materials (e.g., massive electrodes, powder cathodes, polymer film electrodes) and the optimization of reaction conditions have led to highly selective electrocatalytic hydrogenations. These are very suitable for the conversion of aliphatic and aromatic nitro compounds to amines and a, fi-unsaturated ketones to saturated ketones. The field is reviewed with 173 references in [158]. While the reduction of conjugated enones does not always proceed chemoselectively at a Hg cathode, the use of a carbon felt electrode coated with polyviologen/Pd particles provided saturated ketones exclusively (Fig. 34) [159]. 

The synthetic application of organocopper compounds received a major impetus from the study of the catalytic effect of copper salts on reactions of Grignard reagents with y.,(i-unsaturated ketones.1 Whereas Grignard reagents normally add to conjugated enones to give the 1,2-addition product, the presence of catalytic amounts of Cu(I) results in... 

The conjugate addition of heteronucleophiles to activated alkenes has been used very often in organic synthesis to prepare compounds with heteroatoms [3 to various activating functional groups, e.g. ketones, esters, nitriles, sulfones, sulfoxides and nitro groups. As in the Michael reaction, a catalytic amount of a weak base is usually used in these reactions (with amines as nucleophiles, no additional base is added). 

A Michael addition consists of the addition of the enolate of an active-methylene compound, the anion of a nitroalkane, or a ketone enolate to an acceptor-substituted alkene. Such Michael additions can occur in the presence of catalytic amounts of hydroxide or alkoxide. The mechanism of the Michael addition is shown in Figure 13.67. The addition step of the reaction initially leads to the conjugate base of the reaction product. Protonation subsequently gives the product in its neutral and more stable form. The Michael addition is named after the American chemist Arthur Michael. 

The indium hydride compound, generated in situ from sodium borohydride and a catalytic amount of indium(m) chloride, selectively reduces carbon-carbon double bonds in conjugated alkenes such as a,a-dicyano olefins, a,/3-unsaturated nitriles, cyano esters, cyanophosphonates, diesters, and ketones (Scheme 107).372 This combined reagent system in acetonitrile reduces exclusively the a,/3-carbon-carbon double bond in a,/3,7,<5-unsaturated diaryl ketones, dicarboxylic esters, cyano esters, and dicyano compounds (Scheme 108).373... 

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. 

Enol Amination. The Cu[(S,5)-t-Bu-box] (OTf)2 complex was found to be optimal for promoting the enantioselective conjugated addition of enolsilanes to azodicarboxylate derivatives (eq 13). This methodology provides an enantioselective catalytic route to differentially protected ot-hydrazino carbonyl compounds. Isomerically pure enolsilanes of aryl ketones, acylpyrroles, and thioesters add to the azo-imide in greater than 95% ee. The use of an alcohol additive was critical to achieve catalyst turnover. Amination of cyclic enolsilanes was also possible. For example, the enolsilane of 2-methylindanone provides the adduct containing a tetrasubstituted stereogenic center in 96% ee and high yield. Acyclic (Z)-enolsilanes react in the presence of a protic additive with enantioselection up to 99%. ... 

The C-H bond cleavage of active methylene compounds with a transition metal catalyst is another method for the functionalization of these C-H bonds. To date, several reactions have been developed. In particular, the asymmetric version of this type of catalytic reaction provides a new route to the enantioselective construction of quaternary carbon centers. One of the most attractive research subjects is the catalytic addition of active methylene C-H bonds to acetylenes, allenes, conjugate ene-ynes, and nitrile C-N triple bonds. The mthenium-catalyzed reaction active methylene compounds with carbonyl compounds involving aldehyde, ketones, and a,y3-unsatu-rated ketones and esters is described in this section. 

Preparation of imines and enamines from carbonyl compounds and amines can be achieved with a dehydrating agent under acid/base catalysis [563]. Basically, primary amines afford imines unless isomerization to an enamine is favored as a result of conjugation, etc (see Eq. 252), and secondary amines afford iminium salts or enamines. These transformations can be conducted efficiently with a catalytic or stoichiometric amount of a titanium salt such as TiCU or Ti(0-/-Pr)4. Equation (247) illustrates an advantageous feature of this method in the imination of a hindered ketone. f-Butyl propyl ketone resisted the formation of the imine even by some methods reported useful for sterically hindered ketones [564,565]. The TiCU-based method works well, however, for this compound, giving the desired imine in high yield within a relatively short reaction period [566]. Imine derivatives such as iV-sulfonylimines could be... 

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