Reduction conjugate additions

As noted in Chapter 1, this is one of the best methods for generating a specific enolate of a ketone. The enolate generated by conjugate reduction can undergo the characteristic alkylation and addition reactions that are discussed in Chapters 1 and 2. When this is the objective of the reduction, it is important to use only one equivalent of the proton donor. Ammonia, being a weaker acid than an aliphatic ketone, does... 

Literature search showed the dihydro-chromandione motif in 53, or other related system, is relatively unknown and/or under-investigated, and the proposed conjugate reduction to this system was unprecedented. Fortuitously, our attempt employed NaBH4 in MeOH at 0 °C, and while a new spot was rapidly produced, the conversion was slow. When the solution was warmed to ambient temperature and additional aliquots of NaBH4 were added, a mixture of diketone 55 and hydroxy ketone 56 was isolated. In subsequent trials, 55 could be reduced cleanly to 56 especially at elevated temperatures. 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

Reduction of a., -unsaturated carbonyl compounds. Hydrosilanes, particularly (QH,)2SiH2, in the presence of Pd(0), and a Lewis acid, particularly ZnCl2, can effect selective conjugate reduction of unsaturated ketones, aldehydes, and carboxylic acid derivatives. Chloroform is the solvent of choice. In addition, 1 equiv. of water is required. Experiments with D,0 and (C6H,),SiD2 indicate that... 

Conjugate hydrogenation. The combination of zinc and NiCl2 (9 1) effects conjugate reduction of a,(3-enones in an aqueous alcohol in which both the enone and product are completely soluble. Ultrasound increases the rate and the yields. Presumably the salt is reduced to a low-valent form that is absorbed on the zinc. No reduction takes place with a 1 1 Zn-NiCl2 couple. The method is not applicable to a,(3-unsaturated enals. Isolated double bonds are also reduced by this method, but this hydrogenation can be inhibited by addition of ammonia or triethylamine. 

Triple bonds in side chains of aromatics can be reduced to double bonds or completely saturated. The outcome of such reductions depends on the structure of the acetylene and on the method of reduction. If the triple bond is not conjugated with the benzene ring it can be handled in the same way as in aliphatic acetylenes. In addition, electrochemical reduction in a solution of lithium chloride in methylamine has been used for partial reduction to alkenes trans isomers, where applicable) in 40-51% yields (with 2,5-dihydroaromatic alkenes as by-products) [379]. Aromatic acetylenes with triple bonds conjugated with benzene rings can be hydrogenated over Raney nickel to cis olefins [356], or to alkyl aromatics over rhenium sulfide catalyst [54]. Electroreduction in methylamine containing lithium chloride gives 80% yields of alkyl aromatics [379]. 

Cordova has described a reductive Mannich protocol that proceeds with high chemo-, diastereo- and enantioselectivity [179]. Conjugate reduction of p,p-disub-stituted enal 118 with Hantzsch ester 119 in the presence of 30 (10 mol%) and benzoic acid (10 mol%) (63 h, -20 °C) followed by addition of a-iminoglyoxylate 120 and stirring for a further 24 h gave the product (121) with excellent levels of relative and absolute stereocontrol (10 1-50 1 dr 95-99% ee) (Scheme 49). 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

Conjugate addition to 1 proceeded across the open face of the bicyclic system to give an enolate, condensation of which with the enantiomerically-pure aldehyde 8 gave the enone 9. Conjugate reduction of the enone also removed the benzyl ether, to give the alcohol. Conversion of the alcohol to the azide gave 10. Ozonolysis followed by selective reduction then gave 2. 

Lithium butyldimethylzincate, 221 Lithium sec-butyldimethylzincate, 221 Organolithium reagents, 94 Organotitanium reagents, 213 Palladium(II) chloride, 234 Titanium(III) chloride-Diisobutylalu-minum hydride, 303 Tributyltin chloride, 315 Tributyl(trimethylsilyl)tin, 212 3-Trimethylsilyl-l, 2-butadiene, 305 Zinc-copper couple, 348 Intramolecular conjugate additions Alkylaluminum halides, 5 Potassium t-butoxide, 252 Tetrabutylammonium fluoride, 11 Titanium(IV) chloride, 304 Zirconium(IV) propoxide, 352 Miscellaneous reactions 2-(Phenylseleno)acrylonitrile, 244 9-(Phenylseleno)-9-borabicyclo[3.3.1]-nonane, 245 Quina alkaloids, 264 Tributyltin hydride, 316 Conjugate reduction (see Reduction reactions)... 

Conjugate reduction of a,/l-enals and -enones. Tri-n-butyltin hydride in the presence of tetrakis(triphenylphosphine)palladium effects conjugate reduction of a, /J-unsaturated aldehydes and ketones in the presence of a proton source (water, acetic acid). Yields are improved by addition of a radical scavenger.15 Double bonds bearing... 

Conjugate reductions of a,(l-enones.2 a., fi-Enones react with triisobutylaluminum in pentane solution to give products of 1, 2-addition and 1, 2-reduction. The former... 

Conjugate reduction of a, -enones. The combination of BujSnH and Cul solubilized with LiCl (2.5 equiv.) results in a hydridocuprate (1) that reduces a,P-enones to the ketones in 67-98% yield. Addition of ClSi(CH3)3 can be beneficial. 

Many of the copper-mediated transformations summarized in the previous sections of this chapter can also be performed efficiently with catalytic amounts of copper salts or reagents. Indeed, some of the copper-catalyzed reactions have been discovered before the development of stoichiometric organocopper reagents. The focus of the last decade has been put on new copper-catalyzed transformations (e.g., conjugate reductions) and in particular on the discovery of chiral copper catalysts for highly enantioselective 1,4-addition and S -substitution reactions of prochiral substrates. 

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