Reduction of unsaturated aldehydes and ketones

Aluminium isopropoxide is a specific reagent for the reduction of carbonyl group to hydroxyl group. Since it reduces the carbonyl group in presence of other reducible groups like nitro or a double bond which remain unaffected, aluminium isopropoxide is largely employed for the reduction of unsaturated aldehydes and ketones. 

Selective 1,4-reduction of unsaturated aldehydes and ketones by 6 occurs smoothly in THF between —25 °C and room temperature within a few hours (Eq. 5.7). Particularly noteworthy is the realization that phosphines are noticeably absent from the reaction medium. The analogous combination of CuCl/BusSnH in N-methyl-2-pyrrolidinone (NMP) or DMF does not behave identically [22], failing to react with the hindered substrate isophorone, whereas a 72% yield of the corresponding reduced ketone is formed with reagents XCu(H)Li/Bu3SnH. Nonetheless, a form of CuH is being generated in this more polar medium, effectively utilized by Tanaka to arrive at 3-norcephalosporin 8 upon reaction with allenic ester 7 (Scheme 5.3). 

Selective Reduction of Unsaturated Aldehydes and Ketones by a Vapor-Phase Hydrogen Transfer Reaction... 

The continued search for methods to effect lj4-reductions using catalytic quantities of CuH produced several reports late in the last decade. The basis for these new developments lies in an appreciation for the fadlitj with which various silyl hydrides undergo transmetalation vdth copper enolates. Thus a limited amount of (PhjP)CuH (0.5-5 mol%) in the presence of PhSiHj (1.5 equivalents relative to substrate) reduces a varietj of unsaturated aldehydes and ketones in high yields (Eq. 5.14) [29]. Limitations exist with respect to the extent of steric hindrance in the educt Similar results can be achieved using BusSnH in place of PhSiHj although the latter hydride source is the appropriate (albeit expensive) choice from the environmental perspective. 

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

Zinc borohydride has been found to effect very efficient reductive amination in the presence of silica. The amine and carbonyl compound are mixed with silica and the powder is then treated with a solution of Zn(BH4)2. Excellent yields are also obtained for unsaturated aldehydes and ketones.96... 

Very few enzyme-catalysed reactions involving the reduction of alkenes have achieved any degree of recognition in synthetic organic chemistry. Indeed the only transformation of note involves the reduction of a, (3-unsaturated aldehydes and ketones. For example, bakers yeast reduction of (Z)-2-bromo-3-phenylprop-2-enal yields (S)-2-bromo-3-phenylpropanol in practically quantitative yield (99 % ee) when a resin is employed to control substrate concen-tration[50]. Similarly (Z)-3-bromo-4-phenylbut-3-en-2-one yields 2(5), 3(,S)-3-bromo-4-phenylbutan-2-ol (80% yield, >95% ee)[51]. Carbon-carbon double bond reductases can be isolated one such enzyme from bakers yeast catalyses the reduction of enones of the type Ar—CH = C(CH3)—COCH3 to the corresponding (S)-ketones in almost quantitative yields and very high enantiomeric excesses[52]. 

Catalysts suitable specifically for reduction of carbon-oxygen bonds are based on oxides of copper, zinc and chromium Adkins catalysts). The so-called copper chromite (which is not necessarily a stoichiometric compound) is prepared by thermal decomposition of ammonium chromate and copper nitrate [50]. Its activity and stability is improved if barium nitrate is added before the thermal decomposition [57]. Similarly prepared zinc chromite is suitable for reductions of unsaturated acids and esters to unsaturated alcohols [52]. These catalysts are used specifically for reduction of carbonyl- and carboxyl-containing compounds to alcohols. Aldehydes and ketones are reduced at 150-200° and 100-150 atm, whereas esters and acids require temperatures up to 300° and pressures up to 350 atm. Because such conditions require special equipment and because all reductions achievable with copper chromite catalysts can be accomplished by hydrides and complex hydrides the use of Adkins catalyst in the laboratory is very limited. 

Scheme 35 Imidazolidinone catalysed hydride reduction of a, 3-unsaturated aldehydes and ketones...

Reductive silylation of carbonyl compounds.2 This reagent in the presence of a threefold excess of chlorotrimethylsilane reduces saturated and a,/3-unsaturated aldehydes and ketones, even highly enolizable ones, to trimethylsilyl ethers. Indeed this reaction is usually superior, in respect to yield, to reduction with 1 alone. Examples ... 

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... 

Abbreviations Amberlite IRA 400 borohydride resin, commercially available resin for selective reduction of a,/3-unsaturated aldehydes and ketones DBU, 1,8-diazabicyclo [5.4.0]undec-7-en DCM, dichloromethane DMF, dimethylformamide EtOAc, ethyl acetate Et2NH, diethylamine Et3N, triethylamine HBr, hydrobromic acid HC1, hydrochloric acid MS, mass spectrometry MeOH, methyl alcohol NH4OH, ammonium hydroxide NaBHj, sodium borohydride NaOH, sodium hydroxide NaOMe, sodium methanolate PAMAM, polyaminoamide resin (commercially available) RT, room temperature THF, tetrahydrofuran. 

Unconjugated unsaturated aldehydes and ketones can be reduced without affecting the carbonyl group, particularly with a Pd catalyst Ni and Pt have been used, but the reduction must be terminated after the addition of 1 equiv. of hydrogen. The nitrile group also can survive the reduction of carbon-carbon unsaturation in the same molecule. 

The reduction of a,p-unsaturated aldehydes and ketones by NaBH4 leads, in general, to substantial amounts of fully saturated alcohols. In alcoholic solvents, saturated -alkoxy alcohols can be formed via conjugate addition of the solvent. This latter process becomes the main reaction path when reduction is performed in 2-propanol in the presence of sodium isopropoxide. In base, a homoallylic alcohol can become the major product of borohydride reduction of an enone. Analysis of the influence of substrate structure on NaBH4 reduction has shown that increasing steric hindrance on the enone increases 1,2-attack. ... 

Sodium cyanoborohydride (NaBHsCN) or tetrabutylammonium cyanoborohydride in acidic methanol or acidic HMPA reduces a,p-unsaturated aldehydes and ketones to the corresponding allylic alcohols. This system is limited to enones in which the double bond is not further conjugated, in which case the allylic hydrocarbon is formed in substantial amounts. Thus, reduction of chalcone gives mainly 1,3-di-phenylpropene (48%) as well as 26% of the allylic ether. Cyclic enones are also not good substrates, as competing 1,4-addition gives large fractions of saturated alcohols. ... 

Anionic activation of Si—H bonds " by fluorides, such as KF or CsF, or by potassium phthalate, KHCO3, KSCN, etc., yields powerful hydridic reagents that reduce the carbonyl group of aldehydes, ketones and esters, " and 1,2-reductions of a,p-unsaturated aldehydes and ketones occur with high selectivity. " The analogous activation of hydridosllanes by fluoride ions is also achieved under acidic conditions with boron trifluoride etherate, in which the latter compound is consumed and fluorosilanes are formed. ... 

Indeed, a combination of tributyltln hydride, Pd° catalyst and a weak acid, such as ammonium chloride, forms an effective, yet mild tool for conjugate reduction of a, -unsaturated aldehydes and ketones. Similar results are obtained with other acidic cocatalysts, such as zinc chloride, acetic acid and tributyltln triflate. With this system, reductions occur with high regloselectivity, providing a useful approach for deuterium incorporation into either the P- or a-position by using either tributyltln deu-teride or D2O, respectively (Scheme 57). ... 

In a similar manner, iminium salts derived from a, -unsaturated aldehydes and ketones are reduced by Hantzsch ester (Scheme 79). The ratio between the 1,4- and 1,2-reduction products depends upon the p/(a of the amine component. a-Keto-P,y-unsaturated esters are reduced by NAD(P)H models in the presence of Mg(Cl04)2- At room temperature 1 equiv. of the reducing agent effects 1,4-reduction of the... 

Several techniques utilizing miscellaneous reagents, that were not mentioned in the preceding sections, have been reported to effect the 1,4-reduction of a,p-unsaturated aldehydes and ketones. 

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