Aldehydes zinc alkyl addition

Fig. 1 Basic features of zinc alkyl addition to aldehydes...

The slow nucleophilic addition of dialkylzinc reagents to aldehydes can be accelerated by chiral amino alcohols, producing secondary alcohols of high enantiomeric purity. The catalysis and stereochemistry can be interpreted satisfactorily in terms of a six-membered cyclic transition state assembly [46,47], In the absence of amino alcohol, dialkylzincs and benzaldehyde have weak donor-acceptor-type interactions. When amino alcohol and dialkylzinc are mixed, the zinc atom acts as a Lewis acid and activates the carbonyl of the aldehyde. Zinc in this amino alcohol-zinc complex is regarded as a kind of chirally modified Lewis acid. Various kinds of polymer-supported chiral amino alcohol have recently been prepared and used as ligands in dialkylzinc alkylation of aldehydes. 

The product is obtained in 95% yield and 94% ee. In the counterpart in solution, the ee was only 21-50%. Polymeric chiral catalysts have also been used in the addition of zinc alkyls to aldehydes. Use of a proline-based copolymer in a continuous asymmetrical synthesis with an ultra filtration membrane gave 80% ee (10.61).138 There was no deactivation in 7 days. A boron-containing polymer (10.62) gave only 28-51% ee compared with the 65-75% ee found with model compounds in solution.139... 

Among monoamines, both enantiomers of 1-phenylethylamine and their derivatives play a prominent role. They are commercially available, but can also be prepared by resolution of the racemate, obtainable by Leuckart- Wallach reaction of acetophenone1, with malic acid2 or, more conveniently, with tartaric acid in methanol3. They are used as chiral additives for the addition of zinc alkyls to aldehydes in Section D. 1.3.1.4., as copper complexes for the synthesis of biaryls in Section B.2., as lithium salts for enantioselective deprotonation in Section C., and as imines in Sections D.1.1.1.3.1., D.1.1.1,4.. D.1.4.4., D.1.5.2., D.1.5.8., D. 1.6.1.2.1., D.2.3.I., and D.8. A general procedure for the synthesis of imines from carbonyl compounds and primary amines, with many examples of both chiral carbonyl compounds and chiral amines is given in reference 4. 

Amino acid esters can be dimerized to dioxopiperazines, which are conveniently reduced with sodium borohydride,/titanium(IV) chloride to give the corresponding chiral piperazine derivatives. Thus, from valine and phenylalanine, useful auxiliaries 20 and 21 were obtained9, and used for the alkylation of carbanions (Section D. 1.1.1.3.1.) and as catalysts for the addition of zinc alkyls to aldehydes (Section D.1.3.1.4.), as well as for enantioselective deprotonation and elimination (Section C.). 

Quinine [1, (8a,9/Q-6 -methoxy-9-cinchonanol] is the most familiar of the cinchona alkaloids. Quinine has been used as a catalyst in the enantioselective addition of zinc alkyls to aldehydes (together with its acetic ester) (Section D. 1.3.1.4.), for the addition of thiols and selenols to activated double-bond systems (Sections D.2.1., D.5. and D.6.), and as a chiral ligand for cobalt catalysts in the hydrogenation of 1,2-diketones to a-hydroxycarbonyl compounds (Section D.2.3.1.) and C-C double bonds (Section D.2.5.1.2.2.). Quinine and quinidine can also be incorporated into more complex systems (forming ethers and esters with its hydroxy function) where they may act as a chiral leaving group. This technique has been applied to the synthesis of chiral binaphthols (Section D.1.1.2.2.). 

Another group of cinchona alkaloids lacks the 6 -mclhoxy group. Cinchonine (7) and its diastereomer cinchonidine (5) are commercially available and have been used as catalysts in the addition of zinc alkyls to aldehydes (Section D. 1.3.1.4.). Cinchonidine and dihydrocin-chonidine (6) were used to modify the surface of platinum catalysts used in the enantioselective reduction of z-oxo esters to a-hydroxy esters (see Section D.2.3.1. for such applications). Dihydrocinchonidine may conveniently be obtained by catalytic reduction of the double bond of cinchonidine, e.g., with nickel and hydrogen7. Cinchonidine also acts as a catalyst in the enantioselective formation of C-S and C-Se bonds by the addition of thiols and selenols to activated alkenes, such as 1-nitroalkenes (Sections D.5. and D.6.). Another application is the enantioselective protonation of kelenes (SectionD.2.I.). 

Both enantiomers of norephedrine are commercially available and have been applied as chiral auxiliaries in [1 +2] cycloadditions (Section D. 1.6.1.5.), and as starting materials for chiral heterocyclic compounds (Section 2.5.3.). iV,./V-Dibutylation of (lS,2/ )-norephedrine gives a highly selective catalyst 5 for the addition of zinc alkyls to aldehydes (Section D.1.3.1.4.) and chalcones (Section D.I.5.8.). 

Secondary and tertiary alcohols can be prepared from aldehydes and ketones, respectively, by means of zinc alkyls (403) or the compounds formed from the alkyl halides and magnesium. This latter method was investigated by Grignard. As has already been pointed out, when magnesium is added to a solution of an alkyl halide in ether or other appropriate solvent, the metal and the halide unite and form an addition-product —... 

While the mechanism of the ammonium salt catalyzed alkylation is unclear, in polar solvents the enantioselectivity of the addition of dialkylzincs to aldehydes generally drops considerably, probably due to uncatalyzed product formation or complexation of the zinc reagent with the polar solvent rather than with the chiral auxiliary. 

Organozinc reagents have been used in conjunction with a-bromovinylboranes in a tandem route to Z-trisubstituted allylic alcohols. After preparation of the vinylborane, reaction with diethylzinc effects migration of a boron substituent with inversion of configuration and exchange of zinc for boron.176 Addition of an aldehyde then gives the allylic alcohol. The reaction is applicable to formaldehyde alkyl and aryl aldehydes and to methyl, primary, and secondary boranes. 

One of the important new directions in the study of addition reactions of organozinc compounds to aldehydes is the use of ionic liquids. Usually, application of these compounds in reactions with common organometallic reagents has a serious problem ionic solvents are usually reactive toward them, particularly Grignard and organolithium derivatives. It has been recently reported that carbonyl compounds react with allylzinc bromide formed in situ from allyl bromide and zinc in the ionic liquid 3-butyl-l-methylimidazolium tetrafluoroborate, [bmim][BF4].285 Another important finding is that the more reactive ZnEt2 alkylates aldehydes in a number of ionic liquids at room temperature.286 The best yields (up to 96%) were obtained in A-butylpyridinium tetrafluoroborate, [bpy][BF4] (Scheme 107). 

They offer the advantage that reductions can be effected under conditions that permit the conversion of substrates that may be adversely sensitive to the presence of strong Brpnsted acids. For example, in the presence of a 10% excess of triethylsilane, addition of one-half equivalent of boron trifluoride etherate to octanal results, within one hour, in the formation of a 66% yield of dioctyl ether after a basic hydrolytic workup. Benzaldehyde provides a 75% yield of dibenzyl ether under the same reaction conditions. The remainder of the mass is found as the respective alcohol.70 Zinc chloride is also capable of catalyzing this reaction. With its use, simple alkyl aldehydes are converted into the symmetrical ethers in about 50% yields.330... 

As a kind of nucleophilic addition reaction similar to the Grignard reaction, the Reformatsky reaction can afford useful ft-hydroxy esters from alkyl haloacetate, zinc, and aldehydes or ketones. Indeed, this reaction may complement the aldol reaction for asymmetric synthesis of //-hydroxy esters. 

Transition State Models. The stoichiometry of aldehyde, dialkylzinc, and the DAIB auxiliary strongly affects reactivity (Scheme 9) (3). Ethylation of benzaldehyde does not occur in toluene at 0°C without added amino alcohol however, addition of 100 mol % of DAIB to diethylzinc does not cause the reaction either. Only the presence of a small amount (a few percent) of the amino alcohol accelerates the organometallic reaction efficiently to give the alkylation product in high yield. Dialkyl-zincs, upon reaction with DAIB, eliminate alkanes to generate alkylzinc alkoxides, which are unable to alkylate aldehydes. Instead, the alkylzinc alkoxides act as excellent catalysts or, more correctly, catalyst dimers (as shown below) for reaction between dialkylzincs and aldehydes. The unique dependence of the reactivity on the stoichiometry indicates that two zinc atoms per aldehyde are responsible for the alkyl transfer reaction. 

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