Dialkylzinc aldehyde alkylation

Polymer-supported amino alcohols and quaternary ammonium salts catalyze the enan-tioselective addition of dialkylzinc reagents to aldehydes (Table 31). When the quaternary ammonium salt F is used in hexane, it is in the solid state, and it catalyzes the alkylation of benzaldehyde with diethylzinc in good chemical yield and moderate enantioselectivity. On the other hand, when a mixture of dimethylformamide and hexane is used as solvent, the ammonium salt is soluble and no enantioselectivity is observed21. 

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. 

The polymer-bound catalysts A-C. (Table 31) are prepared by reaction of the corresponding amino alcohols with partially chloromethylated 1 -2% cross-linked polystyrene. In the case of A, the enantioselectivity of the addition of dialkylzincs to aldehydes is higher than with the corresponding monomeric ephedrine derivatives (vide supra). Interesting insights into the mechanism of the alkylation of aldehydes by dialkylzinc reagents can be obtained from the experi-... 

Tanaka et al.28 have synthesised a series of (S)-chiral Schiff bases as the highly active (yield 69-99%) and enatioselective (ee 50-96%) catalysts in the reaction of addition of dialkylzinc to aldehydes. The stereochemistry of the asymmetric addition was suggested. In a transition state when S-chiral Schiff base was used as chiral source, the alkyl nucleophile attacked Re face of the activated aldehyde and formed the R-configuration alkylated product [13]. 

Nucleophilic addition of metal alkyls to carbonyl compounds in the presence of a chiral catalyst has been one of the most extensively explored reactions in asymmetric synthesis. Various chiral amino alcohols as well as diamines with C2 symmetry have been developed as excellent chiral ligands in the enantiose-lective catalytic alkylation of aldehydes with organozincs. Although dialkylzinc compounds are inert to ordinary carbonyl substrates, certain additives can be used to enhance their reactivity. Particularly noteworthy is the finding by Oguni and Omi103 that a small amount of (S)-leucinol catalyzes the reaction of diethylzinc to form (R)-l-phenyl-1 -propanol in 49% ee. This is a case where the... 

BINOL and related compounds have proved to be effective catalysts for a variety of reactions. Zhang et al.106a and Mori and Nakai106b used an (R)-BINOL-Ti(OPr )4 catalyst system in the enantioselective diethylzinc alkylation of aldehydes, and the corresponding secondary alcohols were obtained with high enantioselectivity. This catalytic system works well even for aliphatic aldehydes. Dialkylzinc addition promoted by TifOPr1 in the presence of (R)- or (A)-BINOL can give excellent results under very mild conditions. Both conversion of the aldehyde and the ee of the product can be over 90% in most cases. The results are summarized in Table 2-14. 

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. 

In the (—)-DAIB-catalyzed reaction of diethylzinc and benzaldehyde, the rate is first-order in the amino alcohol. The initial alkylation rate is influenced by the concentration of diethylzinc and benzaldehyde but soon becomes unaffected by increased concentration. Thus, under the standard catalytic reaction conditions, the reaction shows saturation kinetics the rate is zeroth order with respect to both dialkylzinc reagent and aldehyde substrate. These data support the presence of the equilibrium of A-D, and alkyl transfer occurs intramolecularly from the dinuclear mixed-ligand complex D. This is the stereo-determining and also turnover-limiting step. 

An amino alcohol was found to accelerate the addition reaction of diethlylzinc to aldehyde [8], and then chiral amino alcohols were proved to be efficient chiral catalysts for asymmetric alkylation by using dialkylzinc reagents [9], Oguni reported a remarkable asymmetric amplification in chiral amino alcohol-promoted alkylation (Scheme 9.4). In the presence of (-)-l-piperidino-3,3-dimethyl-2-butanol (5) of 11% ee, benzaldehyde is alkylated enantioselectively to give (/ )-l-phenylpropanol with 82% ee [10]. Asymmetric amplification was also observed by Noyori using partially resolved (2.S )-3-exo-(dimethylamino)isobomeol (6) [11]. 

The asymmetric alkylation of aldehydes by dialkylzinc reagents is one of the most intensively studied catalytic reactions [60-62]. Following the initial discoveries of Oguni and colleagues, including the recognition that a single... 

With regard to diorganozincs other than primary dialkylzincs, various diorganozincs such as divinylzinc (> 96% ee, addition to benzaldehyde),4 difurylzinc (72% ee, addition to benzaldehyde),5 diphenylzinc (78-82% ee, addition to various aldehydes),6 and diisopropylzinc (93% ee, addition to benzaldehyde)7 have been utilized in the chiral (3-aminoalcohol catalysed reactions. Alkenyl(alkyl)zincs4b,c and alkynyl(alkyl)zincs8 afford the corresponding chiral allylic and propargyl alcohols. 

Introduction. (1 R,25, 3/ ,45 )-3-Dimethylamino-1,7,7-trime-thylbicyclo[2.2.1 ]heptan-2-ol, herein referred to as (—)DAIB, has been shown to be an effective catalyst for enantioselective carbon-carbon bond formation utilizing dialkylzinc reagents with aldehydes and ketones. Attempts to utilize (—)DAIB for asymmetric inductions with other organometallic reagents such as aluminum alkyls, alkyl Grignards, and alkyl lithiums, have been unsuccessful. ... 

Additions of Dialkylzinc Reagents to Aliphatic Aldehydes. Few examples of (-)DAIB-catalyzed 1,2-additions to aliphatic aldehydes by diakylzinc reagents have been reported. Although alkylation yields were high, enantioselectivities ranged firom 90% to 0% ee (eq 5). All examples produced alcohols with S configuration. ... 

Chiral titanates can be employed as catalysts for the alkylation of aldehydes using dialkylzinc reagents. For example, by the use of a catalytic amount of the chiral titanium reagent (4), addition of Diethylzinc to various aldehydes occurs with high enantios-electivity in the presence of Titanium Tetraisopropoxide (eq 4)7... 

Unlike alkyllithium and Grignard reagents, dialkylzinc does not add to ketones even in the presence of (1). Thus the chemo- and enantioselective alkylation of a keto aldehyde (4-benzoylbenzaldehyde) with Et2Zn using (5)-(l) affords the corresponding optically active hydroxy ketone with 93% ee in 99% yield. ... 

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