Aldehydes dialkylzinc addition reactions

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. 

Kitamura and Noyori have reported mechanistic studies on the highly diastere-omeric dialkylzinc addition to aryl aldehydes in the presence of (-)-i-exo-(dimethylamino)isoborneol (DAIB) [33]. They stated that DAIB (a chiral (i-amino alcohol) formed a dimeric complex 57 with dialkylzinc. The dimeric complex is not reactive toward aldehydes but a monomeric complex 58, which exists through equilibrium with the dimer 57, reacts with aldehydes via bimetallic complex 59. The initially formed adduct 60 is transformed into tetramer 61 by reaction with either dialkylzinc or aldehydes and regenerates active intermediates. The high enantiomeric excess is attributed to the facial selectivity achieved by clear steric differentiation of complex 59, as shown in Scheme 1.22. 

Another significant development in oxazoline chemistry is the application of oxazoline-containing ligands for asymmetric catalysis, such as palladium-catalyzed allylic substimtions, Heck reactions, hydrogenations, dialkylzinc additions to aldehydes, and Michael reactions. The discovery of diastereoselective metalation of chiral ferrocenyloxazolines has further expanded the availability of chiral ligands for metal-catalytic reactions. 

These highly enantioselective Lewis-acid/Lewis-base-catalyzed dialkylzinc and phenylzinc addition reactions to imines give rise to arylalkylamides and diaryl-methylamides in excellent yields and enantioselectivities. Due to the simplicity of the process and the good availability of the imine precursors 23 from the corresponding aldehydes, wide applicability of the reported catalytic reaction can be expected. 

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. 

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]. 

Asymmetric alkynyl additions to aldehydes by prior, separate generation of the alkynylides (e.g. dialkylzinc reagents) have recently been reviewed and are a topic of current research [10], They will not be covered in the context of this chapter. Instead, in line with the theme of this book, this chapter will focus on the metala-tion of terminal alkynes by activation of the terminal C-H and the use of the corresponding metal acetylides in aldehyde and ketone addition reactions. 

Conjugate addition reaction of a mixed dialkylzinc reagent to an unsaturated aldehyde preparation of ethyl (Moxomethyljdecanoate28... 

A mechanism has been put fwward in which the rate-determining step in the 1,2-addition reaction is cleavage of the dimeric zinc thiolate into a transient species in which both the aldehyde substrate and the reagent, i.e. dialkylzinc, are present. ... 

The dialkylzinc additions catalyzed by N,N-di-n-alkylnorephedrines (most typically DBNE) are not limited to primary organometallic reagents. Diisopropylzinc (with a secondary alkyl substituent) adds to benzaldehyde in the presence of a catalytic amount of DBNE to afford the corresponding alcohol with high ee (entry 4). The reaction of diisopropylzinc in the presence of other types of catalysts may result in the reduction of aldehydes. 

A very similar model can be invoked to explain the results of catalytic enantioselective dialkylzinc additions to aldehydes. The catalysts used in these reactions are invariably lithium- or zinc-centered Lewis acids. The transition structure shown in Figure has been put forward by several groups... 

One of the earUest demonstrations of the viability of a combinatorial approach in the discovery of asymmetric reactions was reported by Elhnan in 1995 [7]. The Berkeley team s selection of the dialkylzinc addition to aldehydes (Scheme 2) to gauge the potential utility of a combinatorial approach was based on several factors ... 

In this section, the asymmetric synthesis of the vicinal thio- and selenoalcohols 42 — 45 is described based on the highly enantio- and diastereoselective addition of diethylzinc reagent to racemic a-thio- and selenoaldehydes 41, catalyzed by 20o (( —)-DFPE) and S,R)-2Qo ((+)-DFPE) (Scheme 3-20). Although the enantio-selective addition of dialkylzinc reagents to achiral aldehydes using chiral catalysts has been well investigated [10], there are no known catalytic enantio- and di-asteroselective dialkylzinc additions to aldehydes with chiral centers, except for the alkylation of a-methyl- [58, 59], a-chloro- [59], and j5-alkoxyaldehydes [60]. The reaction of diethylzinc with racemic a-thio- and selenoaldehydes 41 was carried out in the presence of 20o or (S,il)-20o (5 — 50 mol%) in hexane at room temperature for 12 —16h. The results are summarized in Table 3-11. 

A complementary reaction towards the construction of secondary alcohols consists of a dialkylzinc addition to aldehydes in the presence of substoichiometric amounts of suitable chiral ligands, mostly amino alcohols [42-44]. For this reaction, which already is one of the classical asymmetric catalytic syntheses, three structurally related catalyst precursors have been described. 

Mixed salt-free dialkylzinc species, obtained from the corresponding Grignard reagents by the method described above, display a very useful selectivity in the transfer of alkyl groups in the addition reaction to aldehydes. The presence of a chiral aminoalcohol as a catalyst permits a practical preparation of chiral secondary alcohols with high enantioselectivity. 

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

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-... 

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