Aldehydes diethylzinc

In accessing chiral allyl vinyl ethers for Claisen rearrangement reactions, Nelson et al. employed the iridium-mediated isomerization strategy. Thus, the requisite enantioenriched diallyl ether substrate 28 was synthesized via a highly enantioselective diethylzinc-aldehyde addition protocol10 (Scheme 1.1k). The enantioselective addition of Et2Zn to cinnamaldehyde catalyzed by (—)-3-exo-morpholinoisobomeol (MIB 26)11 provided an intermediate zinc alkoxide (27). Treatment of 27 with acetic acid followed by 0-allylation in the presence of palladium acetate delivered the 28 in 73% yield and 93% ee. Isomerization of 28 with a catalytic amount of the iridium complex afforded the allyl vinyl ether... 

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 first reported chiral catalysts allowing the enantioselective addition of diethylzinc to aryl aldehydes in up to 60% cc were the palladium and cobalt complexes of 1,7,7-trimethylbicy-clo[2.2.1. ]heptane-2,3-dione dioxime (A,B)3. A number of other, even more effective catalysts, based on the camphor structure (C K, Table 26) have been developed. 

Table 28. Addition of Diethylzinc to Aldehydes under Chiral Catalysis...

After 19 hours, no reaction between the zinc chelate 2 and benzaldehyde can be detected at 20 °C. However, 10 mol % of the zinc chelate effectively catalyzes theenantioselective addition of diethylzinc to aromatic aldehydes. The predominant formation of the S-configurated products, effected by this conformationally unambiguous catalyst, can be explained by a six-mem-bered cyclic transition state assembly17. The fact that the zinc chelate formed from ligand M is an equally effective catalyst clearly demonstrates that activation of the aldehyde moiety does not occur as a consequence of hydrogen bond formation between the ammonium proton of the pyrrolidine unit and the aldehydic oxygen. 

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. 

During our research in this field of small-ring heterocycles we found that functionahzed aziridines are attractive chiral catalysts, e.g., in the diethylzinc addition to aldehydes. Aspects of such uses of aziridines will be discussed as well. This overview does not pretend to be an exhaustive coverage of all existing literature on small-ring aza-heterocycles as that would require a separate monograph. Instead, emphasis is put on functionahzed three-membered aza-heterocycles, that were investigated in the author s laboratory [1], and relevant related literature. The older literature on these heterocycles is adequately summarized in some extensive reviews [2]. Chiral aziridines have been reviewed recently by Tanner [3], by Osborn and Sweeney [4], and by McCoull and Davis [5]. 

In the author s laboratory, ligand 51 (Fig. 3) was investigated and gratifyingly very high ee s were obtained in the diethylzinc addition to both aromatic and aliphatic aldehydes (Scheme 39) [51]. 

A polymer-supported version of our optimal ligand was also developed [52]. Its preparation involves attachment of aziridine carbinols to polymer-bound triphenylchloromethane (Scheme 40). This polymer-bound ligand 53 was almost equally effective in the enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes with ee s ranging from 77-97% for the latter type of substrate [52]. It is of practical interest that this polymer-supported ligand could be reused without losing much of its efficiency. 

On the other hand, S/O ligands have been developed to a lesser extent, but their efficient use as chiral ligands was proven in the enantioselective addition of diethylzinc to aldehydes and also in the copper-catalysed asymmetric conjugate addition. 

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. 

Homoallylation of Aldehydes and Ketones with Dienes Promoted by Diethylzinc... 

The opposite regioselectivity is observed in intermolecular alkylative coupling of terminal alkynes and aldehydes with diethylzinc and with alkenylzirconium/ZnCl2 (Scheme 88). 

In some cases, direct, uncatalyzed 1,2-addition of diethylzinc to aldehydes becomes a significant problem. Triethylsilane for intramolecular reactions or triethylborane for intermolecular reactions is often helpful to address this issue. 

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... 

The optically active reagent (5)-l-methyl-2-(diphenylhydroxymethyl)-azitidine [(5)-114] has also been reported to catalyze the enantioselective addition of diethylzinc to various aldehydes. The resulting chiral secondary alcohols 115 are obtained in up to 100% ee under mild conditions (Scheme 2-44).111 Furthermore, most of the 114-type ligands have also been used in the ox-... 

Chiral quaternary ammonium salts in solid state have also been used as catalysts for the enantioselective addition of diethylzinc to aldehydes (Scheme 2-45).112 In most cases, homogeneous chiral catalysts afford higher enantio-selectivities than heterogeneous ones. Scheme 2-45 presents an unusual asymmetric reaction in which chiral catalysts in the solid state afford much higher enantioselectivities than its homogeneous counterpart.112... 

The optically active //-amino alcohol (1 / . 3 R. 5 / )-3-(di phenyl hydroxymethyl )-2-azabicyclo[3.3.0]octane [(li ,3i ,5i )-121], can be derived from a bicyclic proline analog. It catalyzes the enantioselective addition of diethylzinc to various aldehydes. Under mild conditions, the resulting chiral secondary alcohols are obtained in optical yields up to 100%. The bicyclic catalyst gives much better results than the corresponding (S )-proline derivative (S )-122 (Scheme 2-47).114... 

With the knowledge that the presence of Ti(OPr )4 promotes the alkylation of diethylzinc to benzaldehyde, Ho et al.118 demonstrated that the chiral tetra-dentate sulfonamide ligand 125 catalyzes the addition of diethylzinc to aldehyde in the presence of Ti(OPr )4 with good yield and enantioselectivity (Scheme 2-48). 

Pritchett et al.119 found that Ti(OPr )4 did not react with the bis(sulfon-amide) ligand itself, so they postulated that a chiral ligand initially reacted with the diethylzinc and was subsequently transferred to the titanium in the next step. Based on this assumption, they presented an improved procedure for the asymmetric alkylation of aldehyde to overcome the poor solubility of the li-... 

Both the aldehyde and diethylzinc are activated by the zinc amide, and the ethyl group transformation from diethylzinc to aldehyde furnishes the highly enantioselective alkylation of aromatic aldehydes. 

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. 

In Scheme 2 51, species 133 is formed from the precatalyst 132 and TifOPr )4. It is then converted to complex G upon addition of diethylzinc. Reaction between species G and an aldehyde furnishes intermediate E, which accomplishes the enantioselective addition of the nucleophile to the carbonyl group. Intervention of two molecules of Ti(OPr )4 releases the alkylated product, regenerates the active catalyst 133, and also completes the catalytic cycle. This cycle explains the fact that at least one equivalent of Ti(OPr )4 is required for an effective reaction. 

Zhang and Chan122 found that Hg-BINOL, (R)- or (S )-134, in which the naphthyl rings in the BINOL were partially hydrogenated,123 can give even better results in the diethylzinc reactions. Using (R)- or (5,)-134 as the chiral ligand, addition of diethylzinc to aromatic aldehydes proceeds smoothly with over 95% ee and, in most cases, quantitative conversion.122... 

Since the discovery of amino alcohol induced dialkylzinc addition to aldehydes, many new ligands have been developed. It has recently been reported that chiral amino thiols and amino disulfides can form complexes or structurally strained derivatives with diethylzinc more favorably than chiral amino alcohols and thus enhance the asymmetric induction. Table 2 15 is a brief summary of such chiral catalysts. 

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