Diethylzinc aldehyde addition

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]. 

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. 

Enantioselective addition of CjH zZn to aldehydes.1 Addition of diethylzinc to either aromatic or aliphatic aldehydes catalyzed by 1 (6 mole %) results in (S)-secondary alcohols in generally 90-95% ee. Although several chiral amino alcohols are known to effect enantioselective addition of R2Zn to aromatic aldehydes, this one is the first catalyst to be effective for aliphatic aldehydes. The dibutylamino group of 1 is essential for the high enantioselectivity the dimethylamino analog of 1, (lS,2R)-N-methylephedrine, effects this addition in only about 60% ee. 

To date, the most frequently used ligand for combinatorial approaches to catalyst development have been imine-type ligands. From a synthetic point of view this is logical, since imines are readily accessible from the reaction of aldehydes with primary or secondary amines. Since there are large numbers of aldehydes and amines that are commercially available the synthesis of a variety of imine ligands with different electronic and steric properties is easily achieved. Additionally, catalysts based on imine ligands are useful in a number of different catalytic processes. Libraries of imine ligands have been used in catalysts of the Strecker reaction, the aza-Diels-Alder reaction, diethylzinc addition, epoxidation, carbene insertions, and alkene polymerizations. 

Consequently, matched/mismatched cases [25] can result, and indeed our investigations on cooperative effects of stereogenic elements in such systems revealed 9 be the matched case and 23 (which is also easily prepared by following a directed deprotonation-silylation-deprotonation-trapping-desilylation sequence [11]) to be the mismatched case in diethylzinc additions to aldehydes [26]. Later, these investigations were extended to more complex systems such as 24 [27], but ferrocene 9 still remains superior to all other compounds. 

The 1,2-addition of diethylzinc to aldehydes is a powerful method for C-C bond formation. As there is a wide variety of possible transition states, the reaction is very sensitive to changes in the ligand structure. For this reason the diethylzinc addition in Scheme 2.1.3.2 is a suitable test reaction for developing and establish-... 

After successful application in the diethylzinc addition to aromatic aldehydes, we applied our ligands to aliphatic substrates. These substrates still pose a challenge for most types of ligands. 

In conclusion, one can say that although the effectiveness of our ligands is only moderately good for diethylzinc additions to aromatic aldehydes, it is, however, excellent in applications involving aliphatic aldehydes. The ee values for... 

Scheme 2.1.3.6 Diethylzinc addition to aldehyde 21. Conditions aldehyde 21 (0.5 mmol), ligand (5%), toluene (1 mL), diethylzinc (1.0 mL, 1.0 M in hexane, 2 equiv), 0 °C, 16 h under argon.

Molecular triangle lOd contains chiral dihydroxy functionalities and has been used for highly enantioselective catalytic diethylzinc additions to aromatic aldehydes, affording chiral secondary alcohols upon hydrolytic work-up, as shown in Eq. (4.2) (Table 4.2) [22]. With Ti(IV) complexes of lOd as catalyst, chiral secondary alcohols were obtained in >95% yield and 89-92% ee for a wide range of aromatic aldehydes with varying steric demands and electronic properties (Table 4.2). In comparison, when the free ligand 6,6 -dichloro-4,4 -diethynyl-2,2 -binaphthol was used instead of... 

Table 4.2 Diethylzinc additions to aldehydes catalyzed by Ti(IV) complexes of lOd.

Keywords aldehyde, enantioselective addition, diethylzinc, secondary alcohol... 

New substituted BINOL ligands have been obtained by directed ort/io-lithiation or Suzuki cross-coupling.104 The ligand (R)-(38) has shown improved catalytic properties for the asymmetric diethylzinc addition to aromatic aldehydes. 

Isomers of ris-l-amino-2-indanol have attracted considerably less attention, although improved asymmetric inductions have been reported on several occasions. Diethylzinc addition to aldehydes with m-.V-disubslil tiled-1 -amino-2-indanols as catalysts yielded secondary alcohols with low enantiomeric excesses (40-50%),37 whereas r/.v-N-disubstituted-2-amino-1 -indanols led to increased selectivities (up to 80% ee) (see Section 17.3.2).46 High degrees of enantioselection were eventually achieved in the addition of diethylzinc to aliphatic and aromatic aldehydes with /raw.v-N-dialkyl-l-substituted-2-amino-l-indanols as catalysts (Scheme 17.25).47 Optimal results were obtained with bulky groups at the hydroxy-bearing carbon and at the nitrogen (R = Ph, R1 = ft-Bu), which led to the formation of (R)-l-phenylpropanol in 90% yield and 93% ee. 

Asymmetric amplification in the diethylzinc addition to aldehydes has been observed with many (3-amino alcohols as catalyst, presumably because of a reservoir effect similar to that discovered by Noyori et al. Asymmetric amplification has also been found for other classes of chiral catalysts—diamines, diols, titanium complexes, etc. The various examples are collected in Table 1. The... 

One of the emerging applications of 4,5-dihydroimidazole-based compounds is as chiral auxiliaries in metal complexes used for asymmetric synthesis for example, 457 in ruthenium-catalyzed DielsAlder reactions <2001 J(P 1)1500, 2006JOM(691)3445> 458 in diethylzinc addition to aldehydes <2003SL102> 459 in asymmetric intramolecular Heck reactions <20030L595> and 460 in ruthenium-catalyzed epoxidation <2005OL3393> and iridium-catalyzed hydrogenation of imines <2004TA3365>. 

Several new ligands containing the oxazoline nucleus were synthesized in enantiopure form. Compounds of general structure 165 were obtained from L-serine or L-threonine and found application as catalysts for the zinc addition to aldehydes <03TA3292> or were derived from P-amino alcohols and used in diethylzinc addition to A -(diphenylphosphinoyl) imines <03JOC4322>. Also, compound 166 was derived from a commercially available amino acid and afforded good selectivity in allylic alkylation <03TL6469>. 

Recent advances of the preparation of novel optically active organoselenimn compounds, mainly organic diselenides, and their application as chiral ligands to some transition metal-catalyzed reactions and also as procatalysts for asymmetric diethylzinc addition to aldehydes are reviewed. Recent results of catalytic reactions using some organoselenimn compounds such as aUylic oxidation of alkenes and its asymmetric version as well as epoxidation of alkenes are also summarized. 

Chiral Diselenides and Selenides as Procatalysts for Diethylzinc Addition to Aldehydes... 

Diols and diamines were also found to be highly efficient catalysts for this reaction. Recently it was shown that sulfur compounds containing amines are able to catalyze the diethylzinc addition to aldehydes [12]. 

The chiral ferrocenylselenium reagents were found to act as the effective ligands for Rh(I)-catalyzed asymmetric hydrosilylation and transfer hydrogenation (see Sects. 2.1 and 2.2, respectively). Fukuzawa and Tsudzuki have found that the chiral ferrocenylselenium-based amino alcohols (DASF), prepared by treatment of the chiral diferrocenyl diselenide with NaBH4 in ethanol followed by the addition of epoxides (Scheme 11), efficiently catalyzed the diethylzinc addition to aldehydes to provide the corresponding secondary alcohols with up to 99% ee... 

Wirth and co-workers used various chiral nitrogen-containing diselenides 20 - 24, which worked effectively as procatalysts for diethylzinc addition to aldehydes (see Sect. 3.1) [13] and for the catalytic oxyselenenylation-elimination reaction of frans- -methylstyrene (Scheme 26) [30]. Under the reaction conditions reported by Iwaoka and Tomoda [19], the diselenide 20 yields the product with highest enantioselectivity (up to 56% ee). Potassium peroxodisulfate seems to be superior to sodium and ammonium analogues. Effect of metal salts on stereoselectivity in the catalytic reaction using the diselenide 20 was investigated since it is known that metal ions can accelerate the decomposition of peroxo-... 

A large number of chiral a,a -orz/zo-disubstituted diphenyldiselenides with hydroxy and amino functions (e.g., 244 and 245) have been prepared by Wirth and co-workers. They were used as electrophiles for a number of asymmetric addition and cyclization reactions including the total synthesis of the lignan derivatives (-l-)-samin and (-l-)-membrine as well as catalysts in the asymmetric diethylzinc addition to aldehydes. 

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