Addition of Diethylzinc to Benzaldehyde

Entry lodo ferrocene Solvent T, °C Yield, % % ee Configuration of product 

---

This result is in strong contrast with that obtained by Tanner et al. [49] for ligand 52 (ee of 2% for the addition of diethylzinc to benzaldehyde. Fig. 3). It was argued by Tanner that the M-trityl group would be too large to allow efficient chelate formation with diethylzinc [49], which is however clearly not the case... 

Attached to the periphery of a lst-generation dendrimer, Ti(OCHMe2)2-com-plexes of the six TADDOL moieties in 84 catalyze - in homogeneous solution -the enantioselective addition of diethylzinc to benzaldehyde with about the same selectivity ((S) (R) 97 3) as do six monomeric TADDOL units [105],but, with a molecular weight of only 3833 Da, dendrimer 84 had to be separated by column chromatography rather than by ultrafiltration methods. 

Figure 9 Supported Ti-TADDOLate catalyst for enantioselective addition of diethylzinc to benzaldehyde...

A number of groups have reported the preparation and in situ application of several types of dendrimers with chiral auxiliaries at their periphery in asymmetric catalysis. These chiral dendrimer ligands can be subdivided into three different classes based on the specific position of the chiral auxiliary in the dendrimer structure. The chiral positions may be located at, (1) the periphery, (2) the dendritic core (in the case of a dendron), or (3) throughout the structure. An example of the first class was reported by Meijer et al. [22] who prepared different generations of polypropylene imine) dendrimers which were substituted at the periphery of the dendrimer with chiral aminoalcohols. These surface functionalities act as chiral ligand sites from which chiral alkylzinc aminoalcoholate catalysts can be generated in situ at the dendrimer periphery. These dendrimer systems were tested as catalyst precursors in the catalytic 1,2-addition of diethylzinc to benzaldehyde (see e.g. 13, Scheme 14). 

Another approach was followed by Bolm et al. [24], who prepared dendron ligands consisting of a chiral pyridyl alcohol connected to the core of Frechet type dendrons [25]. The chiral dendron ligands were used for the in situ generation of ethylzinc dendron ligand complexes which catalyze the addition of diethylzinc to benzaldehyde (see e.g., 15, Scheme 16). The size of the dendron appeared to have practically no influence on the enantioselectivity of this reaction. 

DOLate was formed which was tested in the Lewis acid catalyzed enantioselective addition of diethylzinc to benzaldehyde. The authors note that the catalyst can be recovered by simple filtration and was active for at least more than twenty runs (refer also to Section 4.2.3) [102]. 

Several stereoselective dialkylzinc additions have been reported. The oxazolidine catalyst series (64) gives moderate ee% in the addition of diethylzinc to benzaldehyde. Substituent effects on the mechanism of induction have been explored for a range of... 

Enantioselective addition of diethylzinc to benzaldehyde has been promoted by indole-containing chiral oxazolidines (which are able to use both O and N atoms to effect metal coordination in the transition state), and by chiral o-hydroxyphenyl diaza-phospholidine oxide,and by chiral aziridino alcohols.Enantioselective addition of dialkylzinc to prostereogenic ketones has been promoted using chiral camphorsul-fonamide derivatives. 

Using the addition of diethylzinc to benzaldehyde catalyzed by an a,a-diphenyl-L-prolinol bound to a methacrylate polymer 1 (M = 96 000 g moT ) (Fig. 3.1.3, left) the ttn for the catalyst could be increased 10-fold (from 50 to 500) in comparison with the free catalyst via membrane retention [9]. The product was obtained in 80% enantiomeric excess (ee). 

In the enantioselective addition of diethylzinc to benzaldehyde, a wide variety of chiral catalysts 3, 4, 16, 23, 47, 66-73 exhibits asymmetric amplification (equation 36 and Table 1). 

Figure 5.3 Four alternative TS structures for catalyzed addition of diethylzinc to benzaldehyde. The descriptors refer to the side of the four-membered ring on which the aldehyde carbon is found relative to the alkoxide carbon - same (syn) or opposite (anti) - and the absolute configuration of the new stereogenic center formed following ethyl transfer, R or S. In the absence of chirality in the /3-amino alcohol ligand, indicated by the G group(s), the TS structures at opposite corners would be enantiomeric with one another, and no preference for R over 5 product would...

High enantioselectivity has been achieved on addition of diethylzinc to benzaldehyde catalysed by a chiral diamine, (,S )-2-(A,A -disubstitutcd aminomethyl)pyrrolidine,116 and by chiral helical titanate complexes of tetradentate ligands.117 Enantioselective additions of dialkylzinc reagents to A,-(diphcnylphosphiiioyl)imines, promoted by aziridino alcohols,118 and to the carbon-nitrogen double bond of the nitrone 3,4-dihydroisoquinoline A-oxide, promoted by dicyclopentyl(R,R)-tartrate,119 have also been reported. 

A series of chiral (3i ,5 RHlihvdroxypiperidine derivatives have been conveniently prepared from trans -4-hvdrox v- r.-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal.110 The compound (31) has been found to show the best asymmetric induction in promoting the addition of Et2Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee. 

A study of enantioselective additions of diethylzinc to benzaldehyde, using chiral carboline and oxazolidine auxiliaries, has examined the requirements to allow the conformations of the free ligands to be related to the ees and transition states, given that several steps intervene.228... 

Cyclic derivatives of 1,2- and 1,3-amino alcohols have been trialled as chiral catalysts in the addition of diethylzinc to benzaldehyde.229 Enantioselective addition of diethylzinc to benzaldehyde is the subject of other reports,230,231 including the use of triazinyl-BINOLs as enantioselective catalysts of addition to araldehydes, using Ti(IV) tetraisopropoxide.232 Two optically active amino thiocyanate derivatives (60) of (-)-norephedrine act as aprotic ligands for enantioselective addition of diethylzinc to aldehydes in up to 96% ee.233 The ee drops drastically if the -SCN group is changed to -SR. 

The use of bis(sulfonamide) ligands derived from stilbenediamine in the asymmetric addition of diethylzinc to benzaldehyde has resulted in large changes in product ee over the course of the reaction.106 This effect has been attributed to autoinduction. During the reaction the catalyst evolves by incorporation of the product of the asymmetric addition reaction. 

As the nucleophilicity of dialkylzinc is accelerated by the presence of (3 amino-alcohol, diethylzinc adds to benzaldehyde to afford 1-phenylpropanol.2 Several duraTfS-aminoalcohols 1-7 have been proven to be highly enantioselective catalysts for the addition of primary dialkylzincs mostly to aromatic aldehydes. For example, 1-phenylpropanol is prepared with high ee from the enantioselective addition of diethylzinc to benzaldehyde using 1-7 (Fig. 12.1, the ee and configuration of prepared 1-phenylpropanol are shown in parentheses).3 8... 

Enantioselective addition of diethylzinc to benzaldehyde catalysed by titanium-TADDOLate (Structure 16)13... 

Very strong asymmetric amplifications have been observed in the addition of diethylzinc to benzaldehyde catalyzed by various P-amino alcohols. The first experiments were published by Oguni et al. in 19881 and by Noyori et al. in 1989.32 The experimental results are shown in Scheme 7. Using (-)-DAIB 2 of 15% ee, for example, gave the addition product in 92% ee, while using enantiopure (-)-DAIB gave the product in 98% ee. 

Scheme ]3. Reservoir effect in the DAIB-catalyzed addition of diethylzinc to benzaldehyde.32...

In another example of the dendronization of solid supports, Rhee et al. described the design of silica-supported chiral dendritic catalysts for the en-antioselective addition of diethylzinc to benzaldehyde (Fig. 28) [60-62], The immobilized dendritic systems were formed in two different ways one by stepwise propagation of dendrimers and the other by direct immobilization... 

In this work, the synthesis of high surface densities of chlororopropyl groups covalently grafted on mesoporous micelle templated aluminosilicates (Al-MTS) of various initial pore diameters is presented. The hybrid chiral materials resulting from halogen substitution are applied in the enantioselective addition of diethylzinc to benzaldehyde. 

Addition of diethylzinc to benzaldehyde conducted in the presence of the materials leads to the formation of (R)- or (S)-l-phenyl-propan-l-ol (Scheme 3). All experiments were performed at 0°C using the same weight of solid (0.29g) and 2.3 equivalent of diethylzinc to benzaldehyde.8 10... 

Table 3. Asymmetric addition of diethylzinc to benzaldehydes in tbe presence of diselenide...

Enantioselective Addition of Dialkylzincs to Aldehydes Using Chiral Amino Alcohols Derived from Ephedrine. Nucleophilic addition of dialkylzinc to aldehydes is usually very slow. Amino alcohols facilitate the addition of Diethylzinc to benzalde-hyde to afford l-phenylpropanol. When chiral amino alcohols possessing the appropriate stracture are used as a precatalyst, optically active secondary alcohols are obtained. Highly enantioselective chiral catalysts derived from ephedrine are known. (lR,25)-N-Isopropylephedrine functions as a precatalyst for the enantioselective addition of diethylzinc to benzaldehyde to afford (R)-l-phenylpropanol with 80% ee in 72% yield. The use of an excess amount of diethylzinc increases the enantioselectivity up to 97% ee (eq 17). ... 

Addition of Diethylzinc to Benzaldehyde. The addition of Diethylzinc to PhCHO without added catalysts is very sluggish. Amino alcohol (1) acts as a catalyst precursor for the addition of Et2Zn to PhCHO under mild conditions to afford 1 -pheny Ipropan-l-ol in 76% yield (eq Although the obtained alcohol is... 

Hyperbranched and dendritic macromolecules have recently been the subject of considerable interest. Bolm developed chiral hyperbranched macromolecules 57 that catalyzed the enantioselective addition of diethylzinc to benzaldehyde [75]. The enan-tiocontrol of the hyperbranched chiral catalysts was slightly lower than for the low-molecular-weight catalyst. TADDOLs linked with dendritic molecules have been synthesized [59]. For example, use of the first generation dendrimer 58 with six terminal TADDOL units resulted in high enantioselectivity. 

---