Diethylzinc additions

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

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

Molecular weights of poly(propylene oxide) polymers of greater than 100,000 are prepared from catalysts containing FeCl (40,41). The molecular weight of these polymers is gready increased by the addition of small amounts of organic isocyanates (42). Homopolymers of propylene oxide are also prepared by catalysis using diethylzinc—water (43), diphenylzinc—water (44), and trialkyl aluminum (45,46) systems. 

Cesium forms simple alkyl and aryl compounds that are similar to those of the other alkah metals (6). They are colorless, sohd, amorphous, nonvolatile, and insoluble, except by decomposition, in most solvents except diethylzinc. As a result of exceptional reactivity, cesium aryls should be effective in alkylations wherever other alkaline alkyls or Grignard reagents have failed (see Grignard reactions). Cesium reacts with hydrocarbons in which the activity of a C—H link is increased by attachment to the carbon atom of doubly linked or aromatic radicals. A brown, sohd addition product is formed when cesium reacts with ethylene, and a very reactive dark red powder, triphenylmethylcesium [76-83-5] (C H )2CCs, is formed by the reaction of cesium amalgam and a solution of triphenylmethyl chloride in anhydrous ether. 

Although the previous protocol suggests it is not necessary to deprotonate the sulfonamide prior to exposure to the zinc carbenoid, a experimentally simpler procedure can be envisioned wherein the alcohol and promoter are deprotonated in a single flask (Fig. 3.15). In protocol IV, the alcohol and promoter are combined in flask A and are treated with diethylzinc, thus forming the zinc alkoxide and zinc sulfonamide. In sub-protocol IVa, this solution is transferred to flask C which contains the zinc carbenoid. Sub-protocol IVb represents the reversed addition order. Sub-protocol IVa is not only found to be the superior protocol in this sub-set, it is found to out-perform all of the previous protocols Despite the persistence of the induction period, a large rate enhancement over the uncatalyzed process is observed. This considerable rate enhancement also translates to a reduction in the overall reaction time when compared to sub-protocols la and Ilia. Selectivity rises... 

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

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. 

In a flame-dried Schlenk tube 0.37 g(1.88 mmol) of (-)-3-exo-(dimethylamino)isoborneol (C) and 200 mL of dry toluene are placed under an atmosphere of argon. 27 mL of 4.2 M diethylzinc (113 mmol) in toluene are added and the resulting solution is stirred at 15°C for 15 min. After cooling to — 78°C, lOg (94.2 mmol) of benzaldehyde are added and the mixture is wanned to O C. After stirring for 6 h, the reaction is quenched by the addition of sat. NH4C1 soln. Extractive workup is followed by distillation yield 12.4 g (97%) 98% ee [determined by HPLC analysis. Baseline separation of rac-1 -phenyl-1 -propanol was achieved on a Bakerbond dinitrobenzoyl phenylglycine column (eluent 2-propanol/hexanc 1 3 flow rate l.OmL/ min detection UV 254 nm)] [a] 0 —47 (c = 6.11, CHC13). 

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

The tridentate ligands C, L and M are effective catalysts for the enantioselective addition of dialkylzincs to aromatic aldehydes16,17. In particular, ligands L and M qualify as members of the chemical enzyme (chemzyme) class of synthetic reagents17, since they function in a predictable, clear-cut mechanistic way. As demonstrated by X-ray diffraction, the actual catalyst is a monomeric zinc chelate 2 formed in toluene at 50 C by reaction of L or M with one equivalent of diethylzinc. 

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. 

Although it is known that in some cases the lithium salts of chiral amino alcohols are even better catalysts than the chiral ligands themselves, the use of metals other than lithium has rarely been investigated. The oxazaborolidines A and B and the aluminum analog C have been used as catalysts for the enantioselective addition of diethylzinc to benzaldehyde35 (Table 32). 

The synthesis of 4-alkyl-y-butyrolactones 13 and 5-alkyl-<5-valerolactones 14 can be achieved in high enantiomeric excess by alkylation of ethyl 4-oxobutanoate and ethyl 5-oxopentanoate (11, n = 2, 3). The addition of diethylzinc, as well as dimethylzinc, leads to hydroxy esters 12 in high optical purity. When methyl esters instead of ethyl esters are used as substrates, the enantioselectivity of the addition reaction is somewhat lower. Alkaline hydrolysis of the hydroxy esters 12, followed by spontaneous cyclization upon acidification, leads to the corresponding y-butyro- and -valerolactones32. 

A combination of diethylzinc with sulfonamides 18 or 19 offers another possibility for the enantioselective acetate aldol reaction39,41. The addition of silyl enol ethers to glyoxylates can be directed in a highly enantioselective manner when mediated by the binaphthol derived titanium complex 2040. 

Another example of reagent-induced asymmetric synthesis is the enantioselective preparation of phosphoramides 6 by addition of dialkylzine reagents to A-diphenylphosphinoylimincs 4 in the presence of the enantiomerically pure 1,2-amino alcohols 5a or 5 b (diethylzinc does not add to A-silyl- or A-phenylimines)12. Phosphoramides 6 (crystalline solids) are obtained in moderate to good yield and good enantioselectivity. The latter can be enhanced by recrystallization. Acidic hydrolysis with dilute 3 M hydrochloric acid/tetrahydrofuran provides the corresponding amines 7 without any racemization. 

The enantioselective addition of organometallic reagents to, V-(trimethylsilyl)benzaldehyde imine (1) in the presence of enantiomerically pure modifiers has been investigated. The best result is obtained with butyllithium (the corresponding Grignard reagent affords both lower yield and selectivity, 1 fails to react with diethylzinc) and two equivalents of the enantiomerically pure diol 2 in diethyl ether. It should be noted that the choice of the solvent is crucial for the stereoselectivity of the reaction1 2 3 5 7 8 9. 

A series of chiral phosphinous amides bearing pendant oxazoline rings (50, Ri=H,Tr R2=H,Tr, 51, Ri=H,Tr R2=H,Tr and 54, Ri=H,Tr R2=H,Tr in Scheme 41) have been used as ligands in the copper-catalyzed 1,4-addition of diethylzinc to enones. Two model substrates have been investigated, the cyclic 2-cyclohexenone and the acyclic trans-chalcone. The addition products are obtained quantitatively in up to 67% ee [171]. 

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