Ethylmagnesation

Scheme 5 Cyclic mechanism for the Zr-catalyzed ethylmagnesation of alkenes.

The Zr-catalyzed ethylalumination of alkynes under certain conditions1,9 (Scheme 4) and ethylmagnesation of alkenes10 11 (Scheme 5) represent some of the earliest examples of the catalytic carbozirconation proceeding via zirconacycles. In Scheme 5, the carbometallative ring expansion of (ethylene)zirconocene to produce a... 

It is important to note that the Ru-catalyzed RCM and the Zr-catalyzed resolution can be carried out in a single vessel, without recourse to intermediate isolation. The unsaturated medium-ring amides 5 and 8 can be subjected to 10 mol% of the chiral Zr catalyst and EtMgCl, in the same flask, to afford unsaturated 6 and 9 in 81% and 54% isolated yield, respectively. As depicted in Eq. 1, a similar tandem diene metathesis/ethylmagnesation can be carried out on ether 10, leading to the formation of unsaturated chiral alcohol 11 in 73% yield and >99% ee. 

As is clear from the mechanisms, these reactions cannot occur with methylmetals. Their extensions beyond ethylmetallation are possible, but are prone to various side reactions [201,202], In contrast to the widely observable Zr-catalyzed carboalumination of al-kynes discussed earlier, the alkyne version of the Zr-catalyzed ethylmagnesation has not been widely observable, the only successful examples being those of conjugated diynes [203], In this context, further investigation of the Zr-catalyzed carbozincation of alkynes reported as early as 1983 [204,205] appears to be very desirable. 

In these early studies, however, the concept of c-bond metathesis most probably did not exist, and the results were presented just as observed facts. Mainly in the 1990s, a wide variety of c-bond metathesis reactions of both three- and five-membered zirconacycles were reported. In Scheme 1.4, the reaction of the five-membered zirconacycle with EtMgBr via c-bond metathesis followed by another c-bond metathesis (p-H abstraction) produces the ethylmagnesation product along with ethylene-zirconocene [51], Some representative examples of c-bond metathesis reactions of three-membered zirconacycles are shown in Scheme 1.69. These are examples of stoichiometric c-bond metathesis reactions from which the products have been identified. 

Table 6.1. (ebthi)Zr-catalyzed enantioselective ethylmagnesation of unsaturated heterocycles3... 

Scheme 6.1. Demonstration of the utility of (ebthi)Zr-catalyzed ethylmagnesation in the enantioselective synthesis of the macrolactam aglycon of fluvirucin.

Scheme 6.2. Catalytic cycle proposed for the (ebthi)Zr-catalyzed ethylmagnesation of unsaturated...

Scheme 6.3. Zr-catalyzed enantioselective ethylmagnesation and metal-catalyzed alkene metathesis make effective partners. In the two cases shown here, the alkene substrate is synthesized and enantioselectively alkylated in the same vessel.

As in the case of ethylmagnesation shown in Scheme 4.17, kinetic resolution of 2-aryl-2,5-dihydrofurans as indicated in Scheme 4.19 can be achieved by using Et3Al and 8 or 9. Whereas the enantioselectivities observed with 9 were 64-84% ee, those observed with 8 were 96% ee for either product, indicating that 8 is superior to 9 [29] (Scheme 4.19). 

TABLE 4.S. Zirconium-Catalyzed Enantioselective Ethylmagnesation and Ethylalumination of Allyl Derivatives... 

In a simplified picture, the mechanism of the Zr-catalyzed ethylmagnesation can be rationalized as shown in Scheme 1 [8]. At first, the zirconocene-ethene complex 12 is generated from the catalyst precursor Cp2ZrCl2. Complex 12 can also be regarded as a metallacyclopropane 16. After coordination and insertion of the alkene 10, a metalla-cyclopentane 13 is formed, which subsequently reacts with the Grignard reagent regioselectively to the open-chain intermediate... 

The chiral product (39) obtained from the asymmetric ethylmagnesation of dihydrofuran was used as chiral building block in a total syntheses of the Sch 38516 [14]. 

Table 9 Generation and Reactions of Grignard Reagents by Zirconium-Catalyzed Ethylmagnesation...

Hoveyda et al. further oriented their investigation on this zirconium-catalyzed ethylmagnesation to the issue of 1,2-asymmetric induction in the step of ethyl addition to substituted olefin as exemplified in Eq. (18) [70]. Thus, ethylmagnesation of various allyl... 

On the contrary, a wide variety of other terminal alkenes having allylic alkoxy or methyl group afforded unn -diols after the ethylmagnesation followed by the same workup [Eq. (20)]. In these cases, virtually no change of diastereoselectivities was observed by switching the solvent from THF to ether, showing that the origin of this diastereoselection comes from steric repulsion of substituents around the reaction center. 

A bulky TBS group proximal to the terminal olefin blocked the reaction, which enabled the following chemoselective reaction [Eq. (21) 71], However, an additional oxygen functionality near the reaction center assists the ethylmagnesation to again proceed [Eqs. (22) and (23) 70]. 

Norbornenes also underwent regio- and stereoselective ethylmagnesation, even though the synthetic applicability is rather restricted [Eq. (24) 73]. 

Scheme 8 Proposed reaction course for zirconium-catalyzed ethylmagnesation...

Scheme 11 Difference in proposed catalytic cycles of cyclomagnesation of dienes and ethylmagnesation of alkenes...

Allyhc ethers also undergo catalytic ethylmagnesation with excellent selectivity and in good yield. There are, however, notable differences between the reactions of allylic ethers and alcohols ... 

Another notable difference between the Zr-catalyzed ethylmagnesations of allylic ethers and alcohols is the effect of solvent Lewis basicity on reaction selectivity. Thus, as iUustrated in Scheme 3.79, whereas reactions with allylic ethers are entirely insensitive to variations in solvent structure, those of allylic alcohols are strongly influenced. These observations led Hoveyda and coworkers to conclude that for allylic alcohols (allyhc alkoxides after rapid deprotonation by the Grignard reagent) there is chelation between the Lewis basic heteroatom and a metal center (Zr or Mg) this association, which gives rise to transition state organization and high diastereocon-trol, is altered in the presence of Lewis basic THF, with diminution in selectivity. 

---