Copper alkene complexes

The catalytic asymmetric cyclopropanation of an alkene, a reaction which was studied as early as 1966 by Nozaki and Noyori,63 is used in a commercial synthesis of ethyl (+)-(lS)-2,2-dimethylcyclo-propanecarboxylate (18) by the Sumitomo Chemical Company (see Scheme 5).64 In Aratani s Sumitomo Process, ethyl diazoacetate is decomposed in the presence of isobutene (16) and a catalytic amount of the dimeric chiral copper complex 17. Compound 18, produced in 92 % ee, is a key intermediate in Merck s commercial synthesis of cilastatin (19). The latter compound is a reversible... 

Numerous examples have been pubhshed dealing with the heterogeneization of copper complexes, as immobihzed catalysts for the asymmetric cyclo-propanation of alkenes. Some of them have already been mentioned in the text for a direct comparison with their homogeneous coimterparts. Other reusable catalytic systems have been developed and will be described as follows. 

Table 12 Results of reactions of ethyl glyoxylate with different alkenes, catalyzed by several bis(oxazoline)-copper complexes immobilized on Y zeolite...

The well-defined copper complexes 94 and 95 (Fig. 2.16) have been used as catalysts for the intermolecular hydroamination of electron-deficient alkenes [Michael acceptors, X=CN, C(=0)Me, C(=0)(0Me)] and vinyl arenes substituted... 

Fig. 2.17 Nickel and copper complexes as catalysts for the hydrothiolation of alkynes and activated alkenes...

The copper complex of these bis(oxazoline) compounds can also be used for hetero Diels-Alder reactions of acyl phosphonates with enol ethers.43 5 A favorable acyl phosphonate-catalyst association is achieved via complexation between the vicinal C=0 and P=0 functional groups. The acyl phosphonates are activated, leading to facile cycloaddition with electron-rich alkenes such as enol ethers. The product cyclic enol phosphonates can be used as building blocks in the asymmetric synthesis of complicated molecules. Scheme 5-36 shows the results of such reactions. 

Cyclopropanation reactions can be promoted using copper or rhodium catalysts or indeed systems based on other metals. As early as 1965 Nozaki showed that chiral copper complexes could promote asymmetric addition of a carbenoid species (derived from a diazoester) to an alkene. This pioneering study was embroidered by Aratani and co-workers who showed a highly enantioselective process could be obtained by modifying the chiral copper... 

Evans suggests that the catalyst resting state in this reaction is a 55c Cu alkene complex 58, Scheme 4 (35). Variable temperature NMR studies indicate that the catalyst complexes one equivalent of styrene which, in the presence of excess alkene, undergoes ready alkene exchange at ambient temperature but forms only a mono alkene-copper complex at -53°C. Addition of diazoester fails to provide an observable complex. These workers invoke the metallacyclobutane intermediate 60 via a formal [2 + 2] cycloaddition from copper carbenoid alkene complex 59. Formation of 60 is the stereochemistry-determining event in this reaction. The square-planar S Cu(III) intermediate 60 then undergoes a reductive elimination forming the cyclopropane product and Complex 55c-Cu, which binds another alkene molecule. 

Jacobsen and co-workers (61) demonstrated that diimine-copper complexes are moderately selective for the asymmetric cyclopropanation of 1,2-dihydro-naphthalene, Eq. 44. A correlation was found between selectivities in the asymmetric aziridination and the asymmetric cyclopropanation catalyzed by the same species. Jacobsen argues that this supports the notion that the two processes follow similar mechanistic pathways. These workers also studied the complexation event between alkenes and Cu(I)-diimine complexes by NMR and by crystallographic characterization (62). For a thorough treatment of these results, see Section II.B.3. 

In 1965, Denney et al. (98) reported the reaction of a number of alkenes with ferf-butyl hydroperoxide (TBHP) and cupric salts of chiral acids. The use of ethyl camphorate copper complex 144 in the allylic oxidation of cyclopentene provides, upon reduction of the camphorate ester, the allylic alcohol in low yield and low selectivity, Eq. 82. The initial publication only provided the observed rotation of cyclopentenol, but comparison to subsequent literature values (99) reveals that this reaction proceeds in 12% ee and 43% yield (based on the metal complex). 

In Figure 17.7 we show how enantiodiscrimination might take place as proposed by Pfaltz [11], The copper complex in the centre is viewed along the trigonal axis. The alkene will approach always from the left-hand side, to avoid... 

Figure 8 The preparations and crystal structures of copper(I) alkene and alkyne complexes... 

Asymmetric cyclopropanations of alkenes and alkynes with a-diazocarbonyl compounds have been extensively explored in recent years and a number of very effective chiral catalysts have been developed2. Copper complexes modified with such chiral ligands as salicy-laldimines 38202,203, semicorrins 39204 208, bis(oxazolines) 40209-2" and bipyridines 41212 have... 

The idea of a reversible alkene-copper complex had been used to explain the enantioselective alkylation of 2-cyclohexenone using a chiral auxiliary ligand.30 Interaction of the cuprate with the re face of C-3 in 2-cyclohexenone was presumed to be favored over complexation with the si face of C-3 for steric reasons (equation 4). 

Attempts to aziridinate alkenes with iron catalysts in an asymmetric manner have met with only limited success to date [101], In an early report on the use of various chiral metal salen complexes, it was found that only the Mn complex catalyzed the reaction whereas all other metals investigated (Cr, Fe, Co, Ni etc.) gave only unwanted hydrolysis of the iminoiodinane to the corresponding sulfonamide and iodoben-zene [102], Later, Jacobsen and coworkers and Evans et al. achieved good results with chiral copper complexes [103]. 

Allylic oxidation of a variety of cyclic alkenes with copper complexes of different pybox ligands (8) and with various peresters shows high enantioselectivity (80-96% ee). Use of phenylhydrazine as an additive and acetone as solvent accelerates the reaction. It has been suggested that the phenylhydrazone is responsible for the observed acceleration. Using EPR spectra, it has been shown that the Cu(II) species is reduced to Cu(I) by phenylhydrazine and phenylhydrazone. It has been found that the presence of a gem-diphenyl group at C(5) and a secondary or tertiary alkyl substituent at the chiral centre at C(4) of the oxazoline rings is crucial for high enantioselectivity. 

Asymmetric cyclopropanation. Three laboratories have reported that copper complexes of chiral bis(oxazolines) are effective catalysts for asymmetric cyclopropanation of alkenes with diazoacetates. Bis(oxazolines) such as 1 are readily available by condensation of a-amino alcohols with diethyl malonate followed by cyclization, effected with dichlorodimethyltin or thionyl chloride. Cyclopropanation of styrene with ethyl diazoacetate catalyzed by copper complexes of type 1 indicates... 

Interestingly, when using copper(I)triflate, the cyclopentadiene dimer 14 reacts in an intermolecular way, leading to the cydobutane 15 (reaction 5) [22], When the same substrate is transformed in the presence of the triplet sensitizer acetone, an intramolecular [2 + 2] cycloaddition takes place and the cage hydrocarbon compound 16 is formed. Obviously, the formation of a copper complex intermediate involving both alkene double bonds of the substrate is unfavorable in this case. 

More recently, Pfaltz has reported high enantioselectivities for the cyclopropanation of monosubstituted alkenes and dienes with diazo carbonyl compounds using chiral (semicorrinato)copper complexes (P-Cu) (23-25), and Evans, Masamune, and Pfaltz subsequently discovered exceptional enantioselectivities in intermolecular cyclopropanation reactions with the analogous bis-oxazoline copper complexes (26-28). With the exception of the chiral (camphorquinone dioximato)cobalt(II) catalysts (N-Co) reported by Nakamura and coworkers (29,30), whose reactivities and selectivities differ considerably from copper catalysts, chiral complexes of metals other than copper have not exhibited similar promise for high optical yields in cyclopropanation reactions (37). 

Numerous synthetic methods have been developed for the synthesis of cyclopropanes, which represent an important core structure in a number of biologically active compounds. Of these techniques, metal-catalysed cyclopropanation of alkenes with ethyl diazoacetate constitutes a particularly simple and straightforward approach. The metal reacts with the azo compound to form a carbene complex which in turn reacts with the olefin, via formation of a metallabutacycle. Copper-complexes are most commonly employed, but other metals like rhodium and palladium are also used. 

For instance, the reaction of hydrotris(pyrazol-yl)borate-copper complex 15 (Scheme 5) with alkenes and ethyl diazoacetate results in the formation of cyclopropanes in yields in the range 63-78 % [19]. 

Enantioselective Aziridination of Alkenes. Copper complexes with neutral methylenebis(oxazoline) ligands (1) and (2) have also been employed as enantioselective catalysts for the reaction of alkenes with (Al-tosylimino)phenyliodinane, leading to A-tosylaziridines. The best results have been reported for cinna-mate esters as substrates, using 5 mol % of catalyst prepared from CuOTf and the phenyl-substituted ligand (2) (eq 6). The highest enantiomeric excesses are obtained in benzene, whereas in more polar and Lewis basic solvents, such as acetonitrile, the selectiv-ities are markedly lower. The chemical yield can be substantially improved by addition of 4X molecular sieves. Both Cu - and Cu"-bisoxazoline complexes, prepared from Cu or Cu triflate, respectively, are active catalysts, giving similar results. In contrast to the Cu-catalyzed cyclopropanation reactions discussed above, in which only Cu complexes are catalytically active, here Cu complexes are postulated as the actual catalysts. ... 

Cycloaddition Reactions. Bis(oxazoline) copper complex 2 catalyzes the dipolar cycloaddition reaction between electron deficient nitrones and electron rich alkenes. While exo.endo selectivities are marginal, products can be obtained in as high as 94% enantiomeric excess (eq 19). Based on the stereochemical outcome of the reaction, a five-coordinate intermediate has been postulated in which both the nitrone (as a bidentate ligand) andl alkene are coordinated to the Cu center. 

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