Diazoester cyclopropanation

The use of chiral additives with a rhodium complex also leads to cyclopropanes enantioselectively. An important chiral rhodium species is Rh2(5-DOSP)4, which leads to cyclopropanes with excellent enantioselectivity in carbene cyclopro-panation reactions. Asymmetric, intramolecular cyclopropanation reactions have been reported. The copper catalyzed diazoester cyclopropanation was reported in an ionic liquid. ° It is noted that the reaction of a diazoester with a chiral dirhodium catalyst leads to p-lactones with modest enantioselectivity Phosphonate esters have been incorporated into the diazo compound... 

Davies has provided a detailed analysis of how the arrangement of four proli-nate ligands around a dirhodium core can lead to a metal carbene intermediate that reacts further with such high stereocontrol [12]. The two most striking features of the vinyl diazoester cyclopropanations are the excellent diastereoselec-tivity and the total lack of reactivity of frans-disubstituted alkenes. The former is accounted for by the structure of the vinyl diazoester which suggests that high... 

The most significant and widely studied reactivity of the ruthenium and osmium porphyrin carbene complexes is their role in catalyzing both the decomposition of diazoesters to produce alkenes and the cyclopropanation of alkenes by diazoesters. Ethyl diazoacetate is used to prepare the carbene complex 0s(TTP)(=CHC02Et)... 

Iron porphyrins display pronounced substrate preferences for alkene cyclopro-panation with EDA. In general, electron-rich terminal alkenes in conjunction with aromatic moiety or heteroatoms can efficiently undergo cyclopropanation with high catalyst turnover and selectivity. In contrast, 1,2-disubstituted alkenes cannot undergo cyclopropanation with diazoesters. Alkyl alkenes are poor substrates, giving cyclopropanated products in low yields. In both cases, the dimerization product diethyl maleate was obtained in high yield [53]. 

In 2004, ruthenium-catalysed asymmetric cyclopropanations of styrene derivatives with diazoesters were also performed by Masson et al., using chiral 2,6-bis(thiazolines)pyridines. These ligands were prepared from dithioesters and commercially available enantiopure 2-aminoalcohols. When the cyclopropanation of styrene with diazoethylacetate was performed with these ligands in the presence of ruthenium, enantioselectivities of up to 85% ee were obtained (Scheme 6.6). The scope of this methodology was extended to various styrene derivatives and to isopropyl diazomethylphosphonate with good yields and enantioselectivities. The comparative evaluation of enantiocontrol for cyclopropanation of styrene with chiral ruthenium-bis(oxazolines), Ru-Pybox, and chiral ruthenium-bis(thiazolines), Ru-thia-Pybox, have shown many similarities with, in some cases, good enantiomeric excesses. The modification... 

Pd(OAc)2 works well with strained double bonds as well as with styrene and its ring-substituted derivatives. Basic substituents cannot be tolerated, however, as the failures with 4-(dimethylamino)styrene, 4-vinylpyridine and 1 -vinylimidazole show. In contrast to Rh2(OAc)4, Pd(OAe)2 causes preferential cyclopropanation of the terminal or less hindered double bond in intermolecular competition experiments. These facts are in agreement with a mechanism in which olefin coordination to the metal is a determining factor but the reluctance or complete failure of Pd(II)-diene complexes to react with diazoesters sheds some doubt on the hypothesis of Pd-olefin-carbene complexes (see Sect. 11). 

Cu(OTf)2 generally gives yields intermediate between those of the other two catalysts, but with a closer resemblance to rhodium. In competition experiments, the better coordinating norbomene is preferred over styrene, just as in the case with Pd(OAc)2. Cu(acac)2, however, parallels Rh2(OAc)4 in its preference for styrene. These findings illustrate the variability of copper-promoted cyclopropanations, and it was suggested that in the Cu(OTf)2-catalyzed reactions of diazoesters, basic by-products, which are formed as the reaction proceeds, may gradually suppress... 

Whereas control of the rate of addition of the diazoester generally meets with increased yields when Rh OAc), Rh6(CO)16 and CuCl P(OR)3 are used, it has no effect on cyclopropane yields in the case of PdCl2 2 PhCN 59). 

With the rhodium and copper catalysts, even the combination of equimolar amounts of olefin and diazoester will allow high yields of cyclopropanes if the addition rate is controlled meticulously (see Table 6 for examples). This circumstance is particularly useful for cyclopropanation of olefins which are in short supply. In combination with Rhg(CO)16, the easy recovery of the unchanged catalyst (by diluting the mixture with hexane and separating the precipitated catalyst from the liquid65 may render such a procedure particularly attractive from an economical point of view. 

Cyclopropanation of C=C bonds by carbenoids derived from diazoesters usually occurs stereospeciflcally with respect to the configuration of the olefin. This has been confirmed for cyclopropanation with copper 2S,S7,60 85), palladium 86), and rhodium catalysts S9,87>. However, cyclopropanation of c -D2-styrene with ethyl diazoacetate in the presence of a (l,2-dioximato)cobalt(II) complex occurs with considerable geometrical isomerization88). Furthermore, CuCl-catalyzed cyclopropanation of cis-2-butene with co-diazoacetophenone gives a mixture of the cis- and trans-1,2-dimethylcyclopropanes 89). 

As it is known from experience that the metal carbenes operating in most catalyzed reactions of diazo compounds are electrophilic species, it comes as no surprise that only a few examples of efficient catalyzed cyclopropanation of electron-poor alkeiies exist. One of those examples is the copper-catalyzed cyclopropanation of methyl vinyl ketone with ethyl diazoacetate 140), contrasting with the 2-pyrazoline formation in the purely thermal reaction (for failures to obtain cyclopropanes by copper-catalyzed decomposition of diazoesters, see Table VIII in Ref. 6). 

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

EvenPd(OAc)2 is not effective in catalyzing the cyclopropanation of a,P-unsaturated nitriles by ethyl diazoacetate. Instead, vinyloxazoles 92 are formed from acrylonitrile or methacrylonitrile by carbenoid addition to the CsN bond 143 Diethyl maleate and diethyl fumarate as well as polyketocarbenes are by-products in these reactions the 2-pyrazoline which would result from initial [3 + 2] cycloaddition at the C=C bond and which is the sole product of the uncatalyzed reaction at room temperature, can be avoided completely by very slow addition of the diazoester... 

As has already been mentioned for cyclopropanation of olefins, the diazoester should be added slowly to the mixture of alkyne and Rh2(OAc)4, in order to minimize formation of carbene dimers. The reaction works well with mono- and... 

The q1-coordinated carbene complexes 421 (R = Ph)411 and 422412) are rather stable thermally. As metal-free product of thermal decomposition [421 (R = Ph) 110 °C, 422 PPh3, 105 °C], one finds the formal carbene dimer, tetraphenylethylene, in both cases. Carbene transfer from 422 onto 1,1-diphenylethylene does not occur, however. Among all isolated carbene complexes, 422 may be considered the only connecting link between stoichiometric diazoalkane reactions and catalytic decomposition [except for the somewhat different results with rhodium(III) porphyrins, see above] 422 is obtained from diazodiphenylmethane and [Rh(CO)2Cl]2, which is also known to be an efficient catalyst for cyclopropanation and S-ylide formation with diazoesters 66). 

Inhibition of diazoester decomposition by a large excess of olefin speaks in favor of intermediarily liberated W(CO)5 as direct metal precursor of425. Stereoselectivities in the cyclopropanation reaction are very similar to those observed in the Rh2(OAc)4 catalyzed version, which underlines once more the close relationship of tungsten and rhodium carbene complexes. 

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... 

Scheme 1. General mechanism for the copper-catalyzed cyclopropanation of alkenes using diazoesters.

Aratani et al. (21) subsequently found that the use of chiral menthyl diazoacetate esters led to higher trans/cis ratios and improved facial selectivity. A number of bulky diazoesters provided high enantioselectivity in the cyclopropanation reaction, but trans selectivity was highest with /-menthyl esters, Eq. 6. It seems clear from these and subsequent studies that the menthyl group is used because of its bulk and ready availability. The chirality present in the ester has a negligible effect on facial selectivity in the cyclopropanation reaction. Slow addition of diazoester is required (7 h at ambient temperature) for high yields presumably to suppress the formation of fumarate byproducts. 

The popularity of Cu(acac)2, where acac = acetylacetonato, as a precatalyst in alkene cyclopropanation using diazoesters has led to the investigation of chiral 1,3-dicarbonyls as a source of asymmetric induction in this process. Mathn et al. (26) report a selective cyclopropanation of styrene with a dimedone-derived diazocarbonyl in the presence of a camphor-derived diketone, Eq. 12. The reaction is con-... 

Ligand 55c is also efficient in the cyclopropanation of other alkenes. 1,1 -Disub-stituted alkenes afford cyclopropanes in high enantioselectivity with ethyl diazoacetate as carbenoid source, Eq. 25 (34). Internal dissymetric trans alkenes are also excellent substrates. trans-P-Methyl styrene afforded a 95 5 diastereomeric mixture with cyclopropane 56a predominating in 96% ee, when the butylated hydroxy toluene (BHT) diazoester was used, Eq. 26 (35). 

From a practical point of view, it is significant that this cyclopropanation reaction proceeds well on a very large scale. The reaction of isobutylene and ethyl diazoacetate in the presence of 0.1 mol% catalyst (55c CuOTf) (Fig. 4) provides cyclopropane 24a in >99% ee and 91% yield on a 35-gram scale (34). With this catalyst loading, a 5-h addition time of diazoester at 0°C in the presence of 10 equiv of alkene is sufficient to provide high enantioselectivities and yields. Although di-... 

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. 

The stereoselectivities in this reaction are governed by steric interactions in the formation of metallacyclobutane 60 (35). Of two possible intermediates (Fig. 5), 61 suffers from steric interactions between the ligand and the ester functionality. Avoidance of these interactions and minimization of 1,2-interaction in the metallacyclobutane leads to the formation of the observed major enantiomer and dias-tereomer (trans). The model suggests that increased diastereoselectivity should be observed with increasing steric bulk of the diazoester, a relationship that has already been established as discussed (cf. Eqs. 24 and 26). It is interesting to note that this model loosely corresponds to the stereochemical model proposed by Aratani for the Sumitomo cyclopropanation with one important difference the Aratani model is based on a tetrahedral metal while the Evans-Woerpel model is predicated on square-planar copper. Applying the Aratani model to the Evans ligand would predict formation of the opposite enantiomer as the major product (35). 

When internal trans alkenes were subjected to diazoester in the presence of 80 CuOTf, cyclopropane ent-56, formed in high enantioselectivity, was slightly favored over its isomer (56). The use of ethyl diazoacetate improved diastereoselec-tion relative to the bulkier /-Bu ester. Unfortunately, ee values were somewhat lower with the ethyl ester, Eq. 39. Ito and Katsuki (56) propose the model in Fig. 7 to account for this selectivity. Approach of the trans alkene is controlled by the stereocenter on the bipyridines, directing the bulky group cis to the ester moiety. Larger esters lead to an increased steric interaction in this position and the net result is an erosion in reaction diastereoselectivity. 

Kwong et al. (57) examined the use of bipyridines containing chiral carbinol stereocenters in the 2,9 positions. Interestingly, reduction of 84 with diazoester occurred at ambient temperature unlike every other catalyst reported to date. The resulting complex efficiently mediates the cyclopropanation of styrene. 

In their seminal report on homogeneous asymmetric copper-catalyzed cyclopropanation, Nozaki et al. (2) showed that racemic 2-phenyloxetane reacts with the diazoester-derived carbenoid to form cis and trans tetrahydrofurans (THF) in optically active form. Unfortunately, the extent of asymmetric induction could not be determined. 

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