Metal-catalyzed cyclopropanation

Muller et al. have also examined the enantioselectivity and the stereochemical course of copper-catalyzed intramolecular CH insertions of phenyl-iodonium ylides [34]. The decomposition of diazo compounds in the presence of transition metals leads to typical reactions for metal-carbenoid intermediates, such as cyclopropanations, insertions into X - H bonds, and formation of ylides with heteroatoms that have available lone pairs. Since diazo compounds are potentially explosive, toxic, and carcinogenic, the number of industrial applications is limited. Phenyliodonium ylides are potential substitutes for diazo compounds in metal-carbenoid reactions. Their photochemical, thermal, and transition-metal-catalyzed decompositions exhibit some similarities to those of diazo compounds. 

Metal-Catalyzed. Cyclopropanation. Carbene addition reactions can be catalyzed by several transition metal complexes. Most of the synthetic work has been done using copper or rhodium complexes and we focus on these. The copper-catalyzed decomposition of diazo compounds is a useful reaction for formation of substituted cyclopropanes.188 The reaction has been carried out with several copper salts,189 and both Cu(I) and Cu(II) triflate are useful.190 Several Cu(II)salen complexes, such as the (V-f-butyl derivative, which is called Cu(TBS)2, have become popular catalysts.191... 

In most transition metal-catalyzed reactions, one of the carbene substituents is a carbonyl group, which further enhances the electrophilicity of the intermediate. There are two general mechanisms that can be considered for cyclopropane formation. One involves formation of a four-membered ring intermediate that incorporates the metal. The alternative represents an electrophilic attack giving a polar species that undergoes 1,3-bond formation. 

Section B gives some examples of metal-catalyzed cyclopropanations. In Entries 7 and 8, Cu(I) salts are used as catalysts for intermolecular cyclopropanation by ethyl diazoacetate. The exo approach to norbornene is anticipated on steric grounds. In both cases, the Cu(I) salts were used at a rather high ratio to the reactants. Entry 9 illustrates use of Rh2(02CCH3)4 as the catalyst at a much lower ratio. Entry 10 involves ethyl diazopyruvate, with copper acetylacetonate as the catalyst. The stereoselectivity of this reaction was not determined. Entry 11 shows that Pd(02CCH3) is also an active catalyst for cyclopropanation by diazomethane. 

Aziridination of alkenes can be carried out using N-(p- to I ucncsu I I o n y I i m i n o) phenyliodinane and copper triflate or other copper salts.257 These reactions are mechanistically analogous to metal-catalyzed cyclopropanation. Rhodium acetate also acts as a catalyst.258 Other arenesulfonyliminoiodinanes can be used,259 as can chloroamine T260 and bromoamine T.261 The range of substituted alkenes that react includes acrylate esters.262... 

Organic halides play a fundamental role in organic chemistry. These compounds are important precursors for carbocations, carbanions, radicals, and carbenes and thus serve as an important platform for organic functional group transformations. Many classical reactions involve the reactions of organic halides. Examples of these reactions include the nucleophilic substitution reactions, elimination reactions, Grignard-type reactions, various transition-metal catalyzed coupling reactions, carbene-related cyclopropanations reactions, and radical cyclization reactions. All these reactions can be carried out in aqueous media. 

Diazomethane is also decomposed by N O)40 -43 and Pd(0) complexes43 . Electron-poor alkenes such as methyl acrylate are cyclopropanated efficiently with Ni(0) catalysts, whereas with Pd(0) yields were much lower (Scheme 1)43). Cyclopropanes derived from styrene, cyclohexene or 1-hexene were formed only in trace yields. In the uncatalyzed reaction between diazomethane and methyl acrylate, methyl 2-pyrazoline-3-carboxylate and methyl crotonate are formed competitively, but the yield of the latter can be largely reduced by adding an appropriate amount of catalyst. It has been verified that cyclopropane formation does not result from metal-catalyzed ring contraction of the 2-pyrazoline, Instead, a nickel(0)-carbene complex is assumed to be involved in the direct cyclopropanation of the olefin. The preference of such an intermediate for an electron-poor alkene is in agreement with the view that nickel carbenoids are nucleophilic 44). 

The common by-products obtained in the transition-metal catalyzed reactions are the formal carbene dimers, diethyl maleate and diethyl fumarate. In accordance with the assumption that they owe their formation to the competition of olefin and excess diazo ester for an intermediate metal carbene, they can be widely suppressed by keeping the actual concentration of diazo compound as low as possible. Usually, one attempts to verify this condition by slow addition of the diazo compound to an excess (usually five- to tenfold) of olefin. This means that the addition rate will be crucial for the yields of cyclopropanes and carbene dimers. For example, Rh6(CO)16-catalyzed cyclopropanation of -butyl vinyl ether with ethyl diazoacetate proceeds in 69% yield when EDA is added during 30 minutes, but it increases to 87 % for a 6 h period. For styrene, the same differences were observed 65). 

It is not known whether or not this transformation is catalyzed by the transition metal. However, the metal-catalyzed ring-opening reaction of (3-alkoxycyclopropane carboxylates yielding vinyl ethers (e.g. 50 -> 51 and 52 - 53) is well documented 97 120 . Several catalysts are suited [PtCl2 2 PhCN, Rh2(OAc)4, [Rh(CO)2Cl]2, [Ru(CO)3Cl2]2, Cu bronze, CuCl], but with all of them, reaction temperatures higher than those needed for the carbenoid cyclopropanation reaction are required. 

Whereas metal-catalyzed decomposition of simple diazoketones in the presence of ketene acetals yields dihydrofurans 121,124,134), cyclopropanes usually result from reaction with enol ethers, enol acetates and silyl enol ethers, just as with unactivated alkenes 13). l-Acyl-2-alkoxycyclopropanes were thus obtained by copper-catalyzed reactions between diazoacetone and enol ethers 79 105,135), enol acetates 79,135 and... 

It has been widely accepted that the carbene-transfer reaction using a diazo compound and a transition metal complex proceeds via the corresponding metal carbenoid species. Nishiyama et al. characterized spectroscopically the structure of the carbenoid intermediate that underwent the desired cyclopropanation with high enantio- and diastereoselectivity, derived from (91).254,255 They also isolated a stable dicarbonylcarbene complex and demonstrated by X-ray analysis that the carbene moiety of the complex was almost parallel in the Cl—Ru—Cl plane and perpendicular to the pybox plane (vide infra).255 These results suggest that the rate-determining step of metal-catalyzed cyclopropanation is not carbenoid formation, but the carbene-transfer reaction.254... 

The detailed mechanism of transition metal-catalyzed cyclopropanation using diazo compounds as a carbene source is still covered by clouds of controversy, but it is generally accepted that the reaction proceeds through metal-carbenoid complexes,17-21 and the valency of the metal ions (M) changes with carbenoid formation (Scheme 85). 

Metallocyclobutanes from cyclopropanes have been frequently invoked in transition metal-catalyzed rearrangements of strained ring hydrocarbons, and this body of chemistry is quite rich and diverse, as evidenced in the excellent review by Bishop (72). Because of this diversity, the significance of isolated observations should not be overstated nevertheless, certain reactions outlined by Bishop are closely related to the carbene retroadditions reported by Gassman and co-workers using metathesis catalysts. 

Furthermore, cyclopropane structures have often served as intermediates in organic synthesis. For these reasons, olefin cyclopropanation has proved to be a useful tool for synthetic organic chemists. This has led to the development of several methods for cyclopropanation reactions,91 including the metal-catalyzed reactions of diazo compounds with olefins, as well as the Simmons-Smith reaction. 

The use of chiral copper complexes in asymmetric synthesis was inaugurated in 1966 when the first homogeneous asymmetric metal-catalyzed reaction was reported a copper catalyzed cyclopropanation (2). At the end of 1999, more than 25 distinct reactions were reported wherein the use of a chiral copper complex had induced an enantioselective transformation. The field grew quickly and the best is most likely yet to come. 

The transition metal-catalyzed cyclopropanation of alkenes is one of the most efficient methods for the preparation of cyclopropanes. In 1959 Dull and Abend reported [617] their finding that treatment of ketene diethylacetal with diazomethane in the presence of catalytic amounts of copper(I) bromide leads to the formation of cyclopropanone diethylacetal. The same year Wittig described the cyclopropanation of cyclohexene with diazomethane and zinc(II) iodide [494]. Since then many variations and improvements of this reaction have been reported. Today a large number of transition metal complexes are known which react with diazoalkanes or other carbene precursors to yield intermediates capable of cyclopropanating olefins (Figure 3.32). However, from the commonly used catalysts of this type (rhodium(II) or palladium(II) carboxylates, copper salts) no carbene complexes have yet been identified spectroscopically. 

The transition metal-catalyzed cyclopropanation of alkenes with diazomethane is a valuable alternative to Simmons-Smith methodology [645]. Because of the mild reaction conditions under which this reaction takes place, diazomethane is the reagent of choice if sensitive olefins are to be cyclopropanated [646-648]. 

The transition metal-catalyzed reaction of diazoalkanes with acceptor-substituted alkenes is far more intricate than reaction with simple alkenes. With acceptor-substituted alkenes the diazoalkane can undergo (transition metal-catalyzed) 1,3-dipolar cycloaddition to the olefin [651-654]. The resulting 3//-pyrazolines can either be stable or can isomerize to l//-pyrazolines. 3//-Pyrazolines can also eliminate nitrogen and collapse to cyclopropanes, even at low temperatures. Despite these potential side-reactions, several examples of catalyzed cyclopropanations of acceptor-substituted alkenes with diazoalkanes have been reported [648,655]. Substituted 2-cyclohexenones or cinnamates [642,656] have been cyclopropanated in excellent yields by treatment with diazomethane/palladium(II) acetate. Maleates, fumarates, or acrylates [642,657], on the other hand, cannot, however, be cyclopropanated under these conditions. 

Most electrophilic carbene complexes with hydrogen at Cjj will undergo fast 1,2-proton migration with subsequent elimination of the metal and formation of an alkene. For this reason, transition metal-catalyzed cyclopropanations with non-acceptor-substituted diazoalkanes have mainly been limited to the use of diazomethane, aryl-, and diaryldiazomethanes (Tables 3.4 and 3.5). 

Table 3.5. Transition-metal-catalyzed cyclopropanations with diazoalkanes.

Ylide formation, and hence X-H bond insertion, generally proceeds faster than C-H bond insertion or cyclopropanation [1176], 1,2-C-H insertion can, however, compete efficiently with X-H bond insertion [1177]. One problem occasionally encountered in transition metal-catalyzed X-H bond insertion is the deactivation of the (electrophilic) catalyst L M by the substrate RXH. The formation of the intermediate carbene complex requires nucleophilic addition of a carbene precursor (e.g. a diazocarbonyl compound) to the complex Lj,M. Other nucleophiles present in the reaction mixture can compete efficiently with the carbene precursor, or even lead to stable, catalytically inactive adducts L M-XR. For this reason carbene X-H bond insertion with substrates which might form a stable complex with the catalyst (e.g. amines, imidazole derivatives, thiols) often require larger amounts of catalyst and high reaction temperatures. 

Table 4.23. Intramolecular cyclopropanation by transition metal-catalyzed decomposition of diazocarbonyl compounds.

In the past few years, new approaches for the enantioselective synthesis of / -benzyl-y-butyrolactones appeared in the literature. Some of these approaches involve the asymmetric hydrogenation of 2-benzyl-2-butenediols (j [34]), the radical mediated rearrangement of chiral cyclopropanes (r [35]), the transition metal catalyzed asymmetric Bayer-Villiger oxidation of cyclobutanones n [36]), or the enzymatic resolution of racemic succinates (g [37]). 

Carbene, nitrene, and oxo complexes of Mn-Cu represent challenging synthetic targets that would enable a better mechanistic understanding of metal-catalyzed cyclopropanation, aziridination, and oxidation reactions promoted by these complexes. By offering insights into the patterns of selectivity of these complexes, these studies may pave the way toward a rational design of a future generation of more efficient catalysts. 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

Hydrogenative ring opening of cycloalkanes is also a well-studied area.16 252 253 289-292 Mainly cyclopropanes and cyclopentanes were studied, since three- and five-membered adsorbed carbocyclic species are believed to be intermediates in metal-catalyzed isomerization of alkanes (see Section 4.3.1). Ring-opening reactivity of different ring systems decreases in the order cyclopropane > cyclobutane > cyclopentane > cyclohexane.251 Cyclopropane and its substituted derivatives usually react below 100°C. 

SCHEME 92. Transition metal-catalyzed cyclopropanation of olefins with diazoalkanes. 

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