Metal carbenoids

Metal carbenoid-mediated tandem processes in synthesis of azapolycycles 97MI36. 

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. 

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). 

As described in Section 9.4.7.1, some Rh and Ru carbenoid intermediates that undergo cyclopropanation reactions have been spectroscopically identified.294,254 Less reactive metal-carbenoid intermediates (108) and (109) have been isolated and their structures have been determined unequivocally by X-ray analysis.255 258 The isolated carbenoid intermediate (108) undergoes cyclopropanation at high temperature (110°C),255 and another intermediate (109) serves as the catalyst for asymmetric cyclopropanation (Figure 11).258... 

The metal-carbenoid intermediates, especially ones derived from a-diazocarbonyl compounds, are electrophilic, and electron-rich olefins in general react more easily with the carbenoid intermediates than electron-deficient olefins. For the interaction of metal carbenoid and olefin, three different mechanisms have been proposed, based on the stereochemistry of the reactions and the reactivity of the substrates (Figure 12) 21 (i) a nonconcerted, two-step process via a metallacyclobutane 226,264... 

Using the results of an earlier study concerning enantioselective copper-catalyzed intramolecular C—H insertion of metal carbenoids,109 an interesting system for optimizing the proper combination of ligand, transition metal, and solvent for the reaction of the diazo compound (75) was devised (see Scheme 19).110 The reaction parameters were varied systematically on a standard 96-well microtiter/filtration plate. A total of five different ligands, seven metal precursors, and four solvents were tested in an iterative optimization mode. Standard HPLC was used to monitor stereoselectivity following DDQ-induced oxidation. This type of catalyst search led to the... 

The involvement of carbenes has been excluded in the DNA cleavage reactions activated by cupric acetate as these experiments were conducted in the dark. However, the contribution of metal-carbenoids [79] could not be ruled out. In a series of studies dealing with the metal-catalyzed... 

In summary, the intermolecular C-H insertion chemistry of transient metal carbenoids has undergone tremendous growth in the last 10 years. It now can be realistically considered as a viable alternative to many of the classic methodologies used in organic synthesis. 

Intramolecular C-H insertion reactions of metal carbenoids have been widely used for the stereoselective construction of substituted lactams, lactones, cyclopentanones, benzofurans, and benzopyrans. Several excellent reviews have been published covering the general aspects of intramolecular C-H insertion by metal carbenoids.46,47 62 71 99-104 The following section highlights the major advances made since 1994, especially in asymmetric intramolecular C-H insertion. 

For application in organic synthesis, the regiochemistry of insertion of carbenoids into un-symmetrical zirconacydes needs to be predictable. In the case of insertion into mono- and bicydic zirconacydopentenes where there is an wide variety of metal carbenoids insert selectively into the zirconium—alkyl bond [48,59,86], For more complex systems, the regiocon-trol has only been studied for the insertion of lithium chloroallylides (as in Section 3.3.2) [60]. Representative examples of regiocontrol relating to the insertion of lithium chloroal-lylide are shown in Fig. 3.2. 

The use of copper as a catalyst in carbenoid transfer has its roots in the Amdt-Eistert reaction, Eq. 1 (3). Although the original 1935 paper describes the Wolff rearrangement of a-diazo ketones to homologous carboxylic acids using silver, the authors mention that copper may be substituted in this reaction. In 1952, Yates (4) demonstrated that copper bronze induces insertion of diazo compounds into the X-H bond of alcohols, amines, and phenols without rearrangement, Eq. 2. Yates proposal of a distinct metal carbenoid intermediate formed the basis of the currently accepted mechanistic construct for the cyclopropanation reaction using diazo compounds. 

Functionalization of C-H bonds by metal carbenoid or nitrenoid insertions represents a promising alternative to the more traditional approach of direct activation by a metal center. Carbenoids and nitrenoids show unusual regio- and stereoselectivity in insertions into C-H bonds, and unlike insertions of metal centers, these are intrinsically functionalizations rather than activations, which must be followed by functionalization (although in either case, loss of the functionalized group, to regenerate the active metal complex, is still required for catalysis) [129]. The use of dimeric Rh(n) complexes in this area has been extensively developed [129]. 

The cyclopropane moiety is a fundamental class of functional group present in both natural products and numerous therapeutic agents. It has provided the impetus for significant breakthroughs in the use of metal carbenoids [151] and organocatalytic ylide intermediates [152, 153] such that rehable methods exist for most disconnective strategies on this ring system. 

The electrophilic reactivity of lithium carbenoids (reaction b) becomes evident from their reaction with alkyl lithium compounds. A, probably metal-supported, nucleophilic substitution occurs, and the leaving group X is replaced by the alkyl group R with inversion of the configuration . This reaction, typical of metal carbenoids, is not restricted to the vinylidene substitution pattern, but occurs in alkyl and cycloalkyl lithium carbenoids as well ". With respect to the a-heteroatom X, the carbenoid character is... 

The metal-catalyzed decomposition of diazo compounds has broad applications in organic synthesis [1-8]. Transient metal carbenoids provide important reactive intermediates that are capable of a wide variety of useful transformations, in which the catalyst dramatically influences the product distribution [5]. Indeed, the whole field of diazo compound decomposition was revolutionized in the early 1970s with the discovery that dirhodium tetracarboxylates 1 are effective catalysts for this process [9]. Many of the reactions that were previously low-yielding using conventional copper catalysts were found to proceed with unparalleled efficiency using this particular rhodium catalysis. The field has progressed extensively and there are some excellent reviews describing the breadth of this chemistry [5, 7, 10-17]. 

Many different types of 1,3-dipoles have been described [Ij however, those most commonly formed using transition metal catalysis are the carbonyl ylides and associated mesoionic species such as isomiinchnones. Additional examples include the thiocar-bonyl, azomethine, oxonium, ammonium, and nitrile ylides, which have also been generated using rhodium(II) catalysis [8]. The mechanism of dipole formation most often involves the interaction of an electrophilic metal carbenoid with a heteroatom lone pair. In some cases, however, dipoles can be generated via the rearrangement of a reactive species, such as another dipole [40], or the thermolysis of a three-membered het-erocycHc ring [41]. 

Suga et al. (197) reported the first stereocontrolled 1,3-dipolar cycloaddition reactions of carbonyl ylides with electron-deficient alkenes using a Lewis acid catalyst. Carbonyl ylides are highly reactive 1,3-dipoles and cannot be isolated. They are mainly generated through transition metal carbenoid intermediates derived in situ from diazo precursors by treatment with a transition metal catalyst. When methyl o-(diazoacetyl)benzoate is treated with A-methylmaleimide at reflux... 

The reaction, as originally carried out, is of little contemporary use. Metal-mediated catalysis is more-often applied, where the reactive species are metal carbenoids. Buchner-Curtius-Schlotterbeck Reaction... 

The [2+1] cycloaddition between metal carbenoid intermediates and alkenes is a very powerful method for the stereoselective synthesis of cyclopropanes [1-3]. Indeed, the vast majority of chiral catalysts developed for carbenoid chemistry were specifically designed for asymmetric cyclopropanation [1-3]. In recent years, however, a number of other enantioselective cydoadditions have been reported. 

A promising synthetic transformation is the reaction of carbenoid intermediates with heteroatoms to form ylides that are capable of undergoing further transformations [5,6]. Enantioselective transformations in which the ylide intermediates undergo either 1,2- or 2,3-sigmatropic rearrangement were briefly reviewed in the previous issue (Vol. II, pp. 531-532) and several recent examples have appeared [37]. A major breakthrough has been made in the enantioselective transformation of carbonyl ylides derived from capture of the metal carbenoid intermediates by carbonyl groups. The carbonyl ylides have been ex-... 

Another common method for forming cyclopropanes is to react a-diazoketones or esters with olefins under the influence of copper or, better yet, rhodium or ruthenium catalysis. Again a metal carbenoid intermediate is produced which reacts with tire olefin. 

The mechanism has not been fully clarified, but pure carbenes can be excluded, and a metal carbenoid is likely to be involved. The following results may be interpreted to indicate a possible complexation of the active species by hydroxy groups leading to reaction on the same face as this substituent. This would only be possible if an organozinc reagent is present. 

The Tebbe Reagent is a metal carbenoid prepared from the dimetallomethylene species derived by the reaction of trimethyl aluminium with titanocene dichloride this reagent exhibits carbenoid behaviour after the addition of a catalytic amount of pyridine. The Tebbe Reagent reacts with various carbonyl partners to give the product of methylenation ... 

Related to metal complexes are metal carbenoids such as those formed when zinc reacts with di-iodomethane. In early examples, such as the efficient cyclopropanation of cyclohexenone 54, the zinc was activated by some copper.13 The active reagent is the zinc a-complex 56. One might suppose an a-elimination 57 would occur to give the carbene, but this is apparently not so. The active reagent 56, nearly but not quite a carbene, is known as a carbenoid. 

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