Rhodium carbenoid insertion reactions

Since the observation that Rh(II) carboxylates are superior catalysts for the generation of transient electrophilic metal carbenoids from a-diazocar-bonyls compounds, intramolecular carbenoid insertion reactions have assumed strategic importance for C-C bond construction in organic synthesis [1]. Rhodium(ll) compounds catalyze the remote functionalization of carbon-hydrogen bonds to form carbon-carbon bonds with good yield and selectivity. These reactions have been particularly useful in the intramolecular sense to produce preferentially five-membered rings. 

Indoles, when treated with methyl diazomalonate 1035 under catalysis by rhodium(ll) acetate, undergo C-H and N-H carbenoid insertion reactions regioselectively depending on the substitution pattern on the indole moiety (Equations 242-244) <2002JOC6247>. Indoles in which the nitrogen is unprotected yield varying degrees of N-H insertion (Equation 242). 

As already mentioned for rhodium carbene complexes, proof of the existence of electrophilic metal carbenoids relies on indirect evidence, and insight into the nature of intermediates is obtained mostly through reactivity-selectivity relationships and/or comparison with stable Fischer-type metal carbene complexes. A particularly puzzling point is the relevance of metallacyclobutanes as intermediates in cyclopropane formation. The subject is still a matter of debate in the literature. Even if some metallacyclobutanes have been shown to yield cyclopropanes by reductive elimination [15], the intermediacy of metallacyclobutanes in carbene transfer reactions is in most cases borne out neither by direct observation nor by clear-cut mechanistic studies and such a reaction pathway is probably not a general one. Formation of a metallacyclobu-tane requires coordination both of the olefin and of the carbene to the metal center. In many cases, all available evidence points to direct reaction of the metal carbenes with alkenes without prior olefin coordination. Further, it has been proposed that, at least in the context of rhodium carbenoid insertions into C-H bonds, partial release of free carbenes from metal carbene complexes occurs [16]. Of course this does not exclude the possibility that metallacyclobutanes play a pivotal role in some catalyst systems, especially in copper-and palladium-catalyzed reactions. 

In recent years, much attention has been focused on rhodium-mediated carbenoid reactions. One goal has been to understand how the rhodium ligands control reactivity and selectivity, especially in cases in which both addition and insertion reactions are possible. These catalysts contain Rh—Rh bonds but function by mechanisms similar to other transition metal catalysts. 

Rhodium carboxylates have been found to be effective catalysts for intramolecular C—H insertion reactions of a-diazo ketones and esters.215 In flexible systems, five-membered rings are formed in preference to six-membered ones. Insertion into methine hydrogen is preferred to a methylene hydrogen. Intramolecular insertion can be competitive with intramolecular addition. Product ratios can to some extent be controlled by the specific rhodium catalyst that is used.216 In the example shown, insertion is the exclusive reaction with Rh2(02CC4F9)4, whereas only addition occurs with Rh2(caprolactamate)4, which indicates that the more electrophilic carbenoids favor insertion. 

The use of rhodium(II) acetate in carbenoid chemistry has also been extended to promoting intramolecular C/H insertion reactions of ketocarbenoids 277,280,280 ,). From the a-diazo-P-ketoester 305, highly functionalized cyclopentane 306 could thus be constructed in acceptable yields by regiospecific insertion into an unactivated... 

An alternative strategy for selective intermolecular G-H insertions has been the use of rhodium carbenoid systems that are more stable than the conventional carbenoids derived from ethyl diazoacetate. Garbenoids derived from aryldiazoacetates and vinyldiazoacetates, so-called donor/acceptor-substituted carbenoids, have been found to display a very different reactivity profile compared to the traditional carbenoids.44 A clear example of this effect is the rhodium pivalate-catalyzed G-H insertion into cyclohexane.77 The reaction with ethyl diazoacetate gave the product only in 10% yield, while the parallel reaction with ethyl phenyldiazoacetate gave the product in 94% yield (Equation (10)). In the first case, carbene dimerization was the dominant reaction, while this was not observed with the donor/acceptor-substituted carbenoids. 

The reaction of aryldiazoacetates with cyclohexene is a good example of the influence of steric effects on the chemistry of the donor/acceptor-substituted rhodium carbenoids. The Rh2(reaction with cyclohexene resulted in the formation of a mixture of the cyclopropane and the G-H insertion products. The enantios-electivity of the C-H insertion was high but the diastereoselectivity was very low (Equation (31)). 0 In contrast, the introduction of a silyl group on the cyclohexene, as in 15, totally blocked the cyclopropanation, and, furthermore, added sufficient size differentiation between the two substituents at the methylene site to make the reaction to form 16 proceed with high diastereoselectivity (Equation (32)).90 The allylic C-H insertion is applicable to a wide array of cyclic and acyclic substrates, and even systems capable of achieving high levels of kinetic resolution are known.90... 

Activation of a C-H bond requires a metallocarbenoid of suitable reactivity and electrophilicity.105-115 Most of the early literature on metal-catalyzed carbenoid reactions used copper complexes as the catalysts.46,116 Several chiral complexes with Ce-symmetric ligands have been explored for selective C-H insertion in the last decade.117-127 However, only a few isolated cases have been reported of impressive asymmetric induction in copper-catalyzed C-H insertion reactions.118,124 The scope of carbenoid-induced C-H insertion expanded greatly with the introduction of dirhodium complexes as catalysts. Building on initial findings from achiral catalysts, four types of chiral rhodium(n) complexes have been developed for enantioselective catalysis in C-H activation reactions. They are rhodium(n) carboxylates, rhodium(n) carboxamidates, rhodium(n) phosphates, and < // < -metallated arylphosphine rhodium(n) complexes. 

The carbenoid fragment reacts as an electron-deficient carbon centre. Substituents both at rhodium and at the carbene centre can make it more electron-deficient. If the carbenoid is given the choice between a cyclopropanation and C-H insertion reaction, the preference for C-H insertion increases with the electron deficiency [19], Figure 17.10. 

Numerous studies have been directed toward expanding the chemistry of the donor/ac-ceptor-substituted carbenoids to reactions that form new carbon-heteroatom bonds. It is well established that traditional carbenoids will react with heteroatoms to form ylide intermediates [5]. Similar reactions are possible in the rhodium-catalyzed reactions of methyl phenyldiazoacetate (Scheme 14.20). Several examples of O-H insertions to form ethers 158 [109, 110] and S-H insertions to form thioethers 159 [111] have been reported, while reactions with aldehydes and imines lead to the stereoselective formation of epoxides 160 [112, 113] and aziridines 161 [113]. The use of chiral catalysts and pantolactone as a chiral auxiliary has been explored in many of these reactions but overall the results have been rather moderate. Presumably after ylide formation, the rhodium complex disengages before product formation, causing degradation of any initial asymmetric induction. 

Asymmetric allylic C-H activation of more complex substrates reveals some intrinsic features of the Rh2(S-DOSP)4 donor/acceptor carbenoids [135, 136]. Cyclopropanation of trans-disubstituted or highly substituted alkenes is rarely observed, due to the steric demands of these carbenoids [16]. Therefore, the C-H activation pathway is inherently enhanced at substituted allylic sites and the bulky rhodium carbenoid discriminates between accessible secondary sites for diastereoselective C-H insertion. As a result, the asymmetric allylic C-H activation provides alternative methods for the preparation of chiral molecules traditionally derived from classic C-C bond-forming reactions such as the Michael reaction and the Claisen rearrangement [135, 136]. 

Rhodium(II) acetate catalyzes C—H insertion, olefin addition, heteroatom-H insertion, and ylide formation of a-diazocarbonyls via a rhodium carbenoid species (144—147). Intramolecular cyclopentane formation via C—H insertion occurs with retention of stereochemistry (143). Chiral rhodium (TT) carboxamides catalyze enantioselective cyclopropanation and intramolecular C—N insertions of CC-diazoketones (148). Other reactions catalyzed by rhodium complexes include double-bond migration (140), hydrogenation of aromatic aldehydes and ketones to hydrocarbons (150), homologation of esters (151), carbonylation of formaldehyde (152) and amines (140), reductive carbonylation of dimethyl ether or methyl acetate to 1,1-diacetoxy ethane (153), decarbonylation of aldehydes (140), water gas shift reaction (69,154), C—C skeletal rearrangements (132,140), oxidation of olefins to ketones (155) and aldehydes (156), and oxidation of substituted anthracenes to anthraquinones (157). Rhodium-catalyzed hydrosilation of olefins, alkynes, carbonyls, alcohols, and imines is facile and may also be accomplished enantioselectively (140). Rhodium complexes are moderately active alkene and alkyne polymerization catalysts (140). In some cases polymer-supported versions of homogeneous rhodium catalysts have improved activity, compared to their homogenous counterparts. This is the case for the conversion of alkenes direcdy to alcohols under oxo conditions by rhodium—amine polymer catalysts... 

Although C—H insertion reactions rarely occur in intermolecular reactions with diazoacetates, these are common side reactions with diazomalonates3132 (equation 10) and diazo ketones (with a-allyl vinyl ethers).33 Several mechanistic pathways are available to generate the products of an apparent direct C—H insertion reaction and these include dipolar intermediates, ir-allyl complexes and ring opening of cyclopropanes.1 Oxidative problems due to the presence of oxygen are common with copper catalysts, but these are rarely encountered with rhodium catalysts except in systems where the carbenoid is ineffectively captured.34... 

Larger rings such as (36) were made by insertion of a rhodium carbenoid into phenolic OH bonds.37 Triarylamines have been isolated from a rhodium-catalysed reaction of diarylamines with 2-diazocyclohexane-l,3-dione 38... 

The mechanism of these C-H insertion reactions and the rhodium carbenoid reactions in general are still a matter of considerable debate [1]. It is generally... 

In summary, the C-H insertion chemistry of rhodium carbenoids is a very powerful method for transformation of C-H bonds. Highly regioselective and stereoselective reactions are possible and several classes of chiral catalyst are capable of very high asymmetric induction. The chemoselectivity in this chemistry is exceptional, as illustrated by the numerous intermolecular and intramolecular reactions described in this overview. Most notably, this chemistry offers new and practical strategies for enantioselective synthesis of a variety of natural products and pharmaceutical agents. 

The oxime nitrogen lone pair of electrons must be properly oriented so as to interact with the rhodium carbenoid.84 Thus, subjection of the -oximino isomer 182 to a catalytic quantity of Rh2(OAc)4 in CH2C12 (40 °C) with a slight excess of DMAD afforded the bimolecular cycloadduct 184 in 93% yield. In sharp contrast, when the isomeric Z-oximino diazo derivative 183 was exposed to the same reaction conditions, only indanone-oxime 185 (80%) was obtained. The formation of this product is most likely the result of an intramolecular C-H insertion reaction. 

However, all attempts to activate the a-position of the cyclohexanone ring in order to facilitate a subsequent diazotization, which was to be followed by rhodium carbenoid-mediated aryl C-H insertion onto C-4 [21], were unsatisfactory [22], One of the approaches was based on the generation of the silyl enol ether 35, but attempts to achieve its a-acylation led only to the formation of Paal-Knorr-type cyclization products 36. Chemoselective formylation of 34 to 37 was possible by reaction with ethyl formate in the presence of a large excess of sodium ethoxide, but in situ oxidation of the desired compound 37 to 38, which was the major isolated product, made the reaction impractical (Scheme 6). 

Intramolecular Carbon-Hydrogen Insertion. The advantages of rhodium(II) catalysts for carbenoid transformations are nowhere more evident than with carbon-hydrogen insertion reactions. Exceptional regio- and diastereocontrol has been observed for Rh2(OAc)4 catalyzed transformations of a broad selection of diazoketones, a-diazo-p-ketoesters, a-diazo-P-keto-sulfones and -phosphonates which yield cyclopentanone derivatives in moderate to good yields (57-54). In contrast, poor yields and low regioselectivities characterize the corresponding copper catalyzed reactions. Applications of dirhodium(II) catalysts for C-H insertion reactions have even been extended to the synthesis of y-lactones (55), 3(2//)-furanones (56,57), P-laetones (58), and P-lactams (59,60). 

Rhodium-catalyzed intramolecular reaction of diazo ketones like 175 leads mainly to carbenoid insertion into the a-C-H bond but a minor product is the 1,3-dioxolane (Equation 49) <1997JOC4910>. 

Carbene itself ( CH2) is extremely reactive and gives many side reactions, especially insertion reactions (12-21), which greatly reduce yields. This competition is also true with rhodium-catalyzed diazoalkane cyclopropanations (see below). When it is desired to add CH2 for preparative purposes, free carbene is not used, but the Simmons-Smith procedure (p. 1241) or some other method that does not involve free carbenes is employed instead. Halocarbenes are less active than carbenes, and this reaction proceeds quite well, since insertion reactions do not interfereThe absolute rate constant for addition of selected alkoxychlorocar-bene to butenes has been measured to range from 330 to 1 x 10 A few of the many ways in which halocarbenes or carbenoids are generated for... 

Diazocarboxylate esters can be transformed by transition metal catalysts such as rhodium(II) acetate into alkoxycarbonylcarbenes that undergo a wide variety of synthetically useful C-H, C-C, C-X, X-H and X-X insertion reactions (where X = heteroatom) [99]. Chemoselectivity of rhodium carbenoids derived from Rh(II) carboxylates and carboxamides has been found to exhibit striking ligand dependency, for example in work by Padwa showing that perfluorocar-boxamide ligands exclusively promoted aromatic C-H insertions in Rh(II)-cat-alyzed decomposition of diazoamides to give oxindoles, whereas a carboxylate-based rhodium catalyst promoted other types of insertions and addition reactions [100]. 

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