Carbene insertion reactions carbenoid catalysts

One important advantage of the intermolecular carbene insertion reactions is that simple starting materials can be employed and accordingly there is no need for the construction of complex substrates in advance. However, the intermolecular process requires a delicate balance between electronic and steric effects for metal carbenoids. On the other hand, there are several obstacles to be overcome, including chemo-, regio-, and enantioselectivity. Fortunately, great efforts have been devoted in the past decade and a series of carbene precursors and chiral Rh catalysts have been developed, so satisfactory yields and ee can be obtained in some catalytic systems. Generally, suitable carbene precursors, such as donor/acceptor diazo compounds, could reduce the chance of side product formation due to carbene dimerization. 

Carbenoid N-H insertion of amines with diazoacetates provides a useful means for the synthesis of ot-amino esters. Fe(III) porphyrins [64] and Fe(III/IV) corroles [65] are efficient catalysts for N-H carbenoid insertion of various aromatic and aliphatic amines using EDA as a carbene source (Scheme 16). The insertion reactions occur at room temperature and can be completed in short reaction times and with high product yields. It is performed in a one-pot fashion without the need for slow... 

Another remarkable property of iodorhodium(III) porphyrins is their ability to decompose excess diazo compound, thereby initiating carbene transfer reactions 398). This observation led to the use of iodorhodium(III) me.vo-tetraarylporphyrins as cyclopropanation catalysts with enhanced syn anti selectivity (see Sect. 2.2.3) s7, i°o) as wep as catalysts for carbenoid insertion into aliphatic C—H bonds, whereby an unusually high affinity for primary C—H bonds was achieved (see Sect. 6.1)287). These selectivities, unapproached by any other transition metal catalyst,... 

Dirhodium(II) carboxylate catalysts have been used extensively for the catalysis of carbene insertions. In many cases, impressive selectivities have been achieved (19-21). In an effort to find selective catalysts for carbenoid insertions, Moody screened a series of dirhodium(II) carboxylate catalysts for their ability to catalyze carbenoid Si-H insertion (22). The authors surveyed the commercially available carboxylic acids, -10,000 of which are chiral. The members of this group that contained functionality that is incompatible to the reaction were culled out. The remaining chiral carboxylic acids (-2000 compounds) were then grouped into 80 different clusters. There is no discussion presented for the criteria used in the grouping of the acids. A representative acid from each cluster was then chosen for... 

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. 

The asymmetric allylic C—H bond insertion reaction of 1,4-cyclohexadiene was further improved by Denton and Davies in 2009. Using different donor/ acceptor carbenoids derived from a-aryl-a-diazoketones 25 and a chiral dirhodium complex Rh2(S-PTAD)4 instead of methyl phenyldiazoacetate la and Rh2(S-DOSP)4 in previous work (Scheme 1.6, eqn (1)), the corresponding C—H bond insertion products 26 could be obtained in up to 90% yield and 89% ee in refluxing DMB (Scheme 1.7a). Later, the catalytic efficiency was significantly enhanced by conducting the reaction under solvent-free con-ditions. Since donor/acceptor carbenoids are more stable and less prone to catalyst decay and carbene dimerization, they are suitable for reactions... 

Tryptophan offers an indole side chain that can be used for ligation chemistry. A water-compatible rhodium carbene can be added to the indole ring (19) [105,139]. The reactive species is generated in situ by a conjugated diazo compound by a rhodium catalyst like rhodium(II) acetate [63,139,149]. The reaction takes place in the two- and three-position of indole. Thus, a mixture of N-alkylated and C-alkylated product is obtained. It is necessary to add hydroxylamine hydrochloride as an additive to bind to the distal rhodium carbenoid complex. The usage of this salt lowers the pH value below 3.5 and therefore limits the scope of this methodology. As a side reaction, the carbene inserts into the O-H bond of water (Table 6). 

Many rhodium(II) complexes are excellent catalysts for metal-carbenoid-mediated enantioselective C-H insertion reactions [101]. In 2002, computational studies by Nakamura and co-workers suggested the dirhodium tetracarboxylate catalyzed diazo compounds insertion reaction to alkanes C-H bonds proceed through a three-centered hydride-transfer-like transition state (Fig. 25) [102]. Only one rhodium atom of the catalyst is involved in the formation of rhodium carbene intermediate, while the other rhodium atom served as a mobile ligand, which enhanced the electrophilicity of the first one and facilitate the cleavage of rhodium-carbon bond. In this case, the metal-metal bond constitutes a special example of Lewis acid activation of Lewis acidic transition-metal catalyst. 

Similar to the intramolecular insertion into an unactivated C—H bond, the intermolecular version of this reaction meets with greatly improved yields when rhodium carbenes are involved. For the insertion of an alkoxycarbonylcarbene fragment into C—H bonds of acyclic alkanes and cycloalkanes, rhodium(II) perfluorocarb-oxylates 286), rhodium(II) pivalate or some other carboxylates 287,288 and rhodium-(III) porphyrins 287 > proved to be well suited (Tables 19 and 20). In the era of copper catalysts, this reaction type ranked as a quite uncommon process 14), mainly because the yields were low, even in the absence of other functional groups in the substrate which would be more susceptible to carbenoid attack. For example, CuS04(CuCl)-catalyzed decomposition of ethyl diazoacetate in a large excess of cyclohexane was reported to give 24% (15%) of C/H insertion, but 40% (61 %) of the two carbene dimers 289). 

S/S insertion is also part of the reaction scheme when carbenes (or carbenoids) interact with l,6,6aX,4-trithiapentalenes 377 (Scheme 38) 352). The origin of the 4-diphenylmethylene-thiopyran 378 resulting from the reaction at higher catalyst concentration has not been elucidated, however. 

In certain cases, the metal-carbene complex derived from an unsaturated diazocarbonyl compound can be trapped intramolecularly in reactions other than cyclopropanation, e.g. C-H insertion and ylide formation by interaction with a heteroatom with a lone pair. Since the chemoselectivity is influenced by the electrophilicity of the metal-carbene complex, it may be controlled in favorable cases by the catalyst metal and its ligands or by the second substituent at the carbenoid carbon atom. 

When the chemoselectivity hypothesis was tested with cyclohexane as the substrate and Rh2(OPiv)4 (25d) as the catalyst, it was shown to be true (Table 2) [80], Although the reaction with EDA produced predominantly carbene dimer 76 (entry 1), 94% of the C-H insertion product 75 was isolated with methyl phenyldia-zoacetate as the carbenoid precursor under identical reaction conditions (entry 3). This simple comparison indicated that the donor/acceptor carbenoids are indeed more stable and less prone towards undesired dimerization events. Another feature of the donor/acceptor carbenoids that is not shared by EDA is the fact that the carbenoid carbon possesses two substituents. This opens up the opportunity for asymmetric catalysis to occur. Indeed, when a number of aryldiazoacetates 74 were decomposed with Rh2(,S -D0SP)4 (26) in the presence of cyclohexane, up to 95% ee was achieved for 77 [79, 81]. A fluorous prolinate catalyst was also developed to facilitate purification, but the enantioselectivities were not as high [82],... 

Muller chose to examine cyclohexene and 1,4-cyclohexadiene (ten equivalents relative to diazo compound) as model systems, and screened a variety of carbenoid precursors and catalysts (Scheme 24, left). All reactions were conducted in DCM at 25 °C. The results with 1,4-cyclohexadiene were quite clear-cut. With acceptor-substituted carbenes, selectivity was >95 5 in favor of cyclopropanation 108 for Cu° or Rh2(OAc)4 catalysts. For acceptor/acceptor carbenoid precursors, CuCl still favored cyclopropanation >95 5, but with Rh2(OAc)4 insertion 109 now became... 

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