Acceptor-Substituted Carbene Complexes

In contrast with non-acceptor-substituted carbene complexes, most of which are rather stable compounds, only few acceptor-substituted carbene complexes have been isolated [500,502,947,948]. In particular, acceptor-substituted carbene complexes relevant to organic synthesis (e.g. copper or rhodium acylcarbene complexes) are normally highly reactive and have remained elusive to spectroscopic characterization (for theoretical treatments, see Section 1.2). The inference that these intermediates are indeed carbene complexes is in part based on the observation that the modes of generation and the reactivity of these reactive species correlate well with those of less reactive carbene complexes. 

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Electrophilic transition metal complexes can react with organic ylides to yield alkylidene complexes. A possible mechanism would be the initial formation of alkyl complexes, which are converted into the final carbene complexes by electrophilic a-abstraction (Figure 3.18). This process is particularly important for the generation of acceptor-substituted carbene complexes (Section 4.1). 

Carbene C-H (and Si-H, [695]) insertion is characteristic of electrophilic carbene complexes. In particular the insertion reactions of acceptor-substituted carbene complexes (Section 4.2) have become a valuable tool for organic synthesis. 

Electrophilic carbene complexes generated from diazoalkanes and rhodium or copper salts can undergo 0-H insertion reactions and S-alkylations. These highly electrophilic carbene complexes can, moreover, also undergo intramolecular rearrangements. These reactions are characteristic of acceptor-substituted carbene complexes and will be treated in Section 4.2. 

The most important synthetic access to acceptor-substituted carbene complexes is the reaction of ylides with electrophilic, coordinatively unsaturated transition metal complexes (Figure 4.1 see also Section 3.1.3). 

Fig. 4.1. Generation of acceptor-substituted carbene complexes from ylides. X N2, SR2, S(0)Me2, Arl Z COR, CO2R, CONR2, SO2R, CN, P(0)(0R)2.

Because acceptor-substituted carbene complexes can normally not be isolated, generation must occur in the presence of a suitable substrate. If during carbene-transfer from the intermediate carbene complex to the substrate the complex L M (Figure 4.1) is regenerated, then catalytic amounts of this complex only will be... 

Synthetic Applicatiom of Acceptor-Substituted Carbene Complexes 177... 

Acceptor-substituted carbene complexes are highly reactive intermediates, capable of transforming organic compounds in many different ways. Typical reactions include insertion into o-bonds, cyclopropanation, and ylide formation. Generally, acceptor-substituted carbene complexes are not isolated and used in stoichiometric amounts, but generated in situ from a carbene precursor and transition metal derivative. Usually only catalytic quantities of a transition metal complex are required for complete conversion of a carbene precursor via an intermediate carbene complex into the final product. 

In the following sections the synthetically most useful reactions will be presented, ordered according to the type of reaction. Recent reviews covering transformations with acceptor-substituted carbene complexes include [38,995,1072-1079]. 

The different synthetic applications of acceptor-substituted carbene complexes will be discussed in the following sections. The reactions have been ordered according to their mechanism. Because electrophilic carbene complexes can undergo several different types of reaction, elaborate substrates might be transformed with little chemoselectivity. For instance, the phenylalanine-derived diazoamide shown in Figure 4.5 undergoes simultaneous intramolecular C-H insertion into both benzylic positions, intramolecular cyclopropanation of one phenyl group, and hydride abstraction when treated with rhodium(II) acetate. 

Carbenes and transition metal carbene complexes are among the few reagents available for the direct derivatization of simple, unactivated alkanes. Free carbenes, generated, e.g., by photolysis of diazoalkanes, are poorly selective in inter- or intramolecular C-H insertion reactions. Unlike free carbenes, acceptor-substituted carbene complexes often undergo highly regio- and stereoselective intramolecular C-H insertions into aliphatic and aromatic C-H bonds [995,1072-1074,1076,1085,1086],... 

As early as in 1973 it was shown [1089] that the C-H insertion of acceptor-substituted carbene complexes can take place with retention of configuration (e.g. Table 4.5, Entry 3) [953,1090,1091]. In the case of intramolecular C-H insertions into methylene groups high diastereoselectivities are often observed when 4-6-membered rings are formed (see examples in Tables 4.4-4.S). 

In acceptor-substituted carbene complexes with hydrogen at Cp fast hydride migration to the carbene will usually occur [1094,1095]. The resulting olefins are often formed with high stereoselectivity. 1,2-Hydride migration will also occur in P-hydroxy carbene complexes, ketones being formed in high yields (Table 4.2). Intramolecular 1,5-C-H insertion can sometimes compete efficiently with 1,2-insertion [1096]. 

Synthetic Applications of Acceptor-Substituted Carhene Complexes 181 Table 4.2. Intramolecular 1,2-C-H insertion of acceptor-substituted carbene complexes. 

Synthetic Applications of Acceptor-Substituted Carbene Complexes 191 Table 4.9. Intermolecular C-H insertion reactions of electrophilic carbene complexes. 

Silanes can react with acceptor-substituted carbene complexes to yield products resulting from Si-H bond insertion [695,1168-1171]. This reaction has not, however, been extensively used in organic synthesis. Transition metal-catalyzed decomposition of the 2-diazo-2-phenylacetic ester of pantolactone (3-hydroxy-4,4-dimethyltetrahydro-2-furanone) in the presence of dimethyl(phenyl)silane leads to the a-silylester with 80% de (67% yield [991]). Similarly, vinyldiazoacetic esters of pantolactone react with silanes in the presence of rhodium(II) acetate to yield a-silylesters with up to 70% de [956]. 

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

Acceptor-substituted carbene complexes are electrophilic intermediates which react readily with lone pairs, giving the corresponding ylides. These can be valuable intermediates, capable of undergoing a broad range of synthetically useful transformations. This subject has been treated in several reviews [38,995,1077-1079,1086]. 

Fig. 4.8. Formation and Stevens rearrangement of ammonium ylides from acceptor-substituted carbene complexes.

The intermolecular reaction of imines with acceptor-substituted carbene complexes generally leads to the formation of azomethine ylides. These can undergo several types of transformation, such as ring closure to aziridines [1242-1245], 1,3-dipolar cycloadditions [1133,1243,1246-1248], or different types of rearrangement (Figure 4.9). 

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