Carbene complexes electrophilic

MO small energy-difference between metal nd and carbene 2p nucleophilic carbene complex large energy-difference between metal nd and carbene 2p electrophilic carbene complex... 

Fig. 1.5. Orbital interaction in nucleophilic and electrophilic carbene complexes.

The structure of rhodium(II) carboxylate-derived carbene complexes has been assessed both by quantum mechanical calculations [19,20] and by the study of rhodium(II) carboxylate isonitrile complexes [20,21]. Recent investigations [20] suggest, that also in these highly electrophilic carbene complexes there is a significant n backbonding from rhodium to carbon. 

Fig. 1.9. Possible mechanism of the cyclopropanation of alkenes with electrophilic carbene complexes [28].

Closely related to the ring-closing metathesis of enynes (Section 3.2.5.6), catalyzed by non-heteroatom-substituted carbene complexes, is the reaction of stoichiometric amounts of Fischer-type carbene complexes with enynes [266,308 -315] (for catalytic reactions, see [316]). In this reaction [2 + 2] cycloaddition of the carbene complex and the alkyne followed by [2 -t- 2] cycloreversion leads to the intermediate formation of a non-heteroatom-substituted, electrophilic carbene complex. This intermediate, unlike the corresponding nucleophilic carbene... 

Protonation of alkenyl complexes has been used [56,534,544,545] for generating cationic, electrophilic carbene complexes similar to those obtained by a-abstraction of alkoxide or other leaving groups from alkyl complexes (Section 3.1.2). Some representative examples are sketched in Figure 3.27. Similarly, electron-rich alkynyl complexes can react with electrophiles at the P-position to yield vinylidene complexes [144,546-551]. This approach is one of the most appropriate for the preparation of vinylidene complexes [128]. Figure 3.27 shows illustrative examples of such reactions. 

In addition to catalytically active transition metal complexes, several stable, electrophilic carbene complexes have been prepared, which can be used to cyclopropanate alkenes (Figure 3.32). These complexes have to be used in stoichiometric quantities to achieve complete conversion of the substrate. Not surprisingly, this type of carbene complex has not attained such broad acceptance by organic chemists as have catalytic cyclopropanations. However, for certain applications the use of stoichiometric amounts of a transition metal carbene complex offers practical advantages such as mild reaction conditions or safer handling. 

Because electrophilic carbene complexes can cyclopropanate alkenes under mild reaction conditions (Table 3.1) [438,618-620], these complexes can serve as stoichiometric reagents for the cyclopropanation of organic compounds. Thoroughly investigated carbene complexes for this purpose are neutral complexes of the type (C0)5M=CR2 (M Cr, Mo, W) and cationic iron(IV) carbene complexes. The mechanism of cyclopropanation by electrophilic carbene complexes has been discussed in Section 1.3. 

Some transition metal complexes readily react with ylides to yield electrophilic carbene complexes. If these complexes can transfer the carbene to a given substrate in such a way that the original transition metal complex is regenerated then this complex can be used as a catalyst for the transformation of the ylide (carbene precursor) into carbene-derived products (Figure 3.35). 

In cyclopropanations with electrophilic carbene complexes, yields of cyclopropanes tend to improve with increasing electron density of the alkene. As illustrated by the examples in Table 3.5, cyclopropanations of enol ethers with aryldiazomethanes often proceed in high yields. Simple alkyl-substituted olefins are, however, more difficult to cyclopropanate with diazoalkanes. A few examples of the cyclopropanation of enamines with diazoalkanes have been reported [650]. 

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). 

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. 

Fig. 4.3. Possible mechanisms for the formation of vinylcarbene complexes from alkynes and electrophilic carbene complexes.

The intramolecular addition of acylcarbene complexes to alkynes is a general method for the generation of electrophilic vinylcarbene complexes. These reactive intermediates can undergo inter- or intramolecular cyclopropanation reactions [1066 -1068], C-H bond insertions [1061,1068-1070], sulfonium and oxonium ylide formation [1071], carbonyl ylide formation [1067,1069,1071], carbene dimerization [1066], and other reactions characteristic of electrophilic carbene complexes. 

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. 

The successful design of new synthetic sequences using electrophilic carbene complexes thus requires careful assessment of potential side-reactions. 

Fig. 4.6. Possible mechanism of the C-H insertion of electrophilic carbene complexes into aromatic C-H bonds (Z electron-withdrawing group).

C-H Insertions into vinylic C-H bonds are also a common reaction of electrophilic carbene complexes. Insertions into aromatic or heteroaromatic C-H bonds can proceed via cyclopropanation and rearrangement (Figure 4.6). 

Few examples of the formation of cyclopropanes by intramolecular C-H insertion of electrophilic carbene complexes have been reported. This methodology for cyclopropane preparation seems only to be suitable for polycyclic compounds with little conformational flexibility. Illustrative examples are listed in Table 4.3. 

Examples of the formation of four-membered rings by intramolecular C-H insertion of electrophilic carbene complexes are listed in Table 4.4. 

Table 4.3. Intramolecular 1,3-C-H insertion reactions of electrophilic carbene complexes.

Table 4.4. Intramolecular 1,4-C-H insertions of electrophilic carbene complexes generated from diazocarbonyl compounds.

Several examples have been reported for furanone formation by intramolecular C-H insertion of electrophilic carbene complexes [1006,1148] (Table 4.7). Yields can, however, be low with some substrates, possibly as a result of several potential side-reactions. Oxonium ylide formation and hydride abstraction, in particular, [1090,1149-1152] (see Section 4.2.9) seem to compete efficiently with the formation of some types of furanones. 

The formation of six-membered or larger rings by intramolecular C-H bond insertion normally requires the attacked position to be especially activated towards electrophilic attack [1157,1158]. Electron-rich arenes or heteroarenes [1159-1162] and donor-substituted methylene groups can react intramolecularly with electrophilic carbene complexes to yield six- or seven-membered rings. Representative examples are given in Table 4.8. 

Few examples of preparatively useful intermolecular C-H insertions of electrophilic carbene complexes have been reported. Because of the high reactivity of complexes capable of inserting into C-H bonds, the intermolecular reaction is limited to simple substrates (Table 4.9). From the results reported to date it seems that cycloalkanes and electron-rich heteroaromatics are suitable substrates for intermolecular alkylation by carbene complexes [1165]. The examples in Table 4.9 show that intermolecular C-H insertion enables highly convergent syntheses. Elaborate structures can be constructed in a single step from readily available starting materials. Enantioselective, intermolecular C-H insertions with simple cycloalkenes can be realized with up to 93% ee by use of enantiomerically pure rhodium(II) carboxylates [1093]. 

Electrophilic carbene complexes can react with amines, alcohols or thiols to yield the products of a formal X-H bond insertion (X N, O, S). Unlike the insertion of carbene complexes into aliphatic C-H bonds, insertion into X-H bonds can proceed via intermediate formation of ylides (Figure 4.7). 

The first reports of N-H insertion reactions of electrophilic carbene complexes date back to 1952 [497], when it was found that aniline can be N-alkylated by diazoacetophenone upon treatment of both reactants with copper. A further early report is the attempt of Nicoud and Kagan [1178] to prepare enantiomerically pure a-amino acids by copper(I) cyanide-catalyzed decomposition of a-diazoesters in the presence of chiral benzylamines. Low enantiomeric excesses (< 26% ee) were obtained, however. 

Intermolecular N-H insertion of electrophilic carbene complexes has occasionally been used for the preparation of amino acid derivatives and other types of intermediates (Table 4.12) [956,1043,1194-1201]. 

Table 4.11. Preparation of nitrogen-containing heterocycles by intramolecular N-H insertion of electrophilic carbene complexes.

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. 

S-Alkylation of thiols by carbene complexes can be a useful approach to a-(alkylthio)- or a-(arylthio)ketones, although few examples of intramolecular [975,1193] or intermolecular [497,1043,1230-1233] S-H bond insertion reactions of electrophilic carbene complexes have been reported. Yields are sometimes low, probably because of the poisoning of the catalyst by the thiol. Examples are given in Table 4.15. 

Tertiary amines can react with electrophilic carbene complexes to yield ammonium ylides which usually undergo Stevens rearrangement (Figure 4.8) leading to products of a formal carbene C-N bond insertion. 

Table 4.15. Preparation of thioethers by S-alkylation of thiols with electrophilic carbene complexes.

Fig. 4.9. Formation and transformations of azomethine ylides from imines and electrophilic carbene complexes.

The generation of electrophilic carbene complexes in the presence of nitriles or other cyano-group-containing compounds can lead to the formation of nitrile ylides. With acylcarbene complexes the final products are often 1,3-oxazoles [1194], presumably formed by the mechanism sketched in Figure 4.10. 

Fig. 4.11. Generation and transformations of oxonium ylides from electrophilic carbene complexes.

If chiral catalysts are used to generate the intermediate oxonium ylides, non-racemic C-O bond insertion products can be obtained [1265,1266]. Reactions of electrophilic carbene complexes with ethers can also lead to the formation of radical-derived products [1135,1259], an observation consistent with a homolysis-recombination mechanism for 1,2-alkyl shifts. Carbene C-H insertion and hydride abstraction can efficiently compete with oxonium ylide formation. Unlike free car-benes [1267,1268] acceptor-substituted carbene complexes react intermolecularly with aliphatic ethers, mainly yielding products resulting from C-H insertion into the oxygen-bound methylene groups [1071,1093]. 

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