Carbenes C-H insertion reactions

Of course carbene C-H insertion reactions are well known absolute kinetics have been reported for the insertions of ArCCl into isooctane, cyclohexane, and n-hexane,67 and of PhCCl into Si-H, Sn-H, and C-H bonds.68 More recently, detailed studies have appeared of PhCCl insertions into a variety of substrates bearing tertiary C-H bonds, especially adamantane derivatives.69 Nevertheless, because QMT is considered important in the low temperature solution reactions of MeCCl,60,63 and is almost certainly involved in the cryogenic matrix reactions of benzylchlorocarbene,59 its possible intervention in the low temperature solution reactions of the latter is a real possibility. We are therefore faced with two alternative explanations for the Arrhenius curvature exhibited by benzylchlorocarbene in solution at temperatures < 0°C either other classical reactions (besides 1,2-H shift) become competitive (e.g., solvent insertion, azine formation), or QMT becomes significant.7,59,66... 

As shown in the previous two sections, rhodium(n) dimers are superior catalysts for metal carbene C-H insertion reactions. For nitrene C-H insertion reactions, many catalysts found to be effective for carbene transfer are also effective for these reactions. Particularly, Rh2(OAc)4 has demonstrated great effectiveness in the inter- and intramolecular nitrene C-H insertions. The exploration of enantioselective C-H amination using chiral rhodium catalysts has been reported by several groups.225,244,253-255 Hashimoto s dirhodium tetrakis[A-tetrachlorophthaloyl-(A)-/ r/-leuci-nate], Rh2(derived rhodium complex, Rh2(i -BNP)4 48,244 afforded moderate enantiomeric excess for amidation of benzylic C-H bonds with NsN=IPh. 

Tetracyclo[5,2,l,0 , 0 ]dec-4-ene (800) has been prepared in six steps, starting from the Diels-Alder adduct of cyclopentadiene with cyclopentene. The central bond in the plane of symmetry of the molecule was constructed by employing an intramolecular carbene C—H insertion reaction the oleflnic bond is introduced in the final step of the synthesis (by a dehydrobromination) since the carbene-insertion step fails when this unsaturation is present at the earlier stage. Full experimental details are now available for the photochemical preparation of tetra-asterane tetracarboxylic dianhydride (801). ... 

Fukuyama et al. exploited highly reactive rhodium carbenoids as hydride acceptors to constmct tetrahydrofuran moieties in his total syntheses for many times. The mechanism should be the cascade [1,5]-Hydride migration/cyclization, whereas Fukuyama et al. argued that their reactions proceed via metal carbene C-H insertion reactions [130-135]. 

While major advances in the area of C-H functionalization have been made with catalysts based on rare and expensive transition metals such as rhodium, palladium, ruthenium, and iridium [7], increasing interest in the sustainability aspect of catalysis has stimulated researchers toward the development of alternative catalysts based on naturally abundant first-row transition metals including cobalt [8]. As such, a growing number of cobalt-catalyzed C-H functionalization reactions, including those for heterocycle synthesis, have been reported over the last several years to date (early 2015) [9]. The purpose of this chapter is to provide an overview of such recent advancements with classification according to the nature of the catalytically active cobalt species involved in the C-H activation event. Besides inner-sphere C-H activation reactions catalyzed by low-valent and high-valent cobalt complexes, nitrene and carbene C-H insertion reactions promoted by cobalt(II)-porphyrin metalloradical catalysts are also discussed. 

There are numerous examples of metal carbene insertion reactions, usually requiring a catalyst. " The C—H insertion reactions of metal carbenes can be highly selective. Intramolecular insertion reactions are very versatile and tolerate a... 

This key paper was followed by a flurry of activity in this area, spanning several years." " "" A variety of workers reported attempts to deconvolute the temperature dependence of carbene singlet/triplet equilibria and relative reactivities from the influence of solid matrices. Invariably, in low-temperature solids, H-abstraction reactions were found to predominate over other processes. Somewhat similar results were obtained in studies of the temperature and phase dependency of the selectivity of C-H insertion reactions in alkanes. While, for example, primary versus tertiary C-H abstraction became increasingly selective as the temperature was lowered in solution, the reactions became dramatically less selective in the solid phase as temperatures were lowered further. Similar work of Tomioka and co-workers explored variations of OH (singlet reaction) versus C-H (triplet reaction) carbene insertions with alcohols as a function of temperature and medium. Numerous attempts were made in these reports to explain the results based on increases in triplet carbene population... 

Singlet Carbene C-H Insertions Although [1,2]-H shifts are formally carbene C-H insertions, these rearrangements have different orbital symmetry aspects than those of intramolecular insertions. As described above, overwhelming evidence exists that triplet carbenes undergo abstraction-recombination reactions to... 

It might be expected that the aromatic character of (14) would lend unique characteristics to its chemistry. Studies of the olefin addition and C—H insertion reactions of the carbene, however, indicate that it is poorly stabilized and highly reactive.<26)... 

The olefinic products which formally correspond to C—H insertion reactions are thought to arise by stepwise abstraction of hydrogen by triplet carbene and subsequent recombination ... 

B. C-H Insertion Reaction with Chloro(phenyl)carbene. 292... 

The four hitherto known routes of the C-H insertion are shown in Scheme 1. In general, the insertion by singlet carbenes proceeds via route a in one step, whereas the reaction by triplet carbenes proceeds sequentially via route b, i.e., hydrogen abstraction followed by recombination of the radical pairs.4 Other stepwise mechanisms are hydride abstraction (route c) and proton abstraction (route d), both being followed by the recombination of ion pairs. However, extended study on routes c and d for synthetic purposes had not been done before we started, except for a few earlier studies on carbanion-promoted P C-H insertion reactions.5,6 Recent advances in transition metal-catalyzed... 

The intramolecular C-H insertion reaction of carbene species has been used in a number of studies for the synthesis of strained molecules and cage com-... 

While a number of studies have reported on stereochemical and mechanistic aspects of the carbene addition to unsaturated bonds,1 C-H insertion reactions... 

The transition metal-catalyzed C-H insertion reaction of carbenes to organic compounds is a well-established synthetic method, as shown in the first two sections in this chapter. However, nitrene C-H insertion, the corresponding reaction of carbene analog, is much less known. In the past decade, considerable advances have been made in the development of this chemistry into a generally useful C-H amination process by using improved catalysts and protocols, in which readily available amines or amides are used as the starting substrates. Moreover,... 

Thermolysis of 219a and 219b produced the benzofulvenes 221 as expected. However, the formation of 222 from 219c can best be accounted for by regarding the biradical 220a as the carbene 220b to allow an intramolecular C-H insertion reaction. The presence of a carbonyl group in 219 also permits the use of samarium(II) iodide, samarium(III) chloride, boron trifluoride and trifluoroacetic acid to promote the Schmittel cyclization reaction. 

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. 

The reaction of alkoxy(alkyl)carbene chromium complexes with alkynes has been reported to give modest yields of cyclopentenones [368] and a few examples of intramolecular carbene C-H insertions of Fischer-type carbene complexes, leading to five-membered heterocycles, have been reported [369,370] (Table 2.22). 

Cycloreversion of four-membered metallacycles is the most common method for the preparation of high-valent titanium [26,27,31,407,599-606] and zirconium [599,601] carbene complexes. These are usually very reactive, nucleophilic carbene complexes, with a strong tendency to undergo C-H insertion reactions or [2 -F 2] cycloadditions to alkenes or carbonyl compounds (see Section 3.2.3). Figure 3.31 shows examples of the generation of titanium and zirconium carbene complexes by [2 + 2] cycloreversion. 

Low-valent, 18-electron (Fischer-type) carbene complexes with strong n-acceptors usually are electrophilic at the carbene carbon atom (C ). These complexes can undergo reactions similar to those of free carbenes, e.g. cyclopropanation or C-H insertion reactions. The carbene-like character of these complexes becomes more pronounced when electron-accepting groups are directly bound to C (Chapter 4), whereas electron-donating groups strongly attenuate the reactivity (Chapter 2). 

Some Schrock-type carbene complexes, i.e. high-valent, electron-deficient, nucleophilic complexes of early transition metals, can undergo C-H insertion reactions with simple alkanes or arenes. This reaction corresponds to the reversal of the formation of these carbene complexes by elimination of an alkane (Figure 3.36). 

Calculations performed for cyclopropanation with Fischer-type carbene complexes [28] indicate that the electrophilic attack of the carbene complex at the alkene and the final ring closure are concerted. Extrapolation from this result to the C-H insertion reaction (in which a a-bond instead of a 7i-bond is cleaved) suggests that C-H bond cleavage and the formation of the new C-C and C-H bonds might also be concerted (Figure 3.38). 

However, with substrates prone to form carbocations, complete hydride abstraction from the alkane, followed by electrophilic attack of the carbocation on the metal-bound, newly formed alkyl ligand might be a more realistic picture of this process (Figure 3.38). The regioselectivity of C-H insertion reactions of electrophilic transition metal carbene complexes also supports the idea of a carbocation-like transition state or intermediate. 

Table 3.7. Intramolecular C-H insertion reaction of cationic iron carbene complexes generated in situ by S-alkylation of 1-(phenylthio)alkyl complexes (see Experimental Procedure 3.2.3).

Hence, cationic iron carbene complexes such as Cp(CO)2Fe =CHCHZR, in which Z is an electron-withdrawing group, might also be suitable for intermolecular cyclopropanation or C-H insertion reactions. The use of such carbene complexes in organic synthesis has not yet been thoroughly investigated, but could fruitfully supplement the chemistry of acceptor-substituted carbenes. 

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],... 

Table 4.3. Intramolecular 1,3-C-H insertion reactions of 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]. 

On the contrary, a-lithiated epoxides have found wide application in syntheses . The existence of this type of intermediate as well as its carbenoid character became obvious from a transannular reaction of cyclooctene oxide 89 observed by Cope and coworkers. Thus, deuterium-labeling studies revealed that the lithiated epoxide 90 is formed upon treatment of the oxirane 89 with bases like lithium diethylamide. Then, a transannular C—H insertion occurs and the bicyclic carbinol 92 forms after protonation (equation 51). This result can be interpreted as a C—H insertion reaction of the lithium carbenoid 90 itself. On the other hand, this transformation could proceed via the a-alkoxy carbene 91. In both cases, the release of strain due to the opening of the oxirane ring is a significant driving force of the reaction. 

Use of Rh2(OAc)4 suggested that there was no inherent selectivity attributable to the coordinated carbene or to rhodium(ll). However, modification of dirhodium(ll) ligands to imidazolidinones provided exceptional diastereocontrol, obtained by influencing the conformational energies of the intermediate metal carbene [19, 23], as well as high enantiocontrol. Representative examples of products from these highly selective intramolecular C-H insertion reactions with cyclic systems is given in Scheme 15.6. Additional examples of effective insertions in systems from which diastereomeric products can result are illustrated in processes of the synthesis of 2-deoxyxylolactone (Scheme 15.7) [64, 65]. Here the conformation of the reactant metal carbene that is responsible for product formation is 32 rather than 33. Other examples in non-heteroatom-bound systems (for example, as in Eq. 15) confirm this preference. 

In cartoon form, what is needed is a ligand that will extend sterically to set up the local C2-symmetry around the apical position of the rhodium, where the carbene binds and where the C-H insertion reaction is taking place. The resulting chiral environment would then favor transition state 52, leading to one enantiomer, over transition state 53, leading to the competing enantiomer. 

A very elegant synthetic approach was reported a year later by Davies et al., leveraging asymmetric C-H activation chemistry to accomplish a one-pot synthesis of d-threo methyiphenidate (Scheme 17.10) (Davies et al., 1999). A-Boc piperidine (33) was selectively alkylated by the carbene formed by decomposition of diazoester 34 in a reaction mediated by 25 mol% of chiral Rh (II) catalyst 35, giving the A-Boc protected (2R,2 R) isomer in a single step. TFA was added to accomplish removal of the Boc group after the C-H insertion reaction was complete, affording (R,R)-methylphenidate (2) with an ee of 86% in 52% overall yield. 

Intermolecular Insertions. Singlet carbenes undergo insertion reactions with X H bonds such as O—H (alcohols), N—H (amines), Si H (silanes), and so on. The reactions with alcohols can be extremely fast. Here, however, we focus on the C H insertion reactions of singlet carbenes, in which carbon-carbon bonds are created. ... 

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