Carbene insertion reactions carbenes

Insertion reaction of a vinyl carbene (terminal acetylenes)... 

Photolytically generated carbene, as mentioned above, undergoes a variety of undiscriminated addition and insertion reactions and is therefore of limited synthetic utility. The discovery (3) of the generation of carbenes by the zinc-copper couple, however, makes carbene addition to double bonds synthetically useful. The iodo-methylzinc iodide complex is believed to function by electrophilic addition to the double bond in a three-center transition state giving essentially cis addition. Use of the... 

To set the stage for the crucial carbene insertion reaction, the acetic acid side chain in 32 must be homologated. To this end, treatment of 32 with 1,l -carbonyldiimidazole furnishes imidazo-lide 33, a competent acylating agent, which subsequently reacts with the conjugate base of Meldrum s acid (34) to give 35. Solvolysis of this substance with para-nitrobenzyl alcohol in acetonitrile at reflux provides /Mceto ester 36 after loss of one molecule of ace-... 

The insertion of a carbene into a Z-H bond, where Z=C, Si, is generally referred to as an insertion reaction, whereas those occurring from Z=0,N are based on ylide chemistry [75]. These processes are unique to carbene chemistry and are facilitated by dirhodium(II) catalysts in preference to all others [1, 3,4]. The mechanism of this reaction involves simultaneous Z-H bond breaking, Z-car-bene C and carbene C-H bond formation, and the dissociation of the rhodium catalyst from the original carbene center [1]. 

One of the most dramatic recent developments in metal carbene chemistry catalyzed by dirhodium(II) has been demonstration of the feasibility and usefulness of intermolecular carbon-hydrogen insertion reactions [38, 91]. These were made possible by recognition of the unusual reactivity and selectivity of aryl- and vinyldiazoacetates [12] and the high level of electronic control that is possible in their reactions. Some of the products that have been formed in these reactions, and their selectivities with catalysis by Rh2(S-DOSP)4, are reported in Scheme 10. 

An unprecedented carbene insertion reaction was observed on reaction of the cationic re-arene ruthenium amidinates with trimethylsilyldiazo-methane (Scheme 145, TFPB = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate). 

The highly reactive species methylene inserts into C—H bonds,both aliphatic and aromatic,though with aromatic compounds ring expansion is also possible (see 15-62). This version of the reaction is useless for synthetic purposes because of its nonselectivity (see p. 248). This contrasts with the metal carbene insertion reaction, which can be highly selective, and is very useful in synthesis. Alkylcarbenes usually rearrange rather than give insertion (p. 249), but, when this is impossible. 

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... 

That this mechanism can take place under suitable conditions has been demonstrated by isotopic labeling and by other means. However, the formation of disproportionation and dimerization products does not always mean that the free-radical abstraction process takes place. In some cases these products arise in a different manner.We have seen that the product of the reaction between a carbene and a molecule may have excess energy (p. 247). Therefore it is possible for the substrate and the carbene to react by mechanism 1 (the direct-insertion process) and for the excess energy to cause the compound thus formed to cleave to free radicals. When this pathway is in operation, the free radicals are formed after the actual insertion reaction. 

Carbene itself is extremely reactive and gives many side reactions, especially insertion reactions (12-19), which greatly reduce yields. When it is desired to add CH2 for preparative purposes, free carbene is not used, but the Simmons-Smith procedure (p. 1088) 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 interfere.The absolute rate constant for addition of selected alkoxychlorocarbene to butenes has been measured to range from 330 to 1 x 10 A few of the many ways in... 

Carbenes can rearrange to alkenes in many cases. A 1,2-hydrogen shift leads to an alkene, and this is often competitive with insertion reactions.Benzylchlorocarbene (42) rearranges via a 1,2-hydrogen shift to give the alkene.Similarly, carbene (43) rearranges to alkene (44), and replacement of H on the a-carbon with D showed a... 

En grosy the C insertion reactions can be classified as C3 type and as C4 type rearrangements. Furthermore, a two step C4-type process involving chromium carbene addition and a CO insertion has been reported. 

Interestingly, [Ee(F20-TPP)C(Ph)CO2Et] and [Fe(p2o-TPP)CPh2] can react with cyclohexene, THF, and cumene, leading to C-H insertion products (Table 3) [22]. The carbenoid insertion reactions were found to occur at allylic C-H bond of cyclohexene, benzylic C-H bond of cumene, and ot C-H bond of THF. This is the first example of isolated iron carbene complex to undergo intermolecular carbenoid insertion to saturated C-H bonds. 

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... 

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... 

These reactions have very low activation energies when the intermediate is a free carbene. Intermolecular insertion reactions are inherently nonselective. The course of intramolecular reactions is frequently controlled by the proximity of the reacting groups.113 Carbene intermediates can also be involved in rearrangement reactions. In the sections that follow we also consider a number of rearrangement reactions that probably do not involve carbene intermediates, but lead to transformations that correspond to those of carbenes. 

Insertion reactions are processes in which a reactive intermediate, in this case a carbene, interposes itself into an existing bond. In terms of synthesis, this usually involves C—H bonds. Many singlet carbenes are sufficiently reactive that insertion can occur as a one-step process. 

Owing to the high reactivity of the intermediates involved, intermolecular carbene insertion reactions are not very selective. The distribution of products from the photolysis of diazomethane in heptane, for example, is almost exactly that expected on a statistical basis.211... 

There is some increase in selectivity with functionally substituted carbenes, but it is still not high enough to prevent formation of mixtures. Phenylchlorocarbene gives a relative reactivity ratio of 2.1 1 0.09 in insertion reactions with i-propylbenzene, ethylbenzene, and toluene.212 For cycloalkanes, tertiary positions are about 15 times more reactive than secondary positions toward phenylchlorocarbene.213 Carbethoxycarbene inserts at tertiary C—H bonds about three times as fast as at primary C—H bonds in simple alkanes.214 Owing to low selectivity, intermolecular insertion reactions are seldom useful in syntheses. Intramolecular insertion reactions are of considerably more value. Intramolecular insertion reactions usually occur at the C—H bond that is closest to the carbene and good yields can frequently be achieved. Intramolecular insertion reactions can provide routes to highly strained structures that would be difficult to obtain in other ways. 

The most common rearrangement reaction of alkyl carbenes is the shift of hydrogen, generating an alkene. This mode of stabilization predominates to the exclusion of most intermolecular reactions of aliphatic carbenes and often competes with intramolecular insertion reactions. For example, the carbene generated by decomposition of the tosylhydrazone of 2-methylcyclohexanone gives mainly 1- and 3-methylcyclohexene rather than the intramolecular insertion product. 

Carboalkoxynitrenes are somewhat more selective than the corresponding carbenes, showing selectivities of roughly 1 10 40 for the primary, secondary, and tertiary positions in 2-methylbutane in insertion reactions. 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

A second route was devised using chiral /3-keto ester 14, which was identified as our precursor for 2 [7]. This idea was in analogy with the carbapenem chemistry [8], as depicted in Scheme 2.4, where Masamune reaction [9] for carbon elongation, diazo-transfer, and transition metal-mediated carbene insertion reaction [10] were employed as key steps sequentially. 

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 ... 

The a-osmiumdiazo compound 91 decomposes in a thermal reaction to yield the metallacyclic complex 93 (130). This resembles the electrophilic carbene insertion reaction forming OsCl(CO)2(PPh2C6H4CHCl) (PPh3) (77) (see Section V,D,2), and we suggest that a similar insertion reaction of an electrophilic, cationic osmium carbyne 92 is the key step in this transformation. An X-ray structure determination has confirmed the formulation of 93. 

The photoelimination of nitrogen from diazo compounds provides a simple and versatile route for the generation of carbenes, and in certain instances, insertion reactions of carbenes can be employed in the synthesis of heterocycles. Carbenes are believed to be involved at least in part in the photochemically induced conversion of N,N-diethyldiazoacetamide (439) into the y-lactam 440 and the /Mactam 441,365 and a similar approach has been successfully employed in the synthesis of a carbapen-2-em366 and of 7-methylcephalosporin analogues.367 Carbene insertion of a different type has been observed on irradiation of the 6-anilino-5-diazouracils 442 to give the indolo[2,3-d]pyrimidines 443.368 Ring contractions in heterocycles... 

The reactions of the vinylcarbenes 7 and 15 with methanol clearly involve delocalized intermediates. However, the product distributions deviate from those of free (solvated) allyl cations. Competition of the various reaction paths outlined in Scheme 5 could be invoked to explain the results. On the other hand, the effect of charge delocalization in allylic systems may be partially offset by ion pairing. Proton transfer from alcohols to carbenes will give rise to carbocation-alkoxide ion pairs that is, the counterion will be closer to the carbene-derived carbon than to any other site. Unless the paired ions are rapidly separated by solvent molecules, collapse of the ion pair will mimic a concerted O-H insertion reaction. 

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