Carbene, insertion

The cyclohexylpyrazole (376) and the azlrlne (377) are formed by irradiation of 3-dlazo-4-methyl-5-phenylpyrazolenine (378) in cyclohexane (Scheme 35) (77JA633). The former is the result of carbene insertion into cyclohexane followed by a [1,5] hydrogen shift, whereas the latter arises by ring cleavage of nltrene (379) or by a concerted pathway. 

In another experiment tritiated adamantane diazirine fixed to the hydrocarbon core of a membrane gave rise to carbene insertion into the catalytic subunit of ATP-ase. After protolytic degradation adjacent areas of the original structure became evident (80JBC(255)860). 

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

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-... 

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... 

An attempt to measure the IR spectrum of the hydroxy carbene [28] after UV photolysis (A>220 nm) of formaldehyde isolated in an argon matrix was unsuccessful (Sodeau and Lee, 1978). Instead of [28] only hydroxyacetal-dehyde resulting from carbene insertion into the C—H bond of the starting formaldehyde was found in the reaction products. Due to its small size, the... 

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... 

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... 

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. 

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 interaction between catalyst and diazo compound may be initialized by electrophilic attack of the catalyst metal at the diazo carbon, with simultaneous or subsequent loss of N2, whereupon a metal-carbene complex (415) or the product of carbene insertion into a metal/ligand bond (416) or its ionic equivalent (417) are formed. This is outlined in a simplified manner in Scheme 43, which does not speculate on the kinetics of such a sequence, nor on the possible interconversion of 415 and 416/417 or the primarily formed Lewis acid — Lewis base adducts. 

The Lewis acid-Lewis base interaction outlined in Scheme 43 also explains the formation of alkylrhodium complexes 414 from iodorhodium(III) meso-tetraphenyl-porphyrin 409 and various diazo compounds (Scheme 42)398), It seems reasonable to assume that intermediates 418 or 419 (corresponding to 415 and 417 in Scheme 43) are trapped by an added nucleophile in the reaction with ethyl diazoacetate, and that similar intermediates, by proton loss, give rise to vinylrhodium complexes from ethyl 2-diazopropionate or dimethyl diazosuccinate. As the rhodium porphyrin 409 is also an efficient catalyst for cyclopropanation of olefins with ethyl diazoacetate 87,1°°), stj bene formation from aryl diazomethanes 358 and carbene insertion into aliphatic C—H bonds 287, intermediates 418 or 419 are likely to be part of the mechanistic scheme of these reactions, too. 

Photoelimination of nitrogen from diazirines, for example, proceeds via carbene intermediates. 3-tert-Butyldiazirine (395) is converted into the cyclopropane 396 and the alkene 397 with the formation of the carbene insertion product being favored from the singlet state.328 3-Cyclopropyl-3-chlorodiazirine (398) has similarly been converted to the carbene 399 which undergoes both rearrangement to l-chlorocyclobutene(400)329 and addition... 

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... 

Carbene 103 undergoes 1,3-CH insertion to nortricyclene (105), but this reaction is either too rapid for LFP measurement by the pyridine ylide method (r <0.1 ns), or the insertion occurs by RIES of the precursor 2-norbomyldiazirine. Theoretically, a short lifetime is expected for 103 AG for the carbene insertion into the 6-endo-CU bond (103 — 105) is computed at 5.2 kcal/mol, about 6.7 kcal/mol less than the (unobserved) exo- 1,2-H shift to norbomene.16... 

II. Regioselectivity of the Carbene Insertion into a C-H Bonds of Alkoxides. 289... 

II. REGIOSELECTIVITY OF THE CARBENE INSERTION INTO a C-H BONDS OF ALKOXIDES... 

Since alkyllithium compounds and their carbanions have an isoelectronic structure with alkoxides, their reaction behavior with carbenes is expected to be similar to that of alkoxides, showing enhanced reactivity in both C-H insertion and hydride abstraction.35 In this reaction, the hydride abstraction cannot be followed by recombination and, therefore, can be differentiated from the insertion. Indeed, the reaction of alkyllithium compounds 70 or nitrile anions (see Section IV.B) with ethyl(phenylthio)carbenoid, which is generated by the reaction of 1-chloropropyl sulfide 69 with BuLi, takes place at the -position of 70 more or less in a similar manner giving both insertion product 71 and hydride abstraction products 72 and 73, respectively. This again supports a general rule C-H bonds at the vicinal position of a negatively charged atom are activated toward carbene insertion reactions (Scheme 22). 

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