In carbene insertion

Fluoroalkyl Glycosides (RFn-(CH2)2-n-0-sugar) and Perfluor-oalkylidene Acetals Derived from Sugars The very low nucleophilicity of fluoroalcohols makes it difficult to substitute of a hydroxyl (anomeric or not). ° This is the reason why this type of ether is not very common. Such ethers have only been isolated in very small quantities in solvolysis reactions, or in carben insertions, performed in fluorous alcohols.Preparation of these ethers has been solved by means of the Mitsunobu reaction. This reaction is known to be dependent on the pA a of the acceptor of the glycosyl the acidity of fluorous alcohols allows a much easier deprotonation than with non fluorinated alcohols." ... 

Lithiation of (425) results in carbene insertion and formation of bicyclobutane (426). This latter compound proves to be a valuable synthetic intermediate, affording trans-bishomobenzene (in 30-40 % yield, on a multigram scale) and homotropilidene (Scheme 66). Whereas (427), with no suitable C—H bond available for 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-... 

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. 

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. 

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... 

Vinylidenecarbene or allenylidene3 (R)2C=C=C has a lance-shaped, unsubstituted and sp-hybridized carbene center and, therefore, will not be easily subject to steric hindrance in its insertion reactions. On this assumption, (2-methyljpropenylidenecarbene or its carbenoid was chosen as a prototype of typical vinylidenecarbenes and its insertion reaction with several different types of alkoxides was investigated by employing two methods (A and B, Scheme 10) for carbene generation.20 The insertion products 20 were obtained almost exclusively except lithium allyloxide (Table 4, entry 10).21 By-products such as propargyl ether and allenyl ether were not formed at all. To be noted here, in... 

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). 

Not only the formation of these insertion by-products but also the ring-formation described in Section Hf (see also Table 6) proved that the activation of the a C-H bond by a vicinal negative charge for the carbene insertion is more effective than the non-ionic as well as entropy-controlled formation of five-membered rings. 

Most of the carbenes examined in this study have more or less a carbenoid nature because they are generated from halogenated precursors and strong base. In this regard, it still remains as an intriguing problem to verify experimentally the higher electrophilicity and selectivity of carbenoids41,42 in comparison to those of free carbenes in the insertion reaction. 

Dirhodium(II) carboxylate catalysts have been used extensively for the catalysis of carbene insertions. In many cases, impressive selectivities have been achieved (19-21). In an effort to find selective catalysts for carbenoid insertions, Moody screened a series of dirhodium(II) carboxylate catalysts for their ability to catalyze carbenoid Si-H insertion (22). The authors surveyed the commercially available carboxylic acids, -10,000 of which are chiral. The members of this group that contained functionality that is incompatible to the reaction were culled out. The remaining chiral carboxylic acids (-2000 compounds) were then grouped into 80 different clusters. There is no discussion presented for the criteria used in the grouping of the acids. A representative acid from each cluster was then chosen for... 

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