Carbenoid nature

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. 

The chelate formation in lithium complexes 17 or 20 contributes to stabilization. Enhancement of kinetic acidity arises from the formation of pre-complexes 16 and 19, respectively. Here, already a dipole is induced and, in addition, proton exchange can proceed intramolecularly via a five- or six-membered ring. Despite these favourable features, the acidity of alkyl carbamates 15 is lower than those of the 1-proton in butane n-BuLi does not lead to deprotonation. In order to suppress carbonyl attack, a branched amino residue NR2 such as diisopropylamino (in Cb) or 2,2,4,4-tetramethyl-l,3-oxazolidin-3-yl (in Cby) is essential. A study on the carbenoid nature of compounds 17 was undertaken by Boche and coworkers. ... 

Schlosser670 proposed an equivalent mechanism at the phosphorane 64 stage, formed from the corresponding ylide and not from the phosphonium salt the driving force for the migration comes from the carbenoid nature of the carbon in the a-position to the phosphorus. This is consistent with the anionotropic nature of the migration. The mechanism is corroborated by a similar migration from the ylide 65670 (reaction 198). 

The crystal structure of a dimer of 4-i-butyl-2-lithiothiazole incorporating two molecules of diglyme has been determined by X-ray analysis (95AG(E)487). The structure features the lithium atom positioned halfway between nitrogen and C-2, thus providing a carbenoid nature to this metallated thiazole. 

The lithium species (288) is easily accessible by deprotonation with n-butyllithium in THF, as shown by deuteration to give 289 . The concomitant formation of 292 is probably due to the carbenoid nature of 288. Dimerization of the cyclopropylidene 290 should give 291 which under basic conditions isomerizes to give 292 . 

Due to the lack of both a metal centred lone pair and an available coordination site, a nucleophilic substitution reaction is obviously inoperative here. Therefore, a direct insertion into the central M-H bond is responsible for the formation of the phosphonium salt. Such a reactivity has been explained recently, by Nikonov et al, in terms of a new and interesting concept, which considers the carbenoid nature of halophosphines. ... 

Saturated large rings may form nitrogen radicals by H abstraction from N, or abstraction may occur in the a- or /3-positions in nonnitrogen systems. Oxepane gives the radical in the 2-position, with subsequent cleavage and reclosure of the intermediate carbenoid to cyclohexanol (Section 5.17.2.1.5). In unsaturated large systems a variety of reactions, unexceptional in their nature, are found. Some azepines can be brominated by A -bromosuc-cinimide others decompose under similar conditions (Section 5.16.3.7). 

For a reaction as complex as catalytic enantioselective cyclopropanation with zinc carbenoids, there are many experimental variables that influence the rate, yield and selectivity of the process. From an empirical point of view, it is important to identify the optimal combination of variables that affords the best results. From a mechanistic point of view, a great deal of valuable information can be gleaned from the response of a complex reaction system to changes in, inter alia, stoichiometry, addition order, solvent, temperature etc. Each of these features provides some insight into how the reagents and substrates interact with the catalyst or even what is the true nature of the catalytic species. 

These optimization studies are an important step in the study of Simmons-Smith cyciopropanations since they allowed for the development of a selective, catalytic method for introduction of a simple methylene unit. However, they also provide insights into the basic mechanism of this process. Together with earlier studies regarding carbenoid structure, the true nature of the reactive carbenoid, lCH2Znl, was confirmed. On the basis of these results, a revised transition structure was proposed. Although there is no direct evidence for such a transition... 

Finally, metalated epoxides undergo isomerization processes characteristic of traditional carbenoids (Scheme 5.2, Path C). The structure of a metalated epoxide is intermediate in nature between the structures 2a and 2b (Scheme 5.2). The existence of this intermediacy is supported by computational studies, which have shown that the a-C-O bond of oxirane elongates by -12% on a-lithiation [2], Furthermore, experimentally, the a-lithiooxycarbene 4a (Scheme 5.3) returned cydo-pentene oxide 7 among its decomposition products indeed, computational studies of singlet 4a suggest it possesses a structure in the gas phase that is intennediate in nature between an a-lithiocarbene and the lithiated epoxide 4b [3],... 

For many catalytic cyclopropanations, the stereoselectivity describing the stereochemical relation between substituents at the carbenoid and those at the double bond is not very pronounced. EjZ or syn/anti ratios of ca. 1-3 in favor of the less congested isomer may be considered normal (for examples see Tables 6 and 7). The stereochemical outcome can be expected to be governed by the nature of the olefin, the diazo compound and the catalyst. 

The organization of the material in this chapter is naturally subjective, and certain topics could equally well have been discussed in another section or in a different order. For example, the Simmons-Smith reagent is both an alkylzinc iodide and a carbenoid, and because both sections exist in this chapter, it is discussed under the more specific heading of zinc carbenoids. 

The tandem zirconocene-induced co-cyclization of dienes or enynes/insertion of allyl carbenoid/addition of electrophile is a powerful method for assembling organic structures. Two illustrations of its application are the synthesis of the dollabelane natural product acetoxyodontoschismenol 99 [57,62,63] and the one-pot construction of linear terpenoids 100 (Scheme 3.25) [59,64],... 

The cyclopropane moiety is a fundamental class of functional group present in both natural products and numerous therapeutic agents. It has provided the impetus for significant breakthroughs in the use of metal carbenoids [151] and organocatalytic ylide intermediates [152, 153] such that rehable methods exist for most disconnective strategies on this ring system. 

A third mechanistically distinct [3 -1- 2] cycloaddition between vinyl ethers and vinyl-carbenoids was discovered and reported in 2001 [26]. This reaction is remarkable because when Rh2(S-DOSP)4 is used as the catalyst, the cis-cyclopentenes 142 are formed in up to 99% enantiomeric excess. The reaction occurs between vinylcarbenoids unsubstituted or alkyl-substituted at the vinyl terminus and vinyl ethers substituted with an aryl or vinyl group. Some illustrative examples are shown in Tab. 14.12. The reaction is considered to be a concerted process, which would be consistent with the highly stereoselective nature of the reaction [26]. Contrary to the [3-1-2] cycloaddition derived by means of vinylogous carbenoid reactivity, this latest [3 -1- 2] cycloaddition is not influenced by solvent effects. Due to steric demands on the carbenoid, the [3-1-2] cycloaddi-tion only occurs with cis-vinyl ethers. 

A reactive carbenoid would have an early transition state, favoring /9-H elimination over 1,5-insertion. We expect that the increased proportion of eHmination observed with rhodium trifluoroacetate (entry 5) is due to the electron-withdrawing nature of the ligand, which makes the carbene carbon more electron-deficient and thus more reactive. 

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