Carbene insertion pathway

The predominant formation of five-membered carbocydes or heterocycles 122 (Scheme 50) via a sequential conjugate addition-carbene insertion pathway is generally observed in the reactions of the appropriate alkynyliodonium salts 119 (R = long alkyl chain or other group with C-H bond available at C5) with various relatively hard nucleophiles. Typical nucleophiles used to initiate these selective cyclizations are enolate, azide, sulfinate, tosylamide, thioamide and some other anions. 

Reactions of phenyl(propynyl)iodonium triflate (30) with tosylamidate ions possessing N-alkyl chains of two or more carbon atoms follow the carbene insertion pathway leading to AT-tosyldihydropyrroles 31 (Scheme 54) [154,155]. The N-cyclohexyl tosylamidate ion leads stereospecifically to the ds-fused bicyclic dihydropyrrole under these conditions. 

The carbene-insertion pathway has recently been applied in total asymmetric syntheses of the anti-leukemic alkaloid, (—)-agelastatin A, and the dibromo analog, (-)-agelastatin B (02JA9060, 02JOC7096). Treatment of the (oxazolidinonyl)propynyliodonium triflate 250 with sodium />-toluenesulfinate leads to a mixture of the bicyclic oxazolidinone 251 and the carbenic rearrangement product 252 (Scheme 70) compound 251 is a key intermediate in the agelastatin synthesis. 

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. 

Carbenes 100, generated by UV irradiation of methyl (alkoxysilyl)diazoacetates 99, furnish l-oxa-2-silacyclopentanes 101 by 1,5-C,H insertion (equation 25)60. In order to suppress competing reaction pathways of the carbene intermediate (e.g. formation of a ketazine with excess diazo compound), the photolysis was carried out at high dilution, but, even then, yields were rather modest. Carbene insertion at CH2 seems to occur much more easily than at CH3 a preference of 3 0.6 1 for methylene insertion can be calculated from the isolated yields after correction for the number of C—H bonds. It should be noted that for both carbenes, 96 and 100, C,H insertion occurs only in the 1,5 mode whereas no 1,3-, 1,4- or 1,6-C,H insertion products could be detected. 

As shown above, insertion of alkylidene carbenes is highly regioselective. However, when the normal 1,5-C-H insertion pathway is blocked, 1,4- or 1,6-C-H insertion takes place [Eq. (109)]. Thus, the cyclobutene 121 [192] and the six-membered enol ether 123 [193] were obtained in modest yields. Intramolecular insertion into carbon-carbon double bond provides a method for synthesis of cyclopenten-annulated dihydropyrrole 124, which results from homolytic scission of a methylenecyclopropane intermediate [194]. 

Reactions of alkynyliodonium salts 119 with nucleophiles proceed via an addition-elimination mechanism involving alkylidenecarbenes 120 as key intermediates. Depending on the structure of the alkynyliodonium salt, specific reaction conditions, and the nucleophile employed, this process can lead to a substituted alkyne 121 due to the carbene rearrangement, or to a cyclic product 122 via intramolecular 1,5-carbene insertion (Scheme 50). Both of these reaction pathways have been widely utilized as a synthetic tool for the formation of new C-C bonds. In addition, the transition metal mediated cross-coupling reactions of alkynyliodonium salts are increasingly used in organic synthesis. 

The reactions of / -ketoethynyl- and ) -amidoethynyl(phenyl)iodonium triflates, 17 and 18, with sodium / -toluenesulfinate illustrate the synthetic potential of alkynyliodonium salts33. Although the direct attachment of a carbonyl group to the / -carbon atom of the triple bond in alkynyliodonium ions might be expected to facilitate alkynyl sulfone formation via the Ad-E mechanism, this mode of reactivity has not been observed. Instead, the MC pathway with carbenic insertion dominates and affords sulfones containing the... 

Carbenic insertions are similarly useful for syntheses of the benzofurans 239 and furopyridines 240 depicted in Scheme 65 (97JCS(P2)1511, 98TL5375). It is noteworthy that the carbene intermediates in the benzofuran pathway show preference for aromatic over aliphatic CH-bond insertion. 

The carbene insertion route (pathway (b)) has most frequently been implied to explain the thermal cydizations of various ethynyl-substituted aromatic precursors. Although the other two alternatives cannot be excluded at present, since in many cases (see below) no careful mechanistic studies have been undertaken, the carbene hypothesis has the advantage of... 

Chromium- and molybdenum-based carbene complexes condense with ketoalkynes along a CO insertion pathway to afford tricyclic pyran-containing lactone products (29) in variable yield (Equation (9)) (90JA1645, 91JA5459). 

In principle, triplet carbene insertions should follow a two-step radical pathway analogous to their insertion into alkenes. However, very few triplet carbene insertions into C-H bonds have been observed, and the stereochemical consequence of the two-step mechanism (which should result in mixtures of stereoisomers on insertion into a C-H bond at a stereogenic centre) has never been verified. 

C2a-carbanion or enamine as suggested 35 years ago by Breslow. After considerable research by many groups " , the true structure of the former is still unknown, as its existence is too fleeting for direct detection. Suffice it to say that more recent kinetic studies suggest that it is formed with a pA" near 17-19 and its behavior is consistent with a localized carbanion structure similar to that of cyanide ion. While there were some reports favoring a carbene °, rather than nucleophilic reactivity for the C2-carbanion vis-a-vis electrophiles, more recently there was evidence presented reconfirming that the reactivity of this C2-carbanion is best reflected by nucleophilic pathways, and the mechanistic probes developed provided evidence inconsistent with carbene insertion into C—H single bonds or addition across C=C double bonds ... 

One of the more recent applications of carbene insertion into 0-H bond of alcohols includes the synthesis of chorismic (and pseudochoris-mic) acid [81], which occupies in microorganisms and plants, a strategic position in the shikimate pathway [82] as the key branch point intermediate governing the biosynthesis of aromatic aminoacids, isoprenoid qui-nones, bacterial and plant growth regulators, and other vital compounds. 

Using dihydroimidazol-2-ylidene as a model NHC ligand, Straub [12] has calculated the intramolecular methylidene-NHC carbene dimerization pathway (Scheme 7.12). Rotation of the methylidene to the active, horizontal conformation required only 3.3kcalmol . The insertion of methylidene into the Ru-C(NHC)... 

Direct insertions into C—H bonds have been postnlated for reactions that proceed through metal carbenes and nitrenes (12/13). " In these mechanisms, the unsat-nrated M=X intermediates 12 or 13 directly attack the C—H bond and form the prodnct in one concerted step. Often, a preference for cleaving weak C—H bonds is observed however, C—H functionalizations of alkanes are known that have been proposed to follow this so-called C—H insertion pathway. Stereoselective and even enantioselective methodologies have been developed based on this strategy using snitable enantiomerically pure ancillary ligands." ... 

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