Insertion reactions intermolecular into

The intramolecular insertion reactions of nitrenoids into G-H bonds as described above provide an attractive alternative to conventional methods of amine formation. Both carbamate and sulfamate C-H insertions have been applied successfully to the total syntheses of natural products. - The first application of carbamate G-H insertion was reported by Trost in the total synthesis of methyl-L-callipeltose 118 (Equation (92)).230 Intermolecular G-H insertion of carbamate 117 using 10mol% Rh2(OAc)4, PhI(OAc)4, and DTBMP (2,6-di-/ / -butyl-4-methylpyridine) in dichloromethane (40 °C) furnished methyl-L-callipeltose 118 in 63% yield. In an another independent total synthesis of 118, Panek performed this step in refluxing benzene and improved the yield to 93%.231... 

Carbenes and carbenoids can add to double bonds to form cyclopropanes or insert into C—H bonds. 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.53... 

The lifetime of 56 in hydrocarbon solvents at 25 °C is only several nanoseconds, so that its intermolecular chemistry should be difficult to observe. Indeed, intermol-ecular C H insertion reactions of 56 are inefficient, although the carbene can be captured (competitively with 1,2-H shift) by insertions into O H or N H bonds or by addition to isobutene. ... 

Phenyl azides (azidoarenes), introduced by Knowles and co-workers,[8 9] are the most abundantly used class of photophores. Examples include 4-azidophenylalanine (1) and 4-azido-3-nitrophenylalanine (4) (Scheme 1). Irradiation (<300 nm) of phenyl azide (13) generates nitrene 14, electrophilic in nature, which prefers insertion into O—H and N—H bonds over C—H bonds. Nitrenes are considerably less reactive and, therefore, more selective than carbenes. Nevertheless, due to their short life span (0.1-1 ms) they react indiscriminately with virtually any amino add residue in the target protein.1101 Intramolecular rearrangements do not compete effectively with intermolecular proton abstraction and insertion reactions (Scheme 4). 

The palladium-catalyzed reaction of allyl chloride 11 with the benzyne precursor 104 to produces phenanthrene derivatives 131 is also known [83]. A plausible mechanism for this intermolecular benzyne-benzyne-alkene insertion reaction is shown in Scheme 38. Initially n-allyl palladium chloride la is formed from Pd(0) and 11. Benzyne 106, which is generated from the reaction of CsF and 104, inserted into la to afford the aryl palladium intermediate 132. A second benzyne insertion into 132 produce 133 and subsequent carbopalladation to the alkene afford the cyclized intermediate 134. f>- Iydride elimination from 134 followed by isomerization gave 9-methylphenanthrene 131. 

The C—H insertion reaction of nitrenes is a potentially useful way of functionalizing unactivated C—H bonds, converting hydrocarbons into amine derivatives. In its intermolecular form the synthetic utility of the reaction is highly dependent on the substituents on the nitrene, and on the manner in which it is generated. To exemplify these effects, the results for the functionalization of cyclohexane by insertion of various nitrenes (equation 1) are summarized in Table 1. 

Intra- and intermolecularly stabilized iminosilanes are obtained by using heteroaromatic substituted aminofluorosilanes. For example, the bicyclic system 3 is obtained in an insertion reaction of the iminosilane into a polar C-H bond of the pyrrole substituent. Using smaller substituents the [2+2] cycloaddition product 4 is obtained [6]. 

Intermolecular reactions between coordinatively unsaturated metal atoms and the C-H groups of relatively unreactive hydrocarbons such as cyclohexane and even methane have been reported (Scheme 1.4). ° Insertion reactions of carbenes R R C into C-H or other bonds are clearly of the same type, the carbene carbon atom playing the role of the coordinatively unsaturated metal... 

The results above clearly demonstrate that donor/acceptor carbenoids (specifically those derived from aryldiazoacetates) are capable of better reactivity than their acceptor or acceptor/acceptor counterparts with certain catalysts. Cyclohexane, however, is not appropriate for examining the selectivity of intermolecular carbenoid C-H insertion reactions. In order to achieve selective transformations on more complex substrates, it would be crucial to determine what level of differentiation could be obtained between different types of C-H bonds. Thus Davies and coworkers studied the relative rate of insertion of methyl phenyldiazoacetate into a number of simple substrates through competition studies (Fig. 6) [81]. 

The ability of rhodium or copper complexes to promote carbene formation allows the study of asymmetric reactions with chiral ligands attached to the metal centre. Some highly enantioselective transformations are possible in certain cases. For example, the lactone 101 was formed with high optical purity using the complex [Rh2(5S-MEPY)4] (4.79). In the absence of competing intramolecular reactions, intermolecular C—H insertion is possible and such reactions are also amenable to asymmetric induction. Thus, high enantioselectivity in the insertion into a C—H bond of cyclohexane has been reported (4.80). 

Intramolecular insertion reactions present new synthetic solutions. Generally, rigid structures favor such insertions. When an intramolecular insertion is possible, no intermolecular insertions are seen. In flexible structures, five-membered ring formation is preferred to six-membered ring formation. Both inter- and intramolecular insertions are amendable to asymmetric induction by choosing chiral ligands on metal centers. Arylcarbene can be inserted intramolecularly into aromatic C-H bonds (Schemes 5.49 and 5.50). 

There are only a few cases of an intermolecular reaction of a 7r-allylpalladium complex with an alkene. The carbopalladation of norbomadiene with a stoichiometric amount of a TT-allylpalladium complex to yield an allyl-substituted a--norbomenylpalladium species has been reported In the context of mechanistic studies of Pd-catalyzed alkene dimerization, the insertion of ethylene into a cationic 7r-allylpalladium complex was also reported as a stoichiometric reaction in 1996 (Scheme... 

Similar to the ether substrates mentioned above, both cyclic and acyclic N-protected amines could be converted into their corresponding ortho-C—H bond functionalization products via the insertion of metal carbenoids derived from Rh catalysts and donor/acceptor diazo compounds. Thking Af-Boc-protected pyrrolidine 48 as an example (Scheme 1.15), Rh2(S -DOSP)4 catalyzed the decomposition of methyl phenyldiazoacetate la and converted the Af-Boc-pyrrolidine 48 into the corresponding C—H bond insertion product 49 in 72% yield, 94% ee, and 92% de. Furthermore, the C2-symmetric amine 50 could be formed in 78% yield and 97% ee under altered reaction conditions. Further investigation demonstrates that this intermolecular C—H bond insertion could also be applied in the kinetic resolution of 2-substituted pyrrolidine 51. The corresponding C—H bond insertion reaction proceeded smoothly, and subsequent treatment with TFA delivered the deprotected product 52 in high diastereo- and enantioselectivity (45% yield, 91% ee, >94% de). " ... 

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