Intramolecular nucleophilic capture

A similar intramolecular nucleophilic capture of an allylic sulfenate generated thermally from the corresponding sulfoxide was also reported for the facile transformation of the azetidinone 61 into a new 3-acetylthio-2-thiacephem ring system 62 (equation 29)127. 

The existence of a-complex intermediates can be inferred from experiments in which they are trapped by nucleophiles in special circumstances. For example, treatment of the acid 1 with bromine gives the cyclohexadienyl lactone 2. This product results from intramolecular nucleophilic capture of the a complex by the carboxylate group. 

A number of examples of intramolecular nucleophilic capture of cyclohexadienylium intermediates have also been uncovered in the study of nitration of alkylated benzenes in acetic acid. For example, nitration of 3 at 0°C leads to formation of 4 with acetate serving as the nucleophile. ... 

C-Ring substituted indoles, including 4-nitroindole, are also allylated under these conditions. The reaction is believed to proceed by an Sa I mechanism, with the Zn(03SCF3)2 acting as a Lewis acid catalyst. There may also be some N-H deprotonation by the amine. 1-Methylindole reacts under these conditions, but with reduced yield. The Zn(03SCF3)2-mediated reaction was used in tandem with intramolecular nucleophilic capture to synthesize the flustramine structure [89]. 

Conjugate Addition with Intramolecular Nucleophilic Capture... 

The ET photochemistry of (IR, 35)-(+)-c/i-chrysanthemol (c/i-127) proceeds via nucleophilic attack of the internal alcohol function on the vinyl group with simultaneous or rapid replacement of an isopropyl radical as an intramolecular leaving group, forming 128. This reaction is a mechanistic equivalent of an Sn2 reaction the mode of attack underscores the major role of strain relief in governing nucleophilic capture in radical cations. 

Under these conditions, silver-assisted electrocyclic ring opening provided the haloallyl cation, which was subsequently trapped by isocyanate anion. Interception of the cationic species with isocyanate was successful since bromide was removed from the reaction mixture as a precipitate (AgBr). Finally, treatment of intermediate 9 with methanol furnished the desired carbamate in 96% yield. This example demonstrates the usefulness of the silver(I)-mediated process. Removal of free halide from the reaction mixture affords a long-lived cationic species that can be captured by a different nucleophile, such as solvent, the silver(I) counteranion, or an intramolecular nucleophile. This reactivity has been exploited in many different ways throughout the years and is examined in greater detail later in this chapter. 

Many radical cations derived from cyclopropane (or cyclobutane) systems undergo bond formation with nucleophiles, typically neutralizing the positive charge and generating addition products via free-radical intermediates [140, 147). In one sense, these reactions are akin to the well known nucleophilic capture of carbocations, which is the second step of nucleophilic substitution via an Sn 1 mechanism. The capture of cyclopropane radical cations has the special feature that an sp -hybridized carbon center serves as an (intramolecular) leaving group, which changes the reaction, in essence, to a second-order substitution. Whereas the SnI reaction involves two electrons and an empty p-orbital and the Sn2 reaction occurs with redistribution of four electrons, the related radical cation reaction involves three electrons. 

Carbopalladation of dienes yields 7r-allylpalladium intennediates capable of capturing nucleophiles. An example of this type of reaction in natural product synthesis is the conversion of the aryl iodide 168 into pentacycle 169. After 6-exo carbopalladation the free phenol is captured by the resultant Tr-allylpaUadium intermediate to yield aUyUc ether 169 en route to (-)-morphine 120. The domino reaction closes a srx-membered ring, forges a quaternary center, and forms a five-membered furan ring. The reaction sequence has also been effectively reversed in a construction of (+)-y-lycorane 172. Treatment of aUylic benzoate 170 with a palladium catalyst in the presence of sodium hydride triggers tt-allylpalladium formation and intramolecular amide capture. rr-Allylpalladium formation occurs with inversion, as does reaction with the pendant amide, resulting in a net retentive 1,3-transposition of stereochemical information. Subsequent addition of base and thermolysis induces 6-exo intramolecular carbopalladation to yield alkene 171. 

This reaction represents capture of the intermediate a complex as the result of intramolecular nucleophilic attack by the carboxylate group ... 

The TT-allylpalladiLim complexes formed as intermediates in the reaction of 1,3-dienes are trapped by soft carbon nucleophiles such as malonate, cyanoacctate, and malononitrile[ 177-179). The reaction of (o-iodophenyl-methyl) malonate (261) with 1,4-cyclohexadiene is terminated by the capture of malonate via Pd migration to form 262. The intramolecular reaction of 263 generates Tr-allylpalladium, which is trapped by malononitrile to give 264. o-[odophenylmalonate (265) adds to 1,4-cyciohexadiene to form a Tr-allylpalladium intermediate via elimination of H—Pd—X and its readdition, which is trapped intramolecularly with malonate to form 266)176]. 

There are also reactions in which electrophilic radicals react with relatively nucleophilic alkenes. These reactions are exemplified by a group of procedures in which a radical intermediate is formed by oxidation of readily enolizable compounds. This reaction was initially developed for /3-ketoacids,311 and the method has been extended to jS-diketones, malonic acids, and cyanoacetic acid.312 The radicals formed by the addition step are rapidly oxidized to cations, which give rise to the final product by intramolecular capture of a carboxylate group. 

A one-pot synthesis of 3,3-disubstituted indolines was achieved by taking advantage of a sequential carbopalladation of allene, nucleophile attack, intramolecular insertion of an olefm and termination with NaBPh4 (Scheme 16.6) [10]. First, a Pd(0) species reacts with iodothiophene selectively to afford ArPdl, probably because the oxidative addition step is facilitated by coordination with the adjacent sulfur atom. Second, the ArPdl adds to allene, giving a Jt-allylpalladium complex, which is captured by a 2-iodoaniline derivative to afford an isolable allylic compound. Under more severe conditions, the oxidative addition of iodide to Pd(0) followed by the insertion of an internal olefm takes place to give an alkylpalladium complex, which is transmetallated with NaBPh4 to release the product. 

The nucleophiles that are used for synthetic purposes include water, alcohols, carboxylate ions, hydroperoxides, amines, and nitriles. After the addition step is complete, the mercury is usually reductively removed by sodium borohydride. The net result is the addition of hydrogen and the nucleophile to the alkene. The regioselectivity is excellent and is in the same sense as is observed for proton-initiated additions.16 Scheme 4.1 includes examples of these reactions. Electrophilic attack by mercuric ion can affect cyclization by intramolecular capture of a nucleophilic functional group, as illustrated by entries 9-11. Inclusion of triethylboron in the reduction has been found to improve yields (entry 9).17... 

The radicals formed by the addition step are rapidly oxidized to cations, which give rise to the final product by intramolecular capture of a nucleophilic carboxylate group. 

Indenyl ethers were synthesized via intramolecular carboalkoxylation of alkynes. In this process, a benzylic ether group played a nucleophile role to capture a vinyl gold intermediate obtained by alkyne activation. The first catalytic system tested by Toste and Dube in this study was a mixture of [AuClPPh3] and AgBF4. However, the moderate yield prompted them to research the use of more electrophilic gold(I) complexes such as [AuP(p-CF3-C6H4)3]BF4, which increased the yield of cydized products by 70% [107]. 

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