Intramolecular nucleophilic attack Subject

This system was described in one report and has been synthesized by a copper-assisted cycloisomerization of alkynyl imines. The authors proposed the following mechanism at first, 372 could undergo a base-induced propargyl-allenyl isomerization to form 373 next, coordination of copper to the terminal double bond of the allene (intermediate 374) would make it subjected to intramolecular nucleophilic attack to produce a zwitterion 375. The latter would isomerize into the more stable zwitterionic intermediate 376, which would be transformed to the thiazole 377 (Scheme 55) <2001JA2074>. 

Aryloxy derivatives 197 can be cyclized into benzofuroquinoxalines 198 in 50-70% yields on prolonged heating in PPA at 140-160°C (74JCS(P1)129). Under these conditions the more electrophilic protonated form of the substrate is subjected to an intramolecular nucleophilic attack at the carbon atom ortho to the aryloxy group. 

Intramolecular Aminocarbonylation. Aminocarbonylation is defined the same relative to amidocarbonlyation except in the case of the former, the intermediary species is an iminium ion, which is further subject to intramolecular nucleophile attack in the same manner as the JVf-acyliminium of amidocarbonyla-tion (136). 

When the alkene is treated with molecular iodine (I2), the 7C bond functions as a nucleophilic center and attacks I2 (three curved arrows), resulting in an intermediate iodoruum ion. The iodonium ion is then subject to attack by a nucleophile, such as the nucleophilic center that is tethered to the iodonium group. The resulting intramolecular nucleophilic attack (two curved arrows) generates an intermediate which then loses a proton (two curved arrows) to give the product. 

In order to craft the lactone ring, 38 was oxidized to 40 under Swem conditions in a prelude to intramolecular 1,4-addition of the hemiacetal anion [20] formed via nucleophilic attack by methoxide ion at the aldehyde site. With the availability of acetal 41, it became necessary to consider carefully whether to elaborate the epoxy lactone segment in advance of, or subsequent to, introduction of the a,p-unsaturated ester subunit. Since the latter option was considered more workable, 41 was transformed into the enol triflate and subjected to palladium(II) catalyzed methoxycarbonylation [21]. This methodology allowed for proper homologation of 42 to 43, and subsequent conversion to 44, in totally regiocontrolled fashion. 

Alkylation of the enolate of (138) with methallyliodide gave the product (149) whose stereochemistry was assigned on the basis of equilibration experiment. It was converted to the dione (150) by oxidation with osmium tetrooxide and sodiumperiodate. The aldol cyclization of (150) effected with sodium hydride and trace of t-amyl alcohol in refluxing benzene afforded the enone (151) in 88% yield. Normal protic conditions (sodium hydroxide, ethanol) were not effective in this transformation. All attempts for its conversion to aphidicolin (148) by intermolecular additions proved fruitless and therefore were turned to intramolecular methods. Molecular models show clearly that the top face of the carbonyl group is less hindered to nucleophilic attack than is the bottom face. Thus the reduction of (151) with lithium aluminium hydride afforded the alcohol (152) whose vinyl ether (153) was subjected to pyrolysis for 2 hr at 360 C in toluene solution containing a small amount of sodium t-pentoxide to obtain the aldehyde (154) in 69% yield. Reduction and then tosylation afforded the alcohol (155) and tosylate (156) respectively. Treatment of this tosylate with Collman s reagent [67] (a reaction that failed in the model system) afforded the already reported ketoacetonide (145) whose conversion to aphidicolin (148) has been described in "Fig (12)". 

In order to elucidate the mechanism of this reaction, a substrate probe was designed. Diastereomerically pure indole 140 was synthesized and subjected to the aerobic oxidative cyclization (Scheme 9.20). Annulated indole 141 was produced as a single diastereomer. The outcome of this reaction strongly suggested a mechanism involving initial palladation of the indole, followed by alkene insertion and )3-hydride elimination (an intramolecular Fujiwara-Moritani reaction). If the reaction proceeded by alkene activation followed by nucleophilic attack of the indole, then the opposite diastereomer would have been observed. This experiment confirmed that an oxidative Heck reaction pathway was operative in this aerobic indole annulation. 

Oxacyclopropane is subject to bimolecular ring opening by anionic nucleophiles. Because of the symmetry of the substrate, substimtion occurs to the same extent at either carbon. The reaction proceeds by nucleophilic attack, with the ether oxygen functioning as an intramolecular leaving group. 

Following the hint. Exercise 9-25 points out that a 2-chloroethylsulfide can undergo intramolecular Sn2 reaction to an intermediate sulfo-nium ion, which is subject to opening by external nucleophilic attack. Recognizing that the action part of cylindricine A is a 2-chloro-ethylamine substructure, we can apply the same principle here. 

Urea and its derivatives can form imines when treated with aldehydes. In the presence of [3-ketoesters, these imines are subject to nucleophilic attack followed by intramolecular imine formation. This three-component transformation is known as the Biginelli reaction [94]. The resulting products are dihydropyrimidi-nones, which are compounds of high importance in medicinal chemistry [95]. In 2006, Gong and coworkers reported the first organocatalytic Biginelli reactions. Several different aromatic aldehydes 186, ]3-ketoesters 188, and (thio)urea (187) were successfully coupled in the presence of chiral phosphoric acid catalyst 99a (Scheme 42.43). Whereas aromatic aldehydes delivered the desired Biginelli... 

Part one is conversion of the ketone into a hemiacetal. In the first step of the following mechanism, a proton transfer generates a protonated carbonyl group, which is an excellent electrophile and is subject to attack by a nucleophile. In this case, the nucleophilic attack occurs in an intramolecular fashion to give a five-membered ring. This oxonium ion then loses a proton to give the hemiacetal. 

Murakami and coworkers reported a further use for this rhodium migration [80, 81]. Instead of protonolysis, they noticed that the aryl rhodium species after the vinylic to aryl migration is nucleophilic enough to attack an ester moiety in an intramolecular fashion to afford a cyclic ketone. Thus, an internal alkyne equipped with ester groups at a specific place was subjected to the rhodium-catalyzed hydroarylation conditions (Scheme 21). Indeed, the desired ketone was obtained in an 89% yield. Not only methyl esters can serve as acylation agents ethyl esters and isopropyl esters are also suitable substrates. 

---