Cascade intramolecular nucleophilic attack

A copper(I)-catalysed cascade intramolecular nucleophilic attack on A-sulfonyl-ketenimine followed rearrangement of sulfonimidates to sulfonamides results in substituted 8,9-dihydro-5/f-imidazo[l,2-a][l,4]diazepin-7(6/f)-ones (Scheme 101). " ... 

Cyclohydrocarbonylation (CHC) is the hydroformylation of a functionalized olefin followed by concomitant intramolecular nucleophillic attack to the newly formed aldehyde moiety leading to a cyclized product. As a variant, the CHC reaction also includes an intramolecular cascade process involving the hydrocarbonylation of a functional alkene, generating an acyl-metal intermediate, which undergoes an intramolecular nucleophilic attack to give the corresponding cyclic compound. CHC reactions have been developed into sophisticated cascade reactions forming bicylic and polycyclic compounds. ... 

Nitroalkene could also be activated by Lewis acids, e.g., Sc(OTf)3, Yb(OTf)3, and Zn(OTQ2 to increase its electrophilicity. According to the unpublished result in Pfaltz group, the cascade process could be facilitated by Yb(OTf)3, which furnished the cyclized product 91 in 60 % yield at 80 °C within 12 h (Scheme 36). The transformation was diastereospecific and only anti diastereomer was observed. The diastereoselectivity can be explained through Zimmer-Traxler transition state H in which the orientation of substituents would be pseudoequatorial, leading to the anti-product via intramolecular nucleophilic attack. 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

Scheme 3-54). This transformation constitutes a cascade of an intramolecular Heck insertion and subsequent heterocyclization. The initially formed arylpalladium species attacks the bridgehead position of the diene functionality in 238 to foim a JT-allylpalladium complex which is trapped by the internal nucleophilic phenol moiety (cf. Scheme 3-26). Since the starting diene 238 can be prepared in both enantiomeric forms by asymmetric reduction of a ketone, this sequence allows the preparation of both the natural morphine and its unnatural enantiomer. 

The cascade of events that leads to DNA cleavage by calicheamicin is shown in Scheme 19.4. It is initiated by attack on the central atom of the trisulfide by a nucleophile (probably glutathione), that causes the formation of a thiolate which is in a perfect position for adding intramolecularly to the Q ,p-unsaturated ketone to form 12. Now the bridgehead carbon atom is no longer sp hybridized and therefore cycloaromatization is not any more impeded by Bredt s rule. The reactivity of 12 is even higher than that of 10 and rapid formation of the diradical 13 takes place. 

Cyclic sulfites. 1,2-Diols form cyclic sulfites very readily. Although there are few important synthetic uses for these compounds, their oxidation to cyclic sulfates provides excellent substrates for nucleophilic substitutions. Tetrahydrofuran ring closure in an intramolecular attack has enormous implication for the synthesis of a family of natural products, because proper design can precipitate a cascade process. 

Domino or cascade reactions are particularly valuable for the construction of various carbo- and heterooligocyclic systems with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, inter-intra-, as well as all-intramolecular reaction cascades. In this section, such processes with a termination by attack of various nucleophiles will be described. 

Hong and Overman reported the intramolecular termination of cascade reactions by oxygen nucleophiles in their studies on a novel synthesis of morphine (Scheme Starting from an iodophenol derivative tethered with an iodophenol silyl ether, intramolecular carbopalladation provided a bicycUc Tr-allylpalladium intermediate, which in turn was attacked by the oxygen functionality (Scheme 37). 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

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