Cascade reactions nucleophilic termination

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. 

A cascade Heck reaction with termination by nucleophiles is considered to start with an oxidative addition of a heteroatom-carbon bond (starter) onto a palladium(O) species (startup reaction), followed by carbopalladation of a nonaromatic carbon-carbon double or triple bond without subsequent dehydropalladation (relay), a second and possibly further carbopalladation of a carbon-carbon double or triple bond (second etc. relay). The terminating step is a displacement of the palladium residue by an appropriate nucleophile. It is crucial for a successful cascade carbopalladation that no premature dehydropalladation takes place, and that can be prevented by using alkynes and 1,1-disubstituted alkenes (or certain cycloalkenes) as relay stations since they give kinetically stable alkenyl- or neopentylpalladium intermediates, respectively. In addition, reaction of haloalkenes with alkenes in certain cases may form rr-allyl complexes, which are then trapped by various nucleophiles. 

Intramolecular termination by carbon nucleophiles has been achieved with dialkyl malonate moieties. These cascade reactions, developed essentially by Balme, Gore, and colleagues, open an avenue especially to variously substituted methylenecyclopentane derivatives (Scheme 19,and Sect. V.3.4). 

Termination by external nitrogen nucleophiles has been investigated for various systems (cf. Ref. [53]). AUenes, which are excellent relays for cascade reactions, give rise to the formation of Tr-aUylpaUadium complexes. The latter can be reacted in a straightforward manner with amines to yield highly functionalized allylamines (Scheme 30, Eqs. 1 and... 

Intra-intramolecular cascade reactions combined with termination by an external nucleophile provide access to various kinds of ring systems. 

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). 

The Pd(OAc)2/dppb-catalyzed cascade reaction of o-iodophenol with 1,2-nonadiene and CO starts with a CO insertion which is followed by carbopalladation of the allene and subsequently terminated by an intramolecular nucleophilic substitution to afford O-con-taining six-membered a-methylenebenzo-y-dihydropyrones (Scheme 34). ... 

Synthesis of chiral heterocycles by domino organocatalytic processes has also been intensively studied. In particular, various benzo-fused heterocycles, such as chiral chromans, " thiochromanes, hydro-quinolines, dihydropyranes, or thiopyranes were investigated. These organocatalytic sequence were typically initiated by a hetero-Michael addition of a sulfur, oiqrgen or nitrogen nucleophile, which triggers the formation of an enolate/enamine that adds to the ortho electrophile terminating the cascade reaction. An elimination step or an additional cyclisation step follows (Scheme 8.25). 

Intramolecular Heck reactions leading to carbocycles involving domino, tandem, or cascade reactions terminated with tethered alkenes and other nucleophiles will be covered in Sect. IV.3.1 and V.3.2, respectively. 

A three-component reaction for the synthesis of functionalized benzimidazoles from terminal alkynes, o-aminoanilines, and / -tolylsulfonyl azide is developed by Wang and coworkers (Scheme 8.52). The C(sp)-H bond of alkyne was activated in this reaction via Cul-catalyzed azide-alkyne cycloaddtion (CuAAC) reaction which could lead to the formation of a ketenimine intermediate by the release of N2- The benzimidazoles could be obtained by intramolecular nucleophilic addition and subsequent elimination of amide intermediate with 2% H2SO4 under reflux conditions [91]. They also developed another protocol for the synthesis of substituted benzimidazole derivatives via a sequential three-component cascade reaction from sulfonyl azides, alkynes, and 2-bromoanilines using Cul as catalyst. Similarly, the C-H bond of alkyne was activated at the process of copper-catalyzed azide-alkyne cycloaddtion (CuAAC) reaction [92]. 

SCHEME 5.57 Cu(I)-catalyzed three-component cascade reaction of sulfonyl azides, terminal alkynes, and nucleophiles. 

Further development of termination strategies has led to the use of allenes, which trap the organopalladium intermediate to give 7r-allylic complex. The latter undergoes facile reactions with nucleophiles. The overall process becomes a pentamolecular cascade (Scheme 17). 

Terpene synthases, also known as terpene cyclases because most of their products are cyclic, utilize a carbocationic reaction mechanism very similar to that employed by the prenyltransferases. Numerous experiments with inhibitors, substrate analogues and chemical model systems (Croteau, 1987 Cane, 1990, 1998) have revealed that the reaction usually begins with the divalent metal ion-assisted cleavage of the diphosphate moiety (Fig. 5.6). The resulting allylic carbocation may then cyclize by addition of the resonance-stabilized cationic centre to one of the other carbon-carbon double bonds in the substrate. The cyclization is followed by a series of rearrangements that may include hydride shifts, alkyl shifts, deprotonation, reprotonation and additional cyclizations, all mediated through enzyme-bound carbocationic intermed iates. The reaction cascade terminates by deprotonation of the cation to an olefin or capture by a nucleophile, such as water. Since the native substrates of terpene synthases are all configured with trans (E) double bonds, they are unable to cyclize directly to many of the carbon skeletons found in nature. In such cases, the cyclization process is preceded by isomerization of the initial carbocation to an intermediate capable of cyclization. 

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