Domino Reactions Initiated by Nucleophilic Substitution

In the first part of the chapter, we have covered mostly those reactions, initiated by Sjj2 type nucleophibc substitution, followed by a Michael reaction on a a,P-unsaturated ketone moiety, present in the intermediate adduct (S /Michael). A few examples of the reactions with carbonyl compounds and alkyl haHdes (twofold reactions) in the second step are also included. 

Domino Reactions Concepts for Efficient Organic Synthesis, First Edition. Edited by Lutz F. Tietze. 

The third section of the chapter describes recently developed anion relay chemistry (ARC) involving threefold domino Sj -Brook rearrangement/ reactions, discovered by Tietze and extensively explored by Amos Smith 111 and his group. These reactions are also initiated by nucleophihc ring opening of epoxides, usually by silyl-substituted dithiane anions, and find useful apphcation in natural product synthesis. 

The earlier domino reactions initiated by nucleophihc substitution, mostly involve substitution on an alkyl halide or its variants by carbon- or hetero-nucleophiles (amines, alcohols, phenols, thiols, etc.) and subsequent Michael addition of regenerated carbon or hetero-nucleophiles on an enone functionahty present in the alkyl halide precursor, thus resulting in the formation of cychc, bicychc, and sometimes polycyclic compounds [2]. 

In addition to the presented Sjj/Michael transformations, a twofold domino Sn/Sn cycloalkylation of stabilized carbanions from cyclic P-ketoesters with 1,4-dibromobut-2-yne yielding annulated 2-vinyHdenehydrofurans has been reported 

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Smith and coworkers next extended Type II ARC domino protocol beyond dithiane arena by designing a variety of effective ARC linchpins with different ASGs capable of three and four component couplings. In their first effort toward this goal, they developed readily available 2-bromoallylsilane [62a], and subsequently, allyltrimethylsilane 185 [63], and recently o-TMS (trimethylsilyl) benzaldehyde 188 as promising linchpins for Type II ARC process [64, 65]. However, domino anionic relay reactions with these linchpins 185 and 188 are not discussed in this chapter, since they are not initiated by nucleophilic substitution as the first step. 

The domino reaction is initiated by the chemoselective attack of the carbanion 2-458 on the terminal ring carbon atom of epoxyhomoallyl tosylate 2-459 to give the alkoxides 2-460 after a 1,4-carbon-oxygen shift of the silyl group. The final step to give the cyclopentane derivates 2-461 is a nucleophilic substitution. In some cases, using the TBS group and primary tosylates, oxetanes are formed as byproducts. 

In general, the normal DA reaction mechanism is a domino process that is initialized by the polar reaction between the diene and the dienophile to give the primary cicloadduct. These DA reactions have a two-step non-intermediate mechanism characterized by the nucleophilic attack on the non-substituted methylene of the diene to the electrophilically activated position of the dienophile. The subsequent ring-closure affords the primary cicloadduct. This behavior makes the reaction to be regioselective. The latter concerted elimination of the nitrous acid from the primary cicloadduct yields the precursor of the final aromatic product. Spite of the large activation free energy associated with the DA reaction and the endergonic character of formation of the primary cicloadduct, the irreversible extrusion of the nitrous acid make feasible thermodynamically the domino reaction. 

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