Intermolecular Cascade Reactions

1 Cascade Sequences Involving a [2+2+2] Approach Radical multicomponent transformations have emerged as a convenient strategy to elaborate complex architectures in a one-pot process [57], Based on the pioneering contribution from 

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Scheme 4 Inter-intermolecular cascade reactions on a steroidal substrate [28,29]...

Scheme 3-30 An intra-intermolecular cascade reaction involving a stabilized enolate.

All-intermolecular cascade reactions involving nucleophilic attack at the end are at least three-component reactions. For a successful outcome the balance of reactivities of each component in the reaction mixture toward each other must be just right. 

The prototypic substrate for intermolecular cascade reactions is norbomene or one of its analogs. Starting from an aryl halide, addition of the formed palladium species to the strained double bond of norbomene yields a norbomylpalladium derivative, which cannot undergo /3-hydride elimination but can accept hydride, for example, from piperidinium formate (Scheme 1) or potassium formate, the latter reaction occurring even at room temperature. 

Scheme 4.23 Oxazepine synthesis by copper-catalyzed intermolecular cascade reactions between O-propargylic oximes and dipolarophiles.

Nakamura, L, Kudo, Y, Terada, M. (2013). Oxazepine synthesis by copper-catalyzed intermolecular cascade reactions between O-propargylic oximes and dipolarophUes. Ange-wandte Chemie International Edition, 52, 7536-7539. 

Chiral l,3-dioxin-4-ones photochemically react intermolecular with (cyclic) ethers, acetals, and secondary alcohols to give the addition products in reasonable yields. The radical addition was completely stereoselective at C-6 of the heterocycle <1999EJO1057>. The exocyclic diastereoselectivity, where relevant, was about 2 1 (Equation 30). In analogy, an intramolecular cascade reaction of a 1,3-dioxin -one derived from menthone was used to get a terpenoid or a steroid framework in optically active form <1997JA1129, 1999JA4894>. 

Brase reported an intramolecular asymmetric Heck-intermolecular Heck cascade reaction of l,3-bis(enolnonaflates) 131 to the highly congested bicyclic compound 132 [122] (Scheme 5). Although the level of asymmetric induction is low (up to 52% ee), this result shows that the concept of two leaving groups in the desymmetrization reaction can be applied. 

As discussed in conjunction with the intermolecular cascade carbopalladation reaction shown in Scheme 4, it has been very difficult to satisfactorily control both queuing or pair -selectivity and regioselectivity of intermolecular cascade carbopalladation processes. Consequently, essentially all of the cascade carbopalladation reactions discussed here are at least partially intramolecular. The currently known cyclic cascade carbopalladation processes can be classified into a few to several types shown in Scheme 6. 

Abstract The Pauson-Khand [2 + 2 + 1 ] cycloaddition is one of the best ways to construct a cyclopentenone. It implies the formation of three new bonds and one or two cycles in the intermolecular or intramolecular versions, respectively. Furthermore some groups have enhanced the synthetic power of this transformation by combining the PKR with other processes. In addition, some unexpected results imply that successive events have occurred, usually after the cycloaddition process. This review aims to point out the most recent advances in cascade reactions in which the Pauson-Khand and PK-type... 

The carbolithiation of unactivated alkenes has also proven very successful for the synthesis of complex polycyclic systems. This has typically been achieved by reaction sequences utilizing an intramolecular carbolithiation process to generate a variety of carbocycles185 and heterocycles186. To achieve the intermolecular carbolithiation reaction required to initiate a controlled cascade reaction sequence for the generation of indole ring scaffold, Kessler and coworkers44 have expanded the synthetic utility of the styrene... 

Intermolecular Addition-Indole Cyclization Cascade Reactions... 

Indolylacyl radicals participate in a productive cascade reaction featuring an intermolecular alkene addition-indole cyclization sequence to give the cyclopenta[ >]indole... 

Some mechanistic aspects of the above cascade reaction deserve comment. Thus, after the intermolecular addition of the nucleophilic acyl radical to the alkene, the electrophilic radical adduct A, instead of undergoing reduction, reacts intramolecularly at the indole 3-position (formally a 5-endo cyclization) to give a new stabilized captodative radical B, which is oxidized to the fully aromatic system. (For a discussion of this oxidative step, see Section 1.5.)... 

The simultaneous construction of the B and C rings leading to compound 33 was accomplished by a radical cascade reaction. The mechanistic details of this cascade are summarized in Scheme 6, where the reaction of 34 with phenyl isonitrile (8) is shown [12]. First, a trimethylstan-nyl radical, derived from hexamethyldistannane, attacks the C-Br bond of 34. The resulting pyri-done radical 35 reacts intermolecularly with the isonitrile 8 to yield the radical intermediate 36. 

The vast majority of radical cascades initiated by addition of higher main group (VI)-centered radicals to alkynes focus predominantly on S-centered radicals, mainly thiyl radicals, whereas considerably fewer intermolecular addition reactions involving radicals with the unpaired electron located on selenium or even tellurium are known. 

However, their intermolecular addition reactions with alkynes are mostly aimed at synthesizing substituted aLkenes, ° and only very few cascade reactions that are initiated by P radical addition to C = C triple bonds have been reported. Renaud and coworkers developed a simple one-pot procedure for the cyclization of terminal alkynes mediated by dialkyl phosphites (Scheme 2.35). In this radical chain procedure, dialkyl phosphite radicals, (R0)2P =0, undergo addition to the C = C triple bond in 190, which triggers a radical translocation (l,5-HAT)/5-eAO cyclization cascade. The sequence is terminated by hydrogen transfer from dialkyl phosphite to the intermediate 194 and regeneration of P-centered radicals. 

Abstract Radical tandem reactions—and in a wider context radical dominos or cascades—have attracted a lot of attention because of their intrinsic elegance and the construction of a hroad and sometimes unique array of molecular architectiu es they allow in a single step. This review focuses on the latest progress in the design and development of new tandem reactions. The first part is devoted to intramolecular processes the second part covers tandem and domino processes involving both intra- and intermolecular steps. The third part introduces intermolecular-only reactions. Finally, the last part focuses on tandem reactions involving both radical and non-radical elementary steps. 

Following the pioneer work of Kharasch [60], methods involving radical transfer of halides have been developed. The atom transfer method has emerged in the 1980s as one of the best method for conducting intra- and intermolecular radical additions to olefins [61]. This approach is particularly appealing from an atom economy point of view since all atoms remains in the final product. The non-reductive nature of these reactions is also particularly important for the preparation of functionalized molecules. Halides transfers and more particularly iodine atom transfers have found nice applications for cyclizations, annula-tions and cascade reactions [62]. These reactions are based on exothermic radical steps, such as the addition of an alkyl radical to an olefin, followed by an... 

Scheme 3-32 Heterocyclization cascades triggered by palladium-catalyzed intermolecular coupling reactions [184].

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