Intramolecular Cascade Reactions

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>. 

An intramolecular cascade reaction initiated by the addition of an alkenyl radical to a furan was used to synthesize an indene <1998SL1215>. As illustrated in Scheme 31, radical fragmentation in the spiro-dihydrofuran radical 52 provided the intermediate triene 53, which underwent Cope-type rearrangement to form the product. A related reaction with 1-bromocyclohexene that led to unsaturated ketone product was also developed <2003EJ01729>. 

However, oxidations based on addition of O-centered radicals to unsaturated compounds appear to be a highly desirable synthetic goal, especially when the new C—O bond could be formed under the mild conditions that are typical for radical reactions. If this radical addition would involve C = C triple bonds, the resulting reactive vinyl radical would be highly suitable for the promotion of intramolecular cascade reactions. 

Purely intramolecular cascade reactions using triple bonds as a kind of relay station are well known (Schemes 3-10, 3-16, 3-20, 3-21, 3-22, and 3-24). An inter-intramolecular variant was developed as an elegant access route to calcitriol (60) (Scheme 3-18) [170]. 

Scheme 3-29 An intra-intramolecular cascade reaction leading to heterobicycles [181bj.

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

All-intramolecular cascade reactions provide an access to various ring systems with at least two newly formed rings. Stereoelectronic effects exerted by the metal and its ligands are remarkably high, and a vast number of accessible oligocyclic structures can be conceived. Interestingly, compared wiih a number of known examples for cascade... 

Early findings by Heck et al. [149a, 337] revealed that coupling reactions of haloalkenes 126 with aUcenes 125 in the presence of secondary amines gave allylamines (Scheme 8.30 132/133 Nu = NR2). On the basis of this observation, inter-intermolecular as well as intra-intramolecular cascade reactions (Scheme 8.34) [338], the latter ones leading to a variety of bicycles (Scheme 8.35) [339], were developed. 

With this new methodology in hands, Hu et al. [166] explored the trapping of the 1,4-addition intermediate with a different electrophile for the development of a new MCR. RhjCOAc) was again the most active catalyst in the 1,4-addition/aldol-type intramolecular cascade reaction. Under the optimized reaction conditions, this three-component reaction worked well with a broad family of bifunctional substrates 135 bearing different substituents on the aryl group next to the enone moiety and a variety of alcohols 136 (Scheme 3.63). In all cases, 1-indanols 137 were obtained in 60-83% yield and with complete diastereoselectivity. Enantiopure 1-indanol was obtained employing a L-menthol-derived diazo compound. The intermolecular four-component version was also attempted, but the formation of the desired product was not observed. 

SCHEME 3.63 Synthesis of indanols by 1,4-addition/aldol-type intramolecular cascade reaction. 

In 2008, Okano et al. developed an efficient route to fused bicycles 315 from bro-moalkenes 314 using a similar canbopalladation and intramolecular jr-allylpalladium trapping strategy [109] (Scheme 6.82). The yield of this intramolecular cascade reaction is from moderate to good, and various types of fused rings can be provided efficiently. 

Tosylates were recently added to the family of viable migrating groups for such reactions. Gonzalez and co-workers were able to engage these substrates in different inter- and intramolecular cascade reactions, thereby expanding the scope of both NHC-Au catalysts and propargyl-activated alkynes. ... 

The arylation and vinylation of intemd alkynes has not been developed as much as the reactions of alkenes and 1-alkynes. An example of this type of reaction is depicted in equation 28 (78), The alkenylpalladium complexes formed from the reaction of Pd and internal alkynes are usually stable. Internal alkynes have been vinylated by intramolecular cascade reactions. In these reactions the product of insertion into an alkyne bond is able to subsequently insert into an alkene bond. Elimination from this complex gives the final reaction product. Equations 29 (82) and 30 (82) provide examples of this type of reaction. 

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