Cascade intermolecular addition-intramolecular

The gold-catalysed cascade intermolecular addition-intramolecular carbocyclization reaction of dialkynylbenzenes has been reported to occur with regioselective addition of... 

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... 

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.)... 

In contrast to intramolecular cyclizations, the intermolecular addition of O-centered radicals to ti systems as initiating step in complex radical cyclization cascades has only recently attracted considerable attention. The reason for the low number of papers published on O radical addition to alkenes and alkynes could originate from the perception that O-centered radicals, such as alkoxyl radicals, RO, or acyloxyl radicals, RC(0)0", may not react with 7t systems through addition at rates that are competitive to other pathways, for example, allylic hydrogen abstraction and p-fragmentation in the case of RO" or decarboxylation in the case of RC(0)0" (Scheme 2.9). 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Zard also used a xanthate-mediated radical cascade sequence to synthesize indolines from vinyl sulfanilides in three steps [54]. The initial peroxide-initiated intermolecular addition of the xanthate to the vinyl sulfanilide was followed by an intramolecular cyclization onto the ortho position of the aromatic ring. Further heating with DBU generated the dihydroindole through a base-induced isomerization of the olefinic bond followed by conjugate addition. 

When the nucleophilic and the electrophilic positions of the reagent confronted to the aryne are not c-bonded, a cascade intermolecular nucleophilic addition-intramolecular electrophilic cycUzation of arynes can take place. The fragmentation step, which is cmcial for the insertion reaction of arynes into a-bonds, is not involved in annulation processes because the intermediate obtained from the cyclization is usually a stable five- or six-membered ring system. 

In addition to intermolecular reactions, intramolecular variants have been developed. In 1992, Negishi et al. reported the Pd(PPh3)4/AcOH-catalyzed intramolecular [2 -I- 2 -I- 2] cycloaddition of triyne 12 (Scheme 6.4) [9]. In this reaction, cascade-type cycloaddition via generation of Pd—H species from palladium and acetic acid proceeded to afford fused benzene 13 in good yield. The reaction of endiyne 14 bearing an alkenyl bromide moiety in the presence of EtsN also afforded the same product, 13, presumably through a similar mechanism (Scheme 6.4). 

In each of the tandem iminium ion/enamine cascade processes described above, the enamine is trapped in an intramolecular fashion. The ability to perform the trapping seQuence in an intermolecular manner would allow for the one—pot introduction of three points of diversity. IVIacNlillan has realised this goal and described a series of secondary amine catalysed conjugate addition—enamine trapping sequences with oc P Unsaturated aldehydes using tryptophan derived imidazolidinone 115 to give the products in near perfect enantiomeric excess (Scheme 47) [178]. 

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>. 

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

An experimental and computational study describing a cascade transformation that breaks all three C-C bonds in a polarized alkyne moiety has been reported (Scheme 5)." Facile intermolecular Michael addition is followed by the relatively slow intramolecular steps. The slowest step corresponds to the 5-exo trig closure at the carbonyl-substituted alkene. This process is facilitated by the coupling of the intramolecular Michael addition with a concerted proton transfer along a resonance-assisted hydrogen bond path, which avoids the formation of an unfavourable zwitterionic intermediate. 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

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. 

Design of Enomine-Cyclization Cascade Reactions The nucleophilic Y in intermediate 6 can react with other electrophiles intermolecularly (Scheme 1.34a) or intramolecularly (Scheme 1.34b) as well as with the iminium ion. Moreover, the carbonyl group of 6 can also undergo intramolecular aldol reaction with nucleophilic X (Scheme 1.34c). These nucleophilic addition reactions after enamine catalysis induce cyclization reactions to produce versatile five- or six-membered ring structures. 

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