Tandem radical reactions

Radical reactions used in synthesis include additions to double bonds, ring closure, and atom transfer reactions. Several sequences of tandem reactions have been developed that can close a series of rings, followed by introduction of a substituent. Allylic stannanes are prominent in reactions of this type. 

Keywords Catalysis Cyclizations Electron transfer Radicals Tandem reactions... 

A very attractive feature of radical chemistry is the generation of a novel radical after cyclization or any other radical translocation. This feature allows the inclusion of a second carbon—carbon bond-forming event and can, in principle, be extended even further. The resulting tandem reactions [38] can be extremely useful for the construction of complex molecules. Impressive early results have been reported by Stork in applications directed towards the synthesis of prostaglandins [39]. Our catalytic conditions also allow the realization of tandem reactions. An example including a mechanistic proposal is shown in Scheme 12.20. 

Scheme 12.20. Titanocene-catalyzed radical tandem reactions.

The key features of the catalytic cycle are trapping of the radical generated after cycliza-tion by an a,P-unsaturated carbonyl compound, reduction of the enol radical to give an enolate, and subsequent protonation of the titanocene alkoxide and enolate. The diaster-eoselectivity observed is essentially the same as that achieved in the simple cyclization reaction. An important point is that the tandem reactions can be carried out with alkynes as radical acceptors. The trapping of the formed vinyl radical with unsaturated carbonyl compounds occurs with very high stereoselectivity, as shown in Scheme 12.21. 

Thus, our radical tandem reactions offer highly stereoselective access to tri- and tetrasubstituted alkenes that are otherwise difficult to prepare. 

With type iii-e reactions compounds (71) are formed. A radical tandem reaction initiated by the Kolbe electrolysis of (88) gave tricyclic compounds (89) in a one pot reaction (Scheme 32) [111]. The electrochemical decarboxylation avoids the usually applied toxic tin hydride as reagent and... 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The group of activated olefins, which has so far probably received most attention in radical cyclizations, are enamides. Syntheses of various natural products, especially alkaloids, have been successfully completed using this strategy. Cyclizations onto enamides of the 6-endo type led to erysotrine [76] and lycorine alkaloids [77-79]. The skeleton of hydroapoerysopines [80] was successfully constructed by a 1-endo cyclization. Two new examples of radical tandem reactions, which commence with a 1-endo type cyclization, have appeared in recent literature. Construction of the cephalotaxine core structure 29 was achieved from enamide 30 in only one step (Scheme 11) [81]. 

Meerwein type arylations involving radical additions to carbon-heteroatom multiple bonds such as in isothiocyanates have been further extended to tandem reactions leading to heterocycles [117, 118]. 

Fig. 52 Tandem oxidative radical addition/transannular radical cyclization reactions...

Fig. 60 Cobalt-catalyzed tandem reactions involving radical cyclizations...

Radical Additions and Tandem Reactions with Radical Additions as the Initial Step... 

More recently, van der Donk and coworkers reported radical cyclizations catalyzed by vitamin B12 using titanium(III) citrate as a stoichiometric reducing agent (Fig. 69, entry 17) [330]. Here /V-allylic 2-(isopropenyl) pyrroles 290 or allyl 2-phenylallyl ethers serve as the starting material in tandem hydrocobaltation/ radical 5-exo cyclization sequences giving dihydropyrrolizine derivatives 291 or 292. The mechanistic course is not completely clear. However, it is assumed that the reactions start with an initial hydrocobaltation of the isopropenyl unit in the presence of the allylic alkene (see Sect. 5.7). The benzylic cobalt intermediate is subject to homolysis of the very weak cobalt-carbon bond and initiates the radical 5-exo cyclization. Interestingly, the fate of the cyclized radical is dependent on the... 

R2= Me, TMS(CH2)2, p-Tol, 4-N02C6H4, 4-MeOC6H4, 4-CI-C6H4 Fig. 79 Cu(II)-catalyzed tandem amidocupration/radical cyclization reactions... 

The templates can be simply coordinated rather than attached. For example, complex 100 directed the radical relay chlorination to C-9, although the process was not as clean as with the attached templates [173]. We also used template-directed chlorina-tions to determine the conformations of flexible chains, just as we had previously with the benzophenone probes [174]. Also, by use of a set of tandem free radical chain reactions we could direct the formation of carbon-bromine and carbon-sulfur bonds, again with geometric control by the attached template [175]. 

Tandem reactions may also occur by initial allylic hydrogen abstraction (with 1,5-hydrogen transfer) by a vinylic radical, followed by a cyclization process. This methodology has been used to synthesize bicyclic and tricyclic systems (equations 135 and 136)778,793,807-809. Electron-withdrawing groups conjugated to the vinylic halide increase the yields and decrease reaction times considerably. 

The formation of ring systems by the anionic cyclization of olefinic alkyl, aryl and vinyl-lithiums is an interesting synthetic transformation that provides a regiospecific and highly stereoselective route to five-membered carbocycles and heterocycles99. Most importantly, it is possible to functionalize the initially formed cyclization product by a tandem reaction with electrophiles, a reaction that is not generally possible in the case of radical cyclizations. 

The great majority of radical cascades involve sequences of intramolecular steps where the overall propagation is a unimolecular process (with the exclusion of the initiation and termination steps), and recent overviews are given in Refs 1-5. However, meanwhile many tandem reactions involving both intra- and intermolecular steps, as well as multicomponent tandem reactions, have been reported in the literature, which are compiled in recent reviews. " ... 

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. 

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 broad and sometimes unique array of molecular architectures they allow. Contrary to a long-standing idea, efficiency and selectivity requirements can also be met. A good illustration is the one-pot assembly of hnear triquinane 2 from acychc precursor 1 (Scheme 1) [1]. In this ten-elementary radical step process, five C - C bonds are created as well as three quaternary centers and four stereogenic centers, almost all completely controlled. 

Scheme 11 Tandem reactions with aminyl radicals...

Tandem Reactions Involving Radicals and Other Intermediates... 

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