Tandem oxidative cyclization, alkenes

Tandem radical addition/cydization reactions have been performed using unsaturated tertiary amines (Scheme 9.11) [14,15]. Radical attack is highly stereoselective anti with respect to the 5-alkoxy substituent of 2-(5f-J)-furanones, which act as the electron-deficient alkenes. However, the configuration of the a position of the nitrogen cannot be controlled. Likewise, tandem addition cyclization reactions occur with aromatic tertiary amines (Scheme 9.12) in this case, acetone (mild oxidant) must be added to prevent the partial reduction of the unsaturated ketone [14]. 

Tandem addition-cyclization was observed when dimethyl l-p-toluenesulfonylindol-3-ylmethylmalonate was oxidized in the presence of alkenes. 

Tandem Oxidative Cydization of 4 to Afford 8. The utility of tandem cyclizations in which both addends are alkenes was demonstrated in the synthesis of bicyclo[3.2.1]octanone 8 (29, 36, 47). Oxidation of 4 with 2 equivalents of Mn(OAc)3 and 1 equivalent of Cu(OAc)2 in acetic acid afforded 86% of 8. Oxidation of 4 generated the a-keto radical 5 that underwent 6-endo cydization to afford tertiary radical 6. 5-Exo cydization of 5-hexenyl radical 6 provided primary radical 7 as a 2 1 mixture of exo and endo isomers. Oxidation of both stereoisomers of 7 by Cu(OAc)2 yielded alkene 8 and Cu(OAc), which was reoxidized to Cu(OAc)2 by the second equivalent of Mn(OAc)3. This process is therefore catalytic in Cu(OAc)2 but consumes 2 equivalents of Mn(OAc)3. Since this reaction proceeded selectively in very high yield, our initial goal was to make this reaction catalytic in Mn(OAc)3 by either electrochemical or chemical oxidative regeneration of Mn(ni) in the reaction mixture. 

A similar type of oxidative cyclization of alkenes with both Pd and Rh is possible [75, 77, 78]. In particular, Miura showed that benzoic adds could first be oxidatively coupled with terminal alkenes, followed immediately by oxidative lactonization to give a mixture of isocoumarins and phthalides (Scheme 2.30) [75]. Because of the propensity of sp C—H bonds to undergo cyclorhodation, tandem oxidative Heck couplings have also been achieved (Scheme 2.31) [77, 78]. 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

Two other Ni(CO)4 substitutes, Ni(CO)3PPh3 and Ni(COD)2/dppe, prove to be appropriate for the catalysis of tandem metallo-ene/carbonylation reactions of allylic iodides (Scheme 7)399. This process features initial oxidative addition to the alkyl iodide, followed by a metallo-ene reaction with an appropriately substituted double or triple bond, affording an alkyl or vinyl nickel species. This organonickel species may then either alkoxycar-bonylate or carbonylate and undergo a second cyclization on the pendant alkene to give 51, which then alkoxycarbonylates. The choice of nickel catalyst and use of diene versus enyne influences whether mono- or biscyclization predominates (equations 200 and 201). 

Manganese(III)-mediated radical reactions have become a valuable method for the formation of carbon-carbon bonds over the past thirty years since the oxidative addition of acetic acid (1) to alkenes to give y-butyrolactones 6 (Scheme 1) was first reported by Heiba and Dessau [1] and Bush and Finkbeiner [2] in 1968. This method differs from most radical reactions in that it is carried out under oxidative, rather than reductive, conditions leading to more highly functionalized products from simple precursors. Mn(III)-based oxidative free-radical cyclizations have been extensively developed since they were first reported in 1984-1985 [3-5] and extended to tandem, triple and quadruple cyclizations. Since these additions and cyclizations have been exhaustively reviewed recently [6-11], this chapter will present an overview with an emphasis on the recent literature. 

The synthesis of indoles and benzofiirans by the palladium-catalysed cyclization of o-alkynyl anilines and phenols can also form part of tandem processes through interception of the -intermediate (Scheme 6.41). Inclusion of an alkene results in a Heck process, giving 3-vinylated indoles 6.129." As the 3-hydride elimination step causes reduction of the palladium(II) to palladium(O), an oxidizing agent, such as copper(n) must be included to maintain catalysis. The intermediate may also be intercepted by alkoxycarbonylation, giving an ester 6.130." Again an oxidant is needed. 

Another tandem possibility is to use oxidative addition to generate the palladium(II) species that initiates cyclization (Scheme 6.44). The result is formation of both a C-C bond and a bond between an alkene carbon and a heteroatom. The C-C bond is formed by reductive elimination that generates a palladium(O) species. This is then returned to the palladium(II) state by oxidative addition, hence no added oxidant is required. The reaction has often been used in an intramolecular fashion to ensure regioselectivity. If the nucleophilic attack is slow, a by-product may occur, which is the Heck product arising from alkene insertion. Alkynes may also be used as substrates. 

---