Tandem Reactions with Oxidative Addition

Tandem cyclization/3-substitution can be achieved starting with o-(trifluoro-acetamido)phenylacetylenes. Cyclization and coupling with cycloalkenyl trif-lates can be done with Pd(PPh3)4 as the catalyst[9]. The Pd presumably cycles between the (0) and (II) oxidation levels by oxidative addition with the triflate and the reductive elimination which completes the 3-alkenylation. The N-protecting group is removed by solvolysis under the reaction conditions, 3-Aryl groups can also be introduced using aryl iodides[9]. 

Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... 

The mechanism of the catalytic cycle is outlined in Scheme 1.37 [11]. It involves the formation of a reactive 16-electron tricarbonyliron species by coordination of allyl alcohol to pentacarbonyliron and sequential loss of two carbon monoxide ligands. Oxidative addition to a Jt-allyl hydride complex with iron in the oxidation state +2, followed by reductive elimination, affords an alkene-tricarbonyliron complex. As a result of the [1, 3]-hydride shift the allyl alcohol has been converted to an enol, which is released and the catalytically active tricarbonyliron species is regenerated. This example demonstrates that oxidation and reduction steps can be merged to a one-pot procedure by transferring them into oxidative addition and reductive elimination using the transition metal as a reversible switch. Recently, this reaction has been integrated into a tandem isomerization-aldolization reaction which was applied to the synthesis of indanones and indenones [81] and for the transformation of vinylic furanoses into cydopentenones [82]. 

An exciting addition to the armoury of asymmetric phase transfer catalysed reactions has been the oxidative cyclisation of 1,5-dienes (Scheme 13) [21]. This tandem reaction process leads to the formation of tetrahydrofurans such as 35 in a single step from the open chain dienes 34. The step which determines the sense of asymmetry is the initial attack of permanganate anion, and this chiral information is efficiently relayed in the cyclisation to give products with three new stereogenic centres. For example, oxidation of the di-enone 34 with potassium permanganate, catalysed by the salt 36, gave the tetrahydrofuran 35 in 72% ee. 

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). 

Although it probably did not involve a Heck reaction per se, Balme and co-workers employed an interesting tandem reaction in their construction of A 2) capnellene (147) (Scheme 6-26) [54J. Presumably vinyl iodide 144 undergoes initial oxidative addition with the palladium(O) catalyst to furnish a cr-alkenylpalladium(n) intermediate that is complexed to the pendant alkene. Intramolecular addition of the soft malonate nucleophile to this complex, from the opposite face, followed by reductive elimination, then provides tricycle... 

With Mn(OAc)3, generated by oxidation of Mn(OAc)2 as mediator, a tandem reaction consisting of an intermolecular radical addition followed by an intramolecular electrophilic aromatic substitution can be accomplished [Eq. (21b)] [225b]. Further Mn(III)-mediated additions of 1,3-dicarbonyl compound to olefins are shown in Table 11 (numbers 8b,c, and 9a). Mediated by in situ generated Mn(III), methyl dibromoacetate, trichloro-bromomethane, perfluoroctyl iodide, dimethyl bromomalonate, and active methylene compounds have been added via radicals to olefins [225d]. 

The a-hydrogens of nitroalkanes are appreciably acidic due to resonance stabilization of the anion [CH3NO2, 10.2 CH3CH2NO2, 8.5]. The anions derived from nitroalkanes give typical nucleophilic addition reactions with aldehydes (the Henry-Nef tandem reaction). Note that the nitro group can be changed directly to a carbonyl group via the Nef reaction (acidic conditions). Under basic conditions, salts of secondary nitro compounds are converted into ketones by the pyridine-HMPA complex of molybdenum (VI) peroxide. Nitronates from primary nitro compounds yield carboxylic acids since the initially formed aldehyde is rapidly oxidized under the reaction conditions. 

Crafts reactions, and oxidizing reagents like chlorine do not destroy this protection. The regeneration of the carbonyl functions has to be carried out with concentrated aqueous alkali and proceeds as a tandem hetero Michael addition/retro aldol reaction (Scheme 87). Although these drastic conditions set a limit to the general application of this protecting group, it has successfully been used in porphyrine total syn-theses. ... 

A tandem Kornblum ox/daf/on/imidazole formation reaction was used during the preparation of new fluorescent nucleotides by B. Fischer and co-workers.The adenosine monophosphate free acid was mixed with 10 equivalents of 2-bromo-(p-nitro)-acetophenone and dissolved in DMSO. The required pH value was maintained with the addition of DBU which also served as a base. The Kornblum oxidation of the alkyl halide yielded the glyoxal, which reacted in situ with the aromatic amine to form the desired imidazole derivative. 

Neat reactions of liquid substrates can be quite successful. For example, the addition of P(0)-H bonds to alkenes has been accomplished using microwave irradiation in the absence of added solvent or catalyst (Scheme 25.4b). Tandem hydrophosphinylation reactions with alkynes afforded unsymmetrical species such as phosphine oxide—phosphinates. 

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. 

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