Intramolecular oxidative direct

The formation of several 2-aminobenzothiazoles via palladium-catalyzed, direct intramolecular oxidative C-H functionalization was recently demonstrated by Batey at the University of Toronto. The substrates used were A -aryl thioureas which in the presence of an interesting co-catalytic Pd(PPh3)4/Mn02 system under oxygen atmosphere, yielded the desired products. In terms of the mechanism, this transformation proceeded presumably through electrophilic palladation, suggested by the higher reactivity of the more electron-deficient substrates. 

These results may easily be rationalized by assuming that the formation of hydroxy sulphoxides 91, 92 and 93 from hydroperoxysulphides 89 and 90 is an intramolecular oxidation-reduction reaction proceeding through a five-membered transition state 94. However, an alternative intermolecular mechanism in which the approach of the oxidant is directed by the hydroperoxy or the hydroxy function in the reductant cannot be excluded. 

Another elegant use of nonadienoate is the synthesis of a pheromone called brevicomin (148) (132). The ester was converted to 1,6-nonadiene (149). The terminal double bond was selectively converted to glycol via epoxide. The oxidation with PdCI2 produced brevicomin directly by intramolecular oxidative acetal formation. 

Palladium-catalyzed directed intramolecular activations of aryl C-H bonds have been reported, as in the phenyla-tion of heterocycle analogs. Palladacycles are proposed intermediates, acting as effective catalysts, and the mechanism is likely to proceed via oxidation of Pd(ll) to Pd(iv) by the iodonium salt, as for the Equation (57), which described the activation of benzylic i/-CH bonds (Equations (121)—(123).109... 

The electron impact mass spectra of 3-methyl-4-nitro-5-styryl-isoxazoles exhibit, on the contrary, only negligible loss of OH"80. This has been interpreted in terms of an isoxazole-to-azirine rearrangement80. The latter fragments directly to an abundant cinnamoyl ion as well as rearranges to oxazole and an epoxide through an intramolecular oxidation of the ethylenic bond by the nitro group80 see Scheme 10. 

Redox reactions usually lead, however, to a marked change in the species, as reactions 4-6 indicate. Important reactions involve the oxidation of organic and metalloprotein substrates (reactions 5 and 6) by oxidizing complex ions. Here the substrate often has ligand properties, and the first step in the overall process appears to be complex formation between the metal and substrate species. Redox reactions will often then be phenomenologically associated with substitution. After complex formation, the redox reaction can occur in a variety of ways, of which a direct intramolecular electron transfer within the adduct is the most obvious. 

Two separate but somewhat interwoven themes have emerged from the study of inner-sphere reactions. The first is the use of product and rate studies to establish the existence of inner-sphere pathways and then the exploitation of appropriate systems to demonstrate such special features as remote attack . In the second theme the goal has been to assemble the reactants through a chemical bridge and then to study intramolecular electron transfer directly following oxidation or reduction of the resulting dimer (note equation 7). It is convenient to turn first to chemically prepared, intramolecular systems since many of the theoretical ideas and experimental results for outer-sphere reactions can be carried over directly as an initial basis for understanding the experimental observations. 

This rate law places two molecules of HBr in the transition state along with one molecule of Mn(III). This information was used to argue for HBr2" as a key intermediate and against the thermodynamically more energetic Br. Intramolecular oxidation of one of the two coordinated bromide ions followed by direct elimination of HBr2 appears to provide a convenient mechanism for one-electron oxidation of bromide by Mn(ffl). This is followed by rapid reduction of an additional equivalent of Mn(III) by HBr/ ... 

A radical cation is involved in the direct synthesis of chromans by an intramolecular oxidative cyclisation of 3-arylpropanols 32 brought about by a hypervalent iodine(III) reagent <04TL2293> and iodonium species catalyse the intramolecular arylation of alkenes which yields iodo-substituted chromans 33 <04JA3416>. 3-Allenylchroman-4-ols result from a one-pot reaction between salicylaldehydes and 1,4-dibromobut-2-yne in which the intramolecular cyclisation of the intermediate ether is mediated by In metal <04SL45>... 

Undeterred by this first Wessely oxidation obstacle, we set out to modify our design and give the dearomatization step the best opportunity to succeed. We postulated that an intramolecular Wessely oxidatirai approach would have a better chance of directing the oxidant to the desired site for dearomatization. The results of our investigations are presented in Scheme 4. We used the aldol addition product from the previous route (10) and instead of forming a cyclic ketal we developed a mild method to gently form the requisite ori/io-quinone methide, which we trapped in situ with ethyl vinyl ether to provide 11. Deprotection of the acetal and oxidation then afforded lactone 12, which served as precursor to the acetic acid tether (13) we needed for the dearomatization... 

In addition to the several reports of intermolecular Fujiwara-Moritani reactions, there have been a nnmber of examples of intramolecular reactions, both stoichiometric and catalytic in palladinm. In considering an intramolecular oxidative Heck reaction, one can again draw a direct analogy to the classical Heck reaction (Figure 9.3). In the standard Heck reaction, a halogenated arene nndergoes an oxidative addition by palladium(0), followed by alkene insertion and jS-hydride elimination. In an oxidative version, a C—H bond of... 

The mechanism of the direct intramolecular Buchwald-Hartwig indole synthesis is that of a traditional palladium-catalyzed cross-coupling reaction and begins with loss of a ligand on palladium. Oxidative addition of an appropriately substituted Z-vinylhaloarene (1) generates intermediate 2. Deprotonation of 2 and displacement of a halide ligand sets up a reductive elimination on 3 to yield indole 4. 

Arene oxidation leading to direct C—C bond formation allows rapid assembly of complex and ste-reochemically rich carbocyclic ring systems. Crucial to the success of this approach is the identification of carbon nucleophiles that are stable in the presence of oxidation agents typically used to effect arene dearomatization. Enolates and enol ethers are problematic as these species undergo rapid oxidation under mild conditions [62]. Stabilized enolates (such as those derived from activated methylenes) exhibit greater compatibility with oxidation conditions and have been used as nucleophilic participants in intramolecular oxidative dearomatizations initiated by [Fe(CN)g] and PIDA to afford spirocyclic cyclohexadienones [63, 64]. Detailed mechanisms for these reactions have not been defined so it is unclear whether bond formation occurs through ionic or radical intermediates. 

Palladium-catalyzed Direct Arylation of Indoles and Thiophenes. Five-membered ring heterocycles possessing only one heteroatom and no Af-oxide function can also be arylated using palladium(II) complexes, a phosphine ligand, and an inorganic base. In one example, a tandem palladium-catalyzed Heck coupling reaction and direct intramolecular C2 arylation reaction on a )V-(2-chlorobenzyl)-5-bromoindole was reported (eq 30). The procedure, which is catalyzed by palladium acetate, uses tn-tert-butylphosphonium tetrafluoroborate as a ligand and ferf-butyl acrylate as the alkene for the Heck reaction (eq 30). ... 

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