Indoles oxidative olefination

With Pd(0) generated in situ, the oxidative addition of aryl bromide 102 to Pd(0) proceeds to form Pd(II) intermediate 104. Migratory insertion of 104 then occurs to furnish the cyclized indoline intermediate 105. Subsequent reductive elimination of 105 takes place in a cis fashion, giving rise to exo-cyclic olefin 107, which then tautomerizes spontaneously to the thermodynamically more stable indole 103. The reductive elimination by-product as a palladium hydride species 106 reacts with base, regenerating Pd(0) to close the catalytic cycle. 

By using an olefin embedded into the parent molecule Stoltz developed the oxidative annulation of indoles. The optimal catalyst consisted of palladium acetate and ethyl nicotinate, and molecular oxygen was used as the oxidant in the process. The reaction proceeded equally well irrespective of the attachment point of the alkyl chain bearing the pendant olefin bond on the five membered ring, and the formation of five and six membered rings were both effective (6.95.),127... 

Many compounds will undergo dimerization reactions those containing thiols (e.g., disulfide formation) olefins, alcohols, and carboxylic acids (or other carbonyl chemistry e.g., aldol condensation reactions). Indoles have been shown to dimerize under acidic conditions. The dimerization is presumed to occur as shown in Figure 120 via protonation at C3 and nucleophilic attack of a second indole on C2. Phenols have been shown to dimerize under free radical initiated oxidative conditions, usually to ortho phenols. Nalidixic acid API undergoes dimerization under thermolysis conditions to decarboxylate and produce a dimeric structure (Fig. 121) (172). 

An intramolecular cycloaddition reaction is also a vital feature of Oppolzer s synthesis (Scheme 5).336 Here the cycloaddition reaction occurs on an unsaturated nitrone ester (39) (not isolated). Again, the aldehyde derived from oxidation of the diol (40) gave entirely the ( )-olefin on reaction with crystalline a-methoxy-carbonylethylidenetriphenylphosphorane, which allowed the synthesis of (+)-chanoclavine I (34) to be completed in an overall yield of 14% from indole-4-aldehyde. In contrast, the Horner-Emmons reaction on the aldehyde from... 

Hegedus proposed that the mechanism of this transformation proceeds through a Wacker-type reaction mechanism that is promoted by Pd(II). As shown below, coordination of the olefin to Pd(II) results in precipitate 121, which upon treatment with Et,N undergoes intramolecular trany-aminopalladation to afford intermediate 122. As expected, the nitrogen atom attack occurs in a 5-exo-trig fashion to afford 123. [l-Hydride elimination of 123 gives rise to exocyclic olefin 124, which rearranges to indole 120. The final step of this mechanism leads to the formation of catalytically inactive Pd(0). However, addition of oxidants such as benzoquinone allows for catalytic turnover. 

In 1984, Hegedus and Harrington reported a synthesis of 3- and 4-substituled indoles [77] employing Heck s well-established process Pd(O)-catalyzed functionalization of aryl halides by the oxidative addition-olefin insertion-P-hydride elimination. In this instance. 4-bromo-I-tosylindole (161, Scheme 28) was converted to several diversely functionalized 4-substituted I-tosylindoles. Selective electrophilic substitutions at the C(3) position of 161 provided access to 3-(chloromcrcurio)-l-tosylindole and 3-iodo-l-tosylindole (162), which then underwent a Heck... 

An additional application of l-exo Heck cyclization was found in Kelly s synthesis of maxonine (223), which was isolated from the root of a plant Simira maxonii endemic to the Costa Rican tropical forest. As shown in Scheme 39, the migratory insertion step of the intramolecular Heck cyclization of substrate 220 took place to both the pendant olefin and the benzene ring of the indole moiety simultaneously, giving rise to dihydropyridine 221 and seven-membered 222, respectively [104]. Oxidative cleavage of the stilbene double bond in 222 produced maxonine (223), which was identical to authentic maxonine. Kelly s synthesis of maxonine (223) revised the original structural assignment of the natural indole alkaloid. 

This methodology was used to construct several indole and benzofuran derivatives (00T7541). Oxidative insertion of Pd(0) into the aryl-I bond of 653a,b followed by carbopalladation onto the pendant olefin afforded an intermediate organopalladium... 

Stoltz et al. also reported an intramolecular reaction where C-H bond cyclization of indoles onto unactivated olefins was possible using palladium(II) and molecular oxygen as the sole stoichiometric oxidant (Scheme 41) [69]. They found the C2... 

The stereochemical outcome was in agreement with a mechanism for the palladium-catalyzed cyclization/carboalkoxylation of a substituted alkene (Scheme 47) that involves outer-sphere attack of the indole on the palladium-olefin complex I which, coupled with loss of HCI, would form the alkylpalladium intermediate II. 1,1-Migratory insertion of CO into the Pd-C bond of II with retention of stereochemistry would form the acyl-palladium complex III, which could undergo methanolysis to release c/.v-product and form a palladium(0) complex. Oxidation with Cu(II) would then regenerate the active Pd(II) catalyst. 

Makonine shares many of the characteristics of aristotelinone (60), but has one additional olefinic carbon atom, and the non-indolic nitrogen appears to be tertiary. Its structure (61) becomes clear from its formation by the oxidation of aristotelinone... 

With both hemispheres 228 and 229 in hand, treatment of the TMS derivative of 228 with s-BuLi, followed by addition of 229 resulting in acylation and subsequent in situ hetero-Peterson olefination provided 227. Parikh-Doering oxidation, selective removal of the TMS and TES groups, followed by treatment with Sc(OTf)3 in benzene provided indole 243, assembling the AF ring system and installing the complete penitrem D carbon skeleton. Selective acylation, TIPS removal, selena-tion of the resulting primary alcohol, oxidative elimination and final hydrolytic removal of the acetate furnished (-)-penitrem D (226) (Scheme 43). 

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