Intramolecular oxidative cross-coupling

Scheme 64 Intramolecular oxidative cross-coupling for medium-ring synthesis.

After realizing that our hypotheses about oxidative cross-coupling reactions were not as unique as assumed, we quickly turned our attentirai to intermolecular oxidative amination reactions. In the carbazole example, regioselectivity was coti-trolled by the presence of a Lewis base that was attached near the C—H bmid that would be cleaved, resulting in a metallacyle intermediate. For die development of an intramolecular reaction, we chose to take advantage of the selectivity that is often observed in the selective metalation of electron-rich heteroarenes. At the time, the palladation of indoles was presumed to operate by an electrophilic aromatic substitution mechanism. (This has since been demonstrated to be incorrect, vide infra.) We hypothesized that regioselective palladation of an indole substrate could be followed by a subsequent C—N bond reductive elimination. At the time, the exact mechanism by which the intermediate containing Pd—C and Pd—N bonds could be formed was not clear, nor was the order of the two metalation steps, but the overall process seemed plausible. 

Palladium(0)-catalyzed cross-coupling of aryl halides and alkenes (i.e., the Heck reaction) is widely used in organic chemistry. Oxidative Heck reactions can be achieved by forming the Pd -aryl intermediate via direct palladation of an arene C - H bond. Intramolecular reactions of this type were described in Sect. 4.1.2, but considerable effort has also been directed toward the development of intermolecular reactions. Early examples by Fu-jiwara and others used organic peroxides and related oxidants to promote catalytic turnover [182-184]. This section will highlight several recent examples that use BQ or dioxygen as the stoichiometric oxidant. 

Asymmetric induction of central chirality at a carbon atom was achieved by an intramolecular enantioposition-selective asymmetric cross-coupling [12]. Treatment of the prochiral bisbo-rane 46, which was prepared from the alkenyl triflate 45 and 2 equiv. of 9-BBN with 20 mol % of Pd/(S)-(/ )-BPPFOAc (48) catalyst generated in situ in THF, brings about intramolecular Suzuki coupling. The following oxidative workup and p-nitrobcnzoylation affords the chiral cyclopentane derivative (R)-47 in 58% yield and 28% ee (Scheme 8F.14). 

---