An efficient route to natural occurring methyl 6-bromoindolyl-3-acetate 1c from methyl indolyl-3-acetate 3 was achieved in 3 steps and 68% overall yield. Thus, in order to regioselectively brominate 3 at the C6-position, introduction of electron withdrawing substituents at N1 and C8 was affected to give intermediate 4 in 82% yield. Bromination of 4 with 8 equiv of bromine in CCl4 and washings with aqueous Na2SO3 gave 5 in 86% yield, which was N- and C-decarbomethoxylated by treatment with NaCN in DMSO, affording 1c in 97% yield. The regioselectivity of bromination was evidenced by NMR spectroscopy and X-ray diffraction analysis.
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9.
Although Mulliken charges for C4 (-0.196), C5 (-0.139), C6 (-0.149) and C7 (-0.148), derived from DFT calculations at the B3LYP/6-31G(d) level of theory using the SPARTAN04 program, predict that bromination of 4 could also occur at C4, such a process is hindered by the malonate group at C3.
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