Convenient Synthesis of Highly Functionalized, 3,4-Disubstituted Indole Building Blocks

Abstract

Several 3,4-disubstituted indole building blocks were synthesized, containing a one-carbon functional group at C-4 and a three-carbon chain bearing at least one functional group. A C-4 functionalized indole derivative was prepared by application of the Leimgruber-Batcho reaction. Several three-carbon chains were subsequently installed at the indole C-3 position. In the first strategy employed, a Mannich reaction was followed by the creation of a C-C bond by phosphine-induced generation of a 3-methyleneindolenine species, which was trapped by diethyl malonate. Alternatively, a Vilsmeier formylation at C-3 was followed by Knoevenagel or Wittig reactions or by treatment with ethyl diazoacetate in the presence of a Lewis acid. Direct introduction of the three-carbon chain at C-3 using a Lewis acid-catalyzed Michael reaction was also achieved. Further functionalization of the benzylic position attached to C-4 by attachment of a nitro group was carried out, but preparation of a tricyclic welwistatin fragment by intramolecular nitroalkane acylation or intramolecular Henry reactions was not possible.

Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

“…Mp 186-188 ºC. 13 92 was followed with modifications. Under argon atmosphere, dimethylamine (40% aq ) or piperidine (1-1.5 equiv) and formaldehyde (37% aq , 1-2 equiv) were stirred in glacial acetic acid (0.3-5.5 mL/mmol) for 10 min to form the iminium ion, which was the added to a solution of 5-bromo-1H-indole or compounds 2-12 (1 equiv) in glacial acetic acid (0.1-2 mL/mmol) at 0 ºC.…”