Indole synthesis: Knoevenagel/Hemetsberger reaction sequence; Suzuki coupling reactions of basic nitrogen containing substrates

• Main Author: Heaner, William
• Other Authors: Liotta, Charles L.
• Format: Others
• Language: en_US
• Published: Georgia Institute of Technology 2014
• Subjects: Knoevenagel; Hemetsberger; Indole; Suzuki coupling; CO₂
• Online Access: http://hdl.handle.net/1853/52171

A series of substituted indoles have been synthesized by the sequential reaction of aromatic aldehydes with ethyl azidoacetate in the presence of sodium ethoxide to form the corresponding ethyl α-azido-β-arylacrylates (Knoevenagel process) followed by a solvent mediated thermolysis (Hemetsberger process). The isolated yields of the ethyl α-azido-β-arylacrylates were significantly increased when employing the sacrificial electrophile ethyl trifluoroacetate. 1H NMR and coupled 1H-13C NMR analysis of the ethyl α-azido-β-arylacrylates indicate that the condensation is stereospecific—only the Z-isomer could be detected. Solvent mediated thermal treatment of the meta-substituted ethyl α-azido-β-arylacrylates resulted in the formation of both the 5- and 7- substituted indoles—the 5-regioisomer being slightly favored over the 7-regioisomer. Analogous thermal treatment of (2Z, 2Z’)-diethyl 3,3’-(1,3-phenylene)bis(2-azidoacrylate) and (2Z, 2Z’)-diethyl 3,3’-(1,4-phenylene)bis(2-azidoacrylate) exclusively produced pyrroloindoles, diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate and diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate, respectively. Results are also reported which indicate that the α-azido-β-arylacrylates can be used in the subsequent Hemetsberger indolization process without prior purification. Organic substrates containing basic nitrogen centers have been problematic in achieving high yields in the Suzuki coupling process. The origin of this issue is attributed to the complexation of the basic nitrogen center with the palladium catalyst. As a consequence, the use of CO₂ at a variety of pressures was evaluated as a reversible protecting/activating reagent for basic nitrogen containing substrates. The following observations and conclusions were reached. (1) The use of small amounts of water significantly improves the rate and yield of Suzuki coupling reactions. (2) In the presence of aqueous CO₂, careful selection of the base is essential due to formation of bicarbonate and the associated decrease in the amount water. K3PO4 was found to be the most effective base in the presence of CO₂. (3) The yield of product in the Suzuki coupling of 4-amino-2-bromopyridine with phenylboronic acid was evaluated as a function of CO₂ pressure. Compared to reactions in the absence of CO₂, the yield of product increased at all pressures of CO₂ (6.8, 17, and 30.6 atm) - from 15% with no CO₂ to 73% with 30.6 atm of CO₂.