Reissert Indole Synthesis Using Continuous-Flow Hydrogenation

Abstract

A series of substituted indole-2-carboxylic acid ethyl esters and aza-indole analogs have been prepared using continuous-flow hydrogenation. The identification of some key parameters using a design of experiments (DoE)-based approach allowed efficient optimization of each synthesis. The scale-up study for the multigram preparation of one model indole substrate showed the importance of working at steady state with the H-Cube apparatus. A new useful method for the easy preparation of substituted indoles in various quantities is presented.

The expanding utility of continuous flow hydrogenation

“…The reduction of aliphatic nitro groups generally requires more forcing reducing conditions. 29 By contrast batch approaches to perform this transformation employing zinc and 5%Pd/C afforded the hydroxyindole as an undesired by-product. 35 RANEY® nickel catalysis effects the aliphatic nitro reduction of 3 at relatively mild conditions affording amine 4 in near quantitative yields (Scheme 1).…”

“…Hydrodehalogenation has been reported with the use of Pd-, Ni-and Rh-based catalyst 29,33,39,72 and whilst this provides expedient access to dehalogenated derivatives it is also particularly problematic if the halogen atom is required for subsequent synthetic manipulations. Kappe et al have developed approaches for halogen retention in the synthesis of Boscalid® (Scheme 21).…”

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

“…), the equiv. of n-butylacrylate (29), and the solvent (MeCN, 0.6 M of substrate concentration). p-Iodo or p-bromobenzonitrile (30a or 30b) were the substrates of choice.…”

“…Leave one out cross validation (LOOCV) used to evaluate model predictivity Another application that benefits from DoE concerns the use of hydrogenation flow apparatus. An early study by scientists at Abbott described the synthesis of indole-2-carboxylate and azaindole analogs by Reissert reaction-cascade hydrogenolysis under flow modality [29]. Using o-nitrophenylpyruvate (39) as the model substrate, 32 experiments (D-optimal design) were performed on a 0.42-mmol scale to screen different parameters (temperature, pressure, catalyst type, solvent, and the presence of AcOH), to identify their main effects and cross-interactions, as well as to verify the robustness of the experiments (Scheme 11).…”

Tandem catalytic oxidative deacetylation of acetoacetic esters and heteroaromatic cyclizations

“…The reaction with tert-butyl (2aminophenyl)carbamate 19 (0.12 g, 0.60 mmol) produced 20 (105 mg, 0.30 mmol) in 64% yield as pale yellow oil. Data for 20: R f = ppm; 13 C NMR δ 12.5, 14.0, 28.2, 59.7, 80.9, 109.1, 118.8, 120.0, 122.9, 123.6, 128.1, 128.3, 129.3, 135.7, 137.8, 152.5, 160.1 ppm;IR (KBr) 3411, 2981, 2935, 2902, 1738, 1693, 1610, 1527, 1481, 1453, 1378, 1287, 1237, 1163, 1030 Ethyl 6-methylpyridazine-3-carboxylate (21). The reaction with hydrazine monohydrate (0.06 mL, 0.78 mmol) produced 21 (21 mg, 0.13 mmol) in 24% yield as colorless oil.…”