Continuous Flow Synthesis of Heterocycles: A Recent Update on the Flow Synthesis of Indoles

Abstract

Indole derivatives are among the most useful and interesting heterocycles employed in drug discovery and medicinal chemistry. In addition, flow chemistry and flow technology are changing the synthetic paradigm in the field of modern synthesis. In this review, the role of flow technology in the preparation of indole derivatives is showcased. Selected examples have been described with the aim to provide readers with an overview on the tactics and technologies used for targeting indole scaffolds.

Keywords: flow chemistry; indoles; organic synthesis.

Scheme 1

Selected examples of indole-containing biologically active compounds.

Scheme 2

Key steps of the proposed mechanism for the Fischer indolization: (a) N-arylhydrazone generation, (b) enamine formation, (c) [3,3]-sigmatropic rearrangement, (d) re-aromatization, (e) cyclization, (f) indole formation.

Scheme 3

CF-MAOS approach applied to Fischer indole synthesis: (a) first example proposed by Bagley; (b) nonresonant microwave system for continuous flow synthesis developed by Larhed; (c) bench-top single-mode microwave setup presented by Akai.

Scheme 4

Fischer indole synthesis of 7-ET under microwave-assisted continuous flow conditions.

Scheme 5

FC-MAOS setup for the preparation of tryptophol.

Scheme 6

Continuous flow Fischer indole synthesis under high-temperature/pressure conditions.

Scheme 7

Three different approaches for the continuous flow Fischer synthesis of a series of indoles: (a) initial low-productivity set-up; (b,c) modified versions of the system enabling lower back-pressure and higher productivity.

Scheme 8

Multistep continuous flow synthesis of various indolylthiazoles.

Scheme 9

CF synthesis of 7-ET using conventional heating.

Scheme 10

Amberlite IR 120 H-catalyzed continuous flow Fischer indole synthesis of pyrido[2,3-a]carbazoles.

Scheme 11

A continuous-flow Fischer indole synthesis of 3-methylindole in an ionic liquid.

Scheme 12

Hemetsberger-Knittel reaction.

Scheme 13

Hemetsberger–Knittel synthesis under continuous flow conditions.

Scheme 14

Preparation of a series of indoles by Hemetsberger–Knittel synthesis under different conditions.

Scheme 15

Reissert indole synthesis.

Scheme 16

Intensification of the second step of Reissert indole synthesis under CF.

Scheme 17

CF reductive cyclization of o-nitrobenzylcarbonyl en route to indole derivatives of general formula 43.

Scheme 18

Reductive cyclization of o-nitrostyrenes.

Scheme 19

CF reductive cyclization of o-vinylnitrobenzenes using CO as a stoichiometric reductant.

Scheme 20

Reductive cyclization of o-nitrophenylacetonitriles.

Scheme 21

CF synthesis of indole-3-carboxylic ester by reductive cyclization and its derivatization to an auxin mimic.

Scheme 22

CF intensification of three-step Heumann indole synthesis: (a) alkylation of aniline 50; (b) saponification; (c) Heumann cyclization.

Scheme 23

CF synthesis of highly substituted indoles by photochemical benzanullation.

Scheme 24

CF preparation of tricyclo-1,4-benzoxazines library via metal-free visible-light photoredox catalysis.

Scheme 25

CF C-2 acylation of indoles via dual photoredox/palladium catalysis at room temperature.

Scheme 26

CF N-methylation of indole derivatives.

Scheme 27

CF automated multi-step generation of 3-hydroxymethylindoles and their conversion to 77 and 78 via acid-catalyzed nucleophilic substitution.

Scheme 28

Sc(OTf)₃ catalyzed continuous flow synthesis of BIM_S 81.

Scheme 29

NCS-mediated oxidative conversion of sulfonyl indoles 82 into 3-alkylidene-2-oxindoles 83 under CF conditions.

Scheme 30

(a) CF preparation of 3-alkylated indoles by the reduction of sulfonyl indoles and (b) integrate flow setup for the synthesis of 3-alkylindoles directly from their remote precursor’ indoles and aldehydes.

Scheme 31

CF Friedel–Crafts alkylations of N-methylindole with β,γ-unsaturated α-ketoesters catalyzed by a metal-organic framework (copyright of Reference [7]).

Scheme 32

(a) Batch and (b) flow synthesis of dicarbonyl indoles via I₂/DMSO-mediated oxidative coupling.

Scheme 33

CF tandem, bicatalytic cyclopropanation-ring-opening cyclization.