Synthesis of Imidazole-Based Medicinal Molecules Utilizing the van Leusen Imidazole Synthesis

Abstract

Imidazole and its derivatives are one of the most vital and universal heterocycles in medicinal chemistry. Owing to their special structural features, these compounds exhibit a widespread spectrum of significant pharmacological or biological activities, and are widely researched and applied by pharmaceutical companies for drug discovery. The van Leusen reaction based on tosylmethylisocyanides (TosMICs) is one of the most appropriate strategies to synthetize imidazole-based medicinal molecules, which has been increasingly developed on account of its advantages. In this review, we summarize the recent developments of the chemical synthesis and bioactivity of imidazole-containing medicinal small molecules, utilizing the van Leusen imidazole synthesis from 1977.

Keywords: TosMICs; imidazole; synthesis; van Leusen.

Scheme 1

General van Leusen imidazole synthesis.

Scheme 2

The first example of van Leusen imidazole synthesis.

Scheme 3

Mechanism of van Leusen imidazole synthesis.

Scheme 4

The van Leusen methodology as the key step to synthesize glycosidase inhibitor 22.

Scheme 5

Synthesis of imidazole 25 exhibiting potent binding with p38 MAP kinase.

Scheme 6

Synthesis of ketone 29 and 1,4-disubstituted imidazole 30.

Scheme 7

Synthesis of the potential significant therapeutic agent 33.

Scheme 8

High in vitro leishmanicidal activity of compound 33a.

Scheme 9

Synthesis of the fused bicyclic 37 and the fused imidazo azepine derivatives 40.

Scheme 10

Synthesis of fused triazolo imidazoles 44.

Scheme 11

Synthesis of the fused imidazole rings 48 and 50.

Scheme 12

Synthesis of fused imidazole rings 53.

Scheme 13

Synthesis of chemical probes 56.

Scheme 14

Synthesis of potential aspartyl-protease inhibitors 59.

Scheme 15

Synthesis of 1,5-disubstituted-4-methyl imidazoles 63.

Scheme 16

Synthesis of biologically enticing imidazoquinoxaline 66 and 68.

Scheme 17

Synthesis of potential IDO1 inhibitors 71.

Scheme 18

Synthesis of N-fused ImBDs 75.

Scheme 19

Synthesis of 5-HT7 receptor agonists 79.

Scheme 20

Synthesis of 5-HT7 receptor low-basicity agonists 82.

Scheme 21

A potential analgesic 82a.

Scheme 22

Synthesis of highly functionalized molecules 86.

Scheme 23

One-pot synthesis of potential IDO1 inhibitors 89.

Scheme 24

One-pot synthesis of potential IDO1 inhibitors 92.

Scheme 25

One-pot synthesis of antiplasmodial compounds 95.

Scheme 26

Synthesis of C5-substituted imidazoles 97, 98, and 99.

Scheme 27

Synthesis of polysubstituted quinoline derivatives 103.

Scheme 28

Synthesis of inhibitory activity molecules 107a and 107b.

Scheme 29

Synthesis of a novel class of potential inhibitors of microbial pathogen 110.

Scheme 30

Antimicrobial compounds 110a and 110b.

Scheme 31

Synthesis of imidazoles 112 and 114 containing the trifluoromethyl group.

Scheme 32

A possible mechanism for the synthesis of imidazole-containing trifluoromethyl group.

Scheme 33

The first example of an unusual rearrangement in the van Leusen imidazole synthesis.

Scheme 34

The base-free van Leusen imidazole synthesis of cyclic imines in water.

Scheme 35

A possible mechanism for the base-free van Leusen imidazole synthesis.

Scheme 36

Synthesis of 127 by van Leusen imidazole synthesis with two TosMIC.

Scheme 37

A plausible scenario for the van Leusen imidazole synthesis with two TosMIC molecules.

Scheme 38

DNA-compatible van Leusen imidazole heterocyclization.