Efficient Synthesis of Imidazoles from Aldehydes and 1,2-Diketones under Superheating Conditions by Using a Continuous Flow Microreactor System under Pressure

Abstract

A simple and efficient method for the synthesis of 2,4,5-trisubstituted imidazoles has been developed by using a continuous flow microreactor system under pressure; aryl-, alkyl-, and heteroarylsubstituted imidazoles were obtained in high yields within 2 min under superheating conditions.

Catalytic procedures for multicomponent synthesis of imidazoles: selectivity control during the competitive formation of tri- and tetrasubstituted imidazoles

“…The 2,4,5-trisubstituted imidazoles are generally synthesized by the reaction of a 1,2-diketone, α-hydroxy/acetoxy/silyloxyketone or 1,2-ketomonoxime with an aldehyde and ammonium acetate (Route A, Scheme 1) (i) in HOAc under reflux 2-4,6a,c,7,9,12,13 or under microwave/ultrasonic/classical heating in the presence or absence of catalyst 14 or under pressure using a continuous flow micro reactor under superheating conditions, 15 (ii) in the presence of Lewis acid catalysts (Route B), 16 and (iii) Ni-catalysed cyclotrimerisation (with expulsion of NH 3 ) of aromatic nitriles under pressure (60-120 psi) and high temperature (180-230 °C) hydrogenation conditions for a prolonged period (48 h) (Route C, Scheme 1). 17 The reported synthesis of 1,2,4,5-trisubstituted imidazoles involves the reaction of a 1,2-diketone, α-hydroxy/acetoxy/ silyloxyketone or 1,2-ketomonoxime, an aldehyde, an amine and ammonium acetate (Route D, Scheme 1) carried out by (i) microwave irradiation in the presence of silica gel/zeolite HY or silica gel-NaHSO 4 , 18 (ii) heating under reflux in suitable solvents or under neat condition at 140 °C in the presence of catalysts.…”

“…22 Most of these synthetic methods suffer from one or more drawbacks, such as laborious and complex work-up and purification procedure, generation of significant amounts of waste materials, strong acidic conditions, occurrence of side reactions, low yields, use of expensive and moisture sensitive reagents/catalysts, special efforts for the preparation of the starting materials, 6a,21,22 the use of auxiliary reagents, 2b,3,6a,21 and special apparatus/reactors. 15,17 These necessitate the improvement of the tried and tested methodologies for new catalytic procedure to enrich the medicinal chemists' toolbox 23 for convenient synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles, keeping in view the timely need of generating new chemical entities for newer therapeutic applications. 24 We report herein fluoroboric acid derived catalytic systems for a convenient and effective synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles following 3-MCR and 4-MCR processes, respectively, addressing the unattended issue on competitive formation of these heterocycles.…”

Novel Process Windows for Enabling, Accelerating, and Uplifting Flow Chemistry

“…A simple and efficient method for the synthesis of 2,4,5‐trisubstituted imidazoles has been developed by using a microreactor system at high temperature and pressure 113. Aryl‐, alkyl‐, and heteroaryl‐substituted imidazoles were obtained in high yields under superheating conditions within the minute time range.…”

TMSOTf-catalyzed synthesis of trisubstituted imidazoles using hexamethyldisilazane as a nitrogen source under neat and microwave irradiation conditions

“…31 Because of their versatile applications, several approaches have been developed for the chemical synthesis of imidazoles. 6,[31][32][33][34][35][36][37][38][39] The most commonly known synthetic methods are (i) the three-component condensation reaction of benzils with -aryl aldehydes, primary alcohols, and ammonium acetate (NH 4 OAc)/amines using a microwave (MW) irradiation under ionic liquid, 13 HOAc, 35,36,40,41 Fe, 42,43 Ni, 44 and Co 45 catalysis system, in the presence of acids, 6,17,36,39,46,47 urea/hydrogen peroxide (UHP), 48 organic bases, 49 carbon, 50 and transitionmetal (TM) catalysts such as TiCl 4 /SiO 2 , 4 Cu 32 and Fe/Ag nanoparticles (NPs), 51 Zr NPs, 33 La/Mn NPs, 52 Au(I) 38 and Ru(II) 53 59 (Scheme 1a) (ii) via reaction of a,b-unsaturated ketones/aldehydes and internal alkynes with amidoximes using Fe(II)-catalyzed cross-dehydrogenative coupling 60 and Cs 2 CO 3promoted annulation 61 (Scheme 1b) (iii) from a-nitro-epoxides and amidines with an excess base as promoter 62 (Scheme 1c), and (iv) from base-promoted nitrile-alkyne domino-type cyclization 63 (Scheme 1d).…”