Novel Synthetic Routes to Prepare Biologically Active Quinoxalines and Their Derivatives: A Synthetic Review for the Last Two Decades

Abstract

Quinoxalines, a class of N-heterocyclic compounds, are important biological agents, and a significant amount of research activity has been directed towards this class. They have several prominent pharmacological effects like antifungal, antibacterial, antiviral, and antimicrobial. Quinoxaline derivatives have diverse therapeutic uses and have become the crucial component in drugs used to treat cancerous cells, AIDS, plant viruses, schizophrenia, certifying them a great future in medicinal chemistry. Due to the current pandemic situation caused by SARS-COVID 19, it has become essential to synthesize drugs to combat deadly pathogens (bacteria, fungi, viruses) for now and near future. Since quinoxalines is an essential moiety to treat infectious diseases, numerous synthetic routes have been developed by researchers, with a prime focus on green chemistry and cost-effective methods. This review paper highlights the various synthetic routes to prepare quinoxaline and its derivatives, covering the literature for the last two decades. A total of 31 schemes have been explained using the green chemistry approach, cost-effective methods, and quinoxaline derivatives' therapeutic uses.

Keywords: SAR; biological applications; green chemistry; quinoxaline.

Figure 1

Structure of Quinoxaline.

Figure 2

Isomers of Quinoxaline.

Scheme 1

Synthesis of 2,3-diphenylquinoxaline (3) with reagents and conditions: (a) bentonite clay K-10/EtOH/RT/20 min.

Scheme 2

Synthetic pathway to prepare 2,3-diphenylquinoxaline derivatives (6) using phosphate catalyst (MAP, DAP, or TSP).

Scheme 3

Synthetic pathway to prepare quinoxaline derivatives (9) using CAN as a catalyst.

Scheme 4

Synthetic pathway to prepare pyrrolo[1,2-a]quinoxaline derivatives (11,12) with reagents and conditions: (a,b) FeCl₃(20 mol%)/70% TBHP(3equiv)/CF₃SO₃H(10 mol%)/t-BuOH(0.5 mL)/RT/10 h/Ar.

Scheme 5

Synthetic pathway to prepare 2,3-disubstituted quinoxalines (15) with HFIP.

Scheme 6

Synthetic pathway to prepare derivative of 2-phenylquinoxaline (18) using pyridine as a catalyst.

Scheme 7

Synthetic pathway to prepare quinoxaline derivatives (21) using catalyst TiO₂-Pr-SO₃H.

Scheme 8

Synthetic pathway to prepare pyrrolo[1,2-a]quinoxalines (24) using a catalytic amount of acetic acid and substituted aldehydes.

Scheme 9

Synthetic pathway to prepare Indoloquinoxalines (28).

Scheme 10

Synthesis of 6-chloro-7-fluoroquinoxaline derivatives (35) with reagents and conditions: (a) HOAc/Ac₂O, (b) 70% HNO₃/concentrated H₂SO₄ (c) concentrated H₂SO₄, (d) Zn/Hydrazinium monoformate; (e) (i) C₂H₅OH, (ii) CH₃OH, (iii) HOAc:CH₃OH (3:2)/NaOAc, (iv) HOAc/NaOAc.

Scheme 11

Synthetic pathway to prepare quinoxalin-2-mercaptoacetyl urea (38).

Scheme 12

Synthetic pathway to prepare acyclic quinoxaline nucleosides (41,42).

Scheme 13

Synthetic pathway to prepare penta-1,4-dien-3-one oxime (45) with quinoxaline moiety.

Scheme 14

Synthetic pathway to prepare S-alkylation of phenyl quinoxaline-2(1H)-thione (47) with reagents and conditions: (a) triethylamine/ethanol/reflux/78 °C/CH₂=CHCOOC₂H₅.

Scheme 15

Synthetic pathways to prepare methyl-2-[3-(3-phenylquinoxalin-2-ylsulfanyl)propanamidoalkanoates (50) and N-alkyl-3-((phenylquinoxalin-2-yl sulfanyl)propanamides (51) with reagents and conditions: (a) NH₂NH₂/C₂H₅OH/78 °C/reflux/4 h, (b) NaNO₂/HCl/H₂O/reflux/15 min, (c) NH₂(CH₂)nCHRCOOCH₃.HCl/triethylamine/ethyl acetate/25 °C/24 h, (d)NHR1R2/ethyl acetate/25 °C/24 h.

Scheme 16

Synthetic pathway for preparing (55) with reagents and conditions: (a) m-aminobenzoic acid/Bu-OH/conc HCl/reflux/5 h, (b) thionyl chloride/dry benzene/reflux/5 h, (c) aromatic amines/TEA/dry DCM/reflux/5 h.

Scheme 17

Synthetic pathway for the preparation of (57) and (58) with reagents and conditions, (a) p-phenylenediamine/n-butanol/110°, (b) benzene sulphonyl chlorides/dry pyridine/2 h, (c) phenyl isocyanates or isothiocyanates/dry toluene/reflux/5 h.

Scheme 18

Synthetic pathway to prepare the Schiff bases (61) and (63) with reagents and conditions, (a) 4-Hydroxybenzaldehyde/anhydrous K₂CO₃/acetonitrile/reflux, (b) substituted amines/ethanol/reflux. (c) 4-aminophenol/anhydrous K₂CO₃/acetonitrile/reflux, (d) substituted benzaldehyde/ethanol/reflux.

Scheme 19

Synthetic pathway to prepare 2-(5-arylthiazolo[2,3-c][1,2,4]triazol-3-yl)quinoxaline (66) derivatives.

Scheme 20

Synthetic pathway to prepare Spiro[thiadozoline-quinoxaline]derivatives (71).

Scheme 21

Synthetic pathway to prepare bistetrazoloquinoxalines (73) via one-pot synthesis.

Scheme 22

Synthetic pathway to prepare piperazinyl quinoxalines (76,78).

Scheme 23

Synthetic pathway to prepare 4-{4-[2-(4-(2-substitutedquinoxalin-3-yl)piperazin-1-yl)ethyl] phenyl} thiazoles (81).

Scheme 24

Synthetic pathway to prepare quinoxaline-2,3(1H,4H)-dithione (84), using thionating reagents.

Scheme 25

Synthetic pathway to prepare derivatives of quinoxaline-2,3-dithiones (85,86,87), using different reagents, (a) alkynonitriles/dioxane/KOH/heated at temp 20–25 °C/1 h, (b) 3-phenyl-2-propynonitrile/dioxane/KOH/heated at temp 20–25 °C/5 h, (c) acetylene/dioxane/KOH/heated at temp 200–250 °C/1 h.

Scheme 26

Synthetic pathway to prepare [1,2,4]triazolo[4,3-a]quinoxaline (91,92,93) with reagents and conditions (a) NH₂NH₂.H2O/ethanol/room temperature, (b) triethyl orthoformate/reflux/4 h, (c) NH₂NH₂.H₂O/ethanol/reflux/4 h, (d) alkylamines/TEA/reflux/4 h, (e) aliphatic alcohols/TEA/reflux/4 h.

Scheme 27

Synthetic pathway to prepare derivative of bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline (97) with reagents and conditions; (a) absolute ethanol/KOH/CS₂/reflux/6 h, (b) absolute ethanol/KOH/heating/10 min, (c) ethyl-4-bromobutyrate/dry DMF/KI/heating in w.b./3 h.

Scheme 28

Synthetic pathways to prepare derivatives of 6-(morpholine-4-sulfonyl)-1,4-dihydroquinoxaline (97,98,99,100,101) with reagents and conditions: (a) POCl₃, (b) thiocarbohydrazide (i) acetonitrile/reflux/8 h, (c) 5-hydroxy-3-methyl-1H-pyrazole-1-carbothiohydrazide (ii)/acetonitrile/reflux/8 h, (d) 4- amino-5-methyl-4H-1,2,4-triazole-3-thiol (iii) in acetonitrile containing DMF/reflux/5 h.

Scheme 29

Synthetic pathway to prepare 6-[(het)arylthiomethyl]quinoxalines derivatives (104) with reagents and conditions: (a) dry DMF/Cs₂CO₃/70 °C/2.5 h.

Scheme 30

Synthetic pathways to prepare quinoxaline-2-carboxylate-1,4-dioxide derivatives (106, 107, 108, 109) with reagents and conditions: (a, b, c, d) β-keto ester/triethylene amine/diethyl ether.

Scheme 31

Synthetic pathways to prepare derivatives of 4-chloro-8-methyl-[1,2,4]-triazolo[4,3-a] quinoxaline-1-amine (111, 112, 113).