Synthesis of pyrimidine, thiazine, diazepine and quinoxaline derivatives via 3-component reactions (3-CR)

Abstract

Preliminary molecular modeling (virtual screening) in search of bioactive heterocyclic compounds as potential disrupters of HIV-1 integrase and LEDGF/p75 interactions resulted in the identification of fused heterocyclic scaffolds such as hexahydroquinolines, pyrimidines quinoxalines and diazepines. The use of multicomponent reactions (MCRs) for synthesis of heterocyclic scaffolds in synthetic chemistry remains one of the preferred approaches due to atom economy. This thesis describes the use of three-component reactions for the synthesis of fused pyrimidines, thiazines, diazepines and quinoxalines as a strategic approach to accessing these fused heterocycles. The hexahydroquinoline derivatives identified as potential ligands to disrupt the interaction of HIV-1 IN and LEDGF/p75 were chosen for initial synthesis based on availability of reagents and a facile synthetic route. This synthesis resulted in a library of fifteen novel hexahydroquinoline derivatives. The first MCR approach applied involved was 3-CR of isocyanides with electron deficient alkynes (DMAD), giving rise to a zwitterion adduct that was reacted further with a range of prepared five-membered ring substrates containing an acidic proton. The resulting products were 5-6 fused ring heterocycles. When a thiazole derivative was used as a substrate the final racemic products obtained, containing a single stereogenic centre, were (E)-dimethyl 7-(tert-butylamino)-2-(2-methoxy-2-oxoethylidene)-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-5,6-dicarboxylates in good yields. The second five-membered ring substrate used was pyrrolidine which gave dimethyl 2-(tert-butylamino)-6-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-3,4-dicarboxylates, also containing one stereogenic centre. Two substrates tested, 1H-1,2,4-triazole-5-thioland1H-1,2,4-triazol-5-amine each resulted information of two co-products ; rom a three-component reaction as well as a two-component reaction where the substrate reacted directly with DMAD. Substrate 1H-1,2,4-triazole-5-thiol gave rise to dimethyl 5-(tert-butylamino)-7H-[1,2,4]triazolo[5,1-b][1,3]thiazine-6,7-dicarboxylate and methyl 7-oxo-7H-[1,2,4]triazolo[5,1-b][1,3]thiazine-5-carboxylatewhile substrate 1H-1,2,4-triazol-5-amine gave rise to dimethyl 5-(tert-butylamino)-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6,7-dicarboxylate and methyl 5-oxo-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine-7-carboxylate. The substrate scope of the 3-CR was extended by using six-membered 2-amino-4H-1,3-thiazin-4-one derivatives to obtain 6-6 fused ring heterocycles. When this set of substrates was treated with zwitterion adducts this resulted in formation of 4-oxo-4,6-dihydropyrimido[2,1-b][1,3]thiazine-6,7-dicarboxylate derivatives, containing one stereogenic centre, in good yields without use of a catalyst. The Michael reaction of prepared five-membered ring substrates with electron deficient alkynes (DMAD\DEtAD\DTAD) gave rise to fused thiazole-pyrimidine derivatives containing no stereogenic centre. When thiazol-2-amine and its derivatives were treated with electron deficient alkynes they gave average yields of methyl 7-oxo-7H-thiazolo[3,2-a]pyrimidine-5-carboxylate derivatives. The alternative route of employing thiourea, α-haloketone and DMAD gave improved yields of the resulting thiazolo[3,2-a]pyrimidine-5-carboxylate derivatives via 3-CR. When DMAD\DEtAD were treated with 1H-1,2,4-triazol-5-amine or 1H-1,2,4-triazole-5-thiol this resulted in good yields from 2-CR. When 2-imino-1,3-oxazolidine was reacted with DMAD\DEtAD this resulted in a good yield of methyl 5-oxo-3,5-dihydro-2H-oxazolo[3,2-a]pyrimidine-7-carboxylates. The unexpected incorporation of the solvent acetone in reaction with an isocyanide and benzimidazole via 3-CR resulted in fused diazepine scaffolds, 2-methyl-N-(2,2,4-trimethyl-2,3,4,5-tetrahydro-1,4-methanobenzo[b][1,4]diazepin-10-ylidene)propan-2-amine derivatives, when using benzimidazole bearing neutral or activating groups on the benzene ring such as hydrogen and methyl. When using deactivating groups on the benzimidazole such as an ester group, reaction with acetone and isocyanide gave quinoxaline scaffolds instead. These reactions occurred without use of solvent or catalyst. The reaction of phenylenediamine or benzimidazole with DMAD\DEtAD\DTAD gave rise to diazepine scaffolds. Various biological studies were conducted on the synthesised compounds, such as antimicrobial Minimum Inhibitory Concentration (MIC) assays for Gram-positive and Gram-negative organisms; antiviral HIV assays which were conducted in infected MT4 cells; cytotoxicity assays which were conducted in the MT4 cell line at 100 μM; and an assay was conducted on certain substrates to test for inhibition or disruption of the HIV-1 IN-LEDGF/p75 protein-protein interaction.