A novel synthesis of 2-substituted 2H-imidazo[1,5-b]isoquinoline-1,5-diones by in situ desulfurization

Abstract

reported with nickel boride in dry methanol at ambient temperature.Keywords: nickel boride, polycyclic isoquinoline, desulfurization.Polycyclic isoquinoline compounds are well known as anticancer [1] and antitumour [2] agents, and as acetylcholinesterase [3] and human chymase inhibitors [4]. Recently, the synthesis and biological properties of isoquinolines spirofused with carbocycles and heterocycles in position 4 have been reviewed [5]. In view of their importance, we decided to explore the synthesis of a new class of substituted imidazo[1,5-b]isoquinoline-1,5-dione derivatives by reductive desulfurization of 2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones with nickel boride. Nickel boride has been used successfully for desulfurization of the C=S group flanked by the NH group of dialkyl thioureas [6], 2(1H)-benzimidazolinethiones [6], 1,3-diaryl-2-thioxo-2H,5H-1,3-dihydropyrimidine-4,6-diones [6], 2-thioxo-4(3H)-quinazolinones [7], and 4-oxo-2-thioxo-5H-pyrano-[2,3-d]pyrimidines [8] by our research group besides reductions of other functionalities [9][10][11][12][13][14][15][16].We report herein a convenient and efficient synthesis of 2-substituted 2H-imidazo[1,5-b]isoquinoline-1,5-diones 2a-f with nickel boride in dry methanol at ambient temperature following a simple workup procedure. Nickel boride was prepared in situ from anhydrous nickel chloride and sodium borohydride in dry methanol. Various 2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones 1a-f underwent complete reductive desulfurization with nickel boride using a 1:7:7 or 1:9:9 molar ratio of substrate/NiCl 2 /NaBH 4 in dry methanol and yielded the corresponding 2-substituted 2H-imidazo[1,5-b]isoquinoline-1,5-diones 2a-f in nearly quantitative yields. The starting 2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones were prepared by condensation of 2-formylbenzoic acid with 3-substituted 2-thiohydantoins [17]. N N O S O R N N O O R N O NiCl 2 / NaBH 4 MeOH, r. t. 1a-f 2a-f 1,2 a R = H, b R = Me, c R = i-Pr, d R = Ph, e R = CH 2 Ph, f R = CH 2 _________________________________________________________________________________________

Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family

“…To eliminate the potential oxidative liability of the C=S group of this series, the corresponding carbonyl derivative was prepared, unfortunately, this led to significant reduction of activity (66). Reduction of the thio-carbonyl group to a methylene using NiCl 2 and NaBH 4 [72] resulted in complete loss of activity (67). Due to the increased complexity of this series and narrow window for the improvement of physical properties while maintaining the potency, it was decided not to pursue the fused tricyclic scaffold further.…”

Improved multicomponent, one‐pot synthesis of functionalized tetrahydropyrans cardiovascular dysfunction regulators

“…Unfortunately, the reaction was not successful in the presence of P 2 O 5 (entry 3). To improve the yield further, we have applied various catalysts such as Et 3 N, DMAP, [28][29][30][31] and considerably obtained low yields, 53%, 48%, 49%, 43%, 51%, and 56%, respectively (entries 4-9).…”

Efficient one pot preparation of novel 1-oxo-3-aryl-1,5-dihydrobenzo[4,5]imidazo[1,2-a]pyridine-2-carboxylic acid derivatives in a green solvent

“…14 Because the benzo [4,5]imidazo [1,2-a]pyridine scaffold show interesting biological activities, the synthesis of this group of compounds has been realised via several routes, including cycloaddition reactions, 6,9,15 condensation reactions, [16][17][18] multicomponent reactions, 10,[19][20][21][22][23] and multistep approaches. 5,[24][25][26] Also, metallic and non-metallic catalysts, [27][28][29][30] microwave irradiation, 31 and a series of transition metal catalysts have been used for the preparation of these compounds. 1,32 No doubt, the existing methods are useful, but also possess certain limitations such as an extended reaction time, special apparatus, high temperature, expensive catalysts, toxic solvents, and tedious workup processes.…”