Transition-Metal-Free Synthesis of Benzimidazoles Mediated by KOH/DMSO

Abstract

Benzimidazoles are prepared by intramolecular N-arylations of amidines mediated by potassium hydroxide in DMSO at 120 °C. In this manner, diversely substituted products have been obtained in moderate to very good yields.

Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-fused benzimidazoles and anti-tumour benzimidazolequinones

“…3,16,29 There are drawbacks to reported syntheses of alicyclic ring-fused benzimidazoles such as requirements for transition metals, [1][2][3][4][5][6][7][8][9] prior synthesis of cyclization precursors, [10][11][12][13][14][15][16][17] full equivalents of strong base, [17][18][19][20] high molar mass hypervalent iodine reagents, 21 and the formation of mixtures of isomeric products. 22 The most convenient protocol remains the traditional oxidative cyclization of o-cyclic amine substituted anilines, which was first reported in the early 1960s using hydrogen peroxide in the presence of trifluoroacetic acid.…”

Theoretical Investigations on the Intramolecular N-Arylation Mechanism and Reactivity for the Synthesis of Benzimidazoles by Base-Catalyzed

“…然而在反应机理上一 直存在争议. 由于反应在强碱中进行, 因此分子内氮芳 基化 C-N 键耦合的初始物为 N-甲苯磺酰腙阴离子 [49] 或 N-苯基取代脒阴离子 [50,51] , 目前其反应机理主要有四 种假设(图 1): (1)电环化机理 [49] , (2)苯炔机理 [50] , (3)自由 基机理 [49,51] , (4)芳环上亲核取代机理(S N Ar) [51] . Bolm 等 [49] --e le c t r o c y li c r in g c lo s u r e a ry n e m e c h a n is m ra d ic a l m e c h a n is m 图 1 强碱催化分子内氮芳基化 C-N 键耦合可能反应机理 Figure 1 Possible reaction mechanisms of intramolecular N-arylation for the C-N bond coupling reaction by base-catalyzed 对于芳环上的 S N Ar 反应, 通常指的是底物芳环临 位或对位上存在吸电子基团, 即芳环是活化的情况, 其 反应机理通常是加成-消去两步机理, 若离去基团是卤 素, 其反应活性顺序通常为 F＞Cl＞Br＞I, 即加成是决 速步骤 [53] .…”

“…最近 我们研究得出, 没有活化的卤代芳烃上的 S N Ar 亲核取 代反应的能垒同样与 C-X 键极性大小顺序 X＝F＞ Cl＞Br＞I 一致 [77] . 而标题反应的反应活性顺序却是 F＞I＞Br＞Cl [51] , 究竟是什么因素控制着反应的能垒?…”

Copper-incorporated fluorapatite encapsulated iron oxide nanocatalyst for synthesis of benzimidazoles

“…Three years later, Ladenburg procured the identical compound by refluxing 3,4-diaminotoluene with acetic acid [11]. Various methodologies have been used for the synthesis of benzimidazole derivatives, which include conversion of esters using an aluminum reagent [12], the oxidative cyclodehydrogenation of Schiff bases, which is generated from o-phenylenediamine and aldehydes in the presence of several catalysts [13], such as cabalt(II) chloride hexahydrate [14], iodine [15], cetylpyridinium bromide [16], the condensation of o-aryldiamines and aldehyde in refluxing nitrobenzene [17], direct condensation of o-aryldiamines and carboxylic acids [18,19] or their derivatives [20] in the presence of catalysts, such as polyphosphoric acid [21], ionic liquids [22], p-TsOH [23], SiO 2 as solid support [24], microwave irradiation using polyphosphoric acid [25], and intramolecular N-arylations of amidines mediated by potassium hydroxide [26]. Although these reported approaches are significant, but some of them have drawbacks like strict reaction conditions, prolonged reaction period, low yield, expensive catalysts, non-recoverability of the catalysts, use of toxic solvents, and co-occurrence of several side reactions.…”