Aromatic homolytic substitution using solid phase synthesis

Synthesis by Radical Cyclization and Cytotoxicity of Highly Potent Bioreductive Alicyclic Ring Fused [1,2‐a]Benzimidazolequinones

“…The yield of azepinoA C H T U N G T R E N N U N G [1,2-a]benzimidazole 19 a was particularly impressive, as the equivalent seven-membered cyclisations by the ipso-substitution protocol only occurred in yields of < 17 % for radical precursors without functionality on the fused benzene ring. [18,19] The low yield of the fivemembered cyclisation product 17 a was consistent with similar literature radical reactions, and was presumably due to strain associated with forming pyrroloA C H T U N G T R E N N U N G [1,2-a]benzimidazole ring system. [16,18,19] Under non-reducing conditions, the equivalent five-membered cyclisation proceeded in 37-57 % yield by using xanthate radical precursors.…”

“…Phenylselanides were used in place of alkyl bromides and iodides due to their efficient radical, but poor S N 2 leaving group ability enabling facile preparation of diazole radical precursors. [18,19] Radical cyclisation to give pyridoA C H T U N G T R E N N U N G [1,2-a]benzimidazole 12 was carried out over 18 hours by using syringe-pump addition of Bu 3 SnH (2.5 equiv) and 1,1'-azobis(cyclohexanecarbonitrile) (ACN, 4.0 equiv) to a solution of 11 (1 equiv) and CSA (1 equiv) heated under reflux in toluene. The addition of further portions of ACN (1.5 equiv) during the reaction was found to further improve yields of cyclisation products.…”

“…Bowmans group have recently extended the ipso-substitution protocol to 2-(phenylsulfanyl)-benzimidazole radical precursors attached to solid-phase resins, and given an alternative synthesis of the precursors from 2-chlorobenzimidazole and benzenethiols. [19] Purification by using KF/silica-gel column chromatography [21a] (later discussion) was found to be less successful for purification of 12, and the Corey procedure of CsF/CsOH (an anhydrous fluoride source) on silica gel was not attempted.…”

“…This was carried out by using the direct column chromatography procedure devised by Harrowven and Guy [21a] by purification of the concentrated reaction mixture using gradient elution on 10 % w/w of finely ground KF and 90 % silica. The latter procedure was an improvement on the cumbersome workup procedure of repeated washing of the acidic imidazolium salts with petrol to remove tin residues [18,19] and resulted in improved overall recovery yields of diazoles ( % 70-85 %). The yield of azepinoA C H T U N G T R E N N U N G [1,2-a]benzimidazole 19 a was particularly impressive, as the equivalent seven-membered cyclisations by the ipso-substitution protocol only occurred in yields of < 17 % for radical precursors without functionality on the fused benzene ring.…”

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.…”