Incorporating Morpholine and Oxetane into Benzimidazolequinone Antitumor Agents: The Discovery of 1,4,6,9-Tetramethoxyphenazine from Hydrogen Peroxide and Hydroiodic Acid-Mediated Oxidative Cyclizations

Abstract

The reactivity of hydrogen peroxide and catalytic hydroiodic acid towards 3,6-dimethoxy-2-(cycloamino)anilines is tunable to give ring-fused benzimidazoles or 1,4,6,9-tetramethoxyphenazine in high yield. Mechanisms via a detected nitroso-intermediate are proposed for oxidative cyclization and the unexpected intermolecular displacement of the oxazine. An aqueous solution of molecular iodine is capable of the same transformations. Oxidative demethylation gave targeted benzimidazolequinones, including without cleavage of the incorporated oxetane. ASSOCIATED CONTENT Supporting Information. The supporting information is available free of charge via http://pubs.acs.org at DOI: XXXXXXX. GC-MS, 1 H and 13 C NMR spectra, and crystallographic data (PDF).

Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone

“…8 Chlorination of pyrrolo-fused dimer 5a was initially attempted using H 2 O 2 with HCl under conditions which mediated the regioselective chlorination of anilines (Table 1). 17 Reaction monitoring by TLC indicated the complete consumption of 5a after 1 h of reflux, but a low yield of 7′-chloride 9a (21%) was attributed to the formation of intractable baseline decomposition products. The requirement for milder conditions, led us to investigate the room temperature Oxone/NaCl reaction.…”

“…Five to seven-membered alicyclic ring-fused dimethoxybenzimidazoles 6a-6c are readily available, 17 and used to prepare new DMBBQs 5a-5c. DMBBQ 5b was prepared in 73% yield by optimizing the conditions for CAN-oxidation of 6b in MeCN/ H 2 O (Scheme 2).…”

“…The halide with Oxone gives oxidative transformations with an accompanying halogenation of naphthols and phenols, 11 and with and without halogenation for indoles. 12,13 Other metal-free oxidations, such as N-bromosuccinimde (NBS) with a small amount of H 2 SO 4 , 14,15 and PhI(OCOCF 3 ) 2 (PIFA), 8,16,17 are reported to induce conversion of p-dimethoxybenzenes to p-quinones without halogenation. The disadvantage of using NBS and PIFA is the generation of organic waste products.…”

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

“…Another synthetic approach for the incorporation of morpholine into benzimidazolequinone agents with antitumor properties is presented by Conboy et al. (Scheme ) . The target compound is a known substrate for the NAD(P)‐H : quinone oxidoreductase 1 (NQO1), which is overexpressed in many solid tumors.…”

“… Example of incorporation of morpholine into a benzimidazolequinone. Reagents and conditions : a) H 2 O 2 , HI (0.2 equiv), EtOAc (25 mM), reflux, 1 h (yield: 69 %); b) [bis(trifluoroacetoxy)iodo]benzene (PIFA), H 2 O, MeOH, rt, 2 h (yield: 74 %) …”