One-Pot Synthesis of Novel Multisubstituted 1-Alkoxyindoles

Abstract

Studies on a one-pot synthesis of novel multisubstituted 1-alkoxyindoles 1 and their mechanistic investigations are presented. The synthesis of 1 was successfully achieved through consecutive four step reactions from substrates 2. The substrates 2, prepared through a two-step synthetic sequence, underwent three consecutive reactions of nitro reduction, intramolecular condensation, and nucleophilic 1,5-addition to provide the intermediates, 1-hydroxyindoles 8, which then were alkylated in situ with alkyl halide to afford the novel target products 1. We optimized the reaction conditions for 1 focusing on the alkylation step, along with the consideration of formation of intermediates 8. The optimized condition was SnCl2·2H2O (3.3 eq) and alcohols (R1OH, 2.0 eq) for 1–2 h at 40 °C and then, base (10 eq) and alkyl halides (R2Y, 2.0 eq) for 1–4 h at 25–50 °C. Notably, all four step reactions were performed in one-pot to give 1 in good to modest yields. Furthermore, the mechanistic aspects were also discussed regarding the reaction pathways and the formation of side products. The significance lies in development of efficient one-pot reactions and in generation of new 1-alkoxyindoles.

Syntheses of New Multisubstituted 1-Acyloxyindole Compounds

“…In particular, as a base for the acylation reaction, we tested several reagents, such as K 2 CO 3 , triethylamine (TEA), N , N -diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), and 1,8-diazabicyclo [5.4.0]undece-7-ene (DBU). Among them, DBU provided the best results (data not shown), which are consistent with our previous reports [ 25 ]. Thus, we chose DBU for our purpose.…”

“…At first, we prepared the substrate 2 [ 25 , 32 , 33 , 34 ] in two-step reactions using 2-chloro-6-nitrotoluene as a starting material. For this purpose, we applied our previous procedures [ 32 ] with minor modifications.…”

“…We used benzyl alcohol (BnOH) as a template nucleophile and pivaloyl chloride as a template acylating agent in dimethoxyethane (DME) to produce 1dy ( Table 1 ). Considering our previous procedure for synthesis of 1-alkoxyindoles [ 25 ], we applied the range of reagents as such: SnCl 2 ∙2H 2 O 2.5–3.7 eq and DBU 10.6–15.7 eq for synthesis of 1 . Here, we used an increased amount of DBU due to expected extra consumption by carboxylic acids that could be generated by partial hydrolysis of the acylating agents.…”

“…Somei et al developed a synthetic method for structurally concise 1-hydroxyindoles by oxidation of 2,3-dihydroindoles with a catalytic amount of sodium tungstate (Na 2 WO 4 ) [ 19 , 20 ]. Other groups employed Zn/NH 4 Cl [ 2 ], tin chloride (SnCl 2 ) [ 21 , 22 , 23 ], or Pd/triethylammonium formate (TEAF) [ 24 ] for reductive cyclization to produce 1-hydroxyindole moiety, and 1-Alkoxyindole compounds were also synthesized by alkylation of 1-hydroxyindoles [ 25 ] or intramolecular cyclization of methoxime structure [ 26 ]. Although a few simple 1-acyloxyindole derivatives were synthesized by acylation of 1-hydroxyindoles [ 17 , 27 , 28 , 29 , 30 ], the generated 1-acyloxyindoles were unstable and easily hydrolyzed to afford 1-hydroxyindoles [ 31 ].…”