Preparation of Tetrahydroisoquinoline‐3‐ones Via Cyclization of Phenyl Acetamides Using Eaton's Reagent

Abstract

Chlorophenylacetic acid Thionyl chloride Methylamine 2‐(4‐chlorophenyl)‐ N ‐ Methylacetamide Eaton's reagent Paraformaldehyde

Initial Process Development and Scale-Up of the Synthesis of a Triple Reuptake Inhibitor ALB 109780

“…The resulting suspension was filtered to afford the desired amide 3 in 88−94% yields and excellent HPLC purity (96.4 to >99%). 8,9 Initially, the synthesis of 4 was conducted in polyphosphoric acid (PPA) at 160 °C with paraformaldehyde. Upon completion, the reaction was quenched with water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated to dryness to afford an oil.…”

“…Multiple batches of the chemistry from 2 were successfully executed in our kilo laboratories on 2−3-kg scale and afforded the desired product in >90% yield and >92% HPLC purity. 8,9 With a steady supply of 4 in hand, our focus shifted to the evaluation of the downstream chemistry. However, difficulties were quickly encountered during preliminary development investigations.…”

“…Hence, 4-nitrophenyl acetic acid 12 was activated as its acid chloride using thionyl chloride in the presence of DMF in toluene and quenched into aqueous methylamine solution to afford the desired product 13 as a pale-yellow solid in quantitative yield and >99% HPLC purity after filtration and drying. 8,9 The obtained amide 13 was reacted with paraformamide under the Eaton's reagent-mediated cyclization conditions to afford 14 as a yellow solid in 98% yield and >99% HPLC purity. 8,9 Hydrogenation of 14 was conducted in the presence of 10% Pd/C in 1:1 EtOAc/EtOH to afford aniline 15 as a white solid in 89% yield after filtration to remove catalyst and concentration of the filtrates.…”

“…8,9 The obtained amide 13 was reacted with paraformamide under the Eaton's reagent-mediated cyclization conditions to afford 14 as a yellow solid in 98% yield and >99% HPLC purity. 8,9 Hydrogenation of 14 was conducted in the presence of 10% Pd/C in 1:1 EtOAc/EtOH to afford aniline 15 as a white solid in 89% yield after filtration to remove catalyst and concentration of the filtrates. 19 Reaction of 15 with diethylene glycol di(p-toluenesulfonate) 16 in the presence of potassium carbonate in acetone at reflux afforded the desired product 10 as a light-yellow solid in 75% yield after column chromatography purification.…”

Formamide-Catalyzed Nucleophilic Substitutions: Mechanistic Insight and Rationalization of Catalytic Activity

“…This mechanistic proposal was supported by the observations that (1) the reaction of DMF with the highly reactive acid chlorides 9a – c furnishes 9g ; and (2) the reagent 9g allows the synthesis of acid chlorides 4 from 2 Meanwhile, the catalytic property of DMF to access acid chlorides may be considered as “common knowledge”, testified by numerous examples . Despite the original reports, there are no further systematic investigations regarding the scope and mechanism…”