Sustainable Domino C−N/C−C Bond Formation with Outstanding E Factors and High Volume Productivity

• Published in: European journal of organic chemistry Vol. 27; no. 41
• Main Authors: Hwu, Jih Ru, Gupta, Nitesh K., Panja, Avijit, Chang, Chin‐Hwa, Huang, Wen‐Chieh, Tsai, Yu‐Ran, Chung, Kau‐Shu, Tan, Kui‐Thong, Lin, Chun‐Cheng, Hwang, Kuo‐Chu, Tsay, Shwu‐Chen
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 04.11.2024; Wiley Subscription Services, Inc
• Subjects: Acetonitrile; Bond formation; Cascade chemical reactions; Cesium fluorides; Chemical bonds; Chemical synthesis; Chemistry; Chemistry, Organic; Domino reaction; E factor; Imines; Neat; Nitriles; Physical Sciences; Productivity; Reagents; Science & Technology; Solvents; Volume productivity; ORGANIC-SYNTHESIS; COUNTERATTACK REAGENTS; Bond formation; E factor; ARYNES; Neat; Domino reaction; AMINO-ACID; COOPERATIVE CATALYSIS; SOLVENT-FREE; GREEN CHEMISTRY; ACETONITRILE; EFFICIENT; DERIVATIVES; Volume productivity
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202400658

One of the primary concerns in the development of new chemical reactions pertains to the choice of solvents, many of which can have harmful ecological impacts. Additionally, a major portion of waste generated in the chemical and pharmaceutical industries comes from the solvents employed. The elimination of solvent usage is highly desirable for creation of environmentally friendly chemical processes as it leads to a substantial reduction in waste production. Accordingly, a novel neat reaction was developed for the synthesis of (β‐amino)nitriles as a prominent moiety through a domino process. It involved the use of silylphenyl triflates, Schiff bases, and acetonitrile (CH3CN) in a 1 : 1 : 1 ratio, among which CH3CN served as a starting material rather than a solvent. This reaction was initiated by caesium fluoride (CsF) to form an aryne through 1,2‐elimination followed by sequential 1,2‐addition, proton transfer, and a second 1,2‐addition. Complete conversion was carried out at 25 °C for 1.0 h to give (β‐amino)nitriles in 76–88 % yields. This solvent‐free reaction minimized waste production and reduced costs associated with extra reagents, solvents, and labour. It possesses a compelling E factor and impressive volume productivity. This reaction sets a new benchmark for solvent‐free aryne domino processes in green chemistry advancements. This newly developed single‐flask, solvent‐free process accomplishes sequential C−N and C−C bond formations. It leads to (β‐cyano)anilines by use of aryl triflates, Schiff bases, and CH3CN as a reagent. Key features of this neat method include a domino process, ambient temperature, short reaction time, and alignment with sustainability principles.