Continuous flow reaction system for the synthesis of 2,2,2-trichloroacetophenone derivatives and its application Byeng Ha Ko a , Subeen Yu b , Kwang Ho Song a,⇑ , Sunwoo Lee b,⇑ a Department of Chemical & Biological Engineering, Korea University, Seoul 02841, Republic of Korea b Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea article info Article history: Received 30 November 2017 Revised 18 January 2018 Accepted 23 January 2018 Available online 31 January 2018 Keywords: Flow chemistry Trichloroacetophenone Decarboxylative chlorination Propiolic acid Trichloroisocyanuric acid abstract A continuous flow reaction system was developed for the synthesis of 2,2,2-trichloroacetophenone derivatives. When aryl propiolic acids and water were mixed with trichloroisocyanuric acid in DMF at 5 °C, the 2,2,2-trichloroacetophenone derivatives were formed within 5 min with good yields. In addition, the resulting mixture was flowed to react with amines to give the corresponding benzamide. This flow reaction system provided higher yields within shorter times than the batch reaction system. Ó 2018 Elsevier Ltd. All rights reserved. Trichloroacetophenone moieties are found in bioactive com- pounds such as pesticides, herbicides, fungicides, and preservatives and have been used as building blocks in organic syntheses (Fig. 1). 1 In addition, the trichloromethyl ketone group has been used as an acyl chloride surrogate in acyl substitutions. 2 Although it is more stable and less sensitive to moisture com- pared to acyl chloride, synthetic methods for the preparation of trichloroacetophenone derivatives have not been well developed. In most cases, trichlorinated reagents such as chloroform, trichloroacetate, trichloroacetonitrile, and chloral have been used as starting materials for the synthetic process. As the most com- mon method, the reaction with aldehydes and trichlorinated reagents provides the corresponding alcohols, and subsequent oxi- dation affords the desired trichloroacetophenone derivatives. 3 However, two steps are required for this synthesis. As alternative methods, related syntheses using the reactions of Grignard reagents or aryl boronic acids have been developed. 4 However, all previously developed methods have some drawbacks, as Grig- nard reagents are moisture-sensitive and aryl boronic acids require metal catalysts for completion of the reaction. To address these issues, we recently developed a mild synthetic method for the preparation of trichloroacetophenone derivatives via the reaction of aryl alkynoic acid and trichloroisocyanuric acid. 5 The synthesis was carried out at room temperature in the presence of water and afforded the desired products in good yields. In addition, the corresponding esters, amides, and hydrizides from the reaction of alcohols, amines, and hydrazines were easily produced. However, temperature control was required to obtain high yields of the prod- ucts because the reaction with trichloroisocyanuric acid (TCCA) is exothermic. Benzoic acid derivatives were formed as by-products from the reaction of the final product with water. The process of performing chemical reactions using a continu- ously flowing stream, called flow chemistry, has been developed over the past decade. 6 The significant advantages of flow chemistry have led to its application in organic synthesis and it is a rapidly growing field of research. 7 In particular, flow chemistry technology has been successfully applied for the preparation of fine chemicals, natural products, and pharmaceutical building blocks. 8 In a conventional batch reactor, reaction times are long and the product yields are typically low. In addition, it is difficult to scale up due to the difficulty in conducting experiments while maintain- ing same temperature in all regions of the batch reactor. Con- versely, flow chemistry has advantages such as easy control of heat and mass transfer, controlled mixing, and high surface to reac- tor volume ratio. 9 When reaction conditions are optimized in a flow system, several reactors can be placed in series to produce products without scale up. In a batch reactor, it is difficult to con- trol rapid exothermic reactions. However, the high surface to reac- tor volume ratio in flow systems allows for efficient heat transfer and the effective removal of heat generated from the reaction. https://doi.org/10.1016/j.tetlet.2018.01.067 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. E-mail addresses: khsong@korea.ac.kr (K.H. Song), sunwoo@chonnam.ac.kr (S. Lee). Tetrahedron Letters 59 (2018) 991–994 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet