Efficient synthesis of unsymmetric diarylalkynes from decarboxylative coupling in a continuous flow reaction system Hee Joon Lee a , Kyungho Park b , Goun Bae b , Jaehoon Choe c , Kwang Ho Song a,⇑ , Sunwoo Lee b,⇑ a Department of Chemical & Biological Engineering, Korea University, Seoul 136-713, Republic of Korea b Department of Chemistry, Chonnam National University, Gwangju 500-757, Republic of Korea c LG Chem Research Park, Daejeon 305-380, Republic of Korea article info Article history: Received 9 June 2011 Revised 20 July 2011 Accepted 21 July 2011 Available online 27 July 2011 Keywords: Flow chemistry Micromixer Palladium Diaryl alkynes Decarboxylative coupling abstract Unsymmetric diaryl alkynes were synthesized from the palladium-catalyzed decarboxylative coupling of aryl halides and propiolic acid using a continuous flow reaction system. This flow chemistry system con- tinuously gave the desired products in moderate to good yields, and produced less byproduct than was formed in the batch reaction. Ó 2011 Elsevier Ltd. All rights reserved. Aryl alkynes are some of the most important building blocks in the pharmaceutical and electro-material industries. 1 The Sono- gashira coupling reaction, which is the coupling between an sp car- bon and an sp 2 carbon in the presence of a palladium catalyst and copper co-catalyst, has been employed as the key reaction for the synthesis of diaryl alkynes. 2 This traditional method for the syn- thesis of unsymmetrical diaryl alkynes uses protected alkynes, such as trimethylsilylacetylene, 3 and 2-methylbut-3-yn-ol 4 that are coupled with aryl halides, and then a second Sonogashira reac- tion is employed after the deprotection step. These reactions have some drawbacks in that they produce organometallic waste and require a multi-step process. To solve these problems, we have developed the decarboxylative coupling of alkynyl carboxylic acid and aryl halides to afford bond formation between the aryl carbon and alkynyl carbon, and CO 2 is released as a byproduct. 5 Since our first report of this decarboxylative coupling reaction, several re- search groups have developed very useful methodologies using the decarboxylative coupling of alkynyl carboxylic acid. 6 As an alkyne source, propiolic acid has two alkynyl carbons which show different reactivities: one is the terminal alkynyl car- bon that is used in the Sonogashira reaction and the other is the car- bon-bearing carboxylic acid for decarboxylative coupling. We previously reported the one-pot synthesis of unsymmetric diaryl alkynes from propiolic acid, and showed the broad scope of substrates. 5c However, this method has some drawbacks, in that symmetric diaryl alkynes were always formed as a byproduct. Therefore, it requires higher selectivity and a more versatile processing method for application in the fine chemical industry. Miniaturized continuous flow reactor technology has been paid much attention in the pharmaceutical and fine chemical industries due to its heat and mass transfer rate enhancements, higher yields and greater product selectivity. 7 A variety of transition-metal cata- lyzed transformations have been successfully applied in the contin- uous flow system. 8 Conducting organic reactions with microfluidics has a variety of attractive attributes: 9 microfluidic systems provide a high surface area to volume ratio for micromixing, thus affording efficient mass transfer; and the flow aspect allows control over the reactant residence times at large surface areas for selective cataly- sis. In addition, the heat dissipation properties of the microchannels can be employed for the subdued management of exothermic reac- tions and thus achieve high selectivity. When the optimized condi- tions are set up for the continuous flow system, several flow reactors are placed in parallel to produce the coupled product on a large scale without any more scale up reactors being needed. 10 Therefore, we envision that the continuous flow reaction system could provide a more practical and efficient method for the synthe- sis of unsymmetric diaryl alkynes without the formation of sym- metric ones as the side product. Since Ryu’s group first reported the microflow chemistry of Sonogashira coupling reaction, 11 a number of the related works have been published. 12 However, there is no example of the microflow chemistry for the decarboxylative 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.07.091 ⇑ Corresponding authors. Tel.: +82 2 3290 3307 (K.H.S.); tel.: +82 62 530 3385 (S.L.). E-mail addresses: khsong@korea.ac.kr (K.H. Song), sunwoo@chonnam.ac.kr (S. Lee). Tetrahedron Letters 52 (2011) 5064–5067 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet