DOI: 10.1002/adsc.201300741 Suzuki–Miyaura Cross-Coupling under Solvent-Free Conditions Andrey F. Asachenko, a Kristina R. Sorochkina, a,b Pavel B. Dzhevakov, a Maxim A. Topchiy, a and Mikhail S. Nechaev a,b, * a A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy ofSciences, 119991 Moscow, Russian Federation b M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation Fax: (+ 7)-49-5939-2677; e-mail: nechaev@nmr.chem.msu.ru Received: August 15, 2013; Published online: November 27, 2013 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300741. Abstract: A solvent-free reaction protocol for Suzuki–Miyaura cross-couplings was developed. (Hetero)aryl bromides and chlorides are coupled with pinacol arylboronates in high yields. The reac- tion is catalyzed by conventional bis(triphenylphos- phine)palladium(II) chloride [(PPh 3 ) 2 PdCl 2 ] and/or palladium(II) acetate/SPhos [PdACHTUNGTRENNUNG(OAc) 2 /SPhos] under air. Keywords: carbenes; palladium; phosphanes; sol- vent-free reactions; Suzuki–Miyaura cross-coupling A challenge facing organic chemists is the develop- ment of new processes that are not only efficient, se- lective, and high yielding but also environmentally friendly. The measure of “greenness” of a process is the E factor, introduced by Sheldon. [1] It is defined as the ratio of weight of waste to weight of product. The E factor for many pharmaceuticals has been estimat- ed to exceed 100. [2] The largest contributors to the magnitude of E factor are organic solvents, many of which are ecologically harmful and require expensive regeneration. Thus, elimination of solvents from or- ganic synthesis is of high importance. In the last two decades several approaches to elimi- nate solvents from organic synthesis were developed. Of special interest is the Suzuki–Miyaura reaction that is a highly important synthetic tool in medicinal chemistry. [3] Couplings of aryl halides with boronic acids have been performed under microwave irradia- tion, [4] ultrasonic irradiation, [5] and ball mill activa- tion. [6] In this work we have performed a systematic study of the Suzuki–Miyaura reaction under solvent-free conditions using cheap bases, commercially available catalysts, and without use of an inert atmosphere and highly pure reagents. We also focused on the utiliza- tion of conventional and simple heating as activation tool to avoid the use of microwave and ultrasonic ir- radiation or ball mill equipment. One of the key problems of organic reactions under solvent-free conditions is the homogeneity of the re- action medium. Conventional reactants in the Suzuki– Miyaura reaction are arylboronic acids. However, these compounds are solids with high melting points, they are also non-soluble in aryl halides, and exhibit low stability under basic aerobic conditions. To avoid these problems we utilized pinacol arylboronates. These compounds have high thermal and hydrolytic stability. Pinacol arylboronates are liquids or solids with low melting points and are miscible with aryl halides. Various palladium catalysts were tested: well-de- fined NHC complexes 1–5 ; [7] expanded ring NHC complexes recently developed in our group 6 and 7; [8] the well-defined catalytic system PdACHTUNGTRENNUNG(OAc) 2 /SPhos; [9] as well as the conventional commercially available palladium sources PdCl 2 , Pd 2 ACHTUNGTRENNUNG(dba) 3 , PdACHTUNGTRENNUNG(OAc) 2 , and (Ph 3 P) 2 PdCl 2 . As shown in Table 1, the study begins with an opti- mization of the operating conditions on a model reac- tion involving phenyl bromide and pinacol p-tolylbor- onate. When triethylamine or sodium carbonate was used as a base, no coupling products were observed. Stronger bases such as potassium carbonate, lithium, and sodium hydroxides gave moderate yields. When potassium hydroxide was used, a virtually quantitative yield was obtained. The next step of our work was optimization of the catalytic system (Table 2). Tests were performed on a model reaction, the coupling of pinacol p-tolyl- ACHTUNGTRENNUNGboronACHTUNGTRENNUNGate and deactivated sterically hindered 2-bro- moanisole. Ligandless palladium catalysts have shown no or low activity (entries 1–3). All NHC complexes exhibited good catalytic activity giving 62–81% yields (entries 4–12). The PdACHTUNGTRENNUNG(OAc) 2 /SPhos catalytic system gave a virtually quantitative yield. Surprisingly, simple (Ph 3 P) 2 PdCl 2 has shown an excellent performance. Notably, reactions were performed under aerobic con- Adv. Synth. Catal. 2013, 355, 3553 – 3557 # 2013 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 3553 COMMUNICATIONS