Published: November 10, 2010 r2010 American Chemical Society 24 dx.doi.org/10.1021/co100011g | ACS Comb. Sci. 2011, 13, 24–31 RESEARCH ARTICLE pubs.acs.org/acscombsci Microwave-Mediated Synthesis of an Arylboronate Library John Spencer,* ,† Christine B. Baltus, † Hiren Patel, † Neil J. Press, ‡ Samantha K. Callear, § Louise Male, § and Simon J. Coles § † School of Science at Medway, University of Greenwich, Chatham, ME4 4TB, U.K. ‡ Novartis Pharmaceuticals U.K., Horsham, Sussex, RH12 5AB, U.K. § UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton. SO17 1BJ, U.K. b S Supporting Information ABSTRACT: A series of arylboronates has been synthesized from the reaction of 2-(2-, (3-, or (4-(bromomethyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1{1-3} respec- tively with a range of N-, S-, and O-nucleophiles, using microwave-mediated chemistry. For the synthesis of N- and S-substituted boronates, a supported base, PS-NMM, was employed, and many reactions were complete within 15 min. With O-nucleophiles, a mixture of tetrabutylammonium bromide, potassium carbonate, and sodium hydroxide was employed. The resulting aminomethyl, mercaptomethyl, or alkoxy-/phenoxymethyl-arylboronates were subjected to microwave-mediated Suzuki Miyaura coupling reactions to afford a range of biaryls in moderate to good yields. The X-ray structures of five boronates were determined. KEYWORDS: Suzuki coupling, microwave, boronic acid, nucleophilic substitution, biaryls, supported reagents ’ INTRODUCTION The biaryl motif is found in many natural and synthetic products and as a privileged scaffold in medicinal chemistry, notably in a variety of inhibitors of enzymes, transporter proteins, and GPCR ligands as well as in herbicides, 1 fungicides, 2 chiral ligands in catalysis, 3 liquid crystals, 4 and novel materials (organic conductors, organic electric wires) (Figure 1). 5-7 The palladium-catalyzed Suzuki-Miyaura (SM) coupling reaction is one of the most important and efficient strategies for the construction of biaryls. This reaction involves the coupling of organic halides, typically a bromide with organobor- on compounds, in the presence of a base and a catalytic amount of palladium complex. 8 Arylboronic acids are often synthesized by a low-temperature transmetalation reaction and can be difficult to modify or isolate. They are often purchased (many are expensive) for use in SM couplings, which limits the scope of the parallel synthetic process. 8 We 9a,b and others 9c have advocated the deployment of pinacol-ester-protected arylboronic acids (ArBPin) 1 in biaryl synthesis, given their ease of synthesis, purification, and stabil- ity compared with their acid precursors. Moreover, 1 can be functionalized, in parallel, by the use of a simple S N 2 reaction with S- and N-nucleophiles, which can lead to a variety of analogs 3. By introducing a high degree of diversity on the ArBPin coupling partner at an early stage, 9a,10 not only is the scope of the synthetic process increased and the range of biphenyls 5 to be synthesized widened, but also the ArBPin compounds may have interesting structural properties in their own right or applications such as enzyme inhibitors or in molecular recogni- tion (Scheme 1). 8,11 Our previously published preliminary attempted SM coupling reactions on a few analogs 3 were unsuccessful, yielding proto- deboronated species, 9a although we have recently found that the use of MAOS (microwave assisted organic synthesis) can lead to biaryl compounds, 12d notably employing literature conditions. 12 The aim of the current study was to extend the synthetic scope of the S N 2 reaction leading to a library of ArBPin using a variety of N-, S-, and O-nucleophiles and to investigate SM couplings to afford biphenyl products. ’ RESULTS AND DISCUSSION The S N 2 reaction of the pinacol ester 1{1} with a piperazine derivative 2{1} was initially investigated with a view to reducing the reaction time to minutes for it to be amenable to parallel synthesis: previously, 1{1} was found to react at room tempera- ture overnight with S-nucleophiles or at reflux for several hours with N-nucleophiles. 9a For this to be feasible, we attempted microwave-mediated reactions, and using a rapid screen, the best results were obtained when a supported base was employed as base (PS-NMM) as opposed to potassium carbonate or excess nucleophile. When required, supported scavengers, PS-trisa- mine and PS-isocyanate, were used to remove unreacted bromide or amine, respectively, and in general, yields of product Received: September 22, 2010