Synlett, Table of Contents Synlett 2012; 23(17): 2477-2480DOI: 10.1055/s-0032-1317205 letter © Georg Thieme Verlag Stuttgart · New York Microwave-Mediated Suzuki–Miyaura Cross-Couplings of Thioether- and ortho-Substituted Methylphenylboronic Acid Esters Christine B. Baltus a School of Science, University of Greenwich at Medway, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK , Neil J. Press b Novartis Pharmaceuticals UK Ltd, Horsham, Sussex, RH12 5AB, UK Fax: +44(1273)876687 Email: j.spencer@sussex.ac.uk , John Spencer* a School of Science, University of Greenwich at Medway, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK › Author Affiliations Recommend Article Abstract Buy Article All articles of this category Abstract Hiterto unsuccessful cross-couplings of ortho-substituted or thioether-substituted methylphenylboronates have now been achieved, under microwave conditions, enabling the synthesis of a library of novel biaryls. Tetrakis(triphenylphosphine)palladium and various bases, for example, sodium carbonate or cesium fluoride, were found to mediate the crucial C–C bond-forming cross-coupling reaction. Key words Key wordspalladium - catalysis - cross-coupling - biaryls - microwaves Full Text References References and Notes 1 Current address: Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QJ, UK. 2a Spencer J, Baltus CB, Patel H, Press NJ, Callear SK, Male L, Coles SJ. ACS Comb. Sci. 2011; 13: 24 2b Spencer J, Burd AP, Adatia T, Goodwin CA, Merette SA. M, Scully MF, Deadman JJ. Tetrahedron 2002; 58: 1551 2c Spencer J, Baltus CB, Press NJ, Harrington RW, Clegg W. Tetrahedron Lett. 2011; 52: 3963 3 Leadbeater N, Marco M. J. Org. Chem. 2003; 68: 888 4 Itoh T, Mase T. J. Org. Chem. 2006; 71: 2203 5 A total of 27 conditions were evaluated: catalysts: PdCl2, Pd(OAc)2, and Pd(PPh3)4; bases: CsF, K3PO4, and Na2CO3; solvents: H2O, THF, and toluene–EtOH–H2O (1:1:1). 6 General Procedure for the SM Coupling of Sulfur-Substituted Methylphenylboronic Esters Using Conditions A: 2-[(4′-Nitrobiphenyl-4-yl)methylthio]pyrimidine (3a) 1a (164 mg, 0.5 mmol,), 2a (111 mg, 0.55 mmol), CsF (228 mg, 1.5 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), and THF (2 mL) were placed in a sealed microwave vial and stirred under microwave irradiation (maximum power 300 W) at 130 °C for 10 min. The mixture was cooled to r.t., diluted with EtOAc (20 mL) and H2O (10 mL), and extracted with EtOAc. The organic layer was washed with a sat. NaCl solution, dried over anhyd MgSO4, filtered, and concentrated under reduced pressure to give 269 mg of an orange solid. The crude product was purified by chromatography on silica gel (hexane–EtOAc, 8:2) to give 147 mg of the expected product as a yellow solid in 91% yield. 1H NMR (400 MHz, CDCl3): δ = 8.55 (d, 2 H, J = 4.8 Hz), 8.29 (d, 2 H, J = 8.8 Hz), 7.72 (d, 2 H, J = 8.8 Hz), 7.57 (m, 4 H), 6.70 (dd, 1 H, J 1 and 2 = 4.8 Hz), 4.47 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.9, 157.3 (2 C), 147.2, 147.1, 138.8, 137.6, 129.9 (2 C), 127.7 (2 C), 127.5 (2 C), 124.1 (2 C), 116.7, 34.8 ppm. HRMS (ES): m/z calcd for [C17H13O2N3S + H]+ 324.0801; found: 324.0805. Anal. Calcd for C17H13N3O2S: C, 63.1; H, 4.1; N, 13.0. Found: C, 62.9; H, 4.1; N, 12.9. General Procedure for the SM Coupling of Sulfur-Substituted Methylphenylboronic Esters Using Conditions C: 2-[(3′-Nitrobiphenyl-4-yl)methylthio]pyrimidine (3b) 1a (125 mg, 0.38 mmol), 3-bromonitrobenzene (2b, 85 mg, 0.42 mmol), Na2CO3 (121 mg, 1.14 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), toluene (1 mL), EtOH (1 mL), and H2O (1 mL) were placed in a sealed microwave vial and stirred under microwave irradiation (maximum power 300 W) at 130 °C for 10 min. The mixture was cooled to r.t., diluted with EtOAc (20 mL) and H2O (10 mL), and extracted with EtOAc. The organic layer was washed with a sat. NaCl solution, dried over anhyd MgSO4, filtered, and concentrated under reduced pressure to give 195 mg of a brown oil. The crude product was purified by chromatography on silica gel (hexane–EtOAc, 8:2) to give 104 mg of the expected product as a yellow solid in 85% yield. 1H NMR (400 MHz, CDCl3): δ = 8.53 (d, 2 H, J = 4.8 Hz), 4.41 (m, 1 H), 8.17 (dd, 1 H, J 1 = 7.9 Hz, J 2 = 2.2 Hz), 7.87 (d, 1 H, J = 7.9 Hz), 7.62–7.52 (m, 5 H), 6.98 (dd, 1 H, J 1 and 2 = 4.8 Hz), 4.46 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.9, 157.3 (2 C), 148.8, 142.5, 138.3, 137.5, 132.9, 129.9 (2 C), 129.7, 127.2 (2 C), 122.0, 121.8, 116.7, 34.8 ppm. HRMS (ES): m/z calcd for [C17H13O2N3S+H]+ 324.0801; found: 324.0804. Anal. Calcd for C17H13N3O2S: C, 63.1; H, 4.1; N, 13.0. Found: C, 62.9; H, 4.0; N, 13.1. 7a Kozlov VA, Aleksanyan DV, Nelyubina YV, Lyssenko KA, Vasil’ev AA, Petrovskii PV, Odinets IL. Organometallics 2010; 29: 2054 ; and references cited therein 7b The Chemistry of Pincer Compounds . 1st ed. Morales-Morales D, Jensen CM. Elsevier; Amsterdam/Oxford: 2007 8a Spencer, J.; Baltus, C. B.; Press, N. J. unpublished results. 8b Baltus CB. PhD Thesis. University of Greenwich; UK: 2011 Supplementary Material Supplementary Material Supporting Information
