Microwave-Mediated Suzuki–Miyaura Cross-Couplings of Thioether- and ortho-Substituted Methylphenylboronic Acid Esters

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

palladium - catalysis - cross-coupling - biaryls - microwaves

• 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