Direct ortho Arylation of Anisoles via the Formation of Four-Membered Lithiumcycles/Palladacycles

^◊ These authors contributed equally

Abstract

We report here our latest discovery on the directed lithiation and palladium-catalyzed arylation of anisoles. During this research, the formation of a four-membered lithiumcycle followed by transmetalation to the corresponding palladacycle has been achieved, which is difficult to be obtained from palladium-catalyzed C–H activation processes. This approach has provided an alternative way of introducing functionalities to arenes such as anisoles, thioanisoles, and anilines. This approach also features an excellent monoselectivity compared with reactions under transition-metal-catalyzed conditions.

Key words

directed lithiation - lithiumcycle - transmetalation - mono-selectivity - palladium-catalyzed arylation

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• 16 General Procedure for Direct ortho Arylation of Anisoles A 5 mL well-dried round-bottomed flask was charged with nitrogen through Schlenk line. To a solution of the corresponding substrate (0.2 mmol) and TMEDA (34.8 mg, 1.5 equiv) in Et₂O (0.4 M, 0.5 mL), n-BuLi (2.4 M, 0.125 mL, 1.5 equiv) was added dropwise at r.t. Then the reaction was allowed to stir for 0.5 h at r.t. In another 10 mL well-dried flask, the aryl halides (ArX, X = Br or I, 2 equiv), Pd₂(dba)₃ (9.2 mg, 5 mol%) and P(t-Bu)₃ (1.0 M in Tol, 0.04 mL, 20 mol%) were dissolved in toluene (0.4 mL), and the solution was stirred for 5 min. Then the above organolithium solution was added dropwise at 0 °C, and the reaction was then allowed to stir at 50 °C for another 3 h. The mixture was quenched with sat. aq NH₄Cl, extracted with EtOAc (3 × 5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuo. The residue was purified by column chromatography to get the product. (Z)-2-{[5-(1,2-Diphenylbut-1-en-1-yl)-3′-methoxy-(1,1′-biphenyl)-2-yl]oxy}-N,N-dimethylethanamine (8a) Following the general procedure, the amine 8a was obtained after column chromatography as a colorless oil (X = I, 26 mg, 27 % yield). ¹H NMR (600 MHz, CDCl₃): δ = 7.35 (t, J = 6.5 Hz, 2 H), 7.29–7.20 (m, 5 H), 7.19–7.13 (m, 4 H), 6.86 (s, 1 H), 6.77 (d, J = 8.0 Hz, 2 H), 6.69 (m, 2 H), 6.64 (d, J = 8.0 Hz, 1 H), 3.94 (t, J = 5.0 Hz, 2 H), 3.76 (s, 3 H), 2.59 (t, J = 5.0 Hz, 2 H), 2.46 (q, J = 6.5 Hz, 2 H), 2.21 (s, 6 H), 0.93 (t, J = 7.0 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 158.9, 153.7, 143.6, 142.6, 141.6, 139.8, 138.1, 135.7, 133.7, 130.8, 129.8, 129.5, 129.3, 128.4, 128.1, 128.0, 126.6, 126.1, 122.2, 114.7, 112.7, 111.6, 66.7, 58.0, 55.3, 45.9, 29.1, 13.6. ESI-HRMS: m/z [M + H]⁺ calcd for (C₃₃H₃₆NO₂): 478.2746; found: 478.2745.