Metal-Free Iodination of Arylboronic Acids and the Synthesis of Biaryl Derivatives

Abstract

A simple, general and efficient method is developed for the metal-free iodination of arylboronic acids. The protocol uses very cheap molecular iodine as the halide source and potassium carbonate as the base. The method is highly tolerant of various functional groups present in the substrates. Importantly, the iodination strategy can also be applied very effectively in the one-pot, two-step synthesis of biaryl derivatives.

Key words

arylboronic acids - iodination - cross-coupling - Suzuki coupling - biaryl derivatives

• References and Notes


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• 13 K₂CO₃ (99.997%) was purchased from Alfa Aesar and contains Si (1 ppm), Ca (2 ppm) and Na (4 ppm); other elements including: Al, Bi, Cr, Fe, Mn, Sr, V, Sb, B, Co, Pb, Mo, Te, Zn, As, Cd, Cu, Li, Ni, Ag, Sn, Zr, Ba, In, Mg, P and Ti were not detected by ICP/AA (data provided by Alfa Aesar).
• 14 Aryl Iodides (2); General Procedure Arylboronic acid 1 (0.5 mmol) and K₂CO₃ (1 mmol, 138.0 mg) were added to a 20 mL Schlenk-tube equipped with a magnetic stir bar. The tube was evacuated twice and back-filled with N₂. MeCN (2 mL) and I₂ (0.75 mmol, 191 mg) were added to the tube at r.t. under a stream of N₂, and the tube was sealed and placed into a pre-heated oil bath at 80 °C for 8–12 h. The resulting solution was cooled to r.t. and H₂O (10 mL) was added. The aq layer was extracted with EtOAc (3 × 5 mL). For products 2s and 2t, HCl (1 M) was added to the aq solution until pH 2 before extraction. The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated by rotary evaporation. Purification of the residue by column chromatography on silica gel provided the desired product 2a–v. Data for three representative examples are provided. PE = petroleum ether. 1-Iodo-4-methoxybenzene (2g) ^[16] Eluent: PE; yield: 93.6 mg (80%); white solid; mp 49–50 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.54 (d, J = 8.9 Hz, 2 H), 6.68 (d, J = 8.9 Hz, 2 H), 3.77 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 159.6, 138.3, 116.5, 82.8, 55.4. EI-MS: m/z [M]⁺ = 234.0. 1-Chloro-3-iodobenzene (2k) ^[17] Eluent: PE; yield: 86.8 mg (73%); yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.75 (s, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 1 H), 7.02 (t, J = 7.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 137.3, 135.8, 135.2, 131.1, 128.1, 94.3. EI-MS: m/z [M]⁺ = 237.9. 1-Iododibenzo[b,d]furan (2v) ^[8a] Eluent: PE–EtOAc, 20:1; yield: 129.4 mg (88%); white solid; mp 48–49 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.90–7.77 (m, 3 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.47 (d, J = 6.9 Hz, 1 H), 7.37 (d, J = 6.9 Hz, 1 H), 7.08 (t, J = 7.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 156.5, 155.7, 136.0, 127.8, 124.6, 124.5, 124.4, 123.3, 121.3, 120.6, 112.2, 75.6. EI-MS: m/z [M]⁺ = 294.0.
• 15 Biaryls (3); General Procedure Arylboronic acid 1 (0.5 mmol) and K₂CO₃ (1 mmol, 138.0 mg) were added to a 20 mL Schlenk-tube equipped with a magnetic stir bar. The tube was evacuated twice and back-filled with N₂. MeCN (2 mL) and I₂ (0.75 mmol, 191 mg) were added to the tube at r.t. under a stream of N₂, and the tube was sealed and placed into a pre-heated oil bath at 80 °C for 8–12 h. The resulting solution was cooled to r.t., and then arylboronic acid 1′ (0.75 mmol) and Pd(OAc)₂ (0.025 mmol, 5.6 mg) were added, and the mixture stirred at 80 °C for 12–16 h. The resulting solution was cooled to r.t. and H₂O (10 mL) was added. The aq layer was extracted with EtOAc (3 × 5 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated by rotary evaporation, and the residue was purified by column chromatography on silica gel to provide the desired product 3a–v. Data for three representative examples are provided. 3-Methoxy-1,1′-biphenyl (3c) Eluent: PE–EtOAc, 100:1; yield: 70.8 mg (77%); yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 6.9 Hz, 2 H), 7.47 (t, J = 7.3 Hz, 2 H), 7.41–7.37 (m, 2 H), 7.22 (d,  = 8.2 Hz, 1 H), 7.17 (s, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 3.89 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.1, 142.9, 141.2, 129.9, 128.9, 127.5, 127.3, 119.8, 113.0, 112.8, 55.4. EI-MS: m/z [M]⁺ = 184.1. Methyl 4′-Methyl-[1,1′-biphenyl]-4-carboxylate (3n) Eluent: PE–EtOAc, 100:1; yield: 98.4 mg (87%); white solid; mp 102–103 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (d, J = 8.7 Hz, 2 H), 7.64 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.2 Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H), 3.93 (s, 3 H), 2.40 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.1, 145.7, 138.2, 137.2, 130.2, 129.7, 128.7, 127.2, 126.9, 52.2, 21.2. EI-MS: m/z [M]⁺ = 226.1. 3′-Methyl-[1,1′-biphenyl]-4-carbonitrile (3q) Eluent: PE–EtOAc, 100:1; yield: 78.2 mg (81%); colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.71 (d, J = 8.2 Hz, 2 H), 7.67 (d, J = 8.2 Hz, 2 H), 7.39–7.36 (m, 3 H), 7.23 (d, J = 6.0 Hz, 1 H), 2.43 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.9, 139.3, 138.9, 132.6, 129.5, 129.1, 128.1, 127.8, 124.5, 119.1, 110.9, 21.6. EI-MS: m/z [M]⁺ = 193.1.
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