One-Pot Synthesis of Difluorinated ortho-Terphenyls by Site-Selective Suzuki-Miyaura Reactions of 1,2-Dibromo-3,5-difluorobenzene

Abstract

The Suzuki-Miyaura reaction of 1,2-dibromo-3,5-di­fluorobenzene with two equivalents of arylboronic acids gave di­fluorinated ortho-terphenyls. The reaction with one equivalent of arylboronic acid resulted in site-selective formation of 2-bromo-3,5-difluoro-biphenyls. The one-pot reaction of 1,2-dibromo-3,5-difluorobenzene with two different arylboronic acids afforded di­fluorinated ortho-terphenyls containing two different terminal aryl groups.

catalysis - palladium - Suzuki-Miyaura reaction - site ­selectivity - organofluorine compounds

References and Notes

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General Procedure for Suzuki Reactions
A 1,4-dioxane solution (4 mL per 0.3 mmol of 1) of 1, Cs₂CO₃, Pd(PPh₃)₄, and arylboronic acid 2 was stirred at
90 ˚C for 6 or 8 h. After cooling to r.t. the organic and the aqueous layer were separated and the latter was extracted with CH₂Cl₂. The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography.

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1,2-Di(2-Methoxyphenyl)-3,5-difluorobenzene (3f)
Starting with 1 (100 mg, 0.37 mmol), Cs₂CO₃ (263 mg, 0.81 mmol), Pd(PPh₃)₄ (3 mol%), 2-methoxyphenylboronic acid (123 mg, 0.81 mmol), and 1,4-dioxane (4 mL), 3f was isolated as a colorless solid (72 mg, 60%), mp 111-113 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.42 (s, 3 H, OCH₃), 3.55 (s, 3 H, OCH₃), 6.60 (dd, J = 8.3, 0.7 Hz, 1 H, ArH), 6.67-6.88 (m, 6 H, ArH), 6.94 (dd, J = 7.5, 1.7 Hz, 1 H, ArH), 7.05-7.12 (m, 2 H, ArH). ^¹³C NMR (62.89 MHz, CDCl₃): δ = 54.9 (OCH₃), 55.2 (OCH₃), 102.6 (t, ^² J _CF = 26.5 Hz, CH), 110.2 (CH), 110.3 (CH), 113.2 (dd, J _CF = 21.2, 3.5 Hz, CH), 119.7 (CH), 119.9 (CH), 122.1 (dd, J = 17.1, 3.8 Hz, C), 123.1 (C), 128.6 (t, J = 2.1 Hz, C), 128.90 (CH), 128.92 (CH), 131.0 (CH), 131.7 (CH), 141.9 (t, J = 4.9 Hz, C), 156.0 (C), 157.0 (C), 160.1 (dd, J _CF = 247.2, 12.8 Hz, CF), 161.6 (dd, J _CF = 247.2, 13.3 Hz, CF). ^¹9F NMR (282.4 MHz, CDCl₃): δ = -112.82 (CF), -118.20 (CF). IR (ATR): ν = 3067 (w), 2956 (w), 2926 (w), 2835 (w), 1616 (w), 1596 (w), 1503 (w), 1494 (w), 1455 (w), 1421 (w), 1338 (w), 1287 (w), 1247 (m), 1201 (w), 1180 (w), 1120 (w), 1089 (w), 1024 (m), 928 (w), 877 (w), 865 (w), 800 (w), 755 (w), 744 (m), 701 (w), 635 (w), 586 (m), 537 (w) cm^-¹. MS (EI, 70 eV): m/z (%) = 326 (100) [M]⁺, 295 (12), 251 (21), 238 (10). HRMS (EI): m/z calcd for C₂₀H₁₆O₂F₂ [M⁺]: 326.11129; found: 326.11090.

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2-Bromo-3,5-difluoro-2′,4′-dimethoxybiphenyl (4d) Starting with 1 (100 mg, 0.37 mmol), Cs₂CO₃ (119 mg, 0.37 mmol), Pd(PPh₃)₄ (3 mol%), 2,4-dimethoxyphenylboronic acid (67 mg, 0.37 mmol), and 1,4-dioxane (4 mL), 4d was isolated as a colorless solid (81 mg, 67%), mp 64-66 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.75 (s, 3 H, OCH₃), 3.89 (s, 3 H, OCH₃), 6.53-6.57 (m, 2 H, Ar), 6.82-6.88 (m, 2 H, Ar), 7.04 (d, J = 8.9 Hz, 1 H, Ar). ^¹³C NMR (75.46 MHz, CDCl₃): δ = 55.4 (OCH₃), 55.6 (OCH₃), 98.7 (CH), 103.4 (t, ^² J _CF = 26.6 Hz, CH), 104 (CH), 106.9 (dd, J = 20.4, 4.0 Hz, C), 114.5 (dd, J = 22.3, 3.3 Hz, CH), 121.0 (t, J = 2.2, C), 131.1 (CH), 142.9 (d, J = 9.8 Hz, C), 157.4 (C), 159.22 (dd, J = 248.0, 13.7 Hz, CF), 161.3 (dd, J = 248.6, 13.2 Hz, CF) 161.4 (C). ^¹9F NMR (282.4 MHz, CDCl₃): δ = -100.5 (CF), -112.4 (CF). IR (ATR): ν = 3079 (w), 3002 (w), 2958 (w), 2937 (w), 2836 (w), 1692 (s), 1785 (s), 1509 (s), 1463 (m), 1447 (m), 1468 (w), 1435 (s), 1345 (w), 1304 (s), 1281 (m), 1256 (m), 1206 (s), 1146 (m), 1127 (s), 1101 (s), 1031 (s), 997 (s), 924 (m), 833 (s), 796 (m), 716 (w), 637 (w), 599 (s), 587 (m) cm^-¹. MS (EI, 70 eV): m/z (%) = 328 (95) [M]⁺, 330 (93), 329 (15), 331 (14), 235 (15), 234 (100), 219 (35), 204 (12), 191 (20), 175 (26), 163 (13). ESI-HRMS: m/z calcd for C₁₄H₁₂BrF₂O₂ [M + H]⁺: 328.9983; found: 328.9979.

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General Procedure for the Synthesis of 5a-d
The reaction was carried out in a pressure tube. To a dioxane suspension (4 mL) of 1 (200 mg, 0.74 mmol), Pd(PPh₃)₄
(3 mol%), and Ar^¹B(OH)₂ (0.74 mmol) was added Cs₂CO₃ (359 mg, 1.11 mmol), and the resultant solution was degassed by bubbling argon through the solution for 10 min. The mixture was heated at 90 ˚C under Argon atmosphere for 8 h. The mixture was cooled to 20 ˚C and Ar^²B(OH)₂ (0.89 mmol) and Cs₂CO₃ (359 mg, 1.11 mmol) was added. The reaction mixtures were heated under Argon atmosphere for 6 h at 100 ˚C. They were diluted with H₂O and extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc-hexane = 1:4).

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1-(2,4-Dimethoxyphenyl)-2-(4-methylphenyl)-3,5-difluorobenzene (5a) Starting with 1 (200 mg, 0.74 mmol), Cs₂CO₃ (359 mg, 1.11 mmol), Pd(PPh₃)₄ (3 mol%), 2,6-dimethoxyphenylboronic (134 mg, 0.74 mmol), 1,4-dioxane (4 mL), and 4-methyl-boronic acid (123 mg, 0.89 mmol), 5a was isolated as a colorless highly viscous oil (120 mg, 48%). ^¹H NMR (300 MHz, CDCl₃): δ = 2.19 (s, 3 H, ArH), 3.32 (s, 3 H, OCH₃), 3.69 (s, 3 H, OCH₃), 6.17 (d, J = 2.3 Hz, 1 H, Ar), 6.32 (dd, J = 8.3, 2.3 Hz, 1 H, Ar), 6.74-6.83 (m, 2 H, Ar), 6.86-6.91 (m, 5 H, Ar). ^¹³C NMR (62.89 MHz, CDCl₃): δ = 21.2 (CH₃), 55.0 (OCH₃), 55.3 (OCH₃), 98.4 (CH), 102.5 (t, ^² J _CF = 26.3 Hz, CH), 104.1 (CH), 113.6 (dd, J _CF = 21.9, 3.6 Hz, CH), 121.5 (t, ^³ J = 2.8 Hz, C), 125.7 (dd, J = 15.3, 3.6 Hz, C), 128.1 (2 CH), 130.0 (2 CH), 131.1 (C), 131.6 (CH), 136.4 (C), 141.2 (dd, J = 9.6, 4.5 Hz, C), 157.0 (C), 159.8 (dd, J _CF = 246.8, 13.0 Hz, CF), 160.6 (C), 161.1 (dd, J _CF = 247.1, 13.4 Hz, C). ^¹9F NMR (282.4 MHz, CDCl₃): δ = -111.86 (CF), -112.9 (CF). IR (ATR): ν = 3080 (w), 2998 (w), 2956 (w), 2836 (w), 1736 (w), 1609 (s), 1586 (s), 1508 (s), 1454 (s), 1425 (m), 1401 (m), 1372 (w), 1303 (s), 1255 (m), 1184 (w), 1158 (s), 1145 (s), 1092 (s), 1032 (s), 996 (s), 925 (m), 861 (w), 834 (m), 818 (s)796 (m), 736 (w), 718 (w), 663 (w), 607 (w), 587 (m) cm^-¹. MS (EI, 70 eV): m/z (%) = 340 (100) [M]⁺, 294 (11), 265 (13), 238 (12). ESI-HRMS: m/z calcd for C₂₁H₁₉F₂O₂ [M + H]⁺: 341.1348; found: 341.1348.

16

CCDC-762919 and 762920 contain all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: [phone]; or [e-mail].

17 For a simple guide for the prediction of the site selectivity of palladium(0)-catalyzed cross-coupling reactions based on the ^¹H NMR chemical shift values, see: Handy ST. Zhang Y. Chem. Commun.  2006,  299