Synthesis of 3,5-Diaryl-4-fluorophthalates by [4+2]-Cycloaddition and Subsequent Site-Selective Suzuki-Miyaura Reactions

Abstract

The [4+2] cycloaddition of 1-ethoxy-2-fluoro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 4-fluoro-3,5-dihydroxyphthalate. Site-selective Suzuki-Miyaura reactions of its bis(triflate) provide a convenient approach to 3,5-diaryl-4-fluorophthalates.

Key words

arenes - cyclizations - organofluorine compounds - site-selectivity - Suzuki-Miyaura reaction

References and Notes

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11

Synthesis of Dimethyl 4-Fluoro-3,5-dihydroxyphthalate (2): Diene 1 (9.0 g, 30.8 mmol) was added to DMAD (6.5 g, 5.5 mL, 46.2 mmol) at -78 ˚C. The mixture(neat) was allowed to warm to 20 ˚C during 20 h with stirring. To the mixture were added hydrochloric acid (10%) and dichloromethane (50 mL each). The organic and the aqueous layer were separated and the latter was extracted with CH₂Cl_2. The combined organic layers were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give 2 as a crystalline colorless solid (3.0 g, 40%); mp 140-142 ˚C. ^¹H NMR (250 MHz, CDCl₃): δ = 3.87 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 6.15 (s, 1 H, OH), 6.60 (d, 1 H, J _FH = 7.5 Hz, ArH), 10.96 (s, 1 H, OH). ^¹³C NMR (75 MHz, CDCl₃): δ = 52.8 (OMe), 53.0 (OMe), 104.6 (C), 108.4 (CH), 131.6 (d, J _FC = 4.5 Hz, C), 140.5 (d, J _FC = 239 Hz, CF), 148.3 (d, J _FC = 11.7 Hz, COH), 151.1 (d, J _FC = 11.0 Hz, COH), 168.6 (C=O), 168.8 (d, J _FC = 3.0 Hz, C=O). ^¹9F NMR (282 MHz, CDCl₃): δ = -160.80 (F). IR (ATR): 3292 (m), 2962 (w), 2859 (w), 1716 (s), 1682 (s), 1621 (s), 1599 (s), 1515 (w), 1434 (s), 1325 (s), 1236 (s), 1093 (s), 933 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 244 (24) [M⁺], 212 (53), 181 (11), 154 (100), 137 (4), 126 (12), 97 (9). HRMS (EI): m/z [M⁺] calcd for C₁₀H₉O₆F: 244.03777; found: 244.037617.

12

Dimethyl 4-Fluoro-3,5-bis(trifluoromethylsulfonyloxy)-phthalate (3): To a solution of 2 (1.0 equiv) in CH₂Cl₂ (10 mL/mmol) was added pyridine (4.0 equiv) at - 78 ˚C under an argon atmosphere. After 10 min, Tf₂O (2.4 equiv) was added at -78 ˚C. The mixture was allowed to warm up to 0 ˚C and stirred for 4 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The products of the reaction mixture were isolated by rapid column chromatography (flash silica gel, heptanes-EtOAc). Starting with 2 (2.00 g, 8.0 mmol), pyridine (2.6 mL, 32.0 mmol), CH₂Cl₂ (80 mL), Tf₂O (3.2 mL, 19.2 mmol), 3 was isolated as a viscous colorless liquid (3.54 g, 87%). ^¹H NMR (300 MHz, CDCl₃): δ = 3.87 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 7.96 (d, ⁴ J _FH = 6.4 Hz, 1 H, ArH). ^¹³C NMR (75 MHz, CDCl₃): δ = 52.6 (OMe), 52.7 (OMe), 117.5 (q, ^¹ J _CF = 321 Hz, CF₃), 117.6 (q, ^¹ J _CF = 321 Hz, CF₃), 124.3 (br s, CH), 124.9 (d, ^³ J _FC = 5.0 Hz, C), 130.9 (C), 133.8 (d, ^² J _FC = 13.2 Hz, C), 136.7 (d, ^² J = 12.2 Hz, C), 148.0 (d, ^¹ J = 268 Hz, CF), 161 (CO), 161.4 (d, ⁴ J _FC = 1.6 Hz, CO). ^¹9F NMR (282 MHz, CDCl₃): δ = 129.34, -72.81 (d, ⁵ J _FCF3 = 5.1 Hz, CF₃), -72.51 (d, ⁵ J _FCF3 = 14.31 Hz, CF₃). IR (ATR): 2960 (w), 2922 (w), 1739 (s), 1616 (w), 1595 (w), 1502 (w), 1426 (s), 1326 (m), 1209 (s), 1128 (m), 1045 (m), 1011 (s), 971 (s), 887 (m), 821 (m), 787 (s), 750 (m), 736 (m), 650 (w), 601 (s) cm^-¹. GC-MS (70 eV): m/z (%) = 510 (1) [M⁺ + 2], 509 (2) [M⁺ + 1], 508 (12) [M⁺], 477 (100), 439 (5), 413 (44), 349 (52), 283 (33), 253 (6), 222 (19), 183 (16), 155 (14), 127 (4), 81 (8), 69 (63), 59 (15), 45 (4). HRMS (EI): m/z [M⁺] calcd for C₁₂H₇O₁₀F₇S₂: 507.93634; found: 507.936470.

13

CCDC 753087 and CCDC 753088 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

14

General Procedure for Suzuki-Miyaura Reactions:
A 1,4-dioxane solution (4 mL per 3 mmol of 3 ) of 3, K₃PO₄, Pd(PPh₃)₄ and arylboronic acid 4 was stirred at 110 ˚C or 90 ˚C for 8 h. After cooling to 20 ˚C, a saturated aqueous solution of NH₄Cl was added. The organic and the aqueous layers 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.

15

Dimethyl 4-Fluoro-3,5-di(4-ethylphenyl)phthalate (5e): Starting with 3 (152 mg, 0.3 mmol), K₃PO₄ (191 mg, 0.9 mmol), Pd(PPh₃)₄ (3 mol%), 4-ethylphenylboronic acid (105 mg, 0.7 mmol) and 1,4-dioxane (4 mL), 5e was isolated as a colorless solid (91 mg, 72%); mp 151-153 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.19 (t, J = 7.5 Hz, 3 H, Me), 1.20 (t, J = 7.5 Hz, 3 H, Me), 2.62 (q, J = 7.6 Hz, 2 H, CH₂), 2.63 (q,
J = 7.6 Hz, 2 H, CH₂), 3.56 (s, 3 H, OMe), 3.83 (s, 3 H, OMe), 7.16-7.23 (m, 9 H, ArH). ^¹³C NMR (75 MHz, CDCl₃):
δ = 15.3, 15.5 (2 × Me), 28.6 (2 × CH₂), 52.4 (OMe), 52.6 (OMe), 123.6 (d, ^³ J _CF = 4.4 Hz, C), 127.7 (2 × CH), 128.2
(2 × CH), 129.0 (d, ⁴ J _CF = 2.8 Hz, 2 × CH), 129.3 (C), 129.6 (d, ⁴ J _FC = 1.2 Hz, 2 × CH), 130.2 (d, ^² J _FC = 15.9 Hz, C), 131.5 (C), 131.9 (d, ^³ J _FC = 5.5 Hz, CH), 136.6 (d, ⁴ J _FC = 3.8 Hz, C), 144.7 (d, ^² J _FC = 23.7 Hz, C), 159.1 (d, ^¹ J _FC = 256 Hz, CF), 165.4 (CO), 167.9 (d, ⁴ J _FC = 2.7 Hz, CO). ^¹9F NMR (282 MHz, CDCl₃): δ = -111.4. IR (ATR): 3037 (w), 3002 (w), 2961 (m), 2947 (m), 2931 (m), 2671 (w), 1739 (m), 1717 (s), 1613 (w), 1514 (m), 1429 (m), 1396 (m), 1345 (m), 1274 (m), 1247 (m), 1219 (s), 1146 (m), 1118 (m), 1069 (m), 1020 (m), 1003 (m), 968 (m), 848 (m), 835 (m), 794 (m), 683 (m), 575 (m), 531 (m) cm^-¹. GC-MS (70 eV): m/z (%) = 421 (28) [M⁺ + 1], 420 (100) [M⁺], 405 (20), 389 (52), 373 (3), 357 (18), 329 (7), 315 (2), 301 (4), 287 (5), 273 (6), 272 (5), 259 (4), 257 (6), 252 (2), 244 (3), 195 (7), 170 (2), 143 (3), 135 (3), 129 (2), 77 (1), 59 (1), 29 (2). HRMS (EI): m/z [M⁺] calcd for C₂₆H₂₅O₄F: 420.17314: found: 420.173423.

16

Dimethyl 4-Fluoro-5-(3,5-dimethylphenyl)-3-(trifluoro-methylsulfonyloxy)phthalate (6e): Starting with 3 (152 mg, 0.3 mmol), K₃PO₄ (95 mg, 0.45 mmol), Pd(PPh₃)₄ (3 mol%), 3,5-dimethylphenylboronic acid (50 mg, 0.33 mmol) and 1,4-dioxane (4 mL), 6e was isolated as a colorless solid (104 mg, 75%); mp 79-80 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 2.31 (br s, 6 H, 2 × Me), 3.85 (s, 3 H, OMe), 3.92 (s, 3 H, OMe), 7.02 (s, 1 H, ArH), 7.06 (s, 2 H, ArH), 8.01 (d, ⁴ J _FH = 6.6 Hz, 1 H, ArH). ^¹³C NMR (62.90 MHz, CDCl₃): δ = 20.3 (2 × Me), 52.1 (OMe), 52.3 (OMe), 117.5 (q, ^¹ J _CF = 321 Hz, CF₃), 124.4 (d, ^³ J _FC = 4.4 Hz, C), 125.6 (d, ⁴ J _FC = 2.75, 2 × CH), 128.8 (C), 130.1 (CH), 130.9 (d, ^³ J _FC = 4.6 Hz, CH), 131.1 (d, ⁴ J = 1.8 Hz, C), 131.9 (d, ^² J = 13.0 Hz, C), 133.3 (d, ^² J _F,C = 17.0 Hz, C), 137.6 (s, 2 × C), 152.3 (d, ^¹ J _FC = 261 Hz, C), 162.7 (d, ⁴ J _FC = 2.7 Hz, CO). 163.1 (CO). ^¹9F NMR (282 MHz, CDCl₃): δ = -72.58 (d, J = 13.4 Hz, CF₃), -122.34 (q, J = 13.4 Hz, ArF). IR (ATR): 2959 (w), 2921 (w), 1737 (s), 1729 (s), 1620 (w), 1602 (w), 1495 (w), 1428 (s), 1408 (m), 1343 (m), 1275 (s), 1205 (s), 1133 (m), 1006 (m), 945 (m), 854 (m), 813 (s), 757 (m), 731 (m), 598 (s), 532 (s) cm^-¹. GC-MS (70 eV): m/z (%) = 466 (8) [M⁺ + 2], 465 (21) [M⁺ + 1], 464 (100) [M⁺], 433 (35), 395 (2), 369 (16), 331 (6), 303 (10), 272 (9), 242 (15), 214 (10), 185 (6), 160 (7), 99 (1), 69 (5), 59 (2). HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₉H₁₇F₄O₇S: 465.06256; found: 465.06268.

17

General Procedure for the Synthesis of 7a-c: The reaction was carried out in a pressure tube. To a dioxane suspension (4 mL) of 3 (228 mg, 0.45 mmol), Pd(PPh₃)₄ (3 mol%) and Ar^¹B(OH)₂ (0.5 mmol) was added K₃PO₄ (143 mg, 0.67 mmol), and the resultant solution was degassed by bubbling argon through the solution for 10 min. The mixture was heated at 90 ˚C under an argon atmosphere for 9 h. The mixture was cooled to 20 ˚C. Ar^²B(OH)₂ (0.6 mmol) and K₃PO₄ (143 mg, 0.67 mmol) were added. The reaction mixtures were heated under an argon atmosphere for 6 h at 110 ˚C. They were diluted with H₂O and extracted with CH₂Cl₂ (3 × 25 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-heptanes).

18

Dimethyl 4-Fluoro-5-(2-ethoxyphenyl)-3-(4-ethylphenyl)-phthalate (7c): Starting with 3 (228 mg, 0.45 mmol), K₃PO₄ (286 mg, 1.34 mmol), Pd(PPh₃)₄ (3 mol%), 2-ethoxyphenyl-boronic acid (82 mg, 0.5 mmol), 1,4-dioxane (4 mL), and
4-ethylphenylboronic acid (85 mg, 0.6 mmol), 7c was isolated as transparent crystals (114 mg, 58%); mp 104-106 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.15-1.25 (m, 6 H, 2 × Me), 2.61 (q, J = 7.5 Hz, 2 H, CH₂), 3.57 (s, 3 H, OMe), 3.78 (s, 3 H, OMe), 3.95 (q, ^³ J = 7.0 Hz, 2 H, OCH₂), 6.87 (d, J = 8.4 Hz, 1 H, ArH), 6.93 (dt, J = 7.5 Hz, 1 H, ArH), 7.14-7.30 (m, 6 H, ArH), 7.98 (d, ⁴ J _FH = 6.7 Hz, 1 H, ArH). ^¹³C NMR (62.90 MHz, CDCl₃): δ = 14.7 (Me), 15.2 (Me), 28.6 (CH₂), 52.3 (OMe), 52.5 (OMe), 64.0 (OCH₂), 112.1, 120.5 (2 × CH), 123.7 (C), 127.6 (2 × CH), 127.8 (d, ^² J _FC = 19.0 Hz, C), 128.5 (d, ^² J = 20.7 Hz, C), 129.4, 129.5, 130.1 (3 × CH), 131.0 (d, ⁴ J = 1.4 Hz, CH), 133.3 (d, ^³ J _F,C = 5.6 Hz, CH), 136.8 (d, ^³ J _F,C = 4.1 Hz, C), 144.3, 156.3 (2 × C), 159.6 (d, ^¹ J _FC = 256 Hz, CF), 165.5 (C=O), 168.1 (d, ⁴ J = 2.7 Hz, C=O). ^¹9F NMR (282 MHz, CDCl₃): δ =
-106.42 (CF). IR (ATR): 2973 (w), 2944 (w), 2929 (w), 2881 (w), 1724 (br s), 1609 (w), 1580 (w), 1563 (w), 1516 (w), 1497 (m), 1451 (m), 1428 (m), 1390 (m), 1341 (m), 1273 (s), 1249 (s), 1215 (s), 1149 (s), 1123 (m), 1067 (m), 1041 (s), 969 (m), 919 (m), 858 (w), 839 (w), 793 (m), 754 (s), 689 (m), 611 (m), 537 (w) cm^-¹. GC-MS (70 eV): m/z (%) = 438 (5) [M⁺ + 2], 437 (30) [M⁺ +1], 436 (100) [M⁺], 405 (19), 376 (30), 361 (16), 348 (20), 317 (20), 289 (9), 271 (9), 244 (5), 171 (3), 151 (2), 128 (2), 59 (2), 29 (4). HRMS (EI): m/z [M⁺] calcd for C₂₆H₂₅FO₅: 436.16805; found: 436.168135.