Site-Selective Suzuki–Miyaura Cross-Coupling Reactions of the Bis(triflate) of Methyl 3,7-Dihydroxy-2-naphthoate

Abstract

Arylated naphthalenes were prepared by Suzuki–­Miyaura reactions of the bis(triflate) of methyl 3,7-dihydroxy-2-naphthoate. The reactions proceeded with very good site-selectivity in favor of the sterically less hindered position 7, despite the proximity of position 3 to the electron-withdrawing ester group which plays a decisive role for the site-selectivity of Suzuki–Miyaura reactions of related substrates.

Key words

catalysis - palladium - Suzuki–Miyaura reaction - naphthalenes - site-selectivity

• References and Notes

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• 7 Methyl 3,7-Dihydroxy-2-naphthoate (2) To a solution of 3,7-dihydroxy-2-naphthoic acid (1, 2.0 g, 9.79 mmol) in DMF (30 mL), dimethyl sulfate (2.76 g, 21.93 mmol) and DIPEA (1.4 g, 10.76 mmol) were added. The reaction mixture was heated for 1 h at 85 °C. After cooling to r.t., the mixture was poured into ice water. A white precipitate formed which was filtered off, and the filtrate was concentrated in vacuo. The product 2 was isolated by column chromatography (flash silica gel, heptane–EtOAc) as a yellow solid (1.6 g, 77%); mp 101–102 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.95 (s, 3 H, OCH₃), 4.79 (s, 1 H, OH), 7.04–7.05 (m, 1 H, ArH), 7.08 (dd, J = 2.4, 8.8 Hz, 1 H, ArH), 7.20 (s, 1 H, ArH), 7.55 (d, J = 8.9 Hz, 1 H, ArH), 8.25 (s, 1 H, ArH), 10.19 (s, 1 H, OH). ¹³C NMR (62.90 MHz, CDCl₃): δ = 52.5 (OCH₃), 110.1, 111.8 (CH), 114.6 (C), 121.6 (CH), 127.7 (C), 128.1, 130.3 (CH), 133.4, 151.7, 154.7 (C), 170.2 (CO). IR (KBr): ν = 3328 (m), 3038, 3003, 2953 (w), 1681 (m), 1651, 1633, 1609, 1576, 1556 (w), 1531 (m), 1505, 1479, 1462 (w), 1441, 1392, 1345, 1263, 1214 (s), 1180, 1147, 1130, 1072 (m), 1012, 969 (w), 944, 903, (w), 860 (s), 836, 812 (m), 783 (s), 746 (w), 716 (s), 665, 620, 610 (w), 587, 550 (w) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 219 (8) [M + H]⁺, 218 (52) [M]⁺, 187 (17), 186 (100), 185 (10), 159 (10), 158 (80), 130 (45), 102 (20). HRMS (EI, 70 eV): m/z calcd for C₁₂H₁₀O₄ [M]⁺: 218.0579; found: 218.0599.
• 8 Methyl 3,7-Bis[4-(trifluoromethyl)sulfonyloxy-phenyl]-2-naphthoate (3) To a CH₂Cl₂ solution (46 mL) of 2 (1.0 g, 4.6 mmol) was added pyridine (1.5 mL, 18.4 mmol), and the solution was stirred at 20 °C for 10 min under an argon atmosphere. Then Tf₂O (1.8 mL, 11.0 mmol) was added at –78 °C, and the reaction mixture was allowed to warm to r.t. and was stirred for 14 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The product 3 was isolated by column chromatography (flash silica gel, heptane–EtOAc) as a colorless solid (1.9 g, 87%); mp 75–77 °C. ¹H NMR (300 MHz, CDCl₃): δ = 4.06 (s, 3 H, OCH₃), 7.47–7.70 (m, 1 H, ArH), 7.85 (s, 1 H, ArH), 7.94 (d, J = 2.3 Hz, 1 H, ArH), 8.03 (d, J = 9.0 Hz, 1 H, ArH), 8.72 (s, 1 H, ArH). ¹³C NMR (62.90 MHz, CDCl₃): δ = 52.99 (OCH₃), 117.7 (q, J _F–C = 320.2 Hz, CF₃), 117.9 (q, J _F–C = 320.8 Hz, CF₃), 120.4, 121.2, 123.6 (CH), 130.5 (C), 130.5 (CH), 131.8, 133.8 (C), 134.6 (CH), 145.5, 148.3 (C), 163.7 (CO). IR (KBr): ν = 3070, 2963 (w), 1713 (s), 1678, 1633 (w), 1599 (m), 1502, 1461, 1443 (w), 1426, 1398 (s), 1365, 1309 (m), 1276 (s), 1249 (m), 1203, 1131, 1116, 1048 (s), 965 (w), 937, 909, 937, 909, 845, 813, 795 (s), 779, 766, 754, 739 (m), 697 (w), 676 (m), 650, 609, (s), 597, 582 (m), 565 (w) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 483 (10) [M + H]⁺, 482 (61) [M]⁺, 451 (16), 350 (14), 349 (100), 257 (24), 129 (17). HRMS (ESI-TOF/MS): m/z calcd for C₁₄H₉F₆O₈S₂ [M + H]⁺: 482.96375; found: 482.96348.
• 9 General Procedure for the Synthesis of 5a–j A THF solution of 3 (0.145 mmol), K₃PO₄ (1.5 equiv), Pd(PPh₃)₄ (3 mol%), and arylboronic acid 4 (1.2 equiv) was stirred at 20 °C for 9 h under argon atmosphere. To the reaction mixture were added H₂O (20 mL) and CH₂Cl₂ (25 mL). The organic and the aqueous layers were separated, and the latter was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane–EtOAc = 100:5).
• 10 Methyl 7-(3,5-Dimethylphenyl)-3-(trifluoro-methylsulfonyloxy)-2-naphthoate (5a) Starting with 3 (70 mg, 0.145 mmol), 4a (21 mg, 0.145 mmol), Pd(PPh₃)₄ (5 mg, 3 mol%, 0.0043 mmol), K₃PO₄ (30 mg, 0.145 mmol), and THF (4 mL), 5a was isolated as a white solid (45 mg, 70%), mp 102–104 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.35 (s, 6 H, 2CH₃), 3.96 (s, 3 H, OCH₃), 7.01 (s, 1 H, ArH), 7.24 (br s, 2 H, ArH), 7.68–8.08 (m, 4 H, ArH), 8.63 (s, 1 H, ArH). ¹⁹F NMR (282.4 MHz, CDCl₃): δ = –73.1. ¹³C NMR (75.5 MHz, CDCl₃): δ = 20.4 (2 CH₃), 51.7 (OCH₃), 117.8 (q, J _C–F = 321.3, CF₃), 120.8, 125.3, 126.6, 128.1, 129.7, 129.8 (CH), 131.8, 134.0 (C), 135.0 (CH), 138.7, 138.8 139.8, 141.7, 144.6 (C), 164.4 (C=O). IR (KBr,): ν = 3028, 3012, 2958, 2920, 2851 (w), 1721 (s), 1632 (w), 1596 (m), 1462 (w), 1420 (s), 1364, 1319, 1303, 1285, 1261, 1247 (w), 1198 (s), 1134, 1112, 1051, 1018, 946 (m), 919, 903, 886, 852 (w), 826, 807, 776, 764, 722 (s), 698, 667, 631, 612, 594, 574, 536 (m) cm^–1. GC–MS (EI, 70eV): m/z (%) = 438 (44) [M⁺], 305 (100), 277 (8), 275 (15), 247 (39), 219 (20), 202 (24). HRMS (EI, 70 eV): m/z calcd for C₂₁H₁₇O₅F₃S [M]⁺: 438.07433; found: 438.07419.
• 11 CCDC 950296 (5g) and CCDC 950297 (6c) contain all crystallographic details of this publication and are 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, GB-Cambridge CB21EZ; fax: [phone]; or [e-mail].
• 12 General Procedure for the Synthesis of 6a–i A solution of 3 (75 mg, 0.155 mmol), K₃PO₄ (3.0 equiv), Pd(PPh₃)₄ (6 mmol%), and arylboronic acid 3 (2.4 equiv) in 1,4-dioxane (3 mL) was stirred at 120 °C for 4 h under argon atmosphere. To the reaction mixture were added H₂O (20 mL) and CH₂Cl₂ (25 mL). The organic and the aqueous layers were separated, and the latter was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane–EtOAc).
• 13 Methyl 3,7-Bis(3,5-dimethylphenyl)-2-naphthoate (6a) Starting with 3 (75 mg, 0.155 mmol), 4a (47 mg, 0.31 mmol), Pd(PPh₃)₄ (10.7 mg, 6 mol%, 0.0093 mmol), K₃PO₄ (98.5 mg, 0.465 mmol), and 1,4-dioxane (3 mL), 6a was isolated as a white solid (50 mg, 83%), mp 175–176 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.28 (s, 6 H, 2CH₃), 2.32 (s, 6 H, 2 CH₃), 3.62 (s, 3 H, OCH₃), 6.92 (br s, 1 H, ArH), 6.95 (br s, 3 H, ArH), 7.24 (br s, 2 H, ArH), 7.70–7.74 (m, 2 H, ArH), 7.78–7.80 (d, J = 8.6 Hz, 1 H, ArH), 7.99 (br s, 1 H, ArH), 8.29 (s, 1 H, ArH). ¹³C NMR (75.46 MHz, CDCl₃): δ = 21.3, 21.4 (4 CH₃), 52.0 (OCH₃), 125.3, 126.1, 126.3, 128.0, 128.1, 128.8, 129.3 (CH), 129.7 (C), 130.9 (CH), 131.7, 133.4, 137.5, 138.4, 138.8, 139.5, 140.5, 141.2 (C), 169.2 (CO). IR (KBr): ν = 3453, 3026, 2986, 2944, 2914, 2857, 1935, 1841, 1787 (w), 1734 (s), 1693 (w), 1589 (m), 1496, 1454, 1443, 1430, 1397, 1375, 1462, 1325 (w), 1282 (m), 1268, 1258 (s), 1226, 1203, 1192, 1147 (m), 1100 (s), 1047 (m), 969, 943 (w), 922 (s), 897, 943 (w), 922, 897 (m), 852 (s), 833, 8220, 792 (m), 771, 760, 734, 721, 702 (w), 689 (s), 637, 622, 608, 574, 559, 543, 535 (w) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 394 (100) [M]⁺, 363 (13). HRMS (EI, 70 eV): m/z calcd for C₂₈H₂₆O₂ [M]⁺: 394.19273; found: 394.192591.
• 14 Methyl 7-(4-Methoxyphenyl)-3-(4-tolyl)-2-naphthoate (7) The reaction was carried out in a pressure tube. To the THF suspension (4 mL) of 3 (70 mg, 0.145 mmol), arylboronic acid Ar¹B(OH)₂ 4 (21 mg, 0.145 mmol), and Pd(PPh₃)₄ (3 mol%) was added K₃PO₄ (30 mg, 0.145 mmol), and the resulting solution was degassed by bubbling argon through the solution for 10 min. The mixture was stirred at 20 °C under an argon atmosphere for 9 h. Arylboronic acid Ar²B(OH)₂ (0.035 mmol), Pd(PPh₃)₄ (3 mol%), and K₃PO₄ (30 mg, 0.145 mmol) were added. The reaction mixtures were heated under an argon atmosphere at 105 °C for 8 h. 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, heptane–EtAOc) to give 7 as a white solid (55 mg, 85%), mp 82–83 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.36 (s, 3 H, CH₃), 3.83 (s, 3 H, OCH₃), 3.96 (s, 3 H, OCH₃), 6.91 (d, 2 H, J = 8.8 Hz, ArH), 7.23–7.31 (m, 4 H, ArH), 7.56 (d, 2 H, J = 8.8 Hz, ArH), 7.74 (s, 1 H, ArH), 7.75–7.77 (m, 2 H, ArH), 7.82 (s, 1 H, ArH), 8.06 (s, 1 H, ArH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 20.1 (CH₃), 52.7, 55.4 (OCH₃), 113.1, 119.8 (CH), 121.3 (C), 125.3, 126.2, 126.7, 127.1, 128.5, 128.8 (CH), 130.8, 132.9 (C), 133.9 (CH), 134.2, 134.6, 135.8, 137.2, 139.9, 143.6 (C), 164.3 (C=O). FTIR (KBr): ν = 3002, 2954, 2927, 2847 (w), 1726 (s), 1632, 1599, 1509, 1488, 1459 (w), 1422 (s), 1402, 1370, 1314, 1286, 1263, 1249 (w), 1202, 1136 (s), 1052, 1031 (m), 969, 939 (w), 897, 853, 810, 792, 776, 722 (m), 696, 667, 643 (w), 609, 600 (m) cm^–1. GC–MS (EI, 70eV): m/z (%) = 382 (87) [M⁺], 367 (9), 311 (100), 281 (23), 207 (50), 198 (18). HRMS (ESI-TOF): m/z calcd for C₂₆H₂₂O₃ [M + H]⁺: 383.15678; found: 383.15623.