Synthesis of Arylated Pyrazoles by Site-Selective Suzuki-Miyaura Reactions of Tribromopyrazoles

Abstract

The first Suzuki-Miyaura reactions of N-protected tribromopyrazoles are reported. Their reaction with three, two, or one equivalents of arylboronic acids afforded 3,4,5-triarylpyrazoles, 3,5-diaryl-4-bromopyrazoles, or 5-aryl-3,4-dibromopyrazoles, respectively. All reactions proceeded with very good site-selectivity.

Key words

pyrazoles - catalysis - Suzuki-Miyaura reaction - regio­selectivity - palladium

References and Notes

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General Procedure for Suzuki-Miyaura Coupling Reactions
To a 1,4-dioxane solution (4 mL) of 2a,b (152 mg, 0.5 mmol) was added Pd(PPh₃)₄ (3-10 mol%) at 20 ˚C under argon atmosphere. After stirring for 30 min, the arylboronic acid (1.0-1.2 equiv per bromine atom of the substrate), K₃PO₄ (1.5 equiv per bromine atom of the substrate), and H₂O (1.0 mL) were added. The mixture was heated for 12 h at 100 ˚C. After cooling to 20 ˚C, the mixture was diluted with H₂O, extracted with CH₂Cl₂ (3 × 25 mL), dried (Na₂SO₄), and filtered. The solvent of the filtrate was concentrated in vacuo and the residue was purified by column chromatography (heptanes-EtOAc).

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3,4-Dibromo-5-(4-methoxyphenyl)-1-vinyl-1 H -pyrazole (4c)
Starting with 2b (165 mg, 0.50 mmol), Pd(PPh₃)₄ (18 mg, 3 mol%), 1,4-dioxane-H₂O (4:1, 5 mL), K₃PO₄ (159 mg, 0.75 mmol), and 4-methoxyphenylboronic acid (76 mg, 0.50 mmol), 4c was isolated as a white solid (131 mg, 73%). ^¹H NMR (300 MHz, CDCl₃): δ = 3.80 (s, 3 H, OCH₃), 4.77 (d, 1 H, J = 8.7 Hz, vinyl), 5.72 (d, 1 H, J = 15.2 Hz, vinyl), 6.70 (dd, 1 H, J = 15.2, 8.7 Hz vinylic CH), 6.95 (d, 2 H, J = 8.8 Hz, ArH), 7.25 (d, 2 H, J = 8.8 Hz, ArH). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 55.4 (OCH₃), 98.2 (C), 102.7 (CH₂), 114.3 (CH), 119.0 (C), 129.7 (CH), 130.5 (C), 131.5 (CH), 142.4, 160.7 (C). IR (KBr): 3002, 2936, 2835, 1730 (w), 1641 (m), 1574 (w), 1488 (s), 1432 (m), 1392 (w), 1355 (m), 1332 (s), 1290 (m), 1249 (s), 1196 (w), 1174 (s), 1110 (m), 1030, 984 (s), 888 (m), 833 (s), 801 (m), 725 (w), 602 (m), 551 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 358 (^8¹Br, 100) [M]⁺, 343 (13), 327 (22), 277 (39), 246 (22), 198 (23). HRMS (EI, 70 eV): m/z calcd for C₁₂H₁₀N₂Br₂O [M]⁺ (⁷⁹Br): 355.91544; found: 355.91535.

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4-Bromo-3,5-bis(4-methoxyphenyl)-1-vinyl-1 H -pyrazole (5a)
Starting with 2b (165 mg, 0.50 mmol), Pd(PPh₃)₄ (29 mg, 5 mol%), 1,4-dioxane-H₂O (4:1, 5 mL), K₃PO₄ (318 mg, 1.5 mmol), and 4-methoxyphenylboronic acid (152 mg, 1.0 mmol), 5a was isolated as a white crystalline solid (115 mg, 60%). ^¹H NMR (300 MHz, CDCl₃): δ = 3.79 (s, 3 H, OCH₃), 3.81 (s, 3 H, OCH₃), 4.75 (d, 1 H, J = 8.5 Hz, vinyl), 5.75 (d, 1 H, J = 15.4 Hz, vinyl), 6.78 (dd, 1 H, J = 8.8, 15.3 Hz, vinylic CH), 6.92 (d, 2 H, J = 8.9 Hz, ArH), 6.96 (d, 2 H, J = 8.8 Hz, ArH), 7.30 (d, 2 H, J = 8.8 Hz, ArH), 7.86 (d, 2 H, J = 8.9 Hz, ArH). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 55.3, 55.4 (OCH₃), 94.2 (C), 101.6 (CH₂), 113.7, 114.2 (CH), 120.1, 124.5 (C), 129.4 (CH), 130.3, 131.7 (CH), 142.2, 149.3, 159.9, 160.4 (C). IR (KBr): 3090, 2996, 2834, 1789 (w), 1638 (m), 1574 (w), 1489 (s), 1436 (m), 1307 (w), 1207 (m), 1250, 1178 (s), 1161, 1111 (m), 1029 (s), 1114 (m), 975 (s), 943 (m), 834 (s), 795 (w), 736 (m), 635 (w), 528 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 384 (⁷⁹Br, 3) [M]⁺, 365 (8), 332 (7), 281 (13), 207 (100), 175 (09), 135 (04) cm^-¹. HRMS (EI, 70 eV): m/z calcd for C₁₉H₁₇N₂BrO₂ [M]⁺ (⁷⁹Br): 384.04734; found: 384.04711.

15

CCDC-777244 contains all crystallographic details of this publication which 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].

16

3,4,5-Tris(3,5-dimethylphenyl)-1-vinyl-1 H -pyrazole (6f)
Starting with 2b (165 mg, 0.50 mmol), Pd(PPh₃)₄ (58 mg, 10 mol%), 1,4-dioxane-H₂O (4:1, 5 mL), K₃PO₄ (477 mg, 2.25 mmol), and 3,5-dimethylphenylboronic acid (263 mg, 1.75 mmol), 6f was isolated as a white solid (165 mg, 74%). ^¹H NMR (300 MHz, CDCl₃): δ = 2.06 (s, 6 H, 2 CH₃), 2.10 (s, 6 H, 2 CH₃), 2.15 (s, 6 H, 2 CH₃), 4.69 (d, 1 H, J = 8.7 Hz, vinyl), 5.78 (d, 1 H, J = 15.3 Hz, vinyl), 6.61-6.90 (m, 8 H), 7.09 (br s, 2 H, ArH). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 21.1, 21.2, 21.3 (CH₃), 100.5 (CH₂), 120.5 (C), 126.2, 128.1, 128.2, 128.5 (CH), 129.2 (C), 129.3, 130.3, 130.4 (CH), 132.6, 133.0, 137.0, 137.4, 137.8, 141.8, 150.4 (C). IR (KBr): 3002, 2915, 2859 (w), 1738, 1642 (m), 1600 (s), 1550 (w), 1444 (m), 1373 (s), 1303, 1268 (w), 1237 (s), 1203, 1154, 1110, 1096 (w), 1093 (m), 996, 900, 881 (w), 848 (s), 789 (w), 691 (m), 542 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 406 (100) [M]⁺, 391 (26), 375 (2), 259 (4), 203 (3), 180 (2), 132 (4). HRMS (EI, 70 eV): m/z calcd for C₂₉H₃₀N₂ [M]⁺: 406.24090; found: 406.24057.