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Synlett 2010(13): 1923-1926  
DOI: 10.1055/s-0030-1258489
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Rasheed Ahmad Kheraa, Asad Alia, Munawar Hussaina, Jovana Tatara, Alexander Villingera, Peter Langer*a,b
a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Fax: +49(381)4986412; e-Mail: peter.langer@uni-rostock.de;
b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Further Information

Publication History

Received 31 March 2010
Publication Date:
09 July 2010 (online)

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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

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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.

14

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: +44 (1223)336033; or deposit@ccdc.cam.ac.uk.

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.