Synthesis of 2-Aryl-3,4,5,6-tetrachloropyridines and 2,6-Diaryl-3,4,5- trichloropyridines by Site-Selective Suzuki-Miyaura Reactions of Pentachloropyridine

Synlett

Volumn , Issue 10, 2010, Pages 1528-1532

  Ehlers, Peter ^a   Reimann, Sebastian ^a   Erfle, Silke ^a   Villinger, Alexander ^a   Langer, Peter ^a  

^a UNIVERSITY OF ROSTOCK   (Germany)

Author keywords

Catalysis; Palladium; Pyridine; Regioselectivity; Suzuki Miyaura reaction

Indexed keywords

2 ARYL 3,4,5,6 TETRACHLOROPYRIDINE DERIVATIVE; 2,6 DIARYL 3,4,5,6 TRICHLOROPYRIDINE DERIVATIVE; BORONIC ACID DERIVATIVE; DIOXANE; METHANE; N,N DIMETHYLFORMAMIDE; PYRIDINE DERIVATIVE; TETRAHYDROFURAN; TOLUENE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; CONTROLLED STUDY; CROSS COUPLING REACTION; DRUG STRUCTURE; DRUG SYNTHESIS; ONE POT SYNTHESIS; SUZUKI REACTION;

EID: 77953247963     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0029-1219951     Document Type: Article

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52. General Procedure for the Synthesis of 3af A solution of Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (1.8 equiv, 290 mg), and pentachloropyridine (0.5 mmol, 126 mg), dissolved in a 10:1 mixture of MeCN (2 mL) and H2O (0.2 mL) was stirred for 10 min. Subsequently, the boronic acid 2 (2.2 equiv) was added. The solution was stirred for 20 h at r.t. To the reaction mixture was added brine, and the organic and the aqueous layer were separated. The latter was extracted with CH2Cl2 (3?). The combined organic layers were dried (Na2SO4), filtered, and the solution was concentrated in vacuo. The residue was purified by column chromatography (hexaneCH2Cl2).
53. 2,3,4,5-Tetrachloro-6-(4-methoxyphenyl)pyridine (3a) Starting with 2a (1.1 mmol), Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (0.9 mmol, 290 mg), and 1 (0.5 mmol, 126 mg) in MeCN (2 mL) and H2O (0.2 mL), 3a was isolated by column chromatography (hexaneCH2Cl2 = 4:1) as a white solid (108 mg, 67%), mp 129130 C. 1H NMR (300 MHz, CDCl3): d = 3.86 (s, 3 H, OCH3), 6.98 (d, 3J = 9.0 Hz, 2 H, Ar), 7.70 (d, 3J = 9.0 Hz, 2 H, Ar). 13C NMR (75 MHz, CDCl3): d = 55.4 (OCH3), 113.6 (CH), 128.1, 128.2, 128.8 (CAr/Hetar), 131.1 (CH), 143.0, 147.1, 154.6, 160.8 (CAr/Hetar). IR (ATR): 3015 (w), 2955 (w), 2923 (w), 2853 (w), 2728 (w), 2553 (w), 1607 (w), 1505 (s), 1350 (m), 1320 (br, s), 1288 (s), 1084 (s), 815 (s) cm1. MS (EI, 70 eV): m/z (%) = 323 (100) [M+], 321 (78), 280 (19), 278 (15), 245 (13), 243 (13), 210 (6), 208 (9). HRMS (EI, 70 eV): m/z calcd for C12H7ONCl4: 320.92763; found: 320.927630. Anal. Calcd for C12H7Cl4NO (323.0): C, 44.62; H, 2.18; N, 4.34. Found: C, 44.84; H, 2.21; N, 4.33.
54. General Procedure for the Synthesis of 4af A solution of Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (2.4 equiv, 391 mg), and pentachloropyridine (0.5 mmol, 126 mg) in MeCN (2 mL) and H2O (0.2 mL) was stirred for 10 min at 20 C. Subsequently, the boronic acid 2 (2.4 equiv) was added at 20 C. The solution was stirred for 20 h at 90 100 C. The workup was carried out as described for the synthesis of 3af.
55. 3,4,5-Trichloro-2,6-diphenylpyridine (4c) Starting with Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (1.2 mmol, 391 mg), 1 (0.5 mmol, 126 mg), and 2e (1.2 mmol, 146 mg) in MeCN (2 mL) and H2O (0.2 mL), 4e was isolated as a white solid (109 mg, 65%), mp 168170 C; reaction temperature 100 C. 1H NMR (300 MHz, CDCl3): d = 7.34 7.40 (m, 2 H, CH), 7.447.50 (m, 4 H, CH), 7.617.65 (m, 4 H, CH). 13C NMR (75 MHz, CDCl3): d = 127.2, 127.3, 128.8 (CHAr), 129.7, 141.2, 144.7, 146.5 (CHetar). IR (ATR): 3058 (w), 2921 (m), 1731 (m), 1529 (s), 1486 (br, s), 1369 (s), 1329 (s), 1297 (s), 1200 (br, s), 1067 (m), 883 (m), 817 (s), 771 (s), 737 (s), 708 (s), 691 (s), 599 (s) cm1. MS (EI, 70 eV): m/z (%) = 340 (68) [M]+, 294 (11), 302 (11), 299 (20), 298 (100), 263 (13), 227 (30), 160 (25), 149 (11). HRMS (EI, 70 eV): m/z calcd for C17H10Cl3N: 332.98733; found: 332.98738. Anal. Calcd for C17H10NCl3 (334.63): C, 61.02; H, 3.01; N, 4.19. Found: C, 61.35; H, 3.24; N, 3.89.
56. CCDC-771412 contain 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, Cambridge CB21EZ; fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk.
57. General Procedure for the Synthesis of 5ac To a solution of Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (2.4 equiv, 391 mg), and pentachloropyridine (0.5 mmol, 126 mg) in MeCN (2 mL) and H2O (0.2 mL) was added the first boronic acid (2.2 equiv). The solution was stirred for 2 h at 80 C. After cooling to r.t., the second boronic acid (2.2 equiv) was added. The solution was stirred for 12 h at 80 C. The workup was carried out as described for the synthesis of 3af.
58. 1-{4-[3,4,5-Trichloro-6-(p-tolyl)pyrid-2- yl]phenyl}ethanone (5c) Starting with 2f (1.1 mmol, 180 mg), 2h (1.1 mmol, 150 mg), Pd(PPh3)4 (5 mol%, 29 mg), Cs2CO3 (1.2 mmol, 390 mg), and 1 (0.5 mmol, 126 mg) in MeCN (2 mL) and H2O (0.2 mL), 5c was isolated by column chromatography (heptanes EtOAc = 10:1) as a colorless solid (93 mg, 48%), mp 190 192 C. 1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 2.58 (s, 3 H, CH3), 7.21 (d, 3J = 8.3 Hz, 2 H, Ar), 7.57 (d, 3J = 8.2 Hz, 2 H, Ar), 7.77 (d, 3J = 8.6 Hz, 2 H, Ar), 7.98 (d, 3J = 8.6 Hz, 2 H, Ar). 13C NMR (75 MHz, CDCl3): d = 21.5 (CH3), 26.8 (CH3), 128.0 (CAr/Hetar), 128.1 (CH), 128.3, 128.8, 128.9 (CAr/Hetar), 128.9, 129.4 (CH), 129.6 (CAr/Hetar), 129.9 (CH), 134.7, 137.3, 139.7, 142.2 (CAr/Hetar), 197.7 (C=O). IR (ATR): 3339 (w), 3076 (w), 3031 (w), 2997 (w), 2921 (m), 2853 (w), 1674 (w), 1607 (s), 1523 (m), 1493 (m), 1357 (s), 1267 (s), 1186 (m), 959 (m), 815 (s) cm1. MS (EI, 70 eV): m/z (%) = 389 (51) [M+], 378 (33), 376 (100), 374 (98), 346 (20), 276 (10), 240 (9), 187 (9). HRMS (EI, 70 eV): m/z calcd for C20H14O1N1Cl3: 389.01355; found: 389.01319.