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

Abstract

The first Suzuki-Miyaura reactions of pentachloropyridine are reported. The reaction with two equivalents of arylboronic acids gave 2,6-diaryl-3,4,5-trichloropyridines, while the reaction with one equivalent of arylboronic acid afforded 2-aryl-3,4,5,6-tetrachloropyridines. The one-pot reaction of pentachloropyridine with two different arylboronic acids resulted in the formation of 2,6-diaryl-3,4,5-trichloropyridines containing two different aryl groups. All reactions proceeded with very good site selectivity.

Key words

catalysis - palladium - Suzuki-Miyaura reaction - pyridine - regioselectivity

References and Notes

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General Procedure for the Synthesis of 3a-f 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 (hexane-CH₂Cl₂).

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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 (hexane-CH₂Cl₂ = 4:1) as a white solid (108 mg, 67%), mp 129-130 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.86 (s, 3 H, OCH₃), 6.98 (d, ^³ J = 9.0 Hz, 2 H, Ar), 7.70 (d, ^³ J = 9.0 Hz, 2 H, Ar). ^¹³C NMR (75 MHz, CDCl₃): δ = 55.4 (OCH₃), 113.6 (CH), 128.1, 128.2, 128.8 (C_Ar/Hetar), 131.1 (CH), 143.0, 147.1, 154.6, 160.8 (C_Ar/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) cm^-¹. 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.

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General Procedure for the Synthesis of 4a-f 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 3a-f.

24

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 168-170 ˚C; reaction temperature 100 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.34-7.40 (m, 2 H, CH), 7.44-7.50 (m, 4 H, CH), 7.61-7.65 (m, 4 H, CH). ^¹³C NMR (75 MHz, CDCl₃): δ = 127.2, 127.3, 128.8 (CH_Ar), 129.7, 141.2, 144.7, 146.5 (C_Hetar). 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) cm^-¹. 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.

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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: [phone]; or [e-mail].

26

General Procedure for the Synthesis of 5a-c
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 3a-f.

27

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): δ = 2.35 (s, 3 H, CH₃), 2.58 (s, 3 H, CH₃), 7.21 (d, ^³ J = 8.3 Hz, 2 H, Ar), 7.57 (d, ^³ J = 8.2 Hz, 2 H, Ar), 7.77 (d, ^³ J = 8.6 Hz, 2 H, Ar), 7.98 (d, ^³ J = 8.6 Hz, 2 H, Ar). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.5 (CH₃), 26.8 (CH₃), 128.0 (C_Ar/Hetar), 128.1 (CH), 128.3, 128.8, 128.9 (C_Ar/Hetar), 128.9, 129.4 (CH), 129.6 (C_Ar/Hetar), 129.9 (CH), 134.7, 137.3, 139.7, 142.2 (C_Ar/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) cm^-¹. 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.