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DOI: 10.1055/s-0029-1219951
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
Publication History
Publication Date:
25 May 2010 (online)
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
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References and Notes
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).
22
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 (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) 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.
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 (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) 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.
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.
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.
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 (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) 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.