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Synlett 2004(5): 0811-0814  
DOI: 10.1055/s-2004-820019
LETTER
© Georg Thieme Verlag Stuttgart · New York

New N-Halosuccinimide-Mediated Reactions for the Synthesis of Pyridines

Mark C. Bagley*, Christian Glover, Eleanor A. Merritt, Xin Xiong
School of Chemistry, Cardiff University, PO Box 912, Cardiff, CF10 3TB, UK
Fax: +44(29)20874030; e-Mail: Bagleymc@cf.ac.uk;
Further Information

Publication History

Received 20 October 2003
Publication Date:
24 February 2004 (online)

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Abstract

5-Bromo-2,6-dialkylpyridine-4-carboxylates are generated in excellent yield by the Michael addition of enaminoesters and ethynyl ketones followed by bromocyclization using N-bromo­succinimide within 1 hour at 0 °C. Treatment of the same aminopentadienone intermediates with N-iodosuccinimide facilitates a low temperature cyclodehydration under very mild conditions to give 2,3,6-trisubstituted pyridines with total regiocontrol.

Key words

pyridines - β-enaminoesters - bromocyclization - Bohlmann-Rahtz

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General Procedure for Michael Addition of Enamines 1 and Alkynones 2. A solution of enamine 1 (0.36 mmol, 1 equiv) and alkynone (0.56 mmol, 1.5 equiv) in EtOH (5 mL) was stirred at 50 °C for 1-7 h, cooled and evaporated in vacuo. Purification by flash chromatography on silica gel, eluting with EtOAc-light petroleum gave dienone 3.

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General Procedure for the Bromocyclization of Aminodienones 3 using NBS. A solution of aminodienone 3 (0.28 mmol, 1 equiv) and N-bromosuccinimide (0.34 mmol, 1.2 equiv) in EtOH (5 mL) was stirred at 0 °C for 1 h and evaporated in vacuo. Purification by column chromatography on silica gave bromopyridine 11a-g.

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Ethyl 5-bromo-2-methyl-6-phenylpyridine-3-carboxylate (11a). Mp 88-89 °C (aq MeOH). HRMS: m/z [MH] calcd for C15H14 79BrNO2: 320.0286; found [MH+]: 320.0286. IR (KBr): 2974, 2925, 1730, 1571, 1432, 1286, 1259, 1090, 1016, 928, 835, 780, 694 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.41 (s, 1 H, 4-H), 7.64 (m, 2 H, o-PhH), 7.41 (m, 3 H, m,p-PhH), 4.34 (q, J = 7.1 Hz, 2 H, CH2), 2.77 (s, 3 H, 2-Me), 1.36 (t, J = 7.1 Hz, 3 H, Me). 13C NMR (100 MHz, CDCl3) δ = 165.6 (C), 160.2 (C), 158.8 (C), 143.8 (CH), 139.3 (C), 129.8 (CH), 129.7 (CH), 128.5 (CH), 125.4 (C), 116.6 (C), 62.0 (CH2), 25.0 (Me), 14.7 (Me). MS (APcI): m/z (%) = 322 (36) {M[81Br]H+}, 320 (37) {M[79Br]H+}, 242 (9), 93 (23), 79 (100).

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Ethyl 5-bromo-2-methyl-6-(4-methoxyphenyl)pyridine-3-carboxylate (11b). Mp 90-91 °C (MeOH). HRMS: m/z [MH] calcd for C16H16BrNO3: 350.0392; found [MH+]: 350.0393. IR (KBr): 2963, 1724, 1609, 1570, 1512, 1433, 1257, 1178, 1087, 1027, 803, 701 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.38 (s, 1 H, 4-H), 7.66 (d, J = 8.8Hz, 2 H, 2′-H, 6′-H), 6.91 (d, J = 8.8 Hz, 2 H, 3′-H, 5′-H), 4.34 (q, J = 7.1 Hz, 2 H, CH 2Me), 3.79 (s, 3 H, OMe), 2.75 (s, 3 H, Me), 1.34 (t, J = 7.1 Hz, 3 H, CH2 Me). 13C NMR (100 MHz, CDCl3): δ = 165.7 (C), 160.8 (C), 159.6 (C), 158.7 (C), 143.8 (CH), 131.6 (C), 131.4 (CH), 124.8 (C), 116.2 (C), 113.8 (CH), 61.9 (CH2), 55.8 (Me), 25.0 (Me), 14.7 (Me). MS (APcI): m/z (%) = 352 (32) {M[81Br]H+}, 350 (50) {M[79Br]H+}.

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Ethyl 5-bromo-2-methyl-6-(4-chlorophenyl)pyridine-3-carboxylate (11c). Mp 106-108 °C (aq EtOH). HRMS: m/z [MH] calcd for C15H13BrClNO2: 353.9896; found [MH+]: 353.9896. IR (KBr): 2973, 1730, 1595, 1570, 1534, 1492, 1432, 1259, 1089, 1016, 928, 835, 780 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.40 (s, 1 H, 4-H), 7.61 (d, J = 8.6 Hz, 2 H, 2′-H, 6′-H), 7.37 (d, J = 8.6 Hz, 2 H, 3′,5′-H), 4.34 (q, J = 7.1 Hz, 2 H, CH 2Me), 2.75 (s, 3 H, Me), 1.35 (t, J = 7.1 Hz, 3 H, CH2 Me). 13C NMR (100 MHz, CDCl3) δ = 165.1 (C), 158.5 (C), 158.4 (C), 143.5 (CH), 137.2 (C), 135.4 (C), 130.8 (CH), 128.3 (CH), 125.3 (C), 116.0 (C), 61.7 (CH2), 24.5 (Me), 14.3 (Me). MS (APcI): m/z (%) = 358 (16) {M[81Br37Cl]H+}, 356 (100) [MH+], 358 (71) {M[79Br35Cl]H+}, 117 (38), 71 (30).

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Ethyl 5-bromo-2,6-dimethylpyridine-3-carboxylate (11d). Mp 32.1-32.2 °C. Anal. Calcd for C10H12BrNO2: C, 46.5; H, 4.7; N, 5.4. Found: C, 46.5; H, 5.0; N, 5.4. HRMS: m/z [MH] calcd for C10H12 79BrNO2: 258.0129; found [MH+]: 258.0124. IR (film): 2984, 1725, 1576, 1542, 1436, 1392, 1366, 1267, 1232, 1100, 1025, 970, 780, 680 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.23 (s, 1 H, 4-H), 4.30 (q, J = 7.1 Hz, 2 H, CH2), 2.69 (s, 3 H, 6-Me), 2.60 (s, 3 H, 2-Me), 1.33 (t, J = 7.1 Hz, 3 H, Me); 13C NMR (100 MHz, CDCl3): δ = 165.6 (C), 160.3 (C), 158.4 (C), 142.0 (CH), 124.7 (C), 118.3 (C), 61.8 (CH2), 25.4 (Me), 24.7 (Me), 14.6 (Me). MS (APcI): m/z (%) = 260 (100) {M[81Br]H+}, 258 (95) {M[79Br]H+}.

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Ethyl 5-bromo-2,6-diphenylpyridine-3-carboxylate (11e). HRMS: m/z [M] calcd for C20H16NO2Br: 381.0364; found [M+]: 381.0360. IR (KBr): 2976, 1732, 1558, 1426, 1372, 1244, 1114, 1088, 1017, 922, 772, 687 cm-1. 1H NMR (400 MHz, CDCl3) δ = 8.33 (s, 1 H, 4-H), 7.71 (m, 2 H, 6-(o-PhH)], 7.50 (m. 2 H, 2-(o-PhH)], 7.43-7.33 (m, 6 H, m,p-PhH), 4.12 (q, J = 7.1 Hz, 2 H, CH2), 1.02 (t, J = 7.1 Hz, 3 H, CH2 Me). 13C NMR (100 MHz, CDCl3) δ = 166.7 (C), 159.2 (C), 157.2 (C), 143.0 (CH), 139.2 (C), 138.8 (C), 129.6 (CH), 129.3 (CH), 128.9 (CH), 128.7 (CH), 128.1 (CH), 128.0 (CH), 126.5 (C), 117.3 (C), 61.8 (CH2), 13.7 (Me). MS (APcI): m/z (%) = 384 (100) {MH+}, 382 (80) [MH+], 304 (15).

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Ethyl 5-bromo-6-methyl-2-phenylpyridine-3-carboxylate (11f). HRMS: m/z [MH+] calcd for C15H14NO2Br: 320.0281; found: 320.0281. IR (nujol): 2918, 2853, 1725, 1572, 1462, 1377, 1295, 1242, 1112, 1061, 1027, 771, 722, 696 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.18 (s, 1 H, 4-H), 7.50-7.34 (m, 5 H, PhH), 4.05 (q, J = 7.1 Hz, 2 H, CH2), 2.68 (s, 3 H, Me), 1.00 (t, J = 7.1 Hz, 3 H, CH2 Me). 13C NMR (100 MHz, CDCl3): δ = 166.6 (C), 159.6 (C), 157.2 (C), 141.3 (CH), 139.5 (C), 128.7 (CH), 128.5 (CH), 128.2 (CH), 125.8 (C), 119.3 (C), 61.7 (CH2), 25.3 (Me), 13.7 (Me). MS (APcI): m/z (%) = 322 (100) [MH+], 320 (98).

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tert-Butyl 5-bromo-2,6-dimethylpyridine-3-carboxylate (11g). HRMS: m/z [M+] calcd for C12H16NO2Br: 285.0359; found: 285.0359. IR (nujol): 2922, 2852, 1726, 1579, 1462, 1377, 1277, 1167, 1095, 970, 848, 782, 722 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H, 4-H), 2.81 (s, 3 H, Me), 2.62 (s, 3 H, Me), 1.55 (s, 9 H, CMe3). 13C NMR (100 MHz, CDCl3): δ = 177.3 (C), 165.1 (C), 159.9 (C), 157.9 (C), 142.0 (CH), 124.5 (C), 118.1 (C), 24.9 (Me), 24.1 (Me), 14.3 (Me). MS (APcI): m/z (%) = 288 (100) [MH+], 286 (94).

20

For example, stirring a solution of aminodienone 3d in EtOH at 0 °C for 1 h results in the return of unreacted starting material and no cyclodehydration to pyridine 4d.

21

General Procedure for the Cyclodehydration of Aminodienones 3 using NIS. A solution of aminodienone 3 (0.2 mmol, 1 equiv) and N-iodosuccinimide (0.25 mmol, 1.2 equiv) in EtOH (4 mL) was stirred at 0 °C for 1 h and eva-porated in vacuo. Purification by flash chromatography on silica, eluting with EtOAc-light petroleum, gave pyridine 4.