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

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

References

• 1 Bagley MC. Dale JW. Bower J. Synlett  2001,  1149 
• 2 Bagley MC. Dale JW. Hughes DD. Ohnesorge M. Phillips NG. Bower J. Synlett  2001,  1523 
• 3 Bagley MC. Brace C. Dale JW. Ohnesorge M. Phillips NG. Xiong X. Bower J. J. Chem. Soc., Perkin Trans. 1  2002,  1663 
• 4 Bagley MC. Lunn R. Xiong X. Tetrahedron Lett.  2002,  43:  8331 
• 5 Bagley MC. Hughes DD. Lloyd R. Powers VEC. Tetrahedron Lett.  2001,  42:  6585 
• 6 Bagley MC. Hughes DD. Synlett  2002,  1332 
• 7 Bagley MC. Dale JW. Bower J. Chem. Commun.  2002,  1682 
• 8 Bohlmann F. Rahtz D. Chem. Ber.  1957,  90:  2265 
• 9a Agami C. Dechoux L. Hebbe S. Synlett  2001,  1440 
• 9b Agami C. Dechoux L. Hamon L. Hebbe S. Synthesis  2003,  859 
• 10 Agami C. Dechoux L. Hebbe S. Moulinas J. Synlett  2002,  79 

11

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.

12

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.

13

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).

14

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⁺}.

15

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).

16

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).

18

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).

19

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.