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.

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⁺}.

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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).

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.