Efficient Regioselective Preparationof Monobromo and Bromoiodo Hydroxy Pyridines from Dibromoderivativesvia Bromine-Lithium Exchange

Abstract

Annular dibromination of hydroxypyridines with NBS in acetonitrilefollowed by bromine-lithium exchange with RLi and subsequent trappingwith H₂O or I₂ afforded monobromo and bromoiododerivatives in a completely regioselective way. Iodination of bromohydroxypyridines with NIS is totally regioselective.

hydroxypyridines - bromine-lithium exchange - N-bromosuccinimide - N-iodosuccinimide - bromoiodopyridines

References

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14

Unpublished results. Bromination ofmethyl hydroxy-pyridines 3-6 were carried out with 1 equivalent ofNBS in acetonitrile. For 3, 3-bromo-, 5-bromo-and 3,5-dibromo 2-hydroxy-6-methyl pyridines were formed in a 28:54:9ratio. For 4, 3-bromo-, 5-bromo- and 3,5-dibromo2-hydroxy-4-methyl pyridines were formed in a 36:44:8 ratio. For 5, 6-bromo- and 4,6-dibromo 3-hydroxy-2-methylpyridines were formed in a 20:40 ratio. For 6 2-bromo-and 2,4-dibromo 3-hydroxy-6-methyl pyridines were formed in a 23:38ratio. The rest up to 100% were unaltered starting material.

15

Dibromopyridines 9-12 were characterized on the basis of their ¹HNMR (δ in ppm, DMSO-d ₆,300 MHz) and ¹³C NMR (δ inppm, DMSO-d ₆, 75 MHz) spectroscopicdata and elemental analysis.
Compound 9:white solid; mp 223-224 °C (Et₂O/hexane); ¹HNMR: 2.23 (s, 3 H, CH₃), 8.04 (s, 1 H, H-C4), 12.50 (br s,1 H, OH); ¹³C NMR: 19.2 (CH₃),97.0 (C-5), 112.3 (C-3), 144.8 (C-4), 145.7 (C-6), 158.3 (C-2);Anal. Calcd for C₆H₅NOBr₂: C, 27.00;H, 1.89; N, 5.25. Found: C, 27.44; H, 1.98; N, 5.29.
Compound 10: white solid; mp 222-223 °C(methanol); ¹H NMR: 2.41 (s, 3 H, CH₃),7.76 (s, 1 H, H-C6), 12.29 (br s, 1 H, OH); ¹³CNMR: 24.1 (CH₃), 100.5 (C-5), 116.7 (C-3), 135.0 (C-6),149.3 (C-4), 157.7 (C-2); Anal. Calcd. for C₆H₅NOBr₂:C, 27.00; H, 1.89; N, 5.25. Found: C, 27.08; H, 1.95; N, 5.37.
Compound 11: yellow solid; mp 107-108 °C(Et₂O/hexane); ¹H NMR: 2.39(s, 3 H, CH ₃), 7.68 (s, 1H, H-C5), 9.98 (br s, 1 H, OH); ¹³CNMR: 19.9 (CH₃), 122.4 (C-4), 128.4 (C-5), 128.6 (C-6),148.8 and 149.1 (C-2 and C-3); Anal. Calcd for C₆H₅NOBr₂:C, 27.00; H, 1.89; N, 5.25. Found: C, 27.24; H, 2.02; N, 5.34.
Compound 12: yellow solid; mp 100-101°C(Et₂O/hexane); ¹H NMR (DMSO-d ₆): 2.33 (s, 3 H, CH₃),7.52 (s, 1 H, H-C5), 10.30 (br s, 1 H, OH); ¹³CNMR (DMSO-d ₆): 22.2 (CH₃),121.9 (C-4), 127.2 (C-5), 131.3 (C-2), 146.3 (C-6), 150.6 (C-3).Anal. Calcd for C₆H₅NOBr₂: C, 27.00;H, 1.89; N, 5.25. Found: C, 27.44; H, 2.03; N, 5.34.

16 Mongin F. Fourquez J.-M. Rault S. Levacher V. Godard A. Trécourt F. Quéguiner G. Tetrahedron Lett.  1995,  36:  8415 

17

Compounds 13 and 14 had been previously reported. [13] Monobromo hydroxypyridines 15-18 werecharacterized on the basis of their ¹H NMR (δ inppm, 300 MHz) and ¹³C NMR (δ inppm, 75 MHz) spectroscopic data and elemental analysis.
Compound 15: white solid; mp 220-221 °C(Et₂O/hexane); ¹H NMR (CDCl₃):2.38 (s, 3 H, CH₃), 6.00 (d, 1 H, J _5,4 = 7.5 Hz,H-C5), 7.72 (d, 1 H, J _4,5 = 7.5Hz, H-C4), 13.24 (br s, 1 H, OH); ¹³CNMR (CDCl₃): 18.9 (CH₃), 106.7 (C-5), 111.2 (C-3),143.7 (C-4), 145.8 (C-6), 161.7 (C-2); Anal. Calcd for C₆H₆NOBr:C, 38.32; H, 3.22; N, 7.45. Found: C, 38.52; H, 3.18; N, 7.45.
Compound 16: white solid; mp 195-196 °C(acetone); ¹H NMR (DMSO-d ₆):2.25 (s, 3 H, CH ₃), 6.19 (d,1 H, J _5,6 = 6.5 Hz,H-C5), 7.32 (d, 1 H, J _6,5 = 6.5Hz, H-C6), 11.90 (br s, 1 H, OH); ¹³CNMR (DMSO-d ₆): 23.1 (CH₃),107.9 (C-5), 116.0 (C-3), 133.0 (C-6), 151.1 (C-4), 158.4 (C-2);Anal. Calcd for C₆H₆NOBr: C, 38.32; H, 3.22;N, 7.45. Found: C, 38.37; H, 3.22; N, 7.54.
Compound 17: white solid; mp 199-200 °C(Et₂O/hexane); ¹H NMR (CDCl₃):2.42 (s, 3 H, CH ₃), 7.00 (d,1 H, J _4,5 = 8.4 Hz,H-C4), 7.09 (d, 1 H, J _5,4 = 8.4Hz, H-C5), 9.01 (br s, 1 H, OH); ¹³CNMR (CDCl₃): 18.7 (CH₃), 124.8 and 125.7 (C-4and C-5), 128.0 (C-6), 147.5 (C-2), 151.4 (C-3). HRMS (EI) calcdfor C₆H₆NOBr: 186.9632. Found 186.9629.
Compound 18: white solid; ¹HNMR (DMSO-d ₆): 2.31 (s, 3 H,CH₃), 7.05 (d, 1 H, J _4,5 = 8.1Hz, H-C4), 7.15 (d, 1 H, J _5,4 = 8.1Hz, H-C5); ¹³C NMR (DMSO-d ₆): 22.4 (CH₃), 123.3and 123.9 (C-5 and C-4), 129.0 (C-2), 148,6 and 148.7 (C-6 and C-3).

18 For preference for ring lithiationover deprotonation see: Carpentier TA. Jenner PJ. Leeper FJ. Staunton J. J. Chem.Soc., Chem. Commun.  1980,  1227 

19a Bargar TM. Wilson T. Daniel JK. J. Heterocycl. Chem.  1985,  22:  1583 

19b Tee OS. Paventi M. J. Am. Chem.Soc.  1982,  104:  4142 

20

Bromoiodo derivatives 21-26 were characterized on the basis of their ¹HNMR (δ in ppm, 300 MHz) and ¹³CNMR (δ in ppm, 75 MHz) spectroscopic data and elemental analysis.
Compound 21: yellow solid; mp 205-206 °C(acetone/methanol); ¹H NMR (CDCl₃):2.52 (s, 3 H, CH ₃), 8.03 (s, 1H,H-C4), 13.47 (br s, 1 H, OH); ¹³C NMR(CDCl₃): 23.9 (CH₃), 68.9 (C-5), 112.4 (C-3),147.4 (C-6), 151.2 (C-4), 161.3 (C-2). HRMS (EI) calcd. for C₆H₅NOBrI:312.8599. Found: 312.8599.
Compound 22:yellow solid; mp 115-116 °C(acetone); ¹H NMR(DMSO-d ₆): 2.38 (s, 3 H, CH₃),7.78 (s, 1 H, H-C5), 9.85 (br s, 1 H, OH); ¹³CNMR (DMSO-d ₆): 20.1 (CH₃), 100.9(C-4), 129.2 (C-6), 134.1 (C-5), 147.2 (C-2), 151.5 (C-3). HRMS(EI) calcd for C₆H₅NOBrI: 312.8599. Found: 312.8603.
Compound 23: yellow solid; ¹HNMR (DMSO-d ₆): 8.24 (d, 1H, J _2,6 = 0.9 Hz,H-C2), 8.29 (d, 1 H, J _2,6 = 0.9Hz, H-C6); ¹³C NMR (DMSO-d ₆): 89.5 (C-5), 109.3 (C-3),138.7 (C-2), 143.1 (C-6), 169.2 (C-4). HRMS (EI) calcd for C₅H₃NOBrI: 298.8442.Found 298.8434.
Compound 24: yellowsolid; mp 243-244 °C (acetone); ¹H NMR(DMSO-d ₆): 7.71 (d, 1 H, J _4,6 = 1.7 Hz, H-C4),8.08 (d, 1 H, J _4,6 = 1.7Hz, H-C6), 12.29 (br s, 1 H, OH); ¹³CNMR (DMSO-d ₆): 64.3 (C-5),116.4 (C-3), 140.7 (C-4), 148.8 (C-6), 157.5 (C-2). Anal Calcd.for C₅H₃NOBrI: C, 20.02; H, 1.01; N, 4.67.Found: C, 19.93; H, 1.02; N, 4.55.
Compound 25:yellow solid; mp 226-227 °C(acetone); ¹H NMR(DMSO-d ₆): 7.74 (d, 1 H, J _4,6 = 2.4 Hz, H-C4),8.21 (d, 1 H, J _4,6 = 2.4Hz, H-C6), 12.23 (br s, 1 H, OH); ¹³CNMR (DMSO-d ₆): 93.8 (C-5),97.2 (C-3), 136.8 (C-4), 150.8 (C-6), 159.0 (C-2). Anal Calcd. forC₅H₃NOBrI: C, 20.02; H, 1.01; N, 4.67. Found:C, 19.90; H, 0.96; N, 4.57.
Compound 26:yellow solid; mp 218-220 °C (acetone/methanol); ¹HNMR (DMSO-d ₆): 2.45 (s, 3H, CH₃), 7.78 (s, 1 H, H-C6), 12.17 (br s, 1 H, OH); ¹³CNMR (DMSO-d ₆): 29.1 (CH₃),72.3 (C-5), 116.1 (C-3), 139.7 (C-6), 151.4 (C-4), 157.9 (C-2).HRMS (EI) calcd for C₆H₅NOBrI: 312.8599. Found:312.8592.