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Synlett 2003(11): 1678-1682
DOI: 10.1055/s-2003-41013
LETTER
© Georg ThiemeVerlag Stuttgart ˙ New York

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

Ángela Meanaa, Justo F. Rodrígueza, Mª Ascensión Sanz-Tejedor*a, José L. García-Ruano*b
a Organic Chemistry Department (E.T.S.I.I.), Universidad de Valladolid, Pº delCauce s/n, 47011-Valladolid, Spain
Fax: +34(983)423310; e-Mail: atejedor@dali.eis.uva.es ;
b Organic Chemistry Department (C-I), Universidad Autónoma, Cantoblanco,28049-Madrid, Spain
Fax: +34(91)3973966; e-Mail: joseluis.garcia.ruano@uam.es;
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Publication History

Received 23 June 2003
Publication Date:
11 August 2003 (online)

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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.

Key words

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

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Unpublished results.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.

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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.

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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).

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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.