Synlett 2006(10): 1586-1588  
DOI: 10.1055/s-2006-941580
LETTER
© Georg Thieme Verlag Stuttgart · New York

Metal-Halogen Exchange Using tri-n-Butyl Lithium Magnesate in the Diazine Series: Diazine 49

Frédéric Buron, Nelly Plé, Alain Turck*, Francis Marsais
IRCOF, Laboratoire de Chimie Organique Fine et Hétérocyclique, UPRES-A 6014, INSA, B.P. 08, 76131 Mont St Aignan Cedex, France
Fax: +33(2)35522962; e-Mail: alain.turck@insa-rouen.fr;
Further Information

Publication History

Received 14 February 2006
Publication Date:
12 June 2006 (online)

Abstract

We report herein the ‘metal-halogen exchange’ reaction in the diazine series with lithium tri-n-tributylmagnesate. The ­reaction was performed with 2-iodopyrazine, 2-methylsulfanyl-4-iodopyrimidine and 3-iodo-6-phenylpyridazine. Benzophenone, ­aldehydes and diphenylsulfur were used as electrophiles affording alcohols and phenylsulfanyl derivatives with satisfactory to good yields.

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Procedure 1 for 2-Iodopyrazine and 4-Iodo-2-methyl-sulfanylpyrimide. A solution of n-BuLi (1.6 M in hexane, 0.66 mmol) was added to a cold (-10 °C) stirred solution of n-butyl-magnesium chloride (0.33 mmol) in THF (5 mL). After 1 h at -10 °C a solution of iododiazine (1 mmol) in THF (2 mL) was added at -30 °C and the mixture was stirred at -10 °C for 2.5 h. The electrophile (1.5 mmol) was then added at
-10 °C; the mixture was stirred at this temperature for 1 h and kept at r.t. for 18 h before addition of H2O (1 mL). The reaction mixture was diluted with EtOAc (50 mL). The organic layer was dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel.
Representative Spectroscopic Data2-(1-Hydroxy-4-methoxyphenylmethyl) Pyrazine ( 2) Prepared according to procedure 1. 1H NMR (CDCl3): δ = 8.50 (s, 1 H, H3), 8.36 (d, 1 H, J = 2.5 Hz, H6), 8.31 (d, 1 H, J = 2.5 Hz, H5), 7.18 (d, 2 H, J = 8.7 Hz, HPh2,6), 6.76 (d, 2 H, J = 8.7 Hz, HPh3,5), 5.71 (s, 1 H, CH), 4.74 (m, 1 H, OH), 3.68 (s, 3 H, OCH3). 13C NMR (CDCl3): δ = 159.4 (CPh4), 157.5 (C2), 143.2-143.0 (C3, C5 and C6), 134.2 (CPh1), 128.2 (CPh2,6), 114.2 (CPh3,5), 73.9 (CH), 55.3 (OCH3). IR (KBr): 3352, 2930, 2840, 1613, 1513, 1469, 1403, 1304, 1249, 1149, 1064, 832, 582 cm-1. Anal. Calcd for C12H12N2O2 (216.24): C, 66.65; H, 5.59; N, 12.96. Found: C, 66.90; H, 5.47; N, 12.91.
2-Methylsulfanyl-4-(1-hydroxy-4-methoxyphenyl-methyl) Pyrimidine ( 7) Prepared according to procedure 1. 1H NMR (CDCl3): δ = 8.33 (d, 1 H, J = 5.3 Hz, H6), 7.21 (d, 2 H, J = 8.7 Hz, HPh2,6), 6.81 (d, 2 H, J = 8.7 Hz, HPh3,5), 6.72 (d, 1 H, J = 5.1 Hz, H5), 5.53 (d, 1 H, J = 3.8 Hz, CH), 4.51 (m, 1 H, OH), 3.73 (s, 3 H, OCH3), 2.53 (s, 3 H, SCH3). 13C NMR (CDCl3): δ = 172.2 (C2 and C4), 159.8 (CPh4), 157.3 (C6), 133.6 (CPh1), 129.6 (CPh2,6), 114.5 (CPh3,5), 113.5 (C5), 74.3 (CH), 55.4 (OCH3), 14.3 (SCH3). IR (KBr): 3369, 2929, 2836, 1565, 1513, 1349, 1249, 1174, 1032, 832 cm-1. Anal. Calcd for C13H14N2O2S (262.33): C, 59.52; H, 5.38; N, 10.68. Found: C, 59.34; H, 5.42; N, 10.75.

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Procedure 2 for 2-Iodo-6-phenylpyridazine. A solution of n-BuLi (1.6 M in hexane, 0.66 mmol) was added to a cold (-10 °C) stirred solution of n-butyl-magnesium chloride (0.33 mmol) in THF (5 mL). After 1 h at -10 °C, The solution was added in a solution of 2-iodo-6-phenylpyridazine (1 mmol) in THF (2 mL) at -30 °C and the mixture was stirred at -10 °C for 2.5 h. The electrophile (1.5 mmol) was then added at -10 °C; the mixture was stirred at this temperature for 1 h, then brought to, and kept at, 35 °C for 18 h before addition of H2O (1 mL). The reaction mixture was diluted with EtOAc (50 mL). The organic layer was dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel.
Representative Spectroscopic Data3-(1-Hydroxy-4′-methoxyphenylmethyl)-6-phenyl Pyridazine ( 12) Prepared according to procedure 2. Mp 140 °C. 1H NMR (CDCl3): δ = 8.05 (m, 2 H, HPh2,6), 7.77 (d, 1 H, J = 8.9 Hz, H5), 7.40 (m, 6 H, H4, HPh 2,6, HPh3,4,5), 6.88 (d, 2 H, J = 8.7 Hz, HPh 3,5), 6.02 (s, 1 H, CH), 5.02 (m, 1 H, OH), 3.78 (s, 3 H, OCH3). 13C NMR (CDCl3): δ = 161.7 (CPh 4), 159.6 (C3 and C6), 135.9 (CPh1), 134.1 (CPh 1), 130.3-124.9 (C4, C5, CPh2,6, CPh 2,6, CPh4, CPh3,5), 114.3 (CPh 3,5), 74.4 (CH), 55.4 (OCH3). IR (KBr): 3135, 2999, 2933, 2838, 1611, 1514, 1433, 1251, 1171, 1064, 813, 692 cm-1. Anal. Calcd for C18H16N2O2 (292.34): C, 73.96; H, 5.52; N, 9.58. Found: C, 73.68; H, 5.48; N, 9.32.