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

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.

Key words

ate complex - magnesium - diazines - lithium - iodine

References and Notes

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  Stevenson, T. M.; Crouse, B. A.; Thieu, T. V.; Gebreysus, C.; Piotrowski, D. L. Abstracts of Papers, 228^th National Meeting of the American Chemical Society, Philadelphia, 2004; American Chemical Society: Washington DC, 2004.

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8

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, H_Ph2,6), 6.76 (d, 2 H, J = 8.7 Hz, H_Ph3,5), 5.71 (s, 1 H, CH), 4.74 (m, 1 H, OH), 3.68 (s, 3 H, OCH₃). ¹³C NMR (CDCl₃): δ = 159.4 (C_Ph4), 157.5 (C₂), 143.2-143.0 (C₃, C₅ and C₆), 134.2 (C_Ph1), 128.2 (C_Ph2,6), 114.2 (C_Ph3,5), 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, H_Ph2,6), 6.81 (d, 2 H, J = 8.7 Hz, H_Ph3,5), 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 (C_Ph4), 157.3 (C₆), 133.6 (C_Ph1), 129.6 (C_Ph2,6), 114.5 (C_Ph3,5), 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.

9

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, H_Ph2,6), 7.77 (d, 1 H, J = 8.9 Hz, H₅), 7.40 (m, 6 H, H₄, H_{Ph ′ 2,6}, H_Ph3,4,5), 6.88 (d, 2 H, J = 8.7 Hz, H_{Ph ′ 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 (C_{Ph ′ 4}), 159.6 (C₃ and C₆), 135.9 (C_Ph1), 134.1 (C_{Ph ′ 1}), 130.3-124.9 (C₄, C₅, C_Ph2,6, C_{Ph ′ 2,6}, C_Ph4, C_Ph3,5), 114.3 (C_{Ph ′ 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.