Methyl iodide → HCID 59199339, compound

HRID 2089514Notes

Reaction equation

HRID 2089514 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]([C:11]1[N:12]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][S:18][CH2:17]2)[CH:13]=[N:14][CH:15]=1)=O.C1C2C(=CC=CC=2)C(N2C(CO)=CN=C2)CS1.CC(C)([O-])C.[K+].IC>C1COCC1>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]([N:12]2[C:11]([CH2:9][O:8][CH3:7])=[CH:15][N:14]=[CH:13]2)[CH2:17][S:18]1

Participants

7

Reactant 5

HCID 6328Methyl iodideHCID 21226445Aluminium lithium hydrideHCID 23665647Potassium tert-butoxideHCID 67546707HCID 67546707, compoundHCID 67548167HCID 67548167, compound

Product 1

HCID 59199339HCID 59199339, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
48 °C

Procedure

To a solution of LiAlH4 (171 mg, 4.48 mmol) in THF (100 mL) at 0° C. is added a solution of 3-isothiochroman-4-yl-3H-imidazole-4-carboxylic acid methyl ester [which can be prepared from isothiochroman-4-ol (CAS#109819-33-2) as described in Example 2; MS: (ESI) m/z 275.2 (M+H)+] (1.23 g, 4.48 mmol) in THF (50 mL). The reaction is permitted to stir for 4 hours, at which time it is quenched by the slow addition of water. The reaction mixture is then filtered, diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer is dried with Na2SO4, filtered, and concentrated. A portion of the resulting residue containing (3-isothiochroman-4-yl-3H-imidazol-4-yl)-methanol (240 mg, ca. 0.5 mmol) is then dissolved in THF (25 mL) and cooled to 48° C. The reaction mixture is then charged with a 1 M THF solution of potassium t-butoxide (0.75 mL, 0.75 mmol). The reaction is permitted to stir for 30 minutes and then charged with iodomethane (0.2 mL, 0.61 mmol). After 3.5 hours the reaction is quenched with saturated aqueous NaHCO3 and further diluted with ethyl acetate. The organic layer is washed with saturated aqueous NaHCO3, and then dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:19) to provide 1-isothiochroman-4-yl-5-methoxymethyl-1H-imidazole; MS: (ESI) m/z 261.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 3.07-3.30 (m, 2 H), 3.33 (s, 3 H), 3.88 (br. s., 2 H), 4.35-4.57 (m, 2 H), 5.64 (t, J=5.2 Hz, 1 H), 6.93 (d, J=7.1 Hz, 1 H), 7.07 (s, 1 H), 7.15-7.28 (m, 3 H), 7.39 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-isothiochroman-4-yl-5-methoxymethyl-1H-imidazole.

Workup

  1. customis quenched by the slow addition of water
  2. filtrationThe reaction mixture is then filtered
  3. additiondiluted with ethyl acetate
  4. washwashed with saturated aqueous NaHCO3
  5. dry with materialThe organic layer is dried with Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. stirringto stir for 30 minutes
  9. customAfter 3.5 hours the reaction is quenched with saturated aqueous NaHCO3
  10. additionfurther diluted with ethyl acetate
  11. washThe organic layer is washed with saturated aqueous NaHCO3
  12. dry with materialdried with Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThe resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:19)

Sources & evidence

ORD record
ord-f1b64d7df68b477f885f8770c32829b8
Source dataset
uspto-grants-2013_05
Patent number
US08436035B2

Reaction notes

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