Methane, dichloromethoxy- → 2,5-Dihydro-3,6-dimethoxy-2-isopropyl-5-(2'-iodo-4'-methoxy-5'-formylbenzyl)-(2R,55)-pyrazine

HRID 1188753Notes

Reaction equation

HRID 1188753 reaction equation
[CH3:1][O:2][C:3]1[C@@H:4]([CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]([O:19][CH3:20])[C@H:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[I:18])[N:8]=1.[CH3:24][O:25]C(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3]1[C@@H:4]([CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]([O:19][CH3:20])[C@H:7]([CH2:9][C:10]2[CH:15]=[C:14]([CH:24]=[O:25])[C:13]([O:16][CH3:17])=[CH:12][C:11]=2[I:18])[N:8]=1

Participants

6

Reactant 4

HCID 21004Methane, dichloromethoxy-3×HCID 24287Tin tetrachloride2×HCID 25517Ammonium ChlorideHCID 670809982,5-Dihydro-3,6-dimethoxy-2-isopropyl-5-(2'-iodo-4'-methoxybenzyl)-(2R,5S)-pyrazine2×

Product 1

HCID 866559872,5-Dihydro-3,6-dimethoxy-2-isopropyl-5-(2'-iodo-4'-methoxy-5'-formylbenzyl)-(2R,55)-pyrazineYield 48%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Formylation of compound 21 by dichloromethyl methyl ether in the presence of stannic chloride was carried out by a known method [(A. H. Lewin, S. R. Parker, N. B. Fleming, and F. Carroll, “Formylation of Arenes by α,α-Dichloromethyl Methyl Ether. An Improved Experimental Procedure” Org. Prep. Proced. Int., 10, pp 201-204 (1978)]. The pyrazine derivative 21 (100 mg, 0.23 mol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0° C. and a 1M solution of SnCl4 (2.6 mL, 2.6 mol) was added drop wise under argon. After completion of the addition of SnCl4, 1,1-dichloromethyl methyl ether (0.21 mL, 2.32 mmol) was added drop wise to the reaction mixture. The solution turned from light yellow to greenish brown upon the addition of the dichloro derivative. The resulting mixture was stirred for 45 min at 0° C. A saturated solution of ammonium chloride (2 mL) was added to quench the reaction and the light brown suspension that resulted was stirred for 30 min at room temperature. The mixture was then extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated, resulting in an oily product. Flash chromatographic purification of this product provided pure 2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(2′-iodo-4′-methoxy-5′-formylbenzyl)-(2R,5S)-pyrazine (22) as a yellow oil (51 mg, 48%).

Workup

  1. additionwas added drop wise to the reaction mixture
  2. customto quench
  3. customthe reaction
  4. customthe light brown suspension that resulted
  5. stirringwas stirred for 30 min at room temperature
  6. extractionThe mixture was then extracted with dichloromethane
  7. dry with materialThe organic phase was dried over anhydrous Na2SO4
  8. filtrationfiltered
  9. customevaporated
  10. customresulting in an oily product
  11. customFlash chromatographic purification of this product

Sources & evidence

ORD record
ord-8225da5a5e6344508512f96897e145d2
Source dataset
uspto-grants-2014_03
Patent number
US08674101B2

Reaction notes

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