Oxalyl chloride → 3-bromo-N-methoxy-N-methylthiophene-2-carboxamide

HRID 2111156Notes

Reaction equation

HRID 2111156 reaction equation
C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([OH:15])=O.BrC1C=CSC=1C(Cl)=O.Cl.[CH3:26][NH:27][O:28][CH3:29].C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:13]([C:9]1[S:10][CH:11]=[CH:12][C:8]=1[Br:7])=[O:15]

Participants

8

Reactant 5

HCID 65578Oxalyl chlorideHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 27396883-Bromothiophene-2-carboxylic acidHCID 27975693-Bromothiophene-2-carbonyl chloride

Product 1

HCID 576374043-bromo-N-methoxy-N-methylthiophene-2-carboxamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Procedure

Oxalyl chloride (0.601 mL, 6.99 mmol, 1.2 eq) is added to a mixture of 3-bromothiophene-2-carboxylic acid (1.20 g, 5.80 mmol), N,N-dimethylformamide (several drops, catalytic amount), and anhydrous dichloromethane (25 mL) at ambient temperature under nitrogen over 20 minutes. The reaction is stirred for 17 hours, purged with nitrogen, and concentrated under reduced pressure to afford a tan solid. The crude 3-bromothiophene-2-carbonyl chloride is dissolved in dichloromethane (25 mL) and added dropwise, over 10 minutes, to a 0° C. solution of N,O-dimethylhydroxylamine hydrochloride (843 mg, 8.64 mmol), diisopropylethylamine (2.50 mL, 14.3 mmol), and dichloromethane (25 mL). The reaction is allowed to gradually warm to ambient temperature overnight. The reaction is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product is purified by chromatography on silica, eluting with 1:1 ethyl acetate/heptane, to give 3-bromo-thiophene-2-carboxylic acid methoxy-methyl-amide, as a white solid: TLC Rƒ0.33 (silica, 1:1 ethyl acetate/heptane); LC/MS: (M+H 249.94, RT=2.18 minutes); 1H NMR [(CD3)2SO), 300 MHz]: δ 7.85 (d, 1H, J=5.3 Hz), 7.17 (d, 1H, 5.3 Hz), 3.62 (s, 3H), 3.24 (s, 3H).

Workup

  1. custompurged with nitrogen
  2. concentrationconcentrated under reduced pressure
  3. customto afford a tan solid
  4. washThe reaction is washed with water
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe crude product is purified by chromatography on silica
  8. washeluting with 1:1 ethyl acetate/heptane

Sources & evidence

ORD record
ord-0a04e735261d4a19b1d4df45f73d1d94
Source dataset
uspto-grants-2009_04
Patent number
US07518000B2

Reaction notes

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