Carbon Dioxide → 3-Bromo-N-(2,4-Dimethoxybenzyl)-1-Methyl-N-(1,2,4-Thiadiazol-5-yl)-1H-Indole-6-Sulfonamide

HRID 1524385Notes

Reaction equation

HRID 1524385 reaction equation
[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=2)[N:34]([CH3:45])[CH:33]=1>C1COCC1.CC(C)=O>[Br:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([S:41]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:42])=[O:43])=[CH:38][CH:39]=2)[N:34]([CH3:45])[CH:33]=1

Participants

7

Reactant 4

HCID 280Carbon DioxideHCID 2733832Lithium HexamethyldisilazideHCID 57732216N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amineHCID 894076923-Bromo-1-methyl-1H-indole-6-sulfonyl chloride

Product 1

HCID 712592223-Bromo-N-(2,4-Dimethoxybenzyl)-1-Methyl-N-(1,2,4-Thiadiazol-5-yl)-1H-Indole-6-Sulfonamide

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A 1 L round bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (10.36 g, 41.2 mmol) and THF (190 ml) to give a clear, pale-yellow solution. The flask was cooled to −78° C. in a dry ice and acetone bath, then lithium bis(trimethylsilyl)amide (1M in THF) (43.1 ml, 43.1 mmol) was added dropwise. The cooling bath was removed for 10 min, which led to the formation of a clear, orange-colored solution. The flask was placed back in the cooling bath for 5 min, then a solution of 3-bromo-1-methyl-1H-indole-6-sulfonyl chloride (11.56 g, 37.5 mmol) in minimal THF was added dropwise via cannula. Following the addition, the cooling bath was removed and the reaction was stirred for two hours. The reaction mixture was diluted with a saturated aq. ammonium chloride solution and water, and extracted with EtOAc (2×). The aq. layer was filtered to give some desired product as a pink solid. The filtrate was again extracted with EtOAc, and the organic extracts were combined. The combined solution was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with EtOAc, and the resulting solid was collected via filtration to give a second crop of desired product. The filtrate was absorbed onto silica gel, and the impregnated silica gel was eluted onto a silica gel column (0 to 100% EtOAc/Heptane). The material thus obtained was still impure, so it was further purified by chromatography on silica gel (0 to 10% EtOAc/DCM) to give a third crop of desired product. The three crops were combined to afford 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (16.47 g, 31.5 mmol, 84% yield) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.34 (s, 1 H), 8.05 (dd, J=0.6, 1.6 Hz, 1 H), 7.95 (s, 1 H), 7.66-7.52 (m, 2 H), 6.95 (d, J=8.4 Hz, 1 H), 6.47-6.26 (m, 2 H), 5.12 (s, 2 H), 3.88 (s, 3 H), 3.69 (s, 3 H), 3.66 (s, 3 H). m/z (ESI) 545.0 (M+H)+.

Workup

  1. customto give a clear, pale-yellow solution
  2. customThe cooling bath was removed for 10 min
  3. additionthe addition
  4. customthe cooling bath was removed
  5. additionThe reaction mixture was diluted with a saturated aq. ammonium chloride solution and water
  6. extractionextracted with EtOAc (2×)
  7. filtrationThe aq. layer was filtered

Sources & evidence

ORD record
ord-10fd2e23829241a08bdd6504e1690a8d
Source dataset
uspto-grants-2015_07
Patent number
US09079902B2

Reaction notes

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