Tetrahydrofuran → N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide

HRID 1473350Notes

Reaction equation

HRID 1473350 reaction equation
FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2.[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][NH:43][C:44]1[S:48][N:47]=[CH:46][N:45]=1.C1COCC1.CC(C)([O-])C.[Li+]>[Cl-].[NH4+]>[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][N:43]([C:44]1[S:48][N:47]=[CH:46][N:45]=1)[S:23]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[CH:22][C:13]=2[CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:18]=1)(=[O:24])=[O:25]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 236647642-Propanol, 2-methyl-, lithium salt (1:1)HCID 57732216N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amineHCID 86687398Perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate

Product 1

HCID 86687400N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamideYield 64.1%

Reagents, catalysts & solvents 1

HCID 25517Ammonium ChlorideSolvent

Procedure

A round-bottom flask was charged with perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate (104.73 mg, 0.188 mmol), N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (56.7 mg, 0.225 mmol), and THF (1879 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium tert-butoxide (Sigma-Aldrich, St. Louis, Mo., 1M in hexane) (413 μl, 0.413 mmol) was added dropwise. After 35 min, the flask was submerged in an ice-bath for 2 h. The mixture was diluted with saturated aq ammonium chloride, then extracted with EtOAC (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g, 0 to 10% MeOH/DCM) to give N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (61.5 mg, 0.120 mmol, 64.1% yield) as a white foam: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.55 (d, J=2.2 Hz, 1H), 8.41-8.33 (m, 2H), 8.01 (dd, J=7.7, 19.2 Hz, 2H), 7.78 (dd, J=2.2, 9.1 Hz, 1H), 7.68-7.61 (m, 1H), 7.03-6.95 (m, 1H), 6.36 (qd, J=2.3, 4.5 Hz, 2H), 5.18 (s, 2H), 4.77 (t, J=7.4 Hz, 1H), 3.67 (s, 3H), 3.63 (s, 3H), 3.12-2.95 (m, 2H), 2.40-2.30 (m, 1H), 1.83-1.72 (m, 2H), 1.51-1.40 (m, 1H); m/z (ESI) 511.4 (M+H)+.

Workup

  1. customto give a clear solution
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 10 min
  3. waitthe flask was submerged in an ice-bath for 2 h
  4. extractionextracted with EtOAC (3×)
  5. dry with materialThe combined organic extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by chromatography on silica gel (12-g, 0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-53cf7bad4b4f4e25aa353c3b11cb15f0
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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