2-Bromopyridine → 5-(1-(pyridin-2-yl)pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide

HRID 1473423Notes

Reaction equation

HRID 1473423 reaction equation
COC1C=C(OC)C=CC=1C[N:6]([C:25]1[S:29][N:28]=[CH:27][N:26]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH:11]=1)(=[O:9])=[O:8].COC(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>CCOC(C)=O.C1(C)C=CC=CC=1>[N:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][C:10]([S:7]([NH:6][C:25]1[S:29][N:28]=[CH:27][N:26]=1)(=[O:9])=[O:8])=[CH:11]2

Participants

7

Reactant 4

HCID 79732-BromopyridineHCID 10796Cesium carbonate2×HCID 15413tert-Butyl methyl etherHCID 86687400N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide

Product 1

HCID 715865135-(1-(pyridin-2-yl)pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamideYield 33.3%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A vial was charged with N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (INTERMEDIATE KK) (34.01 mg, 0.067 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (Strem Chemical, Newburyport, Mass., 2.72 mg, 3.33 mmol), and cesium carbonate (65.1 mg, 0.200 mmol). The vial was flushed with Ar (g), then toluene (0.3 mL) and 2-bromopyridine (19.05 μl, 0.200 mmol) were added. The vial was sealed and placed in a 100° C. heating bath. After 4 h, an additional portion of catalyst (about 3 mg) was added, and the vial was heated for an additional 16 h. Additional portions of catalyst (6 mg) and cesium carbonate (about 55 mg) were added, and the vial was returned to the heat for 5 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through diatomaceous earth. The filtrate was concentrated. The residue was purified by chromatography on silica gel (12-g column, 0 to 10% MeOH/DCM) to give 5-(1-(pyridin-2-yl)pyrrolidin-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (9.7 mg, 0.022 mmol, 33.3% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.54 (d, J=2.0 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J=9.2 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.02-7.88 (m, 2H), 7.72 (br. s., 1H), 7.56-7.48 (m, 1H), 7.33 (d, J=6.9 Hz, 1H), 6.79 (t, J=6.4 Hz, 1H), 6.61 (br. s., 1H), 5.91 (d, J=7.8 Hz, 1H), 4.04 (t, J=8.6 Hz, 1H), 3.77-3.62 (m, 1H), 2.71-2.59 (m, 1H), 2.17-2.05 (m, 1H), 2.01-1.84 (m, 2H); m/z (ESI) 438.4 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. customThe vial was sealed
  3. customplaced in a 100° C.
  4. temperatureheating bath
  5. temperaturethe vial was heated for an additional 16 h
  6. temperatureheat for 5 h
  7. filtrationfiltered through diatomaceous earth
  8. concentrationThe filtrate was concentrated
  9. customThe residue was purified by chromatography on silica gel (12-g column, 0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-b0ed7ce9fdbb4393b1ee08f2c3a48e13
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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