Potassium Phosphate, Tribasic → 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine

HRID 634196Notes

Reaction equation

HRID 634196 reaction equation
I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH3:17])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.[CH:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[N:33]=1)([CH3:30])[CH3:29].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:28]([O:31][C:32]1[N:33]=[C:34]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH3:17])=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:3]=2)[CH:35]=[CH:36][CH:37]=1)([CH3:30])[CH3:29]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 426146482-Isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 683284815-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine

Product 1

HCID 683280545-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
125 °C

Procedure

A mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine (210 mg, 0.42 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (145 mg, 0.55 mmol) (CombiPhos Catalysts Inc., Cat#BE177), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (16 mg, 0.034 mmol, Strem), Pd2(dba)3 (15 mg, 0.017 mmol, Strem), and potassium phosphate (271 mg, 1.27 mmol) in dioxane (4 mL) and H2O (1 mL) in a sealed glass tube was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 20 min. The mixture was partitioned between 2 mL of 0.5 N NaOH and 10 mL of EtOAc. The organic layer was filtered through a pad of Celite and concentrated to give crude 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine that was used in next step without further purification. MS (ESI, pos. ion) m/z: 504.1 (M+1). A mixture of 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine and KOH (49 mg, 0.88 mmol) in 2 mL of dioxane and 1 mL of H2O was heated in a microwave at 105° C. for 15 min. It was partitioned between 15 mL of EtOAc and 3 mL of H2O. The organic layer was concentrated and purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in AcCN] in [0.1% TFA in H2O] to afford 5-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine 2,2,2-trifluoroacetate (51 mg, 27% overall for 2 steps) as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 350.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br.), 8.99 (1H, s), 8.19 (1H, d, J=2.6 Hz,), 7.66 (2H, m), 7.56 (1H, d, J=8.6 Hz), 7.42 (1H, d, J=7.4 Hz), 6.52 (1H, d, J=8.0 Hz), 5.49 (1H, m), 4.06 (1H, br.), 2.89 (3H, s), 1.44 (6H, d, J=6.1 Hz).

Workup

  1. customThe mixture was partitioned between 2 mL of 0.5 N NaOH and 10 mL of EtOAc
  2. filtrationThe organic layer was filtered through a pad of Celite
  3. concentrationconcentrated

Sources & evidence

ORD record
ord-989bcabcd77b4e25933fe689dd73bf31
Source dataset
uspto-grants-2016_04
Patent number
US09321756B2

Reaction notes

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