Water → (S)-7-(3,3-dimethylbut-1-ynyl)-3-(2-fluoropyridin-4-yl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

HRID 1472421Notes

Reaction equation

HRID 1472421 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC1OCCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]#[C:22][C:12]1[CH:13]=[C:14]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([F:28])[CH:34]=4)[CH:3]=3)[O:8][C:9]2=[CH:10][CH:11]=1

Participants

7

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 27833962-Fluoropyridine-4-boronic acidHCID 67387294(S)-3-bromo-7-(3,3-dimethylbut-1-ynyl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

Product 1

HCID 58465979(S)-7-(3,3-dimethylbut-1-ynyl)-3-(2-fluoropyridin-4-yl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amineYield 46.8%

Reagents, catalysts & solvents 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

A vial was charged with (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine, diisopropylamine (0.785 mL, 5.51 mmol), Pd(PPh3)4 (0.127 g, 0.110 mmol), copper(I) iodide (0.021 g, 0.110 mmol), and 3,3-dimethyl-1-butyne (0.203 mL, 1.652 mmol). DMF (3 mL) were added, the vial was sealed under argon and heated to 90° C. for 60 minutes. The reaction mixture was diluted with 2-MeTHF then washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-3-bromo-7-(3,3-dimethylbut-1-ynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.120 g, 0.281 mmol, 25.6% yield) as a white solid. Step 2: A vial was charged with (S)-3-bromo-7-(3,3-dimethylbut-1-ynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.060 g, 0.141 mmol), 2-fluoropyridin-4-ylboronic acid (0.050 g, 0.352 mmol), potassium phosphate (0.299 g, 1.407 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.98 mg, 7.04 μmol) Dioxane (2 mL) and water (0.5 mL) were added, the vial was sealed under argon and heated to 80° C. for 1 hour. The reaction mixture was then diluted with 2-MeTHF, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (95:5 EtOAc/MeOH)/DCM] gave (S)-7-(3,3-dimethylbut-1-ynyl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.029 g, 0.066 mmol, 46.6% yield) as a yellow solid. [M+H]+=443.0

Workup

  1. additionwere added
  2. customthe vial was sealed under argon
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated
  5. customPurification of the crude residue by column chromatography [0-100% (95:5 EtOAc/MeOH)/DCM]

Sources & evidence

ORD record
ord-35921bf8f535460c97abdb1401d4a4cf
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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