Benzophenone imine → 7-amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

HRID 1987087Notes

Reaction equation

HRID 1987087 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:78])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[NH2:78][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1

Participants

7

Reactant 4

HCID 136809Benzophenone imineHCID 634876Binap, (A+-)-HCID 159808187-Bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-B]pyridin-5-oneHCID 23676156Sodium t-butoxide

Product 1

HCID 159808217-amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.05 g, 3.30 mmol), Pd2(dba)3 (8 mg, 0.00825 mmol), BINAP (15 mg, 0.0248 mmol) and benzophenone imine (0.662 mL, 3.95 mmol) were combined in a dry flask. The flask was charged with 40 mL of dry toluene, followed by sodium tert-butoxide (0.444 g, 4.62 mmol). Argon was bubbled through the solution for 5 minutes. The reaction solution was heated to 110° C. and stirred under argon. After 2.5 hours, the reaction was concentrated, 20 mL of THF and 1 mL of 6N hydrochloric acid were added and the resulting solution was stirred. After 2 hours, the solution was poured into 300 mL of ethyl acetate, 100 mL of saturated sodium bicarbonate and 200 μL of water. The organic layers were separated, dried with magnesium sulfate, filtered, concentrated, and purified by flash column chromatography (0-30% ethyl acetate/hexanes gradient) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.77 (d, 1H); 8.55 (d, 1H); 7.58 (d, 1H); 7.44 (d, 1H); 7.18 (d, 1H); 7.14 (d, 1H); 7.01 (dd, 1H); 4.15 (s, 2H). LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257.0; found 257.1. Method B: 3-chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.1 g, 2.7 mmol) was dissolved in 8 mL methanol and 30 mL dichloromethane. Then 10 mL of trifluoroacetic acid was added and the solution was stirred at ambient temperature. After 1 hour, reaction was concentrated, dissolved in 500 mL of ethyl acetate and washed with 200 mL saturated sodium bicarbonate. The organic layer was separated, dried with magnesium sulfate, filtered, and purified by flash column chromatography (0-10% methanol/dichloromethane gradient) and reverse phase HPLC (20-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford title compound. LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257.0; found 257.1.

Workup

  1. customArgon was bubbled through the solution for 5 minutes
  2. concentrationthe reaction was concentrated
  3. addition20 mL of THF and 1 mL of 6N hydrochloric acid were added
  4. stirringthe resulting solution was stirred
  5. waitAfter 2 hours
  6. additionthe solution was poured into 300 mL of ethyl acetate, 100 mL of saturated sodium bicarbonate and 200 μL of water
  7. customThe organic layers were separated
  8. dry with materialdried with magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. custompurified by flash column chromatography (0-30% ethyl acetate/hexanes gradient)

Sources & evidence

ORD record
ord-5f96ff5f4ab844b58b7a02713b63f1c1
Source dataset
uspto-grants-2009_06
Patent number
US07550478B2

Reaction notes

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