Acetamidine monohydrochloride → 9-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene

HRID 1530704Notes

Reaction equation

HRID 1530704 reaction equation
[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11](I)=[CH:10]3)=[CH:4][C:3]=1[CH3:17].Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20].[CH3:23][C:24]1([CH3:64])C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl.[CH:66]([NH:69]N)(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)=O>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:66]2[N:69]([CH:24]([CH3:64])[CH3:23])[N:22]=[C:19]([CH3:20])[N:21]=2)=[CH:10]3)=[CH:4][C:3]=1[CH3:17]

Participants

8

Reactant 4

HCID 67170Acetamidine monohydrochlorideHCID 855731-Isopropylhydrazine hydrochlorideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 6831288010-Bromo-2-iodo-9-methyl-5,6-dihydrobenzo[F]imidazo[1,2-D][1,4]oxazepine

Product 1

HCID 683128519-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azuleneYield 493.1%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 13-bromo-4-iodo-12-methyl-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (5.00 g, 12.3 mmol), acetamidine hydrochloride (1.29 g, 13.6 mmol), Pd(OAc)2 (277 mg, 1.24 mmol), and Xantphos (1.43 g, 2.47 mmol) in DMF (20.0 mL) and TEA (5.0 mL) was heated at 40° C. under CO (1 atm) for 3 hrs. To above cooled solution was added isopropylhydrazine hydrochloride (1.64 g, 14.8 mmol) and AcOH (20.0 mL). The resulting mixture was heated to 65° C. and stirred at this temperature for 1 hr. At the end of reaction, solvents were removed and the residue was poured into water (2000 mL). The solid was collected by filtration and washed with acetone to give the desired product (4.90 g, 85% yield) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.08 (s, 1H), 5.67 (m, 1H), 4.52-4.49 (m, 4H), 2.33 (s, 3H), 2.25 (s, 3H), 1.46 (s, 6H). LCMS m/z [M+H]+ 402.2.

Workup

  1. temperatureTo above cooled solution
  2. temperatureThe resulting mixture was heated to 65° C.
  3. customAt the end of reaction, solvents
  4. customwere removed
  5. additionthe residue was poured into water (2000 mL)
  6. filtrationThe solid was collected by filtration
  7. washwashed with acetone

Sources & evidence

ORD record
ord-362b79efb9944b46b0a26f225ae8b380
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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