Ethyl 2-((4-bromo-7-cyano-1H-indol-3-yl)methylamino)-3,3-diethoxypropanoate → ethyl 9-bromo-6-cyano-5H-pyrido[4,3-b]indole-3-carboxylate

HRID 2361441Notes

Reaction equation

[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[C:3]=1[C:4]([CH2:13][NH:14][CH:15]([CH:21](OCC)OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][NH:6]2>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[C:4]3[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][C:5]=3[NH:6][C:7]=2[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1

Participants

Conditions

Temperature: 90 °C

Procedure

To a solution of ethyl 2-(((4-bromo-7-cyano-1H-indol-3-yl)methyl)amino)-3,3-diethoxypropanoate (1.12 g, 2.56 mmol) in toluene (51.1 mL) at 0° C. was added dropwise titanium tetrachloride (1 M in CH2Cl2, 8.94 mL, 8.94 mmol). The mixture was heated at 90° C. for 3 h. The mixture was cooled to room temperature and partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated. The resulting dark yellow solid was suspended in methanol, then collected by filtration and air-dried to afford the desired product as a yellow solid (300 mg, 29% yield), contaminated with partially aromatized material (ethyl 9-bromo-6-cyano-4,5-dihydro-3H-pyrido[4,3-b]indole-3-carboxylate and/or ethyl 9-bromo-6-cyano-2,5-dihydro-1H-pyrido[4,3-b]indole-3-carboxylate) and ethyl 9-bromo-6-cyano-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-3-carboxylate, which was used without further purification. LCMS (M+H)+ m/z 343.9, 345.9.

Workup

temperatureThe mixture was cooled to room temperature
custompartitioned between NaHCO3 (aq) and EtOAc
washThe organic phase was washed with brine
customdried
concentrationconcentrated
filtrationcollected by filtration
customair-dried

Sources & evidence

ORD record: ord-92d6fefa0bdb4fba828ae88192d07db0
Source dataset: uspto-grants-2014_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08685969B2

Reaction notes

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