Aniline → HCID 60088383, compound

HRID 1836576Notes

Reaction equation

HRID 1836576 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH2:7][C@@H:6]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:5]23)[CH:11]=1.CC(C)([O-])C.[Na+].Br[C:32]1[CH:33]=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:35]=[CH:36][C:37]=1[Cl:38].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.NC1C=CC=CC=1>C1(C)C=CC=CC=1.CCOCC.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]>[Cl:38][C:37]1[CH:32]=[CH:33][C:34]([C:39]([F:40])([F:41])[F:42])=[CH:35][C:36]=1[NH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH2:7][C@@H:6]3[CH2:15][NH:16][CH2:17][C@@H:5]23)[CH:11]=1

Participants

9

Reactant 5

HCID 6115AnilineHCID 679882-Bromo-1-chloro-4-(trifluoromethyl)benzeneHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 131724537HCID 131724537, compound

Product 1

HCID 60088383HCID 60088383, compoundYield 16.9%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
0 °C

Procedure

A solution of (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate (100 mg, 0.304 mmol), sodium tert-butoxide (58 mg, 0.608 mmol), and 3-bromo-4-chlorobenzotrifluoride (95 mg, 0.365 mmol) in anhydrous toluene (6 mL) were degassed with argon at 85° C. for 15 min. The solution was cooled slightly, and a mixture of solid Pd2(dba)3 (5.6 mg, 6.1 μmol) and solid BINAP (11 mg, μmol) were added to the solution. The flask was capped under a positive pressure of Ar and heating was continued at 85° C. overnight. After the reaction was complete as evidenced by the lack of starting aniline by TLC analysis, the solution was cooled and diluted with ether. The red slurry was filtered through Celite 521® and concentrated under reduced pressure to give crude N-Boc protected biarylamine as a red oil (101 mg). The crude product was purified by silica gel chromatography on the Isco Combi-flash unit using a 10-g RediSep cartridge and a gradient elution of ethyl acetate in hexanes from 5% to 75%. A CH2Cl2 (4 mL) solution of the N-Boc protected product was cooled to 0° C. and treated with trifluoroacetic acid (TFA) (250 μL). The disappearance of N-Boc protected material was followed by TLC analysis (1:1 hexanes:EtOAc) over 8 h. The TFA solution was then basified with 3 N NaOH to pH >12 and extracted with CH2Cl2. Evaporations of the extracts gave 21 mg of the title compound of EXAMPLE 72 as an off-white powder. 1H NMR (500 MHz, CDCl3) δ 1.26 (br s, 1H), 1.95 (m, 1H), 2.0 (m, 1H), 2.15 (m, 1H), 2.74 (m, 4H), 2.90 (t, 1H, J=1.9 Hz), 3.29 (m, 1H), 3.33 (m, 4H), 3.51 (t, 1H, J=1.9 Hz), 5.96 (s, 1H), 6.52 (s, 1H), 6.69 (s, 1H), 6.86 (m, 1H), 7.07 (s, 1H), 7.34 (m, 1H). LRMS (ES)+: 408 (M+H)+.

Workup

  1. temperatureThe solution was cooled slightly
  2. additionwere added to the solution
  3. customThe flask was capped under a positive pressure of Ar
  4. temperatureheating
  5. temperaturethe solution was cooled
  6. filtrationThe red slurry was filtered through Celite 521®
  7. concentrationconcentrated under reduced pressure
  8. customto give crude N-Boc
  9. customThe crude product was purified by silica gel chromatography on the Isco Combi-flash unit
  10. washa gradient elution of ethyl acetate in hexanes from 5% to 75%
  11. additiontreated with trifluoroacetic acid (TFA) (250 μL)
  12. waitThe disappearance of N-Boc protected material was followed by TLC analysis (1:1 hexanes:EtOAc) over 8 h
  13. extractionextracted with CH2Cl2

Sources & evidence

ORD record
ord-d46a4df5136149ae819fa2503eaf21c9
Source dataset
uspto-grants-2004_08
Patent number
US06777406B2

Reaction notes

Loading…