Triphenylphosphine → (R)-[4-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(1-methyl-2-morpholin-4-yl-ethyl)-amine

HRID 1670637Notes

Reaction equation

HRID 1670637 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([CH3:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:47]=1)[O:27][CH2:28][C:29]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>O1CCOCC1.O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:47]=1)[O:27][CH2:28][C:29]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([CH3:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1

Participants

8

Reactant 4

HCID 11776TriphenylphosphineHCID 517044Potassium AcetateHCID 67334620(R)-4-Bromo-N-(1-morpholinopropan-2-yl)-2-nitroanilineHCID 67335490(E)-2-((3,8-difluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Product 1

HCID 57748733(R)-[4-((E)-3,8-Difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(1-methyl-2-morpholin-4-yl-ethyl)-amineYield 48.5%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Procedure

Degas three times a mixture of (R)-(4-bromo-2-nitro-phenyl)-(1-methyl-2-morpholin-4-yl-ethyl)-amine (0.037 mol, 12.8 g), (E)-3,8-difluoro-11-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-ylmethylene)-6,11-dihydro-dibenzo[b,e]oxepine (0.037 mol, 13.7 g), triphenylphosphine (0.007 mol, 2.02 g) and potassium acetate (0.074 mol, 7.29 g) in dioxane/water (3:1) (450 mL) with nitrogen. Add palladium (II) acetate (0.001 mol) to the reaction mixture and degas again three times with nitrogen. Heat the resulting reaction mixture at 85° C. for 16 h. Cool the reaction mixture to room temperature, dilute with water, extract with ethyl acetate, combine organic layer, wash with water and brine. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 7% ethyl acetate in hexanes as eluent to obtain the title compound (9.1 g, 48%) as an orange solid. 1H NMR (400 MHz, CDCl3), δ 1.26 (d, 3H), 2.44-2.57 (m, 6H), 3.66-3.68 (m, 4H), 3.71-3.78 (m, 1H), 4.89 (br s, 1H), 5.63 (br s, 1H), 6.52 (dd, 1H), 6.61 (d, 1H), 6.67 (dt, 1H), 6.76 (s, 1H), 6.89 (d, 1H), 6.95 (dt, 1H), 7.06-7.10 (m, 1H), 7.19 (dd, 1H), 7.29-7.41 (m, 1H), 7.95 (d, 1H), 8.35 (d, 1H, —NH).

Workup

  1. customDegas three times
  2. temperatureHeat
  3. customthe resulting reaction mixture at 85° C. for 16 h
  4. extractionextract with ethyl acetate
  5. washwash with water and brine
  6. dry with materialDry the organic phase over anhydrous sodium sulfate
  7. filtrationfilter
  8. concentrationconcentrate
  9. customPurify on a silica gel column

Sources & evidence

ORD record
ord-8161a9a384864c1394b7e2b4e51f5a0e
Source dataset
uspto-grants-2011_08
Patent number
US07994164B2

Reaction notes

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