Tetrahydrofuran → HCID 89682607, compound

HRID 2278256Notes

Reaction equation

HRID 2278256 reaction equation
Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[O:14])[CH2:9][CH2:8]2)=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>C(Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl.O>[O:30]1[CH2:31][CH2:32][N:27]([C:4]2[CH:3]=[C:2]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=[CH:25][C:5]=2[CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[O:14])[CH2:9][CH2:8]2)[CH2:28][CH2:29]1

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 66827Phenylboronic AcidHCID 71657183HCID 71657183, compound

Product 1

HCID 89682607HCID 89682607, compoundYield 60.3%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

A round bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-bromo-2-morpholinobenzyl)piperazine-1-carboxylate (Example 57, 30 mg, 0.0562 mmol), Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (5 mg, 6.13 μmol), phenylboronic acid (10 mg, 82.0 μmol), and K2CO3 (21 mg, 152 μmol). THF (4 mL) and H2O (0.4 mL) were added and the reaction was heated to 70° C. for 2 h. The reaction was diluted in CH2Cl2 and washed with sat Na2CO3 (2×) and brine (1×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (100% to 80% hexanes in EtOAc) and yielded 1,1,1,3,3,3-hexafluoropropan-2-yl 4-((3-morpholino-[1,1′-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (18 mg, 60%). 1H NMR 400 MHz (CDCl3) δ 7.54-7.48 (m, 2H), 7.45-7.34 (m, 3H), 7.31-7.20 (m, 3H), 5.68 (h, J=6.3 Hz, 1H), 3.84-3.71 (m, 4H), 3.57 (s, 2H), 3.53-3.39 (m, 4H), 3.00-2.93 (m, 4H), 2.47 (dt, J=9.9, 5.0 Hz, 4H). LCMS (ESI, m/z): 532 [M+H]+.

Workup

  1. washwashed
  2. dry with materialThe organics were dried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was chromatographed on a silica gel column (100% to 80% hexanes in EtOAc)

Sources & evidence

ORD record
ord-08e0da0df1c04196ad2274b1d3aa9249
Source dataset
uspto-grants-2015_09
Patent number
US09133148B2

Reaction notes

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