1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → 3-[4-[2-[4-(Benzyloxy)phenoxy]ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine

HRID 2095440Notes

Reaction equation

HRID 2095440 reaction equation
[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([O:31][CH2:32][C@@H:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([O:31][CH2:32][C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 15480235(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl esterHCID 23676156Sodium t-butoxideHCID 540111564-[2-[4-(Benzyloxy)phenoxy]ethyl]piperidine

Product 1

HCID 593716803-[4-[2-[4-(Benzyloxy)phenoxy]ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridineYield 72%

Reagents, catalysts & solvents 2

HCID 11029508Palladium, tris[mu-[(1,2-eta:4,5-eta)-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one]]di-, compd. with trichloromethane (1:1)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A solution/suspension of 4-[2-[4-(benzyloxy)phenoxy]ethyl]piperidine (220 mg, 0.71 mmol), 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (277 mg, 0.78 mmol, 1.1 equiv.), sodium tert-butoxide (136 mg, 1.42 mmol, 2.0 equiv.), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (45 mg, 40 μmol, 0.06 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 50 mg, 90 μmol, 0.12 equiv.) in anhydrous toluene (20 mL) was stirred overnight at 100° C. under N2. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was taken up in 500 mL of EtOAc and washed with brine. The organic layer was dried and concentrated in vacuo, and the residue was applied onto a silica gel column, which was eluted with EtOAc/CH2Cl2 1:5 to 1:2 to provide the title compound (300 mg, 72%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.90 (s, 1H), 7.67 (s, 1H), 7.46-7.34 (m, 5H), 7.08 (s, 1H), 6.93 (d, 2H, J=9.3 Hz), 6.85 (d, 2H, J=9.3 Hz), 5.02 (s, 2H), 4.18-4.13 (m, 3H), 4.00 (t, 2H, J=5.7 Hz), 3.76 (m, 2H), 3.41 (m, 2H), 2.83 (s, 2H), 2.07-2.03 (m, 2H), 1.90-1.72 (m, 3H), 1.77 (m, 3H), 1.49 (s, 9H), 1.40-1.30 (m, 2H), 1.28-1.26 (m, 1H). LC-MS (ESI) m/z 588 (M+H+).

Workup

  1. temperatureAfter cooling to room temperature
  2. concentrationthe mixture was concentrated under vacuum
  3. washwashed with brine
  4. customThe organic layer was dried
  5. concentrationconcentrated in vacuo
  6. washwas eluted with EtOAc/CH2Cl2 1:5 to 1:2

Sources & evidence

ORD record
ord-ffa13fedc3ea4d56849b62edb311d7bc
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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