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2-Bromopyridine → N-[(4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amine

HRID 273080
Notes
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Reaction equation

HRID 273080 reaction equation
[CH:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>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.[Pd].[Pd]>[CH:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 79732-BromopyridineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 598375291-(4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine

Product 1

HCID 59837493N-[(4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amineYield 26%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

1-(4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine was stirred with 2-bromopyridine (60 μl, 0.63 mmol), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.018 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.036 mmol) and sodium tert-butoxide (90 mg, 0.94 mmol) and heated at 80° C. in toluene (5 ml) for 3 hours under nitrogen. The reaction mixture was partitioned between aqueous sodium hydroxide (50 ml) and ethyl acetate (80 ml). The organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 90:10:1 by volume) to give the product which required further purification by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 94:6:0.6 by volume) to give a pale yellow oil which crystallized on standing, this was triturated with diethyl ether (2 ml) to give the title compound as a pale yellow powder (65 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, 1H), 7.31 (t, 1H), 7.25 (d, 2H), 6.91 (d, 2H), 6.50 (t, 1H), 6.20 (d, 1H), 4.09 (d, 2H), 3.99 (t, 1H), 3.82 (m, 2H), 3.59 (m, 2H), 3.48 (d, 2H), 3.45 (m, 2H), 3.03 (m, 2H), 2.88 (m, 1H), 2.33 (m, 1H), 2.13 (m, 2H), 1.92 (m, 2H), 0.93 (d, 6H). LRMS ESI+ m/z 396 [M+H]+. HRMS ESI+ m/z 396.2639 [M+H]+.

Workup

  1. customThe reaction mixture was partitioned between aqueous sodium hydroxide (50 ml) and ethyl acetate (80 ml)
  2. dry with materialThe organics were dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 90:10:1 by volume)
  6. customto give the product which
  7. custompurification by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 94:6:0.6 by volume)
  8. customto give a pale yellow oil which
  9. customcrystallized
  10. customthis was triturated with diethyl ether (2 ml)

Sources & evidence

ORD record
ord-abf41b8f050c4b768eb906c2e9dfc45f
Source dataset
uspto-grants-2008_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07456164B2

Reaction notes

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