Piperidine → 3-tert-butoxycarbonyl-7-chloro-6-(3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 911495Notes

Reaction equation

HRID 911495 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.CC(C)([O-])C.[Na+].C1OCCOCCOCCOCCOCCOC1.[NH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]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.[Pd].[Pd].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>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:20]2[C:10]([S:9][CH2:8][C:5]3[N:6]=[CH:7][C:2]([N:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)=[CH:3][CH:4]=3)=[C:11]([Cl:28])[CH:12]=[CH:13][C:14]=2[CH2:15][CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]

Participants

8

Reactant 4

HCID 8082PiperidineHCID 2855718-Crown-6HCID 23676156Sodium t-butoxideHCID 576562493-tert-butoxycarbonyl-6-(5-bromopyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Product 1

HCID 667065283-tert-butoxycarbonyl-7-chloro-6-(3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 73.2%

Reagents, catalysts & solvents 3

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

In a sealed tube, add tris(dibenzylideneacetone)dipalladium(0) (3.44 mg, 0.00376 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.98 mg, 0.00752 mmol) to a mixture of 6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (242 mg, 0.501 mmol), sodium tert-butoxide (96 mg, 1.0 mmol), 18-crown-6 (13 mg, 0.050 mmol) and piperidine (496 μL, 5.01 mmol) in toluene (3 mL). Flush the mixture with nitrogen and heat overnight. Cool to ambient temperature, dilute with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (179 mg, 73%).

Workup

  1. customFlush the mixture with nitrogen
  2. temperatureheat overnight
  3. additiondilute with water
  4. extractionextract three times with EtOAc
  5. dry with materialDry over anhydrous Na2SO4
  6. concentrationconcentrate in vacuo
  7. customPurify by chromatography on silica gel eluting with hexane/EtOAc (9:1)

Sources & evidence

ORD record
ord-ff4f097300e040d1b4504a220183b140
Source dataset
uspto-grants-2011_09
Patent number
US08022062B2

Reaction notes

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