1,4-Dioxane → 1H-Indole-3-carboxylic acid, 1-[1-[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]ethyl]-2-methyl-, methyl ester

HRID 1527013Notes

Reaction equation

HRID 1527013 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:27]([O:29][CH3:30])=[O:28])=[C:9]([NH:11][CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:13])[CH3:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.O1CCOCC1.C[O-].[Na+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH:12]([N:11]2[C:4]3[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=3)[C:8]([C:27]([O:29][CH3:30])=[O:28])=[C:9]2[CH3:10])[CH3:13])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]

Participants

6

Reactant 4

HCID 312751,4-DioxaneHCID 10942334Sodium MethoxideHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 131733195Tert-butyl 4-(1-(3-(2-bromophenyl)-4-methoxy-4-oxobut-2-en-2-ylamino)ethyl)piperidine-1-carboxylate

Product 1

HCID 1178044371H-Indole-3-carboxylic acid, 1-[1-[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]ethyl]-2-methyl-, methyl esterYield 68.9%

Reagents, catalysts & solvents 1

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylCatalyst

Conditions

Temperature
100 °C

Procedure

A 250 mL round bottom flask was charged with a magnetic stir bar, (R or S,Z)-tert-butyl 4-(1-(3-(2-bromophenyl)-4-methoxy-4-oxobut-2-en-2-ylamino)ethyl)piperidine-1-carboxylate (3.33 g, 6.92 mmol), RuPhos Pre-catalyst II (Chloro-(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl ether adduct) (0.463 g, 0.553 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.387 g, 0.830 mmol), anhydrous 1,4-dioxane (27.7 ml, 6.92 mmol), and sodium methoxide (0.561 g, 10.38 mmol). The reaction mixture was purged and back-filled with nitrogen and heated to 100° C. with stirring overnight before being allowed to cool to rt. The reaction was diluted with ethyl acetate (˜100 ml) and the mixture was filtered through a bed of diatomaceous earth. The filtrate was pre-absorbed onto silica gel (˜30 g) and purified via silica gel chromatography (120 g) using ethyl acetate/hexanes (1:1) as eluent to afford the title compound (2.01 g, 4.77 mmol, 68.9% yield).

Workup

  1. additionA 250 mL round bottom flask was charged with a magnetic stir bar
  2. customThe reaction mixture was purged
  3. additionback-filled with nitrogen
  4. temperatureto cool to rt
  5. additionThe reaction was diluted with ethyl acetate (˜100 ml)
  6. filtrationthe mixture was filtered through a bed of diatomaceous earth
  7. customThe filtrate was pre-absorbed onto silica gel (˜30 g)
  8. custompurified via silica gel chromatography (120 g)

Sources & evidence

ORD record
ord-7ff6b766e14449da976b4180a535323c
Source dataset
uspto-grants-2015_07
Patent number
US09085583B2

Reaction notes

Loading…