Hydrochloric Acid → (+/-)-methyl 6-chloro-5-(4-{[trans-2-hydroxycyclopentyl]oxy}phenyl)-1H-indole-3-carboxylate

HRID 338321Notes

Reaction equation

HRID 338321 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:36]=[CH:35][C:27]([O:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[OH:34])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:36]=[CH:35][C:27]([O:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[OH:34])=[CH:26][CH:25]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 67195959(1R,2R)-2-(4-bromophenoxy)cyclopentan-1-olHCID 86698665methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate

Product 1

HCID 86698668(+/-)-methyl 6-chloro-5-(4-{[trans-2-hydroxycyclopentyl]oxy}phenyl)-1H-indole-3-carboxylateYield 90.7%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (92.6 mg, 0.288 mmol) and (±)-trans-2-(4-bromophenoxy)-cyclopentanol (37 mg, 0.14 mmol) in ethanol (0.2 mL), toluene (0.3 mL), and 2M aqueous potassium carbonate (0.288 mL, 0.576 mmol) was sealed in a microwave vial and degassed with nitrogen for 10 minutes. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.2 mg, 0.014 mmol) was added, and the reaction mixture was resealed and heated to 90° C. in an oil bath for 1 hour. The reaction mixture was cooled to room temperature and poured into 0.5N HCl (10 mL). The product was extracted with ethyl acetate (3×10 mL), and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using silica gel chromatography (4:1 to 1:4 heptane/ethyl acetate) to give the title compound (49 mg, 88%) as a white solid. MS (ES−) 384.2 (M−H)−. 1H NMR (500 MHz, CD3OD) δ 8.00 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.5 Hz, 2H), 4.57 (br. s., 1H), 4.26 (br. s., 1H), 3.87 (s, 3H), 2.25-2.15 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.77 (m, 3H), 1.72-1.62 (m, 1H)

Workup

  1. customwas sealed in a microwave vial
  2. customdegassed with nitrogen for 10 minutes
  3. temperatureThe reaction mixture was cooled to room temperature
  4. extractionThe product was extracted with ethyl acetate (3×10 mL)
  5. dry with materialthe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. customThe crude product was purified

Sources & evidence

ORD record
ord-d7e8427f180b4a99bebcef964a12e89b
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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