Sodium Hydroxide → 9-cyclopropyl-2-methyl-4-(5-methylchroman-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carbaldehyde

HRID 1912638Notes

Reaction equation

HRID 1912638 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:13]2[C:25]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[N:18]([CH:26]4[CH2:28][CH2:27]4)[C:17]=3[N:16]=[C:15]([CH3:29])[C:14]=2[C:30](OCC)=[O:31])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].ClCl.[OH-].[Na+].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>O1CCCC1.ClCCl.O>[CH:26]1([N:18]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=3[C:25]3[C:13]([C:4]4[C:5]([CH3:12])=[C:6]5[C:11](=[CH:2][CH:3]=4)[O:10][CH2:9][CH2:8][CH2:7]5)=[C:14]([CH:30]=[O:31])[C:15]([CH3:29])=[N:16][C:17]2=3)[CH2:27][CH2:28]1

Participants

9

Reactant 5

HCID 14798Sodium HydroxideHCID 24526ChlorineHCID 21226445Aluminium lithium hydride2×HCID 71209267ethyl 4-(8-chloro-5-methylchroman-6-yl)-9-cyclopropyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylateHCID 178418287HCID 178418287, compound2×

Product 1

HCID 893731949-cyclopropyl-2-methyl-4-(5-methylchroman-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carbaldehydeYield 38.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

An ice cold solution of ethyl 4-(8-chloro-5-methylchroman-6-yl)-9-cyclopropyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (348 mg, 0.726 mmol) in tetrahydrofuran (THF) (7 mL) was treated slowly with LAH (1M in THF) (2.179 mL, 2.179 mmol), and then stirred at rt for 18 hours. LCMS indicated mixture of chlorinated and dechlorinated product. Continued adding LAH (total 11 mL over 1 day) until all the chlorine had been reduced. The reaction was cooled to 0° C., treated slowly with 501 uL H2O, followed by 501 uL 15% aq. NaOH and 3×501 uL H2O. The mixture was stirred at rt for 1 hour, filtered, washed with EtOAc, and then concentrated to give crude alcohol as beige solid. The intermediate was suspended in dichloromethane (DCM) (7.00 mL), treated with PCC (235 mg, 1.090 mmol), and stirred at rt for 4.5 hours. The mixture was treated with additional PCC (108 mg), Celite™ (350 mg), DCM (3 mL), and stirred over the weekend. The mixture was filtered through a short pad of Celite™ washed with large amount of EtOAc, and then concentrated. Purification with column chromatography (0-70% EtOAc/Hexane) gave 9-cyclopropyl-2-methyl-4-(5-methylchroman-6-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carbaldehyde (112.5 mg, 0.281 mmol, 38.7% yield) as off white powder, LCMS (m/z) ES+=401 (M+1), NMR was mixed.

Workup

  1. additionmixture of chlorinated and dechlorinated product
  2. temperatureThe reaction was cooled to 0° C.
  3. stirringThe mixture was stirred at rt for 1 hour
  4. filtrationfiltered
  5. washwashed with EtOAc
  6. concentrationconcentrated
  7. customto give crude alcohol as beige solid
  8. stirringstirred at rt for 4.5 hours
  9. stirringstirred over the weekend
  10. filtrationThe mixture was filtered through a short pad of Celite™
  11. washwashed with large amount of EtOAc
  12. concentrationconcentrated
  13. customPurification with column chromatography (0-70% EtOAc/Hexane)

Sources & evidence

ORD record
ord-c47cdaf892c8424c9ef7246ddf815520
Source dataset
uspto-grants-2013_12
Patent number
US08609653B2

Reaction notes

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