Formic Acid → HCID 71209185, compound

HRID 1912633Notes

Reaction equation

HRID 1912633 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:13]2[C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH3:26])[C:17]=3[N:16]=[C:15]([CH3:27])[C:14]=2[C:28](OCC)=[O:29])[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].CCN(CC)CC.C(O)=O>O1CCCC1.CO.[Pd]>[CH3:27][C:15]1[C:14]([CH2:28][OH:29])=[C:13]([C:4]2[C:5]([CH3:12])=[C:6]3[C:11](=[CH:2][CH:3]=2)[O:10][CH2:9][CH2:8][CH2:7]3)[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:26])[C:17]=2[N:16]=1

Participants

8

Reactant 4

HCID 284Formic Acid2×HCID 8471Triethylamine2×HCID 21226445Aluminium lithium hydride2×HCID 71209161HCID 71209161, compound

Product 1

HCID 71209185HCID 71209185, compoundYield 78.1%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalyst4×HCID 887MethanolSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

An ice cold solution of ethyl 4-(8-chloro-5-methylchroman-6-yl)-2,9-dimethyl-9H-pyrido[2,3-b]indole-3-carboxylate (262 mg, 0.584 mmol) in tetrahydrofuran (THF) (5 mL) was treated slowly with LAH (1M in THF) (1.751 mL, 1.751 mmol), and then stirred at rt for 18 hours. The reaction was treated with additional LAH (2×1 mL every two hours), cooled to 0° C., quenched slowly with 163 uL H2O, followed by 163 uL 15% aq. NaOH and 3×163 uL H2O. The mixture was stirred at rt for 2 hours, filtered, washed with EtOAc, and then concentrated to afford mixture of chlorinated and dechlorinated alcohol. The intermediate was dissolved in methanol (5.8 mL), treated with Et3N (0.325 mL, 2.334 mmol), formic acid (0.090 mL, 2.334 mmol), Pd/C (62.1 mg, 0.058 mmol), and stirred at 60° C. for 1 hour. The reaction was treated with additional Pd/C (small scoop) and heated overnight at 60° C. Added MeOH (2 mL), Et3N (330 uL), Pd/C (69 mg), formic acid (100 uL), stirred for 1 hour, added Pd/C (70 mg), and stirred for another hour until no starting material remained. The mixture was filtered through Celite™, washed with EtOAc, DCM, and MeOH, and then concentrated. Purification with column chromatography (0-100% EtOAc/hexane) gave (2,9-dimethyl-4-(5-methylchroman-6-yl)-9H-pyrido[2,3-b]indol-3-yl)methanol (170 mg, 0.456 mmol, 78% yield) as pale yellow oil. The intermediate was suspended in dichloromethane (DCM) (5.00 mL), treated with PCC (189 mg, 0.875 mmol), and stirred at rt for 2 hours. The mixture was diluted with DCM, filtered through Celite™, washed with EtOAc, and then concentrated. Purification by column chromatography (0-100% EtOAc/hexane) gave 2,9-dimethyl-4-(5-methylchroman-6-yl)-9H-pyrido[2,3-b]indole-3-carbaldehyde (122.5 mg, 0.331 mmol, 56.7% yield) as pale yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.01 (s, 1 H), 7.50-7.40 (m, 2 H), 7.06 (ddd, J=2.2, 6.0, 8.0 Hz, 1H), 7.01 (d, J=8.3 Hz, 1 H), 6.85 (t, J=8.4 Hz, 2 H), 4.36-4.21 (m, 2 H), 4.01 (s, 3 H), 3.05 (s, 3 H), 2.81-2.69 (m, 2 H), 2.27-2.07 (m, 2 H), 1.89 (s, 3 H); LCMS (m/z) ES+=371 (M+1).

Workup

  1. temperaturecooled to 0° C.
  2. customquenched slowly with 163 uL H2O
  3. stirringThe mixture was stirred at rt for 2 hours
  4. filtrationfiltered
  5. washwashed with EtOAc
  6. concentrationconcentrated
  7. customto afford
  8. stirringstirred at 60° C. for 1 hour
  9. temperatureheated overnight at 60° C
  10. stirringstirred for another hour until no starting material
  11. filtrationThe mixture was filtered through Celite™
  12. washwashed with EtOAc, DCM, and MeOH
  13. concentrationconcentrated
  14. customPurification with column chromatography (0-100% EtOAc/hexane)

Sources & evidence

ORD record
ord-3fc6159ee12e4a248b414c3733f1ebdf
Source dataset
uspto-grants-2013_12
Patent number
US08609653B2

Reaction notes

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