Acetic Acid → HCID 22896280, compound

HRID 1017197Notes

Reaction equation

HRID 1017197 reaction equation
[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[CH3:23][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[CH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 22896288HCID 22896288, compound

Product 1

HCID 22896280HCID 22896280, compoundYield 18.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

To a solution of 1.1 g (3.8 mmol) of 2-phenyl-3-(piperidin-2(R)-ylmethyl)-1H-indole and 238 mg (3.8 mmol) of sodium cyanoborohydride in methanol (20 ml) at 0° C. was added a solution of formaldehyde (527 mg of a 37% w/w aqueous solution) and glacial acetic acid (0.5 ml, 8.7 mmol) in methanol (10 ml). After stirring at room temperature for 3 hr the reaction was evaporated in vacuo. The residue was partitioned between saturated potassium carbonate (20 ml) and EtOAc (20 ml), the organic layer separated, and the aqueous layer extracted with EtOAc (2×20 ml). The combined EtOAc layers were washed with water (50 ml), saturated sodium chloride (50 ml), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (SiO2; 5% MeOH in CH2Cl2+0.5% NH3) and the product recrystallised from Et2O/hexanes to afford 210 mg (0.7 mmol; 18%) of 3-(1-methylpiperidin-2(R)-ylmethyl)-2-phenyl-1H-indole as a white solid. (Found: C, 81.50; H, 7.98; N, 9.14; C21H24N2.0.25H2O requires C, 81.64; H, 7.99; N, 9.07%); mp 150° C. (from Et2O/hexane); [α]D23+80.0 (c 1.0 in CHCl3); δH (360 MHz; CDCl3) 0.96-1.14 (2H, m, aliphatics), 1.44-1.58 (4H, m, aliphatics), 2.06-2.16 (1H, m, aliphatic), 2.21-2.32 (1H, m, aliphatic), 2.46 (3H, s, CH3), 2.76-2.89 (2H, m, aliphatics), 3.47 (1H, dd, J 13.8 and 3.8, indole CHAHB), 7.14 (1H, m, indole H5), 7.20 (1H, m, indole H6), 7.33-7.38 (2H, m, aromatics), 7.43-7.47 (2H, m, aromatics), 7.57 (2H, d, J 7.1, aromatics), 7.65 (1H, d, J 7.8, aromatic), 8.05 (1H, br s, NH); m/z (ES+) 305 (M++H, 100%).

Workup

  1. customwas evaporated in vacuo
  2. customThe residue was partitioned between saturated potassium carbonate (20 ml) and EtOAc (20 ml)
  3. customthe organic layer separated
  4. extractionthe aqueous layer extracted with EtOAc (2×20 ml)
  5. washThe combined EtOAc layers were washed with water (50 ml), saturated sodium chloride (50 ml)
  6. dry with materialdried over MgSO4
  7. customevaporated in vacuo
  8. customThe residue was purified by column chromatography (SiO2; 5% MeOH in CH2Cl2+0.5% NH3)
  9. customthe product recrystallised from Et2O/hexanes

Sources & evidence

ORD record
ord-a443781a792244f9a850198278cb4018
Source dataset
uspto-grants-2002_11
Patent number
US06479480B1

Reaction notes

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