Formaldehyde → 1-(3-Bromophenyl)-4-methylpiperazine

HRID 570555Notes

Reaction equation

HRID 570555 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:16]([BH3-])#N.[Na+].[Cl-].[NH4+]>CO.O.CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 4

HCID 712FormaldehydeHCID 25517Ammonium ChlorideHCID 27571541-(3-Bromophenyl)piperazineHCID 5003444Sodium cyanoborohydride

Product 1

HCID 534153291-(3-Bromophenyl)-4-methylpiperazineYield 94.5%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 22242641Methanol--water (1/1)Solvent

Procedure

To a solution of 1-(3-bromo-phenyl)-piperazine (about 1 g) and acetic acid (about 0.4 mL) in methanol (about 25 mL) is added 37% formaldehyde in water/methanol (about 56.7:37:6.3, water:formaldehyde:methanol; about 5 mL). The mixture is stirred at room temperature for about 18 hours. The suspension is cooled to about 5° C. in an ice/water bath and sodium cyanoborohydride (about 5 g) is added in small portions. The mixture is stirred and warmed to room temperature for about 18 hours. The mixture is slowly poured into saturated aqueous ammonium chloride (about 200 mL) and stirred for about 1 hour. The mixture is extracted with dichloromethane (3× about 75 mL). The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The material is placed under high vacuum for about 18 hours to yield 1-(3-bromo-phenyl)-4-methyl-piperazine as a pale yellow oil (about 1 g). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, 1H), 7.04 (dd, J=2.1, 2.1 Hz, 1H), 6.95 (ddd, J=7.8, 1.7, 0.7 Hz, 1H), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, 1H), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS=255, 257 (MH)+.

Workup

  1. temperatureThe suspension is cooled to about 5° C. in an ice/water bath
  2. stirringThe mixture is stirred
  3. temperaturewarmed to room temperature for about 18 hours
  4. stirringstirred for about 1 hour
  5. extractionThe mixture is extracted with dichloromethane (3× about 75 mL)
  6. dry with materialThe combined organic layers are dried over magnesium sulfate
  7. filtrationfiltered
  8. customevaporated
  9. waitThe material is placed under high vacuum for about 18 hours

Sources & evidence

ORD record
ord-bdcd30d22d7c4ef798b4a4cd99a01f77
Source dataset
uspto-grants-2015_05
Patent number
US09023853B2

Reaction notes

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