Methylamine → Benzyl 3-fluoro-4-(methylamino)piperidine-1-carboxylate

HRID 2375459Notes

Reaction equation

HRID 2375459 reaction equation
[F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH3:19][NH2:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C1COCC1>[F:1][CH:2]1[CH:7]([NH:20][CH3:19])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1

Participants

6

Reactant 3

HCID 6329MethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 42609253Benzyl 3-fluoro-4-oxopiperidine-1-carboxylate

Product 1

HCID 59854955Benzyl 3-fluoro-4-(methylamino)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 9.4 g (37.5 mmol) of 2-2 in 150 mL of 1,2-dichloroethane was added 37.5 mL (74.9 mmol) of a 2M solution of methylamine in THF and 11.9 g (56.2 mmol) of Na(OAc)3BH. After stirring for 2 h, the reaction was quenched with saturated aqueous K2CO3, partitioned with EtOAc, separated, and the aqueous phase extracted 3×EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with 80:10:10 CHCl3/EtOAc/MeOH to provide both the cis and trans isomers of 2-2a as colorless oils. Data for the trans isomer of 2-2a, first to elute (confirmed by NOE analysis): 1HNMR (600 MHz, CD2Cl2) δ 7.4-7.3 (m, 5H), 5.1 (m, 2H), 4.4-4.1 (m, 2H), 3.9 (m, 1H), 3.15-3.05 (m, 2H), 2.75 (m, 1H), 2.4 (s, 3H), 2.0 (in, 1H), 1.25 (m, 1H) ppm. Data for the cis isomer of 2-2a, second to elute (confirmed by NOE analysis): 1HNMR (600 MHz, CD2Cl2) δ 7.4-7.2 (m, 5H), 5.1 (m, 2H), 4.9-4.7 (m 1H), 4.4 (m, 1H), 4.15 (m, 1H), 3.1-2.9 (m, 2H), 2.6 (m, 1H), 2.4 (s, 3H), 1.8 (m, 1H), 1.6 (m, 1H) ppm. HRMS (ES) calc'd M+H for C14H19F1N2O2: 267.1504. Found: 267.1500.

Workup

  1. customthe reaction was quenched with saturated aqueous K2CO3
  2. custompartitioned with EtOAc
  3. customseparated
  4. extractionthe aqueous phase extracted 3×EtOAc
  5. washThe combined organic extracts were washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated by rotary evaporation
  9. washeluted with 80:10:10 CHCl3/EtOAc/MeOH

Sources & evidence

ORD record
ord-09757b55cfa64641af0fab7545cac3e2
Source dataset
uspto-grants-2008_12
Patent number
US07465746B2

Reaction notes

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