Formaldehyde → (+/-)-(3R,4S)-3-(4-chloro-3-fluorophenyl)-1-methyl-4-nitropyrrolidine

HRID 596071Notes

Reaction equation

HRID 596071 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[F:13].[CH3:14][NH:15][CH2:16]C(O)=O.[CH2:20]=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:9]([N+:10]([O-:12])=[O:11])[CH2:20][N:15]([CH3:16])[CH2:14]2)=[CH:4][C:3]=1[F:13]

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 1088SarcosineHCID 616522621-Chloro-2-fluoro-4-(2-nitroethenyl)benzene

Product 1

HCID 118054567(+/-)-(3R,4S)-3-(4-chloro-3-fluorophenyl)-1-methyl-4-nitropyrrolidineYield 45%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

(E)-1-chloro-2-fluoro-4-(2-nitrovinyl)benzene (4.2 g, 20.84 mmol), 2-(methylamino)acetic acid (4.64 g, 52.1 mmol), paraformaldehyde (3.75 g, 125 mmol) were mixed in dry toluene (104 mL). The reaction mixture was heated at reflux using Dean-stark overnight. The reaction mixture was partitioned between EtOAc and water. The organic was washed by sat. NaCl, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography to yield (+/−)-(3R,4S)-3-(4-chloro-3-fluorophenyl)-1-methyl-4-nitropyrrolidine in 45% yield. LCMS (m/z): 259.2 (MH+), 0.52 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (t, J=8.0 Hz, 1H), 7.15 (dd, J=2.0, 10.2 Hz, 1H), 7.09-7.01 (m, 1H), 4.91-4.82 (m, 1H), 3.98 (d, J=5.1 Hz, 1H), 3.34 (dd, J=4.1, 10.8 Hz, 1H), 3.23 (t, J=8.6 Hz, 1H), 3.10 (dd, J=7.8, 10.6 Hz, 1H), 2.63 (dd, J=7.0, 9.4 Hz, 1H), 2.44 (s, 3H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux
  3. customThe reaction mixture was partitioned between EtOAc and water
  4. washThe organic was washed by sat. NaCl
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe crude material was purified by flash chromatography

Sources & evidence

ORD record
ord-56417b03de5944e1a6c128c9233c4aaf
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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