Hydrochloric Acid → (S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,N,3,3-tetramethylbutanamide

HRID 537374Notes

Reaction equation

HRID 537374 reaction equation
[CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C@@H:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([CH3:8])([CH3:7])[CH3:6].Cl.CCN(CC)CC.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([N:39]=[C:40]=[S:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>O1CCOCC1>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:32]=[C:31]([NH:39][C:40](=[S:41])[NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([N:2]([CH3:18])[CH3:1])=[O:17])[CH:30]=[C:29]([C:28]([F:42])([F:27])[F:43])[CH:34]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 27333953,5-Bis(trifluoromethyl)phenyl isothiocyanateHCID 57635614(S)-tert-butyl 1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

Product 1

HCID 24859431(S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,N,3,3-tetramethylbutanamideYield 71.5%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A 50-mL round-bottomed flask was charged with (S)-tert-butyl 1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (6c) (860 mg, 2.0 mmol, 1.0 equiv) and 4N HCl in dioxane (5.0 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure and maintained at ˜1 torr for 1 h. The resulting white, foamy solid was dissolved in CH2Cl2 (10 mL). Et3N (562 μL, 4.0 mmol, 2.0 equiv) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (596 mg, 2.2 mmol, 1.1 equiv) were added sequentially via syringe. The flask was capped with a plastic stopper, and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to purification by flash column chromatography on silica gel (gradient elution, 3:1 hexanes/Et2O→1:1 hexanes/Et2O) to provide the product (4a) as a white solid (613 mg, 1.43 mmol, 71% yield over two steps). [α]D25=−32.8° (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.06 (1H, s), 7.90 (2H, s), 7.77 (1H, d, J=9 Hz), 7.56 (1H, s), 5.68 (1H, d, J=9 Hz), 3.35 (3H, s), 2.97 (3H, s), 1.12 (9H, s). 13C {1H}NMR (100 MHz, CDCl3): δ 181.8, 174.0, 140.3, 131.7 (q, JC-F=33 Hz), 123.7 (m), 123.3 (q, JC-F=272 Hz), 118.1 (m), 60.9, 39.1, 36.2, 36.0, 27.2. IR (cm−1): 3322 (br m), 2972 (m), 1611 (m), 1532 (s), 1474 (m), 1385 (m), 1274 (s), 1174 (m), 1126 (s), 963 (m), 883 (m), 848 (w), 700 (m), 680 (m). LRMS (ESI): 452.1 (60%) [M+Na]+.

Workup

  1. concentrationconcentrated under reduced pressure
  2. temperaturemaintained at ˜1 torr for 1 h
  3. dissolutionThe resulting white, foamy solid was dissolved in CH2Cl2 (10 mL)
  4. customThe flask was capped with a plastic stopper
  5. stirringthe reaction mixture was stirred at room temperature for 14 h
  6. concentrationThe reaction mixture was concentrated under reduced pressure
  7. customthe residue was subjected to purification by flash column chromatography on silica gel (gradient elution, 3:1 hexanes/Et2O→1:1 hexanes/Et2O)

Sources & evidence

ORD record
ord-9ce3dfc5a80c4b82a5508945739497fd
Source dataset
uspto-grants-2014_10
Patent number
US08859812B2

Reaction notes

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