Trifluoroacetate → Hydrochloric Acid

Participants

Reaction Steps

Adapting literature known protocols (Loudon, et al., J. Org. Chem., 1984, 49(22), 4272-4276; Loudon and Boutin, J. Org. Chem., 1984, 49(22), 4277-4286; Nicolaou, et al., Bioorg. Med. Chem. 1998, 6(8), 1185-1208; and Ji et al., Tetrahedron Lett., 2009, 50(45), 6166-6168), 4-(5-chloro-2-nitro-phenyl)pyrrolidin-2-one (18f) is prepared from methyl 5-amino-3-(5-chloro-2-nitro-phenyl)-5-oxo-pentanoate (18e) (2.87 g, 10.0 mmol) in a mixture of acetonitrile (MeCN) (15 mL) and water (15 mL) through an acidic Hoffmann-rearrangement with [I,I-bis(trifluoroacetoxy)iodo]benzene (phenyl iodosyl bis(trifluoroacetate, PIFA) (4.25 g, 10.0 mmol) followed by partial spontaneous intramolecular lactamization of the intermittent amine at room temperature. The reaction may be monitored by TLC and/or analytical LC/MS to completion. The reaction mixture is diluted with 2.0 M hydrochloric acid (HCl). The aqueous phase is extracted with diethyl ether (Et2O) (3×) to remove ether-soluble iodobenzene dichloride which is discarded. The aqueous phase is frozen and the solvents lyophilized off to yield an intermediate hydrochloride. The hydrochloride is diluted with water and the aqueous phase is adjusted to pH 8-9 with 2.0 M aqueous sodium hydroxide (NaOH). The aqueous phase is extracted with ethyl acetate (EtOAc) (3×). The combined organic extracts are either partially evaporated under reduced pressure followed by heating directly at reflux for about 6 hours to yield the crude title compound (18f). Alternatively, the solvent is evaporated under reduced pressure using a rotary evaporator, the residue is diluted with toluene or benzene and the solution is heated at reflux for about 6 hours. The crude material (18f) may either be used directly in the next step or may be further purified by silica gel chromatography using EtOAc, methanol (MeOH), dichloromethane (DCM), and/or hexanes or by re-crystallization.

Provenance & Evidence