Reaction of α-nitrocinnamic acid esters with pyrrole

Abstract

Synthetically accessible α-nitrocinnamic acid esters may be regarded as promising precursors of β-phenylalanine and its substituted derivatives [1–4]. Undoubtedly, introduction into their molecules of pharmacophoric structural fragments, e.g., pyrrole ring, attracts interest. Pyrrole ring constitutes the key fragment of porphyrin macroring which is the base of a number of important natural compounds, such as hemoglobin, chlorophyll, and cytochrome. Some medical agents, e.g., Ketorolac (analgesic and antiinflammatory drug), Atorvastatin (cholesterol-lowering agent) [5, 6], etc., contain a pyrrole ring in their molecules. We were the first to react α-nitrocinnamic acid esters Ia and Ib with pyrrole and N-methylpyrrole. The reactions were carried out with excess pyrrole reagent at room temperature under solvent-free conditions in the absence of catalyst, and the yields of the corresponding addition products were 48–52%. Ethyl 3-aryl-2-nitro-3-(1H-pyrrol-2-yl)propanoates IIa–IIc were isolated as slightly colored crystalline substances. Compound IIa was isolated as a single diastereoisomer, while esters IIb and IIc were mixtures of erythro and threo isomers. The structure of the products was confirmed by spectral data. The IR spectra of IIa–IIc contained strong absorption bands due to stretching vibrations of nonconjugated nitro (1565–1570, 1370–1375 cm) and carbonyl groups (1750 cm); in addition, compounds IIa and IIc displayed absorption at 3450– 3465 cm due to stretching vibrations of the pyrrole N–H group. In the H NMR spectrum of compound IIa we observed two well-resolved doublets at δ 5.76 and 5.06 ppm, which belong to the HA and HB protons (JAB = 11.03 Hz); protons of the ethoxy group resonated as a triplet and quartet at δ 0.88 and 3.96 ppm, respectively. Signals in the regions δ 7.20–7.40 and 6.10–6.63 ppm were assigned to protons in the benzene and pyrrole rings, and the NH proton gave a downfield signal at δ 8.61 ppm. The H NMR spectra of esters IIb and IIc contained doubled sets of signals, indicating the presence of two diastereoisomers. Initial ethyl α-nitrocinnamates Ia and Ib were synthesized by reactions of ethyl nitroacetate [7] with the corresponding Schiff bases or diacetals according to the procedures described in [8–10] or by direct acidcatalyzed alkenylation of ethyl nitroacetate with aromatic aldehydes according to the procedure proposed previously for the preparation of geminal acylnitroethenes [11–13]. Ethyl 2-nitro-3-phenyl-3-(1H-pyrrol-2-yl)propanoate (IIa). Pyrrole, 0.67 g (10 mmol), was added to 0.22 g (1 mmol) of ethyl 2-nitro-3-phenylprop-2enoate (Ia), and the mixture was left to stand at room temperature in the dark. After 48 h, ethyl acetate and water (4 : 1) were added to the mixture, the aqueous