Synthesis of Derivatives of the Monoterpenoid Pulegone

Abstract

N-containing derivatives that were promising as biologically active compounds were synthesized via a series of transformations of the monoterpenoid pulegone isolated from Ziziphora clinopodioides essential oil.Pulegone (1) is a monocyclic unsaturated ketone of the p-menthane series and the principal component of Ziziphora clinopodioides Lam. [1] and Mentha longifolia L.[2] essential oils.Herein we present results for the synthesis of N-containing derivatives of 1 via a Ritter reaction with acetonitrile (MeCN) in the presence a catalytic amount of conc. H 2 SO 4 . Neutralization of the reaction mixture produced the ketoamide N-[2-(4-methyl-2-oxocyclohexyl)propan-2-yl]acetamide (2) in 56% yield and ~95% purity.Obviously, the process occurred through formation of a tertiary carbonium ion (3) with subsequent addition to it of MeCN and formation of the amide. The reaction was strictly stereoselective and formed the pure ketoamide with both the methyl and isopropylamide in equatorial positions. The properties of synthesized 2 agreed with the literature for 2 prepared via intermolecular Ritter-type C-H amination of menthone [3].Resonances in the PMR spectrum of 2 could not be fully assigned because of the mutual overlap of many of them. Nevertheless, the following conclusions could be drawn based on the spectrum.The C-4 methyl appeared as a doublet at 0.94 ppm. The resonance for the proton geminal to this methyl was a complicated multiplet that appeared at even stronger field (G 0.83 ppm), which indicated that it was axially oriented. Therefore, the ring did not invert during the reaction.The C-8 methyls gave singlets, which indicated unambiguously that MeCN added to this C atom (and not C-1 as an alternative). The resonances of these methyls were distinctly nonequivalent (G 1.17 and 1.33 ppm). This was consistent with hindered rotation around the C-1-C-8 bond that was obviously a consequence of the formation of a strong H-bond between the ketone and the acetamide (NH) H atom. The chemical shift of the acetamide methyl was 1.75 ppm.Conversely, the 13 C NMR spectrum of 2 was easily interpreted. Resonances were assigned by comparing them with those in spectra of previously synthesized analogs. Their multiplicities were determined using DEPT data. Thus, the spectrum showed two weak-field singlets characteristic of carbonyl C atoms at 210.2 and 168.3 ppm (the ketone and amide, respectively).