Synthesis of 2,5-bis(butylsulfanyl)-2,3-dihydro-4H-pyran-2-carbaldehyde acetals and their unexpected isomerization

Abstract

2,5-Bis(alkylsulfanyl)-2,3-dihydro-4H-pyran-2carbaldehydes exhibit bacteriostatic effect [1]. 2,5-Bis(butylsulfanyl)-2,3-dihydro-4H-pyran-2-carbaldehyde is known as a strong and safe antiseptic [2]. We examined its reactions with alcohols in order to obtain new potential biologically active derivatives. Unlike 2,5-dialkoxy-2,3-dihydro-4H-pyran-2-carbaldehydes [3] which take up alcohols at the endocyclic double bond, the reaction of sulfur-containing analog I with alcohols in acid medium at room temperature (i.e., under comparable conditions) occurred at the carbonyl group. However, apart from the expected symmetric dialkyl acetal II, diastereoisomeric mixed acetals III and IV were always formed, regardless of the acid taken as catalyst (p-TsOH, HClO4, CF3COOH) or alcohol (MeOH, EtOH); the products are readily detected by gas chromatography–mass spectrometry. To determine the product structure, isomer mixture obtained in the reaction of aldehyde I with methanol were separated by high-performance liquid chromatography (HPLC). The reaction with methanol was selected as model process, taking into account more facile identification of methyl derivatives by NMR spectroscopy. Judging by the intensities of signals from the acetal CH protons at δ 4.27 (IIa), 4.53 (IIIa), and 4.47 ppm (IVa) in the H NMR spectra, the product ratio changed from 2 : 1 : 1 to 1 : 1 : (1–2) in 7–10 days, the conversion of the initial aldehyde being 80–100%. Analysis of the H and C NMR spectra of the first isomer allowed us to identify it as symmetric dimethyl acetal IIa. Formalistically, two other isomers IIIa and IVa result from exchange of OMe and SBu groups in the vicinal acetal and hemithioketal moieties (at the C and C atoms).