2,5-Bis-(butylsulfanyl)-2,3-dihydro-4 H -pyran-2-carbaldehyde in the synthesis of five-membered heterocycles

Five-membered, nitrogen-containing heterocycles such as oxazole, oxazoline and imidazolidine are important structural motifs of many natural and synthetic compounds, as well as drugs with diverse bioactivity. An efficient strategy for the synthesis of new heterocyclic compounds such as 1,3-oxazole, 1,3-oxazoline and 1,3-imidazolidine from 2,5-bis-(butylsulfanyl)-2,3-dihydro-4 H -pyran-2-carbaldehyde has been developed


Introduction
The dihydropyran structural motif is found in a range of natural products, and is of interest in pharmaceuticalchemistry applications. 1-5For example, a commercial antiviral drug, Zanamivir, contains the dihydropyran core. 6A great deal of attention is currently being paid to the synthesis of functionalized dihydropyrans. 7-122,5-Bis(butylsulfanyl)-2,3-dihydro-4H-pyran-2-carbaldehyde is a compound which exhibits high antibacterial activity with low toxicity. 13 There are few examples of reactions of these thio-substituted dihydropyrans described in the literature.For instance, some new Schiff bases were synthesized by the reaction of 2,5-bis(butylsulfanyl)-2,3-dihydro-4Hpyran-2-carbaldehyde with primary amines, as well as with amino acids and their esters. 14The condensation of pyran 1 with 4-phenylthiosemicarbazide or thiosemicarbazide upon refluxing in EtOH afforded carbazones. 15The synthesis of heterocycles from pyran 1 have not, so far, been implemented.
Herein, we report practical and simple methods to prepare linearly-coupled heterocyclic systems bearing a dihydropyran core in combination with oxazole, oxazoline or imidazolidine ring systems.It is known that fivemembered nitrogen-containing heterocycles such as oxazole, oxazoline and imidazolidine are important scaffolds for a wide range of naturally-occurring and synthetic bioactive compounds, pharmaceuticals, and additional functionally-important materials. 15-20
It was demonstrated that pyran 1, upon reflux with p-tosylmethyl isocyanide (TosMIC) in MeOH, in the presence of K2CO3, can be transformed into 1,3-oxazole 2 (Scheme 1a).These classical conditions of the Van Leusen reaction 22 turned out to be optimum for the formation of 1,3-oxazole 2 in 72% yield.Surprisingly, the reaction of pyran 1 with ethylisocyanoacetate in MeOH gave a trans-esterification product, 1,3-oxazoline 3а (Scheme 1b).When ethanol was used instead of MeOH as a solvent, the target heterocycle 3b was formed.The Et3N (1 equivalent) proved to be an effective catalyst in this reaction compared to those previously used in the literature. 23Three chiral centers in compounds 3a,b explains the presence of diastereomers and the doubling of signals in the NMR spectra (see online Supplementary Material).N,N'-Diphenylethylenediamine is added at the carbonyl group of pyran 1 to deliver 1,3-imidazolidine 4 in 93% yield (Scheme 1c).At room temperature, this reaction takes 12 days, while, upon heating, the duration to reaction completion is reduced to 8 hours.
The structures of compounds 2-4 were established by their NMR spectroscopy ( 1 H, 13 C, and 15 N) including 2D techniques.The 15 N NMR { 1 H-15 N} HMBC spectra of product 4 shows cross-peaks of the nitrogen atom with CH proton, with ortho-protons of the Ph ring and CH2 protons of the imidazolidine ring at -300.5 and -303.5 ppm, respectively.

Experimental Section
General.The 1 Н, 13 С and 15 N NMR spectra were recorded in CDCl3 solutions at room temperature on Bruker DPX-400 and AV-400 spectrometers (400.13,100.61 and 40.56 MHz), respectively). 1 Н, 13 С and 15 N Chemical shifts (δ in ppm) were measured with accuracy of 0.01, 0.02 and 0.1 ppm, respectively, and referenced to TMS ( 1 Н, 13 С) and nitromethane ( 15 N) internal standards.Chromato-mass spectrometry analysis was performed on a Shimadzu GCMS-QP5050A mass spectrometer (EI ionization, 70 eV).The IR spectra of the compounds were recorded on a Varian 3100 FT-IR spectrometer with the sample in thin film.Elemental analysis was performed on a Thermo Finnigan Flash series 1112 Elemental analyzer.