Chemoselective reaction of ethane-1,2-dithiol, hydrazines, and hydroxylamine onto γ -keto allyl phosphonates and phosphine oxides

An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylamine


Introduction
][9][10] Among these reactions, we intended to particularly develop the Wittig-Horner olefination using various aldehydes as electrophiles, which would afford a variety of 1,3-dienes that are employed as useful substrates in the reaction of Diels-Alder. 11irst, we attempted the deprotonation of the γ-keto allyl phosphonate 1a at 0 °C by NaH or LDA (1-6 equiv) in THF, followed by the addition of bromine (1-2 equiv) at room temperature then at reflux for 4 h.Unfortunately, the starting material 1a was completely recovered.Moreover, all the reactions of compound 1a either with NBS (AIBN in CCl4) or under the previous conditions (NaH or LDA), with the considered halogenated derivatives failed. 12ext, we explored the reaction of Wittig-Horner starting from the additon of the ketophosphonate 1a to a suspension of NaH (4 equiv) in THF at 0 °C then at room temperature, followed by the addition of benzaldehyde (2 equiv).][15] On the basis of these unsuccessful preliminary results, we decided to first establish the suitable experimental conditions for the protection of the ketone moiety of the ketophosphonate 1a using ethylene glycol or ethane-1,2-dithiol commonly used for this purpose.At the same time, we envisionned to explore the reaction of other N-nucleophiles including hydrazines, tosylhydrazines, [16][17][18][19][20][21][22][23][24] and hydroxylamine 25-31-32-33 on the enone moiety.Hence, we wish to report in this paper our results on the chemoselective reaction of these Sand N-nucleophiles on a series of γ-keto allyl phosphonates.

Results and discussion
Under the conventional conditions for the protection of ketones with ethane-1,2-diol (1equiv) in the presence of 30% of PTSA, the ketophosphonate 1a (1 equiv) in refluxing toluene, using a Dean-Stark apparatus, was partially converted, within 48 h, into a complex mixture. 12Alternatively, on treatment of phosphonate 1a with ethane-1,2-dithiol (1.2 equiv) and PTSA (1 equiv) in refluxing chloroform, we have observed the formation of the desired thioketal 2a in 80% yield, together with the compound 2a' (15%) resulting from a further conjugate addition of ethane-1,2-dithiol on the enone moiety of the ketal 2a (Scheme 1).Scheme 1. Synthesis of the thioketal 2a and its derivative 2a'.
Next, we turned our attention to improving the selectivity of such reaction in favor of the ketal 2a.We first focused our efforts on the ratios of the ketophosphonate 2a/ethane-1,2-dithiol in the presence of PTSA in refluxing chloroform.After optimising the experimental conditions, we have found that the reaction of a slight excess of the ketophosphonate 1a (1 equiv) and PTSA (1 equiv) with regard to ethane-1,2-dithiol (0.9 equiv), selectively afforded the thioketal phosphonate 2a in 80% (Scheme 2, table 1, entry 1).Scheme 2. Synthesis of thioketals phosphonates 2a-e.This thioketalisation reaction was successfully performed, under the above conditions (refluxing chloroform, 0.9 equiv of ethane-1,2-dithiol) on various ketophosphonates 1b-e differently substituted at the β'-carbon close to the phosphonate moiety.The corresponding thioketals phosphonates 2b-e were obtained in 76-83% yields with a high selectivity (Scheme 2, table 1, entries 2-5).
Encouraged by these successful results, we next focused our efforts on screening various N-nucleophiles likely to react with carbonyl moiety of the keto phosphonates 1a and 1f.Interestingly, on treatment of the ketophosphonate 1f with hydroxylamine chlorohydrate (1.2 equiv) and PTSA (1 equiv) in refluxing methanol, the oximophosphonate 3 was obtained in 83% yield (Scheme 3, table 2, entry 1).Scheme 3. Synthesis of the oximophosphonate 3 and the hydrazonophosphonates 4a-c.
Unfortunately, under the conditions described above (PTSA, refluxing methanol), all the reactions of phosphonate 1a with primary amines including ethylamine, methylamine, isopropylmaine and benzylamine, failed and the starting materials were recovered.

Conclusions
We have shown that PTSA-mediated reaction of ethane-1,2-dithiol in refluxing chloroform as well as hydroxylamine and some hydrazines derivatives in refluxing methanol onto various γ-keto allyl phosphonates, affording the corresponding thioketals, oximo-and hydrazonophosphonates in good yields and with high chemoselectivity.

Experimental Section
General.All 1 H NMR spectra and 13 C NMR spectra were recorded in CDCl3 as the solvent, at 300 and 75 MHz, respectively, using tetramethylsilane.Chemical shifts are given in ppm and the coupling constants J in Hz.
High resolution mass spectra (HRMS) were recorded as TOF-HRMS on a micromass mass spectrometer.The electronic impact (EI) mass spectra were recorded at 70 eV.Analytical thin layer chromatography (TLC) was carried out on aluminium plates precoated with silica gel 60 F254.The Visualization was achieved with UV light at 254 nm.Column chromatography was performed using silicagel (70-230 mesh ASTM) and a gradient solvent system (dichloromethane/ether) as eluents.

General procedure for the preparation of the thioketal phosphonates (2a-e).
A mixture of the ketophosphonate 1 (1 equiv), ethane-1,2-dithiol (0.9 equiv) and PTSA (1 equiv) in 20 mL of CHCl3, was heated with stirring in an oil bath at 80 °C for 4 h.The progress of the reaction was monitored by TLC using dichloromethane-ether.The mixture was neutralized with an aqueous solution of 4M hydrochloric acid and extracted with CHCl3.The combined organic layers were neutralized with NaHCO3 and washed with saturated NaCl solution.These layers were further dried and concentrated.The residue was purified by a column chromatography on silica gel (20% dichloromethane/ether) to give the pure thioketals phosphonates 2a-e as solids except 2a and 2b that are obtained as yellow oils. Diethyl