Synthesis of BF 2 complex of 3-methylthio enaminones

Novel BF 2 complex of 3-methylthio enaminones or 3-methylthio enaminoketonatoboron difluorides have been synthesized via reactions of 3-methylthio enaminones with BF 3 ·Et 2 O in the presence of Et 3 N in good to excellent yields.


Introduction
Enaminones are useful synthetic intermediates that combine the ambident nucleophilicity of enamines with the ambident electrophilicity of enones, and their chemistry has received considerable attention continuously since their first appearance. 1 Enaminones have proved to be versatile building blocks in organic synthesis, 2 especially for the preparation of various heterocycles as potential agrochemicals or intermediates in dye and pharmaceutical industries. 3hile their early use has been limited to serving as synthetic intermediates in organic synthesis, recent exploration on enaminones' applications in pharmaceutical development has made impressive progress. 4The therapeutic potential of these compounds has been realized in a number of areas, such as candidate agents as potential anticonvulsants and as potential modulators of multidrug resistance (MDR).4a 3-Methylthio enaminones or ketene N,S-acetals, 5 a special class of enaminones with a 3-methylthio substitution at the β-position, have attracted our attention due to the polyfunctional feature of these molecules.Because the MeS group is a good leaving group and could be subjected to a number of chemical transformations, the exploration on the synthetic utilities of 3-methylthio enaminones might result in the synthesis of a variety of novel nitrogen-containing heterocycles.In order to explore the chemical reactivity of 3methylthio enaminones, especially the region-selectivity of these bis-nucleophiles, we decided to make the BF 2 complex of 3-methylthio enaminones and examine their chemical reactivity.While the synthesis of BF 2 complexes of enaminones and their applications in organic synthesis have been reported before, 6 the synthesis and applications of the BF 2 complexes of 3-methylthio enaminones are yet to be explored.Due to the availability of a large number of enaminones, this might be resulted in the build-up of novel heterocyclic libraries of BF 2 complexes which could be valuable entities for pharmaceutical and agrochemical applications.

Results and Discussion
[10][11][12][13] The amino group and the carbonyl group of compound 3 are in Z-configuration due to the strong intramolecular hydrogen bonding between these two groups.Treatment of 3 with excess amount of BF 3 •Et 2 O (5 equiv) in the presence of Et 3 N followed by crystallization, afforded BF 2 complex 4 in good to excellent yields (74-98%).The reaction was conducted in the presence of Et 3 N at room temperature for about 30 min (Scheme 1).The results are summarized in Table 1.
As shown in Table 1, the reaction is barely affected by electronic and steric factors of the substitutions.All 3-methylthio enaminones, either with electron-donating or electronwithdrawing aryl groups underwent the reaction smoothly affording the desired products in high yields.Cyclohexyl substituent slightly decreased the yield of the reaction probably due to the steric effect (Table 1, entries 17, 18, 19).In the case of enaminone 3e which bears a fully substituted aryl group, the reaction had to be performed at 50ºCC for 8h. in order to complete the reaction.Steric hindrance might be the cause of this observation (Table 1, entry 5).
All BF 2 complexes were fully characterized by their spectral data.To take compound 4f as an example, in its IR spectrum, there was no signal which could be assigned to C=O group; its 1 H-NMR spectrum did not display the characteristic peak of NH group; and its 13 C NMR spectrum displayed two characteristic signals at δ 174.0 and 166.8 for the two tertiary carbon of BF 2 complex at C-3 and C-1.These evidences, together with the mass spectrum and element analysis, indicated that the transformation of the enaminone structure to the iminium-enol structure and the involvement of the N,O-atoms of the 3-methylthio enaminones in the formation of the six-member ring BF 2 complex.The structure of BF 2 complex 4f was further proved by the single crystal X-ray analysis (Figure 1).

Conclusions
In summary, novel BF 2 complex of 3-methylthio enaminones have been synthesized efficiently via the reactions of 3-methylthio enaminones with BF 3 •Et 2 O in the presence of Et 3 N in good to excellent yields.These novel compounds will be helpful for us to better understand the chemical reactivity of enaminones and might be valuable in pharmaceutical and agrochemical applications.

Experimental Section
General.Melting points were determined using an electrothermal melting point apparatus and were uncorrected.IR spectra were recorded on a JASCO FT/IR-480 spectrometer using KBr pellets. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) were recorded on a Bruker AV300 magnetic resonance spectrometer in CDCl 3 solution.Chemical shifts (δ) are reported in ppm with tetramethylsilane as internal standard.High resolution mass spectra (HRMS) were recorded on an APEXII FT-ICR spectrometer with EI mode.Elemental analysis was performed at the Center for Instrumental Analysis of ICCAS.

General procedure for the synthesis of BF 2 complex from N,S-acetal
To a stirring mixture of ketene N,S-acetal 3 (1.0 equiv) and Et 3 N (3.0 equiv) in dry MeCN (20 mL) was added BF 3 •Et 2 O (5.0 equiv) at room temperature.The reaction was monitored by TLC and after TLC indicated the completion of the reaction, the reaction mixture was quenched by addition of saturated aq.NaHCO 3 (30 mL) and extracted with CH 2 Cl 2 (3×20mL).The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated.The resulting precipitates were crystallized from a mixture of ethyl acetate and petroleum ether (v/v=1/5−1/10) to afford pure BF 2 complexes 4.

Table 1 .
Synthesis of BF 2 complex 4a-s aMonitored by TLC analysis.bIsolatedyields by crystallization of the crude product from petroleum ether and ethyl acetate at room temperature.cThereaction was performed at 50ºC for 8 h.