Glycerol / Hypophosphorous Acid and PhSeSePh : An Efficient and Selective System for Reactions in the Carbon-Carbon Double Bond of ( E )-Chalcones

Este trabalho descreve nossos resultados para a reação entre benzenosselenol, gerado in situ pela reação entre disseleneto de difenila com H3PO2, com uma série de (E)-chalconas utilizando glicerol como solvente. Utilizando as condições de reação otimizadas, uma variedade de produtos de redução 1,4-quimiosseletivas podem ser obtidos em bons rendimentos. A mistura glicerol/H3PO2 pode ser facilmente recuperada e reutilizada em condições de reação de redução 1,4-quimiosseletivas por ciclos sucessivos sem perda de eficiência. Adicionalmente, sob condições de reação de redução 1,4-quimiosseletivas, o produto natural zingerona pode ser sintetizada em bom rendimento.


Introduction
Conjugate addition reactions of sulfur and selenium nucleophiles to electron-deficient olefins are a very useful method for new carbon-chalcogenium bond formation in organic synthesis.][4][5][6][7][8][9][10][11][12][13] Organoselenium compounds are attractive molecules due their selective reactions 14 and the interest in the synthesis of these compounds has increased in the last years because of their use in materials area, 15 as ionic liquids 16 in asymmetric catalysis, 17 and because of their interesting biological activities. 18-Selanylcarbonyl compounds are particularly interesting synthons, because they can be used as intermediates in the synthesis of dihydromevinolin, 19 idesolide 20 and taxol.21 Traditional methods for the synthesis of b-selanylcarbonyl compounds via Michael addition commonly make use of the already available benzeneselenol and some catalysts can be used.[3][4][5] Nevertheless, the use of air-sensitive, highly volatile, and unpleasant smelling benzeneselenol leads to serious ecological and safety problems.To overcome this problem, b-selanylcarbonyl compounds could be synthesized when the benzeneselenol was generated in situ.[6][7][8][9][10][11] Alternatively, Santi and co-workers described the synthesis of b-selanylcarbonyl compounds using PhSeZnCl in reactions of addition to unsaturated ketones.12 Besides being scarce, in most cases these methods are limited to a few functional groups and long reaction times are necessary. Fuhermore, there is still an attention in developing simple, efficient and catalyst-free methodologies to synthesize b-selanylcarbonyl compounds.
In this context, the development of methodologies employing green solvents (recyclable and environmentally friendly) has recently gained much attention, because of the extensive use of solvents in almost all chemical and pharmaceutical industries, and of the predicted disappearance of fossil oil. 22Biodegradability, high availability, no flammability, being obtained from renewable sources are among the desirable characteristics for a green solvent. 23Thus, the use of glycerol 24 and their eutetics 25 as a sustainable green solvent was recently reported and a great number of organic reactions were performed using this solvent.
More recently, glycerol proved to be an efficient and recyclable solvent for the synthesis of a range of organochalcogenium compounds. 26For example, our research group described a methodology to synthesize 2-organylselanyl pyridines by reactions of 2-chloropyridines with organylselenols, generated in situ by reaction of diorganyl diselenides, using glycerol as solvent and hypophosphorous acid (H 3 PO 2 ). 27Using this methodology the products were obtained in high yields and the glycerol/ H 3 PO 2 system can be easily recovered and reused for five times without loss of efficiency.
In view of the explained above, we decided to examine the synthesis of b-selanylcarbonyl compounds via reaction of benzeneselenol, generated in situ by reaction of diphenyl diselenide with H 3 PO 2 , with (E)-chalcones using glycerol as solvent (Scheme 1).

Results and Discussion
Initially, we chose (E)-1,3-diphenyl-prop-2-en-1-one 1a and diphenyl diselenide 2 as model substrates to establish the best conditions for the reaction using glycerol and H 3 PO 2 as the solvent-reducing agent system and some experiments were performed to synthesize compound 3a (Scheme 2).Thus, a mixture of diphenyl diselenide 2 and 0.1 mL of H 3 PO 2 (50 wt.% in H 2 O) in glycerol (1.0 mL) was stirred at 90 ºC for 30 min under N 2 atmosphere to afford in situ benzeneselenol.After this time, (E)-chalcone 1a (0.5 mmol) was added in the reaction vessel and the reaction remained at 90 ºC for additional 24 h.Unfortunately, under these reaction conditions, only traces of the product 3a were formed and to our surprise, the 1,4-reduction product, 1,3-diphenyl-1-propanone 4a was obtained in 42% yield (Table 1, entry 1).The chemoselective 1,4-reduction of a,b-unsaturated carbonyl compounds is an attractive and important tactic in organic synthesis. 28A range of significant advances have been made toward the development of efficient protocols for the chemoselective 1,4-reduction of a,b-unsaturated carbonyl compounds, specially methodologies based on the use of transition metal catalysts. 29For example, Kosal and Ashfeld described that a titanocene complex can be used as an efficient catalyst for the conjugate reduction of a,b-unsaturated carbonyl derivatives.A series of a,bunsaturated aldehydes, ketones, esters, unsubstituted amides and ynones, underwent chemoselective conjugate reduction by utilizing a catalytic quantity of titanocene complex. 30Additionally, selective reducing agents based on chalcogen atoms (Se and Te) were used for the 1,4-reduction of a,b-unsaturated carbonyl compounds. 31n view of this surprising result of 1,4-reduction reaction, we decided to explore these reaction conditions, firstly increasing the quantity of H 3 PO 2 in the reaction (Table 1).Thus, when the reactions were performed increasing the quantity of H 3 PO 2 from 0.2 to 0.5 mL, a mild increase in the yield of product 4a was observed and only traces of product 3a were observed (Table 1, entries 2 and 3).
In view of these moderate results, we decided to explore these reaction conditions to obtain reduced products of (E)-chalcones increasing the amount of PhSeSePh 2. To our delight, when the reaction was carried out in the presence of 0.5 mmol of diphenyl diselenide 2 and 0.2 mL of H 3 PO 2 the reduction product 4a was obtained in 89% yield after 2 hours at 90 ºC under nitrogen atmosphere (Table 1, entry 4).Under these reaction Scheme 1.General purpose of this work.
After the reduction reaction optimization, a study regarding the recovery and reuse of glycerol was performed.Subsequent to the formation of product 4a, the reaction mixture was diluted and extracted with a mixture of hexane/ethyl acetate 95:5 (3 × 5 mL).The upper phase was dried and the solvent evaporated.The inferior, glycerol phase, was dried under vacuum and directly reused in a new reaction with (E)-chalcone 1a and diphenyl diselenide 2 at 90 °C without the addition of more H 3 PO 2 .To our satisfaction, after 2 h at this temperature the corresponding product 4a was obtained in 86% yield.After this successful experiment, we speculate the possible reuse of the glycerol/H 3 PO 2 system for additional cycles (Figure 1).It was observed that a good level of efficiency was maintained even after four reactions.These results showed that the 1,3-diphenyl-1propanone 4a was obtained in 89, 86, 82, 77 and 74% yields after successive cycles (Figure 1).It is important to note that in all reactions performed, PhSeSePh 2 was recovered after chromatographic column in a range of 64-78% yield.
After that, the versatility of our reduction methodology was evaluated, by reacting other (E)-chalcones 1b-k with   diphenyl diselenide 2 under optimized reduction reaction conditions (Table 2).The obtained results reveal the reaction worked well with range (E)-chalcones tested, affording good yields of the products 3b-k (Table 2, entries 2-11).According to these results, the reactions are not sensitive to electronic effects in the aromatic ring of chalcone.Therefore, (E)-chalcones containing either electron-donating (OMe, Me) or electron-withdrawing groups (Br, Cl) in different parts of the molecules gave good yields of the desired reduction products (Table 2, entries 2-11).The position of the substituted groups did not considerably affect reactivity.Additionally, this reducing reaction condition was utilized in the synthesis of zingerone, a natural product.Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone] is a vanillinoid compound and one of the pungent components of ginger (rizhome of Zingiber officinale Roscoe), 32 and this compound is a likely active constituent responsible for the antidiarrheal activity of ginger. 33To synthesize the desired natural product, 2-methoxy-4-(3-oxo-1-butenyl) phenol 1l (0.5 mmol) was reacted with PhSeSePh 2 (0.5 mmol) and H 3 PO 2 (0.2 mL) in glycerol (1.0 mL) at 90 °C under N 2 atmosphere for 30 minutes (Scheme 3).Under these reaction conditions, the desired zingerone 4l was obtained in 68% and unfortunately, 2-methoxy-4-(3hydroxybutyl)phenol 5 was formed as by-product in 19% yield.The formation of this side product 5 proves that the chemoselectivity in the reduction reactions seems to be strongly correlated to the presence of both aromatic substituents in the a,b-unsaturated carbonyl compounds, and when an aliphatic moiety is present, the reduction of the keto group could occur.

General remarks
The reactions were monitored by thin layer chromatography (TLC) carried out on Merck silica gel (60 F 254 ) by using UV light as visualizing agent and 5% vanillin in 10% H 2 SO 4 and heat as developing agents.Baker silica gel (particle size 0.040-0.063mm) was used for flash chromatography.Proton nuclear magnetic resonance ( 1 H NMR) spectra were obtained at 300 MHz on a Varian Gemini NMR and at 400 MHz on Bruker DPX 400 spectrometers.Spectra were recorded in CDCl 3 solutions.Chemical shifts (d) are reported in ppm, referenced to tetramethylsilane (TMS) as the external reference.Coupling constants (J) are reported in Hz.Carbon-13 nuclear magnetic resonance ( 13 C NMR) spectra were obtained at 75 MHz on a Varian Gemini NMR and at 100 MHz on Bruker DPX 400 spectrometers.Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl 3 .Low-resolution mass spectra were obtained with a Shimadzu GC-MS-QP2010 mass spectrometer.Scheme 3. Synthesis of zingerone.

Conclusion
In summary, we described here our results for the reaction of benzeneselenol, generated in situ by reaction of diphenyl diselenide with H 3 PO 2 , with various (E)chalcones using glycerol as solvent at 90 °C under nitrogen atmosphere.Using our optimized reaction conditions, a range of chemoselective 1,4-reduction products were obtained in good yields and a range of chalcones containing electron-donating or electron-withdrawing groups were employed as substrates.In addition, the glycerol/H 3 PO 2 system can be easily recovered and reused in chemoselective 1,4-reductions for successive cycles without loss of efficiency.Under 1,4-reducing reaction conditions, zingerone was synthesized in good yield.

Table 1 .
Optimization of reaction conditions a and H 3 PO 2 in glycerol (1 mL), at 90 °C under N 2 atmosphere; b reaction using 1.5 mL of glycerol.