One-Pot Four-Component Synthesis of 2-Aryl-3 , 3-Dihaloacrylonitriles using Potassium Hexacyanoferrate ( II ) as Environmentally Benign Cyanide Source

Foi descrita uma rota eficiente para reações em uma etapa com quatro componentes incluindo cloretos de aroila, hexacianoferrato(II) de potássio, trifenilfosfina e tetrahaletos de carbono para sintetizar 2-aril-3,3-dicloroacrilonitrilas e 2-aril-3,3-dibromoacrilonitrilas. Este protocolo tem como vantagens o uso de uma fonte não-tóxica de cianeto, alto rendimento e procedimento experimental simples.


Introduction
3,3-Dichloroacrylonitriles and 3,3-dibromoacrylonitriles are well-known as the most important synthetic intermediates. 1 Although 2-aryl-3,3-dichloroacrylonitriles and 2-aryl-3,3-dibromoacrylonitriles could be prepared directly from phosphorus ylides with aroyl cyanides, 2  the commercially available aroyl cyanides are limited and comparatively expensive.Especially, synthesis of aroyl cyanides had to utilize strong toxic reagents as original cyanide sources, such as HgCN, 3 NaCN, 4 CuCN, 5  KCN, 6 and TMSCN, 7 which render the cyanation of aroyl chlorides unsafe and environmentally unfriendly.In addition, the corresponding phosphorus ylides, which are unstable to oxygen and moisture, also required to synthesize by reactions of triphenylphosphine with carbon tetrahalides prior to use.Therefore, there is a need to explore environmentally benign cyanating agents and simple procedure for the synthesis of 2-aryl-3,3dichloroacrylonitriles and 2-aryl-3,3-dibromoacrylonitriles.Potassium hexacyanoferrate(II), K 4 [Fe(CN) 6 ], is non-toxic and is even used in the food industry for metal precipitation.In addition, it has been described as an antiagglutinating auxiliary for table salt (NaCl).K 4 [Fe(CN) 6 ] is commercially available on a ton scale and is even cheaper than KCN.Very recently, K 4 [Fe(CN) 6 ] has been proved to be an efficient cyanide source for the cyanation of halogenated arenes and aroyl chlorides to prepare benzonitriles, 8 and aroyl cyanides. 9 Herein, we wish to report an efficient one-pot fourcomponent synthesis of 2-aryl-3,3-dichloroacrylonitriles and 2-aryl-3,3-dibromoacrylonitriles using potassium hexacyanoferrate(II) as an environmentally benign cyanide source.

Results and Discussion
Initially, the reaction of benzoyl chloride, potassium hexacyanoferrate(II), triphenylphosphine and carbon tetrachloride was selected as a model reaction to examine the feasibility of one-pot four-component synthesis of 2-phenyl-3,3-dichloroacrylonitrile under different conditions (Scheme 1).It was found that the optimal mole ratio of benzoyl chloride to potassium hexacyanoferrate(II) and triphenylphosphine was 1:0.2:2 for the reaction, and the excess carbon tetrachloride were required because it acted both as a reactant and a solvent in this reaction.The 0.2 equivalent of potassium hexacyanoferrate(II) used in the reaction indicated that a small excess of CN -was utilized in the reaction.The best yield was obtained by the procedure of first conducting the reaction of benzoyl chloride and potassium hexacyanoferrate(II) at 160 o C for 3 h, then further Vol. 22, No. 1, 2011 reacting the resulting mixture with triphenylphosphine and carbon tetrachloride at 80 o C for 2 h.Under the optimal conditions, various substituted aroyl chlorides were examined for the one-pot four-component reactions.The results are summarized in Table 1.It was found that aroyl chlorides bearing electron-withdrawing substituents such as chloro, iodo and nitro groups on the aromatic ring gave the corresponding products in high yield (1b-1d, 1i, 1j and 1m).In contrast, aroyl chlorides bearing electron-donating substituents such as methyl, ethyl, methoxy and ethoxy groups on the aromatic ring gave the corresponding products in slightly lower yield under similar conditions (1e-1h, 1k and 1l).For ortho-substituted aroyl chlorides, the corresponding products were obtained in slightly lower yield than para-substituted ones, presumably due to the steric effect (1b, 1e and 1h).Heteroaroyl chloride, furoyl chloride, was also very efficient for the one-pot fourcomponent reaction (1n).
In addition, one-pot four-component reactions of aroyl chlorides, potassium hexacyanoferrate(II), triphenylphosphine and carbon tetrabromide to synthesize various 2-aryl-3,3-dibromoacrylonitriles were also investigated (Scheme 2).In comparison with carbon tetrachloride, carbon tetrabromide is more active for the onepot four-component reaction.Therefore milder conditions are required, such as lower reaction temperature and short reaction time although solvent is needed because carbon tetrabromide can not act as a solvent at low temperatures.The optimal conditions for the selected four-component reaction of benzoyl chloride, potassium hexacyanoferrate(II), triphenylphosphine and carbon tetrabromide were also investigated.It was found that the optimal mole ratio of benzoyl chloride to potassium hexacyanoferrate(II), triphenylphosphine and carbon tetrabromide was 1:0.2:2:1 for the reaction, and the best yield was obtained by the procedure of first conducting the reaction of benzoyl chloride and potassium hexacyanoferrate(II) at 160 o C for 3 h, then further reacting the resulting mixture with triphenylphosphine and carbon tetrabromide in methylene chloride at 10 o C for 0.5 h.

2a-n
Under the optimal conditions, various substituted aroyl chlorides were examined for the reactions.The results are summarized in Table 2.The various substituted aroyl chlorides including electron-withdrawing groups and electron-donating groups are effective for the reactions, which have the similar effect on the yield to carbon tetrachloride.It is noteworthy to mention that 4-phenylbenzoyl chloride and isophthaloyl dichloride could also efficiently participate in the one-pot fourcomponent reactions of carbon tetrabromide, but not for the reactions of carbon tetrachloride under the studied conditions (2l and 2m).Heteroaroyl chloride, furoyl chloride, was also very efficient for the one-pot four-component reaction to obtain 2-(furan-2-yl)-3,3dibromoacrylonitrile (2n).

Conclusions
An efficient route to the one-pot four-component reactions of aroyl chlorides, potassium hexacyanoferrate(II), triphenylphosphine and carbon tetrahalides to synthesize 2-aryl-3,3-dichloroacrylonitriles and 2-aryl-3,3-dibromoacrylonitriles has been developed.The protocol has the advantages of using non-toxic potassium hexacyanoferrate(II) as an environmentally benign cyanide source instead of traditional strong toxic cyanating agents, high yield and simple work-up procedure.

Experimental
IR spectra were recorded using KBr pellets on an Alpha Centauri FTIR spectrophotometer and 1 H NMR and 13 C NMR spectra on a Mercury-400BB instrument using CDCl 3 as solvent and Me 4 Si as internal standard.Melting points were observed in an electrothermal melting point apparatus.Potassium hexacyanoferrate(II) dried at 80 o C under vacuum for 24 h and finely powdered prior to use.All reactions were monitored by TLC.Flash column chromatography was carried out using 200-300 mesh silica gel at increased pressure.

General procedure for the preparation of 2-aryl-3,3dibromoacrylonitriles
The mixture of aroyl chloride (10 mmol) and potassium hexacyanoferrate(II) (0.84 g, 2 mmol) was heated at 160 o C for 3 h.After cooling to 10 o C, triphenylphosphine (5.24 g, 20 mmol) and carbon tetrabromide (3.31 g, 10 mmol) in 10 mL of methylene chloride was slowly added dropwise with stirring.The resulting mixture was further stirred at 10 o C for 0.5 h.Then the solid was removed by filtration, and the filtrate was evaporated to remove solvent under reduced pressure, and the residue was subjected to silica gel flash column chromatography (ethyl acetate, petroleum ether, 1:40, v/v) to obtain pure product.The analytical and spectral data for products are given below; melting points are given in Table 2.