Tetrahedron Letters 52 (2011) 5107–5109
Tetrahedron Letters 52 (2011) 5107–5109
Tetrahedron Letters 52 (2011) 5107–5109

Tetrahedron Letters 52 (2011) 5107–5109

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Tetrahedron Letters 52 (2011) 51075109

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Pd-catalyzed cyanation of benzyl chlorides with nontoxic K4[Fe(CN)6]Yunlai Ren, Mengjie Yan, Shuang Zhao, Yanpei Sun, Jianji Wang , Weiping Yin, Zhifei LiuSchool of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang 471003, Henan, PR China

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a b s t r a c tNon-toxic K4[Fe(CN)6] was demonstrated to be effective as a green cyanating agent for the cyanation of alkyl halides using PPh3/Pd(OAc)2 as a catalyst system. The presented method allowed a series of benzyl chlorides to be smoothly cyanated in up to 88% yield. In order to avoid or suppress the deactivation of the catalyst, the reaction was required to be performed in a stringent inert ambiance. 2011 Elsevier Ltd. All rights reserved.

Article history: Received 16 May 2011 Revised 23 July 2011 Accepted 25 July 2011 Available online 31 July 2011 Keywords: Cyanation Benzyl chlorides Palladium Potassium hexacyanoferrate(II)

Cyanation of alkyl halides plays a crucial role in synthetic organic chemistry since the resulting products can be further transformed into a wide range of important synthetic intermediates including amines, nitrogen-containing heterocycles, carboxylic acids, and carboxylic acid derivatives.1 The most classic method for the cyanation of alkyl halides is the direct reaction between alkyl halides and cyanide salts (NaCN and KCN) by nucleophilic substitution.2 However, an extremely poisonous character of KCN and NaCN seriously restricts their application from environmental perspectives. Therefore, several methods for the cyanation of alkyl halides with lower poisonous trimethylsilyl cyanide (Me3SiCN) as the cyanating agent were developed.3 Unfortunately, the use of Me3SiCN has some inconveniences, it is expensive, sensitive to moisture, and easily liberates highly poisonous hydrogen cyanide. K4[Fe(CN)6] has signicant advantages over the above-mentioned cyanide sources.4 It is non-toxic, commercially available on ton scale, and even cheaper than KCN. However, classic cyanation of alkyl halides is a non-catalytic reaction, and the CN in K4[Fe(CN)6] can not exert its nucleophilic efcacy in the absence of a transition metal catalyst, so that there was no successful example of the reaction between alkyl halides and K4[Fe(CN)6]. So our attention was drawn to developing a catalytic procedure for the cyanation of alkyl halides with non-toxic K4[Fe(CN)6] as the cyanating agent, and the results are reported here. Our investigation began with the cyanation of benzyl chloride with Pd(OAc)2 as the catalyst. In the case of 140 C, a small amount of the desired cyanation product and a considerable amount of benzyl alcohol (41% yield) were obtained after 10 h (Table 1, entry

Corresponding author. Tel.: +86 379 64232156; fax: +86 379 64210415.E-mail address: jwang@mail.haust.edu.cn (J. Wang). 0040-4039/$ - see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.07.112

1). The addition of triphenylphosphine afforded benzyl cyanide in 84% yield (Table 1, entry 4). The ratio of the ligand to Pd(OAc)2 was found to have a signicant effect on the reaction, and the experimental results revealed that a ratio of 24 was optimal. DPPE, DDPPI, and BINAP (see Fig. 1) were also effective as the ligands, while nitrogen ligands including 2,20 -bipyridine, o-phenylenediamine, N,N0 -dimethyl ethylenediamine, and ethylenediamine were almost ineffective (Table 1, entries 614). The reaction was highly dependent on the reaction temperature. Under the reaction condition of 120140 C, the desired cyanation product was afforded in high yields. It was worthy to note that the reaction temperatures of both 160 C and 100 C possibly allowed the cyanation to proceed in high yields, but the resulting experimental results were less reproducible, as was true for a reaction time of 1 h. Our investigation showed that the experimental results were more reproducible in the case of 140 C and 10 h, which prompted us to perform all the following reactions under such a condition. The results in Table 2 revealed that Na2CO3 played an important role in the reaction, and it was necessary to add more than 50 mol % Na2CO3 to allow the cyanation to proceed smoothly. According to some literature on palladium-catalyzed cross-coupling reactions,5 the real catalytically active species was possibly the Pd(0) intermediate, and the role of the base was to facilitate the reduction of Pd(II) intermediate to catalytically active Pd(0) species. Among the screened bases, Na2CO3 turned out to be the most effective one (Table 2, entries 59). K2CO3 was less effective than Na2CO3 although they have similar basicity. The cyanation reactions proceeded efciently with as low as 1 mol % catalyst. We tried to reduce the catalyst loading to 0.5 mol % but found that this was not possible without sacricing the product yield even if the reaction time was prolonged to 30 h. In addition, decreasing the ratio of K4[Fe(CN)6] to benzyl cyanide to 0.2:1 allowed the

5108 Table 1 Palladium-catalyzed cyanation of benzyl chloridea

Y. Ren et al. / Tetrahedron Letters 52 (2011) 51075109 Table 3 Effect of water on the cyanation of benzyl chloridea Entry

K4[Fe(CN)6], Na2CO3

ClEntry 1 2 3 4 5 6 7 8 9 10 11 12 13 14a b

Catalyst, 10 h, 140 oCLigand/Pd(OAc)2 0/1 1/1 2/1 3/1 4/1 1/1 2/1 3/1 4/1 1/1 2/1 2/1 2/1 2/1

CNConversionb (%) 51 $100 99 $100 $100 99 $100 99 98 99 98 80 33 29 Yieldb (%) 8 72 84 84 81 86 79 72 74 77 71 2 5 9 1 2 3 4 5 6a b

Concentration of water (vol %) 0 2.4 5.9 11.3 27.3 38.5

Conversionb (%) 100 99 99 100 99 100

Yield of cyanideb (%) 79 81 81 58 60 53

Yield of alcoholb (%) 3 3 6 23 31 45

Ligand PPh3 PPh3 PPh3 PPh3 PPh3 DPPE DPPE DPPE DPPE DDPPI ()-BINAP 2,20 -Bipyridine Ethylenediamine DMEDA

Reaction conditions were shown in the Ref. 7. Determined by GC.

Table 4 Cyanation of various benzyl chloride catalyzed by Ph3P/Pd(OAc)2a Entry 1 Substrate Productb Yieldc (%) 88

Reaction conditions were shown in the Ref. 7. Determined by GC.




Cl CH3Cl H3C H3C






H 3C


H 3C



Figure 1. Several ligands used in the reactions. 5 Table 2 Palladium-catalyzed cyanation of benzyl chloridea Entry 1 2 3 4 5 6 7 8 9a b



6 Conversionb (%) 8 58 $100 $100 $100 97 72 $100 $100 Yieldb (%) 1 40 88 84 85 46 22 47 3 7




Base Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 K2CO3 KF NaOH K3PO43H2O

Amount of base (mol %) 0 20 50 100 150 150 150 150 100







Cl Cl


Reaction conditions were shown in the Ref. 7. Determined by GC.





cyanation to retain an 80% yield, revealing that basically all the cyanide ions bound to Fe can be transferred to the benzyl group. In some cases, the formation of a small amount of 1,2-diphenylethane by-product was observed. In addition, the cyanation reaction suffered from competing nucleophilic substitution of benzyl chloride by trace amounts of H2O in the solvent. The experimental results (Table 3) revealed that the outcome of the competition between the cyanation and the hydroxylation is highly dependent on the concentration of H2O, and the cyanation product was predominant in the case of less than 5.9 vol % H2O. Attempts to developing a procedure for the cyanation with environmentally benign water as the solvent were not successful. Our experimental results revealed that the presence of oxygen badly prevented benzyl chloride from being cyanated, which possibly resulted from the oxidation destruction of catalytically active Pd(0) species by oxygen.6 Thus the reactions were required to be performed in an inert ambiance to avoid or suppress the deactivation of the catalysts. As a general rule, the activity of the in situ catalyst was dependent on its preparation process. Thus, several experiments were conducted where different addition orders of the reagents were

Cl Cl





a b c

Reaction conditions were shown in the Ref. 7. Identied by 1H NMR, 13C NMR or MS data. Determined by GC with acetophenone as an internal standard.

evaluated to optimize the preparation process of the catalyst. Surprisingly, whether the addition of Na2CO3 was prior to coordination of PPh3 to Pd2+ or not, the cyanation product was obtained in similar yields. Even in the case of the successive addition of Na2CO3, PPh3, K4[Fe(CN)6], and benzyl chloride to a solution of Pd(OAc)2 in NMP, the formed catalytically active species could drive the reaction to near completion. With the optimized results in hand, we set out to evaluate the scope of our novel protocol for the cyanation of benzyl chlorides. It can be seen from Table 4 that several benzyl chlorides with alkyl substituents in the benzene ring were smoothly converted into the desired products. The reactions were able to tolerate several

Y. Ren et al. / Tetrahedron Letters 52 (2011) 51075109


functional groups such as alkyl, uoro, and chloro groups. 2-Methylbenzyl chloride and 4-methylbenzyl chloride gave 72% and 71% yields, respectively (Table 4, entries 2 and 4), while 2,4,6-trimethylbenzyl chloride with two methyl groups in the ortho-position of chloromethyl gave a lower yield under the same condition (Table 4, entry 10). In conclusion, non-toxic K4[Fe(CN)6