Tetrahedron Letters 52 (2011) 5107–5109

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Tetrahedron Letters

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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

a r t i c l e i n f o a b s t r a c t

Article history:Received 16 May 2011Revised 23 July 2011Accepted 25 July 2011Available online 31 July 2011

Keywords:CyanationBenzyl chloridesPalladiumPotassium hexacyanoferrate(II)

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⇑ Corresponding author. Tel.: +86 379 64232156; faE-mail address: jwang@mail.haust.edu.cn (J. Wang

Non-toxic K4[Fe(CN)6] was demonstrated to be effective as a green cyanating agent for the cyanation ofalkyl halides using PPh3/Pd(OAc)2 as a catalyst system. The presented method allowed a series of benzylchlorides to be smoothly cyanated in up to 88% yield. In order to avoid or suppress the deactivation of thecatalyst, the reaction was required to be performed in a stringent inert ambiance.

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Cyanation of alkyl halides plays a crucial role in synthetic or-ganic chemistry since the resulting products can be further trans-formed into a wide range of important synthetic intermediatesincluding amines, nitrogen-containing heterocycles, carboxylicacids, and carboxylic acid derivatives.1 The most classic methodfor the cyanation of alkyl halides is the direct reaction betweenalkyl halides and cyanide salts (NaCN and KCN) by nucleophilicsubstitution.2 However, an extremely poisonous character of KCNand NaCN seriously restricts their application from environmentalperspectives. Therefore, several methods for the cyanation of alkylhalides with lower poisonous trimethylsilyl cyanide (Me3SiCN) asthe cyanating agent were developed.3 Unfortunately, the use ofMe3SiCN has some inconveniences, it is expensive, sensitive tomoisture, and easily liberates highly poisonous hydrogen cyanide.

K4[Fe(CN)6] has significant advantages over the above-men-tioned cyanide sources.4 It is non-toxic, commercially availableon ton scale, and even cheaper than KCN. However, classic cyana-tion of alkyl halides is a non-catalytic reaction, and the CN� inK4[Fe(CN)6] can not exert its nucleophilic efficacy in the absenceof a transition metal catalyst, so that there was no successfulexample of the reaction between alkyl halides and K4[Fe(CN)6].So our attention was drawn to developing a catalytic procedurefor the cyanation of alkyl halides with non-toxic K4[Fe(CN)6] asthe cyanating agent, and the results are reported here.

Our investigation began with the cyanation of benzyl chloridewith Pd(OAc)2 as the catalyst. In the case of 140 �C, a small amountof the desired cyanation product and a considerable amount ofbenzyl alcohol (41% yield) were obtained after 10 h (Table 1, entry

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1). The addition of triphenylphosphine afforded benzyl cyanide in84% yield (Table 1, entry 4). The ratio of the ligand to Pd(OAc)2

was found to have a significant effect on the reaction, and theexperimental results revealed that a ratio of 2–4 was optimal.DPPE, DDPPI, and BINAP (see Fig. 1) were also effective as theligands, while nitrogen ligands including 2,20-bipyridine, o-phenyl-enediamine, N,N0-dimethyl ethylenediamine, and ethylenediaminewere almost ineffective (Table 1, entries 6–14). The reaction washighly dependent on the reaction temperature. Under the reactioncondition of 120–140 �C, the desired cyanation product was affor-ded in high yields. It was worthy to note that the reaction temper-atures of both 160 �C and 100 �C possibly allowed the cyanation toproceed in high yields, but the resulting experimental results wereless reproducible, as was true for a reaction time of 1 h. Ourinvestigation showed that the experimental results were morereproducible in the case of 140 �C and 10 h, which prompted usto perform all the following reactions under such a condition.

The results in Table 2 revealed that Na2CO3 played an importantrole in the reaction, and it was necessary to add more than50 mol % Na2CO3 to allow the cyanation to proceed smoothly.According to some literature on palladium-catalyzed cross-cou-pling reactions,5 the real catalytically active species was possiblythe Pd(0) intermediate, and the role of the base was to facilitatethe reduction of Pd(II) intermediate to catalytically active Pd(0)species. Among the screened bases, Na2CO3 turned out to be themost effective one (Table 2, entries 5–9). K2CO3 was less effectivethan Na2CO3 although they have similar basicity. The cyanationreactions proceeded efficiently with as low as 1 mol % catalyst.We tried to reduce the catalyst loading to 0.5 mol % but found thatthis was not possible without sacrificing the product yield even ifthe reaction time was prolonged to 30 h. In addition, decreasingthe ratio of K4[Fe(CN)6] to benzyl cyanide to 0.2:1 allowed the

Table 3Effect of water on the cyanation of benzyl chloridea

Entry Concentration ofwater (vol %)

Conversionb

(%)Yield ofcyanideb (%)

Yield ofalcoholb (%)

1 0 100 79 32 2.4 99 81 33 5.9 99 81 64 11.3 100 58 235 27.3 99 60 316 38.5 100 53 45

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

Table 4Cyanation of various benzyl chloride catalyzed by Ph3P/Pd(OAc)2

a

Entry Substrate Productb Yieldc (%)

1Cl CN

88

2 ClCH3

CNCH3

72

3 ClH3C

CNH3C

70

4 ClH3C

CNH3C 71

5Cl CN 68

6Cl CN

70

7 ClF

CNF 60

8 ClCl

CNCl 41

9 ClCl

CNCl

22

10Cl CN

40

11Cl CN

2

12

Cl CN

5

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

Table 1Palladium-catalyzed cyanation of benzyl chloridea

ClK4[Fe(CN)6], Na2CO3

Catalyst, 10 h, 140 oC CN

Entry Ligand Ligand/Pd(OAc)2 Conversionb (%) Yieldb (%)

1 PPh3 0/1 51 82 PPh3 1/1 �100 723 PPh3 2/1 99 844 PPh3 3/1 �100 845 PPh3 4/1 �100 816 DPPE 1/1 99 867 DPPE 2/1 �100 798 DPPE 3/1 99 729 DPPE 4/1 98 7410 DDPPI 1/1 99 7711 (±)-BINAP 2/1 98 7112 2,20-Bipyridine 2/1 80 213 Ethylenediamine 2/1 33 514 DMEDA 2/1 29 9

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

Table 2Palladium-catalyzed cyanation of benzyl chloridea

Entry Base Amount of base (mol %) Conversionb (%) Yieldb (%)

1 Na2CO3 0 8 12 Na2CO3 20 58 403 Na2CO3 50 �100 884 Na2CO3 100 �100 845 Na2CO3 150 �100 856 K2CO3 150 97 467 KF 150 72 228 NaOH 150 �100 479 K3PO4�3H2O 100 �100 3

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

PPh2Ph2P

DPPE

O

O

PPh2

Ph2P H

H

DDPPI

PPh2PPh2

(±)-BINAP

NHMeMeHN

DMEDA

Figure 1. Several ligands used in the reactions.

5108 Y. Ren et al. / Tetrahedron Letters 52 (2011) 5107–5109

cyanation to retain an 80% yield, revealing that basically all thecyanide ions bound to Fe can be transferred to the benzyl group.

In some cases, the formation of a small amount of 1,2-diphenyl-ethane by-product was observed. In addition, the cyanation reac-tion suffered from competing nucleophilic substitution of benzylchloride by trace amounts of H2O in the solvent. The experimentalresults (Table 3) revealed that the outcome of the competitionbetween the cyanation and the hydroxylation is highly dependenton the concentration of H2O, and the cyanation product waspredominant in the case of less than 5.9 vol % H2O. Attempts todeveloping a procedure for the cyanation with environmentallybenign water as the solvent were not successful.

Our experimental results revealed that the presence of oxygenbadly prevented benzyl chloride from being cyanated, whichpossibly resulted from the oxidation destruction of catalyticallyactive Pd(0) species by oxygen.6 Thus the reactions were requiredto be performed in an inert ambiance to avoid or suppress thedeactivation of the catalysts.

As a general rule, the activity of the in situ catalyst was depen-dent on its preparation process. Thus, several experiments wereconducted where different addition orders of the reagents were

evaluated to optimize the preparation process of the catalyst.Surprisingly, whether the addition of Na2CO3 was prior to coordi-nation of PPh3 to Pd2+ or not, the cyanation product was obtainedin similar yields. Even in the case of the successive addition ofNa2CO3, PPh3, K4[Fe(CN)6], and benzyl chloride to a solution ofPd(OAc)2 in NMP, the formed catalytically active species coulddrive the reaction to near completion.

With the optimized results in hand, we set out to evaluate thescope of our novel protocol for the cyanation of benzyl chlorides.It can be seen from Table 4 that several benzyl chlorides with alkylsubstituents in the benzene ring were smoothly converted into thedesired products. The reactions were able to tolerate several

Y. Ren et al. / Tetrahedron Letters 52 (2011) 5107–5109 5109

functional groups such as alkyl, fluoro, and chloro groups. 2-Meth-ylbenzyl chloride and 4-methylbenzyl chloride gave 72% and 71%yields, respectively (Table 4, entries 2 and 4), while 2,4,6-trimeth-ylbenzyl chloride with two methyl groups in the ortho-position ofchloromethyl gave a lower yield under the same condition (Table4, entry 10).

In conclusion, non-toxic K4[Fe(CN)6] was demonstrated to beeffective as a cyanating agent for the cyanation of alkyl halideswith PPh3/Pd(OAc)2 as the catalyst. The presented method alloweda series of benzyl chlorides to be cyanated smoothly. In order toavoid or suppress the deactivation of the catalyst, the reactionwas required to be performed in an inert ambiance. It is importantthat the results provide an idea that facilitate K4[Fe(CN)6] to exertits efficacy as the cyanating agent by adding metal catalyst in thecase of classic non-catalytic cyanation. Investigation on the cyana-tion of other alkyl halides with K4[Fe(CN)6] is underway in ourlaboratory.

Acknowledgments

The authors would like to thank the financial supports from theNational Natural Science Foundation of China (Grant No.21002023) and the National Basic Research Program of China(973 Program, Grant No. 2011CB211702).

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.tetlet.2011.07.112.

References and notes

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7. General experimental procedure for the cyanation of benzyl chlorides: 0.06 mmolPPh3, 0.02 mmol Pd(OAc)2, and 0.4 mL NMP were added into a dried 20 mL tubeunder a dry nitrogen atmosphere. After the mixture was stirred at roomtemperature for about 5 min to give a homogeneous solution, 0.3 mmolK4[Fe(CN)6], 1.5 mmol Na2CO3, 1 mmol benzyl chloride, and 0.4 mL NMP wereadded under a dry nitrogen atmosphere. The reaction tube was sealed with aseptum and placed in a constant-temperature oil bath set at 140(±5) �C toperform the reaction for 10 h. Once the reaction time was reached, the mixturewas cooled to room temperature, then acetophenone was added as an internalstandard. GC analysis of the mixture provided the yield of the product (note: inorder to decrease the analysis error, the mixture after the reaction was notpurified or concentrated). The cyanation product was purified by columnchromatography and identified by 1H NMR, 13C NMR or GC–MS data.