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Cyanation of aryl bromides…….…by Yan Zhang, Bulletin of the Catalysis Society of India, 8 (2009) 41-45 Cyanation of aryl bromides catalyzed by N-heterocyclic carbene/Pd(OAc)2 Yan Zhang, Yunlai Ren, Shuang Zhao, Jianji Wang,* Zhifei Liu, Weiping Yin, Wei Wang School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang, Henan 471003, P. * Corresponding author. E-mail: [email protected] Tel.: 86-379-64232156; Fax: 86-379-64210415. Abstract: NHC-Pd complex was applied into Pd-catalyzed cyanations of aryl bromides, and displayed high
catalytic activity. Under the optimized conditions, the cyanations of some aryl bromides were performed and a majority of them gave high yields. Moreover, the cyanation reactions were able to tolerate a wide range of Keywords: Cyanation, Aryl bromide, N-Heterocyclic carbine, Palladium
1. Introduction
organic synthesis. On the one hand, they can be easily transformed to a range of functional groups and heterocycles;[1] on the other hand, Figure 1. Some pharmaceuticals containing aromatic
they are very common structural motifs in some commercial compounds, such as dyes, pharmaceuticals, herbicides and natural prepare aryl nitriles.[4] Thereinto, Rosenmund products.[2] In Figure 1, several examples of –von Braun reaction is a traditional method,[5]
pharmaceuticals containing aromatic nitriles but this method requires stoichiometric CuCN, which would lead to equimolar amounts of heavy metal waste. In order to overcome this drawback, some transition-metal-catalyzed agents for the transition-metal-catalyzed cyanation of aryl halides, such as NaCN,[7] KCN,[8] Me3SiCN,[9] Zn(CN)2.[10] However, Cyanation of aryl bromides…….…by Yan Zhang, Bulletin of the Catalysis Society of India, 8 (2009) 41-45 these cyanating agents have suffered from pleased to find that NHC-Pd(OAc)2 complex some drawbacks. NaCN and KCN are highly displayed high catalytic activity in the poisonous; Me3SiCN is sensitive to air and cyanation. liberate easily virulent HCN; the use of 2. Experimental
an inexpensive cyanating agent, K4[Fe(CN)6] 2.1. Materials and instruments
can overcome those drawbacks of the
Imidazolium salt 1 was synthesized by
above-mentioned agents, and has raised wide standard procedures described in previous literatures.[18] K4[Fe(CN)6] was yielded by In the transition-metal-catalyzed cyanatio- grinding K4[Fe(CN)6]·3H2O to a fine powder n, some effective catalysts are palladium,[12] and drying in 150 . All liquid reagents were nickel[13] and copper compounds.[14] Therein- deoxygenated by a subsurface N2 purge for to, palladium compounds have attracted the 30-45 min prior to use. DMF and NMP most considerable attentions due to their high (1-methyl-2-pyrrolidinone) were freshly catalytic efficiency. The use of some distilled from CaH2 under N2 before use. phosphine ligands was thought to improve the NaOtBu and some aryl bromides were catalytic activity and allow for milder reaction purchased from Aldrich or J&K Chemical Ltd. conditions.[15] However, The phosphine or Aladdin reagent Database Inc., and used as ligands are often air-sensitive and poisonous. Recently, N-heterocyclic carbine (NHC) Shanxi Kaida Chemical Engineering Co. Itd. has represented considerable importance in homogeneous catalysis.[16] Compared with or DMSO-d on a Bruker 400 MHz spectro- phosphine ligands, NHC exhibits stronger meter. GC analysis was performed using a σ-donor property, tighter binding to some capillary column (CP-WAX 57CB 25×0.32). metals, greater thermal stability, and 2.2. Representative procedure for the
increased basicity. These characteristics result cyanation of aryl bromides
in unique catalytic behavior of NHC-metal All the following processes were finished in a dry nitrogen atmosphere. After DMF (0.5 NHC ligands have proven to form highly mL), imidazolium salt 1 (0.02 mmol) and
active electron rich palladium catalysts for NaOtBu (0.02 mmol) were added into a many reactions.[17] Inspired by these behave- flame-dried 10 mL tube, the mixture was iors of NHC ligands, we decided to apply stirred at room temperature for 2 min. Then NHC into Pd-catalyzed cyanation, and were Pd(OAc)2 (0.01 mmol) and DMF (0.5 mL) Cyanation of aryl bromides…….…by Yan Zhang, Bulletin of the Catalysis Society of India, 8 (2009) 41-45 were added, and the stirring was kept for 10 decompose thermally to dimethylamine min. After aryl bromides (3.4 mmol), (DMA), which is possibly a contributing K4[Fe(CN)6] (0.67 mmol), Na2CO3 (0.67 factor for the increase of the yield. Then the mmol) and DMF (1 mL) were added, the reaction temperature was optimized. As reaction was performed for corresponding shown in Table 1 (entry 1~5), with the
time at corresponding temperature. After the reaction temperature increasing gradually cyanation was finished, filtration was from 110 to 150 , the yield increased followed by the GC analysis of corresponding gradually from 28% to 93%, then decreased products in the cyanation of bromobenzene. to 87%. These results implied that 130~140 The desired products were purified by column chromatography, and determined by NMR Table 1. Cyanation of bromobenzene catalyzed by
Imidazolium salt 1 (0.6 mol %), Pd(OAc)2 (0.3 mol %)
3. Results and discussion
NaOtBu (0.6 mol %), K4[Fe(CN)6] (0.2 equiv) Imidazolium salt 1
NHC-Pd complex 3
Figure 2. Generation of the in-situ catalyst
As shown in Figure 2, the catalyst was a Reaction conditions were shown in the experimental section
generated in situ from imidazolium salt 1, of this paper. b Determined by GC.
NaOtBu and Pd(OAc)2. We could not yet ascertain the structure of this catalyst. According to previous reports,[19] the catalyst also optimized. As shown in Table 2 (entry
was possibly NHC-Pd complex 3. However, it
was unsuccessful to attempt to isolate 1~4), 0.1 mol % catalyst was optimal, and
NHC-Pd complex 3 from the as-synthesized 96% yield was obtained. 0.3 mol % catalyst
gave 92% yield, which implied that the use of In our initial study, bromobenzene was an excess amount of catalyst could not used as a model substrate to test the efficiency increase the yield. It was possibly rationalized by assuming high concentrations of Pd(0) 3. With NMP as the
solvent, 73% yield was obtained at 150 catalyst would result in the aggregation of the active Pd(0), and the aggregate Pd(0) was 1, entry 6). When NMP was instead by
DMF, the yield was improved to 87% (Table inactive in the cyanation.[20] Some bases were screened to ascertain the optimal conditions. 1, entry 5). As is known, DMF can
Cyanation of aryl bromides…….…by Yan Zhang, Bulletin of the Catalysis Society of India, 8 (2009) 41-45 As shown in Table 2 (entry 3, 5~8), the choice
of the base has an important influence on the Imidazolium salt 1/Pd(OAc)2
KH2PO4 only gave 7% yield. Among the screened bases, Na2CO3 was optimal. Table 2. Effect of the base and the loading amount
of catalyst on the cyanation of bromobenzenea 1/NaOtBu/Pd(OAc)2 (2:2:1)
3 0.10 Na2CO3 99 96
12 a Reaction conditions were shown in the experimental section of this paper. b Isolated yield. c Determined by GC. a Reaction conditions were shown in the experimental section To sum up, the optimized conditions were active than electron-rich substrates. For that: 0.1 mol % NHC-Pd(OAc)2 was used as example, 4-fluorobromobenzene gave 90%
the catalyst, Na2CO3 was used as the base, yield in 5 h, while 4-methoxybromobenzene
DMF was used as the solvent, the reaction required longer reaction time for giving
temperature was 130 (Table 2, entry 3). satisfying yields (Table 3, entry 4,5). Steric
Applying the optimized conditions, a range of hindrance of the substrate also had an
aryl bromides were screened to determine the important influence on the reactions. For
catalytic effectiveness of NHC-Pd complex 3. example, 4-bromotoluene gave 86% yield in
As shown in Table 3, a majority of the 10 h, while 2-bromotolu- ene gave a lower
substrates gave satisfying yields. Moreover, yield of 62% in a longer reaction time (Table
the cyanation reactions were able to tolerate a 3, entry 6,7).
wide range of functional groups such as alkyl, 4. Conclusion
ketone carbonyl, ester, fluoro and methoxy
was applied into Pd-catalyzed cyanations, and Table 3. Cyanation of aryl bromides catalyzed by
displayed high catalytic activity. Under the Cyanation of aryl bromides…….…by Yan Zhang, Bulletin of the Catalysis Society of India, 8 (2009) 41-45 optimized conditions, the cyanations of some [8] Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837.
[9] Sundermeier, M.; Mutyala, S.; Zapf, A.; Spannenberg, aryl bromides were performed and a majority A.; Beller, M. J. Organomet. Chem. 2003, 684, 50.
of them gave high yields. Moreover, the [10] Ryberg, P. Org. Process Res. Dev. 2008, 12, 540.
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[12] (a) Chobanian, H. R.; Fors, B. P.; Lin, L. S. Acknowledgments
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[15] (a) Mariampillai, B.; Alberico, D.; Bidau, V.; Lautens, M. J. Am. Chem. Soc. 2006, 128, 14436; (b) Schareina,
T.; Zapf, A.; Mägerlein, W.; Müller, N.; Beller, M. [1] (a) Grundmann, C. In Houben-Weyl: Methoden der Tetrahedron Lett. 2007, 48, 1087.
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