Page  95 Raney Ni/KBH4: an efficient and mild system for the reduction of nitriles to amines Bo Wu,a Ji Zhang,a Meng Yang,a Yang Yue,a Li-Jian Ma,a and Xiao-Qi Yua,b* aDepartment of Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education), Sichuan University, Chengdu, Sichuan 610064, China bState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China E-mail: xqyu@tfol.com Abstract A new and efficient method of synthesizing primary amines from their corresponding nitriles with KBH4 in dry ethanol catalyzed by Raney Ni has been discovered. It is proved that this route is so far the most facile, efficient and easy-to-handle method of reducing aliphatic and aromatic nitriles directly to primary amines. Under mild conditions, up to 93% isolated yields were achieved for aromatic or aliphatic nitriles. This approach opens up a new way for the utilization of potassium borohydride and the classical catalyst Raney Ni. Keywords: Raney nickel, potassium borohydride, nitriles, amines, reduction Introduction Nitrile hydrogenation is an important method to obtain amines. The most commonly used approaches in nitriles hydrogenation are using strong hydride donors, such as lithium aluminum hydride, or catalytic hydrogenation.1 However, these methods always lack chemoselectivity and need complicated procedures to obtain target compounds. The difficulty arises because the imine, as an intermediate produced by the reduction of cyano group, could couple with an already formed primary amine, which leads to secondary amine. Furthermore, a secondary amine could also react with another imine molecule to form tertiary amine.2 Therefore, transforming nitriles to primary amines with high selectivity and yields has become an important field to chemists.3,5,6,7,12,13 Except for a few examples,4 KBH4 or NaBH4 alone generally could not reduce nitriles to amines.1a, 5 The reducing ability of NaBH4 could be enhanced by introducing some

Page  96 special additives. For example, CoCl2, ZrCl4, I2 and bis(2-bromoethyl)selenium dibromide 6 are effective additives for the reaction. Recently Khurana et al 7 reported that aromatic nitriles could be reduced to primary amines with NaBH4 using NiCl2 as additive. However, this method is not efficient for aliphatic nitriles. Caddick and co-workers 8 introduced a suitable trapping agent such as acetic anhydride or di-tert-butyl dicarbonate to the reaction (NiCl2/NaBH4), the protected primary amines were firstly obtained, and the product amines were formed by subsequent deprotection treatment. In this method, longer synthesis routes were needed and the yields of primary amines are not high enough. KBH4 is usually used to react with metal salts to prepare metal borides 9 that are used as the catalysts in catalytic hydrogenation. To the best of our knowledge, KBH4 has never been used with additives to enhance its reducing activity in transforming nitriles to amines. On the other hand, Raney nickel is routinely used as catalyst in catalytic hydrogenation 10 and heterogeneous catalytic hydride transfer hydrogenation.11 The scope of its utilization also involves the selective reduction of nitrocompounds, dinitrosubstituted diphenylsulfones, O- and N-benzyl containing nitrocompounds; the conversion of nitro olefins to carbonyl derivatives,12 and the synthesis of halo amines from halo nitro compounds. In these cases, the commonly used hydrogen donors are hydrazine hydrate, hydrazine derivative 13, ammonium formate, formic acid or cyclohexene. In 2002, Gowda et al 14 found that using Raney Ni / N2H4 / HCOOH could transform nitriles to primary amines with the yield of about 70%. Results and Discussion In this context, we first report a simple and convenient procedure (Scheme 1) to directly convert the robust aliphatic and aromatic nitriles 1 to the corresponding primary amines 2 with high isolated yields (over 80%) by using Raney Ni / KBH4 system in dry ethanol at mild temperature. R-CH2NH2dry ethanol, 45min1a-l2a-lRaney Ni/KBH4R-CNR= aliphatic or aromatic substituents Scheme 1 CNNH21a2aRaney Ni / KBH4dry Ethanol (1)

Page  97 Table 1 lists the results of condition optimization experiments. To increase the yield of primary amine and at the same time to restrain the formation of second amines, excess borohydride must be used. We tried various ratio of 2-phenylacetonitrile 1a / KBH4, and the results showed that the more KBH4 was used to increase the ratio from 1:4 to 1:5 (Table 1, entry 4) result no obvious increase of the yield. GC-MS experiment showed that at the ratio of 1:4, the 2-phenylethanamine was the only product, and no secondary or tertiary amine was formed. Temperature also affects the yield (Table 1, entries 5-9), when the reaction was carried out at 0 oC, the yield is higher than the reaction held at room temperature, but longer reaction time was needed. So the best condition for the reduction of aliphatic nitriles is at room temperature, and the molar ratio of substrate / Raney Ni / KBH4 is 1:1:4. Table 1. Optimization of the reaction conditions in the reduction of aliphatic nitrile.a Entry Substrate 1a/KBH4b Temperature (oC) Reaction Time (min)c Yield of 2a (%)d 1 1:2 rt 120 43 2 1:3 rt 60 80 3 1:4 rt 45 92 4 1:5 rt 40 92 5 1:4 0 120 93 6 1:4 40 45 85 7 1:4 50 45 84 8 1:4 60 40 32 9 1:4 78 30 10 aCommonly conditions: 1a (10mmol), Raney Ni (moist weight 0.64g, approximately 10mmol), 25 mL dry ethanol. bMolar ratio. cMonitored by thin layer chromatography (CH2Cl2 : MeOH=15 : 1). dIsolated yield. But, when using benzonitrile 1i as substrate, at room temperature, the reduction needed 2 hours to complete (Table 2, entry 1), which showed that the aromatic nitriles are more difficult to be reduced than aliphatic ones. This result made us to adjust a proper temperature for the reaction using certain substrate (Table 2). 50 oC (Table 2, entry 2) is the better reaction temperature for the reduction of aromatic nitriles.

Page  98 CNNH21i2iRaney Ni / KBH4dry Ethanol (2) Table 2. Optimization of the reaction conditions in the reduction of benzonitrile.a Entry Substrate 1i/KBH4b Temperature (oC) Reaction Time (min)c Yield of 2i (%)d 1 1:4 rt 120 81 2 1:4 50 45 82 3 1:4 78 40 36 aConditions: 1i (10mmol), Raney Ni (moist weight 0.64g, approximately 10mmol), 25 mL dry ethanol. bMolar ratio. cMonitored by thin layer chromatography (CH2Cl2 : MeOH 15 : 1). dIsolated yield. Changing the solvent to tetrahydrofuran (THF) or dichloromethane did dramatically harm to the reduction. The 2-phenlyacetonitrile 1a could not be reduced even in 24 hours. The reductions can work well using methanol as solvent. But due to its toxicity, we chose ethanol as the reaction solvent. Several nitriles were chosen to be reduced under the optimized conditions, Table 3 summarizes the results. High yields were achieved for both aromatic and aliphatic nitriles. For phenylacetonitrile, the substituents, especially the electron donor substituent on phenyl ring of the substrate might lead to small decrease of the yield (Table 3, a-c). But for benzonitrile, the effect was not obvious (Table 3, i-l). For long chain aliphatic nitriles, the results were changeless, and the yields were around 82% (Table 3, d-h). Unfortunately, our new system has no chemoselectivity for some reducible substituents, such as nitro, aldehyde, ketone and alkene group. These were reduced together with nitrile group.

Page  99 Table 3. Reduction of nitrile 1 with Raney Ni /KBH4a system in ethanolb at mild temperaturec in 45 min reaction time Entry Nitrile 1 Temperature (oC) Product 2 Yield(%)d a CN rt NH2 92 b OCN rt ONH2 86 c ClCN rt ClNH2 90 d CH3(CH2)3CN rt CH3(CH2)4NH2 80 e CH3(CH2)4CN rt CH3(CH2)5NH2 82 f CH3(CH2)6CN rt CH3(CH2)7NH2 81 g CH3(CH2)8CN rt CH3(CH2)9NH2 83 h CH3(CH2)10CN rt CH3(CH2)11NH2 82 i CN 50 NH2 82 j CN 50 NH2 80 k CNO 50 ONH2 81 l NC 50 H2N 86 aMolar ratio of substrate to Raney Ni to KBH4 =1 : 1 : 4. b2.5 mL of dry ethanol / mmol of substrate were used. cRt for aliphatic nitriles and 50 oC for aromatic nitriles. dIsolated yields.

Page  100 Conclusions In summary, a mild and efficient method for the direct hydrogenation of nitriles to primary amines has been developed. Using potassium borohydride as reducing agent, ethanol as solvent, catalyzed by readily available Raney nickel, the reaction can be carried out under mild condition without an inert atmosphere. The primary amine products are obtained in good to excellent yields, and only traces of secondary or tertiary amines are formed. Aromatic nitriles and long chain aliphatic nitriles are suitable for the reducing system. Experimental Section General Procedures. Mass spectra (GC/MS) were recorded on an Agilent Technologies 6890-5973N mass spectrometer. 1H NMR spectra were recorded on a Varian Unity Inova-400 spectrometer operating in 400.00 MHz, in deuterated chloroform at room temperature. For TLC plates coated with silica gel were run in CH2Cl2 / MeOH mixture and spots were developed in Ultraviolet and I2. Raney Nickel preparation. 10 g alloy of Ni-Al in batches were added to 50 mL NaOH aqueous solution (6 mol/L). After being stirred at 50 oC for 90 minutes, the catalyst was thoroughly washed by oxygen-free distilled water and absolute ethanol successively, and was airproofed by absolute ethanol. General procedure for the reduction of nitrile (The reduction of 1a): KBH4 2.16 g (40 mmol), Raney Ni (moist weight 0.64 g, approximately 10mmol) and 25 mL dry ethanol were placed in a 50 mL flask, and then 2-phenylacetonitrile 1a 1.2 mL (10 mmol), was added while stirring. After vigorously stirring at room temperature for 45 min, the reaction mixture was filtered. The organic layer was evaporated and residue was dissolved in ethyl acetate, and was washed with water. The organic layer were dried and evaporated, and the product was purified by flash column chromatography on silica gel (CH2Cl2 / CH3OH, 15: 1) to give 2-phenylethanamine 2a as pale yellow liquid (yield: 92%). 2-Phenylethanamine 2a.15,16,17 1H NMR (400 MHz, CDCl3): d 1.26 (s, 2H, NH2), 2.80-2.85 (m, 2H, CH2), 3.50-3.55 (m, 2H, CH2), 7.16 –7.34 (m, 5H, Ph-H); GC-MS (ES): m/z 121 (M)+. 2-(4-Methoxyphenyl)ethanamine 2b.17 1H NMR (400 MHz, CDCl3): d 1.24 (s, 2H, NH2), 2.67-2.71 (t, J 6.8 Hz, 2H, CH2), 2.91-2.95 (t, J 6.8 Hz, 2H, CH2), 3.79 (s, 3H, CH3), 6.84-0.87 (m, 2H, Ph-H), 7.10-7.13 (m, 2H, Ph-H); GC-MS (ES): m/z 151 (M)+. 2-(4-Chlorophenyl)ethanamine 2c.18 1H NMR (400 MHz, CDCl3): d 1.23 (s, 2H, NH2), 2.70-2.85 (m, 2H, CH2), 2.93-2.99 (m, 2H, CH2), 7.07-7.19 (m, 2H, Ph-H), 7.22-7.35 (m, 2H,

Page  101 Ph-H); GC-MS (ES): m/z 155 (M)+. Pentan-1-amine 2d.16,17 1H NMR (400 MHz, CDCl3): d 0.88-0.92 (m, 3H, CH3), 1.19-1.65 (m, 8H, CH2, NH2), 2.70-2.96 (m, 2H, CH2); GC-MS (ES): m/z = 87 (M)+. Hexan-1-amine 2e.16,19 1H NMR (400 MHz, CDCl3): d 0.86-0.90 (m, 3H, CH3), 1.26-1.57 (m, 10H, CH2, NH2), 2.72-2.79 (m, 2H, CH2); GC-MS (ES): m/z 101 (M)+. Octan-1-amine 2f.20 1H NMR (400 MHz, CDCl3): d 0.86-0.90 (t, J 6.8 Hz, 3H, CH3), 1.26-1.36 (m, 10H, CH2), 1.41-1.47 (m, 2H, CH2), 1.62-1.70 (m, 2H, NH2), 2.67-2.70 (t, J 6.8Hz, 2H, CH2); GC-MS (ES): m/z 129 (M)+. Decan-1-amine 2g.20 1H NMR (400 MHz, CDCl3): d 0.86-0.90 (t, J 7.0 Hz, 3H, CH3), 1.26-1.28 (m, 16H, CH2, NH2), 1.43-1.47 (m, 2H, CH2), 2.67-2.71 (t, J 7.0 Hz, 2H, CH2); GC-MS (ES): m/z 157 (M)+. Dodecan-1-amine 2h.16 1H NMR (400 MHz, CDCl3): d = 0.86-0.90 (t, J 6.8 Hz, 3H, CH3), 1.26-1.32 (m, 20H, CH2, NH2), 1.41-1.45 (m, 2H, CH2), 2.66-2.69 (t, J 7.0 Hz, 2H, CH2); GC-MS (ES): m/z 186 (M + H)+. Phenylmethanamine 2i.15,17 1H NMR (400 MHz, CDCl3): d 1.64 (s, 2H, NH2), 3.88 (s, 2H, CH2), 7.23- 7.36 (m, 5H, Ph-H); GC-MS (ES): m/z 106 (M-H)+. m-Tolylmethanamine 2j.15 1H NMR (400 MHz, CDCl3): d 1.64 (s, 2H, NH2), 2.35 (s, 3H, CH3), 3.78 (s, 2H, CH2), 6.94-7.35 (m, 4H, Ph-H) ; GC-MS (ES): m/z 121 (M-H)+. (2-Ethoxyphenyl)methanamine 2k.16 1H NMR (400 MHz, CDCl3) d 1.42-1.46 (t, J 7.2 Hz, 3H, CH3), 1.65 (s, 2H, NH2), 3.82 (s, 2H, CH2), 4.04-4.09 (m,, 2H, CH2), 6.84-6.92 (m, 2H, Ph-H), 7.19-7.23 (m, 2H, Ph-H); GC-MS (ES): m/z 151(M)+. (4'-Methylbiphenyl-2-yl)methanamine 2l. 1H NMR (400 MHz, CDCl3) d 1.39 (s, 2H, NH2), 2.40 (s, 3H, CH3), 3.81 (s, 2H, CH2), 7.21-7.36 (m, 7H, Ph-H), 7.43-7.45 (d, J 8.4 Hz, 1H, Ph-H); GC-MS (ES): m/z 196 (M - H)+. Acknowledgements This work was financially supported by the National Science Foundation of China (Nos. 20725206, 20732004 and 20572075), Specialized Research Fund for the Doctoral Program of Higher Education and Scientific Fund of Sichuan Province for Outstanding Young Scientists. References 1. (a) Walker, E. R. H. Chem. Soc. Rev. 1976, 5, 23. (b) Klenke, B.; Gilbert, I. H. J. Org. Chem. 2001, 66, 2480.

Page  102 2. (a) Winans, C. F.; Adkins, H. J. Am. Chem. Soc. 1932, 54, 306. (b) Juday, R.; Adkins, H. J. Am. Chem. Soc. 1955, 77, 4559. (c) Huang, Y.; Sachtler, W. M. H. J. Catal. 2000, 190, 69. 3. (a) Heinzman, S. W.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 6801. (b) KuKula, P.; Studer, M.; Blaser, H. U. Adv. Synth. Catal. 2004, 346, 1487. (c) Rode, C. V.; Arai, M.; Shirai, M.; Nishiyama, Y. Appl. Catal. A: General 1997, 148, 405. 4. (a) Natsume, M.; Wada, M. Chem. Pharm. Bull. 1975, 23, 2567. (b) Kikugawa, Y.; Kruamoto, M.; Saito, I.; Yamada, S. I. Chem. Pharm. Bull. 1973, 21, 1927. 5. Nair, V.; Chun, B-K. Arkivoc, 2003, (i), 9. 6. For review, see: Periasamy, M.; Thirumalaikumar, M. J. Organometallic Chem. 2000, 609, 137. 7. Khurana, J. M.; Kukreja, G. Synth. Commun. 2002, 32, 1265. 8. (a) Caddick, S.; Haynes, A. K. de K.; Judd D. B.; Williams, M. R. V. Tetrahedron Lett. 2000, 41, 3513. (b) Caddick, S.; Judd, D. B.; Lewis, A. K. de K.; Reich, M. T.; Williams, M. R. V. Tetrahedron 2003, 59, 5417. 9. (a) Liu, B.; Qiao, M. H.; Wang, J. Q.; Xie, S. H.; Li, H. X.; Fan, K. N. J. Chem. Technol. Biotechnol. 2003, 78, 512. (b) Deng, Y.; Zhou, X. S.; Nan, C. W. Phys. Stat. Sol. 2003, 199, 2265. (c) Wang, G. H.; Yu, X. B.; Cao, X. W.; Li, H. X.; Zhang, Z. R. J. Raman Spectrosc. 2000, 31, 1051. (d) Fang, J.; Chen, X. Y.; Liu, B.; Yan, S. R.; Qiao, M. H.; Li, H. X.; He, H. Y.; Fan, K. N. J. Catal. 2005, 229, 97. (e) Zhong, G. Q.; Zhou, H. L.; Zhang, J. R.; Jia, Y. Q. Mater. Lett. 2005, 59, 2252. 10. For review, see: Chen, B.; Dingerdissen, U.; Krauter, J. G. E.; Lansink H. G. J.; Möbus, K.; Ostgard, D. J.; Panster, P.; Riermeier, T. H.; Seebald, S.; Tacke, T.; Trauthwein, H. Appl. Catal. A: General 2005, 280, 17. 11. (a) Yuste, F.; Saldana, M.; Walls, F. Tetrahedron Lett. 1982, 23, 147. (b) Ayyanger, N. R.; Lugade, A. G.; Nikrad, P. V.; Sharma, V. K. Synthesis 1981, 640. 12. Monti, D.; Gramatica, P.; Speranza, G.; Mannito, P. Tetrahedron Lett. 1983, 24, 147. 13. Furst, A.; Berlo, R. C.; Hooton, S. Chem. Rev. 1965, 65, 51. 14. Gowda, S.; Gowda, D. C. Tetrahedron 2002, 58, 2211. 15. Lin, R-H; Zhang, Y-M.; Zhou, Z-N. Gaodeng Xuexiao Huaxue Xuebao, 1990, 11, 889. 16. SDBSWeb : http://riodb01.ibase.aist.go.jp/sdbs/ (National Institute of Advanced Industrial Science and Technology, date of access) 17. Guisado, C.; Waterhouse, J. E. et. al. Org. Biomol. Chem. 2005, 3, 1049. 18. Jouitteau, C.; Perchec, P. Le; et. al. Tetrahedron Lett. 1980, 21, 1719. 19. Mikolasch, A.; Hammer, E.; et al. Tetrahedron, 2002, 58, 7589. 20. Kabalka, G. W.; Sastry, K. A. R.; et. al. J. Org. Chem. 1981, 46, 4296.