1、selectiveavailableng amides is an impor-and industrial points ofout in the presence ofwhich usually cause over-ng carboxylic acids,conditions.2Although underthe process at the amidecontrolorderimportantneutralizationreactionscontaminatof N,N-disubstituted hydroxylamine and oxime, we decided toexplor
2、e the possibility that acetaldoxime could be used in placeof N,N-diethylhydroxylamine in this reaction. As expected, acet-aldoxime can promote the nitrile hydration. However, the conver-sion rate was found to be relatively lower, especially when nitrilehas no electron-withdrawing substituents. To ou
3、r surprise, whena catalytic amount of copper oxide was added into the reactionsystem, the reaction yield was increased significantly. At the sametime, we have also noticed that the hydration of nitriles promotedby the combination of oxime and metal compounds, such asRhCl(PPh3)3,9Pd(OAc)2,10InCl3,11e
4、tc. have been reported. In theseliteratures, the hydration of nitrile to amide was catalyzed bymetal compounds with an excess of oxime (25 equiv) and thereactions were carried out in organic media. Compared with theseAs shown in Table 1, we found that benzonitrile was easilyhydrated to benzamide by
5、the action of copper salt and acet-aldoxime in water. The yield of benzamide is very low when acet-aldoxime was used alone (Table 1, entry 1). Similarly, the use ofcopper salt alone resulted in no product (Table 1, entry 2). In thisreaction, various copper salts listed in Table 1 appear to be effici
6、entto catalyze the reaction (Table 1, entries 3 and 811), and it wasshown that copper oxide (CuO) and copper(II) chloride dihydrate(CuCl2C12H2O) were much more efficient than copper sulfatepentahydrate (CuSO4C15H2O), cupric acetate (Cu(OAc)2) and cupricCorresponding author. Tel.: +86 025 84315514; f
7、ax: +86 025 84315030.Tetrahedron Letters 53 (2012) 449452Contents lists available atelE-mail address: (M. Lu).lution effects.4To overcome these limitations, several protocolsusing enzymes,5heterogeneous catalysts,6and transition-metalcomplexes7have been developed. During our recent studies ofconver
8、sion of nitrile to amide, we disclosed an improved methodfor the preparation of amides from nitriles by the use of N,N-disub-stituted hydroxylamine.8Under this protocol, nitriles weresmoothly hydrated to amides using water as a reaction mediumat refluxing temperature. In view of the similar molecula
9、r structureaid of oxime has not been reported.To further understand the roles of copper salt and acetaldoxime,a comprehensive study of the hydrolysis of nitriles was carried out.In the first stage of the study we focused on the hydrolysis ofbenzonitrile with the aid of copper salt and acetaldoxime.
10、Weexamined the effects of copper salt, acetaldoxime, reactiontemper-atures, and reaction times on the yields of the hydration reaction.The detailed results are listed in Table 1.Hydration of nitriles to the corresponditant transformation from both academicview.1Classically the reaction was carrieda
11、strong acid or base catalyst, methodshydrolysis of the amides into the correspondia faster reaction specially under basicacidic conditions it is possible to stopstage, in these cases it is necessary toature and stoichiometry employed inof polymeric side products.3It is alsoan industrial perspective,
12、 the finaleither in the acid- or base-catalyzedsalt formation with inconvenient product0040-4039/$ - see front matter C211 2011 Elsevier Ltd. Alldoi:10.1016/j.tetlet.2011.11.075carefully the temper-to avoid the formationto note that, fromstep requiredleads to extensiveion and pol-methods, our method
13、 for the conversion of nitriles into their corre-sponding amides is relatively simple and environmentally friendly.For instance, 100% of benzonitrile could be converted into benzam-ide after 12 h of reflux in water with the aid of 0.1 equiv copperoxide and 1.5 equiv acetaldoxime. In addition, to our
14、 knowledgean efficient Cu-catalyzed hydration of nitriles to amides with theCopper(II)-catalyzed hydration of nitrilesXiao-Yun Ma, Ying He, Yu-Lin Hu, Ming LuChemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094,article infoArticle history:Received 20 September 2
15、011Revised 7 November 2011Accepted 15 November 2011Available online 19 November 2011Keywords:HydrationNitrilesAmidesCopper oxideAcetaldoximeabstractAn efficient method for thecatalyst and commerciallythis protocol, nitriles includingverted into the correspondingTetrahedrojournal homepage: www.rights
16、 reserved.with the aid of acetaldoximeChinahydration of nitrile to amide by employing inexpensive copper saltacetaldoxime in environmentally friendly water is described. Underaromatic nitriles, heterocyclic nitriles and aliphatic nitriles were con-amides in good to excellent yields.C211 2011 Elsevie
17、r Ltd. All rights reserved.SciVerse ScienceDirectn L 2Hydration of various nitriles using copper oxide and acetaldoximeaEntry Nitrile Amide Time (h) Yieldb(%)1CNClClNH2O10 942CNClClNH2O10 953CNH3CH3CNH2O12 934CNCH3CH3NH2O12 925CNH3COH3CONH2O14 90c6CNNH2BrNH2ONH2Br14 88c7CNHOHOONH2 12 95CN ONHTable 1
18、Screen of reaction conditionsab450 X.-Y. Ma et al./Tetrahedron Letters 53 (2012) 449452bromide (CuBr2) to perform the hydrolysis reaction. At the sametime, we have also compared the catalytic activity of copper oxide(CuO) and copper(II) chloride dihydrate (CuCl2C12H2O). Althoughcopper(II) chloride d
19、ihydrate has superior water-soluble property,copper oxide exhibits better catalytic performance during thehydrolysis of nitrile bearing electron-donating groups. In addition,we found that the conversion and reaction rate were improved sig-nificantly by increasing the reaction temperature or the reac
20、tiontime (Table 1, entries 3, 4, 6, and 7). When we reduced the amountsof CuO to 5 mol % (Table 1, entry 5), the yield was slightly reducedEntry Conditions Yield(%)1 Acetaldoxime (1.0 equiv), H2O, reflux, 16 h 52 CuO (10 mol %), H2O, reflux, 16 h 03 CuO (10 mol %), acetaldoxime (1.0 equiv), H2O, ref
21、lux, 16 h 924 CuO (10 mol %), acetaldoxime (1.0 equiv), H2O, reflux, 8 h 695 CuO (5 mol %), acetaldoxime (1.0 equiv), H2O, reflux, 16 h 756 CuO (10 mol %), acetaldoxime (1.0 equiv), H2O, rt, 24 h 417 CuO (10 mol %), acetaldoxime (1.0 equiv), H2O, 50 C176C, 16 h 798 CuBr2(10 mol %), acetaldoxime (1.0
22、 equiv), H2O, reflux, 16 h 789 CuCl2C12H2O (10 mol %), acetaldoxime (1.0 equiv), H2O, reflux,16 h9110 CuSO4C15H2O (10 mol %), acetaldoxime (1.0 equiv), H2O, reflux,16 h8211 Cu(OAc)2(10 mol %), acetaldoxime (1.0 equiv), H2O, reflux,16 h8612 CuO (10 mol %), acetaldoxime (0.5 equiv), H2O, reflux, 24 h
23、4513 CuO (10 mol %), acetaldoxime (1.5 equiv), H2O, reflux, 12 h 94aReaction conditions: benzonitrile (2.5 mmol), H2O (10 mL).bIsolated yield.(75%). When we reduced the amounts of acetaldoxime to 0.5 equiv,the yield was significantly reduced (Table 1, entry 12). Conversely,when we increased the amou
24、nts of acetaldoxime to 1.5 equiv, thereaction time was reduced from 16 to 12 h and the yield wasslightly increased (Table 1, entry 13). It should be noted that nobenzoic acid was detected in the reaction mixture at hightemperatures.As show in scheme 1, we have used benzaldoxime in the placeof acetal
25、doxime to carry out the hydration of nitriles, surprisingly,most of benzaldoxime reacted with CuO to produce benzonitrileand benzamide, and a few isonicotinamide was obtained in thisreaction. On the basis of the above results, we can conclude thatboth extending of reaction time and increasing the am
26、ounts ofacetaldoxime will improve the yield of the product and using0.1 equiv CuO and 1.5 equiv acetaldoxime in water at refluxingtemperature is the optimality conditions for benzonitrilehydrolysis.This protocol of hydration was subsequently applied to variousaromatic nitriles, heterocyclic nitriles
27、 and aliphatic nitriles. AsScheme 1. Use of benzaldoxime in place of acetaldoxime in the hydration reaction.8O2NO2N2 10 959NCNNONH229710NCNNONH2 10 9511NCNNONH210 9512NCNClN ClONH210 9613NClCNClNClClONH229714CNONH212 89d15 CH3(CH2)10CN CH3(CH2)10CONH212 90aReaction conditions: nitrile (2.5 mmol), ac
28、etaldoxime (3.75 mmol), copper saltcatalyst (0.25 mmol), H2O (10 mL), reflux.bIsolated yield.c5 mmol acetaldoxime were used.dCuCl2C12H2O was used in place of CuO.shown in Table 2,12various nitriles including aromatic nitriles hav-ing electron-donating or electron-withdrawing substituents (Table2, en
29、tries 18), heterocyclic nitriles (Table 2, entries 913), and ali-phatic nitriles (Table 2, entries 14 and 15) were converted into thecorresponding amides in good to excellent yields. Substrates bear-ing strong electron-donating groups (Table 2, entries 5 and 6) ren-der the nitrile carbon less electr
30、ophilic to nucleophilic attack byacetaldoxime and exhibited slightly lower conversions. When theamount of acetaldoxime was increased (from 1.5 to 2.0 equiv),yield of amides was consequently improved. In contrast, the hydra-tion of nitriles with an electron-withdrawing group proceeds moreeffectively
31、(Table 2, entries 1, 2 and 813). To our surprise, picoli-nonitrile (Table 2, entry 9) and 3,4-dichloropicolinonitrile (Table 2,entry 13) show high reactivity, both picolinonitrile and 3,4-dichlo-ropicolinonitrile were hydrated to the corresponding amides withcomplete conversion by employing 1 equiv
32、acetaldoxime after arelatively short reaction time of 2 h. We thought that there was aneighboring group participation in reaction course, the nitrogenlone pair in pyridine derivatives participated in hydrolyses of ni-triles and then remarkablyaccelerated the reaction rate. In the caseof aliphatic ni
33、triles the hydration process was similar to aromaticnitriles and aliphatic nitriles (Table 2, entries 14 and 15) wassmoothlyhydrated to give the corresponding amides in good yieldsunder the employed reaction conditions. In addition, ortho substit-uents have only slight effects on nitrile hydrolysis
34、due to the tinymolecular volume of acetaldoxime (Table 2, entries 1, 4 and 6).hydration of nitrile to amide using inexpensive copper salt catalystand commercially available acetaldoxime in an environmentallyfriendly water. Under this protocol, nitriles including aromatic ni-triles, heterocyclic nitr
35、iles and aliphatic nitriles were convertedinto the corresponding amides in good to excellent yields. It isworthwhile to note that nitriles having electron-withdrawinggroups could be converted into the corresponding amides in goodyields at room temperature. In addition, the further search for sub-str
36、ate generality and improvement of the catalyst efficiency is nowunderway in our laboratory.AcknowledgmentFinancial support from the National Natural Science Foundationof China-NSAF (Grant No. 11076017) is gratefully acknowledged.Supplementary dataTable 3Hydration of nitriles at room temperatureaEntr
37、y Nitrile Amide Time (h) Yieldb(%)CN OX.-Y. Ma et al./Tetrahedron Letters1ClClNH2 48 752CNO2NO2NONH2 48 763NCNNONH248 844NCNNONH2 48 855NCNNONH248 87 (56)c6NCNClN ClONH248 887NClCNClNClClONH248 88aReaction conditions: nitrile (2.5 mmol), acetaldoxime (3.75 mmol), CuO(0.25 mmol), H2O (5 mL), CH3OH (5
38、 mL), rt.bIsolated yield.cMethanol was not used as a co-solvent.In the course of the study on hydration of nitriles with electron-withdrawing groups to the corresponding amides, we found thatthe hydrolysis of these nitriles can be achieved in good yields atroom temperature. As shown in Table 3,13tre
39、atment of nitrileswith 0.1 equiv copper oxide and 1.5 equiv acetaldoxime in a mixedsolvent of methanol and water at room temperature for 48 h gaveamides in good yield. Methanol was used as a co-solvent in thereaction,only water used as a reaction mediumgives low yield (Ta-ble 3, entry 5). In additio
40、n, we found that picolinamide and 3,4-dichloropicolinamide did not show high reactivity at room temper-ature. It is worth noting that increasing the electron-withdrawingability of the nitrile enhances the rate of the reaction and improvesthe rate of conversion.As can be seen from Table 1, we reduced
41、 the amounts of acet-aldoxime from 1 to 0.5 equiv, the yield of the amide was signifi-cantly reduced from 92% to 45% (Table 1, entry 12). Thus, we arecertain that acetaldoxime did not regenerate in this reaction andacetaldoxime is not a catalyst for the amide formation. Therefore,we thought that the
42、 reaction mechanism is likely to be similar tothe mechanism reported in literature.11The mechanistic rationali-zation is suggested to account for the formation of amides accord-ing to Scheme 2.Initially, coordination of benzonitrile to copper oxide results inan enhanced electrophilicity of the nitri
43、le carbon, then the nucleo-philic addition of acetaldoxime yields the intermediate I and thefollowing disruption of the intermediate I into benzamide and ace-tonitrile proceeds in a concerted manner.In conclusion, we disclosed an efficient method for the selectiveScheme 2. Proposed mechanism of nitr
44、ile hydration via CuO and acetaldoxime.53 (2012) 449452 451Supplementary data (detailed experimental procedures andspectroscopic data for some compounds) associated with thisarticle can be found, in the online version, at doi:10.1016/j.tetlet.2011.11.075.References and notes1. (a) Larock, R. C. Comp
45、rehensive Organic Transformations, 2nd ed.; Wiley-VCH:New York, 1988. p 1988; (b) Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev. 2002,102, 17711802.2. (a) Plummer, B. F.; Menendez, M.; Songster, M. J. Org. Chem. 1989, 54, 718719;(b) Pala Wilgus, C.; Downing, S.; Molitor, E.; Bains, S.; Pagni, R. M.
46、; Kabalka, G.W. Tetrahedron Lett. 1995, 36, 34693472; (c) Moorthy, J. N.; Singhal, N. J. Org.Chem. 2005, 70, 19261929.3. Edward, J. T.; Meacock, S. C. R. J. Chem. Soc. 1957, 20002007.4. Kukushkin, V. Y.; Pombeiro, A. J. L. Inorg. Chim. Acta 2005, 358, 121.5. Black, G. W.; Gregson, T.; McPake, C. B.;
47、 Perry, J. J.; Zhang, M. Tetrahedron Lett.2010, 51, 16391641.6. Yamaguchi, K.; Matsushita, M.; Mizuno, N. Angew. Chem., Int. Ed. 2004, 43,15761580.7. (a) Garcia-Alvarez, R.; Diez, J.; Crochet, P.; Cadierno, V. Organometallics 2010,29, 39553965; (b) Thallaj, N. K.; Przybilla, J.; Welter, R.; Mandon,
48、D. J. Am.Chem. Soc. 2008, 130, 24142415; (c) Kopylovich, M. N.; Kukushkin, V. Y.;Haukka, M.; Frasto da Silva, J. J. R.; Pombeiro, A. J. L. Inorg. Chem. 2002, 41,47984804.8. Ma, X. Y.; Lu, M. J. Chem. Res. 2011, 35, 480483.9. Lee, J.; Kim, M.; Chang, S.; Lee, H.-Y. Org. Lett. 2009, 11, 55985601.10. K
49、im, E. S.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 2009, 50, 29732975.11. Kim, E. S.; Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2010, 51, 15891591.12. Typical procedure for the synthesis of 2-chlorobenzamide: To a 25 mL round-bottom flask equipped with magnetic stirrer were added 2-chlorobenzonitrile344 mg (2.5 mmol), acetaldoxime 221 mg (3.75 mmol), copper oxide 20 mg(0.25 mmol) and H2O (10 mL). The mixture was heated to reflux for 10 h. Aftercooling to room temperature, the solution was directly ev
