FOCUS REVIEW
DOI: 10.1002/ajoc.201300012
Catalytic Methods for Imine Synthesis
Rajendra D. Patil and Subbarayappa Adimurthy*[a]
Asian J. Org. Chem. 2013, 2, 726 – 744 726 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Rajendra D. Patil and Subbarayappa Adimurthy
Abstract: This Focus Review describes different methods that have been reported for the synthe- sis of imines. It is organized according to the methods used for imine synthesis starting with metal catalysis, including Ru, Au, V, Cu, Mn, Co and Pd catalysis. Other methods, such as photo- catalysis, electrocatalysis, organocatalysis, and so on, are also emphasized. Ample information on the condensation of carbonyl compounds/alcohols with amines and direct oxidation of amines to give imines is discussed. Furthermore, among various metal-catalyzed reactions, specific atten- tion has been paid to copper-catalyzed imine synthesis, as copper is less toxic than other heavy metals, comparatively inexpensive, and is easily accessible.
Keywords: amines · carbonyl compounds · catalysis · imine synthesis · oxidation
1. Introduction Much information on the synthesis and chemistry of imines is scattered throughout the literature.[5,6,14–28] Howev- An imine has the general formula R’RC=NR’’, in which R, er, to our knowledge, there has not been a specific and R’, and R’’ can be hydrogen atoms, alkyl groups or aryl comprehensive review on imine synthesis to date. In contin- groups. If R’’ is alkyl or aryl group (not hydrogen) then the uation of our research interest in the development of effi- imine functionality is known as a “Schiff base”, named cient and sustainable methods for imine synthesis,[29–31] as after Hugo Schiff who discovered them in 1864.[1] There are well as for the wider interest of the scientific community, other similar functional groups which slightly differ from an overview of imine chemistry is presented. It is hoped the definition of an imine at the nitrogen center, for exam- that by assembling a comprehensive survey of the widely ple, when R’’=NR2 as in hydrazones and R’’=OH as in scattered information on imine synthesis, it will focus the oximes, and these compounds are not included in this Focus attention of a broad readership because of the potential ap- Review. In the present article, the term imines mainly plications of these compounds. This Focus Review collates refers to Schiff bases. much of the information that is available in the literature Imines are important intermediates in the synthesis of on methods and catalysts used for the synthesis of imines to various biologically active N-heterocyclic compounds and date. in industrial synthetic processes.[2–4] Imines react reversibly Significant progress has been made in recent years in the with amines and aldehydes under particular reaction condi- synthesis of imines, which have been prepared by various tions under thermodynamic control so that initially formed, methods from aldehydes and/or amines and their chemical kinetically competitive intermediates are replaced by ther- equivalents. As depicted in Scheme 1, these methods in- modynamically stable products over time. For this funda- mental reason, the formation of a dynamic covalent imine bond (dynamic covalent bond refers to the influence of re- active substrates, reagents, and particular reaction condi- tions) is an emerging and versatile method with various ap- plications. Formation of imines underlies a discipline known as dynamic covalent chemistry (DCC), which is now used widely in the construction of exotic molecules and ex- tended structures, such as rotaxanes, catenanes, and so on.[5,6] Imines can act as electrophiles in a number of reac- tions, including reductions, additions, condensations, and cy- cloadditions.[7,8] The presence of the lone pair of electrons on the nitrogen atom of the imine group enables coordina- tion to numerous metals, especially when the imine func- tionality is located at the ortho position of aromatic hetero- cycles, such as pyridines. Such molecules are used for inter- esting applications as ligands in homogeneous catalysis.[9,10] Prochiral imines have been widely used for the synthesis of chiral amines.[11–13]
[a] R. D. Patil, S. Adimurthy Central Salt & Marine Chemicals Research Institute (CSIR) G.B. Marg, Bhavnagar 364002, Gujarat (India) Fax : (+91)0278-2567562 Scheme 1. Various synthetic methods that have been reported for imine E-mail: [email protected] synthesis.
Asian J. Org. Chem. 2013, 2, 726 – 744727 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Rajendra D. Patil and Subbarayappa Adimurthy
clude condensation of aldehydes/ketones (A) with amines the reverse reaction, so that azeotropic distillation by (B, method I), addition of aryl halides and liquid ammonia Dean–Stark apparatus is necessary to push the reaction in to aldehydes/ketones (method II), hydroamination of al- the forward direction to favor the imine formation.[32, 33] kynes (method IV), oxidative coupling of amines (B) to There are various factors which influence the equilibrium give imines (method V), oxidative coupling of alcohols and between the imine and the starting aldehyde and amine. amines (method VI), dehydrogenation of secondary amines These factors include concentration, steric and electronic (method VII), coupling of aldehydes/ketones with nitro effects, pH, temperature, and solvents. Condensation reac- compounds (method VIII), and the reaction between chem- tions between carbonyl compounds and amines have been ical equivalents of aldehydes/ketones (X and Y) and carried out in the presence of various catalysts, such as [34] [35] ACHTUNGRE [36] ACHTUNGRE [37] amines (method III). TiO2, CeCl3·H2O, Cu(NO3)2, Er(OTf)3, P2O5/ [38] [39] [40] ACHTUNGRE [41] Al2O3, P2O5/SiO2, NaHSO4·SiO2, Mg(ClO4)2, mo- [42–44] [45–49] lecular sieves, TiCl4, MgSO4–pyridinium p-toluene- [50] [51] [52] [53] [54] 2. Imine Synthesis from Amines and Aldehyde sulfonate, ZnCl2, alumina, Ti(OR)4, CuSO4, and and Ketones montmorillonite K-10 clay.[55,56] In such reactions, these cat- alysts act as Lewis acids to catalyze the nucleophilic attack The synthesis of imines originally reported by Schiff in- of the amine on the carbonyl group and also serve as dehy- volves condensation of a carbonyl compound with an drating agents through irreversible binding with water to fa- amine.[32] Such reactions proceed by nucleophilic addition cilitate the removal of water in the final step. The use of to give a hemiaminal (<-C> C(OH)(NHR)ACHTUNGRE <-C>) inter- dehydrating solvents, such as tetramethyl orthosilicate[57] mediate, then the elimination of water provides the imine and trimethyl orthoformate,[56, 58] were reported to avoid (Scheme 2). The equilibrium in this reaction usually favors azeotropic distillation. In the past two decades, researchers have shown remark- able interest in developing sustainable processes because of environmental concerns, for example, the synthesis of imines with microwaves,[56, 59–64] ultrasound,[65] and IR[66] as energy sources. Furthermore, imine synthesis has also been Scheme 2. Equilibrium in the synthesis of an imine from an aldehyde reported under solvent free conditions.[35,38,39,67,68] Recently, and an amine. ethyl lactate as a tunable solvent has been reported for aryl aldimine synthesis.[59,69] Ethyl lactate can be tuned with a co-solvent to create polarity conditions that are ideal for the synthesis of aryl aldimines, which crystalize directly out Dr. S. Adimurthy was born in 1972 in Ra- of solution in minutes in high yields.[69] Simple, water-medi- mojipalli, Karnataka State, in India. He re- ated procedures for the synthesis of various imines that re- ceived his B.Sc. and M.Sc. degrees in Chemistry from Bangalore University in quire neither catalyst nor any additive were also report- [70–72] 1994 and 1997, respectively. From 2000 to ed. date, he has worked as a Scientist at the In 1962, a review by Layer[73] on imines synthesis focused Central Salt & Marine Chemicals Research on the condensation of carbonyl compounds and amines.[74] Institute, Bhavnagar. He received his Ph.D. in 2005 from Bhavnagar University, India. However, these classical methods have some general limita- He took up a postdoctoral position at the tions. For example, the condensation of primary aliphatic University of Hohenheim, Stuttgart, Germa- aldehydes and amines does not lead to the desired imines, ny, (2007-2008) with Professor U. Beifuss. but instead provides polymeric materials with unreacted He has published over 40 papers and holds amines.[73] Reactions between aliphatic aldehydes and ali- six US patents. His research interests in- clude the synthesis of heterocycles through phatic amines do not easily give imines. Similarly, ketones C H activation, sustainable halogenation, react with amines very slowly and generally require harsh and the development of new oxidative reaction conditions. Moreover, the efficiency of the report- methods. ed procedures is limited to the reaction of highly electro-
Rajendra D. Patil was born in 1983 in Var- philic carbonyl compounds and strongly nucleophilic dhane, India. He received his B.Sc. and amines. Therefore an alternative and efficient strategy with M.Sc. in organic chemistry in 2004 and a broad scope of imine products is highly desirable. Oxida- 2006, respectively, from North Maharashtra tive dehydrogenation of amines (ODH) to give imines has University, India. He joined the Central Salt that potential. and Marine Chemicals Research Institute, Bhavnagar, India in 2007 and received his Ph.D. degree in 2012 under the supervision of Dr. S. Adimurthy. Currently he is work- ing as a Research Fellow at the School of Chemical and Biomedical Engineering, Na- nyang Technological University, Singapore.
Asian J. Org. Chem. 2013, 2, 726 – 744728 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Rajendra D. Patil and Subbarayappa Adimurthy
3. Imines Synthesis through Oxidative Dehydrogenation (ODH) of Amines
Oxidative dehydrogenation (ODH) of amines to give imines is a fundamental approach. However, comparatively little attention has been paid to the oxidation of primary amines to give imines, probably because the intermediates formed from the corresponding primary amines may rapid- ly dehydrogenate into nitriles because of the second a- Scheme 4. Ruthenium-catalyzed aerobic oxidation of amines to give [75–80] amino hydrogen atom. Dehydrogenation of amines to imines. give imines in the laboratory was first reported by Ritter in 1933.[81] Many efforts are underway to develop catalytic sys- protocol is useful for oxidation of aromatic amines as well tems that use sustainable oxidants, mainly oxygen or air, as for aliphatic amines but with a slower reaction rate.[83] for the synthesis of imines from primary or secondary Murahashi et al. reported the catalytic oxidation of sec- amines. ondary amines to give imines by using diruthenium com- ACHTUNGRE plex [Ru2(OAc)4Cl] (4 mol%) in a toluene under mild reac- tion conditions (1 atm. O and 508C).[84] However, under 3.1. Imines Synthesis through ODH of Amines with 2 similar reaction conditions, oxidation of benzylamine af- Transition-metal Catalysts forded the corresponding benzonitrile.[84] Other ruthenium- Oxygen transfer to primary amines can result in a variety catalyzed aerobic oxidations of primary and secondary of oxidized products, such as imines, nitriles, aldehydes, and amines with N-methylmorpholine N-oxide (NMO)[85] and so on, depending on the oxidants and the reaction condi- tert-butyl hydroperoxide[86] have been reported. The catalyt- ACHTUNGRE 2+ tions (Scheme 3). However, a number of transition-metal ic system [Ru(bpy)2(NO)Cl] (bpy= bipyridyl) reacts with based catalytic systems are well-known for selective oxida- benzylamine to produce mainly benzylimine and PhCN as tion of amines to give imines. oxidation products.[87] As oxidation products are generated even in the absence of oxygen, a mechanism in which the nitrosyl ligand acts as an oxidant was proposed.[87] B ckvall and co-workers described an elegant aerobic catalytic system for the generation of aldimines and keti- mines by ruthenium-catalyzed dehydrogenation of amines that involves a biomimetic catalytic system.[88–90] The design Scheme 3. Oxidative coupling of amines to give imines. of the oxidation system was inspired by the biological oxi- dation of secondary alcohols in which the ruthenium com- plex acts as a substrate-selective catalyst instead of NAD+ , 3.1.1. Ruthenium Catalysts the ubiquinone (Q) was replaced by another electron-rich m ACHTUNGRE Bailey and James reported an aerobic oxidative dehydro- quinone, and co-catalyst ML ([Co(salen)] or MnO2)was genation of amines to give imines in 1996 by using a dioxo- used for O2 activation in place of cytochrome-c porphyrin–ruthenium complex.[82] This complex, trans- (Scheme 5).[89, 90] It was predicted that this system could 4+ACHTUNGRE [Ru (tmp)(O)2] (tmp =dianion of 5,10,15,20-tetramesityl- overcome the high energy barriers encountered in the tradi- porphyrin), catalytically dehydrogenates primary and sec- tional oxidation process by allowing reoxidation of the re- ondary amines in the presence of air as an oxidant in ben- duced metal to take place in a series of redox steps. In this zene as solvent and within 24 h. The possible reaction steps system, the quinone acted as a hydrogen acceptor to reduce involve a disproportionation reaction that generates a Ru2+ the metal for the next catalytic cycle. Further, the reduced intermediate, as shown by the isolated bis(benzylamine) quinone was subsequently reoxidized by molecular oxygen 2+ACHTUNGRE ACHTUNGRE complex [Ru (tmp)(PhCH2NH2)2] which was characterized by crystallographically. In another report by Albrecht and co-workers, a series of “[RuACHTUNGRE 2+(ACHTUNGREh6-arene)(NHC)]”ACHTUNGRE complexes (NHC= 1,2,3-triazolylidene, imidazolidene) were prepared and tested for the homocoupling of amines to give imines (Scheme 4).[83] In their report, the loading of catalysts 1–3 was 5 mol% in the absence of an auxiliary base and the re- action was carried out at 1508C. The normal NHC complex catalyst 3 was more active than 1 and the reaction reached full conversion after 12 h.[83] In contrast, the carbonate-con- taining complexes 2 were inactive for this transformation. Scheme 5. Ruthenium-catalyzed aerobic oxidation of amines by using This may be a result of exchange of the carbonate ligand by a biomimetic coupled catalytic system.[88] Yields are based on 1HNMR an amine, which is thermodynamically disfavored.[83] This spectroscopy.
Asian J. Org. Chem. 2013, 2, 726 – 744729 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Rajendra D. Patil and Subbarayappa Adimurthy
typical route for oxidation under aqueous conditions with supported gold nano- particles requires careful washing of the solid to remove the cations and halo- gen ions.[101] The presence of such ions may be responsible for reducing the activity of the catalysts.[101] Further- more, it was necessary to prepare the gold nanoparti- cles in a separate step by chemical reduction or ther- mal decomposition. Howev- er, Baiker and co-workers demonstrated that a highly active gold catalyst could be prepared without following the typical routes men- tioned.[99] The supported gold nanoparticles (Au/ Scheme 6. Ruthenium/quinone-catalyzed dehydrogenation of amines to give imines.[90] Yields are based on CeO2) were generated in situ 1 H NMR spectroscopy. by simple addition of a gold precursor and the support [90] [99] by the co-catalyst. The major advantage of this systems is into an organic solvent. AuCl3,HAuCl4·3H2O, and ACHTUNGRE that aldimines and ketimines can be efficiently prepared Au(OAc)3 were the best gold precursors. In terms of TOFs, (Scheme 6); however, the use of 1.5 equivalents of quinone the acetate-based catalysts were 2–3 times more active than is the concern from the sustainable chemistry point of alumina-supported catalysts and 7000 times active than view.[90] bulk gold.[79,93,95,97–100] Oxidation of amines to give imines by [102] [103] [104] The tetranuclear ruthenium complex {[(PCy3)(CO)RuH]4 using gold supported on TiO2, CeO2, graphite, ACHTUNGRE ACHTUNGRE ACHTUNGRE [105] (m4-O)(m3-OH)(m2-OH)} is a useful catalyst for dehydrogen- porous coordination polymers, and that produced by ation of amines.[91] A pyridine-based pincer ruthenium com- sputtering techniques was also investigated.[106] plex was reported for amine coupling to give imines (ruthe- The notable variance between gold- and ruthenium-cata- nium pincer complex (1 mol%), toluene, argon atmosphere, lyzed oxidation of amines is that gold-catalyzed oxidation at 1158C).[92] of primary amines provides imines as the major products, whereas ruthenium-catalyzed oxidation gives nitriles as the 3.1.2. Gold Catalysts major products (Scheme 7). The first gold catalyzed synthesis of imines from amines It has been suggested that the mechanisms of the rutheni- was reported by Zhu and Angelici in 2007.[93] Bulk gold um- and gold-catalyzed reactions proceed through b-hy- powder (ca. 103 nm particle size) was an active catalyst for dride elimination to provide similar imine intermediates in the ODH of secondary imines to give imines under mild step 1 (Scheme 7).[105] In the subsequent step for ruthenium- conditions (1 atm O2 at 60–1008C) in acetonitrile or toluene catalyzed reactions, second b-hydride elimination may give as the solvent. The gold powder was prepared by the reduc- the corresponding nitrile as the predominant product. How- [94] tion of HAuCl4 with hydroquinone. Zhu et al. continued ever, in the case of gold catalysis, the elimination of the their study on gold catalysis and found that gold supported second b-hydride would be slow or energetically unfavora- on alumina nanoparticles, Au/Al2O3 (20–150 nm), was sig- ble. Moreover, in gold-catalyzed reactions, the pathway for nificantly more active than bulk gold powder.[95] The cata- the imine intermediate to couple with another amine could lytic activity of 5 mg of gold from the Au/Al2O3 catalyst be fast and yield energetically favorable dibenzylimine as was more active than 1 g of bulk gold powder. The support- the predominant product. There has still not been a satisfac- ed gold catalyst was prepared by the incipient wetness im- tory explanation for the discrepancies between the poten- pregnation method. In a recent report, Angelici and co- tial pathways of the gold- and ruthenium-catalyzed reac- workers reported that aliphatic amine N-oxides are effec- tions and it could be important to investigate this. tive oxidants for Au-catalyzed ODH of amines and alco- 3.1.3. Vanadium Catalysts hols.[96] ACHTUNGRE Baiker and co-workers reported the use of gold nanopar- An oxovanadium complex VO(Hhpic)2 (H2hpic =3-hydrox- ticles for the aerobic oxidation of secondary amines.[97–100] A ypicolinic acid) was successfully used as a catalyst for selec-
Asian J. Org. Chem. 2013, 2, 726 – 744730 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Rajendra D. Patil and Subbarayappa Adimurthy
When BrOH was used for the oxidation of benzyla- mine, a small yield of imine was obtained under aqueous conditions (7% at RT and 17% at reflux in water). Other halogenated species, Scheme 7. Possible mechanistic pathways for ruthenium- versus gold-catalyzed oxidation of amines. such as N-bromosuccinimide (NBS), HBr/H2O2, HCl/
H2O2, and iodine were also tive oxidation of benzylamines to obtain the corresponding studied for imine synthesis. benzylimines under aerobic conditions (Scheme 8).[107] In an The results obtained with the bromide- and chloride-based ACHTUNGRE ionic liquid, the VO(Hhpic)2 catalysts were reusable. reagents under similar experimental conditions were not significant. However, the reaction with iodine gave a 68% yield of imine.[29] Iodine is a Lewis acid and was effective for oxidation of benzylamines. Based on these outcomes, we hypothesized that a related transition-metal halide spe- cies may be highly selectivity for imine synthesis under non-aqueous conditions. To our delight, we found that copper chloride functioned well in this context.[29] After ex- Scheme 8. Vanadium-catalyzed oxidation of amines. tensive screening of various copper catalysts and various experimental conditions, 0.5 mol% copper(I) chloride at
Vanadium pentoxide (V2O5) was also reported as a cata- 1008C in atmospheric air were the optimum reaction condi- lyst for efficient oxidation of benzylamines to give imines tions (Scheme 9).[29] This system is very general and is appli- [108] with H2O2 as an environmentally benign oxidant. Inter- cable for a wide range of primary and secondary amines, in- estingly, reactions with benzylamines that have electron- cluding heteroaromatic and cyclic amines (Scheme 9). This withdrawing substituents, such as F, Cl, Br, and COOC2H5, reaction is also efficient for the synthesis of unsymmetrical provide good to quantitative yields of the corresponding imines (Table 1). Under these conditions, the strongly elec- imines; however, electron-donating substituents 4-Me, 4- tron-withdrawing 3-nitroaniline combined with aromatic OMe, 3-OAc, and 1-naphthylamine failed to provide the amine substrates produced only symmetrical imines, possi- corresponding imines under these conditions. bly because of the competitive nucleophilicity of the corre- Mixed vanadium and molybdenum complexes were also sponding amines. reported for ODH of amines.[109–111] An important aspect of In copper(I)-catalyzed oxidation of amines (Scheme 9 these catalysts is their inherent stability under strongly oxi- and Table 1); a small amount of the corresponding alde- dizing conditions. Among different vanadium mixed com- hyde byproduct was formed. To overcome byproduct for- plexes, NPV6Mo6 in particular, is a good catalyst in terms mation, copper powder was used for selective imine synthe- of yield and selectivity.
3.1.4. Copper Catalysts Table 1. Synthesis of unsymmetrical imines. In synthetic organic chemistry, aerobic oxidations of amines has been mainly studied with ruthenium and gold catalysts. The limited availability of these metals and their high price makes it highly desirable to search for more economical al- 2 ternative metal catalysts. The easily and abundantly avail- R Yield [%] unsym./sym. able copper and its complexes are emerging as alternative 78 23:77 catalysts. Various copper complexes have been reported for [112–114] ODH of primary amines to give imines. Recently, our 86 86:14 group developed an environmentally benign brominating reagent for diverse applications.[115–118] This reagent is a com- 82 17:83 bination of a 2:1 mole ratio of bromide/bromate salts, which, upon acidification, generates active species BrOH 93 33:67 [Eq. (1)]. 97 0:100