DOI: 10.1002/ajoc.201300012

Catalytic Methods for Imine Synthesis

Rajendra D. Patil and Subbarayappa Adimurthy*[a]

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FOCUS REVIEW

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 withmetal 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 onthe condensation of carbonyl compounds/alcohols with amines and direct oxidation of amines togive 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 heavymetals, comparatively inexpensive, and is easily accessible.

Keywords: amines · carbonyl compounds · catalysis · imine synthesis · oxidation

1. Introduction

An imine has the general formula R’RC=NR’’, in which R,R’, and R’’ can be hydrogen atoms, alkyl groups or arylgroups. If R’’ is alkyl or aryl group (not hydrogen) then theimine functionality is known as a “Schiff base”, namedafter Hugo Schiff who discovered them in 1864.[1] There areother similar functional groups which slightly differ fromthe definition of an imine at the nitrogen center, for exam-ple, when R’’=NR2 as in hydrazones and R’’=OH as inoximes, and these compounds are not included in this FocusReview. In the present article, the term imines mainlyrefers to Schiff bases.

Imines are important intermediates in the synthesis ofvarious biologically active N-heterocyclic compounds andin industrial synthetic processes.[2–4] Imines react reversiblywith amines and aldehydes under particular reaction condi-tions under thermodynamic control so that initially formed,kinetically competitive intermediates are replaced by ther-modynamically stable products over time. For this funda-mental reason, the formation of a dynamic covalent iminebond (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 disciplineknown as dynamic covalent chemistry (DCC), which is nowused widely in the construction of exotic molecules and ex-tended structures, such as rotaxanes, catenanes, and soon.[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 electronson 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 ofchiral amines.[11–13]

Much information on the synthesis and chemistry ofimines is scattered throughout the literature.[5,6,14–28] Howev-er, to our knowledge, there has not been a specific andcomprehensive review on imine synthesis to date. In contin-uation of our research interest in the development of effi-cient and sustainable methods for imine synthesis,[29–31] aswell as for the wider interest of the scientific community,an overview of imine chemistry is presented. It is hopedthat by assembling a comprehensive survey of the widelyscattered information on imine synthesis, it will focus theattention of a broad readership because of the potential ap-plications of these compounds. This Focus Review collatesmuch of the information that is available in the literatureon methods and catalysts used for the synthesis of imines todate.

Significant progress has been made in recent years in thesynthesis of imines, which have been prepared by variousmethods from aldehydes and/or amines and their chemicalequivalents. As depicted in Scheme 1, these methods in-

[a] R. D. Patil, S. AdimurthyCentral Salt & Marine Chemicals Research Institute (CSIR)G.B. Marg, Bhavnagar 364002, Gujarat (India)Fax: (+91) 0278-2567562E-mail : adimurthy@csmcri.org

Scheme 1. Various synthetic methods that have been reported for iminesynthesis.

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clude condensation of aldehydes/ketones (A) with amines(B, method I), addition of aryl halides and liquid ammoniato aldehydes/ketones (method II), hydroamination of al-kynes (method IV), oxidative coupling of amines (B) togive imines (method V), oxidative coupling of alcohols andamines (method VI), dehydrogenation of secondary amines(method VII), coupling of aldehydes/ketones with nitrocompounds (method VIII), and the reaction between chem-ical equivalents of aldehydes/ketones (X and Y) andamines (method III).

2. Imine Synthesis from Amines and Aldehydeand Ketones

The synthesis of imines originally reported by Schiff in-volves condensation of a carbonyl compound with anamine.[32] Such reactions proceed by nucleophilic additionto give a hemiaminal (<-C>C(OH) ACHTUNGTRENNUNG(NHR)<-C>) inter-mediate, then the elimination of water provides the imine(Scheme 2). The equilibrium in this reaction usually favors

the reverse reaction, so that azeotropic distillation byDean–Stark apparatus is necessary to push the reaction inthe forward direction to favor the imine formation.[32, 33]

There are various factors which influence the equilibriumbetween the imine and the starting aldehyde and amine.These factors include concentration, steric and electroniceffects, pH, temperature, and solvents. Condensation reac-tions between carbonyl compounds and amines have beencarried out in the presence of various catalysts, such asTiO2,

[34] CeCl3·H2O,[35] CuACHTUNGTRENNUNG(NO3)2,[36] ErACHTUNGTRENNUNG(OTf)3,

[37] P2O5/Al2O3,

[38] P2O5/SiO2,[39] NaHSO4·SiO2,

[40] Mg ACHTUNGTRENNUNG(ClO4)2,[41] mo-

lecular sieves,[42–44] TiCl4,[45–49] MgSO4–pyridinium p-toluene-

sulfonate,[50] ZnCl2,[51] alumina,[52] Ti(OR)4,

[53] CuSO4,[54] and

montmorillonite K-10 clay.[55,56] In such reactions, these cat-alysts act as Lewis acids to catalyze the nucleophilic attackof the amine on the carbonyl group and also serve as dehy-drating agents through irreversible binding with water to fa-cilitate the removal of water in the final step. The use ofdehydrating solvents, such as tetramethyl orthosilicate[57]

and trimethyl orthoformate,[56, 58] were reported to avoidazeotropic distillation.

In the past two decades, researchers have shown remark-able interest in developing sustainable processes because ofenvironmental concerns, for example, the synthesis ofimines with microwaves,[56, 59–64] ultrasound,[65] and IR[66] asenergy sources. Furthermore, imine synthesis has also beenreported under solvent free conditions.[35,38, 39,67, 68] Recently,ethyl lactate as a tunable solvent has been reported for arylaldimine synthesis.[59,69] Ethyl lactate can be tuned witha co-solvent to create polarity conditions that are ideal forthe synthesis of aryl aldimines, which crystalize directly outof solution in minutes in high yields.[69] Simple, water-medi-ated procedures for the synthesis of various imines that re-quire neither catalyst nor any additive were also report-ed.[70–72]

In 1962, a review by Layer[73] on imines synthesis focusedon the condensation of carbonyl compounds and amines.[74]

However, these classical methods have some general limita-tions. For example, the condensation of primary aliphaticaldehydes and amines does not lead to the desired imines,but instead provides polymeric materials with unreactedamines.[73] Reactions between aliphatic aldehydes and ali-phatic amines do not easily give imines. Similarly, ketonesreact with amines very slowly and generally require harshreaction conditions. Moreover, the efficiency of the report-ed procedures is limited to the reaction of highly electro-philic carbonyl compounds and strongly nucleophilicamines. Therefore an alternative and efficient strategy witha broad scope of imine products is highly desirable. Oxida-tive dehydrogenation of amines (ODH) to give imines hasthat potential.

Dr. S. Adimurthy was born in 1972 in Ra-mojipalli, Karnataka State, in India. He re-ceived his B.Sc. and M.Sc. degrees inChemistry from Bangalore University in1994 and 1997, respectively. From 2000 todate, he has worked as a Scientist at theCentral Salt & Marine Chemicals ResearchInstitute, Bhavnagar. He received his Ph.D.in 2005 from Bhavnagar University, India.He took up a postdoctoral position at theUniversity of Hohenheim, Stuttgart, Germa-ny, (2007-2008) with Professor U. Beifuss.He has published over 40 papers and holdssix US patents. His research interests in-clude the synthesis of heterocycles throughC�H activation, sustainable halogenation,and the development of new oxidativemethods.

Rajendra D. Patil was born in 1983 in Var-dhane, India. He received his B.Sc. andM.Sc. in organic chemistry in 2004 and2006, respectively, from North MaharashtraUniversity, India. He joined the Central Saltand Marine Chemicals Research Institute,Bhavnagar, India in 2007 and received hisPh.D. degree in 2012 under the supervisionof Dr. S. Adimurthy. Currently he is work-ing as a Research Fellow at the School ofChemical and Biomedical Engineering, Na-nyang Technological University, Singapore.

Scheme 2. Equilibrium in the synthesis of an imine from an aldehydeand an amine.

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3. Imines Synthesis through OxidativeDehydrogenation (ODH) of Amines

Oxidative dehydrogenation (ODH) of amines to giveimines is a fundamental approach. However, comparativelylittle attention has been paid to the oxidation of primaryamines to give imines, probably because the intermediatesformed from the corresponding primary amines may rapid-ly dehydrogenate into nitriles because of the second a-amino hydrogen atom.[75–80] Dehydrogenation of amines togive imines in the laboratory was first reported by Ritter in1933.[81] Many efforts are underway to develop catalytic sys-tems that use sustainable oxidants, mainly oxygen or air,for the synthesis of imines from primary or secondaryamines.

3.1. Imines Synthesis through ODH of Amines withTransition-metal Catalysts

Oxygen transfer to primary amines can result in a varietyof oxidized products, such as imines, nitriles, aldehydes, andso on, depending on the oxidants and the reaction condi-tions (Scheme 3). However, a number of transition-metalbased catalytic systems are well-known for selective oxida-tion of amines to give imines.

3.1.1. Ruthenium Catalysts

Bailey and James reported an aerobic oxidative dehydro-genation of amines to give imines in 1996 by using a dioxo-porphyrin–ruthenium complex.[82] This complex, trans-[Ru4+ ACHTUNGTRENNUNG(tmp)(O)2] (tmp =dianion of 5,10,15,20-tetramesityl-porphyrin), catalytically dehydrogenates primary and sec-ondary amines in the presence of air as an oxidant in ben-zene as solvent and within 24 h. The possible reaction stepsinvolve a disproportionation reaction that generates a Ru2+

intermediate, as shown by the isolated bis(benzylamine)complex [Ru2+ ACHTUNGTRENNUNG(tmp) ACHTUNGTRENNUNG(PhCH2NH2)2] which was characterizedby crystallographically. In another report by Albrecht andco-workers, a series of “ACHTUNGTRENNUNG[Ru2+ ACHTUNGTRENNUNG(h6-arene) ACHTUNGTRENNUNG(NHC)]” complexes(NHC= 1,2,3-triazolylidene, imidazolidene) were preparedand tested for the homocoupling of amines to give imines(Scheme 4).[83] In their report, the loading of catalysts 1–3was 5 mol % in the absence of an auxiliary base and the re-action was carried out at 150 8C. The normal NHC complexcatalyst 3 was more active than 1 and the reaction reachedfull conversion after 12 h.[83] In contrast, the carbonate-con-taining complexes 2 were inactive for this transformation.This may be a result of exchange of the carbonate ligand byan amine, which is thermodynamically disfavored.[83] This

protocol is useful for oxidation of aromatic amines as wellas for aliphatic amines but with a slower reaction rate.[83]

Murahashi et al. reported the catalytic oxidation of sec-ondary amines to give imines by using diruthenium com-plex [Ru2ACHTUNGTRENNUNG(OAc)4Cl] (4 mol %) in a toluene under mild reac-tion conditions (1 atm. O2 and 50 8C).[84] However, undersimilar reaction conditions, oxidation of benzylamine af-forded the corresponding benzonitrile.[84] Other ruthenium-catalyzed aerobic oxidations of primary and secondaryamines with N-methylmorpholine N-oxide (NMO)[85] andtert-butyl hydroperoxide[86] have been reported. The catalyt-ic system [Ru ACHTUNGTRENNUNG(bpy)2(NO)Cl]2+ (bpy= bipyridyl) reacts withbenzylamine to produce mainly benzylimine and PhCN asoxidation products.[87] As oxidation products are generatedeven in the absence of oxygen, a mechanism in which thenitrosyl ligand acts as an oxidant was proposed.[87]

B�ckvall and co-workers described an elegant aerobiccatalytic system for the generation of aldimines and keti-mines by ruthenium-catalyzed dehydrogenation of aminesthat involves a biomimetic catalytic system.[88–90] The designof 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+ ,the ubiquinone (Q) was replaced by another electron-richquinone, and co-catalyst MLm ([Co ACHTUNGTRENNUNG(salen)] or MnO2) wasused for O2 activation in place of cytochrome-c(Scheme 5).[89, 90] It was predicted that this system couldovercome the high energy barriers encountered in the tradi-tional oxidation process by allowing reoxidation of the re-duced metal to take place in a series of redox steps. In thissystem, the quinone acted as a hydrogen acceptor to reducethe metal for the next catalytic cycle. Further, the reducedquinone was subsequently reoxidized by molecular oxygen

Scheme 3. Oxidative coupling of amines to give imines.

Scheme 4. Ruthenium-catalyzed aerobic oxidation of amines to giveimines.

Scheme 5. Ruthenium-catalyzed aerobic oxidation of amines by usinga biomimetic coupled catalytic system.[88] Yields are based on 1H NMRspectroscopy.

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by the co-catalyst.[90] The major advantage of this systems isthat aldimines and ketimines can be efficiently prepared(Scheme 6); however, the use of 1.5 equivalents of quinoneis the concern from the sustainable chemistry point ofview.[90]

The tetranuclear ruthenium complex {[(PCy3)(CO)RuH]4ACHTUNGTRENNUNG(m4-O) ACHTUNGTRENNUNG(m3-OH) ACHTUNGTRENNUNG(m2-OH)} is a useful catalyst for dehydrogen-ation of amines.[91] A pyridine-based pincer ruthenium com-plex was reported for amine coupling to give imines (ruthe-nium pincer complex (1 mol%), toluene, argon atmosphere,at 115 8C).[92]

3.1.2. Gold Catalysts

The first gold catalyzed synthesis of imines from amineswas reported by Zhu and Angelici in 2007.[93] Bulk goldpowder (ca. 103 nm particle size) was an active catalyst forthe ODH of secondary imines to give imines under mildconditions (1 atm O2 at 60–100 8C) in acetonitrile or tolueneas the solvent. The gold powder was prepared by the reduc-tion of HAuCl4 with hydroquinone.[94] Zhu et al. continuedtheir study on gold catalysis and found that gold supportedon alumina nanoparticles, Au/Al2O3 (20–150 nm), was sig-nificantly more active than bulk gold powder.[95] The cata-lytic activity of 5 mg of gold from the Au/Al2O3 catalystwas more active than 1 g of bulk gold powder. The support-ed gold catalyst was prepared by the incipient wetness im-pregnation method. In a recent report, Angelici and co-workers reported that aliphatic amine N-oxides are effec-tive oxidants for Au-catalyzed ODH of amines and alco-hols.[96]

Baiker and co-workers reported the use of gold nanopar-ticles for the aerobic oxidation of secondary amines.[97–100] A

typical route for oxidationunder aqueous conditionswith supported gold nano-particles requires carefulwashing of the solid toremove the cations and halo-gen ions.[101] The presence ofsuch ions may be responsiblefor reducing the activity ofthe catalysts.[101] Further-more, it was necessary toprepare the gold nanoparti-cles in a separate step bychemical reduction or ther-mal decomposition. Howev-er, Baiker and co-workersdemonstrated that a highlyactive gold catalyst could beprepared without followingthe typical routes men-tioned.[99] The supportedgold nanoparticles (Au/CeO2) were generated in situby simple addition of a goldprecursor and the support

into an organic solvent.[99] AuCl3, HAuCl4·3H2O, andAuACHTUNGTRENNUNG(OAc)3 were the best gold precursors. In terms of TOFs,the acetate-based catalysts were 2–3 times more active thanalumina-supported catalysts and 7000 times active thanbulk gold.[79,93, 95,97–100] Oxidation of amines to give imines byusing gold supported on TiO2,

[102] CeO2,[103] graphite,[104]

porous coordination polymers,[105] and that produced bysputtering techniques was also investigated.[106]

The notable variance between gold- and ruthenium-cata-lyzed oxidation of amines is that gold-catalyzed oxidationof primary amines provides imines as the major products,whereas ruthenium-catalyzed oxidation gives nitriles as themajor products (Scheme 7).

It has been suggested that the mechanisms of the rutheni-um- and gold-catalyzed reactions proceed through b-hy-dride elimination to provide similar imine intermediates instep 1 (Scheme 7).[105] In the subsequent step for ruthenium-catalyzed reactions, second b-hydride elimination may givethe corresponding nitrile as the predominant product. How-ever, in the case of gold catalysis, the elimination of thesecond b-hydride would be slow or energetically unfavora-ble. Moreover, in gold-catalyzed reactions, the pathway forthe imine intermediate to couple with another amine couldbe fast and yield energetically favorable dibenzylimine asthe predominant product. There has still not been a satisfac-tory explanation for the discrepancies between the poten-tial pathways of the gold- and ruthenium-catalyzed reac-tions and it could be important to investigate this.

3.1.3. Vanadium Catalysts

An oxovanadium complex VO ACHTUNGTRENNUNG(Hhpic)2 (H2hpic =3-hydrox-ypicolinic acid) was successfully used as a catalyst for selec-

Scheme 6. Ruthenium/quinone-catalyzed dehydrogenation of amines to give imines.[90] Yields are based on1H NMR spectroscopy.

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tive oxidation of benzylamines to obtain the correspondingbenzylimines under aerobic conditions (Scheme 8).[107] In anionic liquid, the VO ACHTUNGTRENNUNG(Hhpic)2 catalysts were reusable.

Vanadium pentoxide (V2O5) was also reported as a cata-lyst for efficient oxidation of benzylamines to give imineswith H2O2 as an environmentally benign oxidant.[108] Inter-estingly, reactions with benzylamines that have electron-withdrawing substituents, such as F, Cl, Br, and COOC2H5,provide good to quantitative yields of the correspondingimines; however, electron-donating substituents 4-Me, 4-OMe, 3-OAc, and 1-naphthylamine failed to provide thecorresponding imines under these conditions.

Mixed vanadium and molybdenum complexes were alsoreported for ODH of amines.[109–111] An important aspect ofthese catalysts is their inherent stability under strongly oxi-dizing conditions. Among different vanadium mixed com-plexes, NPV6Mo6 in particular, is a good catalyst in termsof yield and selectivity.

3.1.4. Copper Catalysts

In synthetic organic chemistry, aerobic oxidations of amineshas been mainly studied with ruthenium and gold catalysts.The limited availability of these metals and their high pricemakes it highly desirable to search for more economical al-ternative metal catalysts. The easily and abundantly avail-able copper and its complexes are emerging as alternativecatalysts. Various copper complexes have been reported forODH of primary amines to give imines.[112–114] Recently, ourgroup developed an environmentally benign brominatingreagent for diverse applications.[115–118] This reagent is a com-bination of a 2:1 mole ratio of bromide/bromate salts,which, upon acidification, generates active species BrOH[Eq. (1)].

2 Br� þ BrO3� þ 3 Hþ ! 3 BrOH ð1Þ

BrOH has been explored in organic synthesis for applica-tions that include oxidation and oxybrominations.[119–122]

When BrOH was used forthe oxidation of benzyla-mine, a small yield of iminewas obtained under aqueousconditions (7 % at RT and17 % at reflux in water).Other halogenated species,such as N-bromosuccinimide(NBS), HBr/H2O2, HCl/H2O2, and iodine were alsostudied for imine synthesis.

The results obtained with the bromide- and chloride-basedreagents under similar experimental conditions were notsignificant. However, the reaction with iodine gave a 68 %yield of imine.[29] Iodine is a Lewis acid and was effectivefor oxidation of benzylamines. Based on these outcomes,we hypothesized that a related transition-metal halide spe-cies may be highly selectivity for imine synthesis undernon-aqueous conditions. To our delight, we found thatcopper chloride functioned well in this context.[29] After ex-tensive screening of various copper catalysts and variousexperimental conditions, 0.5 mol % copper(I) chloride at100 8C in atmospheric air were the optimum reaction condi-tions (Scheme 9).[29] This system is very general and is appli-cable for a wide range of primary and secondary amines, in-cluding heteroaromatic and cyclic amines (Scheme 9). Thisreaction is also efficient for the synthesis of unsymmetricalimines (Table 1). Under these conditions, the strongly elec-tron-withdrawing 3-nitroaniline combined with aromaticamine substrates produced only symmetrical imines, possi-bly because of the competitive nucleophilicity of the corre-sponding amines.

In copper(I)-catalyzed oxidation of amines (Scheme 9and Table 1); a small amount of the corresponding alde-hyde byproduct was formed. To overcome byproduct for-mation, copper powder was used for selective imine synthe-

Scheme 7. Possible mechanistic pathways for ruthenium- versus gold-catalyzed oxidation of amines.

Scheme 8. Vanadium-catalyzed oxidation of amines.

Table 1. Synthesis of unsymmetrical imines.

R2 Yield [%] unsym./sym.

78 23:77

86 86:14

82 17:83

93 33:67

97 0:100

94 0:100

78 56:44

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sis under neat aerobic conditions.[30] Under these conditions,good to excellent yields of the corresponding imines wereobtained with a wide substrate scope, such as benzylamineswith electron-donating and electron-withdrawing substitu-ents, secondary amines, cyclic secondary amines, primary

aliphatic amines, heteroaromatic amines, and unsymmetri-cally coupled imines. The advantages of copper powderover copper chloride are a lower cost, higher stability underaerobic conditions, a lower environmental impact, mild re-action conditions, and easy isolation of products withoutchromatography. Therefore, after completion of the reac-tion, the reaction mixture was filtered through filter paper(cellulose paper sheet) and washed with a minimum quanti-ty of diethyl ether. After removal of the solvent from thefiltrate, pure imine was obtained.

Mechanisms for Copper-catalyzed Imine Synthesis

Similar to ruthenium and gold, copper is not well-recog-nized as a hydride transfer catalyst; therefore reactions cat-alyzed by copper may proceed through a different reactionmechanism, as shown in Scheme 10. In the proposed mech-anism the first step is the formation of a copper(II)–aminecomplex (Scheme 10 A) through the oxidative addition ofcopper to the amine. Further, reductive elimination ofcopper from the copper(II) complex results the imine inter-mediate I. Reaction of intermediate I with another amineleads to the final imine (Path 1, Scheme 10 B). On the otherhand, the presence of water partially hydrolyses intermedia-te I to give an aldehyde (Path 2). In the final step, conden-sation of the aldehyde and amine leads to the desiredimine.

Similar reactions for the aerobic oxidation of amines togive imines were reported with a CuBr2/TEMPO/oxygensystem in aqueous acetonitrile at room temperature.[123] TheTEMPO-catalyzed reaction of benzylamines was carriedout with different catalytic systems, such as CuBr2, CuCl2,CuACHTUNGTRENNUNG(CH3COO)2 and FeCl3, which resulted in 86 %, 58 %,and 62 % conversions and no reaction, respectively.

3.1.5. Manganese Catalysts

Manganese dioxide,[124, 125] potassium permanganate[126]

either in acidic or neutral medium, and manganese sul-fate[127] were used for the oxidation of amines to give the

Scheme 9. Copper(I)-chloride-catalyzed aerobic oxidation of amines togive imines. Ratios are that of imine to aldehyde. Numbers in parenthe-ses are the yields of crude product as determined by 1H NMR spectros-copy.

Scheme 10. Possible mechanism for the copper-catalysed aerobic oxidation of primary amines to give imines.

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corresponding imines. Amanganese–porphyrin com-plex in combination withtert-butyl hydroperoxide asan oxidant in various organicsolvents, such as dichlorome-thane,[128] acetonitrile,[129] andtoluene,[130] was reported to catalyze this reaction. Ji andco-workers demonstrated that a manganese porphyrin/tBuOOH catalytic system is also effective in an aqueousmedium.[131]

3.1.6. Cobalt Catalysts

Cobalt(II) catalytic systems that consist of salen ligands[Co ACHTUNGTRENNUNG(salen)]/O2 catalyze the oxidation of primary[132] andsecondary amines.[133] The reactivity of the catalyst and theefficiency of the reaction depends on the structure of theligand. Several [Co2+ ACHTUNGTRENNUNG(salen)] catalytic systems with differentligand structures were studied[134] and their order of reactiv-ity with tBuOOH as the oxidant follows the order:Co2+(L5)>Co2+(L1)>Co2+(L2)>Co2+(L3)>Co2+(L4)>Co2+(L6) [Figure 1].[134] However, with oxygen as an oxidantCo2+(L5) was inactive. The reactivity of Co2+(L) may be at-tributed to the susceptibility of the Co�O bond inACHTUNGTRENNUNG[Co3+(L) ACHTUNGTRENNUNG(OOtBu)] to homolytic cleavage.

3.1.7. Other Transition-metal Catalysts

A NiSO4/K2S2O8 catalytic system was effective for the oxi-dation of secondary amines to give imines.[135] Garcia andco-workers developed a Ni-catalyzed strategy for in situtransfer hydrogenation from amines to alkynes to produceimines and alkenes as products (Scheme 11).[136] The secon-dary amines were dehydrogenated by the [(dppe)Ni ACHTUNGTRENNUNG(m-H)]catalyst (dppe= 1,2-bis(diphenylphosphino)ethane,0.5 mol %) with simultaneous hydrogen transfer from theamines to the alkynes.

In 1973, Murahashi and co-workers reported the synthe-sis of unsymmetrical secondary and tertiary amines byusing a palladium catalyst (palladium black).[137] Similarly,in 1983 the same group reported catalytic alkyl exchangereaction between primary and secondary amines with palla-

dium black.[138] In these reports, imines were generated asstable intermediates through ODH of amines with the pal-ladium catalyst.[137,138] Palladium catalyst PdCl2/PPh3 isuseful for dehydrogenation of secondary benzylamines butnot for primary benzylamines under aerobic conditions.[139]

Dirhodium caprolactamate [Rh2ACHTUNGTRENNUNG(cap)4] is another effectivecatalyst for dehydrogenation of secondary amines withtBuOOH as oxidant in acetonitrile at room temperature.[140]

Other transition metals used for the oxidation of amines togive imines include iridium,[141] zinc,[142] and mercury.[143]

3.2. Photocatalysis

The photocatalytic properties of TiO2 were discovered byFujishima and Honda in 1967 and published in 1972.[144]

Later, in 1985, photocatalytic formation of imines from pri-mary amines on a platinized TiO2 suspension in acetonitrilewith the elimination of ammonia and hydrogen was report-ed (Scheme 12).[145]

Recently Zhao and co-workers reported aerobic oxida-tion of amines to give imines on the surface of TiO2 in aninert solvent under UV irradiation with high selectivity.[146]

Most photocatalytic organic reactions that have been re-ported for synthetic transformations are performed underUV irradiation and it is difficult to perform such reactionswith visible light. Generally, reactions with visible light re-quire doping of the TiO2 surface with noble-metal com-plexes or nanoparticles. Zhao and co-workers discoveredthat a series of benzylic amines adsorbed on the surface ofTiO2 can absorb light in the visible region.[147] This propertywas used for the aerobic oxidation of amines in atmospher-ic air on an anatase surface of TiO2.

[147]

The reaction mechanism for TiO2-based photocatalysiswas explained as being similar to a semiconductor-type phe-nomenon. This mechanism is different from the ODHmechanism that was reported for transition-metal catalystsas discussed above. In this case, the formation of iminesproceeds through oxygenation of amines to give aldehydesas intermediates, rather than the primary imine RC=NHwhich is generated through oxidation and dehydrogenationof the amines (Scheme 13).

Figure 1. ACHTUNGTRENNUNG[Co2+ ACHTUNGTRENNUNG(salen)] ligand structures.

Scheme 11. Transfer hydrogenation from amines to alkynes to produce imines and alkenes.

Scheme 12. Photocatalytic oxidation of amines to give imines catalyzedby TiO2-supported Pt.

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Under photochemical conditions, an electron is liberatedfrom the TiO2 surface and creates a hole and a liberatedelectron localized within the TiO2 framework (Scheme 14).The created hole initiates the activation of the amine sub-strate and generates an aminal radical. The radical thencombines with dioxygen to form a peroxy intermediate,which subsequently dissociates to give an aldehyde.

Apart from TiO2, other photocatalytic systems have alsobeen reported. Nb2O5 does not absorb visible light directly;however it binds with amine substrates to form a complexthat absorbs at long wavelengths in the visible region.Therefore Nb2O5 is catalytically active with high selectivityunder visible light (l>390).[148] The reaction mechanism forthe Nb2O5 photocatalytic system is different from that ofTiO2. Amine oxidation over Nb2O5 with visible light maybe attributed to direct electron transfer from a 2p orbital ofthe amine nitrogen atom that is bound to Nb2O5. Variousamines, including primary, secondary, and cyclic amines,were converted into the corresponding imines in excellentyields by using Nb2O5 under atmospheric pressure and atroom temperature.

Mesoporous graphite carbon nitride (mpg-C3N4) asa stable, reusable, heterogeneous photocatalytic system thatis free from metals and organic oxidizing agents for the oxi-dation of amines was reported in 2011.[149] This system has

a wide substrate scope for various benzylamines, includingheterocyclic and cyclic amines (Scheme 15). Moreover, thesystem was extended for cascade one-pot synthesis of other

heterocycles, such as benzoxazoles, benzimidazoles, andbenzothiazoles, in high yields. The reaction is initiated byelectron (e�) and hole (h+) pairs that are photogeneratedby irradiation of mpg-C3N4 with visible light (Scheme 16).

The liberated electron reduces molecular oxygen to pro-duce *O2

�, which was confirmed by ESR analysis. In paral-lel, benzylamine also loses an electron to form amine spe-cies PhCH2NH*+ . The collision between PhCH2NH*+ and*O2

� species leads to PhCH= NH, which combines with an-other molecule of benzylamine to give an imine. However,high oxygen pressure (0.5 MPa) and trifluorotoluene as thesolvent are necessary to obtain good yields of products.[149]

Recently Son and co-workers developed phenothiazine-based organic dyes for visible-light-driven, photocatalyticorganic transformations.[150] The oxidative coupling of ben-zylamines to give imines with a 3,7,-disubstituted pheno-thiazine catalyst (0.5 mol %) under visible light irradiationfrom a blue LED in acetonitrile under ambient conditions(1 atm. air, room temperature) was reported.[150]

Scheme 13. Oxidation of amines to give imines on a TiO2 surface undervisible-light (vis) irradiation.

Scheme 14. Proposed mechanism for the oxidation of amines to giveimines on a TiO2 surface under visible-light irradiation.[147]

Scheme 15. Oxidation of various amines to give imines photocatalyzedby visible light with carbon nitride. Numbers in parentheses indicateyield of crude product as determined by 1H NMR spectroscopy.

Scheme 16. Proposed mechanism for the coupling of amines to giveimines photocatalyzed by visible light with carbon nitride.[149]

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Metal organic frameworks (MOFs) are crystalline materi-als that consist of metal ions and organic molecules that arejoined together to form one, two, or three dimensional net-works and are well known for catalysis. N-Hydroxyphthali-mide (NHPI) incorporated into the intracrystalline space ofiron-based MOF NHPI/FeACHTUNGTRENNUNG(BTC) (BTC =1,3,5-benzenetri-carboxylate) is a good catalytic system for imine synthesisfrom various primary and secondary amines under neatconditions.[151] The [NHPI/Fe ACHTUNGTRENNUNG(BTC)] catalyst is heterogene-ous in nature and can be recovered and reused. Lin and co-workers studied the MOF for applications in solar energyharvesting and subsequently for organic photocatalysis.[152]

Singlet oxygen (1O2) is generated through excitation ofmolecular oxygen usually with the help of photosensitizer.Singlet oxygen is highly reactive and, hence, readily reactswith most of molecules because it has the same quantumstate as most of other molecules. A variety of secondarybenzylic amines were oxidized to give imines by singletoxygen generated from oxygen and meso-tetraphenylpor-phyrin photosensitizer H2TPP.[153] The imines were formedin situ and treated with isocyanides and carboxylic acids inan Ugi-type reaction to synthesize C1- and N-functionalizedamines (Scheme 17). Berlicka and Kçnig also studied pho-

tocatalytic oxidation of amines to give imines by using sin-glet oxygen and a 2,7,12,17-tetrapropylporphycene(H2TPrPc) photocatalyst along with blue light-emittingdiodes (LEDs).[154] Photooxidation of benzylamine underphotoirradiation in the presence of 9-mesityl-10-methylacri-dium perchlorate ((Acr+–Mes)ClO4

�) with molecularoxygen affords the corresponding imine.[155] RecentlySadow and co-workers reported oxidant-free conversationof amines into imines under photocatalytic conditions.[156]

The merits associated with photocatalytic aerobic oxidationof organic molecules are efficient conversation and a sus-tainable nature, as well as reusability and durability of thecatalyst.

3.3. Electrocatalysis (Biomimetic Approach)

Many efforts have been made to mimic the biological activ-ities of amine dehydrogenases/oxidases for the oxidation ofamines. In biological systems, the amine is not dehydrogen-ated but reacts with a carbonyl group of a quinone cofactor,which leads to an imine intermediate. Upon hydrolysis, theimine is converted into the corresponding aldehyde and

aminophenol products. The aminophenol is further oxidizedto regenerate the staring quinone co-factor with the elimi-nation of ammonia and the cycle continues. In syntheticchemistry, a similar path to the biological cycle may lead toan aldehyde, which is not suitable for mimicking imine syn-thesis. However, in the absence of water an imine inter-mediate can undergo transamination, which results in thedesired imine product instead of an aldehyde. Consequent-ly, biomimetic approaches which aim to mimic the modelsof amine dehydrogenases/oxidases enzymes for oxidation ofamines have been widely studied.[157–161] Several syntheticmodels of naturally occurring quinones were developed forthe oxidation of amines to give imines under metal-freeconditions. In the elegant catalytic system reported byLargeron and Fleury, 3,4-iminoquinone acts as a catalystfor autorecycling oxidation of benzylamine through thetransamination process of amine oxidase cofactors(Scheme 18).[162] The 3,4-iminoquinone was electrogenerat-ed from its starting precursor 3,4-aminophenol by anodiccontrolled-potential electrolysis at a platinum electrode indeuterated methanol. As alkylimines are unstable, they areconverted into the corresponding 2,4-dinitrophenylhydra-zone derivatives by using 2,4-dinitrophenylhydrazine duringthe work up and isolation process.

Later, the same group extended the scope of their studyon the biomimetic electrocatalytic system to the oxidationof amines.[163–166] The above electrocatalytic method is effi-cient for the oxidation of unactivated primary aliphaticamines to give imines, which is difficult to achieve by othersynthetic methods, particularly in the absence of a metal.However, these electrocatalytic systems are poorly selectivewith a-branched primary amines, and secondary amines didnot react. Okimoto et al. also reported electrochemical oxi-

Scheme 18. Mechanism of catalytic oxidation of primary aliphaticamines mediated by electrogenerated 3,4-iminoquinone model cofactor1ox.

Scheme 17. Synthesis of functionalized amines by photocatalytic oxida-tion.

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dation of benzylic amines to give imines by using a catalyticamount of KI in methanol.[167] It was suggested that iodideions also play the catalytic role of electron carrier, thusiodine acts as an electrocatalyst. Unlike iminoquinone,iodide ions as electrocatalysts failed to facilitate oxidationof alkyl amines effectively.

3.4. Organocatalysis

Recently an azobisisobytyronitrile (AIBN)-catalyzed(7 mol%) oxidative coupling of primary amines to giveimines with oxygen (1 bar) as the oxidant in benzene at80 8C was reported.[168] Organic compounds that are capableof reversible redox functions may be used as organocata-lysts in oxidation reactions. Wendlandt and Stahl reportedthe biomimetic aerobic oxidation of primary and secondaryamines with a quinone species as an organocatalyst andoxygen as the oxidant in acetonitrile at room tempera-ture.[169] Nitta and co-workers extensively studied the syn-thesis, properties, and redox ability of organocatalysts.[170–172]

Conducting polymers, such as polyanilines, have the abilityto interconvert into various oxidation states based on theirconjugate structure, which makes it variable redoxsystem.[173] Hirao et al. reported that p-conjugated polyani-lines serve as synthetic metal catalysts with reversible redoxproperties in the presence of oxygen to induce dehydrogen-ative oxidation of benzylamines and give the correspondingimines.[174–176] It is known that doped polyaniline emeraldine(PANI-ES) synthesized by a self-stabilized dispersionmethod has a nanoporous structure. This nanoporous conju-gated polymer with a high surface area was effectively usedfor the dehydrogenation of amines in the presence or ab-sence of oxygen.[177]

The oxidation of amines to give imines can be achievedby Swern oxidation[178] and with activated DMSO.[179,180]

However, the recovery and reuse of DMSO has not beenaccomplished. Therefore, modification of the DMSO cata-lytic system with polymer supports is beneficial. Polymer-supported sulphoxide (PSS)[181] and polymer-supported per-ruthenate (PPP) are reusable and recyclable catalysts forthis transformation.[182] The process was also extended forthe synthesis of pyrrole [2, 1-c]ACHTUNGTRENNUNG[1,4]benzodiazepine antibiot-ics by the oxidation of a cyclic secondary amine with cata-lytic amounts of tetra-n-propylammonium perruthenate(TPAP) and N-methylmorpholine N-oxide (NMO) as a co-oxidants.[183] Nicolaou et al. developed a new reagent, 2-io-doxybenzoic acid, for oxidations of secondary amines.[184,185]

3.5. Miscellaneous Catalysts

Selenium and its complexes[186–188] were reported for oxida-tion of amines to give imines. A variety of other oxidants,such as hypervalent iodine,[189] Fr�my’s salt,[190] arylsulphon-yl peroxide,[191] N-tert-butylphenylsulfinimidoyl chloride,[192]

sulfurane,[193] and di-tert-butyliminoxyl[194] are also availablefor the oxidation of amines to give imines.[195]

A recent development in aerobic oxidation of amines togive imines involves the use of graphite oxide as catalyst.[196]

The efficiency of the reaction is attributed to the high sur-face area of the catalyst and the reaction was performed at100 8C without any co-solvent. Because graphite oxide isthermally and mechanically stable, it was reused five times.A notable improvement in synthesizing imines from amineswas the use of “on water” reactions.[197] By heating a suspen-sion of an amine and water to reflux under one atmosphereof oxygen pressure and without any additives; an imineformed.[197] A possible reaction pathway for “on water” oxi-dation of amines is one in which the amino group forms hy-drogen bonds with water.[197] This hydrated amine species isfurther oxidized by atmospheric oxygen to form a peroxocomplex, which, after subsequent reactions, provides animine intermediate with release of H2O2 (Scheme 19). Theimine intermediate reacts with another molecule of amineto give the final imine.

4. Imine Synthesis through Oxidative Coupling ofAlcohols and Amines

The coupling of alcohols and amines in the presence of oxi-dants is also a commonly used procedure for imine synthe-sis. Alcohols are desirable starting materials because theyare readily available, inexpensive, and theoretically produceonly hydrogen or water as a byproduct. The selectivity ofthe reaction can be controlled with the catalyst. Many stud-ies have described transient generation of imine intermedi-ates in situ, which are rapidly hydrogenated to give secon-dary amines; however, this section is focused on the con-trolled and selective synthesis of the imine product.

The direct alkylation of amines with alcohols has beenknown since 1909, when Sabatier reported the N-alkylationof amines with alcohols to form secondary amines as finalproducts.[198] In 2001, Blackburn and Taylor reported iminesynthesis through stepwise formation of imines from alco-hols and amines with MnO2 as the oxidant.[199] The oxidantand reductant used in this procedure were then removed byfiltration and the desired products were isolated by simpleevaporation of the solvent. However, the use of largeexcess of MnO2 (10 equiv. with respect to the alcohol sub-strate) and inefficiency of the oxidation with unactivated al-cohols are shortcomings of the method.[199] Another manga-nese-catalyzed process that produces imine directly fromamines and alcohols with manganese octahedral molecularsieves was also reported.[200]

Scheme 19. Possible reaction mechanism for water-mediated oxidationof amines.[197]

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Recently, new dehydrogenative reactions have been de-veloped for the synthesis of imines through the coupling ofalcohols and amines, in which hydrogen gas is liberatedwithout the use of stoichiometric additives (Scheme 20).

For example, reactions catalyzed by ruthenium and iridiumcomplexes proceed through imine intermediates.[201, 202] In2010, Milstein and co-workers reported a reaction with a ho-mogenous dearomatized 2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine (PNN) pincer-type rutheni-um complex in an argon atmosphere that stops at the iminestage without converting the imine into a secondaryamine.[203] Similarly, osmium pincer complexes have alsobeen used for this transformation under anaerobic condi-tions.[204] Pincer ligands have made a tremendous impact onhomogenous catalysis. Especially, methods catalyzed bymetal pincer complexes deserve extra attention from re-searchers because of their ability to efficiently oxidize non-activated aliphatic and cyclic alcohols, which is challengingtask (Table 2).[203,204]

The rigidity of the pincer–metal interaction provides highthermal stability for complexes that are capable of activat-ing inert bonds. These methods produce minimum wasteand are, therefore, considered more environmentallybenign protocols.[203, 204] However, these processes can beimproved by replacing the organic solvent and lowering thetemperature. Impregnated ruthenium on magnetite[205] andsupported ruthenium hydroxide[206] catalysts were intro-duced recently. In the first report, the use of a stoichiomet-ric amount of base was the drawback, whereas the lattermethod was limited to activated alcohols.[206] A convenientsynthesis of a,b-unsaturated imines from allylic alcoholsand amines catalyzed by ruthenium is the most recent de-velopment in this field.[207]

Cao and co-workers reported the use of gold nanoparti-cles supported on hydroxyapatite (Au/HAP) for the synthe-sis of imines through coupling of alcohols and aminesunder solvent-free conditions at 60 8C.[208] The catalyst isheterogeneous and reusable. Later, gold nanoparticles sup-ported on TiO2 with oxygen as the oxidant were investigat-ed and the reactions performed at room temperature.[209]

This type of reaction catalyzed by Pd/AlO(OH) in anoxygen atmosphere yields imines, whereas in a hydrogen at-mosphere it results in secondary amines.[210,211] The latestimprovement, which involves Pd/DNA in water at 50 8C,needs more attention, particularly for a mechanisticstudy.[212]

Scheme 20. Dehydrogenative synthesis of imines.

Table 2. Selective examples of imine synthesis from unactivated alcohols and amines with pincer complexes.

R1 R2 Product Yield [%] Reference

58[a] [203]

86[a] [203]

94[b] [204]

65[a] [203]

57[a] [203]

37[b] [204]

30[b] [204]

20[c] [203]

55[b] [204]

65[b] [204]

[a] Yield of isolated product. [b] Yield based on 1H NMR spectroscopy. [c] Yield based on GC analysis.

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The coupling of amines with alcohols or deaminativeself-coupling of primary amines have been successfully ach-ieved by means of a heterogeneous Pt–Sn bimetallic/g-Al2O3 (0.5 wt % Pt, Pt/Sn molar ratio =1:3) catalyst.[213] Inthe absence of oxygen, imines are hydrogenated to giveamines through a borrowing hydrogen strategy.[213] TiO2

coated onto platinum nanoparticles promotes one-pot syn-thesis of imines from amines and alcohols under UV irradi-ation (l>300) at room temperature.[214] An iridium-thioeth-er-dithiolate complex [Cp*Ir (h3-tpdt)] (Cp*= h5-C5Me5,tpdt= SACHTUNGTRENNUNG(CH2CH2S

�)2) was used for imine formation fromactivated as well as unactivated aliphatic alcohols, but onlymoderate yields of the corresponding imines were obtained,even at 110 8C and with prolonged reaction times (45 h).[215]

Therefore, this method is no more efficient than those cata-lyzed by ruthenium and iridium pincer complexes.[203, 204,215]

It is necessary to explore potential catalysis with commonmetals, such as copper and iron. The homogenous coppercatalyst reported by Kang and Zhang[216] and an impregnat-ed copper catalyst are such examples for imine synthesis.[217]

A noteworthy example is the synthesis of imines from alco-hols and amines at room temperature catalyzed by copperiodide (1 mol %).[218]

The best way to achieve efficient tandem transformationsis with simple laboratorychemicals, for example,alkali bases as catalysts andair/oxygen as an oxidant. Inview of this, we have devel-oped a strategy for iminesynthesis through aerobic ox-idative coupling of aminesand alcohols catalyzed bysodium hydroxide in an airatmosphere without any co-solvent or transitionmetal.[31] Extensive screeningof various conditions showedthat NaOH (10 mol %) at100 8C in air are the opti-mized reaction conditionsfor this transformation(Scheme 21). Under theseconditions, a range of struc-turally diverse primary ben-zylic alcohols and amineswere examined. NaOH ishighly active for catalyzingthe transformation of benzyl-ic and heteroatom-contain-ing alcohols and amines intoimines (Scheme 22).

Based on experimentaldata and literature reports,a probable mechanism wasproposed for this base-cata-lyzed imine synthesis

(Scheme 23). In transition-metal-catalyzed oxidative cou-pling of alcohols and amines, a likely mechanism is b-hy-dride elimination from the alcohol by the transition metalto generate a metal hydride intermediate, which subse-quently provides aldehyde. The generation of metal hy-drides by using simple alkali bases is rare. Moreover, thereaction of benzyl alcohol in the absence of amines doesnot lead to aldehydes (Scheme 24). Therefore, it was pro-posed that activation of the alcohol by NaOH in the pres-ence of an amine and oxygen likely results in the genera-tion of an aldehyde as an intermediate (Scheme 23).[31] Thealdehyde then reacts with the amine to give the imine.

This method has a wide scope for various benzyl alcoholsand amines; however, it has some limitations for aliphaticalcohols. Tang and co-workers obtained similar results forimine synthesis by using KOH as a reagent.[219] In contrastto our conditions (10 mol % NaOH as the catalyst and no

Scheme 21. NaOH-catalyzed aerobic oxidative coupling of amines andalcohols.

Scheme 22. Scope of imine synthesis from alcohols and amines. Reaction conditions: alcohol (6 mmol), aniline(2 mmol), 100 8C, open to air. Numbers in parentheses refer to yield based on GC area %.

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co-solvent)[31] these reactions were performed with tolueneas the solvent and a stoichiometric amount of KOH as a re-agent.[219]

5. Imine Synthesis Through Hydroamination ofAlkynes with Amines

The direct addition of amines to alkynes is a facile, effi-cient, and atom economical route for synthesizing aldi-mines/ketimines.[220–224] Addition of amines across terminalalkynes (when R2 = H) or internal alkynes (when R2 =aryl,alkyl etc.) takes place in Markownikov and/or anti-Mar-kownikov fashion, and the former gives ketimines whilelatter gives aldimes/ketimines as products (Scheme 25). Incase of unsymmetrical terminal alkynes, Markownikov ad-dition is predominant.

In early 1939, Loritsch and Vogt used mercuric oxide andboron trifluoride in stoichiometric amounts for the hydroa-mination of alkynes to give ketimines.[225] Since then,a number of homogenous and heterogeneous metal-basedcatalysts, such as titanium,[226–229] gold,[230, 231] copper,[232]

silver,[233] ruthenium,[234, 235] palladium,[236] zinc,[237] rhodi-um,[238,239] tantalum,[240] zirconium,[241,242] mercury,[243] thalli-um[244] lanthanides,[245] and actinides,[246] have been used to

catalyze intermolecular hydroamination of alkynes withamines to provide Markownikov addition products. Anti-Markownikov addition of amines to alkynes has also beenfrequently reported and generally leads to aldimines asproducts.[247–251] The hydroamination of alkynes is not anideal pathway for imine synthesis as it is associated with thesome drawbacks. For example, when unsymmetrical alkynesare used as substrates, regioisomers are obtained. Also, it ischallenging to achieve hydroamination reactions undermild conditions without use of precious-metal-based cata-lysts.

6. Miscellaneous Imine Synthesis

Various methods which differ from the above mentionedmethods have been studied for imine synthesis(Scheme 26). These methods include reductive imination ofnitro compounds,[252,253] decarboxylative amine coupling,[254]

addition of organometallic reagents to nitriles[255, 256] and N-silylate

d-/N-alkyl-/N-arylformamides,[257] arylation of nitriles,[258]

coupling of aldimines with boronates,[259] addition of arenesor boronic acids to nitriles,[260–262] coupling of aryl halideswith isonitriles and organometallic reagents,[263] reduction ofsecondary amides,[264] coupling of aldehydes with alkyl bro-mides and ammonia,[265] coupling of gem-dibromomethylar-yl compounds and primary amines,[266] addition of isocya-

Scheme 23. Probable mechanism for NaOH-catalyzed coupling ofamines and alcohols.

Scheme 24. Deduction of the mechanism of NaOH-catalyzed coupling ofamines and alcohols.

Scheme 25. Hydroamination of alkynes to aldimines/ketimines.Scheme 26. Various routes for imine synthesis. BBN =9-borabicyclo-ACHTUNGTRENNUNG[3.3.1]nonane.

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nides to electron-rich arenes,[267, 268] and coupling of vinylbromide with amines.[269]

The oxidative imination of toluenes through C�H activa-tion is the latest development in imine synthesis(Scheme 27).[270] The reaction is catalyzed by a heterogene-ous and reusable Au/Pd bimetallic catalyst. It is the first ex-ample of its kind for imine synthesis through primary C�Hactivation of toluenes and its applications extend to hetero-cycle synthesis. In the near future, toluenes or any other un-activated substrates that are chemical equivalents of aminesand aldehydes/ketones could be activated to form imineswithout heavy, precious-metal catalysts under simple andmild conditions. Such findings or methods will deserve truerecognition from the scientific community.

7. Summary and Outlook

Research in the field of imine synthesis has always beenand remains one of the major and important topics in or-ganic synthesis because of their diverse applications. This

Focus Review describes howthe field of imine chemistryhas developed since its in-ception by Hugo Schiff upuntil today. Nowadays, manyefficient methods for thesynthesis of imines are scat-tered throughout the litera-ture. The direct synthesis ofimines through oxidativecondensation of amines aswell as through oxidativecoupling of amines and alco-hols without any metal cata-lysts or by using simple cata-lysts, such as copper, undermild conditions providesa broad scope. As describedabove, pincer ligands havemade tremendous impact inhomogenous catalysis be-cause of their oxidation reac-tions with non-activated ali-phatic and cyclic alcohols.These types of reactionsremain challenging.

The report that describesoxidative imination of tol-uenes by using a palladiumcatalyst certainly intensifiesour interest in activatingother unactivated chemicalequivalents for imine synthe-sis. To date, most of the reac-tions were carried out ata temperature between 60–

110 8C in organic solvents and have product selectivityissues. In the future, methods that are energy efficient (andpossibly proceed at room temperature), use readily avail-able reagents and catalysts, avoid organic solvents, and ach-ieve high conversion as well as selectivity may lead to idealconditions for imine synthesis. The systematic experimentaland theoretical study of mechanisms will help to achievethis goal. It is our hope that this review will provide vitalinformation about the various methods and reagents avail-able for imine synthesis to date, which will be useful toa wider scientific community.

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Scheme 27. Oxidative imination of toluene.[270] Yields in a) are based on GC area %; Yield in b) are yields ofisolated products.

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Received: January 16, 2013Revised: February 15, 2013

Published online: && &&, 0000

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FOCUS REVIEW

Imine Synthesis

Rajendra D. Patil,Subbarayappa Adimurthy* &&&&—&&&&

Catalytic Methods for Imine Synthesis

Know what imine? Methods used forimine synthesis that involve metal cat-alysts, including Ru, Au, V, Cu, Mn,Co, and Pd, as well as photocatalysis,electrocatalysis, organocatalysis, andother techniques are discussed. Specialattention is paid to the condensationof carbonyl compounds/alcohols withamines, direct oxidation of amines togive imines, and copper-catalyzedimine synthesis, as copper offers moresustainable approaches to catalysis.

Asian J. Org. Chem. 2013, 00, 0 – 0 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim20&&

�� These are not the final page numbers!

www.AsianJOC.org Rajendra D. Patil and Subbarayappa Adimurthy