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51, 2495

Catalytic synthesis of amides via aldoximesrearrangement

Pascale Crochet* and Victorio Cadierno*

Amide bond formation reactions are among the most important transformations in organic chemistry

because of the widespread occurrence of amides in pharmaceuticals, natural products and biologically

active compounds. The Beckmann rearrangement is a well-known method to generate secondary amides

from ketoximes. However, under the acidic conditions commonly employed, aldoximes RHCQNOH rarely

rearrange into the corresponding primary amides RC(QO)NH2. In recent years, it was demonstrated that this

atom-economical transformation can be carried out efficiently and selectively with the help of metal

catalysts. Several homogeneous and heterogenous systems have been described. In addition, protocols

offering the option to generate the aldoximes in situ from the corresponding aldehydes and hydroxylamine,

or even from alcohols, have also been developed, as well as a series of tandem processes allowing the

access to N-substituted amide products. In this Feature article a comprehensive overview of the advances

achieved in this particular research area is presented.

Introduction

Amides are one of the most important functional groups inorganic and biological chemistry. The amide functionalityis widely present in pharmaceuticals, drug candidates and

natural products, as well as in a large number of industrialmaterials including polymers, detergents and lubricants.1 Themost popular and general methods for the generation of amidesinvolve the reaction of activated carboxylic acid derivatives, suchas chlorides, anhydrides or esters, with amines or, alternatively,the direct union of the carboxylic acids with amines assisted bystoichiometric amounts of coupling reagents, such as carbodi-imides or 1H-benzotriazole derivatives.1,2 However, these classicalapproaches are low in atom efficiency and generate large amountsof waste products, making their environmental profile unfavour-able. As a result of this, the Pharmaceutical Roundtable, a forum

Laboratorio de Compuestos Organometalicos y Catalisis (Unidad Asociada al CSIC),

Centro de Innovacion en Quımica Avanzada (ORFEO-CINQA), Departamento de

Quımica Organica e Inorganica, Instituto Universitario de Quımica Organometalica

‘‘Enrique Moles’’, Facultad de Quımica, Universidad de Oviedo, Julian Claverıa 8,

33006 Oviedo, Spain. E-mail: [email protected], [email protected];

Fax: +34 985103446; Tel: +34 985103453

Pascale Crochet

Pascale Crochet studied chemistryat the University of Rennes I(France) and obtained her PhD in1996 under the supervision of Prof.P. H. Dixneuf and B. Demerseman.After a two-year post-doctoral stayin the research group of Prof. M. A.Esteruelas (University of Zaragoza,Spain) and one year as AssistantProfessor at the ‘‘National HighSchool of Physics and Chemistry’’of Bordeaux (France), she moved in1999 to the University of Oviedowhere she is currently Associate

Professor of Inorganic Chemistry. Her research interests deal withthe design and synthetic applications of organometallic complexes,with a particular focus on ruthenium compounds.

Victorio Cadierno

Victorio Cadierno studied chemistryat the University of Oviedo andobtained his PhD degree in 1996working under the supervision ofProf. J. Gimeno. He then joinedthe group of Prof. J. P. Majoral atthe LCC-CNRS (Toulouse, France)for a two-year postdoctoral stay.Thereafter, he returned to theUniversity of Oviedo where he iscurrently Associate Professor ofInorganic Chemistry. In 2002 hewas awarded with the SpanishRoyal Society of Chemistry (RSEQ)

Young Investigator Award. His research interests cover the chemistry oforganometallic complexes and their catalytic applications, a field inwhich he has co-authored around 150 publications.

Received 1st November 2014,Accepted 5th December 2014

DOI: 10.1039/c4cc08684h

www.rsc.org/chemcomm

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created by the ACS Green Chemistry Institute and members ofleading pharmaceutical corporations worldwide, identified‘‘amide formation avoiding poor atom economy reagents’’ as oneof the top challenges in organic chemistry.3 New efficient andsustainable synthetic routes to access this important class ofcompounds are therefore needed.4

In the search of more atom-economical and cost-effectiveprotocols, metal-catalyzed transformations have emerged in thelast few years as attractive alternatives, offering the possibility todevelop previously unavailable routes starting from substratesother than carboxylic acids and their derivatives.5 Thus, with thehelp of transition metals, a plethora of functional groups, suchas nitriles, aldehydes, ketones, oximes, primary alcohols oramines, can be now conveniently employed as starting materialsfor the construction of the amide bond. We must stress inthis point that, concerning the use of oximes, the so-calledBeckmann rearrangement6 has been for a long time a commonlyemployed method to generate amides.7,8 This classical reactionhas found countless applications in synthetic organic chemistryand it has been industrially valorized, for example, in the large-scale production of the Nylon 6 precursor e-caprolactam fromcyclohexanone oxime (Scheme 1).9

The Beckmann rearrangement of oximes involves the migrationof the group anti to the hydroxyl unit from the carbon to thenitrogen atom, a process that is generally catalyzed by Brønsted orLewis acids (A+) under severe temperature conditions (Scheme 2).7,10

Aryl and alkyl groups readily migrate, making the process particu-larly useful for the transformation of ketoximes into N-substitutedamides. In contrast, aldoximes (RHCQNOH) rarely rearrangeinto the corresponding primary amides (RC(QO)NH2) becauseof the strong tendency of the H atom to act as a leaving group.

Indeed, under classical Beckmann conditions, the reactions ofaldoximes lead in general to nitriles as the main products,representing one of the major limitations of this textbook trans-formation.7,8 Accordingly, the synthesis of primary amides fromaldoximes has been long regarded as a very difficult transforma-tion and, although there have been reported some examples usingstoichiometric amounts of highly reactive reagents,11 the develop-ment of catalytic procedures has represented a major challengefor organic chemists until very recently.

The use of metal catalysts has allowed overcoming thislimitation and a number of efficient, general and selectivecatalytic systems for this transformation is currently known.In addition, protocols for the direct conversion of aldehydes oralcohols into primary amides, via in situ generation of analdoxime intermediate, have also appeared, as well as syntheticapproaches to secondary or tertiary amides through tandemprocesses. The aim of the present Feature article is to provide acomprehensive overview of the developments reached in thisparticular research area. Literature published up to November2014 is covered.

Mechanistic considerations

Although the metal-catalyzed rearrangements of aldoximes intoprimary amides seem to be very similar to the classical Beckmannreactions, their mechanisms differ notably. The most commonlyinvoked pathway for the rearrangement of aldoximes involves: (i)the initial dehydration of the substrate, and (ii) the subsequentrehydration of the resulting nitrile by means of the water moleculereleased in the first step (Type 1, Scheme 3).12 Usually, it isassumed that both processes are promoted by the metal.

In full agreement with this mechanistic proposal, formationof nitriles is usually observed in the course of the reaction.12,13

Moreover, the two independent processes, i.e. the dehydrationof the aldoxime and the hydration of the nitrile, have beenseparately performed with success in the presence of a wide rangeof metal complexes.14,15 In particular, several catalytic systemsdeveloped for the rearrangement of aldoximes into amides provedto be also efficient for the hydration of nitriles under similarreaction conditions,16 evidencing the feasibility of the second stepof the catalytic cycle. However, this is not always the case, andmany catalysts active in the rearrangement of aldoximes comple-tely failed to promote the formation of amides from nitriles.13,17,18

Such a discrepancy brought to propose an alternative mechanism,

Scheme 1 The Beckmann rearrangement of oximes to amides and itsapplication in the industrial production of Nylon 6.

Scheme 2 Mechanism of the Beckmann rearrangement.Scheme 3 Mechanism through the sequential release and attack of amolecule of water (Type 1).

Feature Article ChemComm


involving, once again, the initial dehydration of the startingaldoxime into the corresponding nitrile. But, unlike the previousproposal, the rehydration into the final amide is now effected by theown substrate, which acts as a water-surrogate (Type 2, Scheme 4).19

The transfer of the water molecule from the aldoxime to thenitrile is supposed to proceed in the coordination sphere of themetal, through the formation of a five-membered metallacyclicintermediate.

This reaction pathway, first suggested by Noltes20 and Chang,21

was nicely confirmed for a representative family of catalysts byWilliams and co-workers in 2011 employing isotopically labeledreagents.22 Thus, in the isomerization of 4-methylbenzaldoximeinto 4-methylbenzamide performed with [RhCl(PPh3)3], [RuH2-(CO)(PPh3)3], Pd(OAc)2, In(NO3)3, ZnCl2 or Cu(OAc)2 in thepresence of one equivalent of 18OH2, they observed in all thecases the exclusive formation of the unlabeled amide (Scheme 5,part a). This fact evidences that free water molecules are notparticipating in the rehydration of the initially formed nitrile, thusdiscarding a mechanism of Type 1.

On the other hand, when a mixture of 18O-labeled 3-phenyl-propanaldoxime and 16O-butyraldoxime was subjected to the actionof the same family of catalysts, reaction mixtures containing16O- and 18O-3-phenylpropamide and 16O- and 18O-butyramide werein all the cases generated (Scheme 5, part b).22 The scramblingof the 18O label allows us to discard mechanisms as those

depicted in Scheme 6, in which all the starting atoms of thealdoxime end up in the same amide molecule. These alternativereaction pathways, involving metal-hydroxo (A)23 or metal-oxo-hydride (B)24 intermediates, have been in some cases proposedin the literature. However, evidence of the formation of suchintermediate species is not given, and all the experimentalobservations discussed in these studies could be explainedthrough a mechanism of Type 2 (Scheme 4), which seems tobe, based on the experiments with isotopically labeled reagentsperformed by Williams and co-workers, the most general forthis catalytic transformation.25

Homogeneous metal catalysts

Although the use of metallic salts to promote the rearrange-ment of aldoximes into primary amides was reported for thefirst time in 1897,26 the process remained scarcely studied formore than a century. The drastic experimental conditionsrequired for the first catalytic systems developed (very hightemperatures and metal loadings, and long reaction times),combined with the low activity, selectivity and scope usuallyobserved,11,12a,20,26,27 made the reaction poorly attractive forsynthetic applications. However, it regained interest in the early2000s after the publication by Chang and co-workers of apractical and efficient rhodium-based protocol.12b In particular,they demonstrated that the Wilkinson’s catalyst [RhCl(PPh3)3]was able to convert in short time a series of aromatic, hetero-aromatic and aliphatic aldoximes into the desired amides ingood yield, along with only trace amounts of the correspondingnitrile intermediates (see mechanistic considerations). The reac-tions were typically completed in 2–5 hours at 150 1C in tolueneor DMF using 5 mol% of [RhCl(PPh3)3]. Lower metal loadings(0.5–1 mol%) were tolerated, albeit at the expense of the reactiontimes (8–12 h required). Since then, a wide range of catalyticsystems based on different transition metals has been described,with those of ruthenium playing a predominant role.5i

Scheme 4 Mechanism in which the aldoxime acts a water surrogate(Type 2).

Scheme 5 The experiments performed by Williams and co-workers withlabeled reagents.

Scheme 6 Alternative mechanisms proposed in the literature for thecatalytic rearrangement of aldoximes.

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Group 8 metal catalysts (Ru, Fe)

In 2007, Williams and co-workers described a general protocol forthe rearrangement of aldoximes using the dihydride rutheniumspecies [RuH2(CO)(PPh3)3] in combination with 1,2-bis(diphenyl-phosphino)ethane (dppe) and p-toluenesulfonic acid (Scheme 7).13

The reactions proceeded in excellent yields with metal loadingsas low as 0.1 mol% in toluene at 110 1C. Both additives, i.e.dppe and TsOH, turned out to be essential for achieving a highselectivity in the desired amides.

A couple of years later, Gnanamgari and Crabtree reportedan additive-free protocol based on the terpyridine-ruthenium(II)derivative cis-[RuCl2(PPh3)(terpy)].17 Using 1 mol% of this complex,in toluene at 110 1C, aldoximes featuring both syn and anticonformation could be efficiently transformed. In addition,cis-[RuCl2(PPh3)(terpy)] proved to be also suitable for the rearrange-ment of aldoximes generated in situ from the correspondingaldehydes (Scheme 8). Thus, when a 1 : 1 : 1 mixture of analdehyde, hydroxylammonium chloride and NaHCO3 was trea-ted with 1 mol% of cis-[RuCl2(PPh3)(terpy)], the correspondingprimary amide was generated in good yield through a sequentialcondensation–rearrangement process. This one-pot synthesis ofamides from aldehydes resulted to be applicable to aromatic,heteroaromatic, aliphatic and a,b-unsaturated aldehydes.

From then on, different research groups have developed othercatalytic systems involving octahedral ruthenium(II) complexescontaining polydentate N-, O- and/or S-donor ligands.28 Represen-tative examples of catalysts employed in the direct rearrangementof aldoximes to amides (complex 1) and in the one-pot two-stepsprocess from aldehydes (complexes 2–6) are shown in Fig. 1. In allthe cases, good yields were achieved after 6–24 hours of heating intoluene or acetonitrile with metal loadings of 0.5–1 mol%. Moresimple ruthenium precursors, such as [RuCl2(DMSO)4], can also beemployed to catalyze these reactions, but higher metal loadings(5 mol%) are required and the scope turned to be quite limited.23

Arene–ruthenium(II) complexes are another class of activecatalysts for these transformations. For example, the dinuclearderivative 7 (Fig. 2) was successfully applied in the preparationof primary amides from aldehydes (0.2 mol% of Ru, toluene,110 1C, aldehyde : NH2OH�HCl : NaHCO3 ratio = 1 : 1 : 1, 12 h; 55–95%yield), showing higher catalytic performances than analogousCp*–iridium(III) or Cp*–rhodium(III) dinuclear complexes.29

On the other hand, the usually high stability of arene–ruthenium(II) complexes in aqueous media30 allowed the develop-ment of greener protocols employing water as an environmentallyfriendly solvent. Thus, with the mononuclear derivative[RuCl2(Z6-C6Me6){P(NMe2)3}] (8 in Fig. 2), which contains thecommercially available and inexpensive tris(dimethylamino)-phosphine as the auxiliary ligand, the reactions proceededefficiently in water, at 100 1C and with a metal loading of5 mol%, starting from a wide variety of aldoximes. Severalfunctional groups, such as halides, hydroxy, nitro, ethers, aminoand thioethers, were tolerated.31 In addition, this methodologywas successfully applied to the preparation of the fragrances(S)-(�)-citronellamide (9), (1R)-(�)-myrtenamide (10) and(S)-(�)-perillamide (11) (Fig. 3). Kinetic studies and experimentsperformed using 18O-labeled water as the solvent evidenced thatmechanisms of Type 1 and 2 are both operative with complex 8,

Scheme 7 Rearrangement of aldoximes into primary amides promotedby the Ru(II) complex [RuH2(CO)(PPh3)3].

Scheme 8 One-pot synthesis of primary amides from aldehydes usingcomplex [RuCl2(PPh3)(terpy)].

Fig. 1 Structure of the ruthenium(II) complexes 1–6.

Fig. 2 Structure of the arene–ruthenium(II) complexes 7, 8 and 12.



albeit the latter occurred at much higher rates (see Schemes 3and 4).

The arene–ruthenium(II) complex 8 resulted to be equallysuitable for synthesizing amides from aldehydes, hydroxyl-ammonium chloride and NaHCO3 (5 mol% of Ru, 100 1C, alde-hyde : NH2OH�HCl : base ratio = 1 : 1.3 : 1.3, in water for 7 h; yieldsranging from 76 to 95%).32 More interestingly, taking advantageof the operability of [RuCl2(Z6-C6Me6){P(NMe2)3}] (8) in water, acleaner procedure, wherein hydroxylammonium chloride andsodium bicarbonate were replaced by commercial hydroxylaminesolution (50 wt% in H2O), could be developed (Scheme 9). By thisway, the generation of wastes was minimized, water being theonly by-product formed. More recently, the highly water-solublearene–ruthenium(II) complex 12 (Fig. 2), functionalized with anhydrophilic tri-cationic thiazolyl-phosphine hydrochloride salt,showed to be highly active in the synthesis of primary amidesfrom aldoximes or aldehydes in water (3 mol% of Ru, 100 1C, 7 h;yields Z78%).33

In contrast to ruthenium, iron-based compounds have beenscarcely explored in this field. The first study, reported by Gowdaand Chakraborty in 2011,34 evidenced the activity of FeCl3 inthe one-pot transformation of aldehydes into amides (5 mol%of FeCl3, aldehyde : NH2OH�HCl : Cs2CO3 ratio = 1 : 1 : 1, in waterat 100 1C for 14–30 h; yields Z83%). Interestingly, the use ofwater as the solvent resulted to be mandatory to achieve a highselectivity in the desired amides, since in anhydrous organicmedia the exclusive formation of nitriles was observed. Theaqueous protocol turned out to be applicable to a wide range offunctionalized aldehydes, either aromatic or aliphatic, and providedan easy access to the chiral compounds 13–17 (Fig. 4) featuringinteresting biological properties. Remarkably, despite the basicityof the reaction medium, epimerization at the a-position of thecarbonyl group did not occur.

When associated with an oxidant, FeCl3 was also able topromote the selective formation of primary amides startingdirectly from alcohols, through a sequential three-step process(Scheme 10).35 The best results were obtained by heating anethylenedichloride solution of the alcohol with 10 mol% of FeCl3,10 mol% of TEMPO, 2 equiv. of iodine, 1 equiv. of hydroxyl-ammonium chloride and 3 equiv. of base. Different primaryalcohols, such as benzylic, aliphatic or propargylic, could be

involved successfully in the reaction. We note that, in markedcontrast to the previous case, water was found to be detrimental,the yield of the amide product dropping dramatically when theexperiments were performed under aqueous conditions.

Group 11 metal catalysts (Cu, Au)

Like ruthenium complexes, copper compounds have been exten-sively studied in the rearrangement of aldoximes into amides.The pioneering work in the field, reported by Comstock in 1897,revealed the capacity of equimolar amounts of CuCl or CuBr topromote this process.26 More recently, Williams and co-workersexplored the activity of a variety of simple Cu(I) and Cu(II) salts,i.e. Cu(NO3)2, Cu(OAc)2, Cu2O, CuO, CuBr, Cu�SMe2, CuSO4,CuCO3, CuCl2, CuBr2 and Cu(OTf)2, disclosing the remarkableperformance of copper(II) acetate.36 Under the reaction condi-tions selected (1–2 mol% of Cu, 80 1C, toluene, 24 h), highconversions (Z79%) in the desired amides were observed,regardless of the electronic properties of the substrates. Thetransformation occurred through a mechanism of Type 2 (seemechanistic considerations), in which the initial formationof the nitrile by dehydration of the oxime appeared to be therate-determining step.22 Accordingly, the addition of 10 mol%of the corresponding nitrile to the medium resulted in a signifi-cant rate acceleration, and the reaction could be completed withina few minutes.22,37

Copper(II) acetate also showed to be effective for the directsynthesis of primary amides from a diverse family of alde-hydes,38 the best results being achieved with the reactionsperformed in aqueous hydroxylamine solutions (2 mol% of Cu,aldehyde : NH2OH(aq) ratio = 1 : 1, water, 110 1C, 48 h; 61–99% yield).

Fig. 3 Structure of citronellamide 9, myrtenamide 10 and perillamide 11.

Scheme 9 Synthesis of amides from aldehydes and an aqueous NH2OHsolution.

Fig. 4 Structure of the optically active amides 13–17.

Scheme 10 Synthesis of primary amides from primary alcohols.



Remarkably, under these conditions, the aqueous phase con-taining the catalytically active species could be separated bysimple extraction with diethyl ether at the end of the process,and reused up to 10 times without significant loss of activity.Similar transformations were also accomplished, under solvent-freeconditions, using CuSO4�5H2O (5 mol% of Cu, aldehyde : NH2OH�HCl : NaOAc ratio = 1 : 1 : 1.1, 110 1C, 2–6 h; 40–98% yield).39

In comparison with copper, gold-based catalysts have been byfar much less studied. Indeed, only two examples, reported byNolan and co-workers, have been described to date.40 Theydemonstrated that the Au(I)–NHC (NHC = N-heterocyclic carbene)complex [AuCl(IPr)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), associated with a silver(I) salt, was able to convert avariety of aldoximes into the corresponding primary amides inmoderate to good yields (5 mol% of Au, 10 mol% AgBF4, 100 1C,neat conditions, 20 h; 24–99% yields).40a The addition of the Ag(I)salt turned out to be essential to achieve high conversions andselectivities. The structurally related hydroxo gold-derivative[AuOH(IPr)] was also able to isomerize benzaldoxime intobenzamide in the presence of HBF4.40b

Other metal catalysts

As commented above, the Wilkinson’s catalyst [RhCl(PPh3)3] wasfound to efficiently promote the rearrangement of aldoximes athigh temperatures (150 1C).12b A more appealing rhodium-basedprotocol, operative at 80 1C, was further developed by Chang andco-workers replacing [RhCl(PPh3)3] by [RhCl(COD)(IMes)] (COD =1,5-cyclooctadiene; IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), and using a TsOH–H2O mixture as a co-catalyst(50–92% yield in the amides after 6 h using 1 mol% of Rh).21b

Noteworthily, addition of small quantities of the complementarynitrile (5 mol%) to the medium accelerated the process, andsignificant yield improvements were achieved with awkward sub-strates, such as electron-rich or sterically congested aldoximes.

The pentamethylcyclopentadienyl-iridium(III) derivatives[{IrCl(m-Cl)Cp*}2] (18)24 and [IrCp*(H2O)3][OTf]3 (19)18 readilyisomerize aldoximes into amides in organic and aqueousmedia, respectively (2.5 mol% of 18, toluene, 110 1C, 4–16 hor 1.5 mol% of 19, water, 110 1C, 12 h; yields Z77%). The tri-aqua complex 19 also proved to be suitable for the one-potsynthesis of amides from aldehydes.18 On the other hand,taking advantage of the ability of the dimer [{IrCl(m-Cl)Cp*}2](18) to promote transfer hydrogenation processes,41 a sequen-tial protocol to transform benzyl alcohols into benzamidescould be developed (Scheme 11).24 Thus, after a first oxidationstep of the alcohol, carried out in the presence of styrene whichacted as a hydrogen acceptor, hydroxylammonium chloride wasadded to the reaction mixture to generate the correspondingbenzamides in moderate to high yield.

More recently, a cobalt-based catalytic system, generated fromCo(OAc)2�4H2O (10 mol%) and 2-nitro-1-naphthol (20 mol%), hasshown to be suitable to promote the transposition of aldoximesinto primary amides in a MeCN : H2O mixture (80 1C, 24 h,55–88% yield).42

A wide variety of aromatic, heteroaromatic, aliphatic anda,b-unsaturated aldehydes could be converted into their amidecounterparts using 5 mol% of Pd(OAc)2 in a DMSO : water mixture(aldehyde : NH2OH�HCl : Cs2CO3 ratio = 1 : 1.2 : 1.2, 100 1C, 5–19 h;yields Z77%).43 The quantity of water employed was crucial forthe outcome of the process. Thus, aldoximes and nitriles werepredominantly obtained in dry DMSO, while good yields of thedesired amides were achieved with a DMSO : H2O ratio of 3 : 1.However, a dramatic decrease in the efficiency was observedwith a great excess of water (DMSO : H2O ratio of 1 : 1). Althoughthis behavior suggests a reaction pathway of Type 1, in whichthe water molecules act as the nucleophile (Scheme 3), themechanistic studies performed by Williams and co-workerswith the same catalyst supported indeed a reaction pathwayof Type 2 (Scheme 4).22

Low temperature protocols for the rearrangement of aldoximeswere developed employing [Pd(en)(NO3)2] (en = 1,2-ethylenediamine)in methanol or water.14e As a representative example, using10 mol% of this complex, the naphthalenediimine dialdoxime20 (mixture of syn/syn, syn/anti and anti/anti isomers; Fig. 5) wasalmost quantitatively isomerized into the correspondingdiamide 21 at 60 1C, and with complete retention of thechirality, after 16 h. By monitoring the course of the reactionby NMR spectroscopy, the authors evidenced that the aldoximeunit featuring an anti configuration underwent faster conver-sion than its syn counterpart. Unfortunately, this palladium-based methodology is restricted to non-conjugated substrates,aromatic and a,b-unsaturated aldoximes remaining unreactedunder the same experimental conditions.

More classical Lewis acids, such as InCl3, In(OTf)3, In(NO3)3,ZnCl2, Zn(NO3)2, Zn(OTf)2 or Sc(OTf)3, can also be employed forthe synthesis of primary amides starting from aldoximes oraldehydes.44,45 However, high metal loading (5–100 mol%) and/or elevated reaction temperatures (110–180 1C) are usually

Scheme 11 Synthesis of aromatic amides from benzyl alcohols throughan oxidation–condensation–rearrangement sequence.

Fig. 5 Structure of the dialdoxime 20 and the diamide 21.



required. Only indium(III) nitrate led to high yields with lowcatalyst loadings (0.4 mol%).44 Combined with choline chloride,ZnCl2 generates a deep eutectic mixture which was used as anefficient promoting medium for the preparation of primary amidesfrom aldehydes via rearrangement of in situ formed aldoximes.46

A more elaborated catalytic system active in the rearrangement ofboth aldoximes and ketoximes (22 in Fig. 6) was also described.However, it featured only a moderate reactivity.47

Application to the synthesis ofN-substituted amides

Although the rearrangement of aldoximes is in principle limitedto the synthesis of primary amides, recent efforts in combiningthis process with a further coupling reaction have led to newsynthetic methodologies for the preparation of N-substitutedamides in a one-pot manner. Thus, such products could besuccessfully obtained, through a rearrangement–transamidationsequence, by treatment of aldoximes with amines in thepresence of catalytic amounts of NiCl2�6H2O (Scheme 12).22,48

The first step is promoted by the metal, while the second oneseems to be facilitated by the aldoxime itself, probably throughhydrogen bonding activation of the intermediate primary amide.Primary and secondary amines, both aliphatic and aromatic,participated in the process. Related transformations startingdirectly from aldehydes and hydroxylamine hydrochloride werealso described employing NiCl2�6H2O (ref. 48) and CuSO4�5H2O(ref. 39) as catalysts.

More recently, a ruthenium/iridium dual-catalyst system wasreported by Li and co-workers for the preparation of N-alkylatedamides starting from aldoximes and primary alcohols (Scheme 13).49

The transformation was achieved by initial heating of the aldoximewith [{RuCl(m-Cl)(Z6-p-cymene)}2] (0.5 mol%) and [{IrCl(m-Cl)Cp*}2]

(18; 0.5 mol%), and subsequent addition of the alcohol andCs2CO3 to the medium. Remarkably, the methodology ledto the selective formation of the corresponding N-substitutedamides, the intermediate primary amides or over-alkylatedN,N-disubstituted products being not detected at the end ofthe reactions. On the other hand, although the two stepsinvolved in the process could be catalyzed by both the ruthe-nium or the iridium dimers alone, the initial rearrangementof the aldoxime was particularly favored in the presence of[{RuCl(m-Cl)(Z6-p-cymene)}2], whereas the N-alkylation of theintermediate primary amide proved to be more effective with18. Therefore, the combination of the two metals displayed ahigher catalytic performance than when they were used sepa-rately. This tandem process appeared to be general and a largevariety of aldoximes and primary alcohols could be employed,allowing the access of a wide range of secondary amides in highyields. However, we must note that, due probably to stericreasons, secondary and tertiary alcohols did not participate inthe reaction.

N-Arylated amides could also be obtained by reacting aldoximeswith aryl halides in the presence CuSO4�5H2O, N,N0-dimethyl-ethylenediamine (DMEDA) and K2CO3 (Scheme 14).50 Both therearrangement and the subsequent C–N coupling process werepromoted by copper. As observed in the tandem rearrangement–transamidation reaction depicted in Scheme 12, the aldoximealso facilitated the overall process. Consequently, better yieldswere achieved when an excess of this reagent (4 equiv.) wasemployed. Good yields of the desired N-substituted amideswere attained with aryl-iodides or -bromides, regardless of theelectronic properties of the aryl ring, but attempts to use theless reactive aryl-chlorides failed.

Fig. 6 Structure of the heterobimetallic Co(III)/Zn(II) complex 22.

Scheme 12 Synthesis of N-substituted amides from aldoximes andamines.

Scheme 13 Synthesis of secondary amides from aldoximes and primaryalcohols.

Scheme 14 Synthesis of secondary amides from aldoximes and arylhalides.



Heterogeneous metal catalysts

Although much less studied than the homogeneous systems,heterogeneous catalysts have recently emerged as attractive alter-natives to promote the rearrangement of aldoximes into primaryamides. The first example, reported by Mizuno and co-workers in2007, was based on rhodium hydroxide supported onto alumina,i.e. Rh(OH)x/Al2O3.51 Employing catalytic amounts of this system(4 mol% of Rh) the conversion of a wide range of aromatic andaliphatic aldoximes could be achieved in water at 160 1C (isolatedyields Z63%). Although the selectivity of the process towardsthe desired primary amides was in general very high, theformation of small amounts of the corresponding nitriles andaldehydes, resulting, respectively, from the dehydration and thehydrolysis of the starting material, was also observed. UnlikeRh(OH)x/Al2O3, under the same experimental conditions, Al2O3

or Rh2O3 on their own did not generate the expected amides.Noteworthily, the reactions performed with Rh(OH)x/Al2O3 inorganic solvents led to nitriles as the major products. Thisobservation, along with the fact that Rh(OH)x/Al2O3 also pro-motes separately the catalytic hydration of nitriles, suggests thatthis heterogeneous system could operate through a sequentialdehydration–hydration mechanism of Type 1 (Scheme 3). Onthe other hand, the Rh(OH)x/Al2O3 system was equally operativefor the rearrangement of aldoximes generated in situ from thecorresponding aldehydes and (NH2OH)2�H2SO4.51 Furthermore,it could be recycled, at least once, without a significant loss ofactivity or selectivity.

Recently, rhodium hydroxide supported onto a titanosilicate(Ti-MWW) was involved in the synthesis of primary amidesfrom aldehydes and aqueous solutions of ammonia and hydro-gen peroxide (Scheme 15).52 The process proceeds through theinitial titanium-catalyzed ammoximation of the aldehyde, asthe consequence of the in situ oxidation of NH3 into NH2OHand further condensation. Subsequent rearrangement of theresulting aldoximes, promoted by rhodium, led to the corre-sponding amides in high yields. The bifunctional Rh/Ti catalystcould be recovered by filtration, regenerated by calcination at200 1C, and reused four times. However, the amide selectivitygradually decreased with the reaction-regeneration cycles. This wasattributed to a partial leaching of Rh(OH)x. Similarly, a rhodiumhydroxide catalyst impregnated on a core–shell material, withthe titanium-containing zeolite TS-1 as the core and fibrous

silica KCC-1 as the shell (Rh(OH)x/TS-1@KCC-1), was preparedand tested with success in the ammoximation–rearrangementprocess.53 The high hydrothermal and mechanical stability ofRh(OH)x/TS-1@KCC-1 limited the rhodium leaching, leading toa superior recyclability in comparison with Rh(OH)x/Ti-MWW(loss of selectivity only after the fifth reuse). Finally, we mustalso mention that primary amides have also been generatedas side-products ( yields r38%) in different polyoxometalate-catalyzed ammoximation reactions of aromatic and heteroaro-matic aldehydes.54

A copper(0) mesoporous silica material, obtained by impreg-nation and reduction of Cu(NO3)2�3H2O on SBA-15, was satis-factorily employed to convert benzaldoxime into benzamideunder solvent-free conditions.55 Addition of molecular sievesto the medium barely affected the efficiency, evidencing thatwater did not play a key role in the process and suggesting thataldoxime, rather than H2O, acted as the real hydrating agent(see the mechanism depicted in Scheme 4). The catalytic systemcould be reused for up to four consecutive runs, albeit with agradual decrease in benzamide selectivity.

On the other hand, an organic–inorganic SBA-15 hybrid featuringethylenediamine groups incorporated within the pores of thesilica was used to support Cu(OAc)2.56 The resulting SBA-15/En-Cumaterial proved to be suitable for the one-pot synthesis of primaryamides from aldehydes and NH2OH�HCl in the presence of abase. The procedure was operative under mild temperature con-ditions (80 1C), albeit long reaction times were required (2–3 days).The high stability of SBA-15/En-Cu allowed its recycling up to14 times without loss of activity and selectivity.

A polyacrylamide grafted polystyrene resin decorated withCu(II)-complexes,57 magnetite nanoparticles coated with rutheniumhydroxide via SePh layers,58 and zinc oxide59 have also beenused to promote the synthesis of primary amides from alde-hydes. In addition, CuO and CuO/ZnO supported on activatedcarbon also provided competent reusable (up to 4 times)heterogeneous catalysts for the rearrangement of aldoximesin toluene at 100 1C.36

Other catalytic systems

Although in a very limited number, transition metal-free protocolsfor the direct conversion of aldehydes to primary amides viaaldoxime rearrangement have also been described. In this context,Chill and Mebane found in 2009 that treatment of aldehydeswith hydroxylamine hydrochloride in DMSO at 100 1C results inthe clean formation of the corresponding nitriles through thedehydration of the in situ generated aldoximes.60 Based on thisreaction, they could develop a protocol for the one-pot conver-sion of aldehydes to primary amides in which the nitrileintermediates are selectively hydrated by the action of H2O2/NaOH.61 Aliphatic, aromatic and a,b-unsaturated aldehydeswere tolerated and the resulting amide products produced ingood yields (67–95%) and purity (495%). Selective conversionof aromatic aldehydes to amides with NH2OH�HCl was alsoachieved using catalytic amounts of a bioglycerol-based carbon

Scheme 15 Synthesis of amides through an ammoximation–rearrangementsequence.



in acetonitrile at 60 1C,62 or silica-chloride under MW irradiation(Scheme 16).62 In the latter case, optimal results were obtained at100 W, the use of a higher MW power (300 W) resulting inthe dehydration of the formed amides to give nitriles.63,64 Therecyclability of both heterogeneous catalysts (3 or 6 times,respectively) was also demonstrated.

Quite recently, several primary aromatic and heteroaromaticamides were synthesized in moderate to excellent yields fromaldehydes and hydroxylamine hydrochloride in the presence ofstoichiometric amounts of Cs2CO3 (Scheme 17).65 Remarkably,the use of other bases, such as K2CO3, Na2CO3, NaOH, KOtBuKOAc or DBU, led to the desired amide products in only traceamounts. Similarly, a rough survey of the reaction conditionsindicated that the effectiveness of this system is largely depen-dent on the volume ratio of the DMSO–H2O solvent mixtureemployed, the best results being obtained with a 3 : 1 v/v ratio. Asin the precedent cases, a reaction pathway involving the initialformation of the corresponding aldoximes, that are transformedinto the amide products through a dehydration–hydration sequence,was proposed on the basis of GC-MS studies in which nitrileintermediates were detected.

Finally, an efficient and general solvent-free procedure forthe direct conversion of aldehydes to amides with NH2OH�HCland methanesulfonyl chloride (MeSO2Cl), that makes use of wetAl2O3 as a catalyst, has also been described (Scheme 18).66 Theprocess involves the initial formation of an aldoxime followed byits reaction with MeSO2Cl to generate the key intermediate C.

Compound C subsequently undergoes elimination of MeSO2H,liberating the corresponding nitrile which undergoes rapidhydration by the wet alumina to produce the amide. In com-plete accord with this reaction pathway, treatment of isolatedaldoximes with MeSO2Cl in the presence of wet Al2O3 also ledto the amide products in high yields. In addition, under thesame reaction conditions, when dry instead of wet alumina wasemployed, the corresponding nitriles were selectively obtained.The same transformations have been very recently describedemploying wet and dry chitosan-supported ionic liquids ascatalysts.67

Conclusions

Amides are one of the most important and prolific functionalgroups in chemistry. Although there are many strategies to preparethem, the enormous amount of wastes generated by using thestandard protocols has made the atom-economical synthesis ofamides a high priority, especially in the pharmaceutical indus-try.3,4 The acid-promoted Beckmann rearrangement of ketoximesis a very efficient approach for the preparation of N-substitutedamides, but similar reactions with aldoximes are, however, morechallenging, and nitriles instead of amides are usually obtained.7,8

Consequently, the search for catalytic systems able to effect theselective rearrangement of aldoximes to primary amides hasreceived considerable attention in the last few years. In thisFeature article we have discussed in a comprehensive mannerthe advances achieved in the field. As the reader would havenoticed, since the publication of the first practical and efficientprotocol employing [RhCl(PPh3)3] by Chang and co-workers in2003,12b a large variety of homogeneous and heterogeneouscatalysts have seen the light, and the reaction can be nowincluded within the toolbox of synthetic organic chemists.In addition, the ease of access to aldoximes from aldehydes,and even alcohols, has allowed the implementation of syntheticroutes to amides starting from these readily available reagents.Some tandem processes allowing the preparation of N-substitutedamides have also been discovered, thus expanding the syntheticutility of the aldoxime rearrangement reaction. We hope thatthis article will serve as an inspiration for future developmentsin the field.

Acknowledgements

Financial support from the Spanish MINECO (projects CTQ2010-14796 and CTQ2013-40591) is gratefully acknowledged.

Notes and references1 See, for example: (a) The Chemistry of Amides, ed. J. Zabicky,

Wiley-Interscience, New York, 1970; (b) The Amide Linkage: StructuralSignificance in Chemistry, Biochemistry and Materials Science,ed. A. Greenberg, C. M. Breneman and J. F. Liebman, John Wiley& Sons, New York, 2000; (c) Polyesters and Polyamides, ed. B. L.Deopura, B. Gupta, M. Joshi and R. Alagirusami, CRC Press, BocaRaton, 2008; (d) I. Johansson, Kirk-Othmer Encyclopedia of ChemicalTechnology, John Wiley & Sons, New York, 2004, vol. 2, pp. 442–463.

Scheme 16 Synthesis of amides from aldehydes catalyzed by silicachloride under MW irradiation.

Scheme 17 Synthesis of amides from aldehydes promoted by Cs2CO3.

Scheme 18 Solvent-free synthesis of amides from aldehydes usingwet alumina.



2 See, for example: (a) Methoden Org. Chem. (Houben Weyl),ed. D. Dopp and H. Dopp, Thieme Verlag, Stuttgart, 1985,vol. E5(2), pp. 1024–1031; (b) P. D. Bailey, T. J. Mills, R. Pettecrewand R. A. Price, in Comprehensive Organic Functional Group Trans-formations II, ed. A. R. Katritzky and R. J. K. Taylor, Elsevier, Oxford,2005, vol. 5, pp. 201–294; (c) C. A. G. N. Montalbetti and V. Falque,Tetrahedron, 2005, 61, 10827; (d) E. Valeur and M. Bradley, Chem.Soc. Rev., 2009, 38, 606.

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