Direct Transamidation Reactions: Mechanism and Recent Advances

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Review Direct Transamidation Reactions: Mechanism and Recent Advances

Paola Acosta-Guzmán, Alejandra Mateus-Gómez and Diego Gamba-Sánchez * Laboratory of Organic Synthesis Bio- and Organocatalysis, Chemistry Department, Universidad de los Andes, Cra. 1 No 18A-12 Q:305, Bogotá 111711, Colombia; [email protected] (P.A.-G.); [email protected] (A.M.-G.) * Correspondence: [email protected]; Tel.: +571-3394949

Academic Editor: Michal Szostak Received: 24 August 2018; Accepted: 13 September 2018; Published: 18 September 2018

Abstract: Amides are undeniably some of the most important compounds in Nature and the chemical industry, being present in biomolecules, materials, pharmaceuticals and many other substances. Unfortunately, the traditional synthesis of amides suffers from some important drawbacks, principally the use of stoichiometric activators or the need to use highly reactive carboxylic acid derivatives. In recent years, the transamidation reaction has emerged as a valuable alternative to prepare amides. The reactivity of amides makes their direct reaction with nitrogen nucleophiles difﬁcult; thus, the direct transamidation reaction needs a catalyst in order to activate the amide moiety and to promote the completion of the reaction because equilibrium is established. In this review, we present research on direct transamidation reactions ranging from studies of the mechanism to the recent developments of more applicable and versatile methodologies, emphasizing those reactions involving activation with metal catalysts.

Keywords: transamidation; amide; amine; catalyst; catalysis

1. Introduction The amide functionality has been recognized as one of the most important functional groups, not only because of its widespread presence in Nature (in proteins, peptides, and alkaloids, among others) [1] but also because of the vast number of synthetic structures bearing this group [2]. It is estimated that approximately 25% of the existing pharmaceuticals contain an amide bond as part of their structures [3] and that approximately 33% of the new drug candidates are “amides” [4], thus making amidation reactions some of the most performed chemical processes in the pharmaceutical industry and in drug discovery activities [5]. Traditional methods to synthesize amides suffer from signiﬁcant issues, principally the use of stoichiometric amounts of activating reagents with the consequent production of waste or the use of corrosive and troublesome reagents such as acyl chlorides or anhydrides. As a consequence, the ACS Green Chemistry Institute assessed the amide bond formation with good atom economy as one of the biggest challenges for organic chemists [6]. In recent years, amide bond synthesis by nontraditional methods has been reviewed, and some alternatives are available to perform acylations on nitrogen [7–10]. Among those unconventional methods, the transamidation reaction appears to be a useful strategy. The acyl exchange between an amide and an amine has been known since 1876 with the studies carried out by Flescher [11]; however, the method was pretty limited. For approximately one hundred years, the transamidation reaction was almost unexplored, and only a few successful examples were published [12–15]. The biggest drawback of this method was the use of high temperatures and very long reaction times. The ﬁrst catalytic transamidation was performed using carbon dioxide [14];

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Molecules 2018, 23, 2382 2 of 17 long reaction times. The first catalytic transamidation was performed using carbon dioxide [14]; however, the quantity used makes it not properly a catalyst but rather a promoter; additionally, the yieldshowever, were thealways quantity lower used than makes 67%. It it notwasproperly not until a 1994 catalyst that but a modern rather aand promoter; complete additionally, study on a the directyields transamidation were always lower was published than 67%. by It was Bertrand not until and 1994 coworkers that a modern [16]. Their and completework was study based on on a directthe usetransamidation of aluminum chloride was published as a promoter by Bertrand, and the and method coworkers was [ 16limited]. Their to workthe use was of basedaliphatic on theamines use of sincealuminum low yields chloride were as obtained a promoter, with and aromatic the method amides. was Chemist limiteds tonoticed the use the of importance aliphatic amines and the since potentiallow yields of the were direct obtained transamidation with aromatic reaction amides. and Chemists developed noticed some the useful importance and general and the method potentials performedof the direct under transamidation the influence of reaction different and types developed of catalysts some. T usefuloday, heterogen and generaleous, methods metallic, performed acidic andunder basic the catalysts inﬂuence are ofavailable different to typesperform of catalysts.transamidation Today, reactions. heterogeneous, In this metallic,review article acidic, we and will basic begincatalysts with arethe availablemechanistic to performstudies for transamidation transamidation reactions. of primary In this and review secondary article, amides, we will followed begin with bythe studies mechanistic of the reaction studies with for transamidationtertiary amides and of primary some other and mechanistic secondary amides, studies followedusing proline by studies as a catalyst.of the In reaction the following with tertiary sections amides, we will and present some othera set of mechanistic selected examples studies usingof direct proline transamidation as a catalyst. reactionIn thes following catalyzed sections, by metals we as will well present as some a set alternative of selected catalyst exampless. of direct transamidation reactions catalyzed by metals as well as some alternative catalysts. 2. Mechanistic Studies 2. Mechanistic Studies In transamidation, an alternative strategy to prepare amides, the direct exchange of the amine moiety In in transamidation, an amide can occur an alternative only under strategy the influence to prepare of amides, a suitable the directcatalytic exchange or stoichiometric of the amine activatingmoiety in agent an amide because can occur of the only poor under electrophilic the inﬂuence nature of a suitable of amides. catalytic Depending or stoichiometric on the reaction activating conditions,agent because the structure of the poor of theelectrophilic amide, and nature the of activating amides. agent Depending employed, on the the reaction reactivity conditions, of these the amidesstructure differs of thefrom amide, reaction and theto reaction activating; however, agent employed, it follow thes the reactivity regular ofpattern these amidesthat the differs primary from amidesreaction are tomore reaction; active however,than the secondary it follows theand regulartertiary pattern amides that. Nevertheless, the primary some amides activating are more agents active capablethan the of secondaryactivating andsecondary tertiary amides amides. have Nevertheless, been described some activating in the literature agents capable with considerable of activating successsecondary [10]. T amideshe order have of reactivity been described shown in before the literature implies that with the considerable structure of success the amide [10]. is The the ordermost of importantreactivity constrain shownt before in transamidation implies that process the structurees. Another of the v amideery important is the most factor important is the acidic constraint nature in of transamidationthe N-H function processes., which could Another hamper very the important process factorby simply is the inactivating acidic nature the of catalytic the N-H species. function, Consideringwhich could these hamper facts, theunderstanding process by simply how this inactivating process occur thes catalytic represents species. one of Considering the main challenges these facts, forunderstanding the organic chemistry how this community process occurs [8]. represents one of the main challenges for the organic chemistry communityIn this sense, [8]. Stahl and coworkers [17–19] studied the mechanism of the transamidation reaction catalyzedIn thisby metals, sense, Stahl focusing and coworkerson the reaction [17–19 between] studied a the secondary mechanism amine of the and transamidation a secondary amide reaction (Schemecatalyzed 1). Theyby metals, evaluated focusing the onbehavior the reaction of nucleophilic between a alkali secondary-metal amine amides, and Lewis a secondary acidic metal amide complexes,(Scheme1 transition). They evaluated metals and the different behavior amides. of nucleophilic The authors alkali-metal found that amides, metallic Lewis complex acidices metal of titaniumcomplexes, and transitionaluminum metals could and catalyze different the transamidationamides. The authors reaction found due that to their metallic relatively complexes low of basititaniumcity; furthermore and aluminum, metallic could complex catalyzees the of transamidationtitanium [Ti(NMe reaction2)4] and due aluminum to their relatively [Al(NMe low2)6] could basicity; catalyzefurthermore, the transamidation metallic complexes reaction of due titanium to an [Ti(NMeincrease2 in)4] electron and aluminum density [Al(NMein the metal2)6] couldcenter catalyze. This effectthe is transamidation related to the reduced reaction basicity due to anof the increase ligand, in which electron increases density the in Lewis the metal acidic center. character This of effect the is metal.related to the reduced basicity of the ligand, which increases the Lewis acidic character of the metal.

SchemeScheme 1. Transamidation 1. Transamidation of a of secondary a secondary amide amide with with a secondary a secondary amine. amine.

BasedBased on onthe the previous previous information information,, the the author author carried carried out out a complete a complete mechanistic mechanistic study, study, which which includeincludedd the the determination determination of ofthe the deuterium deuterium kinetic kinetic isotope isotope effect, effect, the the rate rate law law and and the the identity identity of of thethe catalyst catalyst resting resting state. state. With With the the results results obtained obtained in inthe the kinetic kinetic studies, studies, they they proposed proposed a catalytic a catalytic mechanismmechanism to toexplain explain the the transamidation transamidation process process (Scheme (Scheme 2).2 They). They suggest suggesteded that that in inthe the first ﬁrst step step,, thethe secondary secondary amide amide react reactss with with the the prec precatalystatalyst to toyield yield metal metal-amidate-amidate complex complex I. OnceI. Once this this complex complex is formed,is formed, it enters it enters the the catalytic catalytic cycle cycle by bya bimolecular a bimolecular reaction reaction with with a primary a primary amine amine to togenerate generate adductadduct II. IIAfter. After that, that, a proton a proton transf transferer between between the the nitrogen nitrogen atoms atoms is proposed is proposed to toreach reach intermediate intermediate IIIIII. Later,. Later, an an intramolecular intramolecular nucleophilic nucleophilic attack ofof thethe amido-ligand amido-ligand to to the the carbonyl carbonyl of theof the amide amide forms formsmetallacycle metallacycleIVa .IVa This. This intermediate intermediate is theis the most most important important species species in in the the catalyticcatalytic cyclecycle because it embodies the bifunctional role of the metal center via activation of both the amine and amide substrate.

Molecules 2018, 23, x 2382 FOR PEER REVIEW 33 ofof 1716 it embodies the bifunctional role of the metal center via activation of both the amine and amide substrate.However, this However, intermediate this intermediate can either revert can theeither cycle revert to complex the cycleIII toor continue complex theIII catalyticor continue cycle the by catalyticisomerization cycle toby form isomerizatiIVb. Theon isomerizationto form IVb. Th proceedse isomerization by transition proceeds state byV, wheretransition the state metal V is, where linked theto both metal nitrogen is linked atoms, to both thus nitrogen changing atoms, the thus nitrogen changing coordinated the nitrogen to the coordinated metal center to the and metal providing center andexchanged providing intermediate exchangedIVb intermediate. This product IVb. is This easily product converted is easily into convertedVI, and ﬁnally, into V theI, and breakdown finally, the of breakdownintermediate ofVI intermedipromotedate by VI a promoted second molecule by a second of amide molecule leads of to amide the formation leads to ofthe the formation desired amideof the deandsired the amide liberation and of the an liberation amine molecule of an amine that is molecule responsible, that inis mostresponsible, of the cases, in most for of the the equilibrium cases, for thedisplacements; equilibrium indisplacements other words:; itinis other the drivingwords: forceit is the of thisdriving reaction force[ 18of –this20]. reaction [18–20].

Scheme 2. Proposed catalytic cycle for transamidation reactions between primary or secondary amides Scheme 2. Proposed catalytic cycle for transamidation reactions between primary or secondary with primary amines. amides with primary amines. Careful analysis of the proposed mechanism suggests that tertiary amides are unsuitable reagents for theCareful transamidation analysis of reaction. the proposed This is because mechanism of the suggests absence of that an N-Htertiary bond amides and the are consequently unsuitable reagentsdifferent reactivityfor the transamidation between these reaction amides and. This bases. is because However, of the successful absence examples of an N of-H transamidation bond and the consequentlyreactions with different tertiary amidesreactivity have between been describedthese amides in the and literature, bases. However, suggesting successful that tertiary examples amides of transamidationshould follow areactions different with mechanistic tertiary amides pathway. have Stahlbeen anddescribed coworkers in the confrontedliterature, suggesting this issue that and tertiarydeveloped amides a new should study follow focused a different on the mechanistic mechanisticdetails pathway. ofthe Stahl transamidation and coworker reactions confronted between this issuetertiary and amides develop anded secondary a new study amines focused employing on the mechanistic kinetic, spectroscopic, details of the and transamidation computational reaction studies between(Scheme 3tertiary). According amides to and their secondary results, the amines ﬁrst stepemploying occurs kinetic, when the spectroscopic, amide interacts and withcomputational the metal studiescomplex (Scheme to form 3 intermediate). According toI, wheretheir results the simultaneous, the first step activation occurs when of thethe electrophileamide interacts (amide) with andthe metalthe nucleophile complex to (amine) form intermediate by the metal I center, where is th clear.e simultaneous After that, anactivation intramolecular of the electrophile attack of the (amide) amido andligand the to nucleophile the coordinated (amine) amide by the gives metal rise tocenter metal-stabilized is clear. After tetrahedral that, an intramolecular intermediate IIa attack, which of canthe amiinterconvertdo ligand to to its the isomeric coordinated intermediate amide IIbgivesby arise simple to metal cleavage-stabilized and coordination tetrahedral sequenceintermediate through IIa, wintermediatehich can interconvert III. In the last to step, its isomeric a new amine/amido intermediate pair IIb coordinated by a simple to the cleavage metal IV andis formed,coordination from sequencewhich it is th possiblerough intermedia to obtain thete III desired. In theproduct last step [,21 a ,new22]. amine/amido pair coordinated to the metal IV is formed, from which it is possible to obtain the desired product [21,22].

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Scheme 3. Proposed catalytic cycle for transamidation reaction between tertiary amides with secondary amines. Scheme 3. Proposed catalytic cycle for transamidation reaction between tertiary amides with secondaryComparing amines. the transamidation processes for secondary amides and tertiary amides makes some similarities evident. First, the mechanisms exhibit not only that there are obvious structural similarity betweenCompar the intermediatesing the transamidation but also that process the keyes stepfor secondary in both processes amides isand the tertiary intramolecular amides makes nucleophilic some similaritiesattack of the evident. amido ligandFirst, the on mechanisms a metal-coordinated exhibit not amide. only Regardingthat there are the obvious differences structural between similarity the two betweentransamidation the intermediates processes, perhaps but also the that most the important key step one in is the both identity processes of the is catalystthe intramolecular resting state, nucleophilicimplying substantial attack of differences the amido inligand the kinetic on a metalproperties-coordinate of bothd reactionsamide. Regarding since the transamidationthe differences betweenreaction ofthe secondary two transamidation amides follows processes, first-order perhaps kinetics the with mo regardsst important to the metalone is andthe amineidentity involved of the catalystand the resting amide state, follows implying zero-order substantial kinetics. differences Contrary in to the that, kinetic for the properties tertiary of amide, both reaction the rates law since is thezero-order transamidation for the amine, reaction is of half- secondary to first-order amides for follows the metal first and-order varies kinetic froms with zero-order regards to to saturation the metal andbehavior amine for involved the amide. and The the transamidation amide follows of primaryzero-order amides kinetic is easiers. Contrary than the to cases that, describedfor the tertiary before amidebecause, the ammonia rate law is is produced zero-order in thefor reactionthe amine, medium, is half- thus to first making-order the for reaction the metal simpler and varies and usually from zerobetter-order yielding. to saturation Concerning behavior the mechanisms, for the amide. each The research transamidation team describes of primary its own amides proposal, is easier typically than thebased cases on described the Stahl studies.before because In our ammonia opinion,slight is produce differencesd in the between reaction metals medium, should thus exist, making and the as reactiona consequence, simpler the and reaction usually mechanism better yielding for the. transamidationConcerning the of mechanisms, primary amides each should research be pretty team describesimilar tos thatits own described proposal, for secondarytypically based amides. on Additionally, the Stahl studies the large. In our number opinion of non-metal-catalyzed, slight differences betweentransamidation metals reactionsshould exist makes, and the as investigation a consequence of their, the mechanismsreaction mechanism interesting. for the Unfortunately, transamidation only of primary amides should be pretty similar to that described for secondary amides. Additionally, the one computational study on the reaction catalyzed by L-proline has been described; mechanisms with largeother catalystsnumber remainof non- unexplored.metal-catalyzed transamidation reactions makes the investigation of their mechanismsThe organocatalyzed interesting. Unfortunately, transamidation only reaction one computational has been described study on as the a greenerreaction methodologycatalyzed by L-proline has been described; mechanisms with other catalysts remain unexplored. compared with the metal-catalyzed version of this reaction. L-Proline has received much attention due The organocatalyzed transamidation reaction has been described as a greener methodology to its dual role as a ligand and a catalyst in other reactions. In view of the above perceptions, L-proline wascompared described withas the a usefulmetal-catalyzed catalyst for version the transamidation of this reaction. reaction. L-Proline Adimurthy has received and much coworkers attention [23] due to its dual role as a ligand and a catalyst in other reactions. In view of the above perceptions, L- found that various amides react with a variety of amines in the presence of L-proline as a catalyst. prolineThe reaction was described scope included as a useful benzylamines catalyst for withthe transamidation electron-rich and reaction. deficient Adimurthy substituents and coworkers and alkyl [23] found that various amides react with a variety of amines in the presence of L-proline as a catalyst. The reaction scope included benzylamines with electron-rich and deficient substituents and alkyl aromatic, aliphatic, and secondary amines, which reacted with remarkable ease. Specifically, the

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Molecules 2018, 23, x FOR PEER REVIEW 5 of 16 aromatic, aliphatic, and secondary amines, which reacted with remarkable ease. Specifically, the reactions of benzylamine with primary amides showed good yields compared to reactions with reactions of benzylamine with primary amides showed good yields compared to reactions with secondary and tertiary amides. The authors also demonstrated that the reactions have a high degree secondary and tertiary amides. The authors also demonstrated that the reactions have a high degree of functional group tolerance. The mechanistic study carried out to explain the role of L-proline and of functional group tolerance. The mechanistic study carried out to explain the role of L-proline and to disclose why the transamidation can be efficiently catalyzed by proline was reported by Xue and to disclose why the transamidation can be efficiently catalyzed by proline was reported by Xue and coworkers some years after the reaction was described. They used density functional theory (DFT) coworkers some years after the reaction was described. They used density functional theory (DFT) calculations to achieve a reasonable proposal. calculations to achieve a reasonable proposal. The transamidation of acetamide with benzylamine was selected as the model system. The The transamidation of acetamide with benzylamine was selected as the model system. The calculations revealed that the reactions catalyzed by L-proline follow a stepwise mechanism, which calculations revealed that the reactions catalyzed by L-proline follow a stepwise mechanism, which involves a first step where the activation of the amide takes place through a proton transfer from involves a first step where the activation of the amide takes place through a proton transfer from L- L-proline to the carbonyl group of the amide to form intermediate imidine I. Subsequently, a proline to the carbonyl group of the amide to form intermediate imidine I. Subsequently, a nucleophilic addition of benzylamine to the imidine intermediate occurs to form II. After eliminating nucleophilic addition of benzylamine to the imidine intermediate occurs to form II. After eliminating one molecule of ammonia, a hydrolysis of intermediate III produces the target product. This study one molecule of ammonia, a hydrolysis of intermediate III produces the target product. This study allowed the researchers to identify the hydrolysis reaction as the rate-determining step (RDS) in the allowed the researchers to identify the hydrolysis reaction as the rate-determining step (RDS) in the catalytic cycle with the largest energy barrier (26.0, 26.8 and 29.7 kcal/mol in toluene, ethanol and H O catalytic cycle with the largest energy barrier (26.0, 26.8 and 29.7 kcal/mol in toluene, ethanol and2 respectively) (Scheme4)[24]. H2O respectively) (Scheme 4) [24].

H2O

+ COOH N COO NH2 N

H NH2 O (I) H2N N H

H2O

N COO N COOH

N N H H2N H

(III) (II) HNH 2 Scheme 4. Proposed mechanism to explain the transamidation reaction catalyzed by L-proline. Scheme 4. Proposed mechanism to explain the transamidation reaction catalyzed by L-proline. As already mentioned, the mechanistic studies on the transamidation reaction are quite limited; however,As already the metal-catalyzed mentioned, the version mechanistic presumably studies followson the transamidation similar mechanisms reaction independent are quite limited of the; however,metal identity, the metal with- thecatalyzed mechanistic version pathway presumably depending follows on similar the type mechanisms of amide reacting. independent Concerning of the metalthe non-metal-catalyzed identity, with the mechanis version, sometic pathway examples depending are described on the in type the literature, of amide butreact amonging. Concerning them, only theL-proline non-metal has received-catalyzed enough version, attention some examples that a mechanistic are described study in was the carried literature out., but Nevertheless, among them the, onlysummary L-proline of mechanistic has received studies enough presented attention in thisthat sectiona mechanistic is sufﬁcient study to was understand carried out the. principlesNevertheless and, theparticularities summary of of mechanistic transamidation studies reactions. presented In thein this following section is chapters, sufficient we to will und presenterstand somethe principle selecteds andexamples particularities of transamidations of transamidation and discuss reactions. their particularities In the following and issues. chapters, we will present some selected examples of transamidations and discuss their particularities and issues. 3. Metal-Catalyzed Direct Transamidations 3. Metal-Catalyzed Direct Transamidations Since the pioneering work reported by Stahl and coworkers [18–22], several metal catalysts have beenSince described the pioneering for direct work transamidation reported by reactions. Stahl and Amongcoworkers them, [18– one22], of several the most metal commonly catalysts have used beenis iron(III), described particularly for direct in transamidation the form of simple reactions Fe(III). Among salts, supported them, one in of clay the ormost even commonly as nanoparticles. used is ironThe(III) ﬁrst, studyparticularly was reported in the form in 2014 of simple by Shimizu Fe(III) and salts, coworkers supported [25 in]; theyclay usedor even Fe(III) as nanoparticles. supported in Themontmorillonite first study was to reported perform thein 2014 direct by transamidationShimizu and coworkers of primary [25] amides; they used (Scheme Fe(III)5). supported The authors in montmorilloniteshowed that the reactionto perform can bethe performed direct transamidation under solvent-free of primary conditions amides with (Scheme a slight 5 excess). The ofauthors amine showedat 140 ◦C. that the reaction can be performed under solvent-free conditions with a slight excess of amine at 140 °C.

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Scheme 5. (a) Transamidation of amides (alkyl, aryl, Het-aryl) with amines catalyzed by Fe3+-mont. 3+ Scheme(b) Transamidations 5.5. ((aa)) TransamidationTransamidation of α-hydroxy ofof amidesamidesamides (alkyl, (withalkyl, amines. aryl,aryl, Het-aryl)Het -aryl) withwith aminesamines catalyzedcatalyzed byby FeFe3+--mont.mont. ((b)) TransamidationsTransamidations ofof αα-hydroxyamides-hydroxyamides withwith amines.amines. Unfortunately, the scope of the reaction is limited; only primary amides and primary amines can Unfortunately, the scope of the reaction is limited; only primary amides and primary amines can be usedUnfortunately, (Scheme 5a). the Additionally scope of the, thereaction method is limited; is limited only to primarythe use of amides liquid and starting primary materials amines since can be used (Scheme5a). Additionally, the method is limited to the use of liquid starting materials since at atbe leastused one(Scheme of the 5 a).two Additionally reagents has, the to methodbe a liquid, is limited thus makingto the use th isof method liquid starting unsuitable materials for a largesince least one of the two reagents has to be a liquid, thus making this method unsuitable for a large number numberat least one of reagents.of the two A reagen few examplests has to be with a liquid,free α -thushydroxy making amides this methodwere described unsuitable (Scheme for a large 5b). of reagents. A few examples with free α-hydroxy amides were described (Scheme5b). Typically, Typically,number of reactions reagents. carried A few out examples under solvent with free-free α -conditionshydroxy amides are seen were as good described examples (Scheme of gree 5b).n reactions carried out under solvent-free conditions are seen as good examples of green chemistry chemistryTypically, principlesreactions ;carried however, out the under transamidation solvent-free reaction conditions has areto be seen seen as from good another examples perspective of green. principles; however, the transamidation reaction has to be seen from another perspective. As we Achemistrys we mentioned principles before; however,, amidation the transamidation reactions are reaction one of hasthe to most be seen performed from another process perspectivees in drug. mentioned before, amidation reactions are one of the most performed processes in drug discovery and discoveryAs we mentioned and the pharmaceutical before, amidation industry reactions, and are the one structure of the most of amides performed used in process thosees fields in drug are the pharmaceutical industry, and the structure of amides used in those ﬁelds are somehow complex, somehowdiscovery complex, and the pharmaceuticalmeaning they are industry usually, andpolyfunctional the structure compounds of amides with used more in those than 20 fields carbon are meaning they are usually polyfunctional compounds with more than 20 carbon atoms or, in some cases, atomssomehow or, complex,in some cases meaning, amino they acid are derivatives.usually polyfunctional As a consequence, compounds a good with method more than to synthesize 20 carbon amino acid derivatives. As a consequence, a good method to synthesize amides has to be amenable to amidesatoms or has, in tosome be amenablecases, amino to all acid the derivatives. structures mentionedAs a consequence, before, anda good solid method reagents to aresynthesize highly all the structures mentioned before, and solid reagents are highly desirable even if the use of a solvent desirableamides has even to ifb ethe amenable use of a solvent to all thebecomes structures imperative. mentioned This has before served, and us solid as inspiration reagents to are develop highly becomes imperative. This has served us as inspiration to develop a more general method for direct adesirable more general even if method the use forof a direct solvent transamidations becomes imperative. using Fe(III)This has [26] served. Our usmethod as inspiration is based toon develop the use transamidations using Fe(III) [26]. Our method is based on the use of simple Fe(III) salts. In fact, we ofa more simple general Fe(III) method salts. In for fact, direct we demonstratedtransamidations that using any Fe(III) [26]salt . canOu rbe method used as is abased catalyst on forthe thisuse demonstrated that any Fe(III) salt can be used as a catalyst for this reaction; the sole condition is the reactionof simple; the Fe(III) sole salts. condition In fact, is thewe presencedemonstrated of water, that which any Fe(III) has a salt complementary can be used ascatalytic a catalyst role for in this presence of water, which has a complementary catalytic role in this process. Water can be added or process.reaction ;Water the sole can condition be added is or the obtained presence from of water, hydrated which salts, has the a complementary identity of which catalytic is only rolelimited in this by obtained from hydrated salts, the identity of which is only limited by the availability of the reagents. theprocess. availability Water cofan the be reagentsadded or. Tobtainedechnical from grade hydrated toluene salts,is also the a suitable identity solvent of which. Consequently is only limited, this by Technical grade toluene is also a suitable solvent. Consequently, this method is one of the cheapest methodthe availability is one of of the the cheapest reagents reported. Technical in gradethe literature toluene (isScheme also a 6suitable). solvent. Consequently, this reported in the literature (Scheme6). method is one of the cheapest reported in the literature (Scheme 6).

Scheme 6.6. Transamidation catalyzed byby Fe(III) andand water of (a)) carboxamides.carboxamides. (b) α-amino-amino esters.esters. ( c) Synthesis of 2,3-dihydro-5H-benzo[b]-1,4-thiazepin-4-one by intramolecular transamidation. SynthesisScheme 6 .of Transamidation 2,3-dihydro-5H catalyzed-benzo[b] -by1,4 Fe(III)-thiazepin and- water4-one byof (intramoleculara) carboxamides. transamidation (b) α-amino esters. . (c) Synthesis of 2,3-dihydro-5H-benzo[b]-1,4-thiazepin-4-one by intramolecular transamidation.

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The reaction scope is very good since the reaction can be performed not only with an excess of amidesThe or reaction amines scopebut also is very with good stoichiometric since the reactionquantities. can The be performedreaction time not depends only with on an the excess amide of amidesused, but or it amines is usually but shorter also with with stoichiometric primary amides quantities. and longer The reactionwith secondary time depends and tertiary on the amides. amide used,We also but described it is usually the shortertransamidation with primary of secondary amides amides and longer where with the secondary liberated amine and tertiary is not a amides. gas or Wea volatile also described liquid and the showed transamidation that Fe(III)/water of secondary is a suitable amides wherecatalyst the in liberated those cases. amine It should is not abe gas noted or a volatilethat no liquid previous and functionalizationshowed that Fe(III)/water of the secondary is a suitable amide catalyst was in thoseneeded cases. (Sch Iteme should 6a). be Finally, noted that the noreaction previous was functionalization described with of some the secondary amino acids amide as was the needed amino (Scheme source 6 (Schemea). Finally, 6b), the and reaction one wasintramolecular described withexample some was amino provided acids (Scheme as the amino 6c). A sourcefew years (Scheme later, 6magneticb), and one nanoparticles intramolecular were exampleused in direct was providedtransamidation (Scheme reactions,6c). A fewwith years some later, advantages magnetic and nanoparticles issues. The method were used described in direct by transamidation reactions, with some advantages and issues. The method described by Thale [27] using Thale [27] using Fe3O4 has the same problem that all transamidations performed under solvent-free Feconditions3O4 has theshow same. The problem loading that of the all catalyst transamidations is also high performed (20 wt.%) under, and only solvent-free primary conditionsamines are show.used Theas nucleop loadinghiles of the. H catalystowever, is this also highparticular (20 wt.%), method and hasonly some primary advantages: amines are the used catalyst as nucleophiles. is easily However,recovered thisand particularcan be used method in several has reactions some advantages: without loss the of catalyst activity is. easilyIt is also recovered simple andto prepare can be, usedand the in severalreaction reactions can be performed without loss with of DMF activity. as an It isexample also simple of a totertiary prepare, amide. and On the the reaction other canhand, be performedthe method with described DMF as by an Heidari example and of a tertiary Arefi [28] amide. has On a better the other substrate hand, thescope method and usesdescribed smaller by Heidariquantities and of Areﬁ catalyst [28.] U hasnfortunately a better substrate, the preparation scope and usesprocess smaller for the quantities catalyst ofis catalyst.more complicated Unfortunately, and theuses preparation simple iron processsalts as forprecur thesors catalyst; this is is more potentially complicated problematic and uses since simple the authors iron salts did as not precursors; quantify thisthe free is potentially salts in their problematic catalyst, sinceand it the is authors possible did that not some quantify remaining the free salts salts are in theirresponsible catalyst, for and the it istransformation, possible that someon the remaining other hand salts if the are simple responsible salts are for good the transformation, and suitable cata onlysts the for other this hand reactions, if the simpleprepare salts a catalysts are good that and dosuitable not provide catalysts very for this different reactions, results prepare using a catalysts them a that starting do not materials provide veryconsumes different time results unnecessarily. using them The a startingrecovery materials of the catalyst consumes was time also unnecessarily.described, but The the recoveryidentity of the catalystcatalytic wasspecies also is described, still unclear; but theboth identity Heidari of and the catalyticThale attribute species the is stillcatalytic unclear; activity both to Heidari the metal and Thalecenter. attribute the catalytic activity to the metal center. It is clear thatthat the transamidationtransamidation reaction is an equilibrium,equilibrium, and as such,such, when ammonia or gaseousgaseous amines are liberated in the reaction media, the reaction is easier. On the other hand, when the liberated amine is a liquid,liquid, the reaction becomesbecomes more complicated.complicated. Stahl and Gellman et al.al. [[29]29] faced this problem and developed a method applicable to N-aryl amides. In this case, Ti(NMe ) and faced this problem and developed a method applicable to N-aryl amides. In this case, Ti(NMe22)44 and Sc(OTf) were suitable catalysts affording good yields and acceptable selectivities to the cross-product. Sc(OTf)3 were suitable catalysts affording good yields and acceptable selectivities to the cross- Theproduct reaction. The reaction was performed was performed with nonpolar with nonp solventsolar solvents and at and low at temperatures. low temperature However,s. However, the best the resultsbest results were we obtainedre obtained with anwith excess an excess of aliphatic of aliphatic amines amines (Scheme (Scheme7a); the use7a); of the stoichiometric use of stoichiometric aromatic aminesaromatic produced amines produced mixtures ofmixtures products of (Schemeproducts7 b).(Scheme 7b).

a. O O 5 mol % cat R1 C H N + C6H13 N 6 13 NH2 H H Tol, 90 ˚C, 16 h

R1= Alkyl Yield cat = Sc(OTf)3 = 97% Ti(NMe2) = 99%

O O O Ti(NMe ) 10 mol % Ph 2 4 O C6H13 N + H2N p-xylene,120 ˚C, 20 h C6H13 N H H

Yield 40% Scheme 7. Catalytic transamidation of (a) N-alkyl heptylamines with benzylamine and (b) N-aryl Scheme 7. Catalytic transamidation of (a) N-alkyl heptylamines with benzylamine and (b) N-aryl amides with aryl amines. amides with aryl amines. The reactions described before have some common characteristics: they are all performed in nonpolarThe reactionssolvents, and described an excess before (at least have 1 someequiv.) common of one of characteristics the reagents is: neededthey are to all obtain performed complete in nonpolar solvents, and an excess (at least 1 equiv.) of one of the reagents is needed to obtain complete conversions and good yields. One interesting development was the use of Cu(OAc)2 as a catalyst describedconversion bys and Beller good and yields. coworkers One interesting [30], who useddevelopmenttert-amyl was alcohol the use as theof Cu(OAc) solvent and2 as 0.3a catalyst excess described by Beller and coworkers [30], who used tert-amyl alcohol as the solvent and 0.3 excess equivalents of amine. The reaction is limited to the use of primary amides but has a very good

Molecules 2018, 23, 2382 8 of 17

Molecules 2018, 23, x FOR PEER REVIEW 8 of 16 Molecules 2018, 23, x FOR PEER REVIEW 8 of 16 equivalents of amine. The reaction is limited to the use of primary amides but has a very good substrate scope, as it tolerates free OH groups in the substrate and can be performed with chiral substrate scope,scope, as it tolerates free OH groups in thethe substratesubstrate and can be be performedperformed withwith chiralchiral reagents (amides or amines) without racemization. The sole problem is the use of sealed tubes since reagents (amides or amines) without racemization.racemization. T Thehe sole problem is the use of sealed tubes since high pressures are a safety issue in organic chemistry laboratories. highhigh pressures areare aa safetysafety issueissue inin organicorganic chemistrychemistry laboratories.laboratories. As the reader can notice, several efforts have been made to have more active and general As the the reader reader can can notice, notice, several several efforts efforts have have been been made made to have to more have active more and active general and catalysts general catalysts for transamidations. Simple metal salts have been proven as suitable catalysts for this forcatalysts transamidations. for transamidations Simple metal. Simple salts have metal been salts proven have been as suitable prove catalystsn as suitable for this catalysts transformation, for this transformation, however, the use of more developed metal catalysts may have some advantages. In however,transformation, the use however, of more developed the use of metalmore catalystsdeveloped may metal have catalyst some advantages.s may have some In particular, advantages the use. In particular, the use of sulfated tungstate proved to be effective with α,β-unsaturated amides [31]. ofparticular sulfated, tungstatethe use of proved sulfated to tungsta be effectivete proved with α to,β -unsaturated be effective with amides α,β- [unsaturated31]. These substrates amides [31] can. These substrates can be potentially complicated because of the presence of two reactive sites. Once beThese potentially substrates complicated can be potentially because complicated of the presence because of two of reactive the presence sites. of Once two the reactive amide sites forms. Once the the amide forms the complex with the metal center, the carbonyl is more electrophilic, but the β complexthe amide with forms the themetal complex center, thewith carbonyl the metal is more center, electrophilic, the carbonyl but is the moreβ position electrophilic, suffers but a similar the β position suffers a similar activation; as a consequence, Michael additions are competitive reactions. activation;position suffers as a consequence,a similar activation Michael; as additionsa consequence, are competitive Michael additions reactions. are Incompetitive the case of reactions sulfated. In the case of sulfated tungstate, no Michael product was observed (Scheme 8a). The catalyst was also tungstate,In the case noof sulfated Michael tungstate, product was no observedMichael product (Scheme was8a). observed The catalyst (Scheme was also8a). activeThe catalyst with αwas-amino also active with α-amino acid esters, as observed in Scheme 8b. acidactive esters, with asα-amino observed acid in esters Scheme, as8 observedb. in Scheme 8b.

Scheme 8.8. Transamidation reactionsreactions in the presence of sulfated tungstate of (a)) cinnamidecinnamide with alkyl Scheme 8. Transamidation reactions in the presence of sulfated tungstate of (a) cinnamide with alkyl and aryl amines and (b)) α-amino-amino esters withwith formamide.formamide. and aryl amines and (b) α-amino esters with formamide. The use of tertiary amides is typically exemplified exempliﬁed with DMF DMF,, and very few examples with other The use of tertiary amides is typically exemplified with DMF, and very few0 examples with other tertiary amides have beenbeen described.described. Fortunately,Fortunately, thethe useuse ofof Pd(OAc)Pd(OAc)22 withwith 2,22,2′-bipyridine-bipyridine (bpy) as tertiary amides have been described. Fortunately, the use of Pd(OAc)2 with 2,2′-bipyridine (bpy) as the ligand ligand can can be be used used for for the the transamidation transamidation of tertiary of tertiary amides amides [32] [. 32This]. Thiscatalyst catalyst afforded afforded very good very the ligand can be used for the transamidation of tertiary amides [32]. This catalyst afforded very good goodyields yields with aromat with aromaticic amines, amines, which which are easily are easily oxidized oxidized and consequently and consequently gave gavelower lower yields yields than their than yields with aromatic amines, which are easily oxidized and consequently gave lower yields than their theiraliphatic aliphatic partners partners (Scheme (Scheme 9). The9). biggest The biggest issue of issue this of method this method is the use is the of usea large of a excess large excessof amine of: aliphatic partners (Scheme 9). The biggest issue of this method is the use of a large excess of amine: amine:10 equivalents 10 equivalents are required are required.. However, However, the reaction the reactioncan be performed can be performed on a gram on scale a gram with scale excellent with 10 equivalents are required. However, the reaction can be performed on a gram scale with excellent excellentresults. results. results.

Scheme 9. Transamidation of DMF derivatives with aniline. Scheme 9. Transamidation of DMF derivatives with aniline. Scheme 9. Transamidation of DMF derivatives with aniline. Very recently, Hu and coworkers [33] described a reductive transamidation of tertiary amides (veryVery challenging recently substrates), Hu and coworkers with nitrobenzenes [33] described promoted a red byuctive manganese. transamidation Presumably, of tertiary the manganese amides Very recently, Hu and coworkers [33] described a reductive transamidation of tertiary amides acts(very not challenging only as a reducing substrates) agent with by producing nitrobenzenes the amine promoted in situ by but manganese. also as an activating Presumably agent, the for (very challenging substrates) with nitrobenzenes promoted by manganese. Presumably, the themanganese amide. Thisacts wasnot only proven as a by reducing adding agent some by metals producing usually the found amine as impuritiesin situ but also of manganese, as an activating such manganese acts not only as a reducing agent by producing the amine in situ but also as an activating asagent palladium for the or amide nickel.. T Additionally,his was prove thisn metalby adding has also some been metals described usually as a found useful catalystas impurities in a new of agent for the amide. This was proven by adding some metals usually found as impurities of methodmanganese of transamidations,, such as palladium such or as nickel a reaction. Additionally where the, this amide metal isactivated has also been by the described use of BOC as a or useful tosyl manganese, such as palladium or nickel. Additionally, this metal has also been described as a useful catalyst in a new method of transamidations, such as a reaction where the amide is activated by the catalyst in a new method of transamidations, such as a reaction where the amide is activated by the use of BOC or tosyl groups to increase their reactivity. There are some amazing recent publications use of BOC or tosyl groups to increase their reactivity. There are some amazing recent publications

Molecules 2018, 23, 2382 9 of 17

Molecules 2018, 23, x FOR PEER REVIEW 9 of 16 groups to increase their reactivity. There are some amazing recent publications in this field, but this arein this not field within, but the this scope are ofnot this within review the article. scope of The this reaction review performed article. The by reaction Hu et al performed. showed very by Hu good et substrateal. showed scope very and, good to substrate the best of scope our knowledge, and, to the isbest the of sole our general knowledge method, is forthedirect sole general transamidation method offor tertiary direct transamidation amides. of tertiary amides. From the previous examples, it is clear that the transamidation reaction is a powerful alternative in amideamide synthesis.synthesis. T Thehe use of metal catalyst catalystss has show shownn tremendous tremendous growth growth in in the the last last few few years years,, and many researchers have developed a vast variety of catalystscatalysts using metallic centers. We selected the most most general general and and simplestsimplest methodsmethods to to discuss discuss in in this this review review article. article. Nevertheless,Nevertheless, other less important catalysts have to be superficially mentioned, including manganese oxide (MnO ), which important catalysts have to be superficially mentioned, including manganese oxide (MnO22), which was used under under solve solvent-freent-free conditions conditions [34] [34 with] with a limited a limited substrate substrate scope scope but butwith with good good yields. yields. The Theuse useof lanthanides of lanthanides has hasalso also been been described described;; in inparticular, particular, a abimetallic bimetallic lanthanum lanthanum alk alkoxideoxide [35] [35],, and immobilized Ce(III)Ce(III) [[36]36]were were used used as as heterogeneous heterogeneous catalysts catalyst withs with the the associated associated advantages, advantages such, such as easyas easy catalyst catalyst recovery recovery and and low low catalyst catalyst charge, charge, but but also also with with the the normal normal issues, issues,such such asas thethe catalystcatalyst preparation and and activation. activation. Some Some more more innovative innovative catalysts catalyst have beens have prepared been and prepared used successfully and used insuccessfully transamidation. in transamida Mesoporoustion. niobiumMesoporous oxide niobium spheres oxide [37] and spheresN-heterocyclic [37] and N carbene-heterocyclic ruthenium carbene (II) complexesruthenium [(II)38] complexes are some of [38] the are most some general of the and most easy general to use and catalysts easy withto use the catalysts best substrate with the scope. best Very recently, the use of Co(AcO) ·4H O was described [39] with an excellent substrate scope, but substrate scope. Very recently, the2 use2 of Co(AcO)24H2O was described [39] with an excellent theresubstrate are noscope, special but considerationsthere are no special to mention considerations here. to mention here. Some of the catalyst catalystss presented presented in in this this section section can can be be used used with with ureas, ureas, with with phthalimide phthalimide and and,, in invery very few few cases cases,, with with thioureas. thioureas. The The activation activation of of those those substrates substrates has has prove provenn more more difficultdifficult than than amides, even though the C–NC–N bond has similar features to them. In addition, no details are provided about the application of transamidation reactionsreactions with ureas and phthalimides since it is outside the scope of this review.review. Concerning the catalysts,catalysts, the development of nonmetallicnonmetallic catalystscatalysts has received comparable attention and will bebe discussed inin thethe nextnext chapter.chapter. 4. Other Catalysts 4. Other Catalysts In an effort to develop safe, environmentally benign, economical, and energy saving chemical In an effort to develop safe, environmentally benign, economical, and energy saving chemical reactions, the design and synthesis of recyclable catalysts have become an important objective. reactions, the design and synthesis of recyclable catalysts have become an important objective. In this In this context, innovative catalysts for transamidations have been developed. One of the most context, innovative catalysts for transamidations have been developed. One of the most active active catalysts is the recyclable polymer-based metallic Lewis acid catalyst developed by Cui and catalysts is the recyclable polymer-based metallic Lewis acid catalyst developed by Cui and coworkers [40]. This catalyst, which is based on HfCl4/KSF-polyDMAP, is recyclable and was coworkers [40]. This catalyst, which is based on HfCl4/KSF-polyDMAP, is recyclable and was described for transamidations of different amide/amine pairs (Scheme 10). The authors chose HfCl4 described for transamidations of different amide/amine pairs (Scheme 10). The authors chose HfCl4 because it is active in the direct condensation of carboxylic acids and alcohols and because the Hf(IV) because it is active in the direct condensation of carboxylic acids and alcohols and because the Hf(IV) salts are easily manipulated and applicable in large-scale reactions. During the optimization process, salts are easily manipulated and applicable in large-scale reactions. During the optimization process, the authors tried an HF/KSF system and found it suitable for transamidations with mainly nonpolar or the authors tried an HF/KSF system and found it suitable for transamidations with mainly nonpolar low polarity solvents. Interestingly, this study led them to discover that by using mixtures of solvents or low polarity solvents. Interestingly, this study led them to discover that by using mixtures of such as acetonitrile/water and acetonitrile/NH3, the yield was increased. The use of HfCl4/KSF solvents such as acetonitrile/water and acetonitrile/NH3, the yield was increased. The use of with polyDMAP or NH3 afforded even better yields; presumably, the reaction rate is increased as HfCl4/KSF with polyDMAP or NH3 afforded even better yields; presumably, the reaction rate is a result the change in Lewis acidity when polyDMAP and NH3 coordinate to the metal center (Hf). increased as a result the change in Lewis acidity when polyDMAP and NH3 coordinate to the metal This catalytic system was applied to a variety of aliphatic amides and benzylamines with excellent center (Hf). This catalytic system was applied to a variety of aliphatic amides and benzylamines with results. Additionally, the HfCl4/KSF-polyDMA catalyst can be easily recovered and reused in the same excellent results. Additionally, the HfCl4/KSF-polyDMA catalyst can be easily recovered and reused reaction at least five times without loss of activity. However, the catalytic system has some limitations in the same reaction at least five times without loss of activity. However, the catalytic system has when other aliphatic amines are used. some limitations when other aliphatic amines are used.

Scheme 10. Transamidation reaction catalyzed by HfCl4/KSF-polyDMAP. Scheme 10. Transamidation reaction catalyzed by HfCl4/KSF-polyDMAP.

The use of stoichiometric boron reagents for amidation reactions has also been reported several times in the literature [8]. Borate esters were used by Sheppard et al. [41] to activate amides in

Molecules 2018, 23, 2382 10 of 17

The use of stoichiometric boron reagents for amidation reactions has also been reported several timesMolecules in 2018 the, 23 literature, x FOR PEER [8]. REVIEW Borate esters were used by Sheppard et al. [41] to activate amides10 of in16 transamidations. They evaluated different boron reagents and found that B(OMe)3 and B(OCH2CF3)3 transamidations. They evaluated different boron reagents and found that B(OMe)3 and B(OCH2CF3)3 show the best behavior in carboxamidation and transamidation processes. This B(OCH2CF3)3- show the best behavior in carboxamidation and transamidation processes. This B(OCH2CF3)3- mediated transamidation reaction gave secondary amides in good yields; unfortunately, the main focus mediated transamidation reaction gave secondary amides in good yields; unfortunately, the main of this study was direct carboxamidation, and consequently, very few examples of transamidations focus of this study was direct carboxamidation, and consequently, very few examples of were provided. A big issue in this is the use of stoichiometric amounts of the boron reagent. transamidations were provided. A big issue in this is the use of stoichiometric amounts of the boron Consequently, the development of new methods that use catalytic amounts of boron reagents is reagent. Consequently, the development of new methods that use catalytic amounts of boron highly desirable. reagents is highly desirable. Nguyen et al. [42] developed the ﬁrst transamidation using substoichiometric amounts of boron Nguyen et al. [42] developed the first transamidation using substoichiometric amounts of boron derivatives. In that research, the authors studied boric acid-catalyzed transamidations of amides and derivatives. In that research, the authors studied boric acid-catalyzed transamidations of amides and phthalimide. Different solvents were tested in an attempt to increase the reaction conversion. As is phthalimide. Different solvents were tested in an attempt to increase the reaction conversion. As is typical for this kind of reaction, nonpolar solvents such as toluene or xylene showed good results; typical for this kind of reaction, nonpolar solvents such as toluene or xylene showed good results; however, a higher conversion was observed when the reaction was performed under solvent-free however, a higher conversion was observed when the reaction was performed under solvent-free conditions. Additionally, the presence of water (1–2 equivalent) helped promote the transamidation conditions. Additionally, the presence of water (1–2 equivalent) helped promote the transamidation process. Different substrates were used successfully and good yields were obtained in most cases. process. Different substrates were used successfully and good yields were obtained in most cases. Secondary amines such as morpholine or piperidine proved to be less reactive and higher temperatures Secondary amines such as morpholine or piperidine proved to be less reactive and higher were needed in order to obtain acceptable yields. The most important advantage of this method temperatures were needed in order to obtain acceptable yields. The most important advantage of this compared with the other reports is the applicability on primary, secondary and tertiary amides method compared with the other reports is the applicability on primary, secondary and tertiary (Scheme 11a). amides (Scheme 11a).

Scheme 11. (a) Boron-mediated transamidation of primary, secondary and tertiary amides with Scheme 11. (a) Boron-mediated transamidation of primary, secondary and tertiary amides with different kinds of amines. (b) Formylation of amines catalyzed by a boronic acid. (c) Transamidation different kinds of amines. (b) Formylation of amines catalyzed by a boronic acid. (c) Transamidation catalyzed by boron between α-amino esters and formamide. catalyzed by boron between α-amino esters and formamide. However, the high temperatures needed to carry out this method have limited the reaction to usingHowever, stable achiral the high amides. temperatures To circumvent needed this to problem, carry out Blanchet this method and coworkerhave limited [43 ]the exploited reaction the to using stable achiral amides. To circumvent this problem, Blanchet and coworker [43] exploited the remarkable efficiency of boronic acids as catalysts for the transamidation of DMF with amines under lower temperatures (Scheme 11b). Many tests were carried out, and the results demonstrated that the combination of 10 mol % of boronic acid A and 20 mol % of acetic acid was the best combination to promote the transamidation reactions (Scheme 11b). The authors proposed a cooperation between

Molecules 2018, 23, 2382 11 of 17 remarkable efﬁciency of boronic acids as catalysts for the transamidation of DMF with amines under lower temperatures (Scheme 11b). Many tests were carried out, and the results demonstrated that the

Moleculescombination 2018, 23 of, x 10FOR mol PEER % REVIEW of boronic acid A and 20 mol % of acetic acid was the best combination11 of to16 promote the transamidation reactions (Scheme 11b). The authors proposed a cooperation between both acids and that a Lewis acid acid-assisted-assisted Bronsted acid (LBA) catalytic system system could could be be involved. involved. Excellent yie yieldslds were found in all cases, and the process showed very good behavior with primary and secondary amines as well as α-amino-amino esters. Nonetheless, to to perform the reaction with chiral substrates, the DMF solvent was changed to formamide in order to keep racem racemizationization at a low level (Scheme 1111c).c). The activation of primary amidesamides to promote transamidationstransamidations u usingsing catalytic amounts of hydroxhydroxylamineylamine was was reported reported by by Williams Williams and and coworkers coworkers [44] [44. They]. They screened screened different different catalysts catalysts and foundand found that that the the hydroxylamine hydroxylamine saltsalt produced produced the the best best results results.. The The study study,, performed performed in in ord orderer to compare the differences between base base-free-free and acid salt salts,s, demonstrate demonstratedd that that the the use of salt saltss has a positive effect onon the conversion of primary amides into secondarysecondary amides.amides. The optimal conditions ◦ for this transformation were toluene at a temperature temperature of of 105105 °CC andand thethe amountamount of of NH NH22OH·HCl varied according to the substrate. T Thehe reaction reaction was successful successful with a wide wide range range of of functional functional groups groups,, including halogens, halogens alkenes,, alkenes, alkynes, alkynes, free freephenolic phenolic hydroxyl hydroxyl groups, group and heterocycles.s, and heterocycle Other importants. Other importantobservations observation in the applications in the ofapplication this methodology of this methodology were that the Bocwere protecting that the Boc group protecting was unaffected group waunders unaffected the typical under reaction the typical conditions reaction (Scheme conditions 12a) (Scheme and that 12 aminoa) and acid thatesters amino can acid be estersN-acylated can be withoutN-acylated loss without of the esterloss of functionality the ester functionality (Scheme 12 (Schemeb). The highest 12b). The conversion highest conversion was generally was seengenerally with aliphatic amides; in some cases, only 10 mol % of NH OH·HCl was necessary to reach full conversion seen with aliphatic amides; in some cases, only 10 mol2 % of NH2OH·HCl was necessary to reach full conversionin short reaction in short times. reaction However, times. the However, transamidation the transamidation of secondary amides of secondary using this amide methodologys using this is methodologynot effective. is not effective.

Scheme 12. Hydroxylamine hydrochloride as a catalyst of the transamidation reaction of (a) substrates withScheme a Boc 12 protecting. Hydroxylamine group and hydrochloride (b) α-amino esters as a withcatalyst a benzyl of the group. transamidation reaction of (a) substrates with a Boc protecting group and (b) α-amino esters with a benzyl group. Hypervalent iodine compounds have undergone impressive developments, and their uses are increasingHypervalent in many iodine applications compound in organics have undergone synthesis. impressive This progress development served ass, inspiration and their touse Singhs are increasingand coworkers in many [45] applications to propose the in ﬁrstorganic iodine synthesis (III)-catalyzed. This progress transamidation served as reaction.inspiration The to best Singh results and werecoworkers obtained [45] whento propose the reaction the first was iodine done (III in)- thecatalyzed presence transamidation of 5 mol % of reaction (diacetoxyiodo)benzene. The best results (DIB)were obtained under microwave when the heatingreaction (60–150 was done◦C) in without the presence any solvent. of 5 mol Gratifyingly, % of (diacetoxyiodo)benzene this methodology (showedDIB) under a very microwave good substrate heating scope (60–150 with °C good) without to excellent any solvent. yields. Gratifyingly, A careful analysis this methodology of the crude showedreaction a mixtures very good was substrate performed scope since with the good catalyst to excellent used is anyield oxidants. A careful and products analysis derived of the crude from reactionHoffman mixtures rearrangements was performed were observed. since the In catalyst addition, used the is use an of oxidant stoichiometric and product amountss derived of catalyst from promotedHoffman rearrangement nitrene formations were and observed increased. In the addition, number ofthe byproducts, use of stoichiometric but by using amounts catalytic of amounts, catalyst promotedthe transamidation nitrene formation reaction wasand increas favored.ed the number of byproducts, but by using catalytic amounts, the transamidationAs mentioned reaction earlier in was this favored manuscript,. the use of organocatalysts has also been described in transamidationAs mentioned reactions. earlier The in this study manuscript, reported by the Adimurthy use of organocatalyst [23], where thes ha processs also been was carrieddescribed out in transamidation reactions. The study reported by Adimurthy [23], where the process was carried out in the presence of L-proline as an inexpensive catalyst (10 mol %) under solvent-free conditions, suffers from some weaknesses, principally the need for the temperature to be higher than 80 °C and the complete inactivity other amino acid catalysts. Continuing with the revision of inexpensive catalysts in transamidation reactions, benzoic acid was recently used by Xu and coworkers [46], showing very good activity in transamidations. The

Molecules 2018, 23, 2382 12 of 17

the presence of L-proline as an inexpensive catalyst (10 mol %) under solvent-free conditions, suffers from some weaknesses, principally the need for the temperature to be higher than 80 ◦C and the complete inactivity other amino acid catalysts. Molecules 2018, 23, x FOR PEER REVIEW 12 of 16 Continuing with the revision of inexpensive catalysts in transamidation reactions, benzoic acid was recently used by Xu and coworkers [46], showing very good activity in transamidations. reaction, performed in xylene at 130 °C◦, showed very good functional group tolerance, and many Thesubstrates reaction, demonstrated performed in good xylene reactivity at 130 . AmongC, showed them very, the good use functionalof heterocycl groupic amides tolerance, (nicotinamide and many, substratesfuran-2- and demonstrated thiophene-2 good-carboxamide reactivity.) with Among heterocyclic them, the amines use of heterocyclicshould be noted amides (see (nicotinamide, Scheme 13a). furan-2-Unfortunately and thiophene-2-carboxamide), this method is not effective with heterocyclicwith aromatic amines amines, should with be which noted (seeit only Scheme afforded 13a). Unfortunately,moderate yields. this The method main isadvantage not effectives of with this aromaticmethodology amines, are with the whichavailability it only of afforded the catalysts moderate and yields.the excellent The main selectivity advantages observed of this. The methodology authors performed are the availability a couple of of experiments the catalysts using and the mixtures excellent of selectivitybenzamide observed. with 3-aminobenzylamine The authors performed and a couplebenzamide of experiments with tryptamine, using mixtures showing of benzamide that only with one 3-aminobenzylamineproduct was formed and in each benzamide case and with thus tryptamine, making this showing a potential that only method one product for the was protection formed inof eachprimary case ami andnes thus (Scheme making 13b) this. a potential method for the protection of primary amines (Scheme 13b).

Scheme 13. (a) Benzoic acid as a catalyst of the transamidation reactions of heterocyclic amides and Scheme 13. (a) Benzoic acid as a catalyst of the transamidation reactions of heterocyclic amides and heterocyclic amines. (b) Selectivity of the transamidation reaction using benzoic acid as a catalyst. heterocyclic amines. (b) Selectivity of the transamidation reaction using benzoic acid as a catalyst.

In addition to these metal-free strategies for transamidation, the use of K2S2O8 in aqueous media was recentlyIn addition described to these[ metal47]. The-free reaction strategies can for be transamidation performed under, the theuse influenceof K2S2O8 ofin aqueous microwaves media or was recently described [47]. The reaction can be performed under the influence of microwaves or conventional heating. The study included the screening of other peroxides, such as H2O2, TBHP, conventional heating. The study included the screening of other peroxides, such as H2O2, TBHP, mCPBA and oxone, finding that K2S2O8 was the best reactant for the transamidation reaction. Unfortunately,mCPBA and o stoichiometricxone, finding amounts that K2S2 ofO8 the was promoter the best are reactant required for to achievethe transamidation complete conversions. reaction. ThisUnfortunately method was, stoichiomet applied successfullyric amount tos of L-phenylalanine the promoter are methyl required ester to hydrochloride achieve complete with conversions DMF as the. formylatingThis method reagent, was appli obtaininged successfully the N-formyl to L-phenylalanine amino acid ester methyl in 95% ester yield hydrochloride without any changewith DM inF the as configurationthe formylating and reagent, optical obtaining purity, making the N-formyl this method amino possiblyacid ester advantageous in 95% yield without with chiral any substrates change in (Schemethe configuration 14a). The authors and optical showed purity an application, making this in the method synthesis possibly of some advantageous very important with molecules, chiral suchsubstrates as phenacetin, (Scheme 14 paracetamol,a). The authors lidocaine showed and an piperine application (Scheme in the 14 synthesisb). of some very important molecules, such as phenacetin, paracetamol, lidocaine and piperine (Scheme 14b). Recently, Das and coworkers [48] developed a new H2SO4-SiO2 catalytic system for the direct transamidationRecently, Das of carboxamides, and coworkers describing [48] developed a new methodology a new H2SO4 which-SiO2 catalytic complements system those for previouslythe direct outlinedtransamidation in thisarticle. of carboxamides, Due to the easier describing ability to manipulate a new methodology the catalysts, which it is described complements as ecofriendly those previously outlined in this article. Due to the easier ability to manipulate the ca◦ talysts, it is described and low cost. The reaction is performed using 5 mol % H2SO4-SiO2 at 70 C under solvent-free conditions,as ecofriendly and and the productslow cost. wereThe reaction obtained is without performed any purification.using 5 mol % H2SO4-SiO2 at 70 °C under solvent-free conditions, and the products were obtained without any purification.

Molecules 2018, 23, 2382 13 of 17 Molecules 2018, 23, x FOR PEER REVIEW 13 of 16 Molecules 2018, 23, x FOR PEER REVIEW 13 of 16

a. a. O O O O O O K S O O K 2S2O8 O O 2 2 8 O H N + NH H N + NH 2 Water, 100 ˚C HN H 2 Water, 100 ˚C HN H or or O MW irradiation Yield O MW irradiation Yield 95% 95%

b. b. H H H HN HN HN N N N N N O O O DRUGS O O HO O O DRUGS O HO Phenacetin Paracetamol Lidocaine Phenacetin Paracetamol Lidocaine 95% 96% 95% 95% 96% 95%

N N O O O O NATURAL PRODUCT Piperine NATURAL PRODUCT Piperine O 83% O 83%

α Scheme 1 14.4. ((a)) N--FormylationFormylation of α--aminoamino esters promoted byby KK22S22O8..( (bb)) Natural Natural products products and and drug drugss Scheme 14. (a) N-Formylation of α-amino esters promoted by K2S2O8. (b) Natural products and drugs obtained by transamidation reactionsreactions using K22S2OO88. . obtained by transamidation reactions using K2S2O8. The catalytic system was explored using tertiary amides with substituted aromatic, heteroaromatic, The catalytic system was explored using tertiary amides with substituted aromatic, andheteroaromatic, aliphatic/alicyclic and aliphatic/alicyclic primary amines primary and some amines secondary and some amines secondary as well. amines The as most well important. The most heteroaromatic,application of thisand methodologyaliphatic/alicyclic was primary in the synthesisamines and of someN-aryl/heteroaryl secondary amines pivalamides, as well. The which most importantimportant applicationapplication ofof thisthis methodologymethodology waswas inin thethe synthesissynthesis ofof N-aryl/heteroaryl pivalamides,, arewhich an are important an importan kindt ofkind compound of compound in organic in organic synthesis synthesis due due to their to their use use as directingas directing groups group ins whichmany transition-metalare an important catalyzedkind of compound reactions in (Scheme organic 15synthesisa). Furthermore, due to their following use as directing this optimized groups inin manymany transitiontransition-metal catalyzed reactions (Scheme 15a). Furthermore, following thisis optimized transamidation protocol protocol,, the authors r reportedeported the synthesis of procainamide procainamide,, a drug used for the transamidationtreatment of cardiac protocol arrhythmias, the authors (Scheme reported 15c). the synthesis of procainamide, a drug used for the treatmenttreatment ofof cardiaccardiac arrhythmiasarrhythmias (Scheme 15c)..

Scheme 15. (a) Synthesis of N-aryl/heteroaryl pivalamides via transamidation catalyzed by H2SO4-SiO2. Scheme 15. (a) Synthesis of N-aryl/heteroaryl pivalamides via transamidation catalyzed by H2SO4- Scheme(b) Synthesis 15. (a of) Synthesis procainamide. of N-aryl/heteroaryl pivalamides via transamidation catalyzed by H2SO4- SiO2. (b) Synthesis of procainamide. SiO2. (b) Synthesis of procainamide.

The examples cited in this section make itit clearclear thatthat thethe transamidationtransamidation reactionreaction underunder metalmetal- free conditions isis anan attractive alternative because of its environmentally friendly and inexpensive

Molecules 2018, 23, 2382 14 of 17

The examples cited in this section make it clear that the transamidation reaction under metal-free conditions is an attractive alternative because of its environmentally friendly and inexpensive nature. Other less relevant reports for metal-free transamidations are also described in the literature. Among them, new catalytic systems using ionic liquids [49], OSU-6 (a modiﬁed silica) [50], Fe3O4-guanidine acetic acid nanoparticles [51], chitosan [52], graphene oxide [53] and nanosized zeolite beta [54] have shown good results and a good substrate scope. However, they do not have any special consideration that make a more detailed discussion necessary.

5. Conclusions The amide moiety is one of the most important functional groups in organic, pharmaceutical and biological chemistry. Its synthesis has been the focus of many researchers; alternative methods to obtain amides are still needed, and this field is in continuous growth. Currently, alternative activation methods for amides are among the most innovative and recent methods; however, the simple activation of the C–N bond in amides by coordination with metals or by interaction with small molecules is an important alternative in amide bond synthesis. Herein, we surveyed the direct activation of amides in transamidation reactions and presented selected examples in this field. We hope this overview will not only that help researchers and serve as inspiration in their future work, but also that they will find it useful in understanding some recently described transamidation processes.

Author Contributions: P.A.-G. wrote more than 70% of the manuscript and contributed to editing the schemes and researching cited papers; A.M.-G. drew the schemes and contributed to the editing and research of the cited papers, as well as the discussion; D.G.-S. wrote approximately 30% of the manuscript and made major revisions and edits. Funding: Financial support was provided by Fondo de Investigaciones de la Facultad de Ciencias de la Universidad de los Andes, convocatoria 2018–2019 para la Financiación de Programas de Investigación “Use of threonine as chiral auxiliary”. Acknowledgments: P.A.-G. and A.M.-G. acknowledge the Universidad de los Andes and particularly the Chemistry Department for providing fellowships. D.G.-S. kindly acknowledges the Chemistry Department of Universidad de los Andes for logistical support. Conﬂicts of Interest: The authors have no conﬂicts of interest to declare.

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