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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]; Molecules 2018, 23, 2382; doi:10.3390/molecules23092382

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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 yields were the always lowerused thanmakes 67%. It wasproperly not untila1994 thatbut a modern complete study on athe however, quantity it not catalyst rather aand promoter; additionally, direct transamidation was published Bertrand and1994 coworkers [16]. Their work wasstudy basedonona direct the yields were always lower than 67%. by It was not until that a modern and complete usetransamidation of aluminum chloride as a promoter, and the was[16]. limited to work the use of based aliphatic amines was published by Bertrand andmethod coworkers Their was on the use of since low yields were as obtained withand aromatic amides. Chemists noticed the and the aluminum chloride a promoter, the method was limited to the use of importance aliphatic amines since potential of the direct transamidation reaction andChemists developed somethe useful and general methods low yields were obtained with aromatic amides. noticed importance and the potential performed under the influence of different of catalysts. metallic, acidic of the direct transamidation reaction andtypes developed someToday, useful heterogeneous, and general methods performed and basicthe catalysts are of available to types perform transamidation In this metallic, review article, under influence different of catalysts. Today,reactions. heterogeneous, acidic we andwill basic begin with the mechanistic studies for transamidation of primary and secondary amides, followed catalysts are available to perform transamidation reactions. In this review article, we will begin with bythe studies of the reaction tertiary amides and some other studies followed using proline as a mechanistic studieswith for transamidation of primary and mechanistic secondary amides, by studies catalyst. the following sections, we will a set of selected examples of direct transamidation of the In reaction with tertiary amides andpresent some other mechanistic studies using proline as a catalyst. reactions catalyzedsections, by metals well as some alternative catalysts. In the following weaswill present a set of selected examples 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 an alternative strategy to prepareofamides, the direct exchange of the amine moiety In intransamidation, an amide can occur only under the influence a suitable catalytic or stoichiometric moiety in an amide can occur only under the influence of a suitable catalytic or stoichiometric activating activating agent because of the poor electrophilic nature of amides. Depending on the reaction agent because of the poor electrophilic nature amides. agent Depending on thethe reaction conditions, conditions, the structure of the amide, and the of activating employed, reactivity of thesethe structure of the amide, and the activatinghowever, agent employed, reactivity these amides from amides differs from reaction to reaction; it followsthe the regular of pattern that thediffers primary reaction to reaction; however, it follows the regular pattern that the primary amides are more active amides are more active than the secondary and tertiary amides. Nevertheless, some activating agents than the tertiaryamides amides.have Nevertheless, some activating agents capable of activating capable of secondary activating and secondary been described in the literature with considerable secondary amides have been described the literature withthe considerable [10].isThe success [10]. The order of reactivity showninbefore implies that structure ofsuccess the amide theorder most of reactivity shown before implies that the structure of the amide is the most important constraint important constraint in transamidation processes. Another very important factor is the acidic nature in processes. Another verythe important is theinactivating acidic nature the N-Hspecies. function, of transamidation the N-H function, which could hamper process factor by simply theofcatalytic which could hamper the process by simply inactivating the catalytic species. Considering these facts, Considering these facts, understanding how this process occurs represents one of the main challenges how thiscommunity process occurs forunderstanding the organic chemistry [8].represents one of the main challenges for the organic chemistry community [8]. Stahl and coworkers [17–19] studied the mechanism of the transamidation reaction In this sense, In this sense, Stahl and coworkers [17–19] studiedathe mechanism of the transamidation reaction catalyzed by metals, focusing on the reaction between secondary amine and a secondary amide catalyzed by metals, focusing the reaction between aalkali-metal secondary amine and a secondary amide (Scheme 1). They evaluated the on behavior of nucleophilic amides, Lewis acidic metal (Scheme 1). They evaluated thedifferent behavioramides. of nucleophilic alkali-metal amides, Lewis acidic metal complexes, transition metals and The authors found that metallic complexes of complexes, transition metals and different amides. The authors found that metallic complexes titanium and aluminum could catalyze the transamidation reaction due to their relatively low of titanium and aluminum couldcomplexes catalyze the reaction due to their relatively basicity; basicity; furthermore, metallic of transamidation titanium [Ti(NMe 2)4] and aluminum [Al(NMelow 2)6] could furthermore, metallic complexes of titanium [Ti(NMe ) ] and aluminum [Al(NMe ) ] could catalyze catalyze the transamidation reaction due to an increase2in4 electron density in the metal 2 6 center. This the is transamidation reactionbasicity due to an increase inwhich electron densitythe in Lewis the metal center. This of effect effect related to the reduced of the ligand, increases acidic character the is related to the reduced basicity of the ligand, which increases the Lewis acidic character of the metal. metal.

Scheme 1. Transamidation a secondary amide with a secondary amine. Scheme 1. Transamidation of aofsecondary amide with a secondary amine.

Based previous information, author carried a complete mechanistic study, which Based onon thethe previous information, thethe author carried outout a complete mechanistic study, which included determination deuterium kinetic isotope effect, rate law and identity included thethe determination of of thethe deuterium kinetic isotope effect, thethe rate law and thethe identity of of the catalyst resting state. With the results obtained in the kinetic studies, they proposed a catalytic the catalyst resting state. With the results obtained in the kinetic studies, they proposed a catalytic mechanism explain transamidation process (Scheme They suggested in the first step, mechanism to to explain thethe transamidation process (Scheme 2). 2). They suggested thatthat in the first step, the secondary amide reacts with the precatalyst to yield metal-amidate complex I. Once this complex the secondary amide reacts with the precatalyst to yield metal-amidate complex I. Once this complex is formed, it enters catalytic cycle a bimolecular reaction with a primary amine generate is formed, it enters thethe catalytic cycle byby a bimolecular reaction with a primary amine to to generate adduct After that, a proton transfer between nitrogen atoms is proposed reach intermediate adduct II. II. After that, a proton transfer between thethe nitrogen atoms is proposed to to reach intermediate III. Later, an intramolecular nucleophilic attack of the amido-ligand to the carbonyl of the amide forms III. Later, an intramolecular nucleophilic attack of the amido-ligand to the carbonyl of the amide metallacycle IVa. This intermediate is the most important species in the catalytic cycle because forms metallacycle IVa. This intermediate is the most important species in the catalytic cycle because it embodies the bifunctional role of the metal center via activation of both the amine and amide substrate.

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it embodies the bifunctional role of the metal center via activation of both the amine and amide However, this intermediate can either revert cycle to complex III to or continue cyclethe by substrate. However, this intermediate can the either revert the cycle complex the III catalytic or continue isomerization to form IVb. The isomerization proceeds by transition state V, where the metal is linked catalytic cycle by isomerization to form IVb. The isomerization proceeds by transition state V, where to both nitrogen changing thethus nitrogen coordinated to the metal center and providing the metal is linkedatoms, to boththus nitrogen atoms, changing the nitrogen coordinated to the metal center exchanged intermediate This product easily converted intoconverted VI, and finally, theand breakdown of and providing exchangedIVb. intermediate IVb.isThis product is easily into VI, finally, the intermediate VI promoted by a second molecule of amide leads to the formation of the desired amide breakdown of intermediate VI promoted by a second molecule of amide leads to the formation of the and the amide liberation anliberation amine molecule that ismolecule responsible, of the cases, for of thethe equilibrium desired andofthe of an amine thatin is most responsible, in most cases, for displacements; other words: it the driving of this reaction the equilibriumin displacements; inisother words: force it is the driving force[18–20]. of this 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 Careful analysis of the proposed mechanism that tertiary amides are unsuitable for the transamidation reaction. This is because of thesuggests absence of an N-H bond and the consequently reagents for the transamidation This is because of the absenceexamples of an N-H bond and the different reactivity between these reaction. amides and bases. However, successful of transamidation consequently different reactivity between these amides and bases. However, successful examples of reactions with tertiary amides have been described in the literature, suggesting that tertiary amides transamidation tertiary amides haveStahl been and described in the confronted literature, suggesting should follow areactions differentwith mechanistic pathway. coworkers this issue that and tertiary amides should follow a different mechanistic pathway. Stahl and coworkers confronted this developed a new study focused on the mechanistic details of the transamidation reaction between issue and developed a new study focused on the mechanistic details of the transamidation reaction tertiary amides and secondary amines employing kinetic, spectroscopic, and computational studies between amidestoand secondary amines spectroscopic, and computational (Scheme tertiary 3). According their results, the first employing step occurskinetic, when the amide interacts with the metal studies (Scheme 3). According to their results, the first step occurs when the amide interacts withand the complex to form intermediate I, where the simultaneous activation of the electrophile (amide) metal complex to form intermediate I, where the simultaneous activation of the electrophile (amide) the nucleophile (amine) by the metal center is clear. After that, an intramolecular attack of the amido and thetonucleophile (amine) by the metal center is clear. After that, an intramolecular attack of can the ligand the coordinated amide gives rise to metal-stabilized tetrahedral intermediate IIa, which amido ligand to the coordinated amide gives rise to metal-stabilized tetrahedral intermediate IIa, interconvert to its isomeric intermediate IIb by a simple cleavage and coordination sequence through which can interconvert tostep, its isomeric intermediate IIbcoordinated by a simple cleavage and coordination intermediate III. In the last a new amine/amido pair to the metal IV is formed, from sequence through intermediate III. In the last step, a new amine/amido pair coordinated to the metal which it is possible to obtain the desired product [21,22]. 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 secondary amines. Comparing 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 Comparing the transamidation processes for secondary amides is and amides makes some between the intermediates but also that the key step in both processes thetertiary intramolecular nucleophilic similarities First, the exhibit not onlyRegarding that there are structural similarity attack of theevident. amido ligand on mechanisms a metal-coordinated amide. theobvious differences between the two between the intermediates but also that the key step in both processes is the intramolecular transamidation processes, perhaps the most important one is the identity of the catalyst resting state, nucleophilic attack ofdifferences the amidoinligand on a metal-coordinated amide. Regarding the differences implying substantial the kinetic properties of both reactions since the transamidation between the two transamidation processes, perhaps most important one isand the amine identity of the reaction of secondary amides follows first-order kineticsthe with regards to the metal involved catalyst resting state, implying substantial differences in the kinetic properties of both reactions since and the amide follows zero-order kinetics. Contrary to that, for the tertiary amide, the rate law is the transamidation reaction of secondary amides follows first-order kinetics with regards to the metal zero-order for the amine, is half- to first-order for the metal and varies from zero-order to saturation and amine and amide follows zero-order kinetics. Contrary tocases that, described for the tertiary behavior forinvolved the amide. Thethe transamidation of primary amides is easier than the before amide, the rate law is zero-order for the amine, is halfto first-order for the metal and from because ammonia is produced in the reaction medium, thus making the reaction simpler varies and usually zero-order to saturation behavior for the amide. The transamidation of primary amides is easier than better yielding. Concerning the mechanisms, each research team describes its own proposal, typically the cases described before because ammonia is produced in the reaction medium, thus making based on the Stahl studies. In our opinion, slight differences between metals should exist, andthe as reaction simpler and usually better yielding. Concerning the mechanisms, each research team a consequence, the reaction mechanism for the transamidation of primary amides should be pretty describes its own proposal, typically based onAdditionally, the Stahl studies. In our opinion, slight differences similar to that described for secondary amides. the large number of non-metal-catalyzed between metals should exist, and as a consequence, the reaction mechanism for the transamidation transamidation reactions makes the investigation of their mechanisms interesting. Unfortunately, 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 large number of non-metal-catalyzed transamidation reactions makes the investigation of their other catalysts remain unexplored. mechanisms interesting. Unfortunately, only one computational study onasthe reactionmethodology catalyzed by The organocatalyzed transamidation reaction has been described a greener 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 transamidation reaction has been described as a greener methodology to itsThe dualorganocatalyzed role as a ligand and a catalyst in other reactions. In view of the above perceptions, L-proline compared with the metal-catalyzed version of this reaction. L-Proline has received much attention was described as a useful catalyst for the transamidation reaction. Adimurthy and coworkers [23] due to that its dual role as a ligand and a catalyst in other reactions. view of the perceptions, Lfound various amides react with a variety of amines in theInpresence of Labove -proline as a catalyst. proline was described as a useful catalyst for the transamidation reaction. Adimurthy and coworkers The reaction scope included benzylamines with electron-rich and deficient substituents 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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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 LL -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 H2 O catalytic cycle with the largest energy barrier (26.0, 26.8 and 29.7 kcal/mol in toluene, ethanol and respectively) (Scheme 4) [24]. H2O respectively) (Scheme 4) [24]. H2 O O NH2 +

COOH

N H

COO

N

NH2 (I)

O

H2 N

N H H 2O

COO

N

COOH

N

N H

H2N

(III)

N H (II)

HNH2

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; As already mentioned, theversion mechanistic studies follows on the transamidation reaction are quite limited; however, the metal-catalyzed presumably similar mechanisms independent of the however, the metal-catalyzed version presumably follows mechanisms independent of the metal identity, with the mechanistic pathway depending onsimilar the type of amide reacting. Concerning metal identity, with the mechanistic pathway depending on the of amidebut reacting. the non-metal-catalyzed version, some examples are described in type the literature, amongConcerning them, only the non-metal-catalyzed version, some examples are described thecarried literature, among them, L -proline has received enough attention that a mechanistic studyin was out. but Nevertheless, the only L-proline has received enough attention thatsection a mechanistic study carried out. Nevertheless, summary of mechanistic studies presented in this is sufficient towas understand the principles and the summary ofofmechanistic studies presented in this section is sufficient understand the principles particularities transamidation reactions. In the following chapters, wetowill present some selected and particularities of transamidation reactions. In the following chapters, we will present some examples of transamidations and discuss their particularities and issues. 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 for direct work transamidation them, one of the most commonly used the pioneering reported byreactions. Stahl andAmong coworkers [18–22], several metal catalysts have is iron(III), particularly the form of simple Fe(III)Among salts, supported even as nanoparticles. been described for directintransamidation reactions. them, oneinofclay theor most commonly used is The first study was reported in 2014 by Shimizu coworkers [25]; Fe(III) supported in iron(III), particularly in the form of simple Fe(III)and salts, supported in they clay used or even as nanoparticles. montmorillonite to reported perform the direct of primary amides (Scheme 5). supported The authors The first study was in 2014 bytransamidation Shimizu and coworkers [25]; they used Fe(III) in showed that the reaction can be under solvent-free conditions with a slight 5). excess amine montmorillonite to perform theperformed direct transamidation of primary amides (Scheme Theofauthors at 140 ◦ C. showed 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+ -mont. Scheme 5. of aryl, (b) Transamidations of α-hydroxyamides with amines. Scheme 5. (a) (a) Transamidation Transamidation of amides amides (alkyl, (alkyl, aryl, Het-aryl) Het-aryl) with with amines amines catalyzed catalyzed by byFe Fe3+-mont. (b) (b) Transamidations Transamidationsof ofα-hydroxyamides α-hydroxyamideswith withamines. amines.

Unfortunately, the scope of the reaction is limited; only primary amides and primary amines can Unfortunately, the scope of the the reaction is limited; only amides primary aminessince can be used (Scheme 5a). Additionally, method is limited to primary the use of liquidand starting materials Unfortunately, the scope of the reaction is limited; only primary amides and primary amines can be used (Scheme 5a). Additionally, the method is limited to the use of liquid starting materials since at at of the5a). two reagents hasthe to method be a liquid, thus making this unsuitable for a large be least used one (Scheme Additionally, is limited to the use ofmethod liquid starting materials since least one of of the two reagents to be a liquid, thus α-hydroxy making thisamides methodwere unsuitable for a large number number reagents. fewhas examples with free described (Scheme 5b). at least one of the twoAreagents has to be a liquid, thus making this method unsuitable for a large of reagents. A few examples with free α-hydroxy amides were described (Scheme 5b). Typically, Typically, reactions carried out under solvent-free conditions are seen as good examples of green number of reagents. A few examples with free α-hydroxy amides were described (Scheme 5b). reactions carried out however, under solvent-free conditions are seen astogood examples of green chemistry chemistry transamidation has seen perspective. Typically, principles; reactions carried outthe under solvent-freereaction conditions arebe seen asfrom goodanother examples of green principles; however, the transamidation reaction has to be seen from another perspective. we As we mentioned before, amidation reactions arereaction one of has the to most performed processes inAsdrug chemistry principles; however, the transamidation be seen from another perspective. mentioned before, amidation reactions are one of the most performed processes in drug discovery and discovery and the pharmaceutical industry, and structure of amides used in those fields are As we mentioned before, amidation reactions arethe one of the most performed processes in drug the pharmaceutical industry, and the structure of amides used in those fields are somehow complex, somehow meaning they are usually and polyfunctional compounds more than 20 carbon discovery complex, and the pharmaceutical industry, the structure of amideswith used in those fields are meaning they are usually polyfunctional compoundsAs with more than 20 carbon atoms or, in some cases, atoms or, in some cases, amino acid derivatives. a consequence, a good method to synthesize somehow complex, meaning they are usually polyfunctional compounds with more than 20 carbon amino acid As a consequence, a good method to synthesize amides has to be amenable to amides hasinderivatives. tosome be amenable to all thederivatives. structures mentioned before, and solid reagents highly atoms or, cases, amino acid As a consequence, a good method to are synthesize all the structures mentioned and solid reagents are This highly desirable even if the use oftoadevelop solvent desirable even use of a before, solvent becomes imperative. has served as inspiration amides has to ifbethe amenable to all the structures mentioned before, andussolid reagents are highly becomes imperative. This has served us as inspiration to develop a more general method for direct adesirable more general transamidations using Fe(III) [26]. Our us method is based to ondevelop the use even ifmethod the use for of adirect solvent becomes imperative. This has served as inspiration transamidations using Fe(III) [26]. Our method is based on the use of simple Fe(III) salts. In fact, we of simple Fe(III)method salts. Infor fact, we demonstrated that any Fe(III) [26]. salt can used asisabased catalyst a more general direct transamidations using Ourbe method on for the this use demonstrated that any Fe(III) salt can be used as a catalyst for this reaction; the sole condition is the reaction; solesalts. condition is the of water, has asalt complementary catalytic rolefor in this of simplethe Fe(III) In fact, we presence demonstrated thatwhich any Fe(III) can be used as a catalyst presence of water, which hasor a complementary catalyticsalts, role in this process. Wateriscan belimited added by or process. Water can be added obtained from hydrated the identity of which only reaction; the sole condition is the presence of water, which has a complementary catalytic role in this obtained from hydrated salts, the identitygrade of which is only limited by the availability of the reagents. the availability of the toluene is also a suitable process. Water can be reagents. added or Technical obtained from hydrated salts, the identitysolvent. of whichConsequently, is only limitedthis by Technical grade toluene is also a suitable solvent. Consequently, this method is one of the cheapest method is one of the cheapest reported in the literature (Scheme 6). the availability of the reagents. Technical grade toluene is also a suitable solvent. Consequently, this reported in the literature (Scheme 6). method is one of the cheapest reported in the literature (Scheme 6).

Scheme (c) Scheme 6. 6. Transamidation Transamidation catalyzed catalyzed by by Fe(III) Fe(III) and and water water of of (a) (a) carboxamides. carboxamides. (b) (b) α-amino α-amino esters. esters. (c) Synthesis of 2,3-dihydro-5H-benzo[b]-1,4-thiazepin-4-one by intramolecular transamidation. Synthesis 2,3-dihydro-5H-benzo[b]-1,4-thiazepin-4-one intramolecular transamidation. Scheme 6.ofTransamidation catalyzed by Fe(III) and water by of (a) carboxamides. (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 Theorreaction is very since the reaction canThe be performed not depends only withonanthe excess of amides aminesscope but also withgood stoichiometric quantities. reaction time amide amides or amines but also with stoichiometric quantities. The reaction time depends on the amide used, but it is usually shorter with primary amides and longer with secondary and tertiary amides. used, butdescribed it is usually with primary amides amides and longer with and tertiary We also the shorter transamidation of secondary where thesecondary liberated amine is not aamides. gas or We also described the transamidation of secondary amides where the liberated amine is not abe gas or a a volatile liquid and showed that Fe(III)/water is a suitable catalyst in those cases. It should noted volatile liquid and showed that Fe(III)/water is a suitable catalyst in those cases. It should be noted that that no previous functionalization of the secondary amide was needed (Scheme 6a). Finally, the no previous the secondary amide Finally, theand reaction reaction wasfunctionalization described withofsome amino acids aswas theneeded amino(Scheme source 6a). (Scheme 6b), one was described with some amino acids as the amino source (Scheme 6b), and one intramolecular intramolecular example was provided (Scheme 6c). A few years later, magnetic nanoparticles were example was provided (Scheme 6c). A few magnetic were used in direct used in direct transamidation reactions, withyears somelater, advantages andnanoparticles issues. The method described 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 Fe same problem allcatalyst transamidations performed solvent-free 3 O4 has the conditions show. The loadingthat of the is also high (20 wt.%),under and only primaryconditions amines areshow. used The loading of theHowever, catalyst is this also high (20 wt.%), and has only some primary amines arethe used as nucleophiles. as nucleophiles. particular method advantages: catalyst is easily However, method has reactions some advantages: the of catalyst is easily recovered can be recovered this and particular can be used in several without loss activity. It is also simple and to prepare, used in several reactions without loss of activity. It is also simple to prepare, and the reaction be and the reaction can be performed with DMF as an example of a tertiary amide. On the othercan hand, performed DMF asby an Heidari example and of a tertiary amide. the other hand, the method described by the methodwith described Arefi [28] has On a better substrate scope and uses smaller Heidari and Arefi [28] has a better substrate scope and uses smaller quantities of catalyst. Unfortunately, quantities of catalyst. Unfortunately, the preparation process for the catalyst is more complicated and the the catalyst complicated and uses simple iron salts precursors; usespreparation simple ironprocess salts as for precursors; thisisismore potentially problematic since the authors didasnot quantify this is potentially problematic since the authors did not quantify the free salts in their catalyst, and it the free salts in their catalyst, and it is possible that some remaining salts are responsible for the is possible that some remaining salts are responsible for the transformation, on the other hand if the transformation, on the other hand if the simple salts are good and suitable catalysts for this reactions, simple are goodthat and do suitable catalysts very for this reactions, prepare a catalysts do notmaterials provide preparesalts a catalysts not provide different results using them athat starting very different results using them a starting materials consumes time unnecessarily. The recovery of the the consumes time unnecessarily. The recovery of the catalyst was also described, but the identity of catalyst also is described, but the the catalytic speciesthe is still unclear; both to Heidari and catalyticwas species still unclear; bothidentity Heidariofand Thale attribute catalytic activity the metal Thale attribute the catalytic activity to the metal center. center. It and as as such, or It is is clear clear that that the the transamidation transamidation reaction reaction is is an an equilibrium, equilibrium, and such, when when ammonia ammonia or gaseous amines are are liberated liberated in in the the reaction reaction media, media, the the reaction reaction is is easier. gaseous amines easier. On On the the other other hand, hand, when when the liberated amine is a liquid, the reaction becomes more complicated. Stahl and Gellman et al. the liberated amine is a liquid, the reaction becomes more complicated. Stahl and Gellman et al. [29] [29] faced faced this this problem problem and and developed developed aa method method applicable applicable to to N-aryl N-aryl amides. amides. In In this this case, case, Ti(NMe Ti(NMe22))44 and and Sc(OTf) affording good yields and acceptable selectivities to the cross-product. Sc(OTf)33 were weresuitable suitablecatalysts catalysts affording good yields and acceptable selectivities to the crossThe reaction was performed with nonpolar solvents and at low temperatures. However, the best product. The reaction was performed with nonpolar solvents and at low temperatures. However, the results were obtained with an excess of aliphatic amines (Scheme 7a); the use of stoichiometric aromatic best results were obtained with an excess of aliphatic amines (Scheme 7a); the use of stoichiometric amines mixtures of products aromaticproduced amines produced mixtures of (Scheme products7b). (Scheme 7b). a. O C6H13

N H

R1

5 mol % cat +

NH2

Tol, 90 ˚C, 16 h

R1= Alkyl

O N H

C6H13

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

b. O C6H13

O N H

Ph

+

H 2N

p-xylene,120 ˚C, 20 h

O

O

Ti(NMe2)4 10 mol % C6H13

N 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 The reactions described before have1 some they aretoall performed in nonpolar solvents, and an excess (at least equiv.)common of one ofcharacteristics: the reagents is needed obtain complete 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 conversions good One interesting development the use of Cu(OAc) 2 as a catalyst described byand Beller andyields. coworkers [30], who used tert-amylwas alcohol as the solvent and 0.3 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

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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 substrate scope, scope, as as it it tolerates tolerates free free OH OH groups groups in in the the substrate substrate and and can can be be performed performed with with chiral chiral reagents (amides or amines) without racemization. The sole problem is the use of sealed tubes since reagents The sole reagents (amides (amides or or amines) amines) without without racemization. racemization. The sole problem problem is is the the use use of of sealed sealed tubes tubes since since high pressures are a safety issue in organic chemistry laboratories. high pressures are a safety issue in organic chemistry laboratories. high pressures are a safety issue in organic chemistry laboratories. As the reader can notice, several efforts have been made to have more active and general As notice, several efforts havehave been been mademade to have general As the thereader readercan can notice, several efforts tomore haveactive moreand active andcatalysts general catalysts for transamidations. Simple metal salts have been proven as suitable catalysts for this for transamidations. Simple metal salts have been proven as suitable catalysts for this transformation, catalysts for transamidations. Simple metal salts have been proven as suitable catalysts for this transformation, however, the use of more developed metal catalysts may have some advantages. In however, the usehowever, of more developed may havecatalysts some advantages. In particular, the use transformation, the use of metal more catalysts developed metal may have some advantages. In particular, the use of sulfated tungstate proved to be effective with α,β-unsaturated amides [31]. of sulfated tungstate to tungstate be effective with α,β-unsaturated amides [31]. These substrates can particular, the use ofproved sulfated proved to be effective with α,β-unsaturated amides [31]. These substrates can be potentially complicated because of the presence of two reactive sites. Once be potentially complicated because complicated of the presence of two sites. of Once amidesites. forms the These substrates can be potentially because ofreactive the presence twothe reactive Once the amide forms the complex with the metal center, the carbonyl is more electrophilic, but the β complex with the metal center, the carbonyl is more electrophilic, but the β position suffers a similar the amide forms the complex with the metal center, the carbonyl is more electrophilic, but the β position suffers a similar activation; as a consequence, Michael additions are competitive reactions. activation; as a consequence, Michael are competitive reactions. the case ofreactions. sulfated position suffers a similar activation; as additions a consequence, Michael additions areIn competitive In the case of sulfated tungstate, no Michael product was observed (Scheme 8a). The catalyst was also tungstate, no Michael product was observed (Scheme 8a). The catalyst was also active with α-amino In the case of sulfated tungstate, no Michael product was observed (Scheme 8a). The catalyst was also active with α-amino acid esters, as observed in Scheme 8b. acid esters, observed inesters, Scheme active with as α-amino acid as8b. observed in Scheme 8b.

Scheme 8. Transamidation reactions in the presence presence of sulfated tungstate of (a) cinnamide with alkyl Scheme Transamidation reactions in the presence of sulfated tungstate of (a) cinnamide with alkyl and aryl 8. amines and (b) (b) α-amino α-amino esters esters with with formamide. formamide. and aryl amines and (b) α-amino esters with formamide.

The amides is is typically typically exemplified exemplified with with DMF, DMF, and The use use of of tertiary tertiary amides and very very few few examples examples with with other other 0examples Theamides use of tertiary amides is typically exemplified with DMF, and2 very few with other tertiary have been described. Fortunately, the use of Pd(OAc) with 2,2 -bipyridine tertiary amides have been described. Fortunately, the use of Pd(OAc)2 with 2,2′-bipyridine (bpy) (bpy) as as tertiary amides have been described. Fortunately, the use of Pd(OAc) 2 with 2,2′-bipyridine (bpy) as the ligand canbe be used forthe the transamidation of tertiary amides catalyst afforded very the ligand can used for transamidation of tertiary amides [32].[32]. This This catalyst afforded very good the ligand can be used for the transamidation of tertiary amides [32]. This catalyst afforded very good good with aromatic amines, are easily oxidized and consequently than yieldsyields with aromatic amines, whichwhich are easily oxidized and consequently gave gave lowerlower yieldsyields than their yieldsaliphatic with aromatic amines, which are easily oxidized and consequently gave lower yields than their their partners (Scheme 9). The biggest issue of this method is the use of a large excess of aliphatic partners (Scheme 9). The biggest issue of this method is the use of a large excess of amine: aliphatic partners (Scheme 9). The biggest issue of this method is the use of a large excess of amine: amine: 10 equivalents are required. However, the reaction can be performed onscale a gram with 10 equivalents are required. However, the reaction can be performed on a gram withscale excellent 10 equivalents are required. However, the reaction can be performed on a gram scale with excellent excellent results. 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 recently, Hu and coworkers [33] described a reductive transamidation of tertiary amides (veryVery challenging substrates) with nitrobenzenes promoted by manganese. Presumably, the manganese Very recently, Hu and coworkers [33] described a reductive transamidation of tertiary amides (very challenging substrates) with nitrobenzenes promoted by manganese. Presumably, acts not only as a reducing agent by producing the amine in situ but also as an activating agent the for (very challenging substrates) with nitrobenzenes promoted by manganese. Presumably, the manganese acts was not only as aby reducing producing amine in situ but also as an activating the amide. This proven adding agent some by metals usuallythe found as impurities of manganese, such manganese acts not only as a reducing agent by producing the amine in situ but also as an activating agent for theoramide. was proven by adding some metals usually as impurities of as palladium nickel.This Additionally, this metal has also been described as a found useful catalyst in a new agent for the amide. This was proven by adding some metals usually found as impurities of manganese, such as palladium or nickel. Additionally, this metal has also been described as a useful method of transamidations, such as a reaction where the amide is activated by the use of BOC or 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

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groups to increase their reactivity. There are some amazing recent publications in this field, but this are not field, within thethis scope review The reaction byreaction Hu et al.performed showed very good in this but are of notthis within thearticle. scope of this reviewperformed article. The by Hu et substrate scope and, to the best of our knowledge, is the sole general method for direct transamidation al. showed very good substrate scope and, to the best of our knowledge, is the sole general method of amides. fortertiary direct transamidation of tertiary amides. From the previous examples, transamidation reaction powerful alternative From the previous examples, it it is is clear clear that that the the transamidation reaction is is aa powerful alternative in The use use of of metal metal catalysts catalysts has has shown shown tremendous tremendous growth growth in in the the last last few few years, years, in amide amide synthesis. synthesis. The and many researchers have developed a vast variety of catalysts using metallic centers. We selected and many researchers have developed a vast variety of catalysts using metallic centers. We selected the the most most general general and and simplest simplest methods methods to to discuss discuss in in this this review review article. article. Nevertheless, Nevertheless, other other less less important catalysts have to be superficially mentioned, including manganese oxide (MnO important catalysts have to be superficially mentioned, including manganese oxide (MnO22), ), which which was used under undersolvent-free solvent-freeconditions conditions[34] [34]with with a limited substrate scope yields. was used a limited substrate scope but but withwith goodgood yields. The The use of lanthanides has also been described; in particular, a bimetallic lanthanum alkoxide [35], and use of lanthanides has also been described; in particular, a bimetallic lanthanum alkoxide [35], and immobilized with the associated advantages, such as immobilized Ce(III) Ce(III)[36] [36]were wereused usedasasheterogeneous heterogeneouscatalysts catalysts with the associated advantages, such easy catalyst recovery and low catalyst charge, but also with the normal issues, such as the catalyst as easy catalyst recovery and low catalyst charge, but also with the normal issues, such as the catalyst preparation Some moremore innovative catalysts have been prepared used successfully preparation and andactivation. activation. Some innovative catalysts have been and prepared and used in transamidation. Mesoporous niobium oxide spheres [37] and N-heterocyclic carbene ruthenium (II) successfully in transamidation. Mesoporous niobium oxide spheres [37] and N-heterocyclic carbene complexes are some of[38] theare most general and easy to use and catalysts best substrate scope. ruthenium [38] (II) complexes some of the most general easy with to usethe catalysts with the best · Very recently, the use of Co(AcO) 4H O was described [39] with an excellent substrate scope, but 2 2 substrate scope. Very recently, the use of Co(AcO)24H2O was described [39] with an excellent there are no special considerations to mention here. substrate scope, but there are no special considerations to mention here. Some of the the catalysts catalystspresented presentedin inthis thissection sectioncan canbebeused used with ureas, with phthalimide and, Some of with ureas, with phthalimide and, in in very few cases, with thioureas. The activation of those substrates has proven more difficult than very few cases, with thioureas. The activation of those substrates has proven more difficult than amides, addition, no amides, even even though though the the C–N C–N bond bond has has similar similar features features to to them. them. In In addition, no details details are are provided provided about the application of transamidation reactions with ureas and phthalimides since it is outside about the application of transamidation reactions with ureas and phthalimides since it is outside the the scope scope of of this this review. review. Concerning Concerning the the catalysts, catalysts, the the development development of of nonmetallic nonmetallic catalysts catalysts has has received received comparable comparable attention attention and and will will be be discussed discussed in in the the next next 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

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The use of stoichiometric boron reagents for amidation reactions has also been reported several Molecules 2018, 23, x FOR PEER REVIEW 10 of 16 times in the literature [8]. Borate esters were used by Sheppard et al. [41] to activate amides in transamidations. They evaluated different boron reagents and found that B(OMe)3 and B(OCH2 CF3 )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(OCH2 CF3 )3 show the best behavior in carboxamidation and transamidation processes. This B(OCH2CF3)3mediated 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 the high temperatures needed carry outBlanchet this method have limited reactionthe to usingHowever, stable achiral amides. To circumvent thistoproblem, and coworker [43]the exploited 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

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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 ofx10 mol % REVIEW of boronic acid A and 20 mol % of acetic acid was the best combination Molecules 2018, 23, FOR PEER 11 of to 16 promote the transamidation reactions (Scheme 11b). The authors proposed a cooperation between both acids and that a Lewis acid-assisted acid-assisted Bronsted Bronsted acid acid (LBA) (LBA) catalytic catalytic system system could could be be involved. involved. primary Excellent yields were found in all cases, and the process showed very good behavior with primary and secondary amines as well as α-amino esters. Nonetheless, to perform the reaction with chiral -amino Nonetheless, to perform substrates, the DMF solvent was changed to formamide in order to keep racemization at a low level (Scheme 11c). The activation of primary amides to promote transamidations using catalytic amounts of hydroxylamine was wasreported reportedby byWilliams Williamsand and coworkers [44]. They screened different catalysts hydroxylamine coworkers [44]. They screened different catalysts and and found hydroxylamine produced best results.The Thestudy, study,performed performedin in order order to found that that the the hydroxylamine saltsalt produced thethe best results. compare the differences between base-free and acid salts, demonstrated demonstrated that that the the use of salts has a positive effect on the conversion of primary amides into secondary secondary amides. The optimal conditions ◦ C and the amount of NH OH·HCl for this transformation were toluene at a temperature of for this transformation were toluene at a temperature of 105 105 °C and the amount of NH22OH·HCl varied substrate. The The reaction reaction was was successful successful with with aa wide wide range range of of functional functional groups, groups, varied according according to to the the substrate. including halogens, alkenes, alkynes, free phenolic hydroxyl groups, and heterocycles. Other important including halogens, alkenes, alkynes, free phenolic hydroxyl groups, and heterocycles. Other observations in the application this methodology were that the Boc group was unaffected important observations in the of application of this methodology wereprotecting that the Boc protecting group under the typical reaction conditions (Scheme 12a) (Scheme and that 12a) amino N-acylated was unaffected under the typical reaction conditions andacid thatesters aminocan acidbeesters can be without losswithout of the ester functionality (Scheme 12b). The highest conversion was generally with N-acylated loss of the ester functionality (Scheme 12b). The highest conversion was seen generally aliphatic in amides; some cases, onlycases, 10 molonly % of10NH HCl was necessary reach fulltoconversion 2 OH seen withamides; aliphatic in some mol % ·of NH 2OH· HCl wastonecessary reach full in short reaction times. However, the transamidation of secondary amides using this methodology is conversion in short reaction times. However, the transamidation of secondary amides using this not effective. methodology is not effective.

Scheme 12. Hydroxylamine hydrochloride as a catalyst of the transamidation reaction of (a) substrates Scheme Hydroxylamine hydrochloride as a with catalyst of the transamidation reaction of (a) with a Boc12. protecting group and (b) α-amino esters a benzyl group. 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 Hypervalent iodine compounds have undergone developments, and their to uses are increasing in many applications in organic synthesis. impressive This progress served as inspiration Singh increasing in many applications in organic synthesis. This progress served as inspiration to Singh and and coworkers [45] to propose the first iodine (III)-catalyzed transamidation reaction. The best results coworkers [45] when to propose the firstwas iodine transamidation The best results were obtained the reaction done(III)-catalyzed in the presence of 5 mol % ofreaction. (diacetoxyiodo)benzene ◦ were obtained when the heating reaction(60–150 was done the presence of 5 mol % of (diacetoxyiodo)benzene (DIB) under microwave C)inwithout any solvent. Gratifyingly, this methodology (DIB) under microwave heating (60–150 °C) without any solvent. Gratifyingly, this showed a very good substrate scope with good to excellent yields. A careful analysismethodology of the crude showed very good scope with to excellent yields. A careful analysisderived of the crude reaction amixtures wassubstrate performed since thegood catalyst used is an oxidant and products from reaction was performed since theIncatalyst used anofoxidant and products derived from Hoffmanmixtures rearrangements were observed. addition, the is use stoichiometric amounts of catalyst Hoffman rearrangements were observed. In addition, the use of stoichiometric amounts of catalyst promoted nitrene formation and increased the number of byproducts, but by using catalytic amounts, promoted nitrene formation and increased the transamidation reaction was favored. the number of byproducts, but by using catalytic amounts, the transamidation reaction was As mentioned earlier in thisfavored. manuscript, the use of organocatalysts has also been described in As mentioned earlierThe in this manuscript, use of organocatalysts also been described transamidation reactions. study reported bythe Adimurthy [23], where thehas process was carried out in 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

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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 performed recently used by Xu and coworkers [46],very showing good activity in transamidations. reaction, in xylene at 130 °C, showed good very functional group tolerance, and many ◦ The reaction, performed in xylene at 130 Among C, showed very good group tolerance, and many substrates demonstrated good reactivity. them, the use functional of heterocyclic amides (nicotinamide, substrates demonstrated good reactivity. Among them, the use of heterocyclic amides (nicotinamide, furan-2- and thiophene-2-carboxamide) with heterocyclic amines should be noted (see Scheme 13a). furan-2and thiophene-2-carboxamide) with heterocyclic amines should be which noted (see Scheme 13a). Unfortunately, this method is not effective with aromatic amines, with it only afforded Unfortunately, this method is not effective with aromatic amines, with which it only afforded moderate moderate yields. The main advantages of this methodology are the availability of the catalysts and yields. The main advantages of thisThe methodology are the availability the catalystsusing and the excellent the excellent selectivity observed. authors performed a couple ofofexperiments mixtures of selectivity The authors performed of experiments using mixtures of benzamide benzamideobserved. with 3-aminobenzylamine anda couple benzamide with tryptamine, showing that only with one 3-aminobenzylamine benzamide with tryptamine, showing that only one product formed in product was formed and in each case and thus making this a potential method for thewas protection of each case and thus making this a potential method for the protection of primary amines (Scheme 13b). 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 K2 S2 O8 in aqueous media In addition to these[47]. metal-free strategies thethe useinfluence of K2S2O8 of in aqueous media was recently described The reaction canfor betransamidation, performed under microwaves 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 H2 O2 , TBHP, conventional heating. The study included the screening of other peroxides, such as H 2O2, TBHP, mCPBA and oxone, finding that K2 S2 O8 was the best reactant for the transamidation reaction. mCPBA and oxone, finding amounts that K2S2of O8the was the best the transamidation reaction. Unfortunately, stoichiometric promoter arereactant requiredfor to achieve complete conversions. Unfortunately, stoichiometric amounts of the promoter are required to achieve complete conversions. This method was applied successfully to L-phenylalanine methyl ester hydrochloride with DMF as the This methodreagent, was applied successfully to L-phenylalanine methyl ester hydrochloride with DMF as formylating obtaining the N-formyl amino acid ester in 95% yield without any change in the the formylating reagent, obtaining the N-formyl amino acid ester in 95% yield without any change in configuration and optical purity, making this method possibly advantageous with chiral substrates the configuration and optical purity, making this method possibly advantageous with chiral (Scheme 14a). The authors showed an application in the synthesis of some very important molecules, substrates (Scheme 14a). The authors showed application in the14b). synthesis of some very important such as phenacetin, paracetamol, lidocaine andanpiperine (Scheme molecules, such as phenacetin, paracetamol, lidocaine and piperine 14b). Recently, Das and coworkers [48] developed a new H2 SO4 -SiO(Scheme 2 catalytic system for the direct Recently, Das and coworkers [48] developed a new H 2SO4-SiO2 catalytic system for the direct transamidation of carboxamides, describing a new methodology which complements those previously transamidation of carboxamides, describing a new methodology complements those outlined in this article. Due to the easier ability to manipulate the catalysts,which it is described as ecofriendly ◦ previously outlined in this article. Due to the easier ability to manipulate the catalysts, it is described and low cost. The reaction is performed using 5 mol % H2 SO4 -SiO2 at 70 C under solvent-free as ecofriendly low cost. were The reaction performed using 5 mol % H 2SO4-SiO2 at 70 °C under conditions, andand the products obtainediswithout any purification. solvent-free conditions, and the products were obtained without any purification.

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O O

O O H H

b. b.

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N N

+ +

NH NH22

H H N N O O O O Phenacetin Phenacetin 95% 95%

O O K S O K22S22O88

O O

Water, 100 ˚C Water, 100 ˚C or or MW irradiation MW irradiation

H H N N

N N

O O

N N

DRUGS DRUGS

Lidocaine Lidocaine 95% 95%

O O Piperine Piperine 83% 83%

O O H H

O Yield O Yield 95% 95%

H H N N

O O HO HO Paracetamol Paracetamol 96% 96%

O O

HN HN

O O

NATURAL PRODUCT NATURAL PRODUCT

Scheme 14. (a) (a) N-Formylation N-Formylation of α-amino esters O88.. (b) (b)Natural Natural products products and and drugs drugs Scheme 14. 14. of α-amino α-amino esters esters promoted promoted by byK K222SSS222O O Scheme (a) N-Formylation of promoted by K 8. (b) Natural products and drugs obtained by transamidation reactions O88. . obtained by by transamidation transamidation reactions reactions using using K K222SSS222O O obtained using K 8.

The system was explored using tertiary with substituted heteroaromatic, The catalytic catalytic system was explored explored using amides tertiary amides witharomatic, substituted aromatic, The catalytic system was using tertiary amides with substituted aromatic, and aliphatic/alicyclic primary amines and some secondary amines as well. Theasmost important heteroaromatic, and aliphatic/alicyclic primary amines and some secondary amines well. The most most heteroaromatic, and methodology aliphatic/alicyclic amines andofsome secondary amines as well. The application of this wasprimary in the synthesis N-aryl/heteroaryl pivalamides, which important application of this methodology was in the synthesis of N-aryl/heteroaryl pivalamides, important application this methodology was in the synthesis N-aryl/heteroaryl pivalamides, are an are important kindofof compound in organic synthesis due due tooftheir use use as directing groups in which an important kind of compound in organic synthesis to their as directing groups which are an important kind of compound in organic synthesis due to their use as directing groups many transition-metal catalyzed reactions in many many transition-metal catalyzed reactions(Scheme (Scheme15a). 15a).Furthermore, Furthermore, following following this this optimized optimized in transition-metal catalyzed reactions (Scheme 15a). Furthermore, following this optimized transamidation protocol, the authors reported the synthesis of procainamide, a drug used for the transamidation protocol, the authors reported the synthesis of procainamide, a drug used for the the transamidation protocol, the authors reported the synthesis of procainamide, a drug used for treatment of cardiac arrhythmias (Scheme 15c). treatment of of cardiac cardiac arrhythmias arrhythmias (Scheme (Scheme 15c). 15c). treatment

Scheme 15. (a) Synthesis of N-aryl/heteroaryl pivalamides via transamidation catalyzed by H2 SO4 -SiO2 . Scheme 15. 15. (a) (a) Synthesis Synthesis of of N-aryl/heteroaryl N-aryl/heteroaryl pivalamides pivalamides via via transamidation transamidation catalyzed catalyzed by by H H22SO SO44-Scheme (b) Synthesis of procainamide. SiO 2. (b) Synthesis of procainamide. SiO2. (b) Synthesis of procainamide.

The examples examples cited cited in in this this section section make make it it clear clear that that the the transamidation transamidation reaction reaction under under metalmetalThe free conditions conditions is is an an attractive attractive alternative alternative because because of of its its environmentally environmentally friendly friendly and and inexpensive inexpensive free

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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], Fe3 O4 -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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