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Direct Transamidation Reactions: Mechanism and Recent Advances molecules 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]; Molecules 2018, 23, 2382; doi:10.3390/molecules23092382 www.mdpi.com/journal/molecules Molecules 2018, 23, x FOR PEER REVIEW 2 of 16 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 asobtained a promoter, with andaromatic 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 Inin 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 inagent an amide because can occurof the only poor under electrophilic the influence nature of a suitableof amides. catalytic Depending or stoichiometric on the reaction activating conditions,agent because the structure of the poor of the electrophilic amide, and nature the ofactivating 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 theof secondaryactivating andsecondary tertiary amides amides. have Nevertheless, been described some activatingin the literature agents capablewith 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). They by metals, evaluated focusing the onbehavior the reaction of nucleophilic between aalkali secondary-metal amineamides, 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 metalscould andcatalyze different the transamidation amides. 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
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