Nonclassical Routes for Amide Bond Formation - Chemical Reviews

Review pubs.acs.org/CR

Nonclassical Routes for Amide Bond Formation Renata Marcia de Figueiredo,* Jean-Simon Suppo, and Jean-Marc Campagne* Institut Charles Gerhardt de Montpellier (ICGM), UMR 5253-CNRS-UM-ENSCM, Ecole Nationale Supérieure de Chimie, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France ABSTRACT: The present review offers an overview of nonclassical (e.g., with no preor in situ activation of a carboxylic acid partner) approaches for the construction of amide bonds. The review aims to comprehensively discuss relevant work, which was mainly done in the field in the last 20 years. Organization of the data follows a subdivision according to substrate classes: catalytic direct formation of amides from carboxylic and amines (section 2); the use of carboxylic acid surrogates (section 3); and the use of amine surrogates (section 4). The ligation strategies (NCL, Staudinger, KAHA, KATs, etc.) that could involve both carboxylic acid and amine surrogates are treated separately in section 5.

CONTENTS 1. Introduction 2. Catalytic Amidation of Carboxylic Acids 2.1. Organoboron Derivatives 2.2. Metal-Catalyzed Amidations 2.3. Miscellaneous 3. Carboxylic Acid Surrogates 3.1. Catalytic Amidation of Unactivated Esters 3.2. Catalytic Transamidation 3.3. Redox and Oxidative Amidations with Organo- and Metal-Catalysts 3.3.1. From Alcohols 3.3.2. From Aldehydes 3.3.3. From Ketones 3.3.4. From Aromatic Derivatives 3.3.5. From Nitriles 3.4. Thioacids 3.5. Alkynes and Alkenes Aminocarbonylation 3.5.1. From Alkynes 3.5.2. From Alkenes 4. Amine Surrogates 4.1. Isocyanate Derivatives 4.2. CDI-Activated α-Aminoester Derivatives 4.3. Isonitriles 4.4. Thioamides 4.5. Dithiocarbamates 4.6. Sulfonamides and Sulfinylamides 4.7. Umpolung Strategies Using HalogenoAmines 4.8. Aromatic Imines and Amidines 4.9. Tertiary Amines 4.10. Azides 4.11. Thiocarboxylic Acids and Azides 4.12. Amine Surrogates Miscellaneous 5. Selective Ligation Methods 5.1. Native Chemical Ligation (NCL) 5.1.1. Background 5.1.2. Reaction, Chemoselectivity, and Mechanistic Insights © XXXX American Chemical Society

5.1.3. Reaction Development 5.1.4. Scope, Limitations, Extensions, and Racemization 5.1.5. Other Extensions via Capture Strategies 5.2. Staudinger Ligations (Carboxylic Acid Derivatives and Azides) 5.2.1. Early Discoveries and Recent Developments 5.2.2. Staudinger Ligations as an Organic Synthetic Tool 5.3. Keto-Acid Ligation via N−O Bonds (KAHA and KATs Ligations) 5.3.1. KAHA Ligation 5.3.2. Potassium Acyltrifluoroborates (KATs) 6. Conclusion Author Information Corresponding Authors Notes Biographies Acknowledgments Abbreviations References

A B B H J K K P Q Q W AB AC AD AD AG AG AK AN AN AO AP AQ AQ AQ

AZ BA BG BJ BJ BM BQ BQ BU BW BW BW BW BW BW BW BY

1. INTRODUCTION Amide bonds, as the backbone of proteins, not only play a crucial role in life but are also present in a great number of pharmacological active compounds and materials (such as nylon, hydrogels, artificial silks, supported catalysts, and biocompatible matrices for cell growth). Indeed, the amide bond was found in 2/3 of drugs candidates in a 2006 survey1 and is present in 25% of all pharmaceuticals currently on the market.2 Moreover, it has been estimated that the “acylation of amine” represents, with a 16% occurrence, the most commonly used reaction in the synthesis of pharmaceuticals.3

AQ AT AT AT AU AY AZ AZ AZ

Received: April 13, 2016

AZ A

DOI: 10.1021/acs.chemrev.6b00237 Chem. Rev. XXXX, XXX, XXX−XXX

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The more convenient and simplest way to prepare amides could be the direct condensation of carboxylic acids and amines. Nevertheless, it is known that such “ideal” amidation process needs very harsh conditions (T > 100 °C) in order to circumvent unreactive carboxylate-ammonium salts formation toward the desired amide bond formation (Scheme 1).4−10 As consequence,

Scheme 2. Strategies for Amide Bond Formation

Scheme 1. Thermal Amide Bond Formation

these procedures are very restricted, and sensitive substrates, such as amino acid residues, are not compatible with such forcing conditions. To sidestep thermal conditions for amide bond formation, amides are “traditionally” formed through the pre- or in situ activation of the carboxylic acid partner (e.g., the transformation of the OH group into a better leaving group) in the presence of a stoichiometric “coupling” reagent.11−18 These reagents are highly efficient, as witnessed by the incredible success of peptide synthesis,19 but the process generally suffers from poor atom economy. Indeed, in a 2007 round table devoted to key green chemistry research areas, the “amide formation avoiding poor atom economy reagents” was selected as a top priority area for organic chemistry.20 To follow on from previous work reported in seminal short reviews by Bode and co-workers,21−23 the purpose of this review is thus to provide an overview of the current state of “nonclassical” ways to construct amide bonds with a special emphasis to the more demanding peptide bond formation (Scheme 2). “Textbook” reactions including Beckmann rearrangement,24−28 Ritter reaction,29 Ugi-type multicomponent reactions,30−32 and carbonylation of aryl(vinyl) halides33,34 have been recently covered in comprehensive reviews and thus will not be included here. The functionalization of preformed amides or surrogates through N−H functionalization is beyond the topic of this review and, consequently, will not be reported therein.35−39 This review will be organized in four main sections: (i) transition-metal and organo-catalyzed direct amidation of carboxylic acids with amines (section 2); (ii) the use of carboxylic acid surrogates (thioacids, esters, amides, ketones, alkenes, alkynes, etc.) with amines (section 3); (iii) the use of amino surrogates (amides, azides, and thioamides) with carboxylic acids (section 4); and (iv) the ligation strategies (Staudinger, NCL, KAHA, and KATs) that usually involve, to ensure high chemoselectivity with nonprotected complex biomolecules, both amino and acyl surrogates (section 5). It is noteworthy to mention that sections 3 and 4 also include, when the authors judged appropriated for understanding facilities, the use of both amine and carboxylic acids surrogates. Moreover, the main references therein cited were mostly reported in the literature after 2005, illustrating the growing interest in novel, practical, efficient, and improved atom economy processes.

2. CATALYTIC AMIDATION OF CARBOXYLIC ACIDS The direct amidation of carboxylic acids with amines still represents the more atom-economical way to construct amide bonds. In the last ten years, interesting alternatives involving organo- (boron derivatives) and metal-catalyzed processes have emerged and representative examples will be covered in the following two subsections.40−43 2.1. Organoboron Derivatives

While the use of organoboron derivatives as effective Lewis acids for carbonyl compounds activation is among the oldest examples of catalysis for this class of compounds, their potential on catalyzed amidation processes has been recognized only recently.44−47 Indeed, if the application of stoichiometric amounts of trisdialkylaminoborane derivatives on amide formation has been known since 1965,48 it was only 30 years later that the first report of a catalytic process was published. The Lewis acidity of organoboron compounds can be finally tuned by modulation of substituents, and thus, the optimization of the catalytic condensation between free carboxylic acids and amines has been made possible. Efficient catalysts (Scheme 3) and selected examples of carboxamides (Scheme 4) that emerged from organoboron catalysis are depicted below. On the basis of several studies on the mechanism of arylboronic acid-catalyzed amidations, it was found that the mono(acyloxy)boronic acid 24 (Scheme 5) is the key intermediate, which evolves toward the formation of a bis(acyloxy)boronic acid 25 by further reaction with a free carboxylic acid.49−52 It was also demonstrated that the formation of the acyloxyboronic acid 24 intermediate is kinetically favorable; the removal of water is necessary in order to drive the equilibrium toward amide formation. Either 24 or 25 intermediates are thus prone to react with amines with subsequent regeneration of the arylboronic acid catalyst and liberation of the amide product. The mechanism depicted on Scheme 5 is proposed on the basis of both analytical experiments such as kinetics, proton nuclear magnetic resonance (1H NMR), B


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Scheme 3. Organoboron Derived Catalysts in Amidation Reactions

infrared (IR), and electrospray ionization mass spectrometric (ESI/MS) techniques49,50 and theoretical studies.51,52

Pioneering work on this topic was done by Yamamoto and coworkers, who devised a straightforward route to amides by means C


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Scheme 4. Selected Examples of Carboxamides

removal (molecular sieves in a Soxhlet thimble). Demanding substrates such as aniline and benzoic acid required more forcing conditions (mesitylene reflux). The preparation of lactams was equally possible following the same protocol. The use of S(−)-proline as substrate gave the corresponding diketopiperazine (DKP) in 94% yield. Condensation of optically active aliphatic α-hydroxycarboxylic acids with benzylamine proceeded with less than 2% of racemization, except when enriched mandelic acid was involved for which slight erosion on the enantiopurity was observed (94% ee). In these cases, high chemoselectivities were obtained since no esterifications were detected. Four years later, the same catalyst was employed to perform direct thermal amide polycondensation, process environmentally benign and highly valuable in industry, to form aliphatic polyamides (e.g., nylon-6,6) as well as aromatic polyamides and polyimides.54 For sterically demanding carboxylic acids, Yamamoto and coworkers have shown the catalytic superiority of 4,5,6,7tetrachlorobenzo[d][1,3,2]dioxaborol-2-ol (4) and 4,5,6,7tetrachlorobenzo[d]-[1,3,2]dioxaborole (5).55 Nevertheless, the amidation of Boc-Ala-OH with benzylamine catalyzed by 4 or 5 was followed by a significant decrease on the optical purity of the product (from >99% ee to 86% ee). For the sake of developing more environmentally safe methods, Wang and co-workers designed a polystyrene-bound pyridine-3-boronic acid (17) as catalyst for solid-phase amidation between simple acid and amine compounds.56 The reaction was carried out with 1−5 mol % of catalyst in refluxing toluene with concomitant water removal via a Soxhlet extractor charged with molecular sieves. One example of dipeptide

Scheme 5. Proposed Mechanism for Arylboronic AcidCatalyzed Amidation Reactions51

of catalysts 1−3 (Scheme 3).49,53 The presence of electronwithdrawing substituents at the aryl moiety was crucial to allow an effective catalytic amidation process via more stable electronpoor acyloxyboron intermediates. The use of borate esters, boranes, and cathecolborane derivatives allow the formation of unreactive boron species when the amines react with the acyloxyboron intermediates. Among the top 3 catalysts (1−3), 3,4,5-trifluorobenzeneboronic acid (1) (1 mol %) was found to be the most active. Carboxylic acids and primary or secondary amines produced the amide in high yields (92 → 99%) in refluxing toluene, xylene, or mesitylene with concomitant water D


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synthesis was reported. Whereas Cbz-Phe-Ala-OtBu could be isolated in a good yield (85%), complete epimerization was detected. Yamamoto’s group has proposed 3,5-bis(perfluorodecyl)phenylboronic acid (16)57 as effective catalyst on the fluorous biphasic catalysis (FBC) process.58−60 Additionally, they have taken profit of ionic liquid-toluene biphasic solvents in order to reuse N-alkyl-4-boronopyridinium salts (18) during the synthesis of a range of amides. These salts are thermally stable and could be linked to a polystyrene-type resin affording heterogeneous and reusable catalysts (22). Compared with the homogeneous salts, the use of these heterogeneous catalysts for dehydrative amide condensations took place in the absence of ionic liquids as reaction medium and they were easily recovered by simple filtration.61 The advantage of the abovementioned salts relies on their catalytic effectiveness under polar solvents such as anisole, acetonitrile, and N-methyl-2-pyrrolidinone (NMP), due to the improved Lewis acidity of the boron atom in catalyst (18) in polar solvents.62 Immobilized boronic acids on mesocellular siliceous foam (MCF) were also considered as a novel class of heterogeneous catalysts (23) on direct amidation with carboxylic acids and amines.63 Furthermore, Tang has proposed the use of commercially available, inexpensive and environmentally safe boric acid, B(OH)3 (6), as effective catalyst for direct amidation.64 With dependence on the nature of the substrates, 5 to 25 mol % of the catalyst was used to reach high yields. Around 20 carboxamides were prepared in this study, and unreactive anilines bearing deactivating groups such as carboxylic esters were compatible with the proposed method. Moreover, the simplicity of the operational conditions allowed large-scale preparations. An elegant application of 6 on catalytic amidation reaction was reported by Davis and co-workers in 2006 during a two-step synthesis of efaproxiral (26), developed for the breast cancer therapy (Scheme 6).65

Scheme 7. Proposed Mechanistic Pathway by Whiting for Amidation Supported by DFT Calculations

Therefore, considerable effort concerning both the development of catalytic protocols at lower temperatures than those aforementioned and the increase of substrate functionality (e.g., sensitive substrates such as amino acid residues) have been made. For this purpose, Whiting and co-workers considered direct amidation by means of bifunctional aminoboronic acid catalyst.50,66,67 They synthesized N,N-diisopropylbenzylamine2-boronic acid derivatives 8−10 and evaluated their catalytic power by comparison with direct thermal reaction. From their studies, it arose that both transformations are very substrate- and reaction conditions dependent. Moreover, bifunctional catalyst 850 and its analogs 9 and 10 bearing electron-withdrawing substituents on the aryl ring can efficiently catalyze direct amide formation between benzoic acid and benzylamine in refluxing fluorobenzene (bp 85 °C) with no substantial differences. However, increasing the electron density on the phenyl moiety via methoxy group incorporation led to a significant decrease in the reaction rate. Amino-boronates 9 and 10 showed increased catalytic activity when aryl carboxylic acids were used at lower reaction temperatures. These catalysts might operate through a bifunctional mechanism pathway in which the exact nature remains not yet completely clear.68,69 Only few substrates were evaluated, and whereas the yields obtained were moderate due to incomplete conversion of the substrates, the use of lower reaction temperature (refluxing fluorobenzene) is a clear advantage over the classical thermal conditions. Following this rationale, in 2008, the first direct amidations by means of organoboron derivatives at room temperature were reported by Hall and co-workers.70 Under milder conditions, ortho-halophenylboronic acids were identified as more effective catalysts when compared with the electron-poor catalyst 1 proposed by Yamamoto.49 Carboxamide derivatives were obtained in moderate-to-excellent yields (24−99% yields) by using 10−20 mol % of ortho-iodophenylboronic acid 12 in CH2Cl2 or THF as solvents (c 0.07 M) at room temperature in the presence of molecular sieves. Additionally, the catalyst was recovered in high yields after the reaction workup. The mild conditions devised within this study allowed the amidation of (S)-ibuprofen with either (R)-(+)-α-methylbenzylamine or benzylamine with less than 5% racemization. It might be

Scheme 6. Efaproxiral Synthesis Based on B(OH)3-Catalysis

At this stage, it should be emphasized that direct uncatalyzed amidations can also be observed as background reactions at high temperatures.5−10 Likewise, based on DFT calculations, Whiting reported in 2011 evidence for improving amidation reaction in nonpolar, aprotic solvents.10 It appears that zwitterionic intermediates are avoided in favor of a molecular hydrogen bonding network via carboxylic acid dimerization when the condensation takes place in toluene (Scheme 7). E


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Scheme 8. Halogen Role for Improved Catalytic Efficacy for Catalyst 1252,71

mentioned that under Yamamoto’s conditions (e.g., refluxing toluene) more than 30% racemization was observed for the same transformation.49 Two years later, the high efficiency of 12 was rationalized by Marcelli in DFT studies.52 It appears that the iodide substituent might act as hydrogen-bond acceptor in the orthoaminal transition state increasing the electrophilicity of the boron atom directing, thus, the shuffling of B−O bonds. In this study, it was proposed that the halogen introduction into the ortho position favors an ideal Lewis basic site by formation of a stabilized boron-bound hydroxyl group (Scheme 8). An important aspect pointed out by these calculations is the water role in the amidation. Whereas the formation of TS1 seems paradoxical as dry conditions are necessary for the reaction, a water molecule is however required to generate the amide-bond after orthoaminal breakdown. Altogether, a plausible mechanistic proposal seems premature as multiple variables (e.g., solvent nature, reaction concentration, water and molecular sieves roles, catalyst’s substituents, geometries and electronic effects, and stoichiometry of acid and amine substrates) are involved. Furthermore, supported by Marcelli’s studies and experimental observations, Hall and co-workers proposed, in 2012, that the addition order of the substrates may also be taken into consideration for proposing a mechanism rationale.71 Consequently, the alternate pathway through TS2 (by premixing of the catalyst, acid, and molecular sieves prior to the amine addition) was also postulated (Scheme 8). Curiously, and contrary to Yamamoto’s and Whiting’s catalysts which bear electron-withdrawing substituents on the aromatic ring, the analog 5-methoxy-2-iodophenylboronic acid (13, MIBA) published by Hall in 201271 displayed both higher catalytic efficacy and reaction rate under identical reaction conditions (carboxylic acid 1.1:1.0 mol ratio relative to the amine, 10 mol % of catalytic charge, CH2Cl2 as solvent, and room temperature with molecular sieves) (Scheme 9). Thus, a broader range of carboxamides were synthesized in better yields and in shorter reaction times compared to 12. According to Marcelli’s study,52 the electron-donating 5-

Scheme 9. Comparison of Most Effective Catalysts on a Model Amidation Reaction

methoxy group is supposed to reinforce the activity of the halogen as hydrogen bond acceptor by increasing its electron density. While an acyclic secondary amine failed when engaged under the described conditions, cyclic amines and functionalized substrates bearing phenol, pyridine, indole, furan, or thiophene units worked well, providing the expected amides in high yields (Scheme 10). Less reactive substrates such as aromatic amines, and aromatic carboxylic acids required slightly higher temperatures (50 °C) giving the corresponding amides in poor yields after long reaction periods. Recently, Tam, Chen, and co-workers have identified 2furanylboronic acid (20) as a readily available, inexpensive, and efficient catalyst for condensation between aliphatic carboxylic acids and aliphatic primary and secondary amines.72 Compared to the previously reported boronic acid catalysts, 20 has the advantage of allowing the direct amidation under very mild conditions (room temperature) in the presence of 4 Å molecular sieves as the dehydrating agent in CH2Cl2. If only arylboronic acid derivatives were so far successfully used for direct amidation between simple carboxylic acids and amines, Ishihara and co-workers disclosed in 2013 the use of commercially available primary alkylboronic acids MeB(OH)2 F


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withdrawing substituents on the aryl group of the boronic acid seems necessary for enhancing its catalytic activity through Lewis acidity increasing,52 in this particular case, the electron-donating nature of the Me and Bu groups were crucial to avoid the formation of the less reactive intermediate 28 in favor of 29, promoting thus the dehydrative coupling (Scheme 12). In order to push the reaction forward, additives such as benzoic acid (10− 50 mol %) and water (2.2 equiv) were necessary when less reactive substrates, such as mandelic acid and 3,5-dimethylpiperidine, were used. To minimize racemization on sensitive substrates, toluene (bp 110 °C) could be replaced by 1,2dichloroethane (bp 83 °C). Interestingly, the first example of a kinetic resolution of amines on amide formation with carboxylic acids was published in 2008 by Whiting and co-workers.74 Promising results were disclosed with chiral bifunctional aminoboronic acid catalyst 11 bearing a ferrocene backbone. While catalytic boron-mediated amidation reactions presented above were quite effective when simple and reactive amines and carboxylic acids were used as starting materials, their involvement on peptide couplings were so far avoided. Indeed, high temperatures that are often necessary to reach the amide products by means of these catalysts hamper efforts to successfully devise procedures compatible with peptide syntheses, prone to racemization. Within this purpose, Whiting, Liu, and co-workers have published in 2013 the direct amidation of amino acids leading to dipeptides via the combination of two catalysts, o-nitro- and o-tolylphenyl-boronic acids (14 and 15, respectively).75 Before conceiving the best reaction conditions between two amino acids, the authors have first studied the behavior of amino acids as either the amine or the carboxylic acid partners on direct amidation with simple amines or acids (Scheme 13). From their observations, it emerged that Nprotected amino acids (e.g., N-Boc-phenylalanine and N-Bocproline) react quite efficiently with benzylamine to form the corresponding amide (30 and 31) in the presence of electrondeficient aryl-boronic acids as catalysts with no detected racemization. Nevertheless, switching to the more hindered (R)-(+)-α-methylbenzylamine resulted in a considerable decrease in the chemical yield (32). They also noticed that the reaction kinetics with amino acids were slower, compared with simple carboxylic acids, requiring higher catalyst loadings (25− 50 mol %) to reach reasonable yields. When the corresponding C-protected amino acids were evaluated by direct amidation with

Scheme 10. Second Generation Hall’s Catalyst 13: Selected Amide Synthesis at Room Temperature to 50 °C

and BuB(OH)2 (7) as valid catalysts when α-hydroxycarboxylic acids were used as substrates (Scheme 11).73 If electronScheme 11. Boronic Acids’ Catalytic Activity on Amidation of Mandelic Acid and 3,5-Dimethylpiperidine

Scheme 12. Dehydrative Amide Condensation with α-Hydroxycarboxylic Acids

G


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Scheme 13. Amidation with Amino Acid Residues

procedure,71 at a higher concentration under room temperature or low-heating conditions (up to 60 °C). In order to circumvent catalyst inhibition via complexation with monoprotected αamino acids, doubly protected N-phthaloyl α-amino acids (35) or α-azidoacids (36) are however necessary to enable the formation of the dipeptides in moderate yields (Scheme 15a). Blanchet and co-workers also devised an efficient method for the direct amidation at room temperature in dry CH2Cl2 by means of a bench-stable catalyst 19 bearing a thiophene group.78 A broad scope of substrates, concerning both the amine and carboxylic acid partner, could be successfully used. Moreover, this catalyst was also effective for the preparation of a dipeptide. By mixing equimolar amounts of the carboxylic acid and the amine partners in the presence of fluorobenzene at 65 °C, BocPhe-Val-OMe 37 was obtained in 50% yield without detectable epimerization on NMR spectra (Scheme 16). Following this line, the authors recently proposed the unprecedented use of borinic acid (21) as a more effective catalyst for the synthesis of several dipeptides (Scheme 17).79 It is assumed that both halogen atoms on the aromatic rings probably participate in the rate-determining step via hydrogenhalogen bonds formation that might stabilize the transition state and favor the collapse of TS3 into the amide compound. Indeed, a much lower yield was obtained on a model reaction between phenylacetic acid and benzylamine when unsymmetrical borinic acid (bearing only one chlorine atom) was used (99% vs 27%).

phenylacetic acid, good yields were observed whereas with some enantiopurity erosion (e.g., with H-Phe-OMe·HCl, (33) 64− 68% ee and with H-Val-OMe·HCl, (34) 71 → 99% ee). Upon the previous observations, the authors undertook the combination of two amino acid derivatives in order to develop a way to synthesize dipeptides by means of direct amidation with electron-poor arylboronic acids. While the nature of the Nprotecting group (Ac vs Boc) did not interfere in the reaction outcome, major impact was perceived upon changing the amino donor from a less to a more encumbered one (phenylalanine vs valine) (Scheme 14). Moreover, using amino acids as substrates Scheme 14. Dual Boronic Acids Catalysis on Dipeptide Synthesis

2.2. Metal-Catalyzed Amidations

dramaticaly decreased the reaction rate, hence stoichiometric amounts of boronic acid were necessary to obtain even moderate yields. Interestingly, they observed a synergic effect when combining o-tolyl- and o-nitrophenyl-boronic acids (100 mol %; e.g., 50 mol % loading of each), where higher yields could be achieved compared with the use of each catalyst alone (100 mol %). For the examples described, no epimerization was observed; the dipeptides were isolated as single diastereomers. Although this work is the first one in which two amino acid residues were used on direct amide formation through boronic acids, the scope remains narrow as only a few amino acid residues were evaluated. Nevertheless, it makes a starting point to future developments in this rather reluctant direct amidation between two amino acids or peptide residues. Indeed, in 2015, Hall and co-workers reported a multigramscale lower E-factor76 procedure for direct amidation of α- and βamino acid derivatives with catalyst 13 (Scheme 15).77 One advantage in this report relies on the possibility of using half of the molecular sieves loading prescribed on the original

Although underexplored, metal-catalyzed amidations have been receiving increasing attention in the ten last years. However, for the direct amidation of carboxylic acids with amines in the field of peptide chemistry neither homogeneous nor heterogeneous metal-catalyzed processes have been reported so far. Within this subsection, N-formylation and N-acetylation of amines, with formic acid and acetic acid, respectively, will not be covered. As for the formation of primary amides, previous work on these topics were already well covered elsewhere.40,41 Seminal contributions on metal-catalyzed amidations were independently reported by the groups of Williams and Adolfsson; both works are based on the use of zirconium salts as efficient catalysts.80,81 Following the observations made by Whiting on the role of nonpolar, aprotic solvents on thermal noncatalyzed amide formation,10 Williams and co-workers have shown that 5 mol % of either ZrCl4 or Cp2ZrCl2 in toluene at 110 °C in the absence of a drying agent were sufficient to catalyze carboxamides formation in high levels of conversion from a H


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Scheme 15. Synthesis of α- and β-Dipeptides via MIBA-Catalyst (13)

Scheme 16. Dipeptide Synthesis Catalyzed by ThiopheneBased Boronic Acid (19)

Scheme 17. Dipeptide Synthesis Catalyzed by Borinic Acid (21)

broad range of substrates (Scheme 18).80 Anilines and benzoic acid showed the lowest conversion rates which could be improved when Cp2ZrCl2 was used as a catalyst. Amino acid residues such as Boc-Gly-OH, Boc-(D)-Pro-OH, and H-ValOMe were compatible with the reaction conditions (Scheme 18, compounds 40 and 41). During this study, the authors have also identified FeCl2, CuBr, Ni(NO3)2, and TiCl4 as efficient alternative Lewis acid catalysts for the transformation. Adolfsson and co-workers described a similar procedure where toluene was replaced by dry THF allowing the use of lower temperatures (70 °C).81 In this study, 24 amides were synthesized in high yields by means of 2−10 mol % of ZrCl4 in THF at 70 °C in the presence of molecular sieves in a sealed tube under nitrogen atmosphere. Higher temperature (100 °C) and catalyst loading (10 mol %) were necessary when aromatic acids and secondary amines were used on the amidation process, and

no examples were given with aniline as the amine partner. BocAla-OH, Boc-Pro-OH, and enantiopure 1-phenylethylamine were coupled with no detected racemization (in the presence of 10 mol % of ZrCl4) (Scheme 18, compounds 43−45). In the same year, they surveyed a range of Lewis acids on the direct amidation process of phenylacetic acid and benzylamine under the previously described conditions. Among the most I


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Scheme 18. Zirconium Salts as Amidation Catalysts80,81

Scheme 19. Activated Alumina Balls83 and Sulfated Titania Nanostructures84 Catalyzed Amidations: Selected Examples

active ones, Ti(OiPr)4, Zr(OEt)4, Zn(OtBu)4, Hf(OtBu)4, Nb(OEt)5, and Ti(OBn)4 allowed yields beyond 88%. Choosing to work with Ti(OiPr)4 (10−20 mol %), the authors have synthesized 29 amides in high yields (up to 99%).82 While amino acid residues preserved their optical purity under the reaction conditions, sensitive (S)-ibuprofen underwent substantial racemization (83% ee) when coupled with benzylamine. If the previous methods, based on zirconium and titanium salts, failed with aromatic substrates such as aniline and benzoic acid derivatives, the use of either activated alumina balls83 or sulfated titania nanostructures84 displayed superior catalytic activity with such reluctant substrates (Scheme 19). Moreover, both procedures are solvent-free processes, and the reactions workup were easily done by simple filtration of the catalysts which could, in turn, be reused affording greener and safer options compared to the previous reported works. It is worth mentioning that no background reaction during the condensation of 4-chloroaniline with heptanoic acid was observed (allumine balls studies).83 In sharp contrast, 45% of the amide bond formation could be observed, in a blank control between aniline and phenylacetic acid, in the sulfated titania nanostructures studies.84 Amidation of benzoic acids was also catalyzed by an azobenzene-containing zirconium metal−organic framework (Zr-AzoBDC) in THF at 70 °C (14 examples, 37−97% yields).85 The heterogeneous nature of the catalyst allowed its recycling and reuse up to 5 times without catalytic activity damage. Likewise, the method was used in the synthesis of bioactive amide-containing products such as paracetamol (73%), procainamide (71%), and flutamide (53%). 2.3. Miscellaneous

In 2015, a metal-free procedure using 2,4,6-tris(2,2,2-trifluoroethoxy)-[1,3,5] triazene (TriTFET, 46) as catalyst has been developed allowing amide formation between carboxylic acids and primary and cyclic secondary amines in moderate to J


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excellent yields.86 Nevertheless, the use of the optimized reaction conditions (Scheme 20) failed when the synthesis of a dipeptide was studied from suitably protected α-amino acids (data not shown).

Scheme 21. Main Catalytic Systems for the Aminolysis of Unactivated Esters

Scheme 20. TriTFET-Catalyzed Amidation Reactions

In order to afford more practical alternatives, with respect to the reaction workup and catalyst recovery and reuse, a few heterogeneous catalytic processes have also been devised. Among them (see also the subsection devoted to the organoboron derivatives for more examples), activated silica gel (K60 catalyst activated at 700 °C),87 sulfated tungstate,88 and mesoporous silica MCM-4189 and SBA-1590 revealed interesting catalytic efficiency. Nevertheless, the conditions are generally harsh (refluxing toluene) and thus minimize the scope of the reaction.

3. CARBOXYLIC ACID SURROGATES

with benzylamine with none or minute epimerization (99% ee and 97% ee, respectively). It might be mentioned that the latter substrate gave a moderate conversion of 43% for the uncatalyzed system, and the use of highly base-sensitive Fmoc protecting group for amines failed under the slightly basic reaction conditions. Another interesting point to be mentioned is the high chemoselectivity between ester and lactones versus conjugated ketones and aromatic amine vs aliphatic alcohol (Scheme 22, eqs 1 and 2, respectively). Preliminary studies on the reaction mechanism via the combination of Zr(OtBu)4 with HOAt (47) supported by X-ray crystallographic analysis suggested a dimeric zirconium complex as the effective catalytic system (Scheme 23). Moreover, the authors excluded the pathway through an activated ester. Indeed, addition of 1.0 equiv of the carboxylic acid substrate to a 1:1 Zr(OtBu)4−HOAt mixture in benzene-d6 was not followed by the formation of the corresponding activated ester. Comparable results were observed with HOBt (48) as additive, whereas HYP (49) deserves further experimental studies. In the same year, an approach based on Zn dust (0.5 equiv) was proposed.94 The coupling between aniline derivatives and aromatic and benzylic methyl esters took place either under microwave (MW) irradiation (1−8 min; 70−91% yields) or conventional heating at 70 °C in THF (11−30 h; 64−84% yields). The Zn dust could be recovered by simple washing with diethyl ether and diluted HCl and further reused six times without losing its activity. Nevertheless the proposed procedure is limited to methyl esters and aniline derivatives as substrates. Some examples combining unactivated esters with amino alcohols have also been reported and will be highlighted below. Movassaghi and Schmidt have shown that the higher reactivity of amino alcohols compared to simple amines could be successfully associated with methyl esters and N-heterocyclic carbenes (NHC) in a catalyzed amidation process.95 The optimal reaction

3.1. Catalytic Amidation of Unactivated Esters

A more convenient and attractive alternative to the use of carboxylic acids for the preparation of amides with amines constitutes the use of unactivated esters (for activated esters, definition and reactivity, readers are invited to consult ref 15). Undeniably, moving from carboxylic acid to an ester, the carboxylic group becomes more electrophilic and will certainly stimulate the amidation reaction. Moreover, to the best of our knowledge, few catalytic unactivated ester−amide exchange reactions have been reported to date (Scheme 21). In 1996, a report on stoichiometric antimony-template macrolactamization of tetra-amino esters toward the synthesis of spermine alkaloids was described by Yamamoto and coworkers.91 Accordingly, 5−10 mol % of Sb(OEt)3 were used to catalyze amidation reactions between methyl esters or carboxylic acids with primary amines involving azeotropic removal of methanol (7 examples, 44−91% yields). Seven years later, Ranu and Dutta validated the use of InI3 (20 mol %) in a solvent-free process where several esters (e.g., Bn, Me, Et, iPr, menthyl) and aniline or benzylamine were heated at 110−120 °C for 6−9 h.92 The method is efficient for the amidation of primary amines (13 carboxamides, 83−93% yields), whereas ammonia and secondary amines were not reactive under the reaction conditions. Porco and co-workers have published in 2005 the use of group (IV) metal alkoxide [Ti(OiPr)4, Zr(OtBu)4, and Hf(OtBu)4] combined with additives such as HOAt (47), HOBt (48), and HYP (49) for catalytic aminolysis of unactivated esters (Scheme 22).93 Zr(OtBu)4 (10 mol %) ensured the highest conversions. The reaction proceeded with several substituted aromatic and aliphatic esters (Me, Et, nBu, tBu, Bn, and allyl) and amines without azeotropic reflux to remove the alcohol byproduct. Optically pure substrates such as Boc-Ala-OMe and methyl (S)(+)-mandelate gave the amide products 50 and 51 by coupling K


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workers by means of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 53; 30 mol %) as organocatalyst.96 The amide products were isolated in good yields (60−94%) from the reaction of alkyl esters (e.g., Me, Bn, iPr) with a range of primary and secondary amines under solvent-free conditions (SFC), at 75 °C. Furthermore, this procedure was successfully applied by Weiberth and co-workers on a pilot-plant scale as a key step for the synthesis of a human hematopoietic prostaglandin D synthase inhibitor (H-PGDS, 54) to supply preclinical trials (Scheme 26).97 Another metal-free and recyclable catalyst for amidation with amino alcohols as substrates was proposed by Verkade and coworkers.98 The catalyst consists in a Merrifield resin-bound N3 P(MeNCH2CH2)3N (55) that was used on the amidation reactions under argon atmosphere at 23−25 °C in THF with equimolar amounts of both substrates, the amino alcohol and the methyl ester. Seeking to a more sustainable approach, the group of Jamieson has proposed a base-catalyzed protocol based on the use of BEMP (56, 10 mol %) in acetonitrile at room temperature for 15 h for a quite efficient amidation between esters and amino alcohols.99 Methyl esters were mainly used in this study as lower yields were observed with more bulky tert-butyl esters under the same reaction conditions. For such substrates, the yield could be improved by increasing the reaction temperature to 40 °C. The condensation of Boc-Phe-OMe and L-phenylalaninol provided the corresponding amide in good yield (80%) along with an important epimerization (d.r. = 86:14). When searching for less basic systems compatible with such sensitive substrates, the authors have also proposed an improved and greener procedure in which the BEMP base-catalyst 56 was replaced by K3PO4 (30 mol %) in iPrOH at 60 °C for 22 h.100 With these conditions, the compound (from Boc-Phe-OMe and L-phenylalaninol) was isolated in excellent diastereoselectivity (d.r. = 98:2) albeit in lower chemical yields (42%). It might be mentioned that two phosphazene bases, so-called P1-tBu and BTTP, were also suggested as cost-effective alternatives to the BEMP catalyst. A synergic effect by combining 1,2,4-triazole (57) and DBU (58) (20 mol % each) could be obtained during the aminolysis of unactivated methyl and ethyl esters with a few amine derivatives under solvent-free conditions (SFC).101 In most cases, the use of DBU as single catalyst significantly diminished the reaction rates even though the reaction temperatures were raised. L-Phenylalanine methyl ester smoothly underwent cyclocondensation under the reaction conditions and gave, after 24 h at 90 °C, the expected diketopiperazine (DKP) in 79% yield as a mixture of diastereoisomers (97:3 cis-trans ratio). In contrast to this study, DBU alone (0.5 equiv) was effective for amidations when alkyl cyanoacetates were used as substrates with a few primary and secondary amines.102 Indeed, the presence of a highly electron-withdrawing cyano group facilitates the condensation reaction by increasing the electrophilic character of the carbonyl group. The transformation proceeded in 2-methyltetrahydrofuran at 20 or 40 °C and was effectively applied to the large-scale synthesis of CP-690,550-10, compound under development against autoimmune diseases. A straightforward method based on the catalytic use of NaOMe was proposed by Mashima and co-workers for the direct amidation of methyl esters with primary and secondary amines in toluene at 50 °C.103 Aiming at transferring the present procedure to the synthesis of peptides, the authors have first validated the use of a few substrates bearing amide and carbamate functional groups. Then, they realized a set of trials with some Boc-AA-

Scheme 22. Zr(OtBu)4-HOAt Catalyzed Ester-Amide Exchange

conditions relies on the use of 5 mol % of N,N-bismesitylimidazolylidene (IMes) in THF (c 1.0 M) at 23 °C with equimolar amounts of both substrates (esters and amino alcohols). In a few cases, when substrates with unfavorable electronic and steric factors were engaged, the addition of catalytic amounts of anhydrous lithium chloride (5 mol %) as an additive to the reaction mixture allowed increased reaction rates and yields. Functionalized aromatic, heteroaromatic, and aliphatic esters as well as substituted amino alcohols are well-tolerated. In this study, several amides (14 examples) were synthesized in high yields (34−100%) (Scheme 24). Although the reaction conditions are not compatible with Fmoc urethane-protected esters, the coupling between Boc-Trp(N-Me)-OMe and Lphenylalaninol gave the expected amide product 52 in high yield (88%) and good selectivities (>94% de). Mechanistic insights on this method were strongly supported by studies on carbene−alcohol interactions in both solution and X-ray studies. The authors’ preliminary observations described a surprising stability of carbene-alcohol complexes via hydrogenbonding interactions and suggested an additional and unexplored mode of catalysis via transesterification followed by O → N-acyl transfer to reach the required amido-alcohols (Scheme 25). Nevertheless, as stated by the authors, these carbene−alcohol interactions deserve supplementary studies in order to propose a definitive reaction pathway. The ability of amino alcohols to undergo amidation with unactivated esters was also studied by Mioskowski and coL


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Scheme 23. Zr(OtBu)4-HOAt Proposed Reaction Mechanism

Scheme 24. NHC-Catalyzed Amidation of Esters with Amino Alcohols

OMe [AA = Phe, Ala, Val, Leu, Pro, Met, Glu(OtBu)] and benzylamine. Being aware that peptide couplings under such basic conditions are highly prone to racemization, the authors have envisaged the use of an additive that could be able to moderate the strong basicity of NaOMe even at catalytic amounts. After screening several acidic alcohols and phenols for such purpose, more acidic 4-trifluoromethylphenol was disclosed as the best “additive” with a good compromise between chemical yield and enantioselectivity. Afterward, the optimal reaction

conditions were applied to the preparation of two dipeptides 59 and 60 (Scheme 27). In 2015, Du and co-workers devised an efficient organocatalytic direct amidation procedure between vinyl esters and aniline derivatives (Scheme 28).104 The couplings took place in the presence of (IMes, 61) (5 mol %) in toluene at 60 °C. Aromatic and aliphatic vinyl esters were compatible with the reaction conditions, and several amides were synthesized in moderate-to-excellent yields (51% to quantitative yields). M


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Scheme 27. Peptide Coupling via NaOMe/4-CF3−C6H4−OH Catalysis

Scheme 25. Mechanistic Insights on NHC Amidation of Esters with Amino Alcohols

Scheme 28. Vinyl Esters on Organocatalyzed Amidation with Aniline Derivatives

Scheme 26. Pilot-Plant Scale Synthesis of H-PGDS via TBDCatalyzis

Scheme 29. Amide-Bond Formation through Symmetrical Esters and Secondary Amines

mentioned that ester substrates must be purified prior to the reaction in order to eliminate carboxylic acid impurities that were responsible for catalyst deactivation even in the presence of the amine partner. On the basis of experimental observations, the authors have suggested a plausible reaction pathway (Scheme 31). It is believed that a metal−N−H interaction affording a completely aromatized complex 63 takes place, which in turn evolves to 64 via concomitant dissociation of the hemilabile amine arm by reaction with the symmetrical ester. Intramolecular amidation on 64 affords alkoxy intermediate 65 that upon β-hydrogen elimination gives rise to Ru dihydride complex 66 bearing a coordinated aldehyde. Amine addition into the aldehyde and H2 liberation via proton−hydride interaction furnishes complex 67, which after a second β-hydrogen elimination, evolves toward intermediate 68 and liberates a second molecule of amide. The catalytic cycle ends by dihydrogen loss from 68 and regeneration of the catalyst. Following this rational, each catalytic cycle can be responsible for the formation of two amide products and two H2 molecules as byproducts without any generation of free alcohol

In a completely different approach, through Ru-catalysis, symmetrical esters gave rise to amides in high yields, with the sole formation of H2 (2 equiv) as the byproduct (Scheme 29).105 Impressively, a very low catalyst loading (0.1 mol %) was sufficient to promote the reaction. The reaction settings allowed the combination of secondary amines (two examples with primary amines were also given) and aliphatic esters (15 carboxamides synthesized, 52−99% yields). The optimal conditions consisted in using ruthenium-PNN complex 62 (0.1 mol %), ester/amine 1:2 ratio, in toluene or benzene at 135 °C in a Schlenk tube under inert atmosphere (Scheme 30). Outstandingly, high turnover numbers (up to 1000) were observed for this transformation. The authors N


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which is commonly observed as side compound on ester aminolysis. Overall, the procedure presented here by Milstein is rather close to a “dehydrogenative alcohol and aldehyde activation” process affording amides. This topic is going to be discussed hereafter, in sub-section 3.3. A solvent-free reaction affording amides from esters (1.0 equiv) with primary amines (2.2 equiv) was developed by Hong and co-workers using the commercially available iridium(III) complex [Cp*IrCl2]2, with sodium acetate (Scheme 32).106 It should be emphasized that the concomitant formation of secondary amines was observed.

Scheme 30. Dehydrogenative Amidation with Ruthenium− PNN Complex: Incorporation of Both the Acyl and Alkoxy Parts of Esters

Scheme 32. Tandem and Neat Amides and Secondary Amines Synthesis from Esters via Ir-Catalysis

In 2012, a process based on (i) intermolecular transesterification of lactones and cyanomethyl ester of Boc-valine with β-hydroxyamines and (ii) intramolecular O → N acyl transfer was proposed.107 The success attained with such Scheme 31. Proposed Mechanistic Pathway for Ruthenium−PNN Complex Catalyzed Aminolysis of Esters

O


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activated substrates compared with simple esters pave the way to the use of Boc-valine oxazolidinone 69 (that combine an αaminoester lactone and an acetal functionality) with ethylserinate (70) and alaninol (71) (Scheme 33).

Scheme 35. Dipeptides and Tripeptides from the Combination of HCl Salts of Amino Acid Methyl Esters with Tetrabutylphosphonium AAILs

Scheme 33. Hydroxyamine Ligations with Boc-Valine Oxazolidinone

An indirect one-pot, two-step amide synthesis by aerobic oxidative coupling of alcohols or aldehydes and amines was proposed by Riisager and co-workers (Scheme 34).108 The Scheme 34. Aerobic Oxidative Coupling of Alcohols or Aldehydes with Amine via Ester Intermediates Formation using Supported Gold Nanoparticles and Base as Catalysts

metal complexes, nucleophilic alkali-metal amides, and transition-metal and main-group amides were evaluated on transamidation of primary amines and secondary amides. Gellman and Stahl observed that titanium [Ti(NMe2)4] and aluminum [Al2(NMe2)6] complexes are prone to promote such transformations probably due to their relatively reduced basicity compared to the other classes of complexes. The authors also suggested a dual role for the metal catalyst. It is believed that the substrate might be activated with the Lewis acidic metal center and undergo a nucleophilic attack of the coordinated amide ligand. Interestingly, in this first report, they showed a preferential affinity for alkyl amide and primary alkyl amine substrates when the dimeric aluminum complex Al2(NMe2)6 was used (Scheme 36, eq 1). On the other hand, Ti(NMe2)4 was the catalyst of choice to mediate transamidation of aryl amides with primary aryl amines (Scheme 36, eq 2). As suggested by the authors, these quite intriguing observations pave the way to the possibility of developing catalytic systems with functional group selectivity. Similar yields obtained in both directions (e.g., forward and reverse) showed that a thermodynamic equilibrium was attained. Five years later, the same group has devised a transamidation process of amides with secondary amines by means of Al2(NMe2)6 (Scheme 36, eq 3).111 Furthermore, Zr(NMe2)4 and Hf(NMe2)4 were proposed as both alternatives to Al2(NMe2)6 transamidation catalyst between secondary amines and amides and efficient amide metathesis mediators.112 Recently, a metal-free approach for transamidation of acetamide, formamide, and phthalimide derivatives with alkyl or arylamines was reported by Sawant and co-workers.113

reaction starts with the formation of the methyl ester via goldcatalyzed oxidation of the alcohol or aldehyde in methanol. Then, the amine is added and the methyl ester is transformed into the corresponding amide by base-mediated aminolysis. While the reaction proceeds smoothly with benzylamine, less reactive aniline or encumbered pentan-3-amine did not afford the expected amides. Recently, ionic liquids (ILs) bearing amino acid moieties were used as effective substrates for amidation reactions.109 Indeed, the interesting combination of HCl salts of amino acid methyl ester and tetrabutylphosphonium amino acid ionic liquids (AAILs) has allowed the synthesis of several dipeptides and two tripeptides (Scheme 35). An excess (5.4 equiv) of the AAIL partner is necessary to reach acceptable yields as the use of lower amounts gave slightly poorer yields due to the formation of side products such as oligopeptides and DKP. The reaction proceeds at 60 °C, and the final compounds are isolated via tedious stepwise treatment of the reaction medium with AcOH. 3.2. Catalytic Transamidation

Whereas less studied than the catalytic amidation of unactivated esters, seminal work on catalytic transamidation has been reported by Gellman and Stahl in the past decade.110−112 One of the major challenges within this field relies on the robustness of the amide function together with the relatively acidic N−H fonction that could hamper a catalytic process simply by killing the catalytic species. In a first study, the behavior of Lewis acidic P


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Scheme 36. Catalytic Transamidations Reported by Gellman and Stahl

Scheme 37. Redox and Oxidative Amidations

Scheme 38. Transition-Metal Catalyzed Amidation of Alcohol Derivatives

Generally, the formation of amides from alcohols and amines proceeds as depicted in Scheme 39. Scheme 39. Proposed General Route to Amides from Alcohols and Amines

Stoichiometric amounts of K2S2O8 has been used as the mediator of the reaction in aqueous conditions under thermal heating (100 °C) or microwave irradiation. The authors have applied the method for preparing drugs and natural products such as paracetamol, lidocaine, phenacetin, and piperine.

First, the oxidation of the alcohol 78 into its corresponding aldehyde 79 takes place (release of the first hydrogen molecule). Then, the free amine reacts with the aldehyde generating a hemiaminal intermediate 80 which evolves via a second oxidation step (liberation of the second hydrogen molecule) giving rise to the required amide. Nevertheless, due to the oxidation state changes, another scenario can also be envisaged: the competing N-alkylation reaction. This later pathway can be observed if dehydration is faster than dehydrogenation of the hemiaminal intermediate (formation of 81). To date, N-alkylation of amines with alcohols is far more reported in the literature than amidation processes.114,115 Over the years, many catalytic systems, based on the use of transition-metal catalysis, proved their ability on promoting amidation through the combination of alcohols and amines. Even though Ru-based complexes were extensively reported, other metals such as Rh, Au, Ag, Fe, Cu, and Zn were also effective for catalyzing such transformation. The main catalytic systems are going to be discussed as follows. 3.3.1.1. Ruthenium and Rhodium Complexes. In 1991, RuH2(PPh3)4 was used in combination with a hydrogen

3.3. Redox and Oxidative Amidations with Organo- and Metal-Catalysts

Redox and oxidative amidations with organo- and metal-based catalysts are an emerging area of research regarding more atom economical transformations in the field of direct amide synthesis. The following subsections highlight recent advances on this purpose. Nevertheless, only general amide bond formation from amines and alcohol, aldehyde, nitrile, ketone, and methylarene derivatives will be discussed (Scheme 37), and formylation as well as acetylation processes will not be reported therein. 3.3.1. From Alcohols. Transition-metal catalyzed amide synthesis directly from alcohols and amines has been receiving extensive attention in the last years (Scheme 38).114,115 Indeed, the combination of such substrates in an oxidative process is highly suitable in terms of atom economy and sustainable chemistry as only hydrogen gas is formed as a byproduct. Q


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acceptor, benzalacetone, by Naota and Murahashi in order to catalyze the transformation of 1,4- and 1,5-amino alcohols to the corresponding five- and six-membered lactams.116 In the absence of a hydrogen acceptor, a reductive condensation prevailed and the exclusive formation of cyclic amines was observed. Likewise, the addition of two equivalents of water was necessary to ensure the transformation of the tethered amino alcohols bearing a primary amino group to lactams and, thus, avoid the isolation of cyclic amines (Scheme 40a). Thirteen years after the seminal

Scheme 41. General Mechanism for Dehydrogenative Amidation from Alcohols and Amines with Ru and Rh complexes

Scheme 40. Lactams from Tethered Amino Alcohols via Ru and Rh Catalysis

It is only in 2007 that Milstein and co-workers have proposed an efficient intermolecular process, catalyzed by the dearomatized PNN-Ru(II) hydride (62) for direct amidation between free alcohols and amines.118 In the proposed procedure, there was no need for either basic or acidic promoters as well as a hydrogen acceptor. Generally, equimolar amounts of amine and alcohol substrates were used; consequently, only molecular hydrogen was formed as a byproduct during the condensation process. The authors suggested a mechanism where the pincer ligand, bearing a dearomatized ring, can alternatively aromatize and dearomatize in order to facilitate the dihydrogen formation (see also Scheme 31 on aminolysis of esters via the same catalyst). The catalytic charge was as low as 0.1 mol %, and the reaction was highly chemoselective as in the presence of a mixed primary-secondary amine substrate, the amide formation took place at the primary amine group, without the need for protecting the secondary amine function (Scheme 42). However, the proposed catalytic system was unfruitful with dibenzylamine, and a lower yield was obtained with less reactive aniline (58%). Scheme 42. Chemoselective Amidation with Dearomatized PNN-Ru(II) Hydride work of Naota and Murahashi with ruthenium-based catalysts, Yamaguchi and co-workers have used rhodium complexes to synthesize several five-, six-, and seven-membered lactams from aromatic amino alcohols.117 The best catalytic system was composed of [Cp*RhCl2]2/K2CO3, with acetone playing a dual role, the hydrogen acceptor and the reaction solvent. Several benzo-fused lactams and oxindoles were prepared in high yields (12 examples, 46−97%) (Scheme 40b). In both cases, the proposed mechanistic pathways are in agreement with the general one depicted in Scheme 39. Dehydrogenation of the alcohol is mediated by coordination of the amino alcohol to the ruthenium or rhodium center. Then, βhydrogen elimination took place with concomitant formation of both the aldehyde intermediate and the ruthenium- or rhodiumhydride complexes. Subsequent attack by the amine on the aldehyde conducted to the hemiaminal intermediate which evolved, via a second β-hydrogen elimination, to the desired amide or lactam. Hydrogen acceptors such as benzalacetone and acetone were in charge of the oxidation of the precursor catalysts (e.g., metal-hydride or dihydride intermediates) for the generation of the catalytic active species. A simplified scheme is shown in Scheme 41.

Williams and co-workers identified a novel system based on Ru(II) {e.g., [Ru(p-cymene)Cl2]2 (2.5 mol %)} and low-priced bis(diphenylphosphino)butane (dppb, 5 mol %) as the catalyst, in the presence of a base (Cs2CO3, 10 mol %) and 3-methyl-2butanone.119,120 The choice of the later as hydrogen acceptor was driven by its easier removal from the reaction medium, whereas acetophenone was more effective. While a range of carboxamides was prepared in moderate-to-good yields (up to 81% yield), the activity of the reported catalytic system toward secondary amine reactivity (e.g., morpholine) was poor, and the expected amide was obtained in only 31% yield. Grützmacher and co-workers have used in situ generated Rh(I)-diolefin amido complex [Rh(trop2N)(PPh3)] [trop2N = bis(5-H-dibenzo[a,d]cyclohepten-5-yl)-amide] (0.2 mol %) as the active catalyst in the presence of methyl methacrylate as hydrogen acceptor.121 More remarkable, due to unique R


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higher turnover numbers (TONs) observed with [Ru(pcymene)Cl2]2 might be due to the stronger π-coordination of p-cymene compared to benzene allowing better stability. While few less sterically encumbered secondary amines such as piperidine, morpholine, and benzylmethylamine afforded the required amides in moderate-to-good yields in the presence of [Ru(benzene)Cl2]2, no amide formation was detected with the more hindered dibenzylamine as also observed by Milstein and co-workers. Both catalytic systems are comparable with the one devised by Madsen122 (Scheme 43) under basic conditions, whereas the TON are lower than those reported by Milstein118 under neutral conditions (Scheme 42). Concerning the mechanistic pathway, experimental observations were in agreement with the general accepted mechanism (Scheme 41). Nevertheless, contrary to Madsen’s observations, they have detected the amide formation (48% along with 14% of imine) when benzaldehyde and benzylamine were subjected to the reaction conditions. However, experimental results supported Madsen’s hypothesis in which aldehyde- and hemiaminalmetal coordinated intermediates are formed allowing an easier amide-bond formation. Later on, the Hong group has also studied the behavior of several NHC-based ruthenium complexes in carboxamide synthesis (84−88) (Scheme 44).124 Such work shed some

electronic properties, this catalyst affords a dehydrogenative coupling procedure in the mildest reaction conditions reported to date (room temperature). While the scope remains narrow as only 9 amides (82−94% yields) were synthesized, they have also proposed the synthesis of acids and methyl esters by replacing the amines with water and methanol, respectively. Madsen and co-workers have found that the combination of Nheterocyclic carbenes (NHC) with Ru complexes afforded an efficient catalytic system to synthesize a range of carboxamides from various alcohols and, mainly, primary amines.122 Optically pure substrates could be used without detected racemization (Scheme 43). More hindered substrates, as secondary amines, Scheme 43. NHC/Ru Complexes on Amidation: Selected Examples

Scheme 44. NHCs Ru-Complexes for Amide Synthesis from Alcohols

and less reactive aniline required higher temperatures (163 °C in mesitylene) to allow amide formation. Supported by experimental results, the authors have unveiled the presumed mechanistic pathway. First, they ruled out the possibility of an ester intermediate formation (via nucleophilic attack of the alcohol into the aldehyde with formation of a hemiacetal intermediate). Second, coupling between benzaldehyde and benzylamine did not afford any amide or amine product. Indeed, in this case, the exclusive imine formation was observed, which did not change by adding water or over dihydrogen atmosphere. Such observations suggested that the mechanism involved both an aldehyde and a hemiaminal, and these intermediates might be coordinated to the catalyst (intermediates 82 and 83, respectively), otherwise unreactive imine should have been observed. The pursuit of efficient catalytic systems based on the use of NHCs resulted in the emergence of improved procedures. Hong and co-workers published phosphine-free ruthenium catalytic systems for amide formation between several sterically unhindered alcohols and amines.123 Two catalytic systems were proposed, both derived from the combination of dimeric transition-metal precursors such as [Ru(p-cymene)Cl2]2 or [Ru(benzene)Cl2]2 (2.5 mol %), an NHC ligand (IPr·HBr = 1,3-diisopropylimidazolium bromide, 5 mol %), a base (NaH, 15 mol %), and acetonitrile or pyridine as a ligand (5 mol %). In general, both systems are very effective for amidation, and comparable yields were obtained for the set of examples given (16 carboxamides). It is noteworthy mentioning that the slightly

light on the reaction mechanism, suggesting that the alcohol substrate plays a crucial role during the catalyst activation (transformation of [Ru]Cl2 into [Ru]H2 species) and that the need of a catalytic amount of a strong base (NaH or KOtBu) might be related to the Ru-alkoxide species activation and not only associated with the in situ generation of NHCs from the imidazolium. The same group has also combined readily available RuCl3 (5 mol %) with NHCs and pyridine in the presence of NaH.125 For hindered substrates, the use of a less bulky NHC (IMe·HI = 1,3dimethylimidazolium iodide) allowed better results. Higher temperatures (165 °C in mesitylene) were necessary for aniline and encumbered amine substrates. Moreover, they have also shown that NHC-based olefin metathesis catalysts were, likewise, effective catalysts. Supported by the previous studies on Ru-hydride catalytic intermediates via Ru-chloride precatalyst activation,124 Hong and co-workers have anticipated an in situ formation of the catalytic system from available RuH2(PPh3)4 (that was first used by Naota and Murahashi on lactam synthesis), an NHC precursor (IPr· HBr = 1,3-diisopropylimidazolium bromide), a base (NaH), and acetonitrile as a ligand.126 Their system displayed similar activity for the amide synthesis directly from either alcohols or aldehydes with amines. In addition, other Ru(0)-based complexes were also suggested and exhibited good catalytic activity in the presence of an in situ generated NHC ligand. S


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Besides, the same group also reported an efficient NHC-based Ru complex for the direct amidation of challenging secondary amines and alcohols.127 The protocol is based on the use of [Ru(benzene)(IPr)Cl2 (5 mol %)] in the presence of 35 mol % of KOtBu, in toluene at reflux for 24 h. As previously stated, dibenzylamine was a quite reluctant substrate for direct amidation with alcohols. With the proposed procedure, the desired product was formed in 60% yield (Scheme 45), whereas

Scheme 46. Proposed Mechanism Based on Hong’s Observations with Sterically Encumbered Amines: Ester Intermediate

Scheme 45. Dibenzylamine as Substrate on Direct Amidation with Alcohols

remained unchanged, 1-hexanol was entirely converted into hexyl hexanoate. A full account on seminal work on amidation from alcohols and amines catalyzed by Ru-NHC complexes was given by Madsen and co-workers.131 They have disclosed three different catalytic systems, all of them with similar efficiency and broad substrate scope toward amide bond formation (Scheme 47). In Scheme 47. Madsen’s Catalytic Systems and Selected Examples

no reaction was observed with the aforementioned catalytic system.118,123 Unlike previously reported with less sterically encumbered substrates, a mechanism involving an ester intermediate was postulated (Scheme 46). Independently, during the mechanistic investigation of onepot amide-bond formation by oxidative coupling of alcohols with amines in methanol using supported gold and base as catalysts, Fristrup, Kegnæs, and co-workers have postulated the formation of a methyl ester intermediate using Hammett correlation studies.128 A protocol based on ruthenium/NHC/base-catalysis was also devised by Hong and Chen for selective sp3 C−O cleavage with concomitant amide formation in the presence of 3alkoxy-1-propanol derivatives and amines.129 Following the interest for direct amidation of secondary amines, Milstein and co-workers have proposed a few PNNbipyridil Ru complexes (0.2−1.0 mol %) in order to synthesize amides.130 As previously suspected by Hong, the involvement of ester intermediates was also proposed.127 Nevertheless, contrary to Hong’s conditions, no amide formation was detected when dibenzylamine and 1-hexanol were used under the reaction conditions.127 In this particular case, while dibenzylamine

the first one (I), the active catalyst is generated in situ from [Ru(COD)Cl2], 1,3-diisopropylimidazolium chloride, and PCyp3·HBF4 and base. The second system (II) used the complex [RuCl2(IPr)(p-cymene)] with PCy3 and base. Finally, the third catalytic system (III) was the Hoveyda-Grubbs first generation olefin metathesis catalyst combined with IPr·HCl and base. In a mechanistic viewpoint, it was proposed for all the T


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refluxing toluene or xylene.135 Few primary and secondary amines (2 equiv compared with the alcohol substrate) were used, and the yields were generally high (48−93%). A notable contribution to this field was reported by Wang and co-workers in 2011.136 They have used a water-soluble gold catalyst immobilized on DNA (Au/DNA nanohybrid) to perform amidation reactions with the possibility of catalyst recovery and reuse including the challenging coupling between two aromatic substrates (benzyl alcohol and aniline derivatives) and also secondary amines. The reaction took place mostly at 50 °C in water in the presence of LiOH·H2O (1.1 equiv) under oxygen atmosphere. The products were isolated in high yields (47−97%), and the proposed mechanism is in agreement with hemiaminal oxidation into amide mediated by the combination of the water, the high pH value, and the Au/DNA (Scheme 49). Indeed, literature precedents showed that the imine intermediate was the main product formed when water-insoluble gold catalysts were used under anhydrous conditions.137,138

catalytic systems, the same reaction pathway via formation of the Ru-coordinated aldehyde and hemiaminal intermediates. A protocol involving Ru-diphosphine diamine complexes was reported in 2011 by Crabtree and co-workers.132 Indeed, supported by computational studies, the authors have investigated the involvement of both the diphosphine and diamine ligands on the catalytic complexes during the dehydrogenative oxidation of the alcohol substrates. It has been witnessed that complexes bearing diamine ligands with N−H protons were more efficient catalysts for amide-bond formation, probably due to a hydrogen-bonding interaction between the substrate and the ligand (intermediate 89) that might facilitate the hydrogen release from the metal (Scheme 48). Scheme 48. Amidation via Ru-Diphosphine Diamine Complexes

Scheme 49. Au/DNA Catalyzed Amidation: Mechanism Proposal

Bera and co-workers exploited the use of a Ru(II)-NHC complex bearing two carbonyls and a pyridine functionalized NHC [conditions: Ru(py-NHC)(CO)2Br2 (1 mol %), NaH (5 mol % in toluene at 110 °C] which was obtained from a dimeric RuI precursor.133 The catalytic activity is similar to Madsen’s Ru(II)-p-cymene-based catalyst. Nonetheless, contrary to Madsen’s conditions, this is a phosphine-free procedure. Several primary amines and alcohols were prone to afford the corresponding carboxamides in high yields (24 examples, 45− 92% yields). The direct amidation between aniline and ptolylmethanol gave the desired amide with 72% yield, and the intramolecular formation of γ-butyrolactam was accomplished in 45% yield from 4-amino-1-butanol. Another interesting catalytic system was recently proposed by Guan and Dong based on commercially available Ru-Macho catalyst [e.g., RuHCl(CO)(HN(CH2CH2PPh2)2].134 Direct amides formation via dehydrogenation of primary and secondary amines with alcohols were performed in the presence of 1 mol % of the catalyst, 15 mol % of KOH as base in refluxing toluene or xylene under a nitrogen flow (15 examples, up to 95% yield). 3.3.1.2. Gold and Silver Catalysis. In 2009, Shimizu and coworkers have reported the first heterogeneous catalytic system based on alumina-supported silver cluster (Ag/Al2O3-5) (4 mol %) in the presence of a weak base, Cs2CO3 (20 mol %) in

Another remarkable work was published by Kobayashi and coworkers on the use of heterogeneous-polymer-incarcerated with carbon black (PICB) Au or Au/Co nanoparticles under aerobic conditions.139,140 The reaction conditions are mild (room temperature or 40 °C), and THF/H2O (19:1) was used as the solvent in order to sidestep ester formation. Other important parameters were the need for a strong base such as NaOH and the reaction concentration (0.75 M). Two catalytic systems were proposed according to the alcohol reactivity (Scheme 50). For activated alcohols (e.g., benzylic alcohols), PICB-Au/Co showed better results whereas PICB-Au gave improved outcomes for U


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and molecular oxygen was published by Christensen and coworkers.143 3.3.1.3. Iron, Zinc, and Copper Catalysis. Iron salts were also able to mediate tandem oxidative amidation of alcohols with amines. Chen and co-workers have shown that from the combination of Fe(NO3)3·9H2O with TEMPO (5 mol % of each) emerged an effective catalytic system to mediate amide formation between benzylic alcohol derivatives and amine hydrochloride salts under air and tert-butylhydroperoxide (TBHP) as oxidants.144 The reaction proceeded via Fe(III)TEMPO-mediated alcohol oxidation (Scheme 51). Then,

Scheme 50. PICB-Au/Co and PICB/Au Catalyzed Direct Amidation through Tandem Oxidation Process: Selected Examples

Scheme 51. Selected Examples and Reaction Mechanism for (Fe-TEMPO)-Catalyzed Tandem Oxidative Amidation

nonactivated alcohol substrates (e.g., nonbenzylic alcohols). The combination of PICB-Au was also more effective for secondary or encumbered amine substrates. Among several amides synthesized, optically active amino acid derivatives were used as substrates without any detected racemization. Additionally, one free amino acid derivative (carboxylic acid function free, see product 90) could be engaged under the reaction conditions (Scheme 50).139 Both catalysts could be easily recovered and reused several times. Moreover, PICB-Au/Co displayed very high selectivity for amidation of benzylic alcohol in the presence of aliphatic alcohols. The reaction proceeds through the classical hypothesized mechanism (Scheme 39), and control experiments ruled out either the imine or the ester intermediates formation. Shi and co-workers devised a dehydrogenative amide synthesis catalyzed by hydrotalcite-supported gold nanoparticles (Au/ HT).141 In contrast to the previous procedure via Au/DNA catalysis, the authors suggest a reaction pathway via an ester intermediate. Indeed, in a control reaction between benzyl benzoate and morpholine the expected amide was isolated in 91% yield, whereas a 29% yield was observed with benzaldehyde. Several alcohols and cyclic secondary amines were prone to react under the reaction conditions (Au/HT, KOtBu, o-xylene, 70−90 °C) affording the corresponding carboxamides in high yields (60−98%). The catalyst could be recovered and reused, though with diminished efficacy after the second run (2nd run 97% yield vs third run 54% yield). In 2013, Luque and co-workers have combined localized heating over laser irradiation and gold-nanoparticles (Au/SiO2) in an efficient amide formation between benzyl alcohol and morpholine under a tandem oxidation/amidation process.142 In 2008, the first report on the aerobic oxidation of alcohols and amines into amides in the presence of heterogeneous bifunctional gold nanoparticles supported on titania (Au/TiO2)

hemiaminal formation was reached via amine addition onto the so-obtained aldehyde intermediate. Oxidation of the hemiaminal to the required amide was then accomplished by the Fe(III)TBHP catalytic system via a free radical mechanism. This affirmation corroborates with the complete reaction inhibition observed under the addition of a free radical scavenger such as 2,6-di-tbutyl-4-methylphenol (BHT). Among the substrates used, amino acid derivatives (Gly, Pro, and Phe) can be cited, and the corresponding amides were obtained without detectable racemization (Scheme 51). Besides this work, Lamaty, Bantreil, and co-workers have also devised a straightforward procedure based on the use of FeCl2· 4H2O and TBHP as oxidant to synthesize a broad library of carboxamides from several benzylic alcohols and primary or secondary amine hydrochloride salts.145 Supported by control experiments, the authors suggested a mechanism involving radical species. The method described therein was applied as the key step during the synthesis of the antianxiety drug moclobemide (91) (Scheme 52). Moreover, a protocol for the synthesis of benzamide analogs, catalyzed by iron/caffeineV


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combination via microwave activation, has also been developed.146

Scheme 53. Selected Examples and Reaction Mechanism for (CuO-TBHP)-Catalyzed Domino Oxidative Amidation

Scheme 52. Synthesis of Moclobemide Using FeCl2·4H2OCatalyzed Amidation

De Luca and co-workers used the combination of FeCl3· 6H2O/TBHP in a straightforward oxidative amidation of alcohols with N-chloroamines in a base-free procedure.147 The N-chloroamine substrates were prepared in situ from the corresponding primary or secondary amines and NCS (Nchlorosuccinimide). Moreover, amine hydrochloride salts were used for amidation with benzylic alcohol substrates in the presence of magnetic Fe(OH)3@Fe3O4 nanoparticles.148 In addition of affording amides in good yields, catalyst’s recycling allowed its reuse up to six times without significant loss of its catalytic activity. The Lamaty’s group has also proposed a catalytic system based on copper oxide (CuO) and TBHP for the direct amidation of benzyl alcohols.149 Under the optimal reaction conditions, chiral amino ester derivatives (Phe, Pro) were employed affording the corresponding amides in high yields without racemization. Preliminary mechanistic rationale, supported by experimental observations, suggests that the copper is necessary for both alcohol oxidation and subsequent aldehyde amidation (Scheme 53). Cu-catalysis [e.g., Cu(OAc)2·H2O (6 mol %) and TBHP] was also effective for the synthesis of Weinreb amides (14 examples, 40−90% yields) via oxidative amidation of benzyl alcohol derivatives with N,O-dimethylhydroxylamine hydrochloride salt.150 In 2013, Beller, Wu, and co-workers have considered the use of zinc in order to mediate such condensation reaction. It has been shown that the combination of ZnI2/TBHP in a solvent-free procedure was highly effective for catalyzing the amidation between benzylic alcohols and alkyl/arylamines (Scheme 54).151 The carboxamides (25 examples, 23−85% yields) were isolated in high yields and reluctant substrates such as aniline and tertbutyl amine worked well under the reaction conditions. Nevertheless, with either morpholine or heteroaromatic alcohol derivatives, moderate yields were observed. 3.3.1.4. Metal-Free Processes. Following the same line of research, work was also reported based on metal-free procedures. They rely on the combination of either NaI or DIB (diacetoxyiodobenzene) with TBHP in order to afford efficient oxidant systems.152,153 Hence, NaI (10 mol %) was able to

Scheme 54. Selected Examples on (ZnI2/TBHP)-Catalyzed Oxidative Amidation

catalyze the synthesis of benzamides from aromatic alcohols and primary and secondary amine hydrochloride salts in the presence of TBHP (8.0 equiv), CaCO3 (2.2 equiv) in acetonitrile at 80 °C under argon (18 examples, 53−93% yields) (Scheme 55a).152 The use of few enantiomerically pure amines afforded the desired products in a racemization-free process. Likewise, it was shown that DIB (20 mol %) can replace NaI on such transformation giving rise to the expected products in good yields (19 examples, 65−88% yields) (Scheme 55b).153 3.3.2. From Aldehydes. As for alcohols, the use of aldehydes as substrates for direct amidation processes has also been extensively studied this past decade (Scheme 56). In general, the transformation proceeds via a mechanism analogous to the one above-mentioned (see Scheme 39). Nevertheless, some catalytic combinations used on this particular case provide different reaction pathways, and when necessary, they are going to be discussed in more detail within this W


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Scheme 55. Oxidative Amidation of Aromatic Alcohols in Metal-Free Processes

Scheme 58. Proposed Mechanism for the Pd-Catalyzed Condensation of Aldehydes with Morpholine

Scheme 56. Oxidative Amidation of Aldehydes

In 1991, Naota and Murahashi have extended their Ru-based catalytic system for lactams formation (see Scheme 40) to the direct condensation of aldehydes with amines.116 A few aryl aldehydes were able to react in the presence of cyclic secondary amines and a catalytic amount of [RuH2(PPh3)4] to give the expected amides in moderate-to-good yields (5 examples, 43− 77% yields) (Scheme 59).

subsection. As for direct couplings between alcohols and amines, several efforts were devoted allowing the development of very powerful catalytic systems. However, the scope for such direct oxidative transformations remains poor, being very little explored for more elaborated substrates (as for example, peptide synthesis purposes). As for alcohol derivatives, the field of oxidative amidation of aldehydes is also dominated by the use of transition-metal catalysts. 3.3.2.1. Palladium and Ruthenium Catalysis. In 1983, Yoshida and co-workers have introduced palladium as transitionmetal variant for catalyzing such transformations.154 Indeed, no example of Pd-catalyzed direct amidation of alcohols has been reported so far. The Pd-catalyzed oxidative transformation of aldehydes into the corresponding morpholine amides goes through the use of stoichiometric amount of aryl bromide 92 as the oxidant and a base (K2CO3) (Scheme 57).

Scheme 59. Ru-Catalyzed Amidation of Aldehydes and Secondary Amines

Scheme 57. Pd-Catalyzed Oxidative Transformation of Aldehydes into Morpholine Amides

Ten years later, Beller and co-workers proposed the combination of a cationic rhodium catalyst, [Ru(COD)2]BF4, with triphenylphosphine as a ligand to report the first Rhcatalyzed condensation of aldehydes with secondary amines.155 The success of such a catalytic system was ensured by both the addition of a stoichiometric amount of NMO (N-methylmorpholine N-oxide) that was in charge of regenerating a catalytically active rhodium dehydrogenation catalyst and of K2CO3 (10 mol %) as a cocatalyst. By modulating the aldehyde/amine ratio, good yields were obtained and, in general, the aldehyde partner is used in excess (2:1). Suto, Torisawa, and Yamagiwa have developed a catalytic system based on PdCl2/H2O2-urea combination together with

With regard to the mechanism of this Pd-catalyzed reaction, the formation of an alkoxypalladium derivative 93 is suggested as a key intermediate, which might evolve by releasing the desired amide and hydridopalladium species. As depicted on Scheme 58, this hydridopalladium species is reengaged on the catalytic cycle after a reductive elimination of the aromatic hydrocarbon. X


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Xantphos as ligand under mild acidic conditions (MeOH/ AcOH).156 Concerning the substrate scope, the reaction is very dependent on the steric- and electronic-factors of both partners. Sterically demanding amines as well as electron-rich and aliphatic aldehydes afforded less satisfactory results. No reaction was observed with pyrrolidine. A tentative mechanistic explanation was given based on an oxidation and/or rearrangement through a hydroperoxide intermediate issued from hemiaminal and/or imine intermediates (Scheme 60). One possible explanation on

Scheme 61. Copper-Catalyzed Oxidative Amidation of Aldehydes with Primary Amine Hydrochloride Salts: Selected Example

Scheme 60. PdCl2/H2O2−Urea Catalyzed Oxidative Amidations

starting from the aldehyde intermediate. Moreover, they ruled out the amidation reaction via a carboxylic acid intermediate (that could be derived from the direct oxidation of the aldehyde substrate), as the same reaction with benzoic acid instead of benzaldehyde did not afford the desired amide. In 2015, a simpler catalytic system based on the combination of CuI (10 mol %) and TBHP (3.0 equiv) was published for amidation between arylamines and aldehydes in a solvent-free procedure at room temperature (18 amides, 31−88% yields).158 The use of 2-aminopyridine derivatives 95 in amidation processes by means of copper-catalysis has been investigated by the Huang and Yadav groups (Scheme 62).159,160 Catalytic Scheme 62. Cu-Catalyzed Synthesis of N-(Pyridine-2yl)amides

how this peroxide intermediate evolves to the corresponding amide can be a Baeyer−Villiger type degradation, but further studies to confirm such hypothesis are needed. Hong and co-workers, when developing direct amidations from alcohols with amines via Ru/NHC-catalysis, have also proposed a catalytic system that can be transposed to aldehyde substrates.126 Aryl and aliphatic aldehydes react with primary or cyclic secondary amines to give the corresponding amides in moderate-to-good yields. Nevertheless, from alkyl aldehydes, the corresponding amides are obtained in lower yields due to the competitive formation of imine byproducts. 3.3.2.2. Copper, Iron, and Gold Catalysis. In 2006, a remarkable report by Li and Yoo proposed a procedure for coupling primary amines with aldehydes by means of copper catalysis.157 By using a cheaper catalytic system compared to the previous ones, based on the combination of CuI, AgIO3 as additive and TBHP (70 wt % in water) as oxidant, several primary amines, including amino acid residues, could be successfully used (13 examples, 39−91% yields). Interesting to note, a catalytic loading of copper iodide as low as 1.0 mol % was enough to catalyze the condensation process. Moreover, L-valine methyl ester hydrochloride was engaged under the reaction conditions in the presence of benzaldehyde and the expected corresponding amide 94 was obtained in excellent yield without racemization (Scheme 61). With regard to the mechanism of this Cu/TBHP procedure, the authors proposed a similar reaction pathway, analogous to the general one depicted on Scheme 39,

amounts of CuI (10 mol %) in DMF at 80 °C were the conditions developed by Huang and co-workers in order to prepare several amides from aryl aldehydes in high yields (22 examples, 28−94% yields).159 Yadav’s group proposed an oxidative process by means of a catalytic system based on Cu(OTf)2 (5 mol %) and iodine (50 mol %) in the presence of an aqueous miscellar system [e.g., sodium dodecyl sulfate (SDS)].160 The transformation takes place at room temperature in reaction times lower than 60 min (34 examples, 25−95% yields). Recently, a heterogeneous copper(II)−complex covalently anchoring (2-iminomethyl)phenol moiety supported on HApencapsulated-α-Fe2O3 has been synthesized and used as effective inorganic−organic hybrid magnetic nanocatalyst on an amidation process.161 The reaction of aromatic aldehydes with ammonium chloride or aniline hydrochloride gave primary and secondary amides in good yields in a short reaction time. In 2012, Chen and co-workers illustrated oxidative amidation of aldehydes with a broad range of primary and secondary amine hydrochloride salts via inexpensive FeSO4·7H2O as a catalyst combined with TBHP as a stoichiometric oxidant.162 Even though aryl aldehydes were mainly employed, the scope proposed within this work was wider compared to the previous ones. The protocol could be successfully applied to the synthesis Y


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of the antiarrhythmic drug N-acetylprocainamide (96) (Scheme 63). While a mechanism following the classical pathway (see

mechanistic pathway for this transformation is proposed on Scheme 65.

Scheme 63. Synthesis of N-Acetylprocainamide via FeSO4· 7H2O Catalysis

Scheme 65. Ni-Catalyzed Dehydrogenative Cross-Coupling Affording Amides from Aldehydes

general Scheme 39) has been proposed by the authors, a radical mechanism cannot be ruled out as oxidation reactions with TBHP in the presence of an iron compound can proceed through a free radical process. Alternatively, the iron-salt could be replaced by copper-salt (CuSO4·5H2O) affording several amides in good-to-excellent yields.163 Likewise, FeSO2·4H2O (10 mol %) catalyzed oxidative amidation of aromatic aldehydes with primary and secondary amines in a base-free protocol (21 examples, 37−79% yields). The method goes through in situ sequential protection and deprotection of the amine partners by carbon dioxide with the essential temporary formation of ammonium carbamate salts.164 Wong and co-workers designed a gold-catalyzed amide synthesis from aldehydes and secondary amines in aqueous medium under mild reaction conditions.165 Interestingly, polyhydroxyl oligosaccharide-based aldehydes 97 successfully react with cyclic secondary amines to give the corresponding amides in high conversions (Scheme 64). 3.3.2.3. Nickel Catalysis. A procedure for dehydrogenative cross-coupling of aldehydes and amines by means of Ni-catalysis was devised in 2015 by Dong and Whittaker.166 By combining [Ni(cod)2] (5.0 mol %) and an organic oxidant (α,α,αtrifluoroacetophenone, 99), direct transformation of aldehydes into amides (Scheme 65) and esters was possible. A preliminary

3.3.2.4. Lanthanide-Based Catalysts. The use of lanthanide catalysts on amidations was described in 2008 by Marks and Seo.167 While Ln[N(SiMe3)2]3 (LnLa, Sm, Y) lanthanide amido complexes were able to catalyze such couplings under mild conditions (room temperature) without the need for adding either strong oxidants or base, the reactions must be carried out under inert atmosphere (glovebox) with a large excess of aldehyde (3:1 ratio CHO/NH2) to reach high yields. A few secondary amines, aniline and benzylamine were used in the presence of aryl aldehydes to give the expected amides in moderate-to-good yields (10 examples, 27−98% yields). One year later, the group of Shen has also proposed anionic bridged bis(amidate) lithium lanthanide complexes as efficient catalysts for the condensation of aryl aldehydes with secondary amines and aniline derivatives at room temperature under inert atmosphere.168,169 The optimal ratio between CHO/NH2 was 3:1, affording the amide products in good yields (20 examples, 50−99% yields). 3.3.2.5. Metal-Free Processes. Wolf and Ekoue-Kovi, when working on POPd-catalyzed oxidative amidations of aromatic aldehydes with triaminoborane [B(NMe2)3] or tetraaminosilane

Scheme 64. KAuCl4-Catalyzed Amidation of D-Raffinose Aldehyde with Secondary Amines

Z


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[Si(NMe2)4] reagents, have also suggested a metal-free one-pot oxidative amidation of aromatic aldehydes with secondary cyclic amines as a more convenient approach.170 While the use of such expensive triaminoborane or tetraaminosilane reagents could be avoided, stoichiometric amounts of TBHP as oxidant were required. Approaches based on NHC-catalyzed redox amidations of αfunctionalized aldehydes with primary and secondary amines were independently proposed by the groups of Rovis and Bode.171,172 Rovis and Vora devised a dual catalytic system based on a nucleophilic carbene 100 and HOAt as a catalyst relay.171 A series of amines successfully reacts with α-haloaldehydes 101, the redox substrates, affording the required amide products in high yields (12 examples, 72−89% yields). Furthermore, the scope was extended to other α-reductible aldehydes such as α,β-epoxy and aziridino aldehydes 102 as well as α,β-unsaturated aldehydes 103 (Scheme 66).

Scheme 67. Proposed Catalytic Cycle for NHC-HOAt Catalysis for Amidation Reactions

Scheme 66. Scope of NHC-HOAt Catalysis for Amidation Reactions Scheme 68. NHC-Catalyzed/Imidazole-Mediated Redox Amidations of Enals

The authors suggested that the NHC-catalyst 100 reacts first with the aldehyde substrate affording the acyl azolium intermediate 104. Thus, acyl transfer with HOAt (47) gives the activated carboxylate 105, which is the real acylating agent, which undergoes nucleophilic attack by the amine partner releasing both the amide product and HOAt (Scheme 67). Bode and Sohn developed a NHC-catalyzed process in the presence of stoichiometric amounts of imidazole (107) for the redox amidation of formylcyclopropanes 109 and α,β-unsaturated aldehydes 103 (Scheme 68).172 The imidazole plays a crucial role to promote the condensation via the stoichiometric

formation of the acyl imidazole intermediate 108, which is the active acylating agent in the presence of the amine nucleophile. Studer and De Sakar also developed an oxidative amidation of aldehydes by NHC-catalysis with an organic oxidant (3,3′,5,5′tetra-tert-butyldiphenoquinone) via the stoichiometric formation of activated hexafluoroisopropyl esters for amide bond formation.173 Aromatic and conjugated aldehydes well tolerate the oxidative conditions and combined with primary and secondary amines allowed the synthesis of several carboxamides in excellent yields (78−93% yields). AA


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aldehydes. In addition, the amidation can proceed either under neat conditions at 50 °C or ball-milling conditions at room temperature (Scheme 71). Furthermore, solvent-free ball milling

In the same line, Yamada and co-workers developed an oxidative condensation of α-unbranched aldehydes to amides in the presence of NHC-catalysis combined with N-chlorosuccinimide (NCS) as stoichiometric organic oxidant.174 In this case, HOBt (20 mol %) was used in order to afford a more activated ester that reacts faster with the amine substrates. Aliphatic aldehydes and primary or secondary amines gave the carboxamides in excellent yields (7 examples, 71−91% yields). The reaction between L-phenylalanine tert-butyl ester hydrochloride (111) and hydrocinnamaldehyde (112) gave the corresponding amide 113 without racemization (76% yield) (Scheme 69).

Scheme 71. Oxidative Amidation of Alcohols and Aldehydes with N-Chloramines

Scheme 69. NHC/NCS-Catalyzed Amidation of Aldehydes

conditions afforded an option to allow transformation of primary amines and aldehydes into amides via C−H activation using phenyliodine diacetate (PIDA).178 In 2004, Ishihara and Yano developed a strategy to synthesize N,N′-dialkylcarboxamides via LDA-catalyzed Cannizzaro-type reaction (Scheme 72a).179 The combination of aldehydes with lithium alkylamides afforded the corresponding amides in good yields (10 examples, 52−87% yields).

In 2015, Alanthadka and Maheswari have proposed an oxidative NHC-catalyzed amidation process in which aryl aldehydes reacted with several aliphatic primary (including amino acid derivatives) and secondary amines (Scheme 70).175

Scheme 72. LDA-Catalyzed Cannizzaro and Haller-Bauer Type Reactions for Amide Synthesis

Scheme 70. Oxidative NHC-Catalyzed Amidation with Aryl Aldehydes

3.3.3. From Ketones. Besides, they have also reported the synthesis of carboxamides via LDA-catalyzed Haller−Bauer reactions (Scheme 72b).179 In this particular case, ketones and lithium amides (R4NHLi) were used as substrates to give Nalkylcarboxamides (6 examples, 52−92% yields) in high yields. The well-known iodoform reaction has recently been adapted to amide synthesis using amines as nucleophiles.180 Bode and coworkers disclosed a catalytic amide formation through the combination of NHC 106 and 1,2,4-triazole starting from α′hydroxyenones 115, substrates that can be considered as surrogates for α,β-unsaturated aldehydes.181 Primary and secondary amines, and amino alcohol derivatives well tolerate the reaction conditions affording several amides in high yields (21−99% yields) (Scheme 73). The success of the procedure was guaranteed by the addition of 1,2,4-triazole as cocatalyst, which

A metal-free procedure based on iodine-catalyzed radical oxidative amidation of aldehydes with primary and secondary amines was also developed in 2015.176 The transformation is ensured by the addition of TBHP and NCS (which is in charge of the in situ N-chloramine intermediates formation), thus affording the expected products in good yields (16 examples, 73−89% yields). Moreover, in the same year, a metal and solventfree process, based on radical-induced oxidative amidation of aldehydes and alcohols with N-chloramines has also been studied by Mal and Achar.177 In this work, the combination of TBAITBHP gave the best results via direct C−H activation of AB


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Scheme 73. Dual NHC/1,2,4-Triazole-Catalyzed Amidation Reactions

Scheme 74. Proposed Mechanism for Dual NHC/1,2,4Triazole-Catalyzed Amidation Reactions

allowed much higher yields and chemoselectivities (amine vs alcohol function when amino alcohols were used) via the formation of the active acylating agent (e.g., acyl triazole intermediate 120, Scheme 74). Remarkably, no excess of reagents was required, the reaction conditions are mild, and acetone is the sole byproduct. A mechanistic pathway is disclosed in Scheme 74. Intermediate 116 is obtained after attack of NHC 106 to the α′-hydroxyenone 115. Thus, the intermediate 116 evolves through acetone release giving rise to the Breslow intermediate 117. Formal homoenolate equivalent intermediate 118 is formed via protonation of 117. Tautomerization of 118 affords 119 that nonetheless reacts slowly with amines. Thus, 1,2,4-triazole cocatalyst plays a crucial role for amidation processes as it affords the acyl triazole intermediate 120 that is the real acylating agent in the presence of amines. Cu-catalyzed aerobic oxidative amidation of aryl ketones with azoles gave rise to tertiary amides by means of chemoselective cleavage of the C(CO)-C(alkyl) bond in the aryl ketone substrates.182 3.3.4. From Aromatic Derivatives. 3.3.4.1. Oxidative Amidation. Following pioneering works on oxidative amidation of methylarenes 121,183−186 the groups of Heydari, Sekar, and Zhao have recently and independently reported catalytic procedures via Fe-catalysis (Scheme 75). Heydari, Sekar, and co-workers developed oxidative conditions with TBHP by using amine hydrochloride salts or N-chloroamines.187,188 The method proposed by Zhao and co-workers required the use of TBHP and TBAI (tetrabutylammonium iodide) as cocatalyst in the presence of free primary or secondary amines.189 In addition, Chen, Yin, and co-workers developed an alternative route, via Cu-catalyzed direct aerobic oxidative amidation, in which azaarylmethanes were successfully used as substrates producing amides in high yields, broadening thus the scope of this transformation.190

Scheme 75. Amide Formation through Oxidative Amidation of Methylarene Derivatives

3.3.4.2. Aminocarbonylation of C(sp3)-H Bonds. Early efforts toward amide formation via challenging C(sp3)-H bond functionalization focused on the use of Pd-catalysts (Scheme 76).191,192 Huang and co-workers have investigated the oxidative aminocarbonylation of simple alkyl aromatics and amines (>22 examples, 34−85% yields). The reaction conditions could be transposed to ethylbenzene derivatives (3 examples, 57−75% yields) (Scheme 76a).191 Elaborating on this concept, Dyson and AC


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Scheme 76. Pd-Catalyzed Aminocarbonylation of C(sp3)-H Bonds

Scheme 78. Redox-Neutral Amidation from Alcohols and Nitriles

3.4. Thioacids

The enhanced nucleophilicity (but also solubility) of thioacids compared to carboxylic acids207 has prompted several groups to explore their reactivity in amide formation. Nevertheless, it might be mentioned that thioacids are not easily prepared, and their synthesis can be troublesome. They do not directly react with amines at room temperature, as observed with carboxylic acids, but several mild activation methods have been disclosed in the past few years. Accordingly, the combination of thiocarboxylic acids with various amino-surrogates such as azido, isonitriles, dithiocarbamates, or sulfonamides paved the way to various amide formation procedures. These methods are described infra in sub-sections 4.3, 4.5, 4.6, and 4.11. The direct conversion of thioacids with amines, in the presence of the Sanger’s (122) or the Mukaiyama’s (123) reagents, was investigated by Crich and Sharma (Scheme 79),208 prompted by a seminal study of the reactivity of thioacids in the presence of sulfonamides (see section 4.6).208−210 The thioacids are generated in situ from Fm or Tmob thioesters 124 under basic or acidic conditions, respectively, and next directly used in the coupling reaction with the amine and the coupling reagent (Scheme 79). Good yields were generally observed at room temperature using either Sanger’s or Mukaiyama’s reagents. Nevertheless, when using Fmoc protecting groups, higher yields were usually observed with the Mukaiyama’s reagent. This methodology compares favorably to methods involving carboxylic acids and traditional peptide coupling reagents: in a model reaction of fragment coupling between two tetrapeptides 125 and 126 (Scheme 80), the octapeptide 127 was obtained in good yield with no detectable amount of epimerization. Liebeskind and co-workers have described the pH-neutral formation of amides through the silylation of thiocarboxylic acids in the presence of BSA (bistrimethylsilylacetamide).211 The reaction occurs through two successive silicon migration (Scheme 81). The silylation of the thioacid affords the Ssilylthiol esters 128 that are not stable and undergo a silatropic switch to form an activated O-silylthionoester 129 which in turn reacts with the amine to give a tetrahedral intermediate 130. A migration of the silicon from the oxygen to the sulfur then occurs through a hypervalent silicon intermediate and generates the amide bond (with no formation of the thioamide) after elimination of trimethylsilanethiol. As illustrated in Scheme 81, the reaction proceeds efficiently at room temperature in the

co-workers proposed a procedure for the synthesis of substituted phenyl amides from simple alkanes and anilines (>18 examples, 43−78% yields) (Scheme 76b).192 Recently, Rhodium(III)-catalyzed C(sp3)-H amidation of unactivated alkyl C−H bonds was developed.35 In this work, 3substituted 1,4,2-dioxazol-5-ones acts as the amine surrogate partner. 3.3.5. From Nitriles. Nitriles can also serve as efficient carboxylic acid surrogates in amide formation. The well-known Ritter reaction (Scheme 77a), the addition of a nitrile to an in situ Scheme 77. Nitriles as Carbonyl Sources in Amide Synthesis

formed carbocation, is an efficient method for the construction of amides.29,193,194 Nitriles can also be hydrated in the presence of different metal salts to give nonsubstituted amides (Scheme 77b)195−200 or alternatively treated by differently substituted amines to give the amides (Scheme 77c).201−205 In a different approach, a Ruthenium-catalyzed formation of amides from nitriles and alcohols has been described by Hong and co-workers (Scheme 78).206 On the basis of labeling studies and experimental observations, a redox-neutral mechanism involving both the reduction of the nitrile to a Ru-imine complex and the alcohol oxidation to aldehyde is involved. AD


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Scheme 79. Direct Coupling of Thiocarboxylic Acids and Amines in the Presence of Sanger’s or Mukaiyama’s Reagents

Scheme 80. Comparison of a Model Peptide Fragment Coupling Using Thiocarboxylic (with the Mukaiyama Reagent) and Carboxylic Acids (with Traditional Coupling Reagents)

Scheme 81. Silatropic Switch in the Synthesis of Amides from Thiocarboxylic Acids and Silylating Agents

presence of aromatic and aliphatic thioacids with primary and secondary amines, including anilines and hindered amines. More recently, the direct formation of the reactive O-silylthionoester

species via the silylthioesterification of a carboxylic acid was described by the same group.212 AE


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Scheme 82. Scope of the Silatropic Switch Activation of Thiocarboxylic Acids

Scheme 83. Glycopeptide Synthesis from ω-Thioaspartic Acid

This methodology was next efficiently extended to peptide synthesis. Thioacids (in situ obtained from the corresponding Fm esters)209 are efficiently coupled to amino acids regardless of the nature of the two amino acid partners (Scheme 82). Antenuis and Anderson tests have been carried out to check epimerization levels in the sensitive fragment coupling with phenylalanine amino acids (131 and 132).213 As illustrated in Scheme 82, low levels of epimerization (90% selectivity) α,β-unsaturated amides (Scheme 95).244 Alternatively, Petricci proposed a similar procedure for the regioselective aminocarbonylation of ynamides 140 by using microwave-assisted iron-catalysis {[Fe3(CO)12] (20 mol %)} (Scheme 96).245 The amount of nucleophile (1.2 equiv) as well as the CO pressure (1.3 bar) and reaction times (20 min) are

Scheme 95. Iron-Catalyzed Mono-Aminocarbonylation of Alkynes

substantially reduced compared to the Beller’s protocol. The 3amido acrylamides 141 were obtained in good yields and no traces of either the Z-isomers or succinimide products were observed. It is worth noting, that this microwave-assisted AI


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formamide addition to terminal alkynes in which the branched acrylamides were predominantly obtained. Pd-catalysis was also effective for a tandem transformation based on selenopalladation, CO insertion followed by trapping with sulfenamides affording β-selenyl acrylamides 142 in moderate yields (7 examples, 45−61% yields) and excellent stereoselectivity (100% Z) (Scheme 98).250

Scheme 96. Microwave-Assisted Iron-Catalyzed Monocarbonylation of Ynamides

Scheme 98. Selenocarbonylation of Terminal Alkynes with Sulfenamides

3.5.1.2. Insertion into Acetylenic C−H Bond (Oxidative/ Hydrative Amide Synthesis). The first example of a catalytic oxidative monocarbonylation of alkynes with secondary amines to lead to alkynylamides was reported in 2001 by Gabriele and co-workers.251 Supported by their extensive work on the PdI42−based catalytic system in promoting oxidative carbonylation of alkynes, they proposed a novel procedure that combines alkynes and secondary amines (1:1 molar ratio) in the presence of PdI2 (0.2 mol %), KI (2 mol %), CO/air (4:1, 20 atm), at 100 °C in dioxane. Alkyl and aryl alkynes well tolerate the reaction conditions, and the expected 2-alkynylamides were obtained in moderate yields (Scheme 99). Nevetheless, hindered amines did

monocarbonylation of ynamides and alkynes require higher catalyst loadings in the absence of ligands. In order to bypass the need for toxic and difficult to handle CO, formamides were used as versatile substrates on transitionmetal-catalyzed carbonylative amidation of alkynes. Indeed, pioneering work on this purpose was published in 2005 by Takemoto and co-workers on an intramolecular reaction with Rh-catalyst for preparing lactams (Scheme 97a).247 Then, Scheme 97. Formamides as Amine Surrogates on Carbonylation of Internal Alkynes

Scheme 99. 2-Alkynylamides via PdI2/KI-Catalyzed Oxidative Aminocarbonylation of Terminal Alkynes

not lead to the required products. The reaction might proceed throughout the formation of an alkynylpalladium species 143 as the key intermediate that might be stabilized by iodide ligands. Insertion of CO into the C−Pd bond (144) followed by amine addition give rise to the expected 2-alkynylamides. Later on, this method could find several applications in the synthesis of carbonylated heterocycles via sequential processes involving oxidative aminocarbonylation of terminal alkynes followed by conjugate addition.252

Hyama, Nakao, and co-workers have proposed the dual Ni(0)/ AlMe3-catalysis on an intermolecular addition to internal alkynes (Scheme 97b, conditions A).248 Alternatively, Pd was introduced by the group of Tsuji in order to catalyze intermolecular addition of formamides to alkynes (Scheme 97b, conditions B).249 The catalytic system could be transposed, for the first time, to the AJ


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undergo oxidative amidation in the presence of aromatic, aliphatic terminal, and internal alkynes 146 (Scheme 101). LC−MS/MS analysis established that the procedure takes place with high regio- and chemoselectivities at the N-terminal αamino group without affecting unprotected amino acid side chains (e.g., lysine, tyrosine, threonine, and serine) in the aqueous NaHCO3 buffer. Analogously, five other peptides (100 μM scale) were also able to react with phenylacetylene, and one example could be scaled up (5.3 mg of isolated peptide, 65% yield based on 81% conversion). Nevertheless, in these examples, byproducts from inter- and intramolecular disulfide bond formations on cysteine residues and oxidation of methionines to sulfoxides were observed. However, by treatment with dithiothreitol and N-methylmercaptoacetamide, such sideproducts could be reduced back to free cysteines and methionines, respectively. Miscellaneous. Recently, an interesting procedure for amide synthesis has been published by Maiti and co-workers in a noncatalytic metal-free process.255 The authors have used iodobenzene diacetate [PhI(OAc)2] as both a Lewis acid and an organic oxidant to ensure the acetylene activation for the amidation reaction with amines and water. The reaction proceeds through simultaneous coupling of C−N and CO bonds with amines/alkynes in water in the presence of a base at room temperature. The secondary amide functionality was bent at the internal carbon of the alkyne substrate (Scheme 102). 3.5.2. From Alkenes. Direct aminocarbonylation of alkenes with amines and CO provides a straightforward access to amides.40 Indeed, this transformation does not require the use of vinyl halide derivatives which have been broadly used in a plethora of synthetic transformation allowing amide formation via a sequence of oxidative carbonylation with CO/nucleophilic addition of amines. This section will encompass C−H aminocarbonylation reactions in which the amide bond creation arises from a vinylic functionalization (Scheme 103). Processes involving the intramolecular and intermolecular oxidative aminocarbonylation of aryl C(sp2)-H bond and the carbonylation of aryl and vinyl halides and related compounds33 with amines and CO are not included in this review. Likewise, azacarbonylation of allylic carbonate, phosphate, acetate, and halogen derivatives and carbonylation of allylamines to give the corresponding β,γ-unsaturated amides 148 have been compre-

Following this line, Bhanage and co-workers have proposed an alternative catalytic system using reusable Pd/C catalyst in a phosphine-free process for preparing 2-alkynylamides.253 Compared to the procedure described above, the scope is broader as several secondary amines could be successfully used. The best reaction conditions rely on the use of Pd/C (8 mol %), CO/O2 (5:1 atm), TBAI (0.9 equiv), dioxane at 80 °C for 14 h with an 1:1.5 alkyne/amine ratio, and the Pd/C could be successfully recycled and reused up to four consecutive cycles without losing its catalytic activity. Moving from the synthesis of 2-alkynylamides to the synthesis of simple amides, a remarkable report was published by Wong, Che, and co-workers via manganese porphyrin catalyst combined with an oxidant such as oxone or H2O2.254 The oxidative amidation was effective in the presence of aryl alkynes and primary amines giving rise to amides in good yields (Scheme 100). Scheme 100. Oxidative Amide Synthesis with Alkynes

The procedure could be successfully transposed to peptide synthesis via a so-called “ligation” protocol with unprotected peptides. In this case, oxone was replaced by H2O2 in order to avoid salts formation and simplify the mass spectrum analysis. Peptide H2N-TSSSKNVVR-CO2H 145 (100 μM) was able to

Scheme 101. N-Terminal α-Amino Group Reaction of Unprotected Peptides with Alkynes

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Straightforward transition-metal-catalyzed aminocarbonylation reactions of olefins with amines in the presence of CO have long been undeveloped, in part because of considerable challenges to be met such as the carbonylation of the amine substrates (e.g., formamide byproducts 149 formation) and the amination of the alkenes (side compounds 150) prior to the aminocarbonylation (Scheme 103). Early efforts to develop catalytic processes focused on the use of Co,261−264 Ni,265 Fe,266 and Ru267 complexes. Nevertheless, such catalytic systems required very harsh reaction conditions (>200 °C; > 150 atm), and suffered from poor chemoselectivity. Studies seeking for milder reaction conditions have been reported since the 80s, after the pioneering work of Watanabe and co-workers, who proposed a milder protocol, based on [Ru3(CO)12].268 If lower CO pressure was used (40 atm), the reaction only proceeded under temperatures higher than 150 °C for a period of 6 h. Moreover, the scope of this homogeneous Rucatalyzed hydroamidation of olefins was very limited. In 2002, the catalytic synthesis of N-phenyl alkyl amides from alkenes, aniline, and CO in the presence of cobalt on charcoal (Co/C) was reported by Chung and co-workers.269 The desired products were isolated in moderate-to-good yields. The heterogeneous reaction conditions (150 °C; 70 atm) are still harsh with increased reaction times (3 days). Due to extensive leaching, the catalyst could be recovered and reused only up to two runs. Despite these promising seminal works, it is only in recent times that more chemoselective intermolecular transformations, covering larger substrate scope and under milder conditions, have been reported. 3.5.2.1. Intermolecular Reactions. In a seminal 2013 report, Beller and co-workers investigated homogeneous [Pd(acac)2]/ 151 catalytic system for the aminocarbonylation of alkenes with (hetero)aromatic amines.270 Under CO (40 atm) at 100 °C, the corresponding carboxamides were isolated in good yields (20 examples, 50−98% yields) and high regioselectivity toward the linear products (up to 99:1) (Scheme 105). Additionally, the same catalytic system was effective to mediate the synthesis of Naryl carboxamides from inexpensive nitroarenes 152 (aniline surrogates). Moreover, linear amides could also be selectively synthesized from the aminocarbonylation of long chain alkenes

Scheme 102. Amides through Cleavage of Terminal Alkynes Mediated by PhI(OAc)2

Scheme 103. Metal-Transition-Catalyzed Oxidative Vinylic C−H Aminocarbonylation

hensively covered elsewhere and will not be included here (Scheme 104).256−260 Scheme 104. Azacarbonylations of Allyl Derivatives Not Covered by This Review

Scheme 105. Regioselective Pd-Catalyzed Aminocarbonylation of Alkenes with Aromatic Amines and Nitroarenes: Linear Products Major

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of aliphatic amines as substrates (pKb < 5) hampered the formation of the expected amides as they inhibit the formation of active palladium hydrides during the catalytic cycle. Thus, to circumvent the basicity barrier imparted by aliphatic amines, Beller and Li proposed a novel catalytic system for the hydroamidation of alkenes through the use of Rh(I)-complexes.274 N-alkyl amides were obtained in moderate-to-good yields and excellent chemo- and regioselectivities (Scheme 108).

or unsaturated esters with aniline in the presence of Pd/ DTBPMB complexes [DTBPMB = 1,2-bis(di-tertbutylphosphinomethyl)benzene].271 Alternatively, when PdCl2/tris(2-methoxyphenyl)phosphine system was used, Liu and co-workers showed that a reversed regioselectivity for the branched carboxamides can be obtained (Scheme 106).272 Here, contrary to the above-mentioned Scheme 106. Regioselective Pd-Catalyzed Aminocarbonylation of Alkenes with Aromatic Amines: Branched Products Major

Scheme 108. Catalytic Hydroamidation of Alkenes with Aliphatic Amines

conditions, there is no need for an acidic additive, and the aminocarbonylation goes through a 50 atm CO pressure in THF at 125 °C for a period of 2 or 20 h in the presence of a large excess of alkene. The Beller group has further expanded the scope of Pdcatalyzed aminocarbonylation to 1,3-diene moieties leading to β,γ-unsaturated amides in good yields and selectivities.273 For this transformation, the combination of Pd(TFA)2/153 was suitable, when equimolar amounts of diene and amine substrates were used, to afford several β,γ-unsaturated carboxamides in high yields in the presence of CO (50 atm) at 60−100 °C (Scheme 107, eq 1). Interestingly, by changing the phosphine ligand 153 Scheme 107. Pd-Catalyzed 1,3-Diene Aminocarbonylation

It is assumed that Rh(I) plays a dual role during the amidation process; it may act as the [Rh(I)-H] active species and also selectively activate the N−H bonds of the aliphatic amine substrates. 3.5.2.2. Intramolecular Reactions. The earliest examples of cyclocarbonylation reactions were disclosed by the Alper group, who has first devised an efficient pallado-catalyzed procedure to successfully achieve the synthesis of five-, six-, and sevenmembered ring lactams, fused to an aromatic ring, in high yields and selectivities from 2-aminostyrene or 2-allylaniline derivatives.275 Even though preliminary studies have revealed the combination of Pd(OAc)2 with (−)-DIOP as an effective catalytic system, low enantioselectivities were observed for the preparation of 4-methyl-3,4-dihydroquinolin-2-one derivatives (up to 54% ee).276 These results could be improved by switching from (−)-DIOP to (−)-DDPP as the chiral ligand. In this case, the asymmetric cyclocarbonylation of 2-vinylanilines 154 proceeded in high yields and with up to 84% ee (Scheme 109).277 Following on from this research, Li and co-workers investigated a Pd-catalyzed intramolecular oxidative aminocarbonylation of vinylic C(sp2)-H bonds with amines and CO (1 atm) at room temperature.278 Prior to their disclosure, the Lei group developed a sequential oxidative C−H alkenylation/Ndealkylative carbonylation of tertiary anilines, in the presence of alkenes and CO/O2 as an efficient alternative route to these products on the basis of dual Pd/Cu catalysis.279

to Xantphos and increasing the molar ratio of diene and amine to 5:1, a sequential carbonylation/hydroamination could be alternatively observed (Scheme 107, eq 2). If the scope of alkene aminocarbonylation was dominated by the exclusive use of aromatic amines until 2014, recent works by Beller and Li allowed the possibility to successfully include aliphatic amines into such transformations. Indeed, the basicity AM


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Scheme 109. Asymmetric Cyclocarbonylation with Pd/ (−)-DDPP-Catalysis

Scheme 111. Amides from Isocyanates

4. AMINE SURROGATES In this section, the main amine surrogates (isocyanates, isonitriles, thioamides, dithiocarbamates, sulfonamides, imines etc.) used in amide formation will be described: a brief overview is given in Scheme 110. For the sake of clarity, tertiary amines are also partially treated in sub-section 3.3 and ligation reactions including Staudinger, KAHA, and KAT ligations will be described in section 5. 4.1. Isocyanate Derivatives

Bode and co-workers have next elegantly extended this methodology to access hindered N-acylated α,α′-gem disubstituted amino acids 158 from the corresponding Ncarboxyanhydrides 157 in the presence of two equivalents of organometallics (Scheme 112b). The first equivalent enables the formation of the isocyanate intermediate which next reacts with the second equivalent to yield the amide bond.295 Transition metal catalyzed reactions have also been described starting from aryl halides (pseudohalides) or aryl boronic acids.34,299,300 In the presence of Lewis acids, electron-rich aromatics are able to undergo inter and intramolecular Fridel-Crafts type reactions

Highly electrophilic isocyanates 155 offer the opportunity to react with a wide range of nucleophiles, including organometallic reagents, aromatics (through Friedel−Crafts or C−H functionalization reactions), and carboxylic acids (Scheme 111). The direct addition of organometallics to isocyanates was originally described by Blaise and nicely used by Gilman for the titration of Grignard reagents.280−282 This reaction has become a very popular amidification process. For selected references, see: refs 283−298. This approach proved particularly useful for the construction of highly hindered amides 156 (Scheme 112a).293

Scheme 110. Overview on Amine Surrogates Discussed within This Section

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requires harsh reaction conditions (toluene, 110 °C).316,317 In order to enlarge the scope of the methodology, milder reaction conditions have then been devised, using a catalytic amount of NEt3 and DMAP at 60 and 0 °C, respectively.318,319 In the latter case, an epimerization-free process is observed using the sensitive Anderson test (160, Scheme 114).319 These conditions have next been efficiently applied in various synthetic applications.320−322 In 2011, the use of electron-poor isocyanates with carboxylic acids, in the presence of a stoichiometric amount of NEt2iPr, was described by Crich and co-workers next extended to the reactivity of thioacids.323,324 This approach was next used by Carboni in the synthesis of α-boryl allyl amides.325 In a totally different approach, isocyanates have been used as amine surrogates in Ni-catalyzed coupling reaction with alkenes leading to α,β-unsaturated carboxamides.326 Following the proposed reaction conditions, higher regioselectivities in favor of the branched products were reached (Scheme 115).

Scheme 112. Hindered Amides from Isocyanates

with isocyanates (Scheme 113a). For selected references, see: refs 301−303. This reaction is also known as the Leuckart amide Scheme 113. Amides from Isocyanates and Aromatic Nucleophiles

Scheme 115. Ni(0)/IPr-Catalyzed Aminocarbonylation of Alkenes with Isocyanates

4.2. CDI-Activated α-Aminoester Derivatives

A procedure based on the combination of activated αaminoesters with carboxylic acids has been developed and successfully applied to the synthesis of several dipeptides in a base-free procedure (Scheme 116).327 The CDI-activated aminoester derivatives 161 are readily available from the reaction

synthesis.304 The formation of highly electrophilic isocyanates cations from carbamates was also described under acidic conditions.305 More recently, the transition metal catalyzed amidation of activated aryl and vinyl C−H bonds with isocyanates has been reported (Scheme 113b).306−313 The thermal condensation of isocyanates with carboxylic acids is a long known process,314,315 allowing the formation of an amide bond through the intermediacy of a somehow unstable carbamic carboxylic anhydride 159 followed by the elimination of CO2 (Scheme 114). This process has been used in the synthesis of peptides but

Scheme 116. Dipeptides and a Tetrapeptide Synthesis from Activated α-Aminoesters

Scheme 114. Amides from Carboxylic Acids and Isocyanates

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between free α-aminoesters and commercially available N,N′carbonyldiimidazole (CDI) in high yields. These “activated” amines, prepared under mild conditions and readily purified by simple filtration over silica gel, are stable for months when stored at 4 °C. These amino surrogates 161 proved highly efficient in dipeptide synthesis (12 examples, 54−90% yields) under mild conditions, in the absence of base, and are compatible with Fmoc, Boc, and Cbz protecting groups. Moreover, preliminary racemization studies with sensitive cysteine residues showed encouraging results as no epimerization was detected during the synthesis of the dipeptide Boc-Cys(Bn)Ala-OMe 162. Additionaly, the method could be applied for the synthesis of a tetrapeptide 163 in the challenging reverse N → C direction and also successfully transposed in a large-scale synthesis of Boc-Phe-Ala-OMe dipeptide (34 mmol, 11.7 g).328

Scheme 118. Ia Type Danishefsky’s Coupling of Carboxylic Acids and Isonitriles

4.3. Isonitriles

Prompted by the lack of data about the reaction of carboxylic acid and isonitriles 164, Danishefsky and co-workers have reinvestigated this class of reactions and ultimately devised four different types of couplings, so-called Ia/b and IIa/b types (Scheme 117).329 Types a and b differ by the nature of the acyl donor,

conditions (compound 170), or reduced to the N-alkyl derivatives (compound 171) (Scheme 119).

Scheme 117. Four Different Types of Coupling of (Thio)carboxylic Acids with Isonitriles

Scheme 119. Elimination of the Formyl Group in Ia Type Danishefsky’s Adducts

carboxylic acids, or thioacids, respectively. Types I and II differ by the mechanism involved in the coupling reactions. Isonitriles are usually obtained by dehydration of the corresponding N-alkyl formyl amides in the presence of triphosgene or POCl3, and it should also be noted that isonitriles derived from amino esters are relatively sensitive to epimerization.330 After reaction with the isonitrile partner,331 a formimidate carboxylate mixed anhydride (165, FCMA) is formed. This unstable intermediate has never been isolated,332 but its formation is supported by spectroscopic data and DFT studies.333−335 The FCMA can then evolve through a 1,3 O → N acyl transfer to the formylated amide bond 166 (type I, Scheme 117, eq 1) or either can be trapped by an external nucleophile (type II, Scheme 117, eq 2). The latter one (IIa/b) requires a “sacrificial” amount of isonitrile and is usually observed when bulky isonitriles are used.336 These type II couplings imply an activation of the carboxylic acid and are thus beyond the scope (e.g., nonclassical activations to form amides) of this review and will not be further described.337−340 The reactions with carboxylic acids (Ia type) require high temperature to proceed (150 °C, microwaves)341 and have been particularly useful in the synthesis of glycosylated amino acids (167 and 168, Scheme 118). The formyl group on the newly created amide bond 169 can be readily eliminated under basic

These harsh conditions detract from a general application in peptide and glycopeptide chemistry. Gratifyingly, reactions with thioacids (Ib type) can be performed at room temperature, thus allowing the use of more sensitive substrates 172 (Scheme 120).339,342,343 Scheme 120. Ib Type Danishefsky’s Coupling of Thiocarboxylic Acids and Isonitriles

AP


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The formation of peptide bonds was trickier due to the low stability of the corresponding dithiocarbamate derivatives (formation of unwanted thiohydantoins and symmetrical thioureas). The dithiocarbamates were thus generated in situ, in the presence of CS2, and next reacted with the corresponding peptide thioacids (Scheme 126). As illustrated in Scheme 126, the reaction is very efficient for the construction of various peptides notably allowing fragments condensation and the presence of hindered Aib residues at the coupling site. The reaction is compatible with Fmoc and Boc amino acids protections and the presence of unprotected side-chains (Glu, Arg, Ser, Thr, Asn, Gln, and His) is also very well tolerated. Moreover, the coupling reaction could be carried out with unprotected C-terminal chains using a buffered aqueous media (NMP−Buffer pH = 7, 4:1). The absence of epimerization in the peptide coupling reaction could be checked during the formation of the dipeptide Boc-Val-Phe-OMe which is, however, poorly prone to epimerization.

Accordingly, the thioamide functionality can easily be transformed either by a two-step dethioformylation or transformation into the N-Me derivatives (Scheme 121).339,342,343 Scheme 121. Thioformamide Transformations

4.6. Sulfonamides and Sulfinylamides

In 1998, Tomkinson and co-workers described 2,4-dinitrobenzenesulfonamide 182 as amine surrogates in the efficient formation of amides from thiocarboxylic acids.349 As illustrated in Scheme 127, after the formation of the Meisenheimer intermediate 183 in the SNAr reaction, the elimination of SO2 next allows the formation of the amide bond. High yields have been obtained under mild conditions (Cs2CO3, DMF, rt) with primary/secondary amines and aliphatic/aromatic thioacids. The reaction was further transposed to the synthesis of ureas, thioamides, and thioureas.350 This methodology has been extended to peptide and neoglyconjugates syntheses thanks to the development of an efficient access to peptide thioacids.209 In a striking application, Crich and Bowers described the synthesis of a N-glucosyl asparagine derivative 185 from N-Cbz protected thioaspartic anhydride 184: the successive addition of a nonprotected aminosugar derivative followed by the sulfonamide amino surrogate 185 allows the formation of the expected glycopeptide 186 in a one-pot procedure in 44% yield (Scheme 128).210 The direct reaction of amines with thioacids, in the presence of 2,4dinitrofluorobenzene, was next explored by Crich (vide supra, section 3.4).208 In a different approach, the use of sulfinylamides was recently described by Vogel and co-workers allowing the one pot amidification of carboxylic acids with amines (more than 70 examples).351 As illustrated in Scheme 129, amides and Cbzprotected dipeptides have been obtained in good to high yields in the presence of 20 mol % of DMAP (chloroform at 70 °C). The reaction probably proceeds via the formation of an activated mixed anhydride 187 of sulfinyl and carboxylic acids, through the addition of carboxylate/amine exchange on the sulfur center.

The synthetic potential of these methodologies has been nicely exploited by Danishefsky in a total synthesis of cyclosporin A (175), where Ia, Ib, and IIb type couplings have been successively used (Scheme 122).339 For the use of isonitriles in Ugi and Passerini multicomponent reactions, readers are invited to read the excellent reviews published to date.30−32 It should also be noted that isocyanides can be used in the transition-metal synthesis of aromatic amides from arylhalides.344,345 4.4. Thioamides

Inspired by the work of Danishefsky (see section 3.4) on the reaction of isonitriles with carboxylic and thiocarboxylic acids, Hutton and co-workers explored the reactivity of thioamide 176 with carboxylic acids.346 Thioamides are obtained in good yields from the corresponding acetamide in the presence of the Lawesson’s reagent or alternatively, from the amine in the presence of ethyldithioacetate. The thioamide/carboxylic acid coupling proceeds efficiently at room temperature, without epimerization, in dichloromethane (DMF or acetonitrile) to yield the corresponding imide 177, which could be in turn regioselectively saponified to the expected amide (Scheme 123). As illustrated in Scheme 123, the presence of a thiophilic silver salt is essential to promote the rearrangement of the tetrahedral intermediate 178.347 The synthetic potential of this methodology was nicely illustrated in a reverse N → C synthesis of the pentapeptide thymopentin (179) (Scheme 124) obtained in 10% overall yield and no detectable epimerization. Nevertheless, it should be mentioned that basic sensitive Fmoc-protected AA are not compatible with the reaction conditions.

4.7. Umpolung Strategies Using Halogeno-Amines

Inspired by the possibility to create a carbonyl group from nitro derivatives (the Nef reaction),352 Johnston and Makley have explored the reactivity of α-bromo nitroalkanes 188353 with in situ generated halogeno-amines.354,355 As illustrated in Scheme 130, Johnston has devised simple reaction conditions enabling the synthesis of amide bonds under mild and selective conditions. These conditions are compatible with the presence of various functional groups on both the amino and acyl partners and allow the synthesis of hindered amide bonds. Thanks to the development by the same group of an efficient access to enantiomerically enriched α-bromo nitroalkane

4.5. Dithiocarbamates

The reactivity of dithiocarbamates 180 has been investigated by Houghten, Yu, and co-workers.348 Thiocarboxylic acids are able to add to dithiocarbamates to form a thiocarbamic anhydride 181 which next undergoes a 1,3-S → N-acyl transfer to afford the amide bond with a concomitant loss of CS2 (Scheme 125). The reaction proceeds in good yields, at room temperature, in methanol. AQ


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Scheme 122. Total Synthesis of Cyclosporine A Using Ia, Ib, and IIb Types of Danishefsky Coupling Reactions

derivatives,354,355 arylglycine derivatives 189 have been efficiently coupled with the 20 proteinogenic amino acids (protected as esters) and dipeptides have been obtained in moderate-to-good yields as single diastereomers (Scheme 131). This point highlights the mildness of the reaction conditions since the aryl glycine derivatives are well-known to be prone to epimerization under classical peptide coupling conditions.356 Starting from enantiomerically enriched aryl α-hydroxy acyl surrogates 190, the synthesis of diastereomerically pure α-oxy amides was also described by the same group as illustrated in the synthesis of LY411575 (191), a potent γ-secretase inhibitor (Scheme 132).355

The scope of this Umpolung Amide Synthesis (UmAS) was recently extended to aliphatic α-bromo nitroalkane derivatives, thanks to the development of an organocatalyzed enantioselective Henry reaction from bromonitromethane and Boc-αamido sulfones, thus enabling the synthesis of peptides with canonical amino acids.357 A thorough mechanistic study has been undertaken by Johnston and co-workers using 18O-labeling experiments and underscored two competitive aerobic and anaerobic pathways.358 An ionic mechanism was initially postulated354 and involved the NIS-mediated formation of an N-halamine that could be trapped by the α-bromo nitroalkane derivative to form a tetrahedral AR


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Scheme 123. Mechanistic Rationale for the Coupling of Carboxylic Acids with Thioamides in the Presence of Silver Salts

Scheme 125. Amides from Dithiocarbamates and Thiocarboxylic Acids

intermediate. This intermediate 192 could in turn evolve through the elimination of bromide or nitrite and finally be hydrolyzed to the corresponding amide (Scheme 133, path a). However, the lack of formation of 18O-labeled amide when using H218O suggested a more complex scenario. After a considerable deal of work and the use of 18O-labeled nitroalkane, the role of atmospheric oxygen was considered. Indeed, in the presence of 18O2 and unlabeled nitroalkane, a high degree of isotope incorporation in the amide was observed. Johnston finally proposed a mechanistic pathway that accounts for all observed results. The tetrahedral intermediate 192 can evolve through homolysis to form an aminomethyl 193 and • NO2 radicals. The radical 193 can either recombine (after isomerization) to form a nitrite (Scheme 133, path b), or alternatively reacts with residual oxygen (Scheme 133, path c). Starting from this mechanistic sudy, Johnston was able to disclose a practical procedure for the preparation of 18O-labeled amides in peptides as illustrated in Scheme 134. On the basis of these mechanistic studies, the the source of X+ (bromonium vs iodonium) in the halamine synthesis was next questioned.359 Control experiments brought the Johnston’s

group to develop an aerobic and catalytic version of the reaction where NIS can be used in 5 mol % in the presence of oxygen as the terminal oxidant (Scheme 135). It should be emphasized that yields compare favorably with those obtained in the stoichiometric-NIS version of the reaction. The oxidative amidation of nitroalkanes with amines in the presence of oxygen and iodine was described very recently.360 NCholoroamines have also been used in palladium-catalyzed aminocarbonylation in the presence of boronic acids and CO.361

Scheme 124. N → C Peptide Synthesis through Thioamides and Carboxylic Acids

AS


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Scheme 126. Peptide Bond Formation from Dithiocarbamates and Thiocarboxylic Acids

4.8. Aromatic Imines and Amidines

Tertiary amines have also been successfully used as substrates for an aerobic oxidative N-dealkylative carbonylation reaction via dual Pd/Cu-catalysis (Scheme 139).369 The procedure allows for the synthesis of (E)-α,β-unsaturated amides in moderate yields (16 examples, 30−77% yields). It is noteworthy to mention that poor selectivities (β,γ vs α,β-unsaturated amides) were attained when allylbenzene and oct-1-ene were used as olefin substrates. Tertiary amines were also employed as substrates in the aminolysis of activated esters (aryl esters, anhydrides, etc.) in the presence of Pd-based catalysts.370−372 More recently, the use of copper and iron catalysts has been reported.373,374

Aromatic aldimines and amidines have also recently served as efficient partners in the synthesis of secondary amides involving oxidative processes (Scheme 136).362,363 4.9. Tertiary Amines

The direct amidation of carboxylic acids with tertiary amines as amine surrogates via oxidative C−N bond cleavage has recently emerged as an efficient tool for the construction of amides. In 2014, Zhou and Yin described the Cu-catalyzed direct amidation of carboxylic acids with tertiary amines in the presence of CCl4 (Scheme 137).364 Recently, Li and co-workers have used FeCl3· 6H2O as the catalyst and oxygen as the oxidant to accomplish the same type of transformation.365 Besides carboxylic acid derivatives, the Fe-catalyzed oxidative amidation of aldehydes in the presence of tertiary amines was described in 2013.366 The combination of FeCl2 (2.5−10 mol %) with TBHP (2−3 equiv) as stoichiometric oxidant in acetonitrile at 85 °C for 1 h was efficient in the synthesis of a collection of amides (>20 examples, 32−95% yields). To ensure high yields, five equivalents of aldehyde compared to the amine proved necessary. A metal-free process was also developed in the presence of nBu4NI (20 mol %) and TBHP (4.0 equiv) as the catalytic system.367 The procedure comprises the demethylation of tertiary amines and dehydrogenation of aldehydes without a metal (20 examples, 46−86% yields). The transformation of tertiary amines into tertiary amides has been successfully accomplished in the presence of 2-phenylacetonitrile derivatives 194 via Cu-catalyzed aerobic oxidative amidation (Scheme 138).368 In the same report, other toluene derivatives bearing electron-withdrawing groups were also prone to the transformation.

4.10. Azides

The use of azides with carboxylic acids (and derivatives thereof) for the direct formation of amides, known as the Staudinger ligation, has known a tremendous success in bioconjugation chemistry. These aspects will be covered in section 5.2. Along with their work related to the Ru-catalyzed direct formation of amides from alcohols and amines (see sub-section 3.3.1), Hong and co-workers have also investigated the use of azides as a nitrogen source.375 Benzyl alcohol and aliphatic alcohols afforded the expected compounds in high yields in the presence of benzyl azide 195. Lower yields were observed for slightly more sterically hindered alcohol substrates. Concerning the nature of the azide component, both electron-withdrawing and -donating substituents on the aromatic ring allowed the formation of the amides in the presence of 2-phenylethanol in good yields. Nevertheless, phenyl and sterically encumbered azides conducted to the formation of the corresponding amides in much lower yields (Scheme 140). About the mechanism, supported by experimental studies, the authors have ruled out the involvement of an aza-ylide intermediate that is reported for the AT


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Scheme 127. Amides from Sulfonamides

Scheme 129. Reactivity of Sulfinylamides with Carboxylic Acids

Scheme 130. Scope of the Umpolung Reactivity of α-Bromo Nitroalkanes

Scheme 128. Glycopeptide Synthesis

undergo direct oxidative amidation in the presence of aryl, alkyl, and sulfonyl azides affording the amides in high yields (>25 examples, 64−96% yields) and N2 as the single byproduct.

Staudinger reaction. Thus, based on kinetic studies, they proposed first the azide reduction into amine by hydrogen transfer from the alcohol dehydrogenation in the presence of Rucatalyst. The following steps go through the aforementioned general mechanism via oxidative amidation of an alcohol (alcohol → aldehyde → hemiaminal → amide formation, see Scheme 39). In a mechanistically different approach, Zhou and Li developed a Rh(III)-catalyzed C−H bond activation of aldehydes in the presence of azides and air (no external oxidant was required) (Scheme 141).376 The method relies on the implication of aldehydes bearing remote functional groups able to coordinate to the Rh(III)-catalyst. For instance, a few aldehydes such as 8-quinolinecarbaldehydes 196 and 2(methylthio)benzaldehyde derivatives 197 were prone to

4.11. Thiocarboxylic Acids and Azides

The reductive acetylation of azides was described by Chu and coworkers and others using thioacetic acid as solvent or cosolvent.377−379 Originally suspected to proceed through an in situ reduction of the azido to the amino group, the mechanism of this transformation was next reinvestigated by Williams.380,381 Two distinct mechanistic scenarios have been unveiled depending on the electronic nature of the azido group partner. In the presence of electron-rich azides, the reaction goes through a [3 + 2] cycloaddition to give a thiatriazoline 198 followed by a retro[3 + 2] cycloaddition sequence with concomitant formation of AU


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Scheme 131. Enantioselective Synthesis of Aryl-Glycine Dipeptides

Scheme 132. Enantioselective Synthesis of α-Oxy Amides

Scheme 134. Synthesis of 18O-Labeled Amides

the amide and N2S (Scheme 142). With highly electron-poor ones, the modus operandi is slightly different since the formation of the thiatriazoline is first preceded by the addition of the thiocarboxylate to the azido moiety (intermediate 199) (Scheme 142). It should also be emphasized that this reaction was independently developed by Lim and co-workers.382 Beyond the Scheme 133. Mechanism of the Umpolung Reactivity of α-Bromo Nitroalkanes

AV


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Scheme 135. Umpolung Amide Synthesis in the Presence of a Catalytic Amount of NIS

Scheme 138. Cu-Catalyzed Amidation of 2Phenylacetonitriles with Tertiary Amines

Scheme 139. Pd/Cu-Catalyzed Oxidative Amidation of Olefins with Tertiary Amines

Scheme 136. Aromatic Aldimines and Amidines on Amide Synthesis

Scheme 140. Selected Examples of Dehydrogenative Amide Synthesis from Azides and Alcohols

Scheme 137. Amides from Carboxylic Acids and Tertiary Amines via Cu-Catalysis

elucidation of the reaction mechanism, this study has allowed the development of milder reaction conditions: high yields were obtained with a slight excess of thioacid in the presence of 2,6lutidine with a wide range of solvents (methanol, chloroform, or water). The reaction usually takes place at room temperature to the exception of less reactive alkylazides that require harsher conditions (60 °C, 36 h). Futhermore, this reaction could be extended to the synthesis of acyl-sulfonamides, carbamates, and

enamides from the corresponding azido derivatives.380,381,383−388 Wong and Fazio further described that the reaction could be accelerated in the presence of a catalytic amount of RuCl3, allowing the transformation to proceed at room temperature.389 The reaction with selenocarboxylates was also described.390 A direct formation of aromatic amides from anilines in a tandem one-pot diazotization-azidation of anilines followed by reaction AW


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Scheme 141. Rh-Catalyzed Amidation from Aldehydes and Azides via Chelation-Assisted C−H Bond Activation

Scheme 144. Asparagine Native Peptide Ligation

Scheme 142. Electron-Poor vs Electron-Rich Azides in Thioacid/Azide Coupling Reactions

eGlyGln GlyPheGlyAla-N3 and Boc-Asp(SH)ProAlaPheAlaGln GlyAla-NH2 in DMF at room temperature was obtained in 19% yield, in an epimerization-free process. This low yield results from the unexpected formation of symmetrical imides probably resulting from a thioacid/azido scrambling. After Boc deprotection under acidic conditions, the peptide 201 was finally obtained in 63% yield at pH 7 after a N,N-acyl rearrangement. When the thioacid/azide coupling was applied to an unprotected peptide incorporating lysine, arginine, and ε-azido lysine residues, Hackenberger and co-workers observed extensive formation of nonspecifically acetylated peptides at the lysine residue (Scheme 145).416 The amount of these byproducts could be reduced by conducting the reaction at a lower pH with, however, the concomitant apparition of unexpected thioamide byproduct. Quite surprisingly, the thioamide is, at pH 2, the major observed compound suggesting a competitive mechanism.416

with thiobenzoic acids was proposed by Moses and coworkers.391,392 This methodology has proved particularly useful in carbohydrate chemistry for the reductive acetylation of azides into acetamides. For selected references, see refs 393−406. As illustrated in the synthesis of glycopeptides (Scheme 143),407 this methodology has also found various applications in the synthesis of natural and/or bioactive products.408−414 This methodology was also brilliantly adapted to an asparagine native peptide ligation based on the formation, and capture, of an imide from the reaction of a thioacid and an acyl-azide (see also section 5).415 As a proof of concept, illustrated in Scheme 144, imide 200 resulting from the reaction between Boc-GlyPhScheme 143. Synthesis of Glycopeptides from Thioacid and Azide

AX


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Scheme 145. Chemoselectivity Issues in Thioacids/Azide Couplings

4.12. Amine Surrogates Miscellaneous

Scheme 147. Pd-Catalyzed Hydroamidation of Olefins with Aminals, Aliphatic, and Aromatic Amines

Heterogeneous Co-based catalysts (e.g., Co@C−N; carbon− nitrogen embedded cobalt nanoparticle) were successfully used on oxidative amidation of aldehydes in the presence of various formamide derivatives (Scheme 146).417 Scheme 146. Oxidative Amidation with Formamide derivatives

A Cu(I)-catalyzed reductive cross-coupling of N-tosylhydrazones with amides was developed, allowing the successful synthesis of several secondary amides in good yields.418 The method relies on the combination of aldehydes with Ntosylhydrazide to afford the N-tosylhydrazones which in turn are reductively cross-coupled in situ with primary amides. Along with oxidative strategies herein described, the one-pot synthesis of arylamides from nitroaromatics and aromatic aldehydes was also described in both the presence of a reductant (zinc powder) and an oxidant (sodium chlorate).419 Huang and co-workers have developed a Pd-catalyzed protocol for N-alkyl-substituted amide synthesis starting from olefins, CO, and aminals 202 used as aliphatic amine surrogates (Scheme 147a).420 By tuning the reaction conditions, they have identified that the combination of palladium, paraformaldehyde, and an acid was effective for hydroaminocarbonylation of aliphatic and aromatic amines (Scheme 147b). Recently, a catalytic conversion of N,N-dialkylaryltriazenes 203 to the corresponding amides via N2 extrusion and CO insertion was achieved by means of Pd-catalysis (Scheme 148).421 The procedure affords an interesting alternative to the

more classical Pd-catalyzed aminocarbonylation of electrophilic C−X bonds. N-Cbz- and N-Boc-protected amines can be directly converted into benzamides using a rhodium-catalyzed coupling reaction with arylboroxines.422 AY


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peptide fragments. Thanks to this strategy, hundreds of peptides and proteins could be prepared. Prior to the disclosure of the NCL between a C-terminal peptide thioester (the electrophile equivalent partner) and a Nterminal cysteine peptide (the nucleophile equivalent partner) by the Kent group in 1994,438 early concepts underlying the reactivity of thioesters have been unveiled by Wieland439 and Brenner.440 Later on, ingenious orthogonal coupling strategies based on the proximity-driven intramolecular acyl transfer were described by Kemp (template-mediated ligation without the intermediacy of a thioester),441−446 Tam,447 and Schwabacher (Scheme 150).448 5.1.2. Reaction, Chemoselectivity, and Mechanistic Insights. The combination of an N-terminal cysteine-containing peptide 204 and a C-terminal thioester-containing peptide 205 provides a native peptide bond at the ligation site in a completely chemo- and regioselective manner as the presence of internal cysteine residues and other unprotected AA side-chains do not hamper the reaction (Scheme 151). Moreover, one of the biggest advantages of NCL is the implication of unprotected peptide fragments. In general, C-terminal alkyl thioester peptides are used as precursors due to their higher stability and easier handling. They are prepared by chemical synthesis, mostly via SPPS,449 in order to install the adequate α-COSR (R = alkyl group). However, they are less reactive than aryl thioesters (R = Ar), thus requiring the need for thiol ester exchange by means of exogenous aryl thiol additives. The NCL mechanism was well established and is depicted on Scheme 152.450,451 The first step consists in the reversible thiol-thioester exchange between C-terminal alkyl thioester-containing peptide and an exogenous thiol additive (SR → SR′ transformation). Then, the reversible transthioesterification with the N-terminal cysteinecontaining peptide takes place in the presence of a better thioester leaving group (SR′). Finally, the native peptide ligation is forged via an irreversible intramolecular S → N acyl migration through a 5-membered ring intermediate 206 with concomitant liberation of the free cysteine residue (Scheme 152). As aforementioned, the extremely high chemoselectivity of the transformation ensures the reaction only with the N-terminal Cys residue (207 vs 208). 5.1.3. Reaction Development. Generally, NCLs are performed in aqueous phosphate buffer (neutral pH) at room temperature. These mild conditions are compatible with thioesters, which are sensitive to hydrolysis under strongly basic conditions and high temperatures. On the other hand, acidic conditions are also deleterious to the NCL, reducing the nucleophilicity of both the cysteine thiol and the N-terminal amino group of the peptide involved on the S → N acyl. The use of denaturating agents or detergents, such as guanidine hydrochloride, urea, and dodecylsulfonate (SDS), is particularly useful: they prevent aggregation of the reactants and, consequently, enhance the concentration of peptide segments and the ligation rates. Mostly, the reaction proceeds at peptide concentration in the millimolar range. Moreover, the use of templates452 allows for NCL at lower concentrations as first illustrated by Ghadiri and co-workers during the synthesis of a 32-residue α-helical peptide.453−455 Recently, this concept could be extended to bioorthogonal DNA-templated native chemical ligation during polymerase chain reaction (PCR).456,457 In this work, Roloff and Seitz proposed a nucleic acid template produced by the PCR and used in situ as NCL mediator allowing the transformation at very low DNA concentrations

Scheme 148. Carbonylative Transformation of Aryltriazenes into Tertiary Amides

5. SELECTIVE LIGATION METHODS Despite promising methods for amide bond formation between simple carboxylic acids (or carboxylic acid surrogates) and Scheme 149. Selective Ligation Methods for Peptides and Proteins Synthesis

amines (or amine surrogates), efficient procedures compatible with amino acid residues are slow to develop due to general challenges met in peptide chemistry. Some important achievements within this purpose can be underscored with the discovery of the “ligation strategies”,19,423,424 as well as the seminal work of Merrifield on solid phase peptide synthesis (SPPS).425 Selective ligation methods have appeared as very effective alternatives to SPPS for the preparation of long peptide or protein targets via the creation of an amide linkage between two complex nonprotected peptide fragments under physiological conditions (Scheme 149).19,423 Contrary to SPPS, unprotected peptide fragments can be successfully coupled under very mild conditions, in an atom-economical process (neither the need for a large excess of coupling reagents nor tedious protection/ deprotection steps), and without peptide length limitation. The following section highlights the potential of such methods. First, “native chemical ligation − NCL” (which, to date, can be considered among the most powerful tools for chemical protein synthesis) will be discussed. Following on this topic, the Staudinger ligation will be reported. Since its discovery, this ligation strategy has been receiving extensive interest, and its field of application does not stop growing. At last, but not least, more recent ligation methods such as KAHA and KAT are going to be discussed. 5.1. Native Chemical Ligation (NCL)

5.1.1. Background. NCL is ranked among the most effective methods for the synthesis of complex protein targets, as illustrated by the ever-growing reports on the method itself. For selected reviews, see refs 19 and 426−435 as well as its applications.436,437 NCL allows the construction of peptides and proteins longer than 50 AA residues via a covalent peptide bond formation at the site of the ligation between 2 unprotected AZ


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Scheme 150. Seminal Thiol Capture Ligations

over, disulfide-rich peptides were successfully synthesized, in a one-pot sequence, throughout thiol-free NCL (in the presence of TCEP) and oxidative folding.467 If the ligation commonly takes place in aqueous medium, the use of organic solvents, such as dimethylformamide468 and ionic liquids469−471 afforded efficient alternatives warranting both coupling of hydrophobic peptides and higher solubility. NCL of hydrophobic peptides was also conducted in lipid bilayer systems.472 5.1.4. Scope, Limitations, Extensions, and Racemization. The scope of the ligation has been extensively studied and proved to be compatible with most of proteogenic amino acids on the C-terminus of the peptide thioester partner.473−475 Usually, the reaction is very fast in the presence of glycine residue, going to completion in less than 4 h. Dawson and coworkers observed that the ligations in the presence of histidine and cysteine residues are as fast as in the presence of glycine, suggesting a side-chain-assisted ligation process by means of thiol/imidazole participation into the rate-limiting transthioesterification step.473 On the other hand, β-branched AA such as valine and isoleucine or proline are less suitable as complete conversion is not observed even after 2 days of reaction (Scheme

(e.g., attomolar template loadings vs commonly nanomolar loadings). For previous works, see refs 458−460. Additives were also developed and employed in order to improve both the ligation rate and the yield.461 Thiol additives such as thiophenol,462 benzyl mercaptan, sodium 2-mercaptoethanesulfonate (MESNa), 2-(4-mercaptophenyl)acetic acid (MPAA),450 and more recently, mercaptobenzyl sulfonates463 lead to the formation of more reactive thioesters in an initial reversible transthioesterification. Imidazole464 and sodium ascobarte465 were suggested as alternatives to thiol additives. In order to prevent disulfide formation between the Cys residues, a water-soluble reducing agent tris(2-carboxyethyl)phosphine (TCEP) is often added.465 It might be noted that thiol additives not only increase the reactivity of peptide thioesters but also act, in some cases, as radical scavenger to prevent desulfurization often observed in the presence of TCEP, and as reductant. Recent efforts have been dedicated toward NCL without using exogenous thiols. For instance, Seitz and Schmalisch showed that NCL in a procedure-free of a thiol-additive can take place, via intramolecular S → S acyl transfer, when peptide-mercaptopropionylcysteine (MPA-Cys) thioesters were employed.466 MoreBA


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Scheme 151. Principle of the Native Chemical Ligation

Scheme 153. Reaction Rate Correlated with the AA Nature at the α-Position of the C-Terminal Thioester Peptide

Even though NCL has become one of the most commonly used methods for condensation of unprotected peptides through the chemoselective synthesis of proteins, two limitations restrict, however, its applicability. The first one concerns the synthesis of peptide-α-thioesters.477−482 With consideration of the lability of thioesters toward basic conditions, these fragments are frequently synthesized via conventional Boc-SPPS strategies.483 Nevertheless, inherent disadvantages such as very strong final acidic treatment (HF) and hazardous operation conditions which are often necessary preclude its utilization in the presence of acid-sensitive side chains.438,484−486 Strategies based on Fmoc-SPPS synthesis of peptide α-thioesters have also been investigated even though the need for basic conditions to Fmoc removal after each coupling cycle may exclude its use. To overcome this issue, several milder reaction conditions allowing for Fmoc-cleavage without affecting the thioester group has been proposed. For reviews on Fmoc-

153).474 To circumvent such limitation the use of more reactive thiols is often envisaged.462 With Asp and Glu residues, it is recommended to use a suitable protecting group [e.g., OFm (9-fluorenylmethyl ester) and OPse (phenylsulfonyl)ethyl ester] in order to avoid thioester migration onto the side chain carboxy group. 476 The intermediacy of an anhydride 209 could incite ligation at both sites and, consequently, give a mixture of α-Cys-peptide 210 and ϖ-Cys peptide 211 (Scheme 154). Scheme 152. Native Chemical Ligation Mechanism

BB


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Scheme 154. Possible Side Reaction with Free-Asp and Free-Glu Residues at the C-Terminal Thioester Peptide

Scheme 155. Thiol-Auxiliary Mediated Ligation

Scheme 156. NCL/Desulfurization Process to Afford Alanine Residue after the Ligation

A second concern, and probably the most important limitation of NCL, is the requirement for an N-terminal cysteine-containing peptide. Cysteine is a relatively rare AA in peptides and proteins (1.4% content), and its insertion into a protein structure only for ensuring the ligation process may obstruct the initial biological function.531 One important achievement to circumvent this problem was the use of thiol auxiliaries for mediating NCL.430,436,437,531 The idea behind this concept involves the employment of a free thiol auxiliary group at the N-terminus that mimics the Cys. Upon removal of the auxiliary, the expected product is obtained (Scheme 155). In general, a Gly residue placed at one of the ligation sites is preferred in order to avoid

based synthesis of thioesters, see refs 478, 487, and 488. On the other hand, methodologies in which the thioester is introduced into the peptide chain at a late stage of the synthesis or the use of thioesters (or thioester surrogates, so-called crypto-thioesters) that are compatible with Fmoc chemistry have also been developed as straightforward alternatives.489−529 Thus, in general, the C-terminal peptide thioesters are synthesized on SPPS via Boc or Fmoc strategies, but it might be noted that recombinant protein expression530 and bioengineering449 have also been developed as alternatives for longer polypeptide thioester precursors. BC


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Scheme 157. His and Sec in NCL

Scheme 158. Kinetically Controlled Ligation (KCL)

Following this seminal work, several methodologies that allow for the use of thiol-modified unnatural AA derivatives have been developed in which AA other than Ala (e.g., Phe, Val, Lys, Ser, Thr, Leu, Pro, Glu, Arg, Asp, Glu, and Trp) can be generated after desulfurization. For recent reviews, see refs 430, 436, 437, 534−536, 539, and 540. It is important to mention that two other approaches for ligation with amino acids other than Cys were also studied. The first one employs histidine (His), in which the imidazole ring can act as a nucleophile during the acyl transfer (Scheme 157).541 However, one weakness of the method concerns the need for substrates without additional nucleophilic side-chains to prevent side reactions. The second method involves the use of selenocysteine (the 21st proteinogenic AA;

reaction inhibition due to the steric hindrance of the auxiliary. However, recently, Seitz and co-workers developed a new Nαauxiliary (e.g., 2-mercapto-2-phenethyl) that is not limited to Gly-containing ligation sites, thus allowing the ligation at sterically demanding connections.532 Another very important accomplishment within NCL relies on the concept of ligation followed by desulfurization. For reviews, see refs 471 and 533−537. Pioneering work on this subject was done in 2001 by Yan and Dawson538 through the transformation of the former Cys residue, used to ensure the NCL process, into an Ala residue after the ligation (alanine ligation), which is more abundant than Cys on peptides and proteins (Scheme 156). BD


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Scheme 159. Synthesis of ATAD2 Bromodomain Binding Region [979−1108]556

Sec) (Scheme 157). For reviews, see refs 471 and 533. In the presence of Sec, the ligation takes place following the same mechanism as the original Cys-mediated NCL. The development of chemoselective deselenization without the concomitant desulfurization of Cys residues on the peptide chains, as well as

the chemoselective ligation in the presence of other selenolderived unnatural AA, significantly broaden the applications of NCL toward new protein targets (see also sub-section 5.1.5, other extensions via capture strategies).471,542−550 BE


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Scheme 160. Aldehyde Capture for Amide Bond Formation

racemization levels at the ligation site (90%) were observed when a glycine residue is present at one extremity (C- or N-) of the newly created amide bond, lower yields were usually obtained in the ligation involving two non-Gly residues. Indeed, when bulkier amino acids are employed, the formation of the phosphonamide byproducts 248 become predominant. To expand the scope of the reaction to other AA residues than Gly, Raines thus reinvestigated the parameters of the transformation in an alanine−alanine modelligation reaction. Accordingly, the use of para-methoxysubstituted phosphine Y7 and moving to a less polar solvent such as toluene or dioxane allows the formation of the model BL


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nitrogen electron density and nucleophilicity). Consequently, the formation of the phosphonamide byproduct 252 through oxazaphosphetane 251 is avoided.598 While very efficient, this Y7 linker nonetheless suffers from low solubility in aqueous solvents and detracts from wide application in biomolecule syntheses. Thus, efficient water-soluble linkers such as Y8 and Y9 were finally synthesized.600−603 It should be noted that in some cases the formation of alkoxyimidates or diazo compounds could also be observed as by- or even exclusive products.604−606 A different “nontraceless” approach based on phosphine-modified proline was proposed by Xian and coworkers to increase reaction rates (Scheme 175).607 In just less than 15 years, the Staudinger ligation has emerged as a major technique for labeling biomolecules, cells, or living organisms under mild and bioorthogonal conditions (Scheme 176). The impact of the “Staudinger ligation” is illustrated by the (more than) 300 citations this term has so far received. These aspects have been extensively covered in several critical and comprehensive reviews,436,587,608−617 including a special issue on Account of Chemical Research.618−622 Aside from chemical biology, the Staudinger ligation has also known a tremendous success in peptide synthesis, organic and natural product syntheses, catalysis, microarrays, polymer, and materials science.613,617,622−625 An exhaustive description of the myriad of applications of the Staudinger ligation appears beyond the scope of this review (the formation of amide bonds) and the next section will thus be focused on applications in organic synthesis. 5.2.2. Staudinger Ligations as an Organic Synthetic Tool. The Staudinger ligation either in the Vilarrasa (starting from carboxylic acids or activated esters) or Bertozzi-Raines traceless or nontraceless conditions has become a valuable reaction in the organic chemist’s toolbox. 5.2.2.1. Peptide Chemistry. The traceless Staudinger ligation has found rather limited applications in peptide and glycopeptide chemistry.436,626 As illustrated in the previous section, Raines and co-workers have early recognized the potential of the Staudinger ligation as an alternative method to the native chemical ligation (NCL), thanks to the implicit possibility of coupling peptide segments at any site.621 Raines and co-workers nicely illustrated this concept during the synthesis of RNase A (257) (Scheme 177).627 This 124 amino acid residues protein was assembled from three main fragments. First, a Staudinger ligation between a 110−111 fragment with a C-terminal phosphinothioester 253 and a 112−124 fragment 254 supported on a PEG A resin containing a N-terminal azido-glycine residue enabled the formation of the 110−124 fragment 255 in 61% yield (after final resin cleavage and side-chain deprotections). This fragment (with an N-terminal cysteine) was then ligated (see sub-section 5.1) to the C-terminal thioester of (1−109) RNase A 256 (expressed in E. coli436). After ligation, folding, and purification, the synthesized RNase possess similar enzymatic activity compared to the wild-type enzyme.627 Initially limited to the presence of at least one glycine residue at the ligation site, the Staudinger ligation was progressively extended to other amino acids thanks to a better understanding of the reaction mechanism and the fine-tuning of the phosphine electronic properties (vide supra).592,597−599 Moreover, watersoluble phosphonium derivatives have been developed,600−602 allowing ligations under physiological conditions as illustrated in the synthesis of the phosphinothioster modified C-terminal end of bovine pancreatic ribonuclease.600 The Staudinger ligation has also been used in the synthesis of lactams and cyclopeptides.593,594,628,629 Originally described for

Scheme 178. Staudinger Ligations in Cyclopeptide Ligations

Scheme 179. Staudinger Ligation with Solid-Supported Peptides

dipeptide in higher yields and good reaction rates (k2 = 2.1 × 10−3 M−1 s−1) similar to those observed for the Gly-Gly ligation (Scheme 173). These observations led to refine the previous mechanistic proposal (Scheme 174).598,599 After the formation of the iminophosphorane 249, the tetrahedral intermediate 250 is next obtained after the addition of the nitrogen ylide to the carboxylic group. The latter intermediate can evolve through two different pathways either by (i) elimination of the thiolate and formation of the amide bond (path a) or by (ii) formation of an oxazaphosphetane 251 which evolves to the phosphonamide 252 (path b). Ascertained by DFT studies, both the use of electronrich phosphine as Y7 and low-polar solvents increase electrondensity at the phosphorus atom in 250 (without affecting BM


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Scheme 180. Solid-Phase Total Synthesis of Bogorol A

Scheme 181. Glycoasparagine Synthesis

first built up on a solid support. After resin cleavage, the boraneprotected phosphinothioester is next introduced on the Cterminal end of the peptide. An acidic treatment further allows both the deprotection of the phosphine and the amino acid sidechains. Next, under basic conditions, the intramolecular Staudinger ligation can finally take place. As illustrated in Scheme 178, three cyclopeptides incorporating 11 amino acids have been obtained in good yields using a Gly-Gly Staudinger ligation.628 Lee has developed a core−shell-type resin allowing the onsupport Staudinger ligation and the recycling of the phosphinothiol linker after reduction of the phosphine oxide (Scheme 179). The Staudinger ligation proved also useful in O-Acyl peptide “switch” strategy for “difficult” peptide sequences.630 Inoue and co-workers have recently described the total synthesis of Bogorol A featuring a Staudinger ligation for the stereocontrolled synthesis of thermodynamically unfavored dehydro amino acids (Scheme 180).631

Scheme 182. Traceless Staudinger Access to Glycoasparagines

the challenging synthesis of medium-sized lactams,593 the concept was next extended to cyclopeptides.628 Hackenberger and Kleineweischede described a strategy where the peptide is BN


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Scheme 183. Staudinger Ligation in Bio-Active and Natural Product Synthesis670,681

under refluxing toluene.583 Glycosylasparagine derivatives have next been introduced (SPPS) in a peptide sequence and after transglycosylation, several complex glycopeptides have impressively been obtained.582 Toth and co-workers described a strategy for the solid phase synthesis of glycopeptides where a glycosyl azide is anchored to a Rink MBHA resin. Preactivated (DIC/HOBt) Fmoc-leucine was next successfully introduced to the immobilized sugar in the presence of Bu3P, and then several amino acids could be incorporated to the on-growing glycopeptide chain. The strategy was compatible with Boc and Fmoc protection tactics.580 In 2004, Kiessling and Bernardi independently described the use of “traceless” phosphinothioesters derivatives of protected aspartic acids to form glycosylated asparagine derivatives.595 Interestingly, only β-glycosyl amide products were obtained in whatever the initial configuration of the glycosyl azide.633 Independently, Bernardi and co-workers described the stereoselective formation of perbenzylated α-glycosyl acetamides using Y1 in CCl4 at 70 °C.634,635 Later on, it has been shown that moving from per-benzylated to acetyl-glycosyl azides allows the exclusive formation of βglycosyl amides. When the reaction was carried out at 40 °C, the glycosyl iminophosphorane could be isolated and further transformed into β-glycosyl amides after water addition (Scheme 182, and please compare to Scheme 181).636 The ligation of unprotected azido-sugars was also accomplished with complete retention of the sugar configuration using fluorinated phosphine Y10 and next extended to the ribo and arabino series.637−641 The convergent glycopeptide synthesis by assembling variously substituted acyl donors (C-terminal phophinothioesters glycopeptides) and acyl acceptors (N-terminal azido glycine glycopeptides) could also have been efficiently accomplished using the “traceless” Staudinger methodology.642 Thanks to its chemoselectivity, the Staudinger reaction has also known numerous applications in glycochemistry and bioconjugation (Scheme 176).399,643−660 5.2.2.3. Reductive Ligation of S-Nitrosothiols, and Sulfenic Acids. As for glycosylation, the formation of S-nitroso thiols and

Scheme 184. KAHA Ligations

5.2.2.2. Glycopeptide Chemistry. The post-translational glycosylation of proteins plays a major role in many biological processes such as folding, trafficking, signal transduction, etc. These glycans structures are expressed on cell surfaces and serve as recognition hosts for cell−cell, proteins, and small molecules interactions.615 Among the myriad of glycan structures, N-linked glycans (where an oligosaccharide is covalently attached to an asparagine side-chain in a Asn-X-Ser (or Asn-X-Thr sequence) and O-linked glycans (where an N-acetylgalactosamine is attached to serine or threonine side chains) are the most represented ones. As previously stated (see Scheme 167), seminal work on Staudinger glycosylation has been described by Inazu in 1999 and Boullanger in 1997.582,583,632 Lycosylasparagine and glycosylglutamine derivatives were obtained in high yields. Notably, in the reaction of glycosyl-azide 258 with FmocAsp-OtBu in the presence of Bu3P in acetonitrile at −30 °C, the corresponding amide 259 was obtained in 54% yield along with triazene 260 in 14% yield (Scheme 181). Interestingly, this compound could be retransformed into 259 with acetic acid BO


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Scheme 185. Synthesis of (7-36) GLP-1 Peptide Featuring a KAHA Ligation

sulfenic acids on cysteine side-chains is an important post-

5.2.2.4. Total Synthesis of Natural and Bio-Active Products.

translational modification of proteins. The Staudinger ligation

Due to the development of efficient and selective methods to

has been described as a potential strategy for the detection of S-

construct azido derivatives, and thanks to its orthogonality, the

nitrosylation and sulfenic acids in biological systems and living

traceless Staudinger ligation has also emerged, as illustrated in

661−664

cells.

Scheme 183, as an efficient method in organic synthesis, notably BP


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example, in the synthesis of an hexapeptide 261 (Scheme 184).687 The further development of efficient strategies to construct Cterminal peptide α-keto acids688,689 and N-terminal peptide hydroxylamine,690 both by solid phase synthesis, paved the way to the spectacular KAHA ligation of larger unprotected peptides,691,692 including cyclic ones.693 The synthetic potential of this ligation strategy was notably highlighted in the synthesis of human GLP-1 (7−36) (265), a 30-mer peptide by a KAHA ligation between Glu21 and Gly22 (Scheme 185). The nonprotected 7−21 C-terminal α-keto acid was obtained using solid-phase synthesis with a Fmoc-based/2-Cl-trityl resin tactic. After resin cleavage and side-chains global deprotection under acidic conditions (TFA), the fully unprotected peptide was obtained after purification by preparative HPLC. Finally, the keto-acid functionality was thus delivered by oxidation of the Cterminal cyanosulphurylide function by an excess of oxone in a 3:1 mixture of water and DMF, and 262 was obtained in 65% yield after preparative HPLC purification. The hydroxylamine fragment was in turn obtained by solid phase synthesis from immobilized Pbf-protected arginine on Rink Amide MBHA resin. After the introduction of the 13 AA up to Gln23, bromoacetic acid was then introduced using DIC/ DMAP. This resin-linked peptide was next treated with an excess (10 equiv) of protected hydroxylamine 263 in DMF at 65 °C, in the absence of any traces of water. Under acidic treatment in the presence of scavenger (TFA/TIPS), resin cleavage and deprotection enabled the formation of HO-Gly22-Arg36-NH2 fragment 264. With the two fragments in hands, the ligation occurred in a DMA-DMSO mixture at 60 °C, in 51% yield with a slight excess of the hydroxylamine partner (1.05 equiv). A nonnegligible amount (12% yield) of the D-Glu21 epimer could also be detected. This quite unexpected epimerization, never observed in previously described KAHA ligations, was attributed to the oxidation process of the configurationally sensitive acyl cyanide intermediate. Nevertheless, the synthesis of this fully unprotected 30-mer peptide admirably illustrates the efficiency and the chemoselectivity (unprotected C- and N-terminal chains and His, Glu, Thr, Ser, Asp, Tyr, Gln, Lys, Trp, and Arg side chains) of the KAHA process. The strategy disclosed for cyclic peptides was illustrated in Scheme 186.693 From MBHA resin-bound sulfonium salt, the peptide is constructed using a regular solid phase peptide synthesis via a Fmoc tactic. The ultimate amino acid, bearing a nitrone protected hydroxylamine, was finally introduced by a standard peptide coupling reagent. Under acidic conditions (neat TFA), the peptide was cleaved from the resin and the side-chains deprotected. This cleavage should be carried out in the absence of water, to prevent nitrone deprotection. The keto-acid was then liberated by oxidation of the sulfur ylide with DMDO. At last, the intramolecular ligation proceeded in DMF in the presence of water and oxalic acid under high dilution conditions (10−3 M) to minimize the amount of dimeric cyclic peptides and oligomers. Water and oxalic acid were essential for the liberation of the hydroxylamine. However, the presence of water could also be detrimental for the amide bond formation, and thus the amount of added water should be limited: a 50:1 DMF/H2O was therefore used. Epimerization, a long known problem in the cyclization of peptides, was restricted as only 5% of epimer was detected at the keto-acid residue. This strategy has been used in the synthesis of gramicidin S (and semi gramicidin S), tyocidin A, hymenamide B, and stylostatin A. In the latter case, the Leu-Ala ligation proved to be more

Scheme 186. Synthesis of Cyclic Peptides Using a Staudinger Ligation

for the late introduction of amide bonds or lactamization.651,665−682 5.2.2.5. Catalysis. The heterogenization of homogeneous catalysts through their immobilization on solid supports is a key point for sustainable chemistry. The Staudinger ligation has been used for the immobilization of metal complexes on polymer supports, allowing the recycling of the catalyst by simple filtration.683,684 5.3. Keto-Acid Ligation via N−O Bonds (KAHA and KATs Ligations)

5.3.1. KAHA Ligation. In 2006, Bode and co-workers have described the decarboxylative addition of keto-carboxylic acids with hydroxyl amines (KAHA). For accounts from the Bode’s group, see refs 685 and 686. In the absence of any further reactants or catalysts, the reaction proceeds in high yields in polar organic solvents such as DMF (with 5% H2O). Different ligation sites are authorized as illustrated by Bode in various Phe-Ala, ProAla, Val-Gly, and Ala-Ala coupling reactions.687 Furthermore, the reaction is highly chemoselective since nonprotected carboxylic acids, amines, and alcohols are well tolerated as illustrated, for BQ


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Scheme 187. KAHA Ligations in Glycopeptide Synthesis

hydroxylamine derivative.698 Moreover, the independently prepared potassium salt of oxaziridine acid 266 could be converted into the corresponding amide in the presence of one equivalent of TFA (Scheme 189, eq 4). On the basis of these experimental evidence, a complex mechanistic pathway was unveiled involving the successive formation of hemiaminal, nitrone, α-lactone, and oxaziridine intermediates (Scheme 190).698,694 It should also be noticed that KAHA ligations involving Osubstituted hydroxylamines might imply an alternative mechanistic scenario. Indeed, when the reaction involving a benzoylsubstituted derivative was engaged with 18O-labeled keto-acid, the labeled atom was transferred into the amide bond (compare eqs 1 and 2 in Scheme 191). This striking difference in the reaction mechanism can be correlated with the observation that KAHA ligations with hydroxylamines are sensitive to water (diminished reaction rates), whereas with O-substituted hydroxylamines the presence of water is mandatory. Moreover, the diminished reaction rates observed in aqueous conditions could hamper the development of the hydroxylamine KAHA ligation in the synthesis of larger peptides, usually poorly soluble in organic solvents.692,693 Bode and co-workers have thus explored the use of O-substituted hydroxylamines, able to be good partners in the KAHA under aqueous conditions, but also

challenging due to the reluctant hydrolysis of the alanine nitrone: in this case a p-nitrobenzylidene was used to protect the terminal alanine residue. The KAHA ligation has also been used by Sucheck and coworkers in the synthesis of glycopeptides: Gly-Gly, Gly-Ala, AlaGly, Ala-Ala, and Gly-Val ligations have been obtained in moderate to good yields (Scheme 187).694 The ligation is rather sensitive to steric hindrance since no Val-Val ligation products could be isolated, and oxazoles were also observed in some instances as byproducts. KAHA ligation products with unprotected alcohols on the sugar moiety have also been obtained, albeit in lower yields (Scheme 187). In addition to hydroxylamines, O-substituted derivatives and isoxazolidines can also be used as efficient partners in KAHA ligations with keto-acids.695−697 It is worth noting that, starting from isoxazolidines (Scheme 188), via an iterative process involving the KAHA ligation followed by the saponification of the methyl ester, the synthesis of β-oligo-peptides was achieved. Finally, the oligomer keto-ester was converted into the corresponding carboxylic acid using an oxidative decarboxylation. Among all the mechanistic pathways that were initially postulated, 18O labeling experiments have shown that the oxygen (Scheme 189, eqs 1−3) of the amide bonds stems from the BR


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Scheme 188. Iterative Synthesis of β-Oligo-Peptides via KAHA Ligation

Scheme 190. Mechanistic Proposals in KAHA Ligations

Scheme 189. Labeling Experiments in KAHA Ligations

Scheme 191. Different Mechanistic Scenario Using Hydroxylamines and O-Benzoyl Hydroxylamines

fully compatible with SPPS requirements. They developed Bocoxaproline 267, homoserine surrogates, that can be used as a “regular” amino acid in SPPS and allows a clean ligation under aqueous conditions (DMSO/H2O 6:4) as illustrated in the synthesis of two proteins, Pup and cspA, both containing more than 60 amino acid residues.699 The strategy leading to a homoserine (Hse, T§) at the ligation site, Leu32-Thr33 and Tyr31-Thr32 ligations have been chosen, respectively. The general strategy to obtain these peptides is illustrated in Scheme

192. The keto-acid partner is obtained via an automated SPPS. The oxaproline partner is also obtained via automated SPPS, and only the ultimate Boc-oxaproline was introduced “manually” in the presence of HCTU in the last step. The two nonprotected peptides are finally assembled using the KAHA ligation in DMSO/H2O (6:4), in the presence of oxalic acid, to give the T33T§ Pup and T32T§ cspA proteins in 51% and 53% isolated yields, respectively (Scheme 192). It was also further confirmed that the threonine/homoserine exchange does not affect the folding of the protein. Thanks to the possibility to install an orthogonal protecting group on the oxaproline residue, iterative KAHA ligation/ oxaproline deprotection can be envisioned (Scheme 193).700 An outstanding illustration of this concept has been disclosed by Bode in the synthesis of UFM1 (2-83) protein, by two successive KAHA ligations at Phe29-Thr30 and Ala60-Gln61 sites. After the first KAHA ligation, the Fmoc protecting on the terminal oxaproline is released under optimized basic conditions, allowing the introduction of the third fragment. This ligation was carried BS


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Scheme 192. Oxaproline Ligations

cyanosulfurylide, see Scheme 192). Bode has described a new protecting group allowing upon acidic treatment the resin cleavage, the side chain deprotections, and the liberation of the C-terminal keto-acid.703 The KAHA ligation was also extended to the formation of aspartyl aldehyde residues starting from isoxazolidines, obtained from oxidized oxaproline (Scheme 195).704 By playing on the ring strain, Bode recently disclosed the use of 4-membered oxazetidine amino acids allowing faster KAHA ligations under milder reactions conditions and in the absence of oxalic acid.705 Notably, the primary product is not the depsipetide as observed with oxaproline (Scheme 194) but the expected peptide bond incorporating a serine residue, and more importantly, the reactions are faster and can be carried out at low concentrations (100 μM−5 mM vs 10−15 mM with oxaprolines) at room temperature.

out at 20 mM in 30% water in DMSO with 0.1 M oxalic acid, and the yield, after 24 h at 50 °C, of the corresponding protein is of 45% with no detectable epimerization products. From a mechanistic point of view, it has been recently demonstrated that the KAHA ligation with oxaproline occurs in a different way than initially expected.701 The formation of a depsipeptide occurs first, followed at higher pH by an O → N acyl shift to give the expected amide bond (Scheme 194). The KAHA ligation was recently used in the synthesis of a 184residue protein by assembling five fragments.702 The KAHA ligation is compatible with a wide range of nonprotected side-chains including threonine, serine, lysine, ornithine, histidine, arginine, aspartic, and glutamic acids but incompatible with the presence of oxidation-sensitive cysteine and methionine residues. Indeed, the keto-acid moiety was originally liberated by an oxidative process (oxidation of a BT


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Scheme 193. Orthogonal Three Fragments Synthesis through Two Consecutive KAHA Ligations

Scheme 194. Ligation through a Depsipeptide Intermediate

Scheme 196. Iodine-Mediated Formation of Amides from Keto-Acids and Amines

Scheme 197. Initial Attempts for the use of KATs in Amide Formations

Scheme 195. Aspartyl Aldehydes Residues on KAHA Ligations

5.3.2. Potassium Acyltrifluoroborates (KATs). In parallel to the KAHA ligation, the KAT ligation has been explored by the Bode group. Molander and co-workers have first explored the reactivity of potassium acyltrifluoroborates (KATs) with azides, in the presence of tetrafluoroboric acid diethyl etherate, to give the corresponding amide under mild conditions.707 However, due to the lack of a general method of synthesis, the reactivity of the sole acyltrifluoroborate 268 was explored in this study

In a totally different approach, unprotected keto-acid aldose derivatives can undergo, in the presence of iodine, clean amidification with primary amines (Scheme 196).706 BU


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Scheme 198. Reaction of KATs with O-Benzoyl Hydroxylamines

Scheme 201. Chemoselective Functionalization of a Peptide Lysine Side-Chain Using the KATs Ligation

Scheme 199. KATs and Isoxazolidines

Scheme 200. Mechanistic Rationale for the KATs Ligation

Scheme 202. KAT Ligations with MIDA Acylboronates

(Scheme 197). Good yields have been obtained with alkyl azides, but decomposition was observed with arylazides and azides containing a remote alkene. Thanks to a more general access to KATs,708 Bode and Molander groups have re-explored the reactivity of these derivatives in the presence of O-benzoyl hydroxylamines.709 In polar aqueous solvents (typically H2O/tBuOH) at room temperature, the reactions are fast, allowing the formation of the amides in high yields with a wide range of functional groups compatibility (Scheme 198). The reaction can be performed in the absence of any promoter, to the notable exception of branched hydroxylamines that require the addition of a stoichiometric amount of oxalic acid.

As for the KAHA ligation (see Scheme 188), isoxazolidines 269 can also act as efficient reaction partners leading to ketoesters in good yields (Scheme 199). BV


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robust and effective procedures that could also find industrial applications need to be devised, addressing thus long-standing challenges in the field of amide bond formation for a broad set of substrates.

From a mechanistic point of view, the initial proposed mechanism involving an acyldifluoroborane (Scheme 200, path a) was ruled out due to the absence of any fluorophile able to break the B−F bond,707,710 and this statement was reinforced by the observation of iminium and/or enamine intermediates strongly suggesting that the addition of the hydroxylamine derivative to the KAT (Scheme 200, paths b or c) is the operating mechanism.709 More recently, this methodology could be applied to the functionalization of the lysine side-chain of unprotected peptides.711 Whereas the O-Bz hydroxylamines derivatives proved unproductive (difficult to introduce and unstable in the peptide synthesis reaction conditions) in these series, a screening of differently O-substituted hydroxylamines underscored the use of N,N-diethylcarbamates, which are reactive partners in the ligation reaction and are also orthogonal to Boc and Fmoc protecting groups. As a proof of concept, the fully deprotected 31-amino acid peptide analogue of the antidiabetic peptide GLP1 was modified by the successful introduction of PEG, lipidic (palmitoyl), biotin, and dyes (diazo) residues (Scheme 201). The ligation reaction is high yielding and tolerant to a wide range of nonprotected amino acids side-chains such as arginine, glutamine, tryptophan, glutamic acid, and histidine. It should also be emphasized that, in all reported cases, the reactions are fast (10 min) with a 1:1 stoichiometry of the two reagents under aqueous conditions (the use of DMSO as a cosolvent was recommended in the case of the low aqueous solubility of the KATs) without affecting the reaction outcome. Additionally, the use of MIDA (N-methyliminodiacetyl) acylboronates was reported by Bode.712,713 These reagents proved to be more reactive than the corresponding KATs enabling the reaction with O-Me hydroxylamines. The reaction was efficient with a wide range of branched and functionnalized hydroxylamines using a 1:1 stoichiometric ratio and in the absence of any promoter at room temperature (Scheme 202). Moving to the ligation reaction with nonprotected peptides proved to be more disappointing as 5 equiv of MIDA acylboronate were necessary to achieve completion, due to the moderate stability of this reagent under the slightly acidic ligation conditions.

AUTHOR INFORMATION Corresponding Authors

*E-mail: renata.marcia_de_fi[email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Renata Marcia de Figueiredo was born in Boa Esperança-MG, Brazil. She received her Ph.D. degree from the University of Paris Sud (OrsayFrance) in 2005. Then, she moved to Germany as a postdoctoral research fellow in the group of Prof. M. Christmann in RWTH-Aachen. In 2008, she was appointed CNRS researcher at the Ecole Nationale Supérieur de Chimie de Montpellier (ENSCM) where she has joined the group of Prof. J.-M. Campagne. Her research interests include the development and the application of catalytic asymmetric methodologies to the total synthesis of natural products and biologically active targets as well as peptide synthesis. Jean-Simon Suppo was born in Briançon, France, in 1989. He received his Master’s degree in chemistry from Aix-Marseille University in 2012. In 2015, he completed his Ph.D. in chemistry at the ENSCM under the direction of Prof. J.-M. Campagne and the supervision of Dr. R. M. de Figueiredo. Jean-Marc Campagne was born in Pau, France, in 1967. After studies at the Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), he received his Ph.D. at the University of Montpellier in 1994. After postdoctoral training with Prof B. Trost (Stanford University, USA) and Prof. L. Ghosez (Université Catholique de Louvain, Belgium), he was appointed CNRS researcher at the Institut de Chimie des Substances Naturelles in Gif-sur-Yvette in 1998. Since 2005, he has been at the ENSCM where he was appointed professor. His current interests concern the development of catalytic asymmetric transformations and their application to the total synthesis of natural products.

ACKNOWLEDGMENTS The financial support from the Agence Nationale de la Recherche (ANR JCJC project NIPS: ANR-12-JS07-0008-01) is fully acknowledged. We are also grateful for the support from CNRS and ENSCM. Dr. Eric Leclerc and Sammy DrissiAmraoui are thanked for proof reading the manuscript.

6. CONCLUSION In summary, we have highlighted the most recent and relevant ways to build up amide bonds that are not associated with the conventional carboxylic acid activation procedures. As illustrated, these nonconventional processes have gained a great deal of interest in recent years as useful alternative procedures. Amidations can be performed using a broad range of chemical methods, going from thermal condensation of simple carboxylic acids with amines to the catalytic use of transition-metal or organo-catalysts. In addition, both carboxylic acid and amine surrogates could also be successfully engaged in several redox procedures. The sustained growth on amide-containing compounds, not only due to their biological and pharmacological properties but also referred to their rising potential on material and polymer sciences, has inspired several groups to develop new and innovating strategies in the past decade. However, apart from a few methodologies, most of them do not meet all the requirements for application in peptide synthesis. Indeed, in most cases, to engage sensitive amino acid residues lowers reaction rates and selectivities and heightens racemization levels. Outstanding work that answers several criteria for peptide chemistry has been developed. Yet, we anticipate that more

ABBREVIATIONS AA amino acid Ac acetyl ACL aldehyde capture ligation Acm acetamidomethyl acac acetylacetonate Ala alanine Act activated AIBN 2,2′-azobis(2-methylpropionitrile) Ar aryl Arg arginine Asp asparagine AzoBDC azobenzene-4,4′-dicarboxylic acid BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine BW


Chemical Reviews Boc bp BHT [bmin][Tf2N] Bn brsm BSA BTTP nBu Bz Cbz CDI COD Cp Cy Cys Cyp DBU DCE DCC (−)-DDPP de DFT DIB DIC (−)-DIOP DIPEA DPPPen DKP DMA DMAP DMDO DMNB DMF DMSO DNA dppp dppb dr DTBP DTBPMB ee Et FBC FCMA Fg Fm Fmoc Gly Gln Glu Gnd HAp HCTU His HOAt HOBt HYP IL

Review

tert-butoxycarbonyl boiling point 2,6-di-tbutyl-4-methylphenol 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide benzyl based on recovered starting materials bistrimethylsilylacetamide tert-butylimino-tri(pyrrolidino)phosphorane nbutyl benzoyl benzyloxycarbonyl N,N′-carbonyldiimidazole 1,5-cyclooctadiene cyclopentadienyl cyclohexyl cysteine cyclopentyl 1,8-diazabicyclo[5.4.0]undec-7-ene dichloroethane N,N′-dicyclohexylcarbodiimide [(2S,4S)-(−)-4-diphenylphosphino-2(diphenylphosphinomethyl)pyrrolidine] diastereomeric excess density functional theory diacetoxyiodobenzene N,N′-diisopropylcarbodiimide (−)-2,3-O-isopropylidene-2,3-dihydroxy-1,4bis(diphenylphosphino)butane N,N-diisopropylethylamine 1,5-diphenylphosphinopentane diketopiperazine N,N-dimethylacetamide p-(dimethylamino)pyridine dimethyldioxirane 4,5-dimethoxy-2-nitrobenzyl/oxycarbonyl N,N-dimethylformamide dimethyl sulfoxide DNA 1,3-bis(diphenylphosphino)propane 1,4-bis(diphenylphosphino)butane diastereomeric ratio di-tert-butyl peroxide 1,2-bis(diterbutylphosphinomethyl)benzene anantiomeric excess ethyl fluorous biphasic catalysis formimidate carboxylate mixed anhydride functional group 9-fluorenylmethyl 9-fluorenylmethoxycarbonyl glycine glutamine glutamic acid guanidinium hydrochloride hydroxyapatite 1-[bis(dimethylamino)methylen]-5-chlorobenzotriazolium 3-oxide hexafluorophosphate hystidine 1-hydroxy-7-azabenzotriazole 1-hydroxybenzotriazole 2-hydroxypyridine ionic liquid

Ile IMes IMe·HCl IPr IPr·HCl iPr ItBu KAHA KAT KCL LDA Leu Lys MBHA MCPBA MCF MCM-41 Me Mes MESNa Met MIDA MPAA MS MW NCL NCS NHC NIS NMO NMP NMR Orn o-Tol Pbf PCy3 PCyp3 PCR PEG Ph Phe PICB PIDA PNA PNN Pro Pse P1-tBu Py PyBOP RNA rt SBA-15 SDS Sec Ser SFC BX

isoleucine N,N-bismesitylimidazolylidene 1,3-dimethylimidazolium iodide 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene 1,3-diisopropylimidazolium bromide isopropyl 1,3-di-tert-butylimidazolin-2-yl-idene keto-carboxylic acids with hydroxylamines potassium acyltrifluoroborates kinetically controlled ligation lithium diisopropylamide leucine lysine 4-methylbenzhydrylamine 3-chloroperoxybenzoic acid mesocellular silicious foam mesoporous silica (Mobil composition of matter N° 41) methyl mesityl sodium 2-mercaptoethanesulfonate methionine N-methyliminodiacetyl 2-(4-mercaptophenol)acetic acid molecular sieves microwave native chemical ligation N-chlorosuccinimide N-heterocyclic carbene N-iodosuccinimide N-methylmorpholine N-oxide N-methyl-2-pyrrolidinone nuclear magnetic resonance ornithine o-tolyl pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl tricyclohexylphosphine tricyclopentylphosphine polymerase chain reaction polyethylene glycol phenyl phenylalanine polymer-incarcerated with carbon black phenyliodine diacetate peptide nucleic acid 2-(di-tert-butylphosphinomethyl)-6(diethylaminomethyl)pyridine proline (phenylsulfonyl)ethyl tert-butylimino-tris(dimethylamino)phosphorane, N′-tert-Butyl-N,N,N′,N′,N″,N″hexamethylphosphorimidic triamide pyridine benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate ribonucleic acid room temperature mesoporous silica (Santa Barbara amorphous) sodium dodecyl sulfate selenocysteine serine solvent-free conditions DOI: 10.1021/acs.chemrev.6b00237 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews SPPS SNAr Su T TBAI TBD TBHP tBu TCEP TEMPO TFA THF Thz TIPS Tmob TMS TONs TriTFET trop2N Thr Trp TS Tyr UmAS Val

Review

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solid-phase peptide synthesis aromatic nucleophilic substitution succinimidyl temperature tetrabutylammonium iodide 1,5,7-triazabicyclo[4.4.0]dec-5-ene tert-butylhydroperoxide tert-butyl tris(2-carboxyethyl)phosphine 2,2,6,6-tetramethylpiperidine 1-oxyl trifluoroacetic acid tetrahydrofuran L-4-thiazolidinecarboxylic acid triisopropylsilane 2,4,6-trimethoxybenzyl trimethylsilyl turnover numbers 2,4,6-tris(2,2,2-trifluoro-ethoxy)-[1,3,5]triazene bis(5-H-dibenzo[a,d]cyclohepten-5-yl)-amide threonine tryptophan transition state tyrosine umpolung amide synthesis valine

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