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MICROREVIEW

DOI: 10.1002/ejoc.201300573

Recent Developments in Amide Synthesis: Direct Amidation of CarboxylicAcids and Transamidation Reactions

Rachel M. Lanigan[a] and Tom D. Sheppard*[a]

Keywords: Amides / Amines / Carboxylic acids / Amidation / Transamidation

The synthesis of amides is of huge importance in a wide vari-ety of industrial and academic fields and is of particular sig-nificance in the synthesis of pharmaceuticals. Many of thewell established methods for amide synthesis involve rea-gents that are difficult to handle and lead to the generationof large quantities of waste products. As a consequence,there has been a considerable amount of interest in the de-velopment of new approaches to amide synthesis. Over thepast few years a wide range of new reagents and catalysts

Introduction

Amide bonds are present in a vast array of useful mole-cules including numerous industrially important com-pounds, as well as a wide selection of bioactive naturalproducts. The synthesis of amides is hugely important inthe preparation of compounds in a wide variety of indus-tries, with amide synthesis attaining particular significancein the pharmaceutical industry: amides are present inaround 25% of top-selling pharmaceuticals and in manyother medicinally important compounds.[1] Despite thehuge importance of amides in organic chemistry, most ofthe well-established methods for their formation are rela-tively inefficient, with large quantities of potentially hazard-ous waste products being produced, leading to adverse envi-

[a] Department of Chemistry, University College London,Christopher Ingold Laboratories,London WC1H 0AJ, U.K.E-mail: [email protected]: www.tomsheppard.eu

Rachel Lanigan was born in Edinburgh. She received her MChem from the University of Edinburgh in 2010,carrying out her MChem research project under the supervision of Professor Hamish McNab working onradical cyclisations of substituted pyrroles by flash vacuum pyrolysis. She is currently pursuing a PhD inorganic chemistry under the guidance of Dr Tom Sheppard at University College London with a focus on thedevelopment of B(OCH2CF3)3-mediated amidation reactions.

Tom Sheppard was born in Lancashire. He obtained his MSci degree from the University of Cambridge in1999. After a year working in the pharmaceutical industry at GlaxoWellcome, he went on to obtain his PhD

from the University of Cambridge in 2004, working under the supervision of Professor Steven Ley on the development of butane-2,3-diacetaldesymmetrised glycolic acid. He then carried out postdoctoral research with Professor William Motherwell at University College London,working on new methods for cyclopropane synthesis and new multi-component reactions. In 2007, he was awarded an EPSRC AdvancedResearch Fellowship and appointed to a lectureship at University College London, where his research is focussed on the development andapplication of new organocatalytic and metal-catalysed reactions.

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for direct amidation of carboxylic acids have been reported.In addition, the interconversion of amide derivatives throughtransamidation is emerging as a potential alternative strategyfor accessing certain amides. This microreview covers recentdevelopments in the direct amidation of carboxylic acids andthe interconversion of amides through transamidation. Theadvantages and disadvantages of the various methods arediscussed, as well as the possible mechanisms of the reac-tions.

ronmental impacts and difficulties in purification of the de-sired amide products. As a consequence, there have beenseveral articles written by representatives of the pharmaceu-tical industry (such as the ACS Green Chemistry InstitutePharmaceutical Roundtable), which have identified amidebond formation as perhaps the most important synthetictransformation for which improved methods are required.[2]

The environmental aspects of a variety of established amideformation reactions have also been evaluated in several re-cent articles from representatives of the pharmaceutical in-dustry.[3] The industrial importance of amide synthesis hasstimulated increased interest from the research communityin the development of new and efficient approaches, andmany new developments have been reported over the pastdecade.[4]

Amides can be prepared from a wide variety of precur-sors by a range of different reaction pathways. Althoughrecent progress has been made in oxidative amidation reac-tions employing alcohol or aldehyde precursors, by far themost common approach is condensation between a carbox-

R. M. Lanigan, T. D. SheppardMICROREVIEWylic acid and an amine. This is usually achieved by the useof a coupling reagent, which activates the carboxylic acidcomponent and drives the dehydration reaction. More re-cently, the discovery of effective catalysts for direct amid-ation has led to processes that offer considerably increasedefficiency,[5] although as yet they often have relatively lim-ited substrate scope. Nevertheless, over the next few yearsit is likely that catalytic amidation reactions will becomeincreasingly competitive with the more traditional couplingreagent approaches. Alternative strategies that employ es-ters[6] or amides as acyl donors have also begun to emerge,and in some cases such strategies might offer advantagesover carboxylic acid activation methods.

A number of recent reviews of the area have coveredmetal-catalysed amide bond formation[7–9] and the use ofmore traditional coupling reagents.[10] This microreviewhighlights recently reported developments both in the directamidation of carboxylic acids and in the interconversion ofamides through transamidation.

Amidation of Carboxylic Acids

The direct thermal condensation of carboxylic acids andamines in the absence of reagents or catalysts has tradition-ally been viewed as an unviable approach, due to the pre-sumed formation of ammonium carboxylate salts(Scheme 1), and extremely harsh conditions have been re-ported to be required.[11] However, thermal amidation hasrecently attracted renewed interest because it has becomeapparent that ammonium carboxylate salt formation doesnot always readily take place, and need not necessarily pre-vent condensation from occurring. Indeed, the degree ofammonium carboxylate salt formation is strongly depend-ent both on the substrates employed and on the reactionconditions.

Scheme 1. Ammonium carboxylate salt formation versus condensa-tion.

In a recent experimental and computational study of themechanism of thermal amidation reactions in nonpolar sol-vents, a strong correlation between the acidity of a carbox-ylic acid and its reactivity was observed, with more acidicsystems being largely unreactive. This was attributed to thehigh degree of ammonium carboxylate salt formation ob-

Scheme 2. Proposed mechanism for direct thermal amidation.

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served with stronger acids. Trends in the reactivity of theamine component were much more difficult to identify, andamine reactivity was thought to be down to a complex bal-ance of steric and electronic effects. On the basis of a com-putational study it was proposed that the key step of thereaction mechanism is nucleophilic attack of the amine on ahydrogen-bonded carboxylic acid dimer (Scheme 2).[12] Thegeneral reactivity trends identified in this mechanistic studyhave been corroborated by several recent papers on thermalamidation, which are discussed below. Similar reactivitytrends have also been observed in amidation reactions me-diated by a variety of reagents and catalysts.

The direct thermal condensation of carboxylic acids andamines at 160 °C under neat conditions in the presence of3 Å molecular sieves (MS) to remove the water generatedin the reaction has been described (Scheme 3).[13] Duringoptimisation of this method it was observed that molecularsieves were not necessary for good conversion, althoughthey were still employed in order to limit any pressure build-up in the sealed reaction vessel. Only a limited selectionof functionalised acids and amines were explored, but freealcohols and phenols were tolerated under the reaction con-ditions and the corresponding ester products were not ob-served.

Scheme 3. Direct high-temperature thermal amidation. [a] Reactiontime 24 h. [b] Reaction time 12 h.

The use of radiofrequency heating to promote direct am-idation under solvent-free conditions has also been reported(Scheme 4).[14] Nickel ferrite nanoparticles act as a radiofre-quency-absorbing material that can generate localised heatin the reaction flask when exposed to alternating current(AC) magnetic fields. This method benefits from fast reac-tion times (�20 min) and easy removal of the nickel ferriteparticles by magnetic separation. A range of substrates in-

Recent Developments in Amide Synthesis

cluding α-chiral acids, benzoic acids, anilines and secondaryamines can be used, and no drop in stereochemical puritywas observed during the amidation of N-Boc- or N-Cbz-l-proline. Acid-sensitive protecting groups and free phenolswere also tolerated in these reactions.

Scheme 4. Examples of radiofrequency-mediated amidation.

The direct amidation of carboxylic acids was reported tooccur for many substrates on heating in PhMe at 110 °C(Scheme 5).[15] This method does not require active waterremoval (Dean–Stark, etc.), but anhydrous reaction condi-tions were employed. Because of the nonpolar nature of thesolvent, ammonium carboxylate salt formation is disfa-voured. This method works well for secondary amines, ali-phatic, aromatic and heteroaromatic amines and a rangeof carboxylic acids. In one case an amidation reaction wassuccessfully performed on a 400 mmol scale to give 93 g ofproduct. Less reactive systems such as anilines and benzoicacids gave lower yields under the standard conditions, al-though yields from less reactive substrates could be im-proved by increasing the reaction temperature to 150 °C(xylenes) or by the addition of a zirconium catalyst (ZrCl4or Cp2ZrCl2). An amidation product derived from N-Boc-proline was determined to have �99% ee.

Scheme 5. Examples of thermal and Zr-catalysed amidation.

A ZrCl4-catalysed direct amidation was also reported byanother research group at the same time.[16] In this case,4 Å MS were employed as a dehydrating agent and the reac-

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tion could be carried out at a lower temperature (70 °C)under anhydrous conditions (Scheme 6). No racemisationwas observed in the coupling of two N-protected amino ac-ids, and acid-sensitive N-protecting groups were tolerated.Alkyl, aromatic and heteroaromatic acids and aminesunderwent amidation in moderate to excellent yield underthese conditions. Less active substrates such as benzoic ac-ids and secondary amines, however, required a higher reac-tion temperature of 100 °C. This method was also shown tobe suitable for larger-scale synthesis (�5 g of amide). Interms of functional group compatibility, a few examples offunctionalised substrates, including compounds containingacetals/ketals and nitro groups, were investigated. The back-ground reaction observed under these conditions for the re-action between phenylacetic acid and benzylamine was low(10–13 %) in comparison with the catalysed reaction (99%).

Scheme 6. Examples of ZrCl4-catalysed amidation. [a] 1.5 equiv.amine at 100 °C.

It has been proposed that zirconium catalysts activate thecarboxylic acid through several different coordinationmodes (Figure 1), including: a) Lewis acid activation of thecarbonyl group either in the acid or in the hydrogen-bondeddimer, b) Lewis acid activation of the carbonyl group withsimultaneous activation of the leaving group by hydrogenbonding, and c) zirconium activation of the carboxylateoxygen as a leaving group.

Figure 1. Proposed carboxylic activation modes in Zr catalysis.

In a similar fashion, Ti(OiPr)4 was also reported to bea suitable catalyst for direct amidation,[17] under reactionconditions related to those reported for ZrCl4 (Scheme 7).Amidation reactions with both primary and secondaryamines in combination with aliphatic acids, unsaturated ac-ids, aromatic acids or heteroaromatic acids proceeded well

R. M. Lanigan, T. D. SheppardMICROREVIEWunder the reaction conditions. A selection of α-chiral acidswere explored: no racemisation was observed with Boc-l-proline or Boc-l-alanine, but some epimerisation was ob-served with ibuprofen (83 % ee). Acid-sensitive groups in-cluding Boc-protected nitrogens and ketals were toleratedunder the reaction conditions. A range of transition-metalchlorides and alkoxides were also found to act as suitableamidation catalysts, although Ti(OiPr)4 was judged to bethe most suitable candidate due to its ready availability andlow price. This reaction probably proceeds by a mode ofactivation similar to that of the Zr-mediated processes (Fig-ure 1). The background reaction between benzylamine andphenylacetic acid under these reaction conditions was lower(10%) than in the Ti(OiPr)4-catalysed process (91%).

Scheme 7. Examples of Ti(OiPr)4-catalysed amidation. [a] Ti-(OiPr)4 (20 mol-%) at 100 °C.

Stoichiometric quantities of AlMe3 have been reportedto mediate amidation reactions, but these processes requireexclusion of air or moisture, long reaction times and ex-cesses of both amine and AlMe3 (3 equiv.).[18] The dimeth-ylaluminium amide must also be pre-formed before the acidcan be added to the reaction mixture (Scheme 8). A rangeof amides, including those derived from secondary aminesand from very electron-deficient amines, can be synthesisedin moderate to excellent yield (Scheme 9). However, fewfunctional groups were reported to be compatible with thereaction conditions. In the synthesis of the chiral penta-fluoroaniline-derived amide (Scheme 9), no racemisation ofthe α-chiral centre was observed. The yields of amide ob-tained due to thermal background reaction under theseconditions were not measured and might be significant inthe case of more reactive combinations of acid and amine.This method is noteworthy, however, because activationboth of the carboxylic acid and of the amine occurs duringthe reaction mechanism, leading to more effective acylationof poorly nucleophilic amines. This is in contrast to mostother methods, which proceed solely through activation ofthe carboxylic acid component.

XtalFluor-E (and related derivative XtalFluor-M) hasbeen described as a direct amidation reagent that can beused under mild conditions and inert atmosphere(Scheme 10).[19] Many amides can be accessed effectively,but hindered amines do not readily undergo amidation, andthe corresponding diethylamide is formed as a significantbyproduct in some cases. It is possible to couple a range ofacids and amines including deactivated and sterically hin-dered acids, as well as substrates containing free phenols.


Scheme 8. Proposed AlMe3-mediated amidation mechanism.

Scheme 9. Selected examples of AlMe3-mediated amidation.

Scheme 10. Examples of XtalFluor-E-mediated amidation.

A PPh3/I2 combination has also been shown to be effec-tive for the direct amidation of carboxylic acids under inertconditions,[20] when used along with an excess of Hünig’sbase to facilitate acid deprotonation. However, more chal-lenging substrates require up to two equivalents of the rea-gents and the products must be separated from the phos-phane oxide byproduct by recrystallisation, chromatog-raphy or a polymer-supported phosphane must be used.

1-tert-Butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquin-oline (BBDI, Scheme 11) has been reported as a new cou-pling reagent that can mediate amidation reactions effec-tively at room temperature.[21] The carboxylic acid is acti-vated as the mixed anhydride after elimination of the iso-quinoline leaving group and tBuOH. This procedure is car-


ried out in CH2Cl2 and requires an excess of both the BBDIand the amine. Aliphatic amines, anilines and secondaryamines could, however, be coupled with aliphatic, benzoic,heteroaromatic and unsaturated acids effectively under thereaction conditions (Scheme 12). Lower yields were ob-served for bulky acids and amines such as adamantane-carboxylic acid and tert-butylamine, but these reactionscould be improved by increasing the reaction temperatureto reflux. Low levels of racemisation were observed forsome α-chiral acids, but measured enantiopurities were notreported for all chiral amides synthesised.

Scheme 11. Mechanism of BBDI-mediated amidation.

Scheme 12. Examples of amides prepared by BBDI-mediated cou-pling. [a] Reaction time of 5 h. [b] No enantiopurity reported.

Sulfated tungstate has been reported as a heterogeneouscatalyst for the direct preparation of amides.[22] Thismethod requires azeotropic reflux in PhMe or xylene in thepresence of excess carboxylic acid (Scheme 13). The synthe-sis of amides derived from primary/secondary aliphaticamines and anilines by condensation with aliphatic, unsatu-rated and aromatic carboxylic acids was described. How-ever, only a few functionalised systems were examined.There is a significant background reaction reported in somecases, which can be expected in view of the high tempera-tures involved. This heterogeneous catalyst offers a con-siderable advantage in terms of purification because it caneasily be separated from the reaction mixture by filtration,and the catalyst can be reused up to four times with only asmall loss in amide yield. After catalyst removal, the amideproduct was purified by aqueous workup.


Scheme 13. Sulfated tungstate mediated amidation. [a] Thermalyield.

The use of boron-based reagents and catalysts for directamidation has attracted significant attention. In very earlyreports on organoboron chemistry, the ability of boronicacids to promote acylation of amines was noted. For exam-ple, catalytic reduction of o-nitrobenzeneboronic acid (1,Scheme 14) in acetic acid led to the formation of a com-pound tentatively assigned the structure 2, which upon de-boronation gave acetanilide 3.[23] More recent work hasfound further evidence to support this proposed structureof 2.[24] It was hypothesised that a mixed anhydride 4 wasgenerated between the boronic acid group and acetic acid,and that this then reacted with the amine to give 2.

Scheme 14. Boron-mediated acylation reaction during the re-duction of 2-nitrobenzeneboronic acid in AcOH.

Subsequently, the direct formation of amides with the aidof a variety of boron reagents including BF3·OEt2,[25] bor-ane,[26] catechol borane[27] and tris-(dialkylamino)bor-anes[28] has been reported. However, these reagents requireanhydrous reaction conditions due to the sensitivity of thereagents towards moisture, and in some cases an excesseither of the amine or of the carboxylic acid is also needed.

Borate esters are potentially attractive amidation rea-gents because they are readily prepared and easy to handle.The use of B(OMe)3 as a direct amidation reagent in thepresence of sulfonic acid was reported for a single examplein the early 1970s.[29] More recently we have explored thisprocess in considerable detail and found that B(OMe)3 andB(OCH2CF3)3 are highly effective reagents for direct amid-ation reactions in MeCN, in the absence of any addedacid.[30,31] Background experiments were carried out todemonstrate that the thermal amidation rates were largelyinsignificant under the reaction conditions. Both B(OMe)3

and B(OCH2CF3)3[32] are available commercially, and the

latter compound can be easily prepared on a 50 g scale from

R. M. Lanigan, T. D. SheppardMICROREVIEW

Figure 2. Solid-phase workup of borate-mediated amidation reactions.

B2O3 and trifluoroethanol.[31] The B(OCH2CF3)3 reagent isconsiderably more effective than B(OMe)3 and can be usedfor amidation reactions with a wide range of amines andcarboxylic acids including many functionalised examples,which show low or poor reactivity with other boron-basedsystems (Scheme 15). The products can be purified by aque-ous workup or by a simple solid-phase workup with com-mercially available resins (Figure 2). The resins scavengeany unreacted amine and carboxylic acid, along withboron-containing byproducts, leaving the pure amide insolution.

Scheme 15. Examples of B(OCH2CF3)3-mediated amidation reac-tions. [a] 80 °C for 15 h. [b] 100 °C for 24 h in sealed tube.

A variety of Boc- and Cbz-protected amino acids can beconverted into the corresponding amides in good yields andwith very low levels of racemisation, despite the elevatedreaction temperatures employed (Scheme 15).[31] Dipeptidescan also be synthesised in good yield with excellent dia-stereoselectivity.

Each of the above boron-containing reagents can, inprinciple, generate an acyloxyboron species in situ; this isgenerally considered to be the active acylating reagent in thereaction medium (Scheme 16). By analogy with mechanisticstudies on boronic acid catalysed amidation reactions (videinfra), the reactive acylating agent could contain either atrigonal or a tetrahedral boron atom.

The use of boronic acids (Figure 3) as catalysts for theamidation of carboxylic acids with amines was first re-ported by Yamamoto in 1996 with catalyst 5,[33] and this


Scheme 16. Possible acyloxyboron intermediates in amidation reac-tions with boron-based reagents.

area of research has attracted considerable interest(Scheme 17). These reactions require heating at reflux inPhMe, xylene or mesitylene with molecular sieves as a dry-ing agent. Although excellent yields were generally ob-tained, there was a limited substrate scope, and long reac-tion times (up to 29 h) were required in many cases. Itshould be noted that the thermal background amidationrates under these conditions are likely to be considerablefor those cases involving relatively reactive combinations ofacid and amine.[15] Subsequent reports included the use ofrecyclable boronic acid 6 (Figure 3) as an efficient amid-ation catalyst that can be fully recovered into a fluorousphase after completion of the reaction.[34] Pyridinium bor-onic acid 7 is also notable as a boronic acid catalyst thatcan be used in relatively polar organic solvents.[35] Chlorin-ated catechol derivatives 8 and 9 were developed as catalystsfor the amidation of hindered carboxylic acids.[36] More re-cently, efforts have been directed towards reducing the reac-tion temperature needed for effective catalysis. Tertiary-amine-containing boronic acid 10 is able to mediate severalamidation reactions in fluorobenzene at reflux (85 °C).[37]

Remarkably, ortho-iodobenzeneboronic acid (11) is able tocatalyse amide formation at room temperature in the pres-ence of molecular sieves as a dehydrating agent.[38] The elec-tron-rich variant 12 was recently reported to show evengreater reactivity.[39]

Figure 3. Boronic acid catalysts for direct amidation.

The use of catalytic boric acid for amidation reactionshas also been described.[40,41] Although this approach is


Scheme 17. Boronic acid catalysed amidation reactions.

very attractive, due to the low cost of this compound, highreaction temperatures are required and the substrate scopeis limited in comparison with that of the boronic acid cata-lysed processes. In general, the reactivities of substrates inthese boron-mediated amidation processes follow a similartrend to their reactivities in thermal amidation reac-tions.[12,15]

The exact mechanism of boronic acid catalysed amid-ation reactions is still a matter of debate. However, there isa general consensus in the literature that the active acylatingagent is likely to be an acyloxyboron species generated byformation of a mixed anhydride between the carboxylic andthe boronic acids (Scheme 18). In two recent computationalstudies it was proposed that the rate-determining step (rds)of the reaction is the collapse of the tetrahedral intermedi-ate after attack of the amine.[42,43] In the earlier report, thereaction pathway involves the amine attacking the tetrava-lent boron species 13 to give 14, prior to dehydration andrate-determining expulsion of the boronic acid catalyst. Inthe more recent report, which sought to provide a morerealistic model of the solvent role in the process, dehy-dration to give acyl boronate 15 precedes attack of theamine to form tetrahedral zwitterion 16, which then un-dergoes rate-determining collapse to give the product andregenerate the catalyst.

For the most reactive boronic acid catalysts[38,39] it is pro-posed that the adjacent iodine atom accelerates the collapse


Scheme 18. Proposed mechanisms for boronic acid catalysed amid-ation.

of the tetrahedral intermediates, through a favourable hy-drogen-bonding interaction, an interaction with the vacantorbital on the boron atom or steric destabilisation of thetetrahedral intermediate.[42,43]

Given the fact that boron compounds are potentiallycheap, widely available and environmentally benign, furtherdevelopments in this field could well lead to a widelyadopted amidation method that offers considerable costand environmental benefits over existing approaches. As yetthe substrate scope of boronic acid catalysed amidationprocesses is still somewhat limited in comparison with bet-ter-established methods, however.

Transamidation Reactions

The direct interconversion of amides, known as trans-amidation (Scheme 19), is a fairly unusual reaction that israpidly gaining prominence, because it offers an alternativestrategy for preparing amides that avoids the use of carbox-ylic acids. Although amides themselves are generally poorelectrophiles, in the presence of a suitable catalytic or stoi-chiometric activating agent, reaction with an amine can oc-cur, leading to interconversion of amide derivatives. Manysimple amides are readily available, so this process can pro-vide a synthetically useful route to more complex deriva-tives.

Scheme 19. A general transamidation reaction.

The reactivities of primary, secondary and tertiaryamides towards transamidation differ greatly, depending onthe reaction conditions and activating agent employed, aswell as on the structure of the amide itself (Scheme 19). Inprinciple, the transamidation of primary amides (R2 = R3

= H) should be most synthetically useful because it can pro-vide a route to higher amides through expulsion of a mole-cule of ammonia. Thanks to its low boiling point, this canreadily be removed from the reaction, providing secondaryor tertiary amides efficiently. Secondary or tertiary amides

R. M. Lanigan, T. D. SheppardMICROREVIEWare generally less reactive towards transamidation, althoughthere are several activating agents capable of mediatingtransamidation of these compounds. Formamides (R1 = H)are inherently more reactive towards transamidation andwill readily undergo transamidation at high temperatures,in the absence of reagents or catalysts. Transamidation is inprinciple reversible, so care must be taken to select reactionconditions that enable the selective formation of the desiredamide product. As with ammonia, if the expelled amine isvolatile, it can be driven off by heating to provide high levelsof conversion into the desired product. Alternatively, con-trol can be achieved by exploitation of differences in thenucleophilicities of the two amines, or by addition of a largeexcess of the starting amine.

In a very early report, the boron trifluoride complex ofacetamide was reported to react with a range of primaryand secondary amines to yield secondary and tertiaryamides, respectively.[44] Interestingly, in this case the reac-tions with aniline as the nucleophile were particularly ef-ficient. Since this early publication, a variety of other Lewisacids have been reported to mediate transamidation reac-tions; they include salts of aluminium,[45,46] scandium,[45]

hafnium,[47] zirconium[45] and titanium.[45,48]

We have reported that B(OCH2CF3)3 is an effective rea-gent for the transamidation of primary amides to secondaryamides (Scheme 20).[30] Moderate to good yields of amidescould be obtained by transamidation of propionamide orglycolamide. The reagent does not generally mediate thetransamidation of secondary amides, so efficient conversionto the product can be achieved with only one equivalent ofamine.

Scheme 20. Transamidation of primary amides with B(OCH2-CF3)3.

Although B(OCH2CF3)3 does not generally mediate thetransamidation of secondary and tertiary amides, it is ableto activate N-methylformamide and DMF towards trans-amidation.[31] The latter process is potentially useful for theformylation of amines because DMF is cheap and availableas a reagent, and excess DMF can readily be separated fromthe product by evaporation (Scheme 21).

Very recently, the use of catalytic quantities of boric acidfor transamidation of primary, secondary and tertiaryamides has been reported.[49] The reactions are carried outneat at high temperatures (100–160 °C) in the presence ofone equivalent of water (Table 1). Good yields of second-ary/tertiary amide products were obtained through expul-sion of a volatile (NH3 or Me2NH) or less nucleophilic(PhNH2) amine. The formylation of a range of amines withformamide was found to proceed at lower temperatures(25–60 °C) with more nucleophilic amines, though highertemperatures were required for secondary amines and anil-ine derivatives (100–150 °C).


Scheme 21. B(OCH2CF3)3-mediated synthesis of formamides bytransamidation of DMF. [a] Reaction carried out at 100 °C.

Table 1. Boric acid catalysed transamidation reactions.

R1 R2 R3 Temp. [°C ] Yield

Me H H 120 81%Ph H H 150 40 %H H H 100 88%Me Me H 150 51%Me Ph H 150 63%H Me Me 140 83%Me Me Me 160 56%

A further interesting application of this process was theconversion of phthalimide into N-substituted derivativesthrough expulsion of ammonia (Scheme 22). This offers aconvenient approach to the synthesis of phthalimide-pro-tected amines. Its extension to amino acid derivatives wasnot reported, however, so it is unclear whether such a trans-formation could be carried out without epimerisation of ne-arby chiral centres. This could be worth investigating as aneconomical route to phthalimide-protected derivatives.

Scheme 22. Transamidation of phthalimide catalysed by B(OH)3.

The proposed mechanism involves coordination of theamide oxygen to the boron, followed by the formation ofa hydrogen bond stabilised tetrahedral intermediate uponattack of the amine (Scheme 23).


Scheme 23. Proposed mechanism for B(OH)3-catalysed transamid-ation.

Remarkably, readily available hydroxylamine hydro-chloride was shown to act as an efficient catalyst for thetransamidation of primary amides to secondary amides.[50]

The reactions were carried out in PhMe at 105 °C and goodto excellent yields of a variety of secondary amides wereobtained (Scheme 24). A tertiary amide could also be gen-erated in good yield, and the catalyst could also be em-ployed for the transamidation of a primary urea. Hydroxyl-amine hydrochloride was completely unreactive for trans-amidation of secondary amides.

Scheme 24. Examples of transamidation mediated by hydroxyl-amine hydrochloride. [a] Reaction could also be carried out at20 °C with 30 mol-% catalyst.

The proposed mechanism involves formation of a hydro-gen-bonded complex between hydroxylamine hydrochlorideand the amide, followed by attack of the amine on this acti-vated complex (Scheme 25). A second pathway discussedwas initial attack of hydroxylamine on the complex to gen-erate an intermediate hydroxamic acid. The pathway involv-ing direct attack of the amine was preferred by the authorson the basis of some preliminary kinetic data.

Scheme 25. Proposed mechanism of transamidation catalysed byhydroxylamine hydrochloride.

Copper acetate is able to catalyse the transamidation ofprimary amides at high temperature (140 °C) in alcohol sol-vent (Scheme 26).[51] Reactions with α-hydroxyamides were


particularly efficient; this might be due to coordination ofthe proximal hydroxy group to the metal during activation.The transamidation of enantiopure mandelic acid pro-ceeded without any observable epimerisation. Interestingly,with this catalyst the transamidation of primary ureas andN-aryl ureas was also possible (Scheme 27).

Scheme 26. Examples of Cu(OAc)2-catalysed transamidation.

Scheme 27. Transamidation of ureas catalysed by Cu(OAc)2.

The proposed mechanism involves coordination of cop-per to the amide to form an imidate complex, which thenundergoes nucleophilic attack (Scheme 28a). The relativeease with which ureas underwent transamidation might sug-gest that an alternative mechanism in which an isocyanate

R. M. Lanigan, T. D. SheppardMICROREVIEWis generated by expulsion of one of the nitrogen atoms priorto attack of the incoming amine (Scheme 28b) could be op-erative.

Scheme 28. Possible mechanisms for (a) Cu(OAc)2-catalysed trans-amidation of amides via imidate complexes, and (b) Cu(OAc)2-cat-alysed transamidation of ureas via isocyanate intermediates.

Cp2ZrCl2 has been reported to catalyse the transamid-ation of primary amides at relatively moderate temperatures(30–80 °C) in cyclohexane (Scheme 29).[52] A wide range ofboth amides and amines were examined, and in some acti-vated examples such as formamides, the reactions pro-ceeded to completion within 5 h at only 30 °C.

Scheme 29. Cp2ZrCl2-catalysed transamidation. [a] Carried out at30 °C.

The transamidation of ethyl carbamate to generate N-substituted derivatives was also catalysed by this reagent,although a higher temperature of 100 °C was required(Scheme 30).


Scheme 30. Transamidation of ethyl carbamate catalysed byCp2ZrCl2.

It was proposed on the basis of preliminary kinetic stud-ies that the mechanism involves the interaction of the cata-lyst and the amide with two molecules of amine(Scheme 31).

Scheme 31. Proposed mechanism of Cp2ZrCl2 transamidation.

Solid CeO2 has been reported to act as a recoverableheterogeneous catalyst for transamidation of primaryamides to secondary amides.[53] This reaction requires hightemperatures (160 °C) but works with a range of (largelyunfunctionalised) amides and amines (Scheme 32). The ab-sorption of the amides and amines onto the CeO2 surfacewas studied by infrared spectroscopy; on the basis of theseobservations it was proposed that the mechanism proceedsthrough activation of both reaction partners on the surfaceof the catalyst.

Scheme 32. Examples of CeO2-catalysed transamidation.

PhI(OAc)2 is able to catalyse the transamidation of pri-mary amides under neat conditions (Scheme 33) at hightemperatures (120–150 °C).[54] The transamidation ofphthalimide and of a secondary anilide was possible underthese conditions, and activated systems such as formamide


underwent transamidation at much lower temperature (60–100 °C). The thermal background yields were not deter-mined but could well be significant for more reactive sys-tems such as DMF.

Scheme 33. Examples of PhI(OAc)2-catalysed transamidation.

In a very recent report, l-proline has been reported tocatalyse transamidation of primary amides to give second-ary and tertiary amides (Scheme 34).[55] The reactions werecarried out neat at 100–150 °C and were applicable to arange of primary amides and amines, although less reactiveamines such as anilines gave considerably lower yields inmost cases. As with many of the other systems, formylationreactions were considerably easier to achieve, and trans-amidation of formamide took place even at room tempera-ture. The catalyst was also effective for transamidation ofphthalimide to give phthalyl-protected amines in a similarmanner to boric acid.

Scheme 34. Examples of l-proline-catalysed amidation. [a] Reac-tion carried out at room temp.

Interestingly, other amino acids were also reported to ca-talyse the transamidation of primary amides. Lysine andglycine gave very good levels of conversion, but the authorsdid not comment on whether competing acylation of theamino acid catalyst was observed in any of these cases. Al-though a mechanism based on formation of an iminium-like intermediate was proposed, it seems plausible that thistransamidation protocol might well proceed through hydro-


gen-bonding interactions in an analogous fashion to the hy-droxylamine-catalysed process described above (Figure 4).

Figure 4. Proposed active intermediates.

Conclusions

There have been many developments in the past fewyears in the search for new and more effective amidationreagents. Several studies on both thermal and catalyticamidations of carboxylic acids have shed considerable lighton the relative reactivities of different combinations ofcarboxylic acids and amines. For more reactive combina-tions, the thermal approach is extremely practical and ef-ficient and ought to be considered a method of choice.[15]

It is clear, however, that catalysts and/or reagents are essen-tial for mediating the amidation of less reactive substratesand of those containing more delicate functionality. As yet,none of the catalytic systems reported to date show thebroad substrate scope of reagent-based systems, though fur-ther improvements in catalyst activity can be expected inthe coming years. At present, most thermal and catalyticamidations proceed better in relatively nonpolar solvents,which are not always suitable for many substrates. This iscertainly an issue that will need to be addressed before cata-lytic amidation reactions become widely adopted.

Transamidation has emerged as a useful alternative strat-egy for amide synthesis with the discovery of a variety ofnew reagents and catalysts that enable this process to takeplace under milder conditions, and with a range of sub-strates. This transformation could be especially valuable formultistep synthetic sequences in which an unfunctionalised(and unreactive) amide could be carried through multiplesteps, before conversion into the desired functionalisedproduct by transamidation at a later stage. Transamidationmight also offer a useful approach to amide synthesis incases in which the corresponding carboxylic acid is unstable(e.g., 1,3-ketoacids).

In both cases, little attention has been paid to the devel-opment of more efficient purification methods for isolatingthe amide product. It is clear, however, that heterogeneouscatalysts and/or solid-phase workup procedures to enableamides to be isolated without the need for aqueous workupor chromatography offer considerable advantages. The ap-plication of scavenger resins, as used in the borate-mediatedamidations developed in our laboratory, could readily beextended to other amidation methods to enable convenientpurification of the products.

It is clear that a considerable amount of ongoing re-search effort is directed towards the improvement of amid-ation methods through the discovery of more efficient rea-gents, catalysts and protocols. The mechanistic understand-

R. M. Lanigan, T. D. SheppardMICROREVIEWing of many of the reactions described above is still some-what limited, but with further research it is likely that con-siderable improvements will result, either through the op-timisation of existing catalytic systems, or through the evol-ution of new classes of catalyst from existing stoichiometricreagents. The degree to which there is widespread adoptionof the above methods by synthetic chemists will serve todemonstrate whether or not they truly offer advantagesover existing more established approaches. As efficiency andenvironmental considerations become ever more important,it is surely desirable that chemists consider these recent de-velopments when planning the synthesis of molecules in thelaboratory.

Acknowledgments

The authors would like to thank the UCL Chemistry Departmentfor providing a UCL Impact Studentship (to R. M. L.).

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Received: April 19, 2013Published Online: August 6, 2013

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