1 Chem Soc Rev 1 5 REVIEW ARTICLE 5 Catalytic amide formation from non-activated Q1 Q2 10 carboxylic acids and amines 10 Cite this: DOI: 10.1039/c3cs60345h Helena Lundberg, Fredrik Tinnis, Nicklas Selander* and Hans Adolfsson* The amide functionality is found in a wide variety of biological and synthetic structures such as proteins, 15 polymers, pesticides and pharmaceuticals. Due to the fact that synthetic amides are still mainly 15 produced by the aid of coupling reagents with poor atom-economy, the direct catalytic formation of amides from carboxylic acids and amines has become a field of emerging importance. A general, efficient and selective catalytic method for this transformation would meet well with the increasing Received 30th September 2013 criteria for green chemistry. This review covers catalytic and synthetically relevant methods for direct Q4 20 DOI: 10.1039/c3cs60345h condensation of carboxylic acids and amines. A comprehensive overview of homogeneous and 20 heterogeneous catalytic methods is presented, covering biocatalysts, Lewis acid catalysts based on www.rsc.org/csr boron and metals as well an assortment of other types of catalysts. 25 1. Introduction theseproblems,theamidebondisusuallyformedvia an activated 25 carboxylic acid. The carboxylic activation is usually taking place with The amide functionality is one of the most fundamental the aid of a coupling reagent,7 oralternativelybyturningthe chemical building blocks found in nature. It constitutes the carboxylic acid into the corresponding acid chloride (the Schotten– backbone of the biologically crucial proteins, and it is present in Baumann reaction). The use of coupling reagents usually results in 30 a vast number of synthetic structures. For example, the amide mild reaction conditions and good yields, but requires stoichio- 30 bond is found in up to 25% of all pharmaceuticals on the metric amounts of the reagent. Hence, at least one equivalent of market,1 and it was present in 2/3 of drug candidates which waste is generated per product molecule formed, leading to an were surveyed by three leading pharmaceutical companies in overall low atom economy. The removal of this waste from the 2006.2 It has been estimated that 16% of all reactions involved in reaction mixture is also a tedious and expensive process in addition 35 the synthesis of modern pharmaceuticals was the acylation of an to the cost and toxicity of the coupling reagent itself. Due to these 35 amine, which makes it the most commonly performed reaction issues, as well as the importance of the amide bond in the in this field.3 Polymers based on the amide linkage are of pharmaceutical industry, a catalytic and waste-free production of importance in a wide range of applications, from everyday amides was voted a highlighted area of research by the American materials such as nylons, to more advanced uses in drug delivery Chemical Society’s (ACS) Green Chemistry Institute (GCI) Pharma- 40 systems, adhesives and wound healing.4 In addition, the amide ceutical Roundtable (PR) in 2005.8 40 bond is commonly found as a key structural element in agro- Many catalytic methods for the formation of amides have been chemicals and in products from the fine chemicals industry. developed, utilising starting materials such as alcohols, aldehydes, Formally, the amide bond is formed through the condensation of nitriles and aryl halides.9 However, relatively few protocols are known a carboxylic acid and an amine with the release of one equivalent of where carboxylic acids are used as starting materials, even though 45 water. This reaction has been considered challenging due to the this catalytic transformation could easily be envisioned to be highly 45 competing acid–base reaction, which occurs when the amine and valuable in e.g. peptide synthesis. In recent times, the direct catalytic the carboxylic acid are mixed. Although the amide bond can be amidation of non-activated carboxylic acids has attracted more formed from the corresponding ammonium carboxylate salt upon attention, with an increasing number of groups focusing on this heating, this reaction has generally been considered to be of limited area of research. Although several reviews cover parts of the material 50 preparative value.5 Furthermore, the high activation barrier for the presented herein,10 there is to the best of our knowledge none which 50 direct coupling of a carboxylic acid and an amine can only be compiles all types of catalytic methods for direct amidation. Thus, overcome using forcing reaction conditions.6 In order to circumvent the aim of this review is to provide an easily accessible and comprehensive overview of synthetically relevant literature on all Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 types of catalysts for direct amidation, ranging from biocatalysts, 55 91, Stockholm, Sweden. E-mail: [email protected], [email protected]; Lewis acid catalysts based on boron reagents and different metal 55 Fax: +46-8-154908 complexes, as well as other catalyst types. Both homogeneous and This journal is c The Royal Society of Chemistry 2014 Chem. Soc. Rev., 2014, 00,1À29 | 1 Review Article Chem Soc Rev 1 heterogeneous catalytic protocols are included, and the scope and 1 limitations of the different systems are discussed. To date, most catalytic protocols for direct amidation require elevated reaction temperatures and water scavengers and/or suffer from a limited 5 substratescope.Wehopethatthisreviewwillinspiretheresearch 5 community to continue to develop novel and general catalytic methods for a broad range of substrates under ambient reaction conditions for this highly important synthetic transformation. 13 Scheme 1 Condition dependence in thermal amidation (Williams, 2012). Q5 10 2. Comments on thermal amidation 10 As mentioned above, it is well-known that amides can be benzylamine were allowed to react in THF at 70 1Cata formed by the thermal treatment of a carboxylic acid and concentration of 0.4 M and a reaction time of 24 hours.15 The an amine without any catalyst present, generally at reaction literature on thermal amidation is not covered in this review 15 temperatures of >140 1C.11 Recently, it was shown that a unless the non-catalysed reaction is specifically mentioned by 15 significant amount of the amide product can be formed even the authors. at lower temperatures, usually with azeotropic removal of It should be pointed out that the thermal reaction, which water.12–14 The yield of the thermal amidation reaction is highly indeed gives the targeted amide product, is sometimes not substrate dependent, as well as dependent on temperature, investigated or commented upon throughout the literature. In 20 substrate concentration, solvent and other reaction parameters. general, the thermal amide bond formation is not a synthetic 20 As an example, the thermal yield of N-(4-methylbenzyl)-3- problem unless the process involves a kinetic resolution of the phenylpropanamide at 110 1C under neat conditions was starting material. Although the background reaction can be reported to be 58%, whereas the same product was formed substantial under certain reaction conditions, and sometimes quantitatively in toluene at 2 M concentration with the same raises the question regarding the importance of the catalyst, an 25 reaction time and temperature (Scheme 1).13 For comparison, added catalyst is often shown to enhance the reaction rate 25 the structurally similar N-benzylphenylacetamide was formed further. At lower reaction temperatures, the thermal amidation in only 13% yield or less, when phenylacetic acid and is most often negligible and the product formation can solely 30 Helena Lundberg received her bachelor’s degree from Lund 30 University, Sweden, and obtained a master’s degree in 2009 from the Department of Organic Chemistry, Stockholm University, Sweden. She is currently pursuing her PhD studies under the supervision of Professor Hans Adolfsson, mainly focusing on 35 asymmetric transfer hydrogenation and catalytic amide formation. 35 Fredrik Tinnis earned his master’s degree in 2009 from the Department of Organic Chemistry, Stockholm University, Sweden. He is currently conducting his PhD studies in the research group of Professor Hans Adolfsson where he initially focused on the 40 development of catalytic reduction methods. Fredrik has made 40 contributions within the fields of asymmetric transfer hydro- From left to right: Helena Lundberg, Fredrik Tinnis, genation and iron-catalysed hydrosilylation. More recently he moved Dr Nicklas Selander, and Professor Hans Adolfsson in to the area of direct catalytic amidation and is also currently involved in heterogeneous palladium catalysed aminocarbonylation. 45 Dr Nicklas Selander obtained his PhD in 2010 under the guidance of Professor Ka´lma´n Szabo´ from Stockholm University, Sweden. The 45 thesis work was focused on novel methods for the generation of allylic boron species and the development of multi-component reactions. Thereafter, he carried out postdoctoral research with Professor Valery V. Fokin at The Scripps Research Institute, La Jolla, USA, studying Rh-catalysed transformations of 1-sulfonyl-1,2,3-triazoles. In 2013 he returned to Stockholm University to establish his own research group with interests in catalysis, heterocycles and new synthetic methodology. 50 Hans Adolfsson, professor of organometallic chemistry since 2007, is currently the Pro Vice-Chancellor of Stockholm University. He 50 conducted his undergraduate studies at Stockholm University and graduated in 1989. He moved to the Royal Institute of Technology (KTH) in Stockholm for PhD studies under the guidance of Professor Christina Moberg. After his graduation in November 1995 he continued as a post-doctoral fellow at KTH until August 1996 when he moved to The Scripps Research Institute for a two-year post- doctoral stay with Prof. K. Barry Sharpless. In November 1998 he moved back to Sweden and started as an assistant professor at 55 Stockholm University. In 2002 he was promoted to associate professor, and in 2007 to full professor. His research interests are in the field 55 of practical and selective catalysis comprising oxidations, reductions and addition reactions.