Amide bond formation is a fundamentally important reaction in organic synthesis, and is typically mediated by one of a myriad of so-called coupling reagents. This critical review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of “acronym” based reagents. It aims to demystify the process allowing the chemist to make a sensible and educated choice when carrying out an amide coupling reaction (179 references).

http://www.chtf.stuba.sk/~szolcsanyi/education/files/Organicka%20chemia%20II/Prednaska%208_Aminokyseliny%20a%20peptidy/Doplnkove%20studijne%20materialy/Amide%20bond%20formation/Amide%20bond%20formation%20-%20beyond%20the%20myth%20of%20coupling%20reagents.pdf

Amide bond formation: beyond the myth of coupling reagents

http://www.chtf.stuba.sk/~szolcsanyi/education/files/Organicka%20chemia%20II/Prednaska%208_Aminokyseliny%20a%20peptidy/Doplnkove%20studijne%20materialy/Amide%20bond%20formation/Amide%20bond%20formation.pdf

Amide bond formation and peptide coupling

Peptide Coupling Reagents, More than a Letter Soup Ayman El-Faham* and Fernando Albericio* Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain Alexandria University, Faculty of Science, Department of Chemistry, P.O. Box 426, Ibrahimia, 21321 Alexandria, Egypt CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain. Department of Organic Chemistry, University of Barcelona, Martí i Franqu es 1-11, 08028-Barcelona, Spain

Peptide coupling reagents, more than a letter soup

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals

4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride: an efficient condensing agent leading to the formation of amides and esters

Formation of carboxamides by direct condensation of carboxylic acids and amines in alcohols using a new alcohol- and water-soluble condensing agent: DMT-MM

Synthesis and characterization of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

Esterification of Carboxylic Acids with Alcohols by 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium Chloride (DMTMM)

The reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) with various nitrogen-containing compounds, particularly tertiary amines (tert-amines), has been studied for the preparation of 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkylammonium salts [DMT-Am(s)]. DMT-Ams derived from aliphatic tert-amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT-Ams and tert-amines by NMR and X-ray diffraction methods, we concluded that a β-alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert-amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β-alkyl groups in the stable conformations, does not react at all. The theory of "gauche β-alkyl group effect" proposed here provides useful guidelines for the preparation of DMT-Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert-amines in a CDMT/tert-amine system that involves in situ generation of DMT-Am, showed that the gauche effect of the β-alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert-amines possessing an unavoidable gauche β-alkyl group. Thus, the tert-amine/CDMT systems are useful for judging whether tert-amines can readily react with CDMT without isolation of DMT-Ams.

Chiho Kawachi

Papers

4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride: an efficient condensing agent leading to the formation of amides and esters

Formation of carboxamides by direct condensation of carboxylic acids and amines in alcohols using a new alcohol- and water-soluble condensing agent: DMT-MM

Synthesis and characterization of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

Esterification of Carboxylic Acids with Alcohols by 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium Chloride (DMTMM)

Study on 1,3,5‐Triazine Chemistry in Dehydrocondensation: Gauche Effect on the Generation of Active Triazinylammonium Species