Angewandte Minireviews Chemie How to cite: Angew. Chem. Int. Ed. 2020, 59, 12293–12307 1,3-Dipolar Cycloadditions International Edition: doi.org/10.1002/anie.202003115 German Edition: doi.org/10.1002/ange.202003115 The Huisgen Reaction: Milestones of the 1,3-Dipolar Cycloaddition Martin Breugst* and Hans-Ulrich Reissig* Keywords: In memory of Professor Rolf Huisgen 1,3-dipolar cycloadditions · (June 13, 1920—March 26, 2020) click chemistry · computational chemistry · heterocycles · reaction mechanisms Angewandte Chemie Angew. Chem. Int. Ed. 2020, 59, 12293 – 12307 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 12293 Angewandte Minireviews Chemie The concept of 1,3-dipolar cycloadditions was presented by Rolf heteropropargyl anion systems react Huisgen 60 years ago. Previously unknown reactive intermediates, for with a variety of double- and triple- bond systems to provide five-mem- example azomethine ylides, were introduced to organic chemistry and bered cycloadducts with neutralization the (3+2) cycloadditions of 1,3-dipoles to multiple-bond systems of the formal charges. (Huisgen reaction) developed into one of the most versatile synthetic R. Huisgen and his co-workers methods in heterocyclic chemistry. In this Review, we present the recognized that 1,3-dipoles “abc” can history of this research area, highlight important older reports, and be subdivided in two comprehensive classes (Scheme 2). For the twelve allyl describe the evolution and further development of the concept. The type 1,3-dipoles, the central atom “b” most important mechanistic and synthetic results are discussed. can be nitrogen or oxygen. For the six Quantum-mechanical calculations support the concerted mechanism allenyl-propargyl type 1,3-dipoles, only always favored by R. Huisgen; however, in extreme cases intermediates nitrogen is possible; their second or- may be involved. The impact of 1,3-dipolar cycloadditions on the click thogonally located double bond causes the linear structure, but it is not chemistry concept of K. B. Sharpless will also be discussed. involved in the cycloaddition. This system was used not only to classify already known compounds but it also helped identify gaps and led to the “The elucidation of a reaction mechanism does not provide development of new routes to hitherto unknown 1,3-dipoles. conclusions for eternity, rather it is a process in steps intending In Scheme 2 only elements of the second period of the an increasingly deeper understanding of the reaction process- periodic table are considered. The involvement of sulfur, es.” – Rolf Huisgen (translation by the authors), 1960.[1a] phosphorus, or other hetero atoms broadens the scope of possible 1,3-dipoles.[3] At the start of the studies in the Munich laboratories 1. Introduction (1957–1959), only nine of the eighteen 1,3-dipoles were known as compound classes and for only five of these had In several lectures in 1960 Rolf Huisgen introduced the cycloadditions been reported (diazoalkanes, azides, nitrones, concept of 1,3-dipolar cycloadditions providing five-mem- nitrile oxides, ozones). The recognition of common reaction bered heterocycles; the first reports were published shortly features and their systematic expansion made the Huisgen afterwards.[1] In analogy to the Diels–Alder reaction, a 1,3- reaction[4] one of the most important principles for the dipole reacts as a 4p system with the general formula “abc” synthesis of heterocyclic compounds. The reaction was also with a dipolarophile “d=e” or “de” (delivering 2p electrons) employed for the preparation of natural products, and it was in a (3+2) cycloaddition to give the five-membered product involved in new, unexpected applications in very different (Scheme 1). The 1,3-dipoles “abc” cannot be described by fields of science through the development of click chemistry. neutral octet formulas, but they bear a positive charge at the Voluminous compilations, edited by A. Padwa, describe in center atom “b”; the two sextet formulas with neutral “b” ca. 2500 pages with more than 7500 citations the results up to explain the choice of the name 1,3-dipole for these com- the early 1980s and 2000.[5] The evolution of the research area pounds.[2] The four formulas depicted in Scheme 1 reflect the is presented in the insightful introductory chapter by R. ambivalent character of 1,3-dipoles with nucleophilic and Huisgen.[6] He later supplemented many aspects in his electrophilic properties; possible diradical mesomeric formu- autobiography.[7] In this Review, we discuss selected mile- las are not shown in this illustration. These heteroallyl or stones along the way to the Huisgen reaction and we also [*] Priv.-Doz. Dr. M. Breugst Department fr Chemie, Universitt zu Kçln Greinstrasse 4, 50939 Kçln (Germany) E-mail: [email protected] Prof. Dr. H.-U. Reissig Institut fr Chemie und Biochemie, Freie Universitt Berlin Takustrasse 3, 14195 Berlin (Germany) E-mail: [email protected] The ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.202003115. 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Scheme 1. (3+2) Cycloadditions of 1,3-dipoles “abc” to dipolarophiles Commons Attribution License, which permits use, distribution and “de” to give five-membered heterocycles (only lone pairs relevant for reproduction in any medium, provided the original work is properly the 4p system are drawn). cited. 12294 www.angewandte.org 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2020, 59, 12293 – 12307 Angewandte Minireviews Chemie comment on the most important synthetic and mechanistic advancements (also see the summarizing Tables 1 and 2). 2. The Beginnings Already in the early 19th century, J. L. Gay-Lussac and J. von Liebig studied “fulminic acid” H-CNO (formonitrile oxide), the parent compound of nitrile oxides; however, the propensity of nitriles oxides to undergo cycloadditions was explored only much later.[8] Historically more important are the classes of azides and diazoalkanes, for which the first (3+2) cycloadditions were reported. In 1864 P. Griess prepared phenyl azide[9] without investigating its ability to react in cycloadditions. Important early contributions came Scheme 2. Classification of 1,3-dipoles (the Lewis structures show only lone pairs relevant for the 4p system). from the Munich laboratories (at that time “Chemisches Laboratorium der Kçniglichen Akademie der Wissenschaften zu Mnchen”). In 1883 T. Curtius (Figure 1) prepared ethyl [10] Martin Breugst (right) studied chemistry at the Ludwig-Maximilians- diazoacetate, the very first diazoalkane and he encouraged Universitt in Munich (Germany). He completed his PhD there in 2010 his colleague and friend E. Buchner to examine its reactions under the guidance of Prof. Dr. Herbert Mayr in the area of physical- with unsaturated carboxylic acid esters. In 1888 E. Buchner organic chemistry. Subsequently, he worked as a Feodor-Lynen postdoc- reported the reaction of methyl diazoacetate with dimethyl toral fellow of the Alexander-von-Humboldt foundation with Prof. Dr. fumaric acid, the first 1,3-dipolar cycloaddition (Scheme Kendall N. Houk at the University of California, Los Angeles (UCLA) on 3a).[11] The equation as provided by E. Buchner is shown in different aspects of computational organic chemistry. In 2013, he started his independent career as a Liebig fellow of the Fonds der Chemischen Scheme 3b, with a cyclic formula for the diazo compound, Industrie at the Department of Chemistry of the University of Cologne. which should be assessed considering the lack of knowledge After his habilitation in 2017, he served as an interim professor at the about structural chemistry and bonding theory in those days. University Regensburg and RWTH Aachen University. His research is No better description of diazoalkanes was available. The currently focused on noncovalent interactions and experimental and bicyclic structure of the product contradicted the formation of computational elucidation of reaction mechanisms. a cyclopropane derivative after heating, but E. Buchner already recognized the formation of five-membered hetero- Hans-Ulrich Reissig studied chemistry at the Ludwig-Maximilians-Universi- tt in Munich. He worked on diazoalkane cycloadditions under the cycles (pyrazole derivatives) when he continued these stud- [12] guidance of Prof. Dr. Rolf Huisgen and was promoted to Dr. rer. nat. in ies. 1978. After a postdoctoral stint with Prof. Dr. Edward Piers at the University of British Columbia, Vancouver (Canada), he started independ- ent research for his habilitation at the Universitt Wrzburg (mentor: Prof. Dr. Siegfried Hnig). He has held professorships in Darmstadt (from 1986), in Dresden (from 1993) and in Berlin (1999–2015). His research activities concentrated on the development of stereoselective synthetic methods (donor–acceptor cyclopropanes, samarium diiodide induced cyclizations), heterocyclic chemistry (alkoxyallenes), and natural product synthesis (rubromycin, strychnine). He was elected as a corresponding member of the Bavarian Academy of Sciences and Humanities, received the Liebig Memorial Medal of the GDCh, and has been honorary member Figure 1. Theodor Curtius, Eduard Buchner, Arthur Michael, and Otto of the Polish Chemical Society since 2017. Dimroth. Angew. Chem. Int. Ed. 2020, 59, 12293 – 12307 2020 The Authors. Published by