Abstract
The concept of 1,3‐dipolar cycloadditions was presented by Rolf Huisgen 60 years ago. Previously unknown reactive intermediates, for example azomethine ylides, were introduced to organic chemistry and the (3+2) cycloadditions of 1,3‐dipoles to multiple‐bond systems (Huisgen reaction) developed into one of the most versatile synthetic methods in heterocyclic chemistry. In this Review, we present the history of this research area, highlight important older reports, and describe the evolution and further development of the concept. The most important mechanistic and synthetic results are discussed. Quantum‐mechanical calculations support the concerted mechanism always favored by R. Huisgen; however, in extreme cases intermediates may be involved. The impact of 1,3‐dipolar cycloadditions on the click chemistry concept of K. B. Sharpless will also be discussed.
Highlights
Neutral octet formulas, but they bear a positive charge at the Voluminous compilations, edited by A
The experiment provided 19.2 kg of the desired stereoisomer, which was converted to the drug candidate ABBV-3221 in a few steps. This example is impressive in all aspects and benefits from the vast experience with asymmetric 1,3-dipolar cycloadditions gained in the past decades.[73]
During the last 60 years the Huisgen reaction, known as the 1,3-dipolar cycloaddition, has become an indispensable tool of chemistry and many colleagues think that it should have been honored by the Nobel prize
Summary
(1957–1959), only nine of the eighteen 1,3-dipoles were known as compound classes and for only five of these had. 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. 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 milelas are not shown in this illustration. Comment on the most important synthetic and mechanistic advancements ( see the summarizing Tables 1 and 2)
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