SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2017, 49, 3183–3214 review 3183 en Syn thesis G. Evano et al. Review Keteniminium Ions: Unique and Versatile Reactive Intermediates for Chemical Synthesis Gwilherm Evano* Morgan Lecomte Pierre Thilmany Cédric Theunissen Laboratoire de Chimie Organique, Service de Chimie et Physico- Chimie Organiques, Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium [email protected] Dedicated to Prof. Herbert Mayr, a truly inspiring chemist, on the occasion of his 70th birthday Received: 15.05.2017 are especially useful to understand the underlying reaction Accepted after revision: 16.05.2017 mechanisms and selectivities of organic reactions and for Published online: 17.07.2017 1 DOI: 10.1055/s-0036-1588452; Art ID: ss-2017-z0326-r the de novo design of innovative chemical transformations. Apart from neutral and metal-containing intermediates, Abstract Keteniminium ions have been demonstrated to be remark- these reaction intermediates can be roughly classified into ably useful and versatile reactive intermediates in chemical synthesis. four main categories: cationic, anionic, or radical species and These unique heterocumulenes are pivotal electrophilic species in- volved in a number of efficient and selective transformations. More re- carbenes. Among these intermediates, cationic species are cently, even more reactive ‘activated’ keteniminium ions bearing an ad- of prime importance, the tremendous developments of ditional electron-withdrawing group on the nitrogen atom have been chemical synthesis due to the chemistry of carbocations, extensively investigated. The chemistry of these unique reactive inter- which culminated in Olah’s Nobel Prize in Chemistry in mediates, including representative methods for their in situ generation, will be overviewed in this review article. 1994, being the most representative and iconic examples. 1 Introduction Besides ‘pure’ carbocations, cationic intermediates also in- 2 The Chemistry of Keteniminium Ions clude oxonium and iminium ions as well as their heterocu- 3 The Chemistry of Activated Keteniminium Ions mulene congeners, ketenium and keteniminium ions. While 4 Keteniminium Ions: Pivotal Intermediates for the Synthesis of ketenium ions are still scarcely used in chemical synthesis, Natural and/or Biologically Relevant Molecules 5 Conclusions and Perspectives mostly due to difficulties associated with their generation, the chemistry of keteniminium ions 1 (Figure 1) has a rich Key words keteniminium ions, ketenimines, ynamines, ynamides, history; these unique electrophilic heterocumulenes are amides, reactive intermediates pivotal reactive intermediates in a number of synthetic transformations. The chemistry of these intermediates, 1 Introduction which has been extremely revisited lately with the discov- ery of new methods for their in situ generation and with the exploration of the reactivity of activated keteniminium Most reactions in organic chemistry do not proceed ions 2 bearing an additional electron-withdrawing group through a single step but rather involve several elementary on the nitrogen atom, will be overviewed in this review ar- steps, in the course of which reactive intermediates are ticle. All reactions reviewed will be classified primarily generated, to yield the desired products. These reactive in- based on the nature (activated or not) of the keteniminium termediates are short-lived, high-energy, and highly reac- ion and according to the reaction in which these reactive tive molecules. They are at the core of organic synthesis by intermediates are involved (addition of a nucleophile, cy- enabling the conversion of reactants into the reaction prod- cloaddition, etc.). Each section will start with an overview uct(s), the evolution of reactive intermediates into more of the methods available for the in situ generation of keten- stable molecules being one of the driving force of most iminium ions and the application of the chemistry of these transformations in chemical synthesis. Moreover, these re- reactive intermediates for the synthesis of natural and/or active intermediates, whose evidence and structures can be biologically relevant products will be overviewed at the end proved by a set of experimental and theoretical methods, of this review article. © Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3183–3214 3184 Syn thesis G. Evano et al. Review R1 R1 As an important note, this review does not intend to be 3 • N R X • N EWG X 4 3 exhaustive, it will rather focus on the synthetically most 2 R 2 R R R relevant transformations, and the reader should refer to ex- "classical" "activated" keteniminium ions 1 keteniminium ions 2 cellent review articles previously published on the chemis- 2 Figure 1 ‘Classical’ and ‘activated’ keteniminium ions try of keteniminium ions. Finally, it should to be men- tioned that keteniminium ions in which R3 and/or R4 are a hydrogen atom do not fall within the scope of this manu- script since they are more properly described as protonated Biographical Sketches Gwilherm Evano was born in Agami. After postdoctoral stud- 2012. His research program cur- Paris in 1977 and studied chem- ies with Prof. James S. Panek at rently focuses on natural/bioac- istry at the Ecole Normale Boston University, he joined the tive product synthesis, copper Supérieure. He received his CNRS as associate professor in catalysis, the chemistry of Ph.D. from the Université Pierre 2004. He then moved to the hetero-substituted alkynes, and et Marie Curie in 2002 under Université libre de Bruxelles, reactive intermediates. the supervision of Profs. where he is the head of the Lab- François Couty and Claude oratory of Organic Chemistry, in Morgan Lecomte was born in of Profs. Ivan Jabin and Gwil- on the study of the reactivity of Arlon, in the countryside of Bel- herm Evano on the use of hete- ynamides and activated keten- gium, in 1988 and studied ro-substituted alkynes for the iminium ions, and on the devel- chemistry at the Université libre selective functionalization of ca- opment of new reactions and de Bruxelles. In 2012, he joined lixarenes. He obtained a F.R.I.A. processes from these building the Laboratory of Organic Ph.D. fellowship in 2013 to work blocks. Chemistry as a master student in the group of Prof. Gwilherm working under the supervision Evano and his research focuses Pierre Thilmany was born in the Laboratory of Organic based on the reactivity of Uccle (Belgium) in 1995 and Chemistry under the supervi- ynamide-derived keteniminium studied chemistry at the Univer- sion of Prof. Gwilherm Evano ions. sité libre de Bruxelles. He start- where his work focuses on the ed his master thesis in 2017 in development of new reactions Cédric Theunissen was born complexes designed to interact ed transformations and on the in Brussels in 1989 and studied with DNA in an anticancer ap- study of the reactivity of chemistry at the Université libre proach. He then obtained a ynamides and keteniminium de Bruxelles. In 2012, he ob- F.R.I.A. fellowship and joined ions. After graduating in Octo- tained his master thesis, under the group of Prof. Gwilherm ber 2016, he moved to Colum- the supervision of Prof. Cécile Evano as a Ph.D. student where bia University as a BAEF post- Moucheron, which focused on his work focused on the devel- doctoral fellow in the group of the synthesis of new ruthenium opment of new copper-mediat- Prof. Tomislav Rovis. © Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3183–3214 3185 Syn thesis G. Evano et al. Review ketenimines than keteniminium ions. For clarity and sim- the corresponding keteniminium ion 1. As an important plicity, keteniminium and activated keteniminium ions are note, chloro-enamines 7 can also be prepared by deproton- given the number 1 and 2, respectively, regardless on the ation of the starting amide 5 with LDA followed by reaction nature of their substituents and counteranions unless these with diphenyl phosphoryl chloride, which avoids the isola- substituents play a crucial role in further transformations. tion of the rather sensitive chloro-enamines.7 O Cl Et3N or Cl COCl Cl pyridine R1 R3 2 R1 R3 R1 R3 2 The Chemistry of Keteniminium Ions N N N R2 R4 R2 R4 R2 R4 5 6 7 The chemistry of keteniminium ions was mainly initiat- Lewis acid (eg. AgBF4, ZnCl2) ed by the pioneering work of Viehe who reported efficient methods for their in situ generation and extensively studied R1 R1 3 3 their reactivity. The main methods that can be used for the • N R X • N R Cl R4 R4 formation of keteniminium ions, reactive intermediates R2 R2 that are rarely isolated and/or characterized due to their 1 1 low stability,3 will be briefly overviewed before focusing on Scheme 2 Viehe’s generation of keteniminium ions from enolizable reactions involving such species. amides with phosgene and a base 2.1 Main Methods for the Generation of Keten- While this equilibrium is typically in favor of the chloro- iminium Ions enamine 7, the use of Lewis acids such as silver tetrafluo- roborate, zinc chloride, or titanium chloride favors the for- Keteniminium ions 1 can be mostly generated by three mation of the keteniminium ion 1.8 Besides the use of phos- different routes relying on the direct alkylation of the corre- gene, which is not an ideal reagent, the main limitation of sponding ketenimines 3,3b,4 on the reaction of ynamines 4 this route actually lies in its scope; while ‘keto’ ketenimini- with an electrophile,2a,c,5 or on the