Keteniminium Ions: Unique and Versatile Reactive Intermediates for Chemical Synthesis

SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2017, 49, 3183–3214 review 3183 en

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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 involved 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 discovery 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.

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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 mentioned 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.

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 tetrafluoroborate, 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 electrophilic activation um ions (R1 and R2 ≠ H) are smoothly generated from the of an amide 5 followed by elimination (Scheme 1). corresponding α-chloro-enamines, ‘aldo’ keteniminium ions (R1 and/or R2 = H) rapidly react with these precursors.9 1 3 R R R4X Based on this limitation and capitalizing on the fact that • N 2 this side reaction should not occur with non-nucleophilic R 3 precursors of the keteniminium salt, Ghosez reported in 3 1 1981 what would become the synthetically most useful R R2X R R3 R1 N • N X R4 method for the generation of keteniminium ions from the R4 R2 4 1 corresponding amides (Scheme 3).9 Electrophilic activation

O of the starting amide 5 with triflic anhydride provides a EX R1 R3 transient O-triflyliminium triflate 6, which, upon reaction N R2 R4 with collidine, gives the corresponding α-trifloyl-enamine 5 7 that then undergoes elimination to the desired keten- Scheme 1 Main routes for the generation of keteniminium ions iminium triflate 1, which could also result from direct elimination from 6. The first two routes rely on the use of starting materials O OTf TfO OTf 3 and 4 that are less attractive than amides 5 and are clearly Tf O collidine R1 R3 2 R1 R3 R1 R3 less general than the third route which is definitely the N N N R2 R4 R2 R4 R2 R4 most synthetically useful entry to keteniminium ions. The 5 6′ 7′ nature of the starting amide and the reagent(s) and/or addi- collidine tives used for this transformation have, however, been R1 3 shown to have a dramatic impact on the outcome of the re- • N R TfO R4 action. R2 1 Several conditions and reagents have been indeed reported for the generation of keteniminium ions from am- Scheme 3 Ghosez’s generation of keteniminium ions from enolizable ides, one of the first ones being Viehe’s procedure relying on amides with triflic anhydride and collidine the use of phosgene in the presence of triethylamine or pyridine (Scheme 2).6 Electrophilic activation of the starting While Ghosez’s procedure is the one that is typically amide 5 with phosgene produces an intermediate chloroi- used nowadays for the generation of keteniminium ions minium ion 6 which, upon addition of the base, yields from the corresponding enolizable amides, the nature of chloro-enamine 7, a compound that is in equilibrium with the pyridine used as the base was often shown to have a

Syn thesis G. Evano et al. Review dramatic impact on the outcome of the reaction. Based on 2.2 Reactions of Keteniminium Ions with Nucleo- extensive NMR studies, Charette has indeed proposed the philes mechanistic pathway depicted in Scheme 4 for the electrophilic activation of enolizable amides using pyridine as the The most trivial chemical transformation involving base.10 The triflating agent would be N-triflylpyridinium keteniminium ions is their reaction with a nucleophile. De- triflate, which would be formed by initial reaction of triflic pending on the nature of the nucleophile, the reaction can anhydride with pyridine. Reaction of the starting amide 5 either stop at the addition step, yielding the corresponding with this reagent would form an intermediate O-triflyli- substituted enamine, or initiate further transformations minium triflate 6 that could directly form the ketenimini- based on the reactivity of this newly installed enamine um triflate 1. Pyridine is sufficiently nucleophilic to add to moiety. These processes will be overviewed in the following this reactive intermediate 1, which would result in the for- sections, starting with simple reactions of keteniminium mation of N-(aminoalkenyl)pyridinium triflate 9, the main ions with nucleophiles without further transformations. species that could be detected in the reaction mixture. Al- ternatively, the addition might proceed before the elimina- 2.2.1 Trapping Keteniminium Ions with Nucleophiles tion through bis(cationic) intermediate 8. A close examination of all reaction intermediates, which are all potentially A broad range of nucleophiles have been used to trap in equilibrium, reveals the importance of the nature of the keteniminium ions: most representative examples are pyridine base used for the generation of keteniminium shown in Scheme 5. As demonstrated in early studies by the triflates from the corresponding enolizable amides via Viehe6 and Ghosez13 groups, these include water, which Ghosez’s procedure. Indeed, the use of hindered and/or yields the corresponding amide 5, alkoxides, sulfides, lithi- poorly nucleophilic pyridine derivatives such as collidine or um amides, and cyanides, the addition of all these nucleo- 2-halopyridines avoids trapping the keteniminium ion and philes to the keteniminium ion providing the corresponding increases its proportion in the reaction mixture, a phenom- substituted enamides 10–13 in excellent yields. Ethers can enon that has been elegantly exploited in several reactions also be used to trap keteniminium ions, a strategy that has based on the generation of keteniminium triflates.11,12 been used for the depolymerization of cellulose.14 As a direct consequence, which is of importance in the Interestingly, keteniminium ions can also be used as context of this review article, keteniminium ions, although electrophiles in Friedel–Crafts reactions with electron-rich potentially generated upon activation of amides, are not arenes without the need for an acid catalyst.13 Indeed, upon systematically drawn as reactive intermediates in reactions reaction with furan or pyrrole, a clean electrophilic aromat- involving the electrophilic activation of enolizable amides. ic substitution occurs to afford the corresponding C2-ami- noalkenylated arenes 14, a reaction that can also be performed with other electron-rich arenes such as N,N-dial- O OTf 1 3 1 3 N TfO kylanilines. R R R R TfO N N 1 3 Tf N R R Finally, organolithium and Grignard reagents were also R2 R4 R2 R4 N N TfO TfO R2 R4 found to be suitable nucleophiles, providing an efficient en- 5 6 8 try to polysubstituted enamines 15 that can be obtained in fair to good yields.6 – TfOH – TfOH As an important note, the stereoselectivity of these re- Tf2O + actions has not been addressed in most cases since they N were mostly performed on symmetrical keteniminium ions R1 1 2 3 N TfO (R = R ). • N R TfO 4 1 3 2 R N R R Since the 1990s, the groups of Charette and Huang have R N R2 R4 extensively revisited and modernized this chemistry based 1 9 on Ghosez’s method for the electrophilic activation of am- Scheme 4 Possible intermediates generated upon reaction of enoliz- ides. While the reactions they developed, which usually able amides with triflic anhydride and pyridine work equally well with enolizable and non-enolizable amides, are typically described to proceed through O-triflyli- After reviewing the most common methods for the gen- minium triflates, the intermediacy of keteniminium ions eration of keteniminium ions, we will now focus on their cannot be ruled out starting from enolizable amides and chemistry and on reactions designed on the basis of their these reactions will therefore be briefly overviewed.15 unique reactivity. Charette and Huang indeed reported a set of efficient methods enabling the direct transformation of amides to other synthetically useful building blocks such as thioamides or

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OEt lysis the corresponding ketones 19, is probably the most re- EtONa R1 R3 markable example and represent an especially useful alter- THF, r.t. N O R2 R4 native to the use of Weinreb amides typically required for R1 R3 10 N such a transformation. When switching to polyfunctional R2 R4 SEt nucleophiles such as 1,2-aminothiols or triols, further con- 5 EtSNa R1 R3 N densation of the remaining nucleophilic moieties enables THF, r.t. R2 R4 the direct synthesis of thiazolines20 and bridged ortho- H2O 11 r.t. esters,21 respectively, from amides. Alternatively, the nucleo- NCy Cl 1 2 phile can be embedded in the starting amide, as demon- R Cy2NLi R1 R3 R3 R1 R3 • N Cl N strated by the Maulide group who reported in 2013 an effi- N R4 0 °C, Et O R2 2 R2 R4 R2 R4 cient room-temperature lactonization of hydroxy- and tert- 7 1 12 butyldimethylsiloxy-substituted amides.22 It is noteworthy R5M KCN, CH3CN CN Et2O, r.t. reflux that this reaction might not, however, proceed through a R1 R3 (M = Li, MgBr) N or Zn(CN)2 keteniminium intermediate due to the absence of a base for 2 4 5 CHCl3, reflux R R R 13 the electrophilic activation of the starting amide. R1 R3 N Other nucleophiles can be used to trap a transient X R2 R4 X keteniminium ion and initiate further chemical transforma- 15 1 3 CH CN or Et O R R 3 2 N tions. This strategy has proven over the years to be especial- r.t. to reflux (X = O, NH) R2 R4 ly versatile and selected representative examples will be 14 overviewed in Section 2.2.2. Scheme 5 Trapping keteniminium chlorides with nucleophiles 2.2.2 Trapping Keteniminium Ions with Nucleophiles and Subsequent Rearrangement 18O-labelled amides 16,16 esters 17,17 amidines 18,18 or ketones 1919 (Scheme 6). With nucleophiles such as hydrogen Some enamides formed after trapping a keteniminium 18 sulfide, H2 O, ethanol, or primary amines, activation of the ion with a nucleophile can indeed further react without the starting amide 5 followed by trapping with the nucleophile need for additional reactants, which provides excellent op- and prototropy indeed provides an especially efficient en- portunities for the development of efficient and innovative try to these building blocks with high levels of chemoselec- processes. One of the simplest examples was reported in tivity and under especially mild reaction conditions. The addition of Grignard reagents, which provides after hydro- Cl N 1 3 R NaN3 R1 R3 R3 R1 R3 N • N Cl N R4 O R2 R2 R4 R2 R4 1 3 R R 7 20 N 1 R2 R4 5

Tf2O N H N N N N N R1 N N R3 or R1 or 5 2 N 3 R R 2 N R 1 R3 H S or R4 R R N 2 S/18O 4 18 R 4 H2 O R R5 R1 R3 21 22 23 (from R2 = H) r.t. N OTf R2 R4 16 Tf O R1 R3 2 N TfO N TfO N F 1 3 O 4 + 2 4 R R O R N2 R R N EtOH 1 2 4 N TfO TfO R 1 2 R R N3 2 4 OEt R R • N TfO 2 R R r.t. 3 R 6 8 N 1 R R2 CH2Cl2 R N R3 0 °C to r.t. 17 R1 R3 5 1 24 NR6 5 6 R R NH2 R1 R3 N R1 r.t. R3 R2 R4 • N TfO N TfO 18 R4 R4 R2 R1 R3 O O N 6 NaHCO N TfO R MgX R1 R2 3 2 4 R1 2 R R 6 N R 1 9 R R1 N –78 °C 4 3 2 NHR R then HCl/H2O R R3 19 26 25 Scheme 6 Trapping keteniminium triflates with nucleophiles Scheme 7 Trapping keteniminium ions with azides

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1970 by Ghosez;23 trapping keteniminium ions 1 generated Another interesting strategy relies on trapping a keten- from the corresponding α-chloro-enamines 7 with sodium iminium ion with a nucleophile possessing an alkene or an azide yields intermediate vinyl azides 20, which then rear- arene at the β-position, which can be used to trigger a sig- range to the corresponding 3-amino-2H-azirines 21,24 5- matropic [3,3]-rearrangement, the most famous example amino-4H-1,2,3-triazoles 22,25 or 4-amino-2H-1,2,3-tri- being the Ficini–Claisen rearrangement initiated by con- azoles 2326 depending on the substitution pattern of the densation of an ynamine 4 with an allyl alcohol 27 in the starting α-chloro-enamines (Scheme 7). presence of a Lewis acid which provides an efficient entry This reaction was revisited and extended to the direct to α-allylamides 29 (Scheme 8).28 This rearrangement pro- amination of amides by the Maulide group some 46 years ceeds equally well with propargyl alcohols, which provide later.27 In this case, the keteniminium ion was generated in β-allenylamides,29 and was recently nicely extended by the situ by electrophilic activation of the corresponding amide Maulide group to the use of aryl sulfoxides 30.30 In this case, 5 by triflic anhydride in the presence of 2-fluoropyridine keteniminium ion 1 is generated by treatment of the corre- and then trapped by an alkyl azide. Subsequent rearrange- sponding amide 5 with triflic anhydride and 2-iodopyri- ment of 24 with concomitant loss of dinitrogen would then dine; trapping this reactive intermediate with an aryl sulf- afford an intermediate cyclic amidinium ion 25 whose fac- oxide 30 yields intermediate 31 which spontaneously rear- ile hydrolytic ring opening would afford the aminated am- ranges upon warming the reaction mixture to room ide 26. Remarkably, good levels of stereoinduction can be temperature to afford α-arylated amide 32. obtained starting from chiral amides, further increasing the By using properly designed precursors of keteniminium synthetic potential of this procedure which compares well ions embedded with an internal nucleophile, the intramo- with others available for the direct amination of amides. lecular trapping can be used to trigger remarkably efficient processes enabling the conversion of readily available starting materials to useful cyclic building blocks. This strategy R5 will be described in Section 2.2.3. R6 OH R7 7 4 R R 6 4 2.2.3 Intramolecular Trapping of Keteniminium Ions 27 R R R2 BF3·OEt2 cat. R2 1 • N X 5 R N R3 R O Et O, r.t. R1 One of the first examples of such a strategy was de- R3 2 4 1 R1 N R2 scribed by Ghosez in 1981 who reported an efficient entry R3 to 3-aminobenzothiophenes 35 by an intramolecular Friedel– 28 Crafts-type reaction from (arylthio)keteniminium ions 34 generated from the corresponding β-(arylthio)-α-chloro- enamines 33 (Scheme 9).31 This reaction was extended in

O 2015 to the use of α-(arylthio)amides 36 by De Mesmaeker R1 R2 who in addition showed, by combined experimental/theo- N 6 R5 R R3 retical studies, that the cyclization proceeded through a 6π- R7 electrocyclization,32 and that replacing the aryl thioether by R4 29 a styrene also enabled intramolecular trapping of a tran-

R5 sient keteniminium ion yielding aminonaphthalene deriva- 4 33 Tf2O R 5 tives. N I S R R4 O O Tf O 2 30 S TfO 2 R1 R2 • N R 1 1 3 TfO O R 1 N F R N 1 R R CH2Cl2 R R3 0 °C 5 1 R1 N R2 ZnCl2 3 Cl X O R S CDCl S R3 3 3 S R3 31 • N R r.t. N R4 N R2 R2 R4 R2 R4 33 34 36

O R1 R2 N R1 R4S R3 R5 R3 S N 32 R4 R2 35 Scheme 8 Trapping keteniminium ions with allyl alcohols or aryl sulfoxides Scheme 9 Intramolecular trapping of keteniminium ions with arenes

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4 4 An interesting application of the intramolecular trap- R O Tf2O R collidine N ping of a keteniminium ion was reported in 2010 by the R5 O R5 O • N TfO CH2Cl2 Maulide group. Attempting to initiate an intramolecular R3 R2 R1 μW (120 °C) R3 R2 R1 [2+2] cycloaddition between a keteniminium and an allylic 37 38 ether (see Section 2.3 for this transformation), they noted the formation of a lactone, resulting from the initial trap- R2 R2 O O R3 TfO R4 ping of the keteniminium ion by the ether, instead of the R2 H O 34 O 2 N O expected cyclobutanone cycloadduct. This reaction was 1 1 TfO 5 R R5 R R5 R extensively studied and its generality unambiguously R4 R4 N demonstrated. Mechanistic studies revealed that activation R1 R3 R3 of the amide 37 generates the corresponding keteniminium 41 40 39 triflate 38 which is then trapped intramolecularly by the Tf2O ether moiety to generate an allylvinyloxonium ion 39 N F O (Scheme 10). A Claisen-type sigmatropic [3,3] rearrange- 1 R1 Ph R • Ph N N ment transferring the allyl group from oxygen to carbon, TfO O O followed by hydrolysis furnishes the final lactone 41. Inter- CH2Cl2 0 °C 42 43 2 estingly, good levels of stereoinduction were observed R2 R starting from E- or Z-alkenes or from chiral amides. Replac- O O ing the allyl ether in the starting amide 37 by a propargylic TfO R1 R1 R2 N R2 N H OH ether yields the corresponding α-allenyllactones and the in- or O O termediate iminium ether 40 can be opened by a nucleo- R2 R2 Ph Ph 1 1 TfO phile before hydrolysis.35 Finally, placing an aromatic ring R R 47 46 45 44 within the tether and/or switching to allylic amines pro- (after reduction (after vides interesting extensions of the electrophilic rearrange- with K- hydrolysis with selectride and H2SO4) ment of amides to the preparation of α-prenyl-hydrocou- hydrolysis with wet silica) marins, indoles, isoquinolines, and dihydroisoquinoli- nones.36 Scheme 10 Intramolecular trapping of keteniminium ions with ethers By capitalizing on this strategy and moving the allyl ether to the other side of the amide as well as adding a chi- O ral tether between these two moieties, the Maulide group Tf2O N I 1 O N R was next able to develop a remarkable traceless electrophil- N TfO 1 2 R R 2 O ic α-allylation providing enantioenriched α-allylic carbox- N • R 50 N TfO R1 R2 ylic acids 46 or aldehydes 47. Electrophilic activation of O- N CH2Cl2 R3 0 °C allylpseudoephedrine-derived amides 42 indeed triggers a R3 highly diastereoselective sigmatropic rearrangement pro- R3 ducing iminium ethers 45 which are finally transformed to 48 49 51 the desired carboxylic acids 46 or aldehydes 47 by acidic hydrolysis and reduction/hydrolysis, respectively.37,38 While the electrophilic activation of amides such as 36, O 37, or 42 to the corresponding keteniminium ions facilitates R1 R2 the addition of an internal nucleophile to the carbonyl N group of the starting amides, an interesting switch to the α- R3 position was recently designed by trapping the intermediate keteniminium ion first with an external nucleophile 52 embedded with a masked leaving group.39 A successful ex- Scheme 11 Trapping keteniminium ions with pyridine N-oxides and ample of this strategy was reported in 2017 by the Maulide subsequent intramolecular arylation group who developed an efficient procedure for the intramolecular α-arylation of amides 48 based on an umpolung When reacted with keteniminium ions, some nucleo- of their α-position (Scheme 11). This reversal of polarity philes generate an electrophilic center that can be trapped was made possible by trapping an amide-derived keten- intramolecularly with the newly installed enamine moiety, iminium triflate 49 by 2,6-lutidine N-oxide (50) yielding an which enables a formal [2+2] cycloaddition with the keteni- electrophilic enolium triflate 51 which, upon intramolecu- minium ion: such processes will now be briefly overviewed lar addition of the arene and elimination of 2,6-lutidine, in Section 2.2.4. provides the cyclic amide 52.

Syn thesis G. Evano et al. Review

6 2.2.4 Trapping Keteniminium Ions with Nucleophiles 7R R R6 and Subsequent Ring Closure: Formal [2+2] Cycloaddi- N Cl 5 7 N R tion • R R1 R5 Cl 1 R R3 R2 N R2 N R3 Other nucleophiles which, after addition to ketenimini- R4 R4 um ions, initiate a subsequent transformation were indeed 54 55 reported in 1969 by Viehe who described an interesting formal [2+2] cycloaddition of keteniminium chlorides 1 with R6 R5 N 7 ynamines 53 that readily proceeds at room temperature 53 R and furnishes cyclobutenecyanines 55 in high yields Et2O, r.t. Cl (Scheme 12).6 This sequence actually involves two keten- R1 R1 R3 3 • N R Cl N 4 iminium ions, the second one, 54, being generated upon ad- 2 R 2 4 R R R 7 dition of the ynamine to the starting keteniminium chlo- R R5 7 1 R6 ride 1 and then trapped intramolecularly by the enamine N R6 R1 moiety in 54. N R2 O R7 R5 59 In 1974, Ghosez reported that imines 56 are interesting 56 nucleophiles that also react with keteniminium ions CH2Cl2, r.t. NaOH through a formal [2+2] cycloaddition, consisting of nucleo- 7 R 7 R 5 6 R philic addition of the imine to the keteniminium ion fol- R Cl R6 1 5 N R N R Cl lowed by intramolecular addition of the resulting enamine 1 R R3 2 N to the iminium ion 57 to give 58. Further hydrolysis of 58 R2 N R3 R R4 provides the corresponding β-lactams 59 in excellent R4 57 58 yields.40 Computational analysis of this reaction indicates a stepwise mechanism in which the C–N bond is formed pri- Scheme 12 Trapping keteniminium ions with ynamines and imines or to the C–C bond.41 The stereoselectivity of the reaction is determined by the second step: this step is subjected to torquoelectronic effects (a conrotatory electrocyclic ring 2.3 [2+2] Cycloaddition of Keteniminium Ions with closure for the transformation of 57 to 58 in combination Alkenes, Allenes, and Alkynes with the preferential transition structure for an E-config- ured imine determines the stereochemical outcome of the 2.3.1 Intermolecular [2+2] Cycloaddition of Keten- formal cycloaddition) and was found to strongly depend on iminium Ions with Alkenes the nature of the counterion of the keteniminium ion, which is in turn related to the method used for its genera- The use of keteniminium ions as an attractive alterna- tion. Indeed, non-nucleophilic counterions such as a triflate tive to ketenes for cycloaddition with alkenes was pio- favor a conrotatory electrocyclization, while nucleophilic neered by Ghosez. Compared to ketenes, keteniminium ions anions such as a chloride favor a SN2 reaction, which can ac- do not dimerize or polymerize. As discussed in Section 2.1, count for the stereodivergence of reactions involving imines they are easily prepared from readily available starting ma- and keteniminium chlorides or triflates. An asymmetric terials, they can be stored in solution, and they easily pro- variant of this reaction was reported by Ghosez in 1987 vide access to homochiral cycloadducts by introducing chi- starting from chiral pyrrolidine-derived keteniminium ions, ral substituents on the nitrogen atom. readily generated by electrophilic activation of the corre- The first examples of the cycloaddition of keteniminium sponding amides; while the corresponding lactams could ions with alkenes were reported in 1972 by Ghosez; upon be obtained with excellent optical purities, the yields were, reaction with alkenes 60 in the presence of silver tetrafluo- however, rather modest in most cases.42 roborate, α-chloro-enamines 7 reacted with exceptional While they could be classified as reactions of keten- ease to provide the corresponding cyclobutylideneiminium iminium ions with nucleophiles and discussed in this sec- salts 61, in situ hydrolysis of which gave the corresponding tion, their [2+2] cycloadditions with alkenes and alkynes, cyclobutanones 62 in excellent yields (Scheme 13).8a,23b which is the most iconic transformation involving these re- Note, buffered solutions and short reaction times should be active intermediates, clearly deserve a separate section; used for the hydrolysis to prevent epimerization if neces- they will be overviewed in Section 2.3. As this chemistry sary. Alternatively, the keteniminium ion can be generated has been thoroughly covered in previous reviews,2b,f,h only by direct electrophilic activation of the corresponding am- the main features and the most representative examples ide 5,9 the method that is now commonly used in most cas- will be discussed. es to promote Ghosez’s cycloaddition. In addition to the formation of cyclobutanones by hydrolysis of the cyclobutylideneiminium cycloadducts, these intermediates can

Syn thesis G. Evano et al. Review

43 also be trapped by various nucleophiles such as hydrides, O Ph Tf2O, collidine cyanides,44 or various organometallic reagents,44 which + Ph N CHCl3, reflux O contribute to the versatility of the [2+2] cycloaddition of then H2O 63 64 65 keteniminium ions with alkenes in organic synthesis. 70%

Cl Tf2O O Cl AgBF R1 collidine AgBF4 R1 R3 4 3 R1 R3 + • N R X N N 4 N CH2Cl2 CH2Cl2 2 R CH2Cl2 O R 2 4 –60 °C R2 R4 –60 °C R R 71 5 then hydrolysis 66 67 68 86% R6 R7

R5 R8 60 Cl AgBF4 + R6 R7 N R6 R7 CH2Cl2 BF4 R5 R8 –60 °C R5 R8 hydrolysis N X 66 Z-69 88% R1 3 R1 R cis-70 R2 N R2 O R4 62 61

Cl Scheme 13 [2+2] Cycloaddition of keteniminium ions with alkenes AgBF4 + N CH2Cl2 BF4 –60 °C N The main features of this [2+2] cycloaddition are sum- 66 E-69 87% marized in Scheme 14. The reaction has been shown to be trans-70 highly regioselective, as notably demonstrated with the use Cl 8a of styrene (64) or buta-1,3-diene (67) which yield cy- AgBF4 + BF4 + BF4 N clobutanones 65 and 68 with substituents at C2 and C3 on- CH2Cl2 N N –60 °C ly. These high levels of regioselectivity can be explained by 66 Z-71 65% cis-72 trans-72 the interactions between the LUMO orbital of the keten- 90 : 10 iminium ion and the HOMO orbital of the alkene. Impor- Cl tantly, the reaction with butadiene only gives the [2+2] cy- AgBF4 + BF4 + BF4 N cloadduct without competing [4+2] cycloaddition, a selec- CH2Cl2 N N –60 °C tivity that actually depends on the nature of the diene (see 66 E-71 68% cis-72 trans-72 Section 2.4 for details). The stereospecificity of the reaction 7 : 93 with regards to the stereochemistry of the alkene was found to be more subtle and to depend on the nature of Cl AgBF4 BF BF 8c + 4 + 4 both the alkene and the keteniminium ion. Indeed, while N N N CH2Cl2 the reaction of α-chloro-enamine 66 with Z- and E-cyclooc- –60 °C 63% tene 69 was shown to be highly stereospecific, yielding the 73 Z-71 cis-74 trans-74 70 : 30 corresponding cis- and trans-cycloadducts 70, respectively, lower levels of selectivity were observed when switching to Scheme 14 Main features of the [2+2] cycloaddition of keteniminium ions with alkenes Z- and E-but-2-ene 71. The nature of the substituent on the nitrogen atom of the keteniminium ion was shown to have a stronger influence on the stereoselectivity of the reaction, Cl X ZnCl2 (1.2 equiv) COX R3 1 O CH2Cl2, reflux as evidenced by the difference in selectivity observed in the R + N or Zn(OTf)2 (25 mol%) R2 reactions of α-chloro-enamines 66 and 73 with Z-but-2- 2 3 R R neat, 35 °C, XX R1 O ene Z-71, which was attributed to the contribution of a then hydrolysis 75 76 77 stepwise cationic mechanism. (X = Me, OMe, OEt, NMe2, N(Me)OMe) The [2+2] cycloaddition was extended to the use of elec- Scheme 15 [2+2] Cycloaddition of keteniminium ions with electron- tron-poor alkenes, such as conjugated ketones, esters and deficient alkenes amides 76 in the presence of stoichiometric amounts of zinc chloride or catalytic zinc triflate, the zinc salts activat- 47 8a ing both the starting α-chloro-enamines 75 and the conju- dition with ketenes, as a concerted [π2s+π2a] process, am- gated alkenes 76 (Scheme 15).45,46 ple evidence for asynchronous or even stepwise cationic The mechanism of this (formal) [2+2] cycloaddition has mechanisms are available. Indeed, the lack of stereospeci- been a matter of debate: initially proposed, by analogy to ficity observed in some cases (see Scheme 14) prompted Woodward and Hoffmann’s analysis of the related cycload- Ghosez to formulate the mechanism depicted in Scheme 16 for the reaction of 78 with Z-but-2-ene Z-71. The least hin-

Syn thesis G. Evano et al. Review dered approach between 78 and Z-71 would initially lead to 2.3.2 Intermolecular [2+2] Cycloaddition of Keten- intermediate 79. Rotation along the C–N and C–C bonds iminium Ions with Alkynes and Allenes would enable conjugation of the nitrogen lone pair with the double bond, thereby ‘creating’ the enamine system in 80 In continuation of their studies, Ghosez and co-workers and allowing for the formation of the second C–C bond reported in 1981 the extension of their chemistry to acety- yielding cis-72. Isomerization of 79 to 79′ prior to the cy- lenes: keteniminium ions 1 readily react with a range of clization would yield the trans isomer trans-72. terminal 84 or symmetrical alkynes 85 to yield the corre- The mechanism of this cycloaddition was theoretically sponding cyclobutenylideneiminium ions 86 with excellent studied at BH and HLYP/6-31G* levels by Fang in 2001.48 yields and selectivity, their further hydrolysis providing a The reactions involving a keteniminium ion bearing hydro- remarkably useful route to cyclobutenones 87 (Scheme gens on the nitrogen atom were found to initially proceed 17).9 Here again, the keteniminium ions can be prepared ei- by a hydrogen-bonded complex, one hydrogen being par- ther from the corresponding α-chloro-enamides 749 or am- tially bonded to the alkene. This intermediate, which obvi- ides 5.9,50 ously could not be observed when the nitrogen atom bears Cl AgBF Tf O O 4 1 2 substituents different from hydrogen, might not be relevant or ZnCl R collidine R1 R3 2 3 R1 R3 • N R X since keteniminium ions involved in [2+2] cycloaddition do N 4 N CH Cl R CH2Cl2 2 2 R2 R2 R4 –60 °C R2 R4 not bear such hydrogens. The DFT analysis of the reaction 715 of keteniminium ion 81 with ethene 82 is however closer to R5 84 a real system and deserves some comments. When the two or 5 5 reactants 81 and 82 approach, a fairly loose complex result- R R 85 ing from a gauche approach is formed. This complex evolves R5 H/R5 to the cycloadduct 83 through a transition state in which R5 H/R5 hydrolysis the double bond lengths are lengthened and the C–C–N an- X R1 3 R1 R gle decreases. Interestingly, this geometry is in good agree- R2 N R2 O R4 ment with the transition state proposed by Ghosez and re- 87 86 veals a concerted asynchronous reaction. Scheme 17 [2+2] Cycloaddition of keteniminium ions with alkynes Compared to alkenes, the [2+2] cycloaddition of keteniminium ions with alkynes and allenes has been far less investigated: these reactions are discussed in Section 2.3.2. Cyclobutenylideneiminium ions 86 were, in addition, found to be excellent substrates for Diels–Alder reac- tions49,50b,c or 1,4-addition,50d which further extend the synthetic usefulness of this [2+2] cycloaddition of keteniminium ions with alkynes, a reaction that is, however, still rarely used despite its efficiency. DFT studies of the reaction mechanism were reported in 2015 and revealed a two-step mechanism involving an initial rate-determining nucleophilic attack of the alkyne to the central carbon atom of the keteniminium ion yielding an intermediate cyclopropane followed by its conversion to the more stable cyclobutenylideneiminium ion.51 This study, in addition, highlighted the strong electrophilic character of the keteniminium ion, which accounts for the feasibility of the cycloaddition. Their cycloaddition with allenes have been even less- well investigated and therefore these reactions will not discussed here.2a Since its discovery by Ghosez in 1972, this [2+2] cycloaddition has evolved as a remarkably powerful tool for the formation of cyclobutanes. Intramolecular versions of this reaction have been reported and they will be overviewed in Section 2.3.3.

Scheme 16 Stepwise and concerted asynchronous mechanisms proposed for the [2+2] cycloaddition of keteniminium ions with alkenes

Syn thesis G. Evano et al. Review

2.3.3 Intramolecular [2+2] Cycloaddition of Keten- stereoselective formation of 94 was attributed to the most iminium Ions with Alkenes stable conformation of the intermediate keteniminium triflate 93. The intramolecular version of this cycloaddition offers A higher level of asymmetric induction was obtained by straightforward routes for the regio- and stereocontrolled placing a silyl substituent in the allylic position; this sub- synthesis of polycyclic cyclobutanones.2b Ghosez reported stituent not only controls the facial selectivity but also acti- the first systematic study of this reaction in 1985, demon- vates the alkene towards nucleophilic attack.58 Indeed, strating one more time the high efficiency of the [2+2] keteniminium triflate 97 derived from amido-alkene 96 cycloaddition of keteniminium ions, notably compared to provided, after acidic hydrolysis, cycloadducts 100 and 101 its analogous reaction involving ketenes.52 This reaction, in a 97:3 ratio. Computational analysis of this reaction leads which is depicted in Scheme 18, was found to be rather to the lowest energy transition states TSA and TSB for the general and provided polycyclic cyclobutanones 91 in yields formation of 98 and 99 yielding 100 and 101, respectively; generally superior to those obtained starting from acyl TSA is more stable than TSB due to its nearly perfect stag- chlorides – generating the corresponding ketenes upon gered tether between the keteniminium and alkene moi- treatment with trimethylamine – instead of amides 88. The eties and the C–Si bond being aligned with the alkene π or- reaction produces cis-fused cycloadducts in most cases, ex- bitals. cept if epimerization occurs during the hydrolysis of bicy- BnO O clic iminium ion 90, and the main limitation is the substitu- Tf2O tion pattern of the alkene: β,β-disubstituted alkenes favor collidine N N TsN Ts DCE TfO intramolecular acylation rather than cycloaddition. OBn reflux • N 92 68% 93

O Tf2O collidine n R2 R3 TfO 3 R n N DCE • N BnO 2 1 H BnO R R reflux R1 88 89 (n = 1–5) TsN + TsN O

H O R2 2 R3 94 95 R 3 R 91 : 9 H2O n TfO (after hydrolysis) n CCl 4 1 N reflux R Tf O R1 O 2 tBu N tBu 91 90

Si Scheme 18 Intramolecular [2+2] cycloaddition of keteniminium ions O with alkenes Si N CH2Cl2, r.t. AcO TfO OAc • N 68% This intramolecular [2+2] cycloaddition of ketenimini- 96 97 (Si = SiMe Ph) um ions with alkenes was later extended to alkoxyketen- 2 53 54 iminium ions and other tethers between the ketenimin- Si Si ium and alkene moieties; these reactions typically proceed AcO OAc well unless a functional group within the tether can com- N N 34,54 petitively trap the keteniminium ion or interrupt the TSA TSB cycloaddition.55 They were also extended to the synthesis of higher ring systems by using sequential ring expansion.56 Si Si Applications of this reaction in natural product synthesis AcO OAc are described in Section 4. N N To bring this reaction a step further, asymmetric induc- 98 99 tion starting from amido-alkenes linked through a chiral tether has been intensely studied. In this context, Zapia re- PhMe2Si H PhMe2Si H ported in 2000 a diastereoselective intramolecular [2+2] cy- AcO + AcO cloaddition from vinylglycinol-derived substrate 92 H O H O 57 (Scheme 19). Upon reaction with triflic anhydride and 100 101 collidine in refluxing dichloromethane, a 91:9 mixture of 97 : 3 (after hydrolysis) regioisomeric cycloadducts 94 and 95 were obtained in 68% yield and with high levels of diastereoselectivity. The dia- Scheme 19 Diastereoselective intramolecular [2+2] cycloaddition of keteniminium ions with alkenes

Syn thesis G. Evano et al. Review

An even more appealing approach for the synthesis of O Tf2O • N enantioenriched cyclobutanones consists of the use of chi- N collidine ral pyrrolidine derivatives acting as chiral traceless auxilia- TfO CH2Cl2 then reflux ries. This strategy is discussed in Section 2.3.4. OMe hydrolysis O OMe 30% 102 103 104 2.3.4 Chiral Traceless Auxiliaries in [2+2] Cycloaddi- (55% ee) tion of Keteniminium Ions with Alkenes N N R • R • OMe OMe R R Another advantage associated with the use of keten- AB iminium ions compared to ketenes lies in the possibility of Cl • N using chiral keteniminium ions generated from chiral pyr- N ZnCl2 Cl rolidine-derived amides. This strategy was investigated in CH2Cl2, r.t. then hydrolysis 1982 by Ghosez who demonstrated its feasibility and effi- OMe O OMe 70% 8c,59 105 106 107 ciency. O-Methyl-(S)-prolinol-derived keteniminium (>97% ee) ions 103 and 106 were found to provide moderate to high Tf2O levels of asymmetric induction, the corresponding cyclobu- tBu N tBu tanones 104 and 107 being isolated with 55% and >97% ee, respectively (Scheme 20). An interesting reversal of selec- O TfO tivity was observed, which was attributed to a favored ap- N CH2Cl2 or DCE • N r.t. to reflux R* proach depicted as A in Scheme 20 with ‘aldo’ ketenimini- 108 R* 109 um ion 103 while the other approach B would be favored N with ‘keto’ keteniminium ion 106 to avoid steric clash with N N OMe the methyl groups. The counterintuitive approach of the = N R* alkene towards the methoxymethyl group was attributed to OMe OMe O 108a 108b 108c a stabilizing interaction between the oxygen lone pair and 104 the developing positive charge on the olefinic carbon atom. (after hydrolysis) Moving to keteniminium ions bearing two different from 108a: 70%, 27% ee; from 108b: 74%, 8% ee; substituents on the β-carbon atom could be expected to be from 108c: 88%, 98% ee. problematic due to the possible formation of diastereoiso- Tf2O t t mers of this reactive intermediate. Indeed, attempts at a Bu N Bu diastereoselective intramolecular [2+2] cycloaddition start- O ing from O-methyl-(S)-prolinol-derived amidoalkene 108a TsMeN TsMeN TfO N 60 • N gave the corresponding cycloadduct 104 with only 27% ee. CH2Cl2 or DCE r.t. R* To avoid the problematic formation of diastereoisomeric 110 R* 111 N keteniminium triflates, C2-symmetrical amides 108b and N 108c were used; when the two stereocenters are sufficient- = N R* ly close to the keteniminium, such as when starting from OMe 108c, excellent levels of chiral induction were obtained.60 110a 110b

Further studies on the extension of this reaction involv- H ing unsymmetrical keteniminium intermediates to an in- TsMeN H TsMeN O R H •N 112 tramolecular version by the Ghosez group actually revealed R H (after hydrolysis) H H that non-C -symmetrical chiral auxiliaries can provide the from 110a: 70%, 92% ee; 2 C corresponding cycloadducts with enantiomeric excesses from 110b: 81%, 93% ee. that compare well with those obtained with C2-symmetri- Scheme 20 Chiral traceless auxiliaries in [2+2] cycloaddition of keten- cal pyrrolidines. This is nicely exemplified in Scheme 20 by iminium ions with alkenes the cycloaddition from sarcosine-derived amides 110a and 110b with cyclohexene yielding bicyclic cyclobutenone 112 in similar yields and enantioselectivities.61 These compara- 5-substituents in pseudoequatorial positions. Minimization ble results, which enable the use of readily available and of the steric interactions of the incoming alkene, which ap- cheap prolinol derivatives as traceless chiral auxiliaries proaches, as depicted in C (Scheme 20), on the opposite rather than C2-symmetrical pyrrolidines, has been rational- side of the bulky sulfonamide, with the pseudoaxial hydro- ized by a twisted conformation of the pyrrolidine ring in gen atoms of the pyrrolidine ring would account for the ste- the intermediate keteniminium ion 111 placing the 2- and reoselectivity observed.

Syn thesis G. Evano et al. Review

While the scope of this reaction was extensively studied A dramatically different outcome was observed with with α-amino-amides and a broad variety of alkenes, its ex- aminoketeniminium triflate 122, which also underwent tension to the use of other unsymmetrical keteniminium [4+2] cycloaddition with cyclopentadiene 116, but now in- intermediates has not been, to the best of our knowledge, volving the C=C bond of the keteniminium ion yielding 123 reported. (Scheme 22).63 This reaction, which is still limited to keten- As evidenced by all results overviewed in this section, iminium ions derived from N-tosylsarcosinamides, was ex- the [2+2] cycloaddition of keteniminium ions with alkenes tended to an asymmetric version relying on the use of chiral has become a powerful synthetic tool enabling the synthe- pyrrolidines. sis of a variety of cyclobutane derivatives, even in an asymmetric manner. As previously described, the reaction can Tf2O tBu N tBu even be extended to dienes such as butadiene (Scheme 14) without competing [4+2] cycloaddition. This actually de- O 116 pends on the nature of the starting diene and some of them TsMeN TsMeN TfO N CH Cl , r.t. • N then H O 2 2 2 O predominantly undergo a Diels–Alder-type cycloaddition, CCl4 TsMeN which will be briefly described in Section 2.4. 121 122 123 (69%) 2.4 [4+2] Cycloaddition of Keteniminium Ions with Scheme 22 [4+2] Cycloaddition involving the C=C bond of ketenimini- Dienes um ions with s-cis dienes

The competition between the [2+2] and [4+2] cycload- From the discussion so far, the synthetic utility of keten- ditions indeed depends on the nature of the diene used: iminium ions should be evident at this point. They clearly while acyclic dienes such as penta-1,3-diene (114) general- are more than stable synthetic equivalents of ketenes and ly undergo [2+2] cycloaddition with keteniminium ions at their rich chemistry has found many applications. the less substituted double bond, cyclic dienes such as cy- The chemistry of even more reactive heterocumulenes clopentadiene or cyclohexadiene 116 that are locked in an in which one of the substituents on the nitrogen atom of s-cis conformation exclusively provide the [4+2] cycload- the keteniminium ions is replaced by an electron-with- ducts 117 (Scheme 21).62 Originally assigned as a product drawing group has been intensively explored recently, involving the C=C bond of the keteniminium ion, it was later mostly due to the development of efficient methods for shown that it was actually the C=N bond that participated their generation. The reactivity of these activated keten- in the [4+2] cycloaddition, which is not surprising in view iminium ions is reviewed in Section 3. of the dienophilic properties of iminium ions. With an acyclic diene with a low energy barrier between the s-cis and s-trans conformations such as 2,3-dimethylbuta-1,3-diene 3 The Chemistry of Activated Keteniminium (118), a mixture of [2+2] 119 and [4+2] 120 cycloadducts Ions are formed. As described and extensively exemplified in Section 2, the chemistry of keteniminium ions is mostly based on their electrophilicity, which even accounts for their suc- 114 cessful use in cycloaddition reactions. More recently, even r.t. more reactive intermediates containing an electron-with- N BF4 drawing group on the nitrogen atom, which will be referred 115 (82%) to as ‘activated keteniminium ions’ in this review, have been extensively studied and used for the design of a series of re- 1,2 Cl 1,2 AgBF4 116 markably efficient transformations, the success of which is • N N NMe2 CH2Cl2 r.t. due, in most cases, to their exceptional reactivity. Methods BF4 -60 °C BF4 66 113 for the in situ generation of these reactive intermediates 117 (75-88%) and reactions based on such species will be the focus of this section.

118 + 3.1 Main Methods for the Generation of Activated r.t. Me2N N Keteniminium Ions BF4 BF4 119 120 (>20%) (46%) Such activated keteniminium ions 2 are mostly generated by reaction of an ynamide 1242c,e,g with an electrophile Scheme 21 [4+2] Cycloaddition involving the C=N bond of keteniminium ions with s-cis dienes (Scheme 23). The choice of the electrophile is crucial for

Syn thesis G. Evano et al. Review two main reasons: it must react selectively at the nucleo- 3.2.1 Trapping Activated Keteniminium Ions with philic carbon atom of the starting ynamide and not with Nucleophiles the electron-withdrawing group, which would result in a loss of stabilization of the ynamine moiety, and its coun- A range of acids have been reported for the generation teranion must be a weak nucleophile in order to avoid trap- of activated keteniminium ions by protonation of the corre- ping the keteniminium ion, a side reaction commonly ob- sponding ynamides 124 and their subsequent trapping by served, even with poorly nucleophilic counteranions. the conjugated base providing polysubstituted enamides The electrophiles used for the generation of ketenimini- 125 (Scheme 24). They include: carboxylic acids,68 HCl, HBr, um ions from the corresponding ynamides can be classified and HI (which are best generated in situ from the corre- into five main categories: acids (strong acids are typically sponding magnesium69 or trimethylsilyl70 halides in wet di- used although not strictly required), halogenium ions, chal- chloromethane),71 HF,72 sulfonates,73 or diarylsulfonimid- cogenyl halides,64 C-electrophiles, and electrophilic metal es.74 The successful reactions with these last three acids, complexes/organometallic reagents; the use of these re- which readily proceed at room temperature or below, clear- agents will be discussed throughout Section 3. Activated ly highlights the remarkable electrophilicity of the tran- keteniminium ions have also been postulated as intermedi- sient keteniminium ion which is easily trapped by poor nu- ates resulting from the cyclopropenation65 and epoxida- cleophiles such as a fluoride, sulfonates, or a bis-sulfonami- tion66 of ynamides followed by ring opening, although they date. This can actually be especially problematic in some are more properly described as ‘push-pull’ carbenes in the cases since such side reactions can be difficult to avoid. As a latter case. note, some of the corresponding adducts, notably with sulfonates, have been shown to be poorly stable, which can be EWG EX E 73a,c 1 EWG used for their further in situ transformation or result in R N • N X R2 R2 R1 a formal hydrolysis of the starting ynamide, a commonly 124 2 encountered side reaction which is often tricky to suppress. Scheme 23 Main route for the generation of activated keteniminium Such additions are usually found to be highly stereose- ions lective and to proceed in a syn fashion, which can be rationalized by nucleophilic addition of the incoming nucleo- The development of efficient and broadly applicable phile from the less hindered side of the keteniminium ion 2. methods for the synthesis of ynamides,67 some of which are While alcohols and silanols are not sufficiently acidic to now commercially available, clearly contributed to the tre- protonate an ynamide, Gaunt demonstrated that the addi- mendous developments reported in the chemistry of acti- tion of catalytic amounts of zinc or scandium triflate gener- vated keteniminium ions. Their exceptional reactivity was, ates traces of triflic acid which protonates the ynamide, indeed, used to design a series of innovative and efficient therefore generating the corresponding activated keten- chemical transformations in which non-activated keteniminium ion 2 that undergoes selective addition of the alco- iminium ions often fail. The number and structures of nu- hol or silanol over the C–H bond to form the E-enol/silyl cleophiles that can trap such reactive intermediates gives a enol ether derivative 126. A subsequent Mukayama aldol rather good illustration of their high electrophilicity. reaction involving the latter furnished the corresponding

3.2 Reactions of Activated Keteniminium Ions with X EWG HX H H EWG Nucleophiles R1 N • N EWG 2 X N R2 1 R R R1 R2 As with simple keteniminium ions, the most trivial 124 2 125 3 chemical transformation involving activated ones is their HX = HO2CR HS PPh reaction with a nucleophile. Depending on its nature, it can 2 2 HCl, HBr, HI (from MgX2 or TMSX in wet CH2Cl2) either be trapped by the counteranion of the electrophilic HF or HF·pyridine species used for the generation of the activated ketenimini- HN(SO2Ph)2 um ion or by a more nucleophilic reactant present in the re- R3OH or 3 action mixture, which can initiate further transformations. R 3SiOH Zn(OTf)2 or We will first overview the most simple case in which the Sc(OTf)3 3 3 OR /OSiR 3 EWG (10 mol%) H reaction stops after trapping the keteniminium ions with H EWG R1 N • N EWG 2 TfO N the nucleophile. R2 1 R R R1 R2 124 2 126 Scheme 24 Generation of activated keteniminium ions by protonation of ynamides with acids and subsequent trapping with the conjugated base

Syn thesis G. Evano et al. Review

anti-aldol products with moderate to good levels of diaste- R3 HN reoselectivity, this reaction being catalyzed by the Lewis R3 75 HN acid present in the reaction mixture. 128 An interesting way to reverse the stereoselectivity of H EWG N such reactions involves the activation of the starting R1 R2 ynamide with a π-electrophilic metal generating a metalat- 129 R3 ed keteniminium ion that can be trapped by a nucleophile, R3 O which adds to the opposite side of the metal, followed by Tf2NH EWG 1 (10 mol%) R 130 O hydrolysis of the resulting metalated enamide. The trans 1 R N • N EWG 2 76 2 CH2Cl2 R hydrofluorination of ynamides to 127 with silver fluoride R H Tf N H EWG –35 °C 2 N 124 2 (Scheme 25) is representative of this strategy and nicely 1 2 3 R R 72 R complements the cis selectivity obtained with HF. 131 HN R3

F HN EWG AgF R1 R1 EWG 132 R1 N • N EWG 2 F N 2 CH3CN R R Ag 2 80 °C H R H EWG 124 2 127 N R1 R2 Scheme 25 trans Hydrofluorination of ynamides by activation with a 133 π-electrophilic metal and subsequent trapping with fluoride and hydrolysis Scheme 26 Generation of activated keteniminium ions by protonation of ynamides with bistriflimide and subsequent trapping with heteroarenes While the hydrofunctionalization of ynamides with acids is of limited synthetic utility in some cases, it does, however, provide crucial information on the nature of the monobromide was shown to selectively react with acid that can be used for the generation of keteniminium ynamides 124 to generate iodinated keteniminium bromide ions from ynamides and, more importantly, on the ease 2 which then gives α-bromo-β-iodo enamide 134 with ex- with which they can be trapped by its conjugated base. If cellent levels of regioselectivity (Scheme 27).78 Other elec- the keteniminium ion must react with another reactant or trophilic halogenation reagents, such as iodine,78,79 N-iodo- functional group, a strong acid, therefore, must be used. An succinimide,80 Barluenga’s reagent,81 or bromine,78 have interesting example was reported by Zhang in 2005 who been reported for the generation of halogenated ketenimin- described an efficient intermolecular reaction between ium ions from the corresponding ynamides, and various pyrroles 128, furans 130, and indoles 132 with ketenimini- nucleophiles, including halides,78 amines,79b pyridines,81 um ions 2 yielding the corresponding vinylpyrroles 129, fu- water,79a or DMSO,80 were shown to efficiently trap these rans 131, and indoles 133 (Scheme 26).77 The nature of the reactive intermediates. In addition to providing an efficient acid used for the generation of the activated keteniminium and stereoselective entry to halogenated enamides, the ion was found to have a dramatic influence and catalytic combination of the correct electrophilic halogenation re- amounts of bistriflimide, whose conjugated based is suffi- agent and nucleophile can be used to trigger efficient trans- ciently poorly nucleophilic to avoid its reaction with 2, formations via a transient halogenated keteniminium ion. were found to efficiently promote the reaction. Br EWG R1 Besides acids and π-electrophilic metals, the use of IBr 1 1 EWG R EWG R N • N Br N which for the generation of activated keteniminium ions toluene/Et O R2 R2 2 I –78 °C to r.t. I R2 will be discussed later, other electrophiles have also been 124 2 134 reported to efficiently and selectively react with ynamides Scheme 27 Generation of activated keteniminium ions by iodination to generate the corresponding functionalized keteniminium of ynamides and subsequent trapping with bromide ions which can then be trapped by a nucleophile. As an important note, the stereoselectivity of this last step is too often overlooked since the nucleophile should trap the keten- In sharp contrast, the use of carbon-based electrophiles iminium ions from its less hindered face, which therefore for the generation of keteniminium ions is much less docu- depends on the relative size of the substituent of the start- mented, despite its clear synthetic potential. Indeed, being ynamide and the electrophile: care should therefore be sides benzhydryl halides82 and aldehydes/ketones83 activat- taken when looking at such reactions. ed with a strong Lewis acid highlighted in Scheme 28 (in- Halogenium ions have been shown to be excellent re- tramolecular versions using such electrophiles will be agents for the generation of activated keteniminium ions described in Section 3.2.4), the use of other C-electrophiles from the corresponding ynamides. As an example, iodine is rarely discussed.81 While many of such electrophiles are sufficiently electrophilic to react with ynamides, as evi-

Syn thesis G. Evano et al. Review denced by examination of the nucleophilicity parameters of 138 (Scheme 29).89 This reactive intermediate was generat- ynamides84 and the electrophilicity parameters of C-elec- ed by activation of a chiral ynamide 137 by catalytic trophiles on Mayr’s reactivity scale,85,86 the low efficiency amounts of p-nitrobenzenesulfonic acid (PNBSAH) and sub- of these reactions is most certainly due to competing reac- sequently trapped by an allylic alcohol 27 yielding E-ketene tions of these electrophiles with the electron-withdrawing N,O-acetal 139. The latter underwent a sigmatropic [3,3]- group rather than with the alkyne. rearrangement to give 140 with excellent levels of diastereoselectivity resulting from a chairlike transition state in Ar Ar which the dipole and steric interactions are minimized. Cl R1 Cl EWG This reaction was later shown to be efficiently catalyzed by ZnCl2 EWG R1 EWG 1 • N R N R2 N zinc or scandium triflate (in the presence of additional sub- toluene, r.t. Ar R2 2 75 Cl Zn R Ar 3 Ar Ar stoichiometric pivalic acid or not) and the use of N-bro- 1242 135 mosuccinimide to generate a brominated keteniminium ion

O was shown to initiate a sigmatropic rearrangement followed by dehydrobromination yielding dienamides instead 3 4 Cl R R R1 90 EWG 1 of brominated Claisen products. Finally, it should be men- TiCl4 EWG R EWG 1 3 • N N R N R R2 2 toluene 2 tioned that non-Claisen pathways have been reported in R R4 Cl 3 R –78 °C OH R OH R4 the gold-catalyzed reaction between enynamides and high- 1242 136 ly activated allylic and propargylic alcohols.91 Scheme 28 Generation of activated keteniminium ions by reaction of ynamides with C-electrophiles and subsequent trapping

As discussed, π-electrophilic metals such as gold, silver, R3 OH and zinc are also especially suitable reagents that can be R2 R3 O 27 O used for the generation of metalated keteniminium ions PNBSAH 1 R2 O 1 (10–20 mol%) R O from ynamides. This strategy is especially appealing when R N O • N H O toluene PNBSA R1 N the nucleophiles that are used to trap the intermediate Ph 70–125 °C Ph 87 Ph O keteniminium ions are not compatible with an acid, when Ph Ph a metal catalyst is more efficient than an acid,88 or simply 137 138 Ph 139 when the metalated keteniminium ion displays a reactivity R2 that could not be achieved with its protonated equivalent. O Examples of the peculiar and remarkable reactivity of such Ph R3 R1 intermediates, notably as carbenoid species, will be over- Ph N O viewed in Section 3.2.3, after describing reactions involving O the trapping of activated keteniminium ions with nucleophiles initiating a tandem transformation that will be over- 3 viewed in Section 3.2.2. R O O N O R2 R1 3.2.2 Trapping Activated Keteniminium Ions with Ph Nucleophiles and Subsequent Rearrangement 140 Ph

R2 R3 As with amide- or α-chloro-enamine-derived keten- OH iminium ions, the use of nucleophiles that, after nucleophil- R2 4 142 R3 O R O 4 ic addition to an activated keteniminium ion generate an PNBSAH R (10–20 mol%) 1 O 1 R O enamine that can undergo a tandem skeletal rearrange- R N O • N toluene H O ment, has been extensively studied due to the extraordi- 60–100 °C PNBSA R1 N Ph Ph nary synthetic potential of this strategy. The development Ph O 141 143 144 of efficient methods for the synthesis of ynamides in addition facilitated the design and study of an impressive and ever-growing number of processes based on trapping an ac- R4 O O tivated, ynamide-derived keteniminium ion followed by • N O subsequent rearrangement. 2 R R1 R3 One of the first successful example was reported by the Ph 145 Hsung group in 2002 who developed an interesting diastereoselective extension of the Ficini–Claisen rearrangement Scheme 29 Trapping activated keteniminium ions with allyl/propargyl alcohols and subsequent sigmatropic rearrangement (Scheme 8) based on the use of chiral keteniminium ions

Syn thesis G. Evano et al. Review

The extension of this reaction to propargyl alcohols 142 after extrusion of nitrogen, a series of ring-closure and ring- was also found to be efficient and this version of the Saucy– opening reactions yielding, after hydrolysis, oxazolidine- Marbet rearrangement provides an efficient entry to chiral, 2,4-diones 152 (Scheme 31).97 Starting from sulfonyl-pro- optically enriched homoallenylamides 145 in which both tected ynamines and benzylic azides, a concerted deproton- the central and axial chirality are controlled.92 In this case, ation/protonation yielding 2-azabuta-1,2-dienes occurs af- the use of homochiral propargyl alcohols had a strong inter the extrusion of nitrogen.98 Switching to dioxazoles, 153 fluence on the diastereoselectivity of the rearrangement promotes another rearrangement from aminovinyldioxaz- due to match and mismatched pairs. Starting from N-sulfo- olium ions 154 affording 4-aminooxazoles 155 resulting nyl-ynamines, the rearrangement was promoted by stoi- from a formal [3+2] cycloaddition.99 chiometric zinc bromide93 or catalytic silver triflate.94 The successful outcome of these two reactions in which While all attempts to extend these rearrangements to an activated keteniminium ion is trapped with azides or di- benzylic alcohols failed, the Maulide group, in continuation oxazoles is actually based on the electrophilic character of of their studies of sigmatropic rearrangements involving ketene acetals cations 150 and 154. An interesting and par- non-activated keteniminium ions,37 reported in 2014 and ticularly relevant extension of this reactivity was reported 2017 an interesting extension of their work involving acti- in 2017 by the Shin group, who devised a remarkable oxi- vated keteniminium ions and aryl sulfoxides. First they dative intermolecular Friedel–Crafts-type coupling of elec- demonstrated the feasibility and efficiency of such a pro- tron-rich arenes or silyl enol ethers (Scheme 32).100 The de- cess. Compared to the analogous reaction with non-activat- sign of this reaction, which is closely related to the intramo- ed keteniminium ions that required activation of the start- lecular version reported by the Maulide group (Scheme ing amides with stoichiometric amounts of triflic anhy- 11),39 is actually based on the trapping of keteniminium dride and 2-iodopyridine (Scheme 8), this reaction indeed bistriflimidate 2 with 2-chloropyridine N-oxide (156) gen- only necessitated mixing the starting ynamide and aryl erating an electrophilic enolium ion 157 which can then be sulfoxide with catalytic amounts of an acid.95 They then de- efficiently trapped by indoles 132, pyrroles 128, phe- scribed an interesting use of chiral aryl sulfoxides 30 pro- nols/anisoles/anilines 160 or silyl enol ethers 162 to give viding, after nucleophilic addition to keteniminium ion 2 the corresponding substituted amides 158, 159, 161, and and sigmatropic rearrangement, the optically enriched α- arylamides 147 resulting from chirality transfer from sulfur 96 O O R3 N to carbon (Scheme 30). R3N 2 3 N O Besides sigmatropic [3,3]-rearrangement, other types of O TfOH R1 O TfO 1 R N • N N CH Cl H skeletal rearrangements consecutive to the trapping of acti- 2 2 TfO O 0 °C to r.t. R1 2 2 vated keteniminium ions with various nucleophiles have R R R2 148 149 been reported. Such nucleophiles include alkyl azides, 150 which were previously shown to react with non-activated

27 3 2 keteniminium ions (Scheme 7), whose reaction with yne- O R R oxazolidinone-derived keteniminium triflates 149 yield NHR3 TfO N R1 NaOH N R1 transient aminovinyltriazinium triflates 150 that undergo, 2 N O R O O O 152 151 R4 R3 S O O O R4 30 3 N R 3 Tf2NH 1 R EWG R S Tf N 153 (50 mol%) 2 O 1 • N EWG Tf NH R N 2 O 2 R1 R EWG (5 mol%) O R2 DCE, 0 °C H EWG R3 Tf2N R1 N • N N 1 R2 R N EWG 2 DCE, r.t. H Tf N 124 2 R Tf N 2 EWG R2 2 N 124 2 146 R1 R2 154

O R3 R1 EWG N N R3S R2 O EWG R4 N R1 R2 147 155

Scheme 30 Trapping activated keteniminium ions with aryl sulfoxides Scheme 31 Trapping activated keteniminium ions with azides and di- and subsequent sigmatropic rearrangement. oxazoles and subsequent rearrangement

Syn thesis G. Evano et al. Review

163 with high efficiency. This reaction was also shown to LG O LG 1 O be efficiently catalyzed by gold complexes and the use of EWG [M] R 164 1 EWG R N • N R1 EWG R2 N chiral, C2 symmetric bipyridine N,N′-dioxides provided R2 [M] good levels of enantio-induction. [M] R2 124 2 165

O Cl N

156 Cl R1 EWG N Tf2NH 1 R 2 EWG (10 mol%) N [M] R EWG R1 N • N O R2 166 R2 DCE, r.t. H Tf2N EWG Tf2N N Scheme 33 Generation of α-oxo-carbenoids by trapping activated 124 2 R1 R2 keteniminium ions with mild oxidants 157

R4 R3 R3 N tially hazardous diazo derivatives, this strategy only re- N 3 4 quires mild oxidants and readily available ynamides and is R EDG TBSO R 132 128 160 162 therefore strongly appealing. An early example of this strategy was reported in 2011 O O by the Davies group who described the in situ generation of O R1 EWG O R1 EWG 1 N 1 N R EWG 2 R EWG α-oxo-gold carbenoids 170 initiated by trapping ynamide- 2 N R N R 2 4 R2 R R O derived gold keteniminium ion 2 with pyridine N-oxide R3 3 N R 102 N (168) and elimination of pyridine (Scheme 34). Subse- R4 R3 EDG quent 1,2-CH insertion then provided the corresponding 158 159 161 163 α,β-unsaturated amides 171. This strategy was later ex- (EDG = NMe2 OH, OMe) Scheme 32 Trapping activated keteniminium ions with pyridine N-ox- O ides and subsequent intermolecular arylation N

III [Au ] R1 Cl R1 EWG Cl N As highlighted with these examples, the generation of (5 mol%) R2 168 R1 O N EWG DCE, 70 °C • N EWG R2 R3 R3 2 enolium ions from activated keteniminium ions provides an [Au] R N efficient method for the synthesis of a wide range of α-ary- 167 2 [Au] R3 169 lated amines. This strategy was later extended to the preparation of α-aryloxy-, α-arylthio-, α-azido-, α-thiocyanato-, O N and α-haloamides by using the correct nucleophile/pyri- 1 Cl Au O R1 O R O dine N-oxide combination.101 Cl EWG EWG R2 N R2 N The reactions of enolium ion 157 with indoles and pyr- [AuIII] Cl R3 [Au] R3 roles is actually reminiscent of a carbenoid reactivity, a 171 170 concept which has been extensively explored and which will be overviewed in Section 3.2.3. Cl 1 IPrAuNTf2 R 1 Cl R EWG (5 mol%) 2 Cl 172 R Ts N 3.2.3 Trapping Activated Metalated Keteniminium N EWG R1 N Cl DCE, r.t. • N R2 R3 R3 Ions with Nucleophiles Yielding α-Oxo/Imido-carbenes/ [Au] EWG R2 N carbenoids 167 2 [Au] R3 173 Ts Trapping metalated keteniminium ions 2, which are N conveniently generated in situ by reaction between an N R1 NTs R1 NTs ynamide 124 with a π-electrophilic metal complex, with Cl Cl EWG + – EWG 2 nucleophilic mild oxidants LG –O 164 indeed yields a tran- 172 R2 N R N Cl sient metalated ketene N,O-acetal 165 which can further R3 [Au] R3 evolve to α-oxo-carbenoid species 166 (Scheme 33). Com- 175 174 pared to the classical route to such carbenes involving met- Scheme 34 Generation of α-oxo/imido-carbenoids by trapping acti- al-promoted decomposition of the corresponding poten- vated keteniminium ions with pyridine N-oxide or an iminopyridinium ylide and subsequent 1,2-CH insertion

Syn thesis G. Evano et al. Review tended to the generation of α-imido-gold carbenoids 174 oxo-carbenoids, the imine 184 released in this case upon by the Zhang group by replacing pyridine N-oxide with an generation of carbenoid 166 trapping this reactive interme- iminopyridinium ylide 172103 while the use of diphenyl diate to give, after hydrolysis, α-amino-amides 185.107 Note, sulfoxide was shown to give α-keto-imides104a or cy- the use of nitrosoarenes in place of the nitrone was also clobutenecarboxamides starting from cyclopropyl-substi- found to be efficient and promoted an efficient oxoimina- tuted keteniminium ions (Scheme 34).104b tion instead of the oxoamination observed with ni- The full potential of this strategy was later demonstrat- trones.107,108 ed by trapping the α-oxo-carbenoid 166 with, for example, In the last example, the nitrone plays a dual role, first allylic sulfides 178, which promotes the formation of sulfur oxidizing the gold keteniminium ion and then trapping the ylides followed by a [2,3]-sigmatropic rearrangement to resulting gold carbenoid. With other reagents that allow in- 179,105 or indoles 132, giving the corresponding α-arylated tramolecular trapping of this metal carbenoid, such dual re- amides 158 (Scheme 35).106 While efficient, it should how- activity can actually be used to promote efficient cycliza- ever be noted that the exact same transformation yielding tions. This was exemplified by the Davies group who re- 158 can be performed using catalytic amounts of bistriflim- ported in 2011 an interesting and original entry to 4- ide instead of the gold catalyst (Scheme 32).100 The use of aminooxazoles 155 (Scheme 36).109 Upon activation of other oxidants such as nitrones 182 also highlights the syn- ynamide 124 with a gold(III) catalyst and nucleophilic addi- thetic usefulness of this method for the generation of α- tion of N-acyliminopyridinium ylide 186 followed by elimination of pyridine, gold carbenoid 188 is generated and its

O further cyclization yields the desired 4-aminooxazole 155.

N CO2Me MeO2C O (ArO) PAuNTf 3 2 Tf2N 3 EWG (5 mol%) R1 176 N N R O R1 N • N EWG N CH Cl , r.t. 2 1 2 2 2 2 R R R 3 R [Au] Tf2N N III R t [Au ] Cl Ar = 2,4- Bu2-C6H3- 1 N 124 2 [Au] EWG EWG (5 mol%) R 186 1 EWG O N 3 177 R N • N SR toluene R2 R1 EWG O R2 90 °C [Au] Cl N R1 R2 178 124 2 N [Au] R2 3 SR EWG 187 179 O R1 R2 O N N Tf N 3 4 2 R3 R O R [Au] EWG Cl Au O 1 2 N Cl R R N O N N 166 132 R3 [AuIII] O EWG R1 EWG EWG N N R1 Cl R2 [Au] R2 N O R4 155 188 R3 N Br 158 Br Scheme 36 Generation of α-imido-carbenoids by trapping activated

IPrAuNTf2 Tf2N keteniminium ions with N-acyl-iminopyridinium ylides and subsequent EWG R1 N (5 mol%) 180 O cyclization R1 N • N EWG 2 1 2 2 H2O, 80 °C R R R R [Au] Tf2N N 124 2 [Au] EWG 181 In addition to pyridine N-oxides, N-acyliminopyridini- Ar um ylides or nitrones, which release pyridines or imines af- N Ar ter reacting with the gold keteniminium ion, other re- JohnPhosAuSbF6 Ph O F6Sb EWG (5 mol%) R1 N 182 O agents, in which the leaving group is revealed after this R1 N • N EWG 2 1 Ph 2 DCE, r.t. R R 2 step, can be used for the generation of gold–carbenoids and R [Au] F Sb N R 6 promote cyclization yielding various heterocyclic systems. 124 2 [Au] EWG 183 Such reactions have been extensively studied since 2015 and representative examples are summarized in Scheme 37: they include the use of dioxazoles 153,110 isoxazoles Ar 111 112 113 N 191, anthranils 196, oxadiazoles 199, pyridoinda- O Ph O zoles 202,114 or azirines 205115 which result in the forma- R1 R2 184 R1 R2 N N tion of various heterocyclic scaffolds. It is important to note then hydrolysis F6Sb NHAr EWG [Au] EWG that some reactions were also shown to be efficiently cata- 185 166 lyzed by an acid instead of a gold catalyst (e.g., reaction of Scheme 35 Generation of α-oxo-carbenoids by trapping activated ynamides and dioxazoles 153 in Schemes 3199 and 37109), keteniminium ions with mild oxidants and subsequent transformation and both the nature of the metal catalyst and the starting

Syn thesis G. Evano et al. Review ynamide can result in the formation of different heterocy- sure occurs yielding an overall formal [2+x] cycloaddition clic systems. Indeed, while gold complex 192 gives 2-amin- from the starting ynamide. Selected examples of such reac- opyrrole 193,111a,b the analogous platinum complex 194 tions will now be reviewed in Section 3.2.4. gives 2-amino-1,3-oxazepines 195,111c and the presence of a TBS-protected propargylic ether in the starting ynamide 3.2.4 Intramolecular Trapping of Activated Keten- 124 shifts their gold-catalyzed reaction with anthranils 196 iminium Ions with Nucleophiles: Formal [2+2], [2+3], to the formation of 2-aminoquinolines.116 Finally, it should [2+4], and [2+2+2] Cycloadditions of Ynamides with be mentioned that some reagents, whose availability can Bifunctional Electrophiles greatly vary, can actually provide the exact same heterocycles, 2-aminopyrroles 193 being, for example, obtained af- One of the first example of such an intramolecular nuc- ter trapping the intermediate gold keteniminium ion with leophilic addition to an activated keteniminium ion was re- isoxazoles 191,111a,b azirines 205,115 or vinyl azides.115,117 ported in 2007 by the Hsung group who designed a remark- As demonstrated with selected examples overviewed in ably efficient [2+2] cycloaddition between ynamides and Sections 3.2.1 and 3.2.2, ynamide-derived activated keten- aldehydes and ketones (Scheme 38).118 This formal cycload- iminium ions can be simply trapped with a nucleophile, dition is initiated by addition of ynamide 124 to an alde- which yields the corresponding enamides or more complex hyde or a ketone 207 activated by a Lewis acid yielding building blocks if a subsequent rearrangement occurs. As keteniminium ion 208. Intramolecular addition of the re- highlighted in Section 3.2.3, metalated keteniminium ions sulting alkoxide to this keteniminium ion then generates a are in addition shown to be remarkably useful precursors of transient oxetene 209 whose electrocyclic ring opening re- carbenoid species when trapped with suitable nucleo- sults in the formation of an α,β-conjugated amide 171. This philes. When the electrophilic reagent used for the genera- reaction was later extended to an intramolecular version119 tion of the activated keteniminium ions is embedded with and to the synthesis of α,β-conjugated amidines by replac- an internal nucleophilic center, which is revealed after its ing the starting aldehyde or ketone with an imine.120 reaction with the starting ynamide, a subsequent ring clo-

EWG R1 N R2 124

IPrAuNTf2 (ArO)3PAuNTf2 PtCl2 IPrAuCl/AgNTf2 IPrAuCl/AgNTf2 JohnPhosAu(MeCN)SbF6 JohnPhosAu(MeCN)SbF6 (5 mol%) (5 mol%) (10 mol%) (5 mol%) (5 mol%) (5 mol%) (3 mol%) DCE, r.t. DCE, 80 °C CO (1 atm) PhCF3, –20 °C PhCF3, 80 °C DCE, 100 °C CH2Cl2, r.t. t toluene, 60 °C Ar = 2,4- Bu2-C6H3-

R1 • N EWG R2 [M] X 2

5 5 4 R4 R R R4 R X R4 4 4 O O R R R3 O O O N O R3 N N N N N N N 3 3 N R R R3 R3 R3 153 191 191 196 199 202 205 3 4 5 4 5 R 4 R3 R R R R R4 R X 4 R3 R4 O N R

3 O 3 O 3 O 3 O N R N R R O R N F6Sb Tf N N N N N N 2 Tf2N Cl Tf2N F Sb R1 EWG 1 1 1 Tf2N 1 6 R EWG R EWG R EWG 1 R EWG 1 N N R EWG R EWG N N N N N [Au] R2 [Au] R2 2 2 2 [Au] R [Pt] R [Au] R2 [Au] R [Au] R2 189 192 194 197 200 203 206

R4 R4 4 X 3 3 R 3 R4 3 R R R O R3 R 3 R5 R3 R N NH N O N NH O R4 N R4 NH N EWG EWG 1 EWG HN EWG N N R O EWG N N 1 1 N EWG EWG 1 R 2 R 2 R1 R 2 R R 2 N 2 N R R 1 R 1 R 2 R 2 190 193 195 198 R 201 204 R 193 Scheme 37 Generation of α-imido-carbenoids by trapping activated keteniminium ions with N-heterocycles and subsequent cyclization

Syn thesis G. Evano et al. Review

O research groups; it was indeed shown in 2015 to be effi- 122 3 4 ciently catalyzed by silver bistriflimide and enantioselec- R R EWG 207 R1 123 EWG R1 N tive versions catalyzed by chiral ruthenium or copper BF3·OEt2 EWG R2 1 3 • N 124 R N R R2 complexes have been reported. 2 CH2Cl2 R R4 3 O –78 °C O R As for propargyl silyl ethers 213, their activation with R4 124 208 209 boron trifluoride generates an intermediate allenyl carbocation whose reaction with ynamide 124 gives keteniminium ion 214.125 Further intramolecular addition of the allene R3 O to the keteniminium moiety in 214 yields cyclobutenylid- EWG R4 N eneiminium ion 215, precursor of cyclobutenone 216. R1 R2 Reaction of ynamide 124 with benzyl silyl ethers 217 171 activated by zinc bromide was shown to promote a formal Scheme 38 Intramolecular trapping of activated keteniminium ions cationic [2+3] cycloaddition to give 1-amino-3H-indenes with alkoxides; formal [2+2] cycloaddition of ynamides and alde- 219 through keteniminium ions 128 (Scheme 40).126 In con- hydes/ketones trast, the presence of an additional methoxy group in 221 provided 2-aminochromenes 222 from a formal [2+4] cy- Other electrophiles, when reacted with an ynamide, cloaddition,126 a reaction that was also shown to proceed generate keteniminium ions that can be trapped intramo- starting from 2-methoxyaroyl chorides,127a oxetanes, and lecularly by the newly formed nucleophilic center include aziridines.127b From a similar perspective, a modular syn- cyclic enones 210 and propargyl silyl ethers 213 (Scheme thesis of 4-aminoquinolines 225, an especially relevant 39). In the first case, the enone 210 was found to be scaffold for the design of antimalarial drugs, was recently smoothly activated with catalytic amounts of copper(II) reported by the Bräse group.128 The key to the design of this chloride; nucleophilic 1,4-addition of ynamide 124 to this synthesis was the cyclization of keteniminium ion 224, activated enone generates keteniminium ion 211 whose in- smoothly generated by condensation of acetanilide 223, tramolecular condensation with the copper enolate affords pre-activated with triflic anhydride in the presence of Ficini’s cis-cycloadduct 212.121 Starting from acyclic enones, 2-chloropyridine, and ynamide 124. the trans-cycloadducts are formed. The strong synthetic potential of this reaction has attracted the attention of various R3 R4

O TMSO R5 EWG R1 Br R1 N R2 1,2 217 • N EWG EWG R3 2 ZnBr2 R 1 3 210 R N R4 R 1 EWG 2 CH2Cl2, r.t. 4 CuCl2 (20 mol%) R R R EWG 1 AgSbF6 (60 mol%) • N R N 2 EWG 2 R 5 4Å MS R R R5 1 R N F6Sb 124 218 219 R2 CH2Cl2 0 °C 1,2 O R3 R4 O[Cu] 1,2 124 211 212 TMSO R5 EWG 1 Br Ar Ar MeO R 1 R N R2 220 • N EWG EWG R3 2 TMSO 1 ZnBr2 R 3 R EWG 1 OMe R R N R4 O 3 EWG 1 4 213 R • N R N 2 2 CH2Cl2, r.t. R EWG R2 R R BF3·OEt2 3 1 R R N TMSO TMSO 5 • R 5 R2 CH2Cl2, r.t. R R3 Ar Ar 124 221 222 Ar Ar 124 214 215 O R4 R3 N H 223 EWG R1 TfO R1 O Tf2O, 4Å MS R1 N R2 EWG 2-chloropyridine • N EWG 1 2 R N 3 R R 3 2 CH2Cl2, 0 °C R 3 Ar R R N N R4 Ar R4 216 124 224 225 Scheme 39 Intramolecular trapping of activated keteniminium ions Scheme 40 Intramolecular trapping of activated keteniminium ions with enolates and allenes; formal [2+2] cycloaddition of ynamides with with arenes and anisoles; formal [2+3] and [2+4] cycloaddition with enones and allenyl cations ynamides

Syn thesis G. Evano et al. Review

Other electrophiles, such as nitriles 226, can be used to R3 R3 trap an activated keteniminium ion 2 in a Ritter-type pro- Tf2N N N N N cess. The subsequent 4-endo-dig cyclization of the resulting R2 R3 R1 R2 aminovinyl nitrilium ion 227 being disfavored for geometri- R3 N N R1 EWG [Au] EWG cal and electronical reasons, it can then be trapped either 229 228 by a second equivalent of nitrile 226 yielding nitrilium 228 3 whose cyclization provides 4-aminopyrimidines 229 R N Ph2PAuNTf2 226 (Scheme 41).129 Alternatively, a second ynamide 124 can re- (5 mol%) or Ph3PAuCl 3 (5 mol%) R act with aminovinyl nitrilium ion 227 to yield ketenimini- 3 AgNTf R N 2 1 EWG (5 mol%) R um intermediate 230 whose cyclization now provides 2,4- 226 Tf N R1 N • N EWG 2 N 130 2 diaminopyridines 231. Although less favorable, alterna- DCE R 1 2 R2 [Au] Tf N R R r.t. to 75 °C 2 N tive pathways accounting for the formal [2+2+2] cycloaddi- 124 2 [Au] EWG tions to 229 and 231 involve the dimerization of nitrile 226 227 or ynamide 124 prior to their reaction with 124 or 226, re- EWG spectively. These reactions, which were shown to be effi- R1 N R2 ciently catalyzed by gold complexes as shown in Scheme 124 129,130 41 were also found to be efficiently mediated by triflic 3 EWG 3 R R2 R 131 N acid in the case of 4-aminopyrimidines 229, and by bis- R1 • N N 132 133 Tf2N 1 triflimide and TMSOTf in the case of 2,4-diaminopyri- 2 2 R 2 R R 1 R dines 231. Besides nitriles, enol ethers have also been N N R N EWG R1 EWG shown to participate in a formal [2+2+2] cycloaddition in- [Au] EWG 231 230 volving an intermediate gold keteniminium ion.134 X Alkynes clearly cannot be used to trap an aminovinyl ni- 1-3 trilium ion such as 227 because of their limited nucleo- X philicity, as indicated by comparing Mayr’s nucleophilicity N R3 1-3 84 EWG R1 parameters of phenylacetylene (N: –0.04, SN: 0.77) with TfOH 232 R1 N • N EWG N 135 2 TfO those reported for acetonitrile (N: 2.23 S : 0.84), N-ben- 2 CH Cl R 3 N R 2 2 H TfO R R2 0 °C to r.t. (X = O, CH2 84 124 2 H N zyl-N-tosylbut-1-ynylamine (N: 5.16, SN: 0.85), or 1- C6H4) 1 84 R EWG (phenylethynyl)pyrrolidin-2-one (N: 3.12, SN: 0.85). How- 233 ever, intramolecular trapping was shown to be possible by the Maulide group who reported in 2016 an interesting entry to bicyclic 2-aminopyridines 234 by trapping ynamide- derived keteniminium ions with alkynylnitriles 232.136 The X 1-3 resulting nitrilium ion 233 was efficiently trapped in an in- N tramolecular fashion by the tethered alkyne to provide the R2 R3 N formal [2+2+2] cycloadduct 234. R1 EWG As shown in this section, the development of formal cy- 234 cloaddition processes relying on the generation of activated Scheme 41 Trapping activated keteniminium ions with nitriles and keteniminium ions with bifunctional electrophilic reagents subsequent reaction with nitriles, ynamides and alkynes: formal containing internal nucleophiles that can be revealed after [2+2+2] cycloadditions of ynamides with nitriles and alkynes their reaction with the starting ynamide has been an especially prolific area which has resulted in the design of efficient processes for the synthesis of a variety of (hetero)cy- 236, readily generated upon electrophilic activation of the clic systems. A complementary strategy, which has been ex- corresponding ynamide 235 with iodine, NBS, or NCS tensively studied, relies on the use of bifunctional ynamides (Scheme 42).137 A fast intramolecular addition of the me- rather than bifunctional electrophilic reagents. Representa- thoxy onto the keteniminium moiety of 236 follows, yield- tive examples will be at the core of Section 3.2.5. ing 2-aminobenzofurans 237. An ethoxyethyl ether in place of the methoxy group gives a similar outcome138 while a 3.2.5 Intramolecular Trapping of Activated Ketenim- methyl thioether provides the corresponding 2-aminoben- inium Ions with Nucleophiles: Cyclizations Involving zothiophenes.137 The keteniminium ion was also found to Bifunctional Ynamides be readily generated upon activation of 235 with stabilized carbocations139 or by reaction with a gold catalyst.140 In this One of the simplest application of such a strategy in- last case, the introduction of an allyl ether in the gold volves the generation of o-anisyl-haloketeniminium ions keteniminium ion induces a shift of the allyl group from the oxygen to the C3 position of the final benzofuran. Note that

Syn thesis G. Evano et al. Review the intermediacy of keteniminium ions in these reactions is Cyclizations of keteniminium ions containing an unpro- not obvious since they might actually involve concerted tected alcohol have also been reported and utilized for the processes. This will actually be the case with most reac- design of remarkably efficient processes. In this context, the tions overviewed in this section, but we felt that they clear- Yorimitsu group developed an elegant regioselective aryla- ly could not be left out of this review article. tive cyclization of hydroxy-ynamide 243 to 245 proceeding Benzyl acetals also efficiently trap activated ketenimini- through the intramolecular addition of the alcohol to the um ions, such as 240, in an intramolecular fashion, as nicely keteniminium moiety in 244, this intermediate being gen- utilized by the Yu group who developed new glycosyl do- erated by electrophilic palladation of 243 with an arylpalla- nors 238 for the latent glycosylation of a wide range of alco- dium(II) complex.143 An even more impressive and especial- hols 239 including protected glucose and galactose deriva- ly useful sequence proceeding through cyclization and [3,3] tives, oligosaccharides, adamantanol, and cholesterol.141 Re- sigmatropic rearrangement from yttrium keteniminium lated benzyl ether-substituted gold keteniminium species species 247 was reported in 2017 by the Ye group.144 This were also shown to undergo intramolecular trapping by the intramolecular Ficini–Claisen rearrangement affords an es- ether group, which initiates a ring-opening/ring-closing se- pecially efficient entry to medium- and large-sized lactams quence yielding unique α-hemiaminal ether gold carbenes 248. which finally undergoes a 1,2-N-migration to indenes.142 Other internal O- and N-nucleophiles including alkoxides,119 esters/amides,145 and sulfinamides/sulfonamides146 1 1 R I2 R have also been shown to efficiently trap activated keten- OMe or NBS or NCS iminium ions intramolecularly. Arenes are equally efficient, 1 EWG OMe R O N CH2Cl2, r.t. Hsung’s keteniminium Pictet–Spengler cyclization from EWG R2 • N R2 R2 keteniminium ions such as 250 being the most representa- X X N Y 147 EWG tive example (Scheme 43). The use of arenes as internal 235 236 237 (X = I, Br, Cl) nucleophiles is especially relevant for the synthesis of poly-

(OP)n cyclic heterocycles, and has therefore been extensively ex- R2OH 239 (OP)n ploited.148 Tethering the arene and the keteniminium moi- TMSOTf O O 4Å MS O eties through the nitrogen or carbon atoms of the latter O CH2Cl2, r.t. EWG leads to totally different heterocyclic systems as exempli- EWG • N R1 N H TfO fied in Scheme 43 with the cyclization of 250 and 253 lead- 1 147 238 R 240 ing to 251 and 254, respectively. Compared to the intermolecular version of this reaction (Scheme 26),77 which is restricted to the use of electron-rich heteroarenes such as furan, pyrrole, or indole derivatives, it should be noted that

O (OP)n simple, non-activated arenes can be used in this case. The + R2O 1 O N R 3 3 R EWG R3 R 241 242 Tf2NH (5 mol%) 2 2 2 R ArX R 1 R CH Cl R Pd (dba) 1 2 2 • N N 2 3 R N 30 °C H (2.5 mol%) EWG EWG EWG Tf2N 1 Xantphos R1 R OH (5 mol%) R1 OH O 249 250 251 EWG K2CO3 1,2 1,2 EWG R1 N • N 1,2 DMA, 80 °C 2 2 II R Ar N R R2 Ar[Pd ] TfO X Tf2NH X EWG (5 mol%) 243244 245 X EWG EWG CH2Cl2 • N 4 4 N 30 °C R1 N EWG R R 3 Y(OTf) R H Tf2N 3 R1 R1 (10 mol%) 3 3 4 252 253 254 R 5Å MS R R (X = O, CH2) R2 R2 R2 PhCl, 80 °C 1 n 4 4 HO 1 HO R R R n R n N 3 R1 N • N R O EWG 2 [Y] R N EWG TfO EWG Ph3PAuSbF6 (5 mol%) O 246 247 248 R4 (n = 1-5,8,12) R3 N R3 N R1 DCE, r.t. HO Scheme 42 Intramolecular trapping of activated keteniminium ions HO R2 R2 N N R1 • N EWG with O-nucleophiles and illustrative consecutive transformations 1 [Au] R EWG Tf2N EWG 255 256 257 Scheme 43 Intramolecular trapping of activated keteniminium ions with arenes

Syn thesis G. Evano et al. Review use of such arene-keteniminium cyclizations combined the alkene by the electrophilic iron center induces its iron- with a tandem cyclization provides unique opportunities chlorination which is followed by a reductive elimination, for the synthesis of remarkably complex and intricate mo- highlighting again the dramatic influence of the metal on lecular scaffolds, as demonstrated by the gold-catalyzed cy- such processes. clization of 255 to 257 via gold keteniminium intermediate

149 3 3 256. R R3 R In(OTf)3 Alkenes, alkynes, and allenes are also excellent reaction 2 1 (3 mol%) R R R2 partners for the intramolecular trapping of activated keten- 1 N CH2Cl2, r.t. • N R EWG EWG N R1 iminium ions. Except in some rare peculiar cases, the keten- [In] TfO R2 EWG iminium ion is best generated from the corresponding 258259 260 ynamide with an electrophilic metal rather than with a

2 strong acid, the overall process corresponding to a cy- In(OTf)3 R 150 151 R1 (5 mol%) cloisomerization of the starting alkenyl-, alkynyl-, or R2 N 152 CH2Cl2, r.t. R1 allenyl-substituted ynamide. As with arene-ketenimini- • N 1 EWG EWG N R 2 [In] um cyclizations, these reactions offer innovative entries to R TfO EWG various (hetero)cyclic systems from readily available start- 261262 263 ing materials. In this perspective, the Yeh group reported a Ar X X InBr X X 3 Ar R Ar series of divergent alkene-keteniminium cyclizations de- (3 mol%) 150d X R pending on the nature of the alkene (Scheme 44). Upon DCE N X 80 °C • N N generation of indium keteniminium 259, 262, and 265 by EWG EWG [In] Br R EWG activation of the starting ynamides 258, 261, and 264 with 264 265 266 indium triflate or indium bromide, cyclization of 259 to the (X = Br, Cl)

1 more stabilized carbocation yields 2-aminonaphthalenes OTBS OTBS R EWG AgNTf2 2 2 R N 260, while preferred pathways from 262 and 265 result in R (1 mol%) 0-4 0-4 1-3 1 1–3 the formation of a 5-membered ring, followed by a further 1–3 DCE, r.t. R 2 1 • N O R R N Ag cyclization starting from 265, yielding 2-aminoindenes 263 EWG 0–4 EWG Tf2N or dihydroindenopyridines 266, respectively. 267 268 269

A remarkably elegant and efficient enol ether-keten- R2 1 iminium cyclization from 268 was reported in 2016 by [AuI] R [Au] 1 EWG 150f R (5 mol%) N Miesch and co-workers. This cyclization, which readily R2 N toluene • N R2 proceeds at room temperature, provides a straightforward 80 °C EWG EWG [Au] F6P entry to bridged azabicyclic frameworks 269 in excellent 1 270 AuIPrPF 271R 272 yields. The stereochemistry of the enamide formed in the 6 AuIPr process was rationalized by a more favorable addition of the [AuI] silyl enol ether on the less shielded face of the keten- 2 R2 R R3 1 H C/H iminium ion, i.e. opposite to the R group. H3C/H • AgOTf 3 • H/H C R2 3 3 2 In contrast to arene- and alkene-keteniminium cycliza- R (10 mol%) R CH Cl , r.t. 1 tions, there are only rare examples of related processes in- 1,2 2 2 R 1,2 R1 N • N R1 N Ag 1,2 volving alkynes and allenes. Ohno and Hashmi reported in EWG TfO EWG EWG 2015 a cycloisomerization of alkynyl-ynamides 270 relying 273 274 275 on a dual activation of both the ynamide and terminal Scheme 44 Intramolecular trapping of activated keteniminium ions alkyne in 270 to the gold keteniminium and acetylide moi- with alkenes, alkynes, and allenes eties in 271, respectively.151 Addition of the latter to the for- mer and further Friedel–Crafts-type reaction or formal 3.2.6 Trapping Metalated Activated Keteniminium C(sp3)–H activation yields the corresponding bicyclic and Ions with Nucleophiles Yielding α-Oxo/Imido-carbenes/ tricyclic pyrroles 272. In a similar perspective, intramolecu- carbenoids and Further Cyclization lar trapping of silver keteniminium triflate 274 by an internal allene followed by subsequent demetalation and loss of As described in Section 3.2.3, trapping metalated keten- a proton yields unsaturated piperidines 275, the substitu- iminium ions with nucleophilic pyridine N-oxides or azides tion pattern of the allene in 274 dictating the positions of yields transient metalated ketene acetals which further re- the double bonds.152 act to α-oxo- or α-imido-carbenoid species that can then As an important note, other metals such as iron(II) chlo- undergo a broad range of transformations. This strategy has ride or bromide, used in stoichiometric amounts, smoothly also been utilized with keteniminium ions containing a re- generate N-allyl-iron keteniminium halides from the corre- active group susceptible to intercept this transient carbene, sponding N-allyl-ynamides.153 Intramolecular activation of such as an arene or an alkene. One of the first example was

Syn thesis G. Evano et al. Review reported in 2013 by the Li group who designed an interest- which can also be trapped intramolecularly by arenes and ing entry to oxindoles 280 relying on trapping N-aryl-gold alkenes, as exemplified by the synthesis of 2-aminoin- keteniminium species 277 with pyridine N-oxide (168) fol- doles158 and -pyrroles159 by gold-catalyzed reactions be- lowed by extrusion of pyridine leading to carbenoid 279 tween azides and N-aryl-ynamides and enynamides, re- and C–H insertion (Scheme 45).154 Incorporating one car- spectively. One major interest in the use of azides for the bon atom between the keteniminium and the arene pro- generation of carbenoids from keteniminium ions is their vides isoquinolinones and replacing the benzene ring by an stability and limited reactivity. They can therefore be em- indole gives β-carbolines.155 The carbenoid reactivity can bedded within the ynamide used for the generation of the also be exploited starting from N-allyl-gold keteniminium activated keteniminium ion and trap this reactive interme- species 282, a precursor of carbenoid 284 whose intramo- diate in an intramolecular fashion. In the presence of an ad- lecular cyclopropanation provides an efficient entry to aza- ditional internal functional group able to react with the bicyclohexanones 285.156 As in previous cases, tethering the carbene, fully intramolecular versions can, therefore, be de- keteniminium and the arene/alkene through the nitrogen veloped,160 as illustrated by the impressive gold ketenimini- provides nitrogen heterocycles such as 280 and 285 while um initiated cyclization of 286 to 290 which proceeds in ex- C-tethered precursors yield substituted carbocycles.157 cellent yields (Scheme 46).160a Azides can be used in place of pyridine N-oxides to gen- (4-CF -C H ) PAuCl N3 3 6 4 3 N erate α-imido-carbenoids, instead of α-oxo-carbenoids, (5 mol%) 3 EWG EWG AgOTf • N N (5 mol%) [Au] TfO O DCE, r.t. N 1 R1 Ph3PAuCl R F Sb 2 EWG (4 mol%) EWG 6 N R2 R H O N AgSbF6 • N 286 287 (4 mol%) [Au] 168 H EWG F6Sb N CH2Cl2 0 °C to r.t. [Au] R R + 276 277 N2 R N N N TfO 278 EWG EWG EWG R1 N TfO N N [Au] [Au] R2 H R1 R1

R2 R2 O O 290 289 288 H EWG EWG N N Scheme 46 Generation of α-imido-carbenoids by intramolecular trap- [Au] ping trifunctional activated keteniminium ions with azides and subse- F Sb 6 quent intramolecular cyclopropanation R R 280 279 All examples discussed in this section involve the cy- O IMesAuCl N clization of bifunctional keteniminium ions, or even tri- (4 mol%) EWG AgBF EWG F4B 4 R1 N functional ones, which are simply generated by electrophil- R1 N (4 mol%) • N O ic activation of the corresponding ynamides. Related pro- MsOH [Au] 1 F4B 168 R EWG 2 2 N R DCE, r.t. R cesses involve the addition of nucleophiles to bifunctional 2 R4 R4 [Au] R keteniminium ions – aryl-substituted keteniminium ions, 3 3 R R such as 292 in most cases – followed by cyclization. These 281 282 R4 R3 283 reactions correspond to formal [4+2] cycloadditions from the starting ynamides (Scheme 47). Nucleophiles that can successfully participate in such processes include styrenes 134 161 131a O 293a, imines 293b, and nitriles 293c; addition of O R1 EWG these nucleophiles to keteniminium ions 292 yields cationic R1 EWG N N intermediates 294 whose intramolecular Friedel–Crafts- R4 [Au] R2 R3 F4B type reaction provides 2-amino-dihydronaphthalenes, 2- R2 R4 R3 amino-dihydroisoquinolines, and 2-aminoquinolines 295. 285 284 Formal [4+3] cycloadditions involving epoxides have also Scheme 45 Generation of α-oxo-carbenoids by trapping bifunctional been reported.162 activated keteniminium ions with pyridine N-oxide and subsequent intramolecular reaction with arenes and alkenes

Syn thesis G. Evano et al. Review

with 293a: R3 IPrAuCl (5 mol%) EWG R1 AgNTf2 (5 mol%) 2 N 1 Ph3PAuNTf2 R Tf2N R 2 2 2 EWG DCE, r.t. R EWG 1 R • R (2 mol%) R 167 H N N EWG EWG • N 1 with 293b: • N CH2Cl2 3 R R2 R2 R1 R3 R R1 IPrAuNTf2 (5 mol%) 40 °C [Au] Tf N H/[Au] Y 2 3 DCE, 60 °C 167 296 [Au] N R with 293c: 291 292 EWG TfOH 297 DCE, 120 °C (MW) R3 X

293a: X = CH2 EWG 293b: X = NR4 EWG R3 EWG R3 N N 3 293c: X = N N R R2 2 1 H R 1,2 R 1 or 1 R 1 R3 1 1,2 R R R 1 R3 Tf2N R R3 R3 X H H N N [Au] N R3 X Y EWG EWG EWG 298 N R2 H/[Au] N R2 300 299 (if R1 2 (if R2 EWG EWG -R = cycloalkyl) = H)

295 294 Ar Ar

Scheme 47 Tandem intermolecular trapping of arylketeniminium ions F4B Ar Ar H EWG H and cyclization- formal [4+2] cycloadditions of aryl-ynamides 301 2 1 Ar EWG R R N • N Ar N 2 CH2Cl2 R2 R R1 F4B 1 r.t. F4B R EWG The synthetic usefulness of keteniminium ions, which 124 302 have been used for the design and development of an array Ar H of efficient and innovative chemical transformations, F4B R2 should be quite evident at this point of this review article. Ar N An additional testimony of the exceptional reactivity of R1 EWG these intermediates is their ability to promote sigmatropic 303 shifts of hydrogen or hydride shifts; reactions involving Scheme 48 Keteniminium-induced [1,5]- and [1,3]-hydride shifts such a step will be overviewed in Section 3.3.

3.3 Keteniminium-Induced [1,3]- and [1,5]-H Shifts The synthetic potential of keteniminium-initiated hydride shifts was demonstrated later on, first by the Davies The high electrophilicity of ynamide-derived activated group who designed a remarkably efficient synthesis of keteniminium ions can indeed be used to promote sigma- polycyclic nitrogen heterocycles initiated by a [1,5]-hydride tropic shifts of hydrogen or hydride shifts, even from unac- shift from gold keteniminium chloride 305 (Scheme 49).164 tivated positions, reactions that cannot be promoted with This hydride shift provides stabilized carbocation 306 less reactive amide- or α-chloro-enamide-derived keteni- whose electrocyclic ring closure followed by intramolecular minium ions. cyclopropanation of the internal alkene yields 307. In 2016, This was actually first noted in 2011 by Gagosz, we reported that ynamide-derived keteniminium ions were Skrydstrup and co-workers who, during some studies on sufficiently nucleophilic to initiate [1,5]-hydride shifts from the addition of nucleophiles onto ynamide-derived activat- non-activated positions. Indeed, the generation of keten- ed gold keteniminium ions 296, noted that they could in iminium triflates 309 by protonation of the corresponding fact be trapped by the starting ynamide 167, yielding a sec- ynamides 308 promotes a [1,5]-hydride shift from a non- ond keteniminium intermediate 297 (Scheme 48).163 A activated side chain yielding carbocations 310, the intramo- [1,5]-hydride shift follows, yielding stabilized carbocation lecular trapping of which by the newly installed enamide 298, in resonance with a conjugated iminium ion, whose affords tetrahydropyridines 311.165 Importantly, all at- metalla-Nazarov cyclization followed by [1,2]-hydride shift tempts at initiating this cyclization from a non-activated, or C–H insertion, depending on the nature of the substitu- amide-derived keteniminium ion failed, therefore high- ents, afford 299 and 300, respectively. The electron-with- lighting the unique and higher reactivity of activated drawing group has a dramatic influence on the [1,5]-hy- ynamide-derived keteniminium species. dride shift; while N-sulfonyl-keteniminium ions 297 under- Keteniminium ions can also initiate [1,5]-sigmatropic go the hydride shift, analogous species containing a hydrogen shifts which can trigger further cyclizations to carbamate did not. [1,3]-Hydride shifts are also possible, as polycyclic nitrogen heterocycles as shown in Scheme demonstrated by the formation of conjugated iminium ion 50.73b,81 We indeed reported in 2014 a novel keteniminium- 303 from keteniminium tetrafluoroborate 302.84 initiated cationic polycyclization from key intermediate 313, readily generated by protonation of the starting

Syn thesis G. Evano et al. Review

X ately trapped 313 prior to the hydrogen shift and only the X III X [Au ] OR1 poorly nucleophilic bistriflimidate enabled a catalytic pro- 1 1 Cl OR (5 mol%) OR H 2 R H cess. A comparison of the structures of the starting toluene N • N R2 [Au] N EWG ynamide and the final polycyclic products clearly highlights r.t. to 120 °C EWG EWG [Au] Cl R2 the usefulness of the chemistry of keteniminium ions for 304 305 306 the synthesis of complex molecular architectures. (Y = Ar, OR1) O The synthetic utility of these reactive intermediates will N be further highlighted in the Section 4 of this review article Cl Au O Cl X dealing with the use of the chemistry of keteniminium ions [AuIII] OR1 for the synthesis of natural and/or biologically relevant H N molecules. EWG

R2 307 4 Keteniminium Ions: Pivotal Intermediates 5 R 5 4 R 4 R R4 R R5 for the Synthesis of Natural and/or Biological- H R3 R1 TfO R3 TfOH 1 H R 3 2 R2 R ly Relevant Molecules R CH2Cl2 • N 1 EWG N R N –60 °C H TfO EWG R2 EWG The chemistry of keteniminium ions has been indeed 308 309 310 used for the preparation of various natural products, even if the number of synthetic applications is still limited com- R5 R4 pared to the synthetic potential of reactions involving these 1 3 R R reactive intermediates.

N R2 The main applications of keteniminium ions in natural EWG product synthesis rely on their [2+2] cycloaddition with 311 alkenes, even if the cyclobutane formed in the process is Scheme 49 Cyclizations based on a keteniminium-induced [1,5]-hy- rarely found in the target molecules but rather used as a dride shifts synthetic handle for the formation of larger ring systems. Indeed, one of the only synthesis of a naturally occurring cyclobutane using Ghosez’s cycloaddition was reported in ynamide 312 by triflic acid or bistriflimide. The generation 1991 by Granguillot and Rouessac (Scheme 51).166 With the of this activated keteniminium ion triggers a [1,5]-sigma- aim of developing a practical and scalable synthesis of gran- tropic hydrogen shift yielding 314 and subsequent electro- disol (320) (a monoterpenic pheromone of the cotton boll cyclization and intramolecular Friedel–Crafts-type reac- weevil Anthonomus grandis from which it gets its name), tions afford 315. The nature of the counteranion of keten- which is the main component of a mixture known as iminium ion 313 was found to have a dramatic influence on ‘grandlure’ used to protect cotton crops from the boll wee- the outcome of the polycyclization since a chloride immedi- vil, they envisioned that the cyclobutane ring could be installed by a [2+2] cycloaddition between a properly substi-

1 R2 R tuted keteniminium and a suitable alkene. The best combi- R2 TfOH nation found relied on keteniminium ion 317, readily CH Cl R1 EWG 2 2 –78 °C H N EWG • N 3 R3 or Tf NH R 2 H X (20 mol%) CH2Cl2, r.t. Cl R4 R4 BnO N ZnCl2 • N 318 BnO 312 313 Cl3Zn then NaOH CH2Cl2 O r.t. PMPO OPMP PMPO 316 317 319 1 (79%, cis/trans: 65:35) 1 R R R2 X R2 H and H H N EWG N EWG

3 HO HO 4 3 R R R 4 320: (±)-grandisol 321: (±)-fragranol 315 R 314 Scheme 50 Keteniminium-induced [1,5]-sigmatropic hydrogen shift Scheme 51 Total synthesis of (±)-grandisol and (±)-fragranol featuring and subsequent polycyclization an alkene/keteniminium [2+2] cycloaddition

Syn thesis G. Evano et al. Review

Tf2O F2α (327) and E2, depicted in Scheme 52 is illustrative of this tBu N tBu strategy. Other (formal) total syntheses relying on a key alkene/keteniminium [2+2] cycloaddition include de De O Mesmaeker’s synthesis of (+)-5-deoxystrigol (328),167g N TBDPSO 167d DCE, r.t., Shishido’s formal synthesis of (–)-anastrephin (329), OTBDPS • N H 168 TfO and Kim’s formal synthesis of (+)-gibberellic acid (330). 322 95% 323 In this last case, a ring enlargement of the cyclobutanone adduct with diazomethane was used in place of the Baeyer– Villiger oxidation. m-CPBA NaHCO3 In comparison, the use of ynamide-derived, activated keteniminium ions in total synthesis has been much less TBDPSO O CH2Cl2 TBDPSO r.t. O O exploited to date, which is actually fairly logical since their 325 95% 324 (after hydrolysis) chemistry has been thoroughly investigated only recently. The two total syntheses relying on activated keteniminium O OH C5H11 ions essentially involve an arene-keteniminium cyclization. C5H11 CO2H 3 The first example was reported by the Hsung group who further demonstrated the synthetic potential of their keten- PBO O HO iminium Pictet–Spengler cyclization by using it as a key O OH step for the synthesis of 10-desbromoarborescidine A (334) 326 327: prostaglandin F2α and 11-desbromoarborescidine C (335) (Scheme 53).147 O O They indeed demonstrated that the common tricyclic tetra- O O O H OH hydropyridoindole core of these natural products could be

O O efficiently installed by an indole-keteniminium cyclization O O HO from 332. A related strategy was utilized later by the Yama- H CO2H oka and Takasu group for the preparation of marinoquino-

328: (+)-5-deoxystrigol 329: (–)-anastrephin 330: (+)-gibberellic acid line A (338) and C (339) as well as aplidiopsamine A (not shown) using a pyrrole-keteniminium cyclization from 337, Scheme 52 Formal total synthesis of prostaglandin F2α featuring an asymmetric alkene/keteniminium [2+2] cycloaddition and other natural in situ deprotection of the Boc groups, and aromatization 148b products prepared via this reaction (grey circles indicate the carbon at- directly providing the target molecules. oms originating from the keteniminium, blue circles those from the alkene)

PNBSAH HN HN (15 mol%) X HN toluene prepared by reacting the corresponding α-methyl-γ-buty- 70–90 °C N • N TsN rolactone-derived α-chloro-enamine 316 with zinc chlo- Ts H 56–67% PNBSA Ts X X ride, and alkene 318 providing, after basic hydrolysis, cyc- 332 333 331 loadduct 319 obtained as a mixture of diastereoisomers in (X = Cl, OBn) which the cis isomers are formed predominantly. Wolff– Kishner reduction of the ketone followed by simple functional group manipulations and separation of the diastereo- OH HN isomers finally gave racemic grandisol (320) and fraganol N (321). H N Apart from this example, most uses of this cycloaddition N for the preparation of naturally occurring and/or biological- 334: 10-desbromo- 335: 11-desbromo- ly relevant molecules actually rely on the combination of an arborescidine A arborescidine C intramolecular cycloaddition with a subsequent Baeyer– Villiger oxidation of the cyclobutanone cycloadduct.167 This BocN BocN TfOH HN strategy was found to be especially relevant for the prepara- R R N CH2Cl2 • N N r.t. H tion of prostaglandins, prostanoids, and analogues, the ste- Boc TfO Boc R 73–74% reochemical outcome of the cycloaddition relying on the 336 337 338: R = H: marinoquinoline A; use of either stereocenters incorporated within the tether 339: R = Ph: or on the amine which then acts as a traceless auxiliary, or marinoquinoline C both. Ghosez’s synthesis of bicyclic lactone 325,167c an ad- Scheme 53 Applications of the intramolecular arene-keteniminium vanced intermediate in Corey’s synthesis of prostaglandins cyclization in total synthesis

Syn thesis G. Evano et al. Review

5 Conclusions and Perspectives 7575. (d) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. (e) Evano, G.; Since the pioneering work of Viehe in the late 1960s, the Coste, A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49, 2840. chemistry of keteniminium ions has been considerably (f) Madelaine, C.; Valerio, V.; Maulide, N. Chem. Asian J. 2011, 6, 2224. (g) Evano, G.; Theunissen, C.; Lecomte, M. Aldrichimica studied, which resulted in the development of a series of re- Acta 2015, 48, 59. (h) Li, X.; Yan, S.; Lei, Z.; Bo, P. Chin. J. Org. markably efficient synthetic procedures enabling the Chem. 2016, 36, 2530. preparation of a broad diversity of building blocks, from the (3) For examples of characterization of keteniminium ions, see: simplest to the most sophisticated ones. They can be easily (a) Weingaeten, H. J. Org. Chem. 1970, 35, 3970. (b) Lambrecht, generated in situ from readily available starting materials J.; Zsolnai, L.; Huttner, G.; Jochims, J. C. Chem. Ber. 1982, 115, such as amides under mild conditions and their high elec- 172. (4) For an example, see: Deyrup, J. A.; Kuta, G. S. J. Org. Chem. 1978, trophilicity has been elegantly exploited in chemical syn- 43, 501. thesis; many research groups worldwide being especially (5) For an example, see: Viehe, H. G.; Buijle, R.; Fuks, R.; Merényi, active in this area which has undergone a clear renaissance R.; Oth, J. M. F. Angew. Chem. Int. Ed. 1967, 6, 77. recently. (6) Ghosez, L.; Haveaux, B.; Viehe, H. G. Angew. Chem. Int. Ed. 1969, Recent developments in the chemistry of ynamides, 8, 454. which can now be easily prepared from an array of re- (7) Villalgordo, J. M.; Heimgartner, H. Helv. Chim. Acta 1992, 75, agents, have also clearly contributed to the chemistry of 1866. (8) (a) Marchand-Brynaert, J.; Ghosez, L. J. Am. Chem. Soc. 1972, 94, keteniminium ions, the presence of an electron-withdraw- 2870. (b) Sidani, A.; Marchand-Brynaert, J.; Ghosez, L. Angew. ing group on the nitrogen atom in this case considerably in- Chem. Int. Ed. 1974, 13, 267. (c) Saimoto, H.; Houge, C.; Hesbain- creasing their reactivity and allowing for the development Frisque, A.-M.; Mockel, A.; Ghosez, L. Tetrahedron Lett. 1983, 24, of reactions in which simple, unactivated keteniminium 2251. fail. (9) Falmagne, J.-B.; Escudero, J.; Taleb-Sahraoui, S.; Ghosez, L. There is little doubt that the chemistry of these highly Angew. Chem. Int. Ed. 1981, 20, 879. reactive intermediates will continue to find various syn- (10) Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694. (11) For reviews on the activation of amides with triflic anhydride, thetic applications in the years to come and will attract see: (a) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tet- more and more research groups. In this perspective, a bet- rahedron 2000, 56, 3077. (b) Kaiser, D.; Maulide, N. J. Org. Chem. ter understanding of their electrophilicity and of the influ- 2016, 81, 4421. ence of the substituents of the cationic heterocumulene (12) For major references on the use of 2-halopyridines in the elec- will be crucial; the measurement of the electrophilicity pa- trophilic activation of amides, see: (a) Myers, A. G.; Tom, N. J.; rameters E of a set of representative keteniminium ions Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem. Soc. 1997, 119, 6072. (b) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, would represent a major step forward and we hope to see 128, 14254. (c) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. these remarkable reactive intermediates included in the Chem. Soc. 2007, 129, 10096. Mayr reactivity scale in the near future. (13) Marchand-Brynaert, J.; Ghosez, L. J. Am. Chem. Soc. 1972, 94, 2869. 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