Metal-catalyzed formation of 3- and 4-membered rings Von der Fakultät Chemie der Universität Stuttgart zur Erlangung der Würde eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigte Abhandlung vorgelegt von Marie-Idrissa Picher aus Caen, Frankreich Hauptberichter: Prof. Dr. Bernd Plietker Mitberichter: Tag der mündlichen Prüfung: Prof. Dr. René Peters 14 Juni 2021 Institut für Organische Chemie der Universität Stuttgart 2021 i Die vorliegende Arbeit entstand auf Anregung und unter Anleitung von Herrn Prof. Dr. Bernd Plietker am Institut für Organische Chemie der Universität Stuttgart im Zeitraum von Juni 2016 bis März 2020. Parts of this thesis have been published: 1. “Fe-catalyzed selective cyclopropanation of enynes under photochemical or thermal conditions", M.-I. Picher, B. Plietker, Org. Lett. 2020, 22, 340−344. 2. “Determining the relative configuration of propargyl cyclopropanes by co- crystallization”, F. Krupp, M.-I. Picher, W. Frey, B. Plietker, C. Richert, Synlett, 2021, 32, 350−353. 3. “Silver-catalyzed oxidative ring expansion of propargyl cyclopropanes”, M.-I. Picher, H. Yuan, B. Plietker, Manuscript in preparation. ii Erklärung über die Eigenständigkeit der Dissertation Hiermit erkläre ich, dass ich die vorliegende Dissertation „Metal-catalyzed formation of 3- and 4-membered rings“ selbstständig verfasst und keine anderen als die genannten Quellen und Hilfsmittel verwendet habe. Die aus fremden Quellen entnommenen Passagen und Gedanken sind als solche kenntlich gemacht. Berlin, den 20.06.21 Marie-Idrissa Picher iii Acknowledgements I am grateful to Prof. Dr. Bernd Plietker for giving me the opportunity to conduct my doctoral studies in his group. I would like to express my gratitude for his supervision, support and guidance, and for giving me the chance to work on challenging topics. I would also like to extend my appreciation to Prof. Dr. René Peters and Prof. Dr. Bernhard Hauer for kindly accepting to be part of my examination committee. I wish to thank all the past and current members of the Plietker group for welcoming me into the research group, the nice working atmosphere and the fruitful discussions, whether they were related to chemistry or not. I would like to particularly thank Johannes Teske, Che-Hung Lin, Isabel Alt, Fabian Rami, Pascal Eisele and Frank Kraus for all the helpful advice they gave me and the valuable exchanges we had over our respective research topics. Sincere thanks to all the members of the so-called “girls lab” and more particularly to Claudia Guttroff, Aslihan Eisele, Franziska Bächtle and Samuel Lorenz for the very nice moments in the lab, the encouragements and for expanding my musical horizons. I wish to warmly thank Frank Kraus for the ability to match and at times surpass my terrible sense of humor, all his support and the great moments during those four years. I would also like to thank Flavia Izzo and Min Zheng for the good times we had in the lab or outside of it. Special thanks to Hongdong Yuan for his valuable help and for overtaking the last research topic I worked on, and to Johannes Teske and Aslihan Eisele for correcting my thesis and for their helpful input. I wish to thank Felix Krupp and Dr. Wolfgang Frey for the chance to work on a joint project, the fruitful discussions and the opportunity to learn more about different fields of chemistry. I would like to sincerely thank Dr. Wolfgang Frey for the X-Ray analyses as well as all the members of the analytical department for their kind help and support. Very warm thanks to Aurélie Lacroix, Tuyet-Van Vu, Alain Li, Sosthène Ung, Franck Le Vaillant, Guillaume Furet and Cécile Majesté for their encouragement and their friendship dating back to the first day we started studying chemistry together, and growing stronger every year. I also wish to sincerely thank Madeleine Alliez for her continuous inspiration iv and strength she shared since we met in high school, and for our treasured friendship. Finally, my deepest thanks to my family for their love and their endless support throughout my studies. I am extremely grateful to my parents for their intellectual curiosity and for the open-minded education my siblings and I received. Their continuous encouragement to find a path of my own vastly contributed to my achievements. v À ma famille vi “Au-dessus des étangs, au-dessus des vallées Des montagnes, des bois, des nuages, des mers, Par delà le soleil, par delà les éthers. Par delà les confins des sphères étoilées. Mon esprit, tu te meus avec agilité, Et, comme un bon nageur qui se pâme dans l’onde, Tu sillonnes gaiement l’immensité profonde Avec une indicible et mâle volupté. Envole-toi bien loin de ces miasmes morbides ; Va te purifier dans l’air supérieur, Et bois, comme une pure et divine liqueur, Le feu clair qui remplit les espaces limpides. Derrière les ennuis et les vastes chagrins Qui chargent de leur poids l’existence brumeuse Heureux celui qui peut d’une aile vigoureuse S’élancer vers les champs lumineux et sereins ; Celui dont les pensers, comme les alouettes, Vers les cieux le matin prennent un libre essor −Qui plane sur la vie, et comprend sans effort Le langage des fleurs, et des choses muettes !” ― Charles Baudelaire, Élévation vii Table of Contents Erklärung über die Eigenständigkeit der Dissertation...................................................ii Acknowledgements ..................................................................................................... iii Table of Contents ....................................................................................................... vii List of Abbreviations ....................................................................................................ix I. Theoretical Section ...................................................................................................... 1 1. Introduction ......................................................................................................... 2 1.1. Transition Metal-Catalyzed Cyclopropanation of Olefins ................................ 2 1.2. Photochemical Cyclopropanation of Olefins ................................................. 24 1.3. Transformation of Cyclopropanes ................................................................ 29 1.4. Synthesis of Cyclobutenes ........................................................................... 34 2. TBA[Fe]-Catalyzed Cyclopropanation of Aryl Alkenes and 1,3-Enynes under Photochemical or Thermal Activation ........................................................................ 43 2.1. Purpose of this Research ............................................................................. 43 2.2. Results and Discussion ................................................................................ 44 2.3. Conclusion .................................................................................................... 76 3. Silver-Catalyzed Oxidative Ring Expansion of Propargyl Cyclopropanes. ....... 78 3.1. Purpose of this Research ............................................................................. 78 3.2. Results and Discussion ................................................................................ 79 3.3. Conclusion and Outlook ............................................................................... 95 4. Summary and Future Work .............................................................................. 97 5. Abstract (English) ............................................................................................. 99 6. Abstract (Deutsch) .......................................................................................... 101 II. Experimental Section .............................................................................................. 103 1. General Remarks ........................................................................................... 104 2. Iron-Catalyzed Cyclopropanation of Aryl Alkenes .......................................... 105 2.1. Aryl Alkenes Synthesis ............................................................................... 105 2.2. Iron-Catalyzed Cyclopropanation of Alkenes under Thermal or Photochemical Activation .......................................................................................................... 112 3. Iron-Catalyzed Cyclopropanation of 1,3-Enynes ............................................ 138 viii 3.1. 1,3-Enynes Synthesis ................................................................................. 138 3.2. Iron-Catalyzed Cyclopropanation of 1,3-Enynes under Thermal or Photochemical Activation .................................................................................. 158 3.3. Propargyl Cyclopropanes Derivatization..................................................... 190 4. Silver-Catalyzed Oxidative Ring Expansion of Propargyl Cyclopropanes ...... 192 4.1. Synthesis of Cobalt(II)-Salen Catalyst 34 ................................................... 192 4.2. Preparation of the Propargyl Cyclopropanes .............................................. 199 4.3. Silver-Catalyzed Oxidative Ring Expansion of Propargyl Cyclopropanes .. 211 4.4. Comparison and Stability Experiments ....................................................... 219 4.5. Cuprate Addition ......................................................................................... 220 5. X-Ray Diffraction Analysis .............................................................................. 223 6. References ..................................................................................................... 354 ix List of Abbreviations 1,2-DCE 1,2-Dichloroethane A. U. Arbitrary Unit Ac Acetyl acac Acetylacetone ACP Arylcyclopropane Alk Alkyl Ar Aryl ATR Attenuated Total Reflection BArF Tetrakis(3,5-bis(trifluoromethyl)phenyl)borate BHT 2,6-Di-tert-butyl-4-methylphenol BINOL 1,1′-Binaphthalene-2,2′-diol Bn Benzyl Boc tert-Butyloxycarbonyl BOX Bisoxazoline bpy Bipyridyl Bu Butyl calcd. Calculated cat Catalyst CFL Compact Fluorescent Lamp COD 1,5-Cyclooctadiene Cp Cyclopentadienyl Cy Cyclohexyl d.e. Diastereomeric Excess d.r. Diastereomeric Ratio DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane x dfp 2,6-Difluorophenyl DIBAL-H Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine DMAP 4-(Dimethylamino)pyridine DMF Dimethylformamide DMP Dess-Martin Periodinane DMSO Dimethyl Sulfoxide dppp 1,3-Bis(diphenylphosphino)propane e.e. Enantiomeric Excess EDA Ethyl Diazoacetate EDG Electron-Donating Group EI Electron Ionization eq. Equivalent e.r. Enantiomeric Ratio ESI Electrospray Ionization esp α,α,α′,α′-Tetramethyl-1,3-benzenedipropionic Acid Et Ethyl Et2O Diethyl Ether EWG Electron-Withdrawing Group FG Functional Group GC Gas Chromatography GC/MS Gas Chromatography/Mass Spectrometry h Hour Hex Hexyl HFIP Hexafluoroisopropanol HMDS Hexamethyldisilazane h Light Irradiation HPLC High Pressure Liquid Chromatography xi HRMS High Resolution Mass Spectrometry Hz Hertz i iso IR Infrared Spectroscopy ISC Intersystem Crossing J Coupling Constant  Wavelength LED Light-Emitting Diode M Molarity Mb Myoglobin Me Methyl MeCN Acetonitrile MeOH Methanol min Minute MOM Methoxymethyl Ms Mesyl MTBE Methyl tert-Butyl Ether MW Microwave Irradiation n Linear n.d. Not Determined NBS N-Bromosuccinimide NHPI N-Hydroxyphtalimide NIS N-Iodosuccinimide NMI N-Methylimidazole NMR Nuclear Magnetic Resonance OTf Trifluoromethanesulfonate p para Ph Phenyl xii Pheox Phenyloxazoline pin Pinacol ppm Parts Per Million Pr Propyl Pybox Pyridine-2,6-bis(oxazoline) quant. Quantitative r.t. Room Temperature rac Racemic Rf Retention Factor SCE Saturated Calomel Electrode S-DOSP N-(Dodecylphenylsulfonyl)-(S)-prolinate S-TCPTAD (S)-Adamantan-1-yl-(4,5,6,7-tetrachloro-1,3-dioxo-1,3-dihydro- isoindol-2yl)-acetate t tert TBA[Fe] Bu4N[Fe(CO3)(NO)] TBDPS tert-Butyldiphenylsilyl TEMPO 2,2,6,6-Tetramethylpiperidine 1-Oxyl THF Tetrahydrofuran TLC Thin Layer Chromatography TMANO Trimethylamine N-Oxide TMS Trimethylsilyl Tol Tolyl TPP Tetraphenylporphyrin Ts Tosyl UV Ultraviolet VCP Vinylcyclopropane 1 I. Theoretical Section 2 1. Introduction 1.1. Transition Metal-Catalyzed Cyclopropanation of Olefins 1.1.1. Introduction Cyclopropanes have been widely employed as versatile intermediates in the synthesis of medium-sized rings or highly functionalized molecules.[1,2] They present a ring strain of approximately 27.5 kcalmol-1 and possess shorter C-H bonds than their linear counterpart, due to an increased s character in these bonds, as well as shorter C-C bonds, thus providing them with similar reactivity properties to C=C double bonds.[3,4] A wide variety of biologically-relevant compounds containing this small cycloalkane unit have been isolated since the discovery of (+)-trans-chrysanthemic acid 1 (Figure 1) in 1924,[5] thus prompting considerable attraction for the synthesis of cyclopropanes in academic research.[2] Figure 1: Structure of (+)-trans-chrysanthemic acid Simmons and Smith reported the first cyclopropanation of alkenes in 1958, employing a iodomethylzinc species formed in situ.[6] The Simmons-Smith cyclopropanation is characterized by a “butterfly-type” transition state in which the carbenoid species IZnCH2I reacts with an olefin, thus affording cyclopropanes with excellent stereospecificity as well as chemoselectivity (Figure 2).[1] 3 Figure 2: Simmons-Smith cyclopropanation A few years later, Nozaki et al. reported the first example of olefin cyclopropanation via metal-catalyzed decomposition of diazo compounds,[7] opening a new field of studies to develop a reaction class that is nowadays one of the most common processes to form cyclopropanes.[8] 1.1.2. Transition Metal-Catalyzed Cyclopropanation of Olefins The cyclopropanation of alkenes employing diazo compounds as carbene precursors catalyzed by transition metals typically follows the general catalytic cycle described in Scheme 1. Scheme 1: Proposed mechanism for the metal-catalyzed cyclopropanation of olefins with diazo compounds 4 In this process, a metal-carbene species LnM=CRR’ is formed by reaction of a diazo compound to a metal complex and subsequent extrusion of N2. The carbene CRR’ group is then transferred to an olefin, through a [2+1] cycloaddition process (I) or the formation of a metallacyclobutane intermediate (II), resulting in the formation of two diastereomers, namely cis- and trans-cyclopropanes. In most of the cases Rh-, Cu-, Ru-, Co-, Fe- and Pd-based catalysts are employed for this reaction.[1] A common side-reaction is the catalytic homo-coupling of the diazo compound, responsible for the decrease in cyclopropanation yields. To circumvent this undesired reaction, most of the developed catalytic processes require slow addition of the diazo compound to the reaction mixture to maintain a low concentration of this reactant in solution. 1.1.2.1. Copper After the first report by Nozaki et al.,[7] a broad range of asymmetric copper complexes were developed for the cyclopropanation of olefins. The pioneering work of Pfaltz[9], Evans[10] and Kanemasa[11] contributed to the development of the copper- catalyzed cyclopropanation with high enantiocontrol. Scheme 2: Asymmetric styrene cyclopropanation with Pfaltz, Evans and Kanemasa’s catalytic systems 5 Combining a chiral copper catalyst such as Cu-semicorrin 3 (Pfaltz), Cu-bis(oxazoline) 4 (Evans) or Cu-diamine 5 (Kanemasa) with a chiral or sterically hindered diazo ester allowed for the formation of cyclopropanes from styrene in high diastereocontrol and enantioselectivities (Scheme 2). Despite the main use of bis(oxazolines) as ligands other catalytic systems employing ligands including bipyridines, diamines or amino alcohols were shown to be successfully applied to the asymmetric cyclopropanation of olefins.[1,12– 15] A few examples are shown in Scheme 3. Scheme 3: Examples of asymmetric cyclopropanation of styrene with EDA While most of the developed copper catalysts lead to the selective formation of trans- cyclopropanes, the group of Pérez developed a tris(pyrazolylborate) ligand that efficiently catalyzed the reaction is a cis-selective fashion.[16] As depicted in Scheme 4, with 2 mol% of copper homoscorpionate catalyst 9 and an excess of 2, the corresponding cyclopropane was obtained in high yield and almost exclusive cis-selectivity. 6 Scheme 4: Cis-selective cyclopropanation of styrene Finally, the copper-catalyzed cyclopropanation of olefins was recently applied in the synthesis of complex polycyclic scaffolds. Zhou and coworkers reported the first intramolecular enantioselective cyclopropanation of Boc-protected indoles using a copper complex of chiral spiro bis-oxazoline ligand 12.[17] The reaction, proceeding with high yields and excellent enantioselectivities, led to the formation of an all-carbon quaternary stereogenic center at the 3-position of the indole moiety (Scheme 5). Scheme 5: Enantioselective intramolecular cyclopropanation of indole derivatives 7 1.1.2.2. Rhodium Because of their high activity, rhodium and more particularly dirhodium(II) catalysts are extensively used in cyclopropanation reactions, despite a diastereocontrol generally lower than that exhibited by copper-based catalysts.[1,18–20] Dirhodium complexes are generally divided into two main classes; dirhodium(II) carboxylates and carboxamidates. Early works from the groups of Doyle, Achiwa and Lahuerta revealed that rhodium complexes 13 to 15 allowed for the formation of aryl cyclopropanes in moderate diastereoselectivities and good to excellent enantioselectivities (Figure 3).[21–23] Even though trans-cyclopropane formation was preferred, the corresponding cis- cyclopropanes displayed higher e.e. values than their trans-counterparts. Figure 3: Selected examples of dirhodium(II) catalysts Higher diastereoselectivities were obtained through the use of donor/acceptor carbenoids, first introduced by Davies.[24] For instance, he was able to demonstrate that employing Rh2(S-DOSP)4 17 and diazo ester 16 as carbene precursor led to propargyl cyclopropane 18 in 84 % d.e. and 89 % e.e. (Scheme 6).[25] 8 Scheme 6: Asymmetric synthesis of propargyl cyclopropane 18 The application of rhodium in the cyclopropanation of olefins is mostly confined to electron-rich or -neutral alkenes, due to the electrophilic nature of Rh-bound carbenes.[20] The group of Davies reported in 2013 the first enantioselective cyclopropanation of electron-poor alkenes.[26] Rh2(S-TCPTAD)4 19 efficiently catalyzed the cyclopropanation of acrylates with aryl diazoacetates in high yields and excellent diastereo- and enantiocontrol as exemplified in Scheme 7. Scheme 7: Enantioselective cyclopropanation of electron-poor alkenes Lastly, Fox and co-workers successfully applied a rhodium(II)-catalyzed cyclopropanation to form a key intermediate in the total synthesis of Piperarborenine B.[27] As depicted in 9 Scheme 8, the cyclobutane core of 23 was obtained enantioselectively after an intramolecular cyclopropanation catalyzed by a novel Rh(II)-complex and subsequent nucleophilic opening of the dicyclopropane intermediate and BHT-proton quenching.[2] Scheme 8: Total synthesis of Piperarborenine B 24 via cyclopropanation/ring-opening sequence 1.1.2.3. Ruthenium Ruthenium-based catalysts have also been investigated in the cyclopropanation of olefins. As complexes of Ru can be found in various oxidation states, they allow for a great diversity to be evaluated. However, one of the drawbacks of Ru-based complexes is their propensity to catalyze metathesis as well as alkene homologation reactions.[13,28] In 1994, Nishiyama reported the first very effective catalyst in the asymmetric 10 cyclopropanation of olefins.[29] Employing Ru-Pybox complex 25 and a sterically hindered diazo ester, he showed that styrene could be efficiently cyclopropanated in 97:3 diastereomeric ratio (trans:cis) and excellent enantioselectivities were obtained for each diastereomer (Figure 4). The group of Che introduced later on the use of porphyrin-based Ru catalysts such as 26 that exhibited excellent enantio- and diastereocontrol (Figure 4).[1,30,31] Figure 4: Nishiyama and Che’s systems used in the Ru-catalyzed cyclopropanation of styrene A few Ru-based complexes can be employed for the cis-selective cyclopropanation of olefins with high enantioselectivity. Early examples include the works of Mezzetti, who reported that employing [RuCl(PNNP)]+ catalyst 27 efficiently led to the formation of cyclopropanes in cis-selective fashion, and Katsuki, who developed Ru-salen complex 28 to catalyze the cyclopropanation of alkenes under light irradiation in excellent cis- selectivity (Scheme 9).[32,33] 11 Scheme 9: Ru-catalyzed cis-selective cyclopropanation Very recently, Mendoza et al. successfully applied the use of a Ru(II)-Pheox initially developed by the group of Iwasa,[34] in the first unified asymmetric synthesis of functionalized cyclopropanes.[35] As shown in Scheme 10, they designed the redox-active diazo compound 29 containing an N-hydroxyphtalimide ester leaving group to allow for the formation of a wide range of substituted cyclopropanes in high enantioselectivities. Scheme 10: Unified assembly of diverse chiral cyclopropanes employing a Ru(II)-Pheox catalyst 12 The method was not only applicable to aryl- or alkyl-substituted alkenes but also to olefins containing alcohols, esters, amines, amides or silyl substituents. Removal of the NHPI leaving group introduced further functionalities on the resulting cyclopropanes, with conservation of the chiral information. 1.1.2.4. Cobalt Cobalt complexes have also been shown to display good reactivity in the cyclopropanation of olefins. The first enantioselective cyclopropanation catalyzed by a cobalt complex was reported in 1978 by the group of Nakamura.[36] By employing the camphor-derived Co(II) complex 31 (Figure 5), they could obtain cyclopropanes with up to 88 % e.e. Figure 5: Nakamura’s Co(II) catalyst A few years later, Yamada reported a trans-selective cyclopropanation catalyzed by 33,[37] while Katsuki employed a new salen ligand for the cis-selective Co(II)-catalyzed cyclopropanation of olefins[38] (Scheme 11). In both cases, addition of a catalytic amount of NMI was shown to increase the reaction rate as well as to form the corresponding products with higher diastereo- and enantioselectivities by acting as an additional ligand on the cobalt center.[38] 13 Scheme 11: Trans- and cis-selective Co(II)-catalyzed cyclopropanation Important contributions were made by Zhang and co-workers who designed new Co(II)- porphyrin complexes to enable the formation of cyclopropanes in high diastereo- and enantioselectivities. The reaction is postulated to proceed via a Co(III)-carbene radical intermediate.[20] As shown in Scheme 12, Co(II)-porphyrin complex 36 was employed in the cyclopropanation of olefins with various acceptor/acceptor diazo esters. 14 Scheme 12: Co-catalyzed cyclopropanation of olefins with acceptor/acceptor diazo esters Electron-rich as well as electron-poor olefins were converted in high yields using nitro-, cyano-, keto- and formyl-diazoacetates as carbene precursors.[39–42] The use of bulky ligands on the porphyrin core as well as the introduction of O--H-N and X--H-N hydrogen bonding interactions between the diazoacetate substituents and the porphyrin helped rigidifying the structure of the cobalt(III)-carbene radical intermediate to achieve high diastereo- and enantioselectivities. 15 1.1.3. Iron-Catalyzed Cyclopropanation 1.1.3.1. Iron Complexes Despite being less investigated than other metals such as Cu, Rh, Ru or Co for the cyclopropanation of olefins, Fe still remains of high interest due to its relative non-toxicity, abundancy and its availability in different oxidation states.[43–49] The first report on iron- catalyzed cyclopropanation of olefins with diazo esters was made by the group of Hossain in 1993.[50] Employing the Lewis-acid catalyst [(5-C5Me6)Fe(CO)2]BF4 40, they showed that styrene and α-methylstyrene reacted smoothly with ethyl diazoacetate to give the corresponding cyclopropanes in moderate cis-selectivity (Figure 6). Figure 6: Cyclopropanation of olefins with EDA catalyzed by [(5-C5Me6)Fe(CO)2]BF4 The authors postulated the formation of the short-lived carbocation 41 during the catalytic cycle, that collapses before occurrence of the rotation of the Cβ-Cγ bond, and thus would be accountable for the resulting cis-selectivity. This cyclopropanation reaction was later extended to non-conjugated olefins as well as vinyl ethers.[51,52] Kodadek and Woo reported the use of Fe(II) and Fe(III) porphyrin complexes for the 16 cyclopropanation of olefins (Figure 7).[53] The active Fe(II)-porphyrin complex could be obtained from the corresponding Fe(III) species through in situ reduction by CoCp2 or, in the case of Fe complexes bearing electron-poor porphyrins ligands, ethyl diazoacetate.[48] In general, the reaction exhibited a preferred trans-selectivity, and up to 96:4 d.r. (trans:cis) was obtained by Pastorini upon using Fe(III)-porphyrin 45.[54] Figure 7: Iron porphyrins for the cyclopropanation of olefins and proposed transition state The reaction is proposed to go via an iron-carbene species formed by reaction of the FeII- porphyrin complex with the diazo ester followed by the formation of carbene transfer transition states depicted in Figure 7.[53] The selectivity arises from the orientation of the approaching alkenes; minimizing steric interaction between the carbene and the larger olefin substituent (RL) is favored and hence results in the formation of the trans- cyclopropane as the major product. Che and co-workers reported the isolation and characterization by X-ray crystallography of the stable Fe-porphyrin(CPh2) carbene complex formed by reaction of FeII(46) with N2CPh2, and its further use in the intermolecular cyclopropanation of styrene derivatives as well as in the intramolecular cyclopropanation of allylic diazoacetates.[55] More recently, the group of Deng described the use of a stable open-shell iron complex, obtained after reaction of diazo compound 48 and iron species 47 (Scheme 13), and its application in the cyclopropanation of olefins.[56] 17 Scheme 13: Formation of the iron(II) carbene complex 49 and subsequent cyclopropanation with alkenes Complex 49 was shown to react with a variety of electron-rich and -poor alkenes to form the corresponding cyclopropanes in very good yields, and extensive mechanistic studies led the authors to postulate that the cyclopropanation step occurred through a radical- type process. Attempts to develop an asymmetric iron-catalyzed cyclopropanation of olefins with diazo compounds were made by Woo by using chiral porphyrins (Figure 8, 54 and 57) and tetraaza macrocyclic ligands (56).[57] However, despite an increase in diastereoselectivity, the enantioselectivities displayed were modest. Higher enantioselectivities were obtained by Simonneaux (up to 99:1 trans:cis ratio and 75 % e.e. for the trans isomer) and Che (up to 23:1 trans:cis ratio and 86 % e.e. for the trans isomer) using Halterman porphyrin 58 as ligand for the cyclopropanation of alkenes with trifluoromethyl diazoacetate and ethyl diazoacetate, respectively.[58,59] Moreover, the use of the water-soluble complex Fe(59)Cl allowed for the cyclopropanation of styrene with ethyl diazoacetate to be performed in water, resulting in the formation of the corresponding cyclopropane in 85 % yield, 98:2 d.r. (trans:cis) and 83 % e.e. (trans).[60] 18 Figure 8: Ligands for the iron-catalyzed asymmetric cyclopropanation of olefins More recently, up to 99:1 d.r. (trans:cis) and 80 % e.e. (trans) were reported by the groups of Boitrel and Gallo when chiral bis-strapped porphyrin 55 was employed in the cyclopropanation of aryl and non-aryl olefins with diazo esters.[61,62] Spiro-bisoxazoline iron complexes were successfully used in highly selective intramolecular cyclopropanation reactions[63,64] as exemplified in Scheme 14. 19 Scheme 14: Intramolecular cyclopropanation of olefins using chiral BOX-Fe complexes In 2014, Zhou et al. reported a highly enantioselective intramolecular cyclopropanation of various allylic diazoesters to form [3.1.0]bicycloalkanes in excellent yields (equation (a)).[63] The authors reported that the outcome of the reaction was dependent of the electronic properties of the substrates; while electron-withdrawing substituents on the aromatic ring led to high e.e. values, the presence of electron-donating group drastically lowered the enantioselectivity. Notably, despite the presence of water no O-H insertion products were detected in the reaction course. A similar system was employed by Lin, resulting in the formation of chiral [3.1.0]bicycloalkanes in high yields and enantioselectivities (equation (b)).[64] In this case, not only electron-withdrawing but also electron-donating groups on the aromatic ring afforded the desired product with high e.e. values. 20 1.1.3.2. Iron-based Biocatalysts Additionally, biocatalysts derived from hemoproteins have recently been developed for the cyclopropanation of olefins with generally very high turnover numbers.[65,66] Arnold and co-workers reported in 2013 the engineering of cytochrome P450 from Bacillus megaterium (P450BM3) and the successful application of the variants thus obtained in the asymmetric synthesis of cyclopropanes with ethyl diazoacetate.[67,68] The engineered variants exhibited high diastereo- and enantioselectivities, and could be tuned to respectively favor the formation of the trans- or cis-cyclopropanes (Scheme 15). The authors reported that the reaction did not proceed without the presence of a reducing agent in sub-stoichiometric amounts, implying that, as in the case of iron-porphyrin complexes described in Section 1.1.3.1, the reaction involved the in situ formation of an iron(II) complex as active species. Scheme 15: Stereoselective cyclopropanation of styrene with EDA catalyzed by engineered cytochrome P450 enzymes Further mutations of the P450BM3 enzyme residues allowed the same group to extend this process to electron-deficient and aliphatic olefins.[69,70] In the same fashion, the group of Fasan developed an engineered myoglobin-based catalyst for the cyclopropanation of olefins in high diastereo- and enantioselectivities.[71] Mb(H64V,V68A), a variant of sperm whale myoglobin (Mb) with mutations at the positions 64 and 68, catalyzed the trans- selective cyclopropanation of various aryl olefins with ethyl diazoacetate in high yields and up to 99.9 % d.e. and e.e. values. More recently, another Mb variant was successfully applied to the intramolecular cyclopropanation of allyl diazoacetamides to form bicyclic cyclopropane-γ-lactams with high enantioselectivity (Scheme 16).[72] 21 Scheme 16: Biocatalytic iron-catalyzed intramolecular cyclopropanation 1.1.3.3. Diazo surrogates While diazo compounds bearing electron withdrawing substituents are generally stable, easily available and safe to handle, the use of more reactive semi-stabilized (bearing vinyl or aryl substituents) or non-stabilized diazo compounds (bearing aliphatic substituents) in the cyclopropanation of olefins requires the development of safer protocols.[47,48,73,74] In this context, Aggarwal reported the use of tosylhydrazones and their corresponding sodium salts in the Fe(TPP)Cl-catalyzed cyclopropanation of olefins.[75,76] The diazo compounds were obtained in situ from the corresponding tosylhydrazones via a Bamford-Stevens reaction, and, with help of a phase-transfer catalyst, a range of olefins were cyclopropanated in good yields with trans- or cis-selectivity (Scheme 17, (a)). 22 Scheme 17: Cyclopropanation of olefins using hydrazones as diazo surrogates This methodology was extended to a wider range of electronically and sterically modified diazo compounds generated in situ by Charette and co-workers, who employed N- nosylhydrazones as diazo surrogates.[77] As depicted in Scheme 17 (equation (b)), hydrazones bearing electron-donating and -withdrawing substituents successfully led to the trans-cyclopropanation of olefins in good yields and diastereoselectivities. Carreira and Morandi developed a diazotization/cyclopropanation tandem process using trifluoroethylamine hydrochloride as safe carbene precursor, generating trifluoromethyl diazomethane in situ in the presence of NaNO2 in aqueous solution.[78,79] 23 Scheme 18: Tandem diazotization/cyclopropanation of olefins The process was successfully applied to the cyclopropanation of various styrene derivatives with electron-withdrawing or -donating substituents, leading to cyclopropanes formed as single trans-diastereomers, and later extended to the regioselective cyclopropanation of dienes and 1,3-enynes (Scheme 18). In the same fashion, glycine ester hydrochloride was used as carbene precursor in the cyclopropanation of styrenes in satisfying yields and diastereoselectivities.[80] Koenigs et al. reported the synthesis of nitrile-substituted cyclopropanes from aryl or heteroaryl alkenes following the same procedure.[81] Employing Fe(TPP)Cl and aminoacetonitrile hydrochloride as diazo acetonitrile precursor under biphasic conditions allowed for the safe synthesis of trans- cyclopropyl nitriles in good yields. A safe protocol was established by Carreira and Morandi for the use of highly reactive diazomethane in cyclopropanation reactions.[82] Treatment of water-soluble diazald analog 70 with base leads to the in situ formation of diazomethane, which transfers to the organic phase and reacts with air-stable Fe(TPP)Cl to form an iron-carbene species and subsequently reacts with the olefin (Figure 9). 24 Figure 9: In situ generation of diazomethane from nitrosamide 70 The strongly basic and oxidizing conditions were well-tolerated by the iron catalyst, and furnished a wide range of aryl, as well as vinyl and alkynyl cyclopropanes in very good yields (Figure 10). The non-miscibility of the olefin substrates with water ensured a selective carbene transfer to the olefin over O-H insertion reaction with water. Figure 10: Selected products of the tandem diazomethane generation/iron-catalyzed cyclopropanation 1.2. Photochemical Cyclopropanation of Olefins While thermal decomposition of diazo compounds is the most studied route for transition metal-catalyzed cyclopropanation of olefins, diazo compounds can also be decomposed into the corresponding carbene species under light irradiation, in the absence or presence of a photocatalyst, and be employed in light-induced cyclopropanation reactions.[83,84] In general, singlet carbenes are generated in the absence of a photocatalyst, while the presence of a photocatalyst leads to the formation of triplet carbenes. The singlet carbenes can also decay to the triplet state by intersystem 25 spin crossing (ISC). The stereochemical outcome of the reaction depends of the carbene state; (Z)-olefins will give cis-cyclopropanes and (E)-olefins trans-cyclopropanes upon reaction with singlet carbenes, whereas both cis- and trans-isomers will be formed in the case of triplet carbenes, independently of the olefin configuration.[84] 1.2.1. Metal-free Photochemical Cyclopropanation The groups of Davies[85] and Zhou[86] reported the photolysis of aryl diazoacetates promoted by blue light. The free carbenes thus obtained were shown to effectively react with excess styrene under air to form the corresponding trans-cyclopropanes in good to excellent yields and diastereoselectivities (Scheme 19).[85] Scheme 19: Blue light-induced cyclopropanation of styrene Interestingly, Koenigs and co-workers observed a reverse diastereoselective outcome upon performing the same reaction in continuous flow. A few examples are shown in Scheme 20.[87] Later on, they reported the cyclopropanation of poly-unsaturated carbocycles with donor-acceptor diazo compounds under visible light.[88] 26 Scheme 20: Continuous-flow photochemical cyclopropanation of styrene 1.2.2. Metal-catalyzed Photochemical Cyclopropanation As mentioned in Section 1.1.2, Ru-catalyst 28 was successfully applied by Katsuki et al. for the cis-selective cyclopropanation of olefins under light irradiation ( = 440 nm).[33] Using the same catalyst as well as similar salen-type Ru complexes 81 and 82, they extended the reaction to alkenyl diazo compounds, affording the corresponding bicyclic products in good enantioselectivities (Scheme 21).[89] 27 Scheme 21: Intramolecular cyclopropanation under light irradiation As those complexes are coordinatively saturated and thus catalytically inactive, the authors postulated that dissociation of the NO-ligand is promoted by photo-irradiation to liberate a coordination site and allow the formation of the Ru-carbene species. More recently, a chromium-catalyzed cyclopropanation of internal alkenes under visible light irradiation was reported by Ferreira.[90] Photocatalyst 87 enabled the cyclopropanation of electron-rich alkenes with various diazo esters and aryl ketone under near-UV irradiation in good yields but little diastereoselectivity (Scheme 22). 28 Scheme 22: Chromium-catalyzed cyclopropanation of electron-rich alkenes The chemoselectivity of the reaction is dictated by the electronic properties of the starting materials; cyclopropanation was observed for alkenes with reduction potentials between E1/2= + 1.11 V and + 1.80 V (vs SCE) while no reactivity was observed outside of this range. Taking this observation into account, the authors proposed that the reaction goes via the formation of radical cation intermediate I that undergoes nucleophilic addition by the diazo compound to form species II. Subsequent loss of nitrogen and electron transfer generates the desired cyclopropane (Scheme 23). Scheme 23: Proposed mechanism of the Cr-catalyzed cyclopropanation under visible light irradiation 29 1.3. Transformation of Cyclopropanes Due to their high ring strain, cyclopropanes can undergo a variety of transformations to generate new scaffolds. Cyclopropane activation strategies include C-C bond polarization, generally promoted by Lewis acid species, transition-metal-catalyzed C-C bond activation and β-carbon elimination, and electrophilic activation with Lewis acids.[91– 94] Donor-acceptor cyclopropanes and cyclopropanes bearing geminal electron- withdrawing substituents are known as activated cyclopropanes and are the most explored building blocks for subsequent transformations, while mono-activated cyclopropanes and non-activated cyclopropanes are usually more challenging substrates (Figure 11). Figure 11: Cyclopropane classes Activated cyclopropanes, and more particularly donor-acceptor cyclopropanes, are generally employed in three main classes of reactions; ring-opening reactions, cycloadditions and rearrangements.[92,95] 1.3.1. Ring-Opening Reactions In 2010, Charette reported the successful application of propargyl cyclopropanes for the synthesis of enantioenriched allenes.[96] Enantiopure propargyl cyclopropanes underwent SN2’ addition of aryl- and alkylcuprates to furnish the desired allenes with full retention of the stereogenic information (Scheme 24, (a)). Very recently, sulfenamides were employed by Biju et al. in the 1,3-aminothiolation of donor-acceptor cyclopropanes.[97] In the presence of 10 mol% of Lewis acid Yb(OTf)3, donor-acceptor cyclopropanes bearing various aryl substituents underwent insertion to sulfenamides in an SN2-like process to furnish γ-aminated α-thiolated malonic esters in good yields (Scheme 24, (b)). 30 Scheme 24: Ring-opening of donor-acceptor cyclopropanes 1.3.2. Cycloadditions A Lewis-catalyzed [3+2]-cycloaddition with four-membered thioketones as ketene surrogates was reported by Werz.[98] As monosubstituted ketenes are moisture-sensitive and need to be synthesized directly before use, the authors employed α,β-unsaturated ketone 99 containing a 1,3-dithiane unit that was cleaved by NIS after the cycloaddition step to obtain the five-membered 1,3-diketones (Scheme 25). Scheme 25: Lewis-acid-catalyzed [3+2]-cycloaddition of donor-acceptor cyclopropanes 31 Zhou demonstrated that spirocyclopropyl oxindoles could undergo a [3+3]-cycloaddition reaction with nitrones in a highly enantioselective fashion.[99] Protecting the oxindole moiety with an electron-withdrawing group increased the activity of this specific donor- acceptor cyclopropane as well as the enantiocontrol of the reaction (Scheme 26). Scheme 26: [3+3]-Cycloaddition of spirocyclopropyl oxindoles Employing nitrones as well, the group of Zhang developed a [4+3]-cycloaddition of (alkynyl)cyclopropyl ketones.[100,101] In the presence of Ph3PAuOTf, enantioenriched (alkynyl)cyclopropyl ketones reacted with a wide range of nitrones to give 5,7-fused bicyclic furo[3,4-d][1,2]oxazepines in good yields and excellent enantioselectivities.[101] The reaction is proposed to go through formation of intermediate I upon coordination of the AuI species to the alkyne moiety and the carbonyl. After heterocyclization and SN2 addition of the nitrone to the three-membered ring, furanyl-gold intermediate III is produced, and the desired product is obtained after ring closure, along with regeneration of the catalytic species (Scheme 27). 32 Scheme 27: [3+4]-Cycloaddition of (alkynyl)cyclopropyl ketones and proposed mechanism 1.3.3. Rearrangements The iron-catalyzed Cloke-Wilson rearrangement of vinyl- and arylcyclopropanes was described by the group of Plietker.[102] The nucleophilic iron complex Bu4N[Fe(CO3)(NO)] 101 (TBA[Fe]) could be either thermally or photochemically activated to give the corresponding vinyl- or aryldihydrofurans in very good yields (Scheme 28, (a) and (b)). 33 Scheme 28: TBA[Fe]-catalyzed Cloke-Wilson rearrangement of vinyl- and arylcyclopropanes Under light irradiation, the catalytic species [Fe(CO3)(NO)] is in the T1-state and adopts a distorted trigonal-bipyramidal configuration, liberating an open binding site to facilitate the coordination of the substrates without undergoing decarbonylation. While VCPs could 34 undergo the rearrangement via a SN2- or SN2’-anti pathway,[103] the authors postulated that the rearrangement of ACPs followed a SN2-anti mechanism. A vinylogous Cloke- Wilson rearrangement was successfully applied by Kerr in the synthesis of (±)-β- Allokainic acid 113 (Scheme 29).[104] Precursor 111 was obtained through a tandem cyclization/Cloke-Wilson rearrangement and key intermediate 112 was then formed after a Lewis-acid-mediated rearrangement and subsequent palladium-catalyzed oxygen to nitrogen transposition.[105] Scheme 29: Synthesis of (±)-β-Allokainic acid 113 1.4. Synthesis of Cyclobutenes With 27 kcalmol-1 and 31 kcalmol-1 respectively, cyclobutanes and cyclobutenes possess a ring strain energy close to that of cyclopropanes (27.5 kcalmol-1).[106] Despite being less explored than cyclobutanes and cyclopropanes, cyclobutenes remain of high interest, particularly in total synthesis, as they are often employed as key intermediates for the synthesis of natural products and numerous cyclobutene-containing natural compounds present potent biological activities.[107–109] Examples include Salvileucalin C 114,[110] β-Lumicolchicine 115[111] and (+)-Fommanosin 116,[112] displayed in Figure 12. 35 Figure 12: Cyclobutene-containing natural products Among the various methods developed to form cyclobutene rings, intermolecular alkyne- alkene [2+2]-cycloaddition, cycloisomerization of enynes and ring expansion of cyclopropanes are some of the most employed reactions.[113–116] 1.4.1. Intermolecular [2+2]-Cycloadditions In 2014, Bach reported the [2+2]-photocycloaddition between 2-pyridones and acetylene dicarboxylates.[117] Chiral xanthone 117 was employed as triplet sensitizer in 2.5 to 5 mol%, leading to the formation of the bicyclic products in high yields and enantioselectivities (Scheme 30). The enantioselective outcome of the reaction was rationalized by the binding of the 2-pyridone substrates to the xanthone catalyst through hydrogen bonds. 36 Scheme 30: [2+2]-Photocycloaddition catalyzed by chiral xanthone 117 Very recently, an alkyne-alkene [2+2]-cycloaddition under visible light was developed by the group of Park.[118] In the presence of iridium photocatalyst 121 the reaction proceeded with a broad scope of alkynes and alkenes (Scheme 31). While both electron-poor and -rich alkynes were well tolerated, only alkenes bearing an electron withdrawing group led to good conversions. Overall, this process furnished a wide range of cyclobutenes presenting various substituents in good to excellent yields. 37 Scheme 31: Alkene-alkyne [2+2]-cycloaddition under light irradiation RajanBabu reported a cobalt-catalyzed enantioselective synthesis of cyclobutenes from alkenes and alkynes.[119] Excellent yields and enantioselectivities were obtained in the [2+2]-cycloaddition of alkenes with alkynes or 1,3-enynes, leading to a vast array of optically active cyclobutenes displaying diverse functional groups (Scheme 32). Scheme 32: Cobalt-catalyzed enantioselective synthesis of cyclobutenes 38 1.4.2. Cycloisomerization of enynes One of the first examples of the formation of cyclobutenes through cycloisomerization of enynes was reported by Fensterbank and Malacria in 2004.[120] PtCl2 was shown to catalyze the cycloisomerization of enynes possessing a tosylamide bridge, furnishing the desired cyclobutenyl bicyclic products in good to excellent yields (Scheme 33). Scheme 33: Pt-Catalyzed cycloisomerization of ene-tosylamides Due to the lability of the bicyclic compounds thus obtained, the latter were directly transformed into more stable products in a one-pot fashion. The authors postulated that the reaction went through the formation of cationic intermediate II after π-complexation of the alkyne (Scheme 34). Following elimination of Pt, intermediate III would be obtained and could isomerize to furnish the desired cyclobutene. Scheme 34: Postulated mechanism of the cycloisomerization reaction 39 More recently, cyclobutene-fused eight-membered rings were obtained from 1,9-enynes as reported by Sawamura.[121] The cycloisomerization of the 1,9-enynes substrates furnished the desired carbocycles in excellent yields upon use of a gold complex of triethynylphosphine 132 (Scheme 35). Scheme 35: Gold-catalyzed cycloisomerization of 1,9-enynes 1.4.3. Ring expansions Barluenga and co-workers described a copper-catalyzed cyclization of vinyl diazoacetates and diazo compounds to form substituted cyclobutenes (Scheme 36).[122] The reaction is postulated to proceed through formation of the copper-carbene species I that reacts with the vinyl diazoacetate substrate to form cyclopropane II. The regioisomers are obtained after rearrangement of copper-carbene III. The process was extended to propargylic esters to furnish the corresponding furyl-substituted cyclobutenes in good yields. 40 Scheme 36: Copper-catalyzed synthesis of cyclobutenes and proposed mechanism Building on this precedent, a silver-catalyzed ring expansion of cyclopropyl diazoacetates was reported by the group of Tang.[123] The resulting cyclobutenes were obtained in good yields and regioselectivities, with retention of the chiral information of the substrates (Scheme 37, (a)). The same group reported a few years later a copper- and silver- catalyzed ring expansion of propargyl cyclopropanes via formation of a triazole intermediate (Scheme 37, (b)).[124] 41 Scheme 37: Ring expansion of diazo- and propargyl cyclopropanes Finally, Liu developed a gold-catalyzed oxidative ring expansion of alkynyl cyclopropanes.[125] Ph2SO was employed as oxygen donor and the cyclobutenyl ketones were obtained in good to excellent yields from various propargyl cyclopropanes (Scheme 38). 42 Scheme 38: Gold-catalyzed oxidative ring expansion of propargyl cyclopropanes 43 2. TBA[Fe]-Catalyzed Cyclopropanation of Aryl Alkenes and 1,3-Enynes under Photochemical or Thermal Activation 2.1. Purpose of this Research The investigation of the catalytic activity of the nucleophilic iron complex Bu4N[Fe(CO3)(NO)] (TBA[Fe]) in various chemical transformations has been of interest in our group for many years.[126–135] As mentioned in Section 1.3.3, TBA[Fe] has been shown to successfully catalyze the Cloke-Wilson rearrangement of vinyl- and aryl cyclopropanes under both thermal and photochemical activation.[102] This electron-rich iron complex can also activate diazo compounds in various carbene-transfer reactions, notably in X-H insertion reactions as well as the Doyle-Kirmse reaction.[136,137] Despite the progress that has been made in the development of iron-catalyzed cyclopropanation of olefins over the last years (Section 1.1.3), many catalytic systems are based on the use of Fe-porphyrin complexes and often require protection of functional groups to prevent undesired reactions such as carbene insertions into various X-H bonds. As preliminary observations in the study of the TBA[Fe]-catalyzed Doyle-Kirmse reaction showed no reactivity towards olefin insertions, we were interested in investigating suitable conditions in which this iron complex could efficiently catalyze the cyclopropanation of olefins with diazo compounds as carbene precursors, while preventing other carbene-transfer side reactions. Moreover, only a few examples of transition metal-catalyzed cyclopropanation of olefins under photochemical conditions have been reported thus far, with none of the developed methods employing an iron-based catalytic system (Section 1.2.2). As studies of the TBA[Fe]-catalyzed Cloke-Wilson rearrangement of VCPs and ACPs revealed that the catalyst could be successfully activated upon irradiation with light, we were eager to know if this iron catalyst could also show activity towards olefin insertion under such conditions. Finally, we were also interested in investigating 1,3-enynes substrates as the cyclopropanation of such a compound class have been less documented than aryl- or alkyl-substituted olefins; and while Carreira reported the successful cyclopropanation of non-isomerizable 1,3-enynes employing a Fe-porphyrin complex,[80,82] the cyclopropanation of isomerizable 1,3-enynes was only reported with Cu-, Rh- and Ag- 44 based catalysts.[138–141] 2.2. Results and Discussion 2.2.1. Iron-Catalyzed Cyclopropanation of Aryl Alkenes 2.2.1.1. Optimization of the Thermal Cyclopropanation of Aryl Alkenes We initiated our investigations of the reactivity of TBA[Fe] in the cyclopropanation of alkenes by employing readily available ethyl diazoacetate and styrene to the standard carbene-transfer reaction conditions.[136] Table 1: Solvent screening Entry[a] Solvent Yield[b] trans:cis[c] 1 DMF 16 % 3.3:1 2 MTBE 41 % 6.1:1 3 THF 27 % 6.7:1 4 1,4-dioxane 45 % 4.5:1 5 1,2-DCE 59 % 5.2:1 6 MeCN 55 % 4.9:1 7 Et2O 42 % 4.9:1 8 DMSO 17 % 3.8:1 9 DCM 28 % 4.9:1 10 toluene 39 % 4.5:1 11 MeOH 37 % 4.5:1 [a]All reactions were performed on 0.50 mmol scale in dry solvents under a nitrogen atmosphere; [b]Isolated yield; [c]Determined by GC-analysis on the crude mixture. 45 The desired cyclopropanation occurred in a variety of solvents, and satisfying yields were obtained without requiring ethyl diazoacetate 6 to be added slowly over time (Table 1). In addition, the resulting yield and diastereomeric ratio did not seem to be highly influenced by their polarity. We proceeded with the optimization using 1,2-DCE, solvent that exhibited the optimal performance for the formation of 7 (entry 5). Table 2: Variation of the catalyst loading, concentration, temperature and reaction time Entry[a] Catalyst loading Temperature Time Concentration Yield[b] trans:cis[c] 1 10 mol% r. t. 6 h 1 M 23 % 3.8:1 2 10 mol% 40 °C 6 h 1 M 59 %[d] 5.2:1 3 10 mol% 50 °C 6 h 1 M 62 % 5.2:1 4 5 mol% 40 °C 6 h 1 M 49 % 4.9:1 5 2.5 mol% 40 °C 6 h 1 M 39 % 4.9:1 6 1.25 mol% 40 °C 6 h 1 M 55 % 4.0:1 7 - 40 °C 6 h 1 M 0 % n.d. 8 2.5 mol% 40 °C 6 h 2 M 52 % 5.2:1 9 2.5 mol% 40 °C 14 h 2 M 72 % 5.2:1 10 2.5 mol% 40 °C 24 h 2 M 77 % 5.1:1 [a]All reactions were performed on 0.50 mmol scale in dry 1,2-DCE under a nitrogen atmosphere; [b]Yield determined by 1H NMR integration, using mesitylene as internal standard; [c]Determined by GC-analysis on the crude mixture; [d]Isolated yield. Decreasing the temperature from 40 °C to room temperature both led to a lower yield and diastereomeric ratio, while an increase to 50 °C did not significantly impact the reaction yield (Table 2, entries 1 and 3). By performing the reaction in higher solvent concentration, we could obtain satisfying yields with only 2.5 mol% of TBA[Fe]. Finally, longer reaction 46 times allowed us to achieve optimal conditions for the thermal cyclopropanation of aryl alkenes (entry 10). 2.2.1.2. Optimization of the Photochemical Cyclopropanation of Aryl Alkenes Based on our results in the optimization of the TBA[Fe]-catalyzed cyclopropanation of alkenes under thermal conditions, we set up the optimization for photochemical conditions using the most promising solvents (Table 3). Table 3: Optimization of the iron-catalyzed cyclopropanation of aryl alkenes under photochemical conditions Entry[a] Solvent Light source Time Yield[b] 1 MeCN Xe lamp (75 W) 6 h 45 % 2 1,2-DCE Xe lamp (75 W) 6 h 63 % 3 1,2-DCE Hg lamp (180 W) 6 h 59 % 4 1,2-DCE Blue LEDs ( = 405 nm) 6 h 46 % 5 1,2-DCE none 6 h 28 % 6 1,2-DCE Xe lamp (75 W) 8 h 82 % 7[c] 1,2-DCE none 8 h 34 % 8 1,2-DCE Xe lamp (75 W) 24 h 84 % 9[d] 1,2-DCE Xe lamp (75 W) 8 h 0 % [a]All reactions were performed on 0.50 mmol scale in dry solvents at room temperature under a nitrogen atmosphere; [b]Yield determined by 1H-NMR integration, using mesitylene as internal standard; [c]Temperature: 30 °C; [d]In the absence of TBA[Fe]. A screening of light sources revealed that the reaction proceeded under both UV- and visible light, with a slightly higher yield when employing the Xe-lamp (entries 1−4). 47 Adjusting the reaction time to 8 hours led to the formation of 7 in 82 % yield (entry 6). To exclude a possible influence of the heat emitted by the Xenon lamp during the reaction course, the temperature was monitored throughout the reaction using in situ IR spectroscopy with a coupled temperature probe. An increase of temperature from room temperature (23 °C) to 30 °C was recorded. However, we found that performing the reaction at 30 °C or 23 °C in the absence of light resulted in comparable yields (entries 5 and 7). 2.2.1.3. Scope and limitations of the Iron-Catalyzed Cyclopropanation of Aryl Alkenes under Thermal or Photochemical Activation With the optimized conditions in hand, we turned our attention to the scope of the TBA[Fe] catalyzed cyclopropanation of aryl alkenes under both photochemical and thermal conditions (Table 4). Table 4: Scope of the TBA[Fe]-catalyzed cyclopropanation of aryl alkenes[a] Entry Substrate Product Conditions Yield (%) trans:cis 1 A B 69 79 5.3:1 5.3:1 48 Entry Substrate Product Conditions Yield (%) trans:cis 2 A B 71 70 5.3:1 5.3:1 3 A B 65 55 4.9:1 5.3:1 4 A B 78 71 4.9:1 4.9:1 5 A B 73 92 4.9:1 5.3:1 6 A B 92 89 5.7:1 6.1:1 49 Entry Substrate Product Conditions Yield (%) trans:cis 7 A B 51 76 4.3:1 5.3:1 8 A B 84 76 4.0:1 4.0:1 9 A B 76 68 4.0:1 3.8:1 10 A B 80 67 7.3:1 6.7:1 11 A B 51 25 1:1.3 1:1.3 50 Entry Substrate Product Conditions Yield (%) trans:cis 12 A B 0 15 - 1:1.2 13 A B 90 77 4.3:1 4.6:1 14 A B 87 85 - 15 A B 76 80 1.5:1 1.5:1 16 A B 31 41 8.1:1 9.0:1 51 Entry Substrate Product Conditions Yield (%) trans:cis 17 A B 76 65 4.0:1 2.2:1 [a]All reactions were performed on a 0.5 mmol scale. Yields of isolated products are reported, the trans:cis ratio was determined by GC-analysis on the crude mixture. A broad range of aryl alkenes were tolerated under both reaction conditions. Styrene derivatives possessing electron-donating or -withdrawing groups were smoothly converted in good to excellent yields and heteroaryl compounds led to the corresponding cyclopropanes in satisfactory yields. Notably, the presence of a nitro substituent was compatible with the reaction conditions, as exemplified by cyclopropane 168, an observation reported only in a few TBA[Fe]-catalyzed processes.[131,132,134,142,143] While the diastereomeric ratio remained around 5.0:1 (trans:cis) in the case of para-substituted styrene derivatives (entries 1−9), a change of substitution pattern showed an impact on the selectivity. A methoxy group in the meta position resulted in higher trans-selectivity (entry 10) whereas, in the examples of 1,3-dichloro-2-vinylbenzene 158 and 1,3,5- trimethyl-2-vinylbenzene 159, a drop in selectivity was observed, the corresponding cis- cyclopropanes being formed with a slight preference (entries 11 and 12). Pleasingly, unprotected vinylindole 164 underwent cyclopropanation smoothly without any competing N-H insertion reaction (entry 17). The presence of a second substituent in -position did not impair the reaction course as 1,1-disubstituted alkenes reacted in high yields (entries 13−15). The notable change in trans:cis selectivity in product 178 could have resulted from steric repulsion induced by the cyclopropyl moiety (entry 15). 52 Figure 13: Limitations of the TBA[Fe]-catalyzed cyclopropanation of aryl alkenes Unfortunately, nor 4-vinylphenol 181 neither 4-vinylaniline 182 reacted to give the corresponding cyclopropanes, however no product corresponding to the insertion of ethyl diazoacetate into the O-H or N-H bond was observed, suggesting a possible poisoning of the catalyst by coordination of the substrate to the metal center (Figure 13). Aliphatic alkenes as well as internal alkenes were not reactive under the developed conditions (183 to 187). Similarly, no cyclopropene formation was observed when employing phenylacetylene as substrate under our conditions. Finally, enones were not tolerated. Scheme 39: TBA[Fe]-catalyzed cyclopropanation of styrene in the presence of TEMPO Addition of TEMPO to the reaction proceeded in a slight decrease of the yield under thermal conditions, while the reaction was completely inhibited under photochemical 53 conditions (Scheme 39). However, these observations pointed towards an inhibition of the catalyst by TEMPO rather than the formation of radicals during the reaction course as the cyclopropyl moiety of 162 remained unaffected (Table 4, entry 15). 2.2.2. Iron-Catalyzed Cyclopropanation of 1,3-Enynes 2.2.2.1. Optimization of the Thermal Cyclopropanation of 1,3-Enynes Having successfully developed a method for the cyclopropanation of aryl alkenes using TBA[Fe], and with the observation that triple bonds seemed to remain unaffected, we set out to expand the reaction scope to 1,3-enynes and began our optimization of the thermal cyclopropanation using the previously developed conditions (Table 5). Table 5: Solvent screening Entry[a] Solvent (ratio) Yield[b] 1 1,2-DCE 66 %[c] 2 nitromethane 37 % 3 1,2-DCE:nitromethane (4:1) 94 % (81 %[c]) 4 MeCN:nitromethane (4:1) 69 % 5 1,4-dioxane:nitromethane (4:1) 74 % 6 THF:nitromethane (4:1) 71 % 7 DCM:nitromethane (4:1) 63 % 8 toluene:nitromethane (4:1) 68 % 9 MTBE:nitromethane (4:1) 69 % 10 DMF:nitromethane (4:1) 11 % 11 1,4-dioxane:nitromethane (4:1) 74 % 12 MeOH:nitromethane (4:1) 35 % 54 Entry[a] Solvent (ratio) Yield[b] 13 1,2-DCE:nitromethane (9:1) 91 % (82 %[c]) 14 1,2-DCE:nitromethane (1:1) 81 % (74 %[c]) 15[d] 1,2-DCE:nitromethane (9:1) 40 % 16[e] 1,2-DCE:nitromethane (9:1) 55 % 17[f] 1,2-DCE:nitromethane (9:1) 69 % [a]All reactions were performed on 0.25 mmol scale in dry solvents at 40 °C under a nitrogen atmosphere for 24 h; [b]Yield determined by 1H NMR integration using mesitylene as internal standard; [c]Isolated yield; [d]Reaction carried out at 23 °C; [e]Solvent concentration: [1 M]; [f]With 1.25 mol% TBA[Fe]. The initial conditions led to the cyclopropanation of enyne 190 in 66 % yield (entry 1). Intrigued by the fact that a nitro-substituted aryl olefin was compatible with the use of TBA[Fe] as catalyst in the cyclopropanation reaction (Section 2.2.1.3), we decided to investigate whether the use of a nitro-containing solvent could have a positive influence on the reaction yield. While conducting the reaction in pure nitromethane led to a disappointing yield of 37 % (entry 2), employing nitromethane as co-solvent with 1,2-DCE resulted to the formation of the desired propargyl cyclopropane in excellent yield (entry 3), and prompted us to screen additional solvent mixtures containing nitromethane (entries 4−12). Further adjustments on solvent ratios and temperature revealed that the best results were obtained in a 9:1 mixture of 1,2-DCE and nitromethane with 2.5 mol% of TBA[Fe] at 40 °C (entry 13). 55 Table 6: Screening of additives Entry[a] Additive Equivalents Yield[b] 1 Nitromethane 0.89 87 % 2 Nitromethane 0.5 80 % 3 Nitrobenzene 0.5 87 % 4 4-Nitrotoluene 0.5 77 % 5 4-Nitroanisole 0.5 88 % 6 4-Nitroanisole 0.025 81 % 7 4-Nitroanisole 0.0125 80 % 8 4-Nitroanisole 0.005 82 % 9 TMANO 0.005 61 % 10 - - 68 % 11[c] 4-Nitroanisole 0.005 15 % 12[c] - - 13 % [a]All reactions were performed on 0.25 mmol scale in dry solvents at 40 °C under a nitrogen atmosphere for 24 h; [b]Yield determined by 1H NMR integration using mesitylene as internal standard; [c]In the absence of TBA[Fe]. As lowering the amount of nitromethane did not have a negative impact on the reaction yield (Table 6, entries 1 and 2), we tested different nitroarenes in sub-stoichiometric quantities (entries 2−9). Interestingly, with only 0.5 mol% of 4-nitroanisole the propargyl cyclopropane 191 could be obtained in 82 % yield (entry 8). To understand the role of 4- nitroanisole in the increase of the reaction yield (entry 8 vs 10), mechanistic investigations were carried out (see Section 2.2.3). 56 2.2.2.2. Optimization of the Photochemical Cyclopropanation of 1,3 Enynes In the same fashion, we initiated our optimization of the photochemical cyclopropanation of 1,3-enynes with the conditions developed for the aryl alkenes (Table 7). Table 7: Solvent screening Entry[a] Solvent (ratio) Yield[b] 1 1,2-DCE 34 %[c] 2 nitromethane 33 % 3 THF:nitromethane (4:1) 34 % 4 1,2-DCE:nitromethane (4:1) 35 % 5 MeCN:nitromethane (4:1) 49 % 6 DCM:nitromethane (4:1) 39 % 7 toluene:nitromethane (4:1) 24 % 8 MTBE:nitromethane (4:1) 35 % 9 DMF:nitromethane (4:1) 38 % 10 1,4-dioxane:nitromethane (4:1) 51 % 11 MeOH:nitromethane (4:1) 22 % 12 1,4-dioxane:nitromethane (9:1) 46 % 13 1,4-dioxane:nitromethane (7:3) 39 % 14[d] 1,4-dioxane:nitromethane (4:1) 20 % 15[e] 1,4-dioxane:nitromethane (4:1) 66 % 16[e],[f] 1,4-dioxane:nitromethane (4:1) 69 % (62 %[c]) [a]All reactions were performed on 0.25 mmol scale in dry solvents at room temperature under a nitrogen atmosphere for 8 h; [b]Yield determined by 1H NMR integration using mesitylene as internal standard; [c]Isolated yield; [d]Solvent concentration: [1 M]; [e]With 5 mol% TBA[Fe]; [f]16 h reaction time. 57 Similar to our observations under thermal conditions, the use of nitromethane as solvent alone did not increase the reaction yield (entry 2). In this case, a mixture of 1,4-dioxane and nitromethane led to the highest conversion (entry 10). Adjusting the reaction time and catalyst loading allowed us to obtain propargyl cyclopropane 191 in satisfying yields (entries 15 and 16). Table 8: Screening of additives Entry[a] Additive Equivalents Yield[b] 1 Nitromethane 1.85 79 % (80 %[c]) 2 Nitromethane 0.5 64 % 3 4-Nitroanisole 0.5 33 % 4 4-Ntrotoluene 0.5 23 % 5 Nitrobenzene 0.5 33 % 6 none - 73% 7[d] Nitromethane 1.85 traces 8[d] none - traces 9[e] Nitromethane 1.85 43 % [a]All reactions were performed on 0.25 mmol scale in dry solvents at room temperature under a nitrogen atmosphere for 16 h; [b]Yield determined by 1H NMR integration using mesitylene as internal standard; [c]Isolated yield; [d]In the absence of TBA[Fe]; [e]Shielded from light. As opposed to the thermal activation, screening of different nitro-containing compounds revealed that nitromethane acted under those conditions as a co-solvent rather than as an additive (Table 8). Indeed, decreasing the amount of nitromethane resulted in a significant drop of the reaction yield (entry 2), and other nitroarenes performed poorly (entries 3−5). 58 Unfortunately, attempts to scale up the reaction from 0.25 mmol to 0.50 mmol scale under the same reaction conditions led to lower yields. Another optimization of the reaction conditions had to be carried out on 0.50 mmol scale to achieve reproducible yields (Table 9). Table 9: Reaction optimization on 0.50 mmol scale and light source comparison Entry[a] Solvent ratio Concentration Time Yield[b] 1 5:1 1.66 M 16 h 65 %[c] 2 10:1 1.82 M 16 h 66 % 3 5:1 3.33 M 16 h 70 % 4 5:1 3.33 M 20 h 79 % (81 %[c]) 5[d] 5:1 3.33 M 20 h 38 % 6[e] 5:1 3.33 M 20 h 45 % [a]All reactions were performed on 0.50 mmol scale in dry solvents at room temperature under a nitrogen atmosphere; [b]Yield determined by 1H NMR integration using mesitylene as internal standard; [c]Isolated yield; [d]Light source: Hg lamp (180 W); [e]Light source: blue LEDs ( = 405 nm). As with the aryl olefins, comparing different light sources revealed that the reaction performed better using a 75 W Xe-lamp than when a 180 W Hg-lamp or blue LEDs were employed (entry 1 vs entries 5 and 6). 2.2.2.3. Scope of the Iron-Catalyzed Cyclopropanation of 1,3-Enynes Under Thermal or Photochemical Conditions With the optimized conditions in hand, we next investigated the scope of the TBA[Fe]- catalyzed cyclopropanation of 1,3-enynes under photochemical or thermal conditions (Table 10). 59 Table 10: Scope of the TBA[Fe]-catalyzed cyclopropanation of 1,3-enynes[a] Entry Substrate Product Conditions Yield (%) trans:cis 1 A B 53 92 2.2:1 2.0:1 2 A B 85 94 2.2:1 1.9:1 3 A B 94 100 2.1:1 2.2:1 4 A B 80 82 1.8:1 1.8:1 60 Entry Substrate Product Conditions Yield (%) trans:cis 5 A B 85 98 1.9:1 2.1:1 6 A B 99 100 2.0:1 2.2:1 7 A B 69 90 2.6:1 2.2:1 8 A B 56 74 1.7:1 1.8:1 9 A B 93 81 1.9:1 2.3:1 61 Entry Substrate Product Conditions Yield (%) trans:cis 10 A B 71 81 2.8:1 2.8:1 11 A B 57 72 2.7:1 2.6:1 12 A B 52 52 Only cis 13 A B 0 57 - 1.5:1 14 A B 52 54 1.04:1 1.3:1 15 A B 51 75 1.8:1 1.7:1 62 Entry Substrate Product Conditions Yield (%) trans:cis 16 A B 38 53 2.4:1 2.3:1 17 A B 19 39 1.8:1 3.2:1 18 A B 27 72 2.0:1 2.4:1 [a]All reactions were performed on a 0.5 mmol scale. Yields of isolated products are reported, the trans:cis ratio was determined by GC-analysis on the crude mixture. A broad range of 1,3-enynes were successfully converted into the corresponding propargyl cyclopropanes under both thermal and photochemical conditions, with a slight preference towards the formation of the trans products, and generally higher yields under photochemical conditions. Aryl enynes possessing an electron-withdrawing of -donating group in the para position reacted in good to quantitative yields (entries 1−7). Aliphatic 1,3-enynes were also tolerated (entries 10−12 and 14−18) and no isomerization within the π-bond system was observed in any of the tested substrates. Propargylic alcohols, esters, ketones and amines reacted smoothly without any competing processes such as rearrangement or ring-enlargement reactions (entries 13−18). Furthermore, in line with our observations on aryl alkenes (Section 2.2.1) and as reported with substrate 208, non- conjugated double bonds remained unreactive (entry 18). We were pleased to see that no X-H insertion reactions occurred under our conditions, as 220 and 224 were formed as the exclusive products (entries 13 and 17). While 1,1-disubstituted enynes were also tolerated (entries 8, 9 and 12), the size of the substituents had an impact on the diastereoselectivity; a bulky tert-butyl group forced the cyclopropanation to occur with 63 complete cis-selectivity whereas relatively small substituents such as a methyl or cyclopropyl moiety resulted in the formation of the corresponding propargyl cyclopropanes with only a slight decrease in trans:cis selectivity. Scheme 40: Cyclopropanation of 1,3-enyne 190 in the presence of TEMPO To probe a possible formation of radicals the reaction was performed in the presence of 20 mol% of TEMPO (Scheme 40). Under both thermal and photochemical conditions the yield decreased but the catalytic activity was not suppressed. Moreover, the cyclopropyl moiety in substrate 200 (Table 10, entry 9) remained intact, thus rendering a radical pathway for both modes of activation highly unlikely. 64 Table 11: Cyclopropanation of 1,3-enyne 190 using different catalysts[a] Entry Catalyst trans:cis (191) Yield (191) Yield (226)[b] 1 Rh2(OAc)2 1.6:1 22 % 9 % 2 Fe(TPP)Cl 2.7:1 20 % - 3[c] AgOTf 2.1:1 6 % - 4 CuOTf 2.3:1 11 % 7 % 5 Cu(acac)2 3.8:1 14 % traces 6 AuCl 2.1:1 11 % - 7 AuCl3 - traces - 8 Cp*RuCl(COD) - traces - [a]All reactions were performed on 0.5 mmol scale in dry DCM at 40 °C under a nitrogen atmosphere for 24 h, the trans:cis ratio was determined by GC-analysis on the crude mixture, yields of isolated products are reported; [b]Yield determined by 1H NMR integration, using mesitylene as internal standard; [c]Shielded from light. Employing previously established catalysts for the cyclopropanation of enynes on substrate 190 using ethyl diazoacetate as carbene precursor resulted in the formation of 191 in unsatisfactory yields (Table 11). Moreover, upon using Rh- or Cu-based catalysts a competing cyclopropenation process was observed (entries 1, 4 and 5). Diethyl fumarate and -maleate were also formed as a result of homodimerization of ethyl diazoacetate when Rh, Cu or Au were tested (entries 1, 4, 5 and 7). We then attempted to perform the reaction employing different diazo compounds (Figure 14). Unfortunately, applying trimethylsilyl diazomethane under thermal or photochemical conditions did not lead to the formation of the desired cyclopropane as only starting material was recovered in both cases. Attempts to perform the reaction with diazo compounds formed in situ following a previously established protocol[137] remained unsuccessful as well. 65 Figure 14: Cyclopropanation attempts using various diazo compounds Finally, the synthetic value of the propargyl cyclopropanes was explored (Figure 15). Unfortunately, modifying the cyclopropane moiety proved to be difficult, as attempts to increase the ring substitution via nucleophilic additions or C-H functionalization,[144] as well as ring-opening of the propargyl cyclopropanes following classical methods to open 66 donor-acceptor cyclopropanes[145] remained unfruitful (equations (1) to (3)). Reduction of the ester moiety of cyclopropane 209 with DIBAL-H led however to the corresponding alcohol 233 in good yield (equation (4)), and cyclopropane 220 could be efficiently converted into pyrazole 234 (equation (5)). Figure 15: Derivatization attempts on propargyl cyclopropanes 67 2.2.3. Investigation of the Reaction Mechanism To gain insights into the reaction mechanism of the cyclopropanation of aryl alkenes as well as of 1,3-enynes, we conducted several experiments using in situ IR-ATR spectroscopy and monitored changes in the IR-spectrum of TBA[Fe] (Figure 16). Figure 16: IR spectrum of TBA[Fe] in 1,2-DCE at room temperature We started our investigations by carrying out the cyclopropanation of styrene under our standard photochemical conditions, using 100 mol% of catalyst to monitor a possible evolution of the band intensities characterizing the ligands of TBA[Fe] (Figure 17). During the reaction course, we observed a decrease in intensity of the bands corresponding to the CO ligands of the iron catalyst, hinting at a decarbonylation process of the catalyst upon light irradiation. Importantly, irradiating a solution of TBA[Fe] alone in 1,2-DCE did not result in significant changes in the IR-spectrum. -0,1 0 0,1 0,2 0,3 0,4 0,5 1000120014001600180020002200 A . U . Wavenumber (cm-1) Fe-CO (1999 cm-1) Fe-CO (1885 cm-1) Fe-NO (1642 cm-1) 68 Figure 17: IR spectra of the reaction mixture at the beginning of the reaction and after 16.5 hours Stirring one equivalent of TBA[Fe] with one equivalent of ethyl diazoacetate in 1,2-DCE at 40 °C for 24 hours in the absence or presence of an equivalent of 4-nitroanisole resulted in a modification of the IR spectrum of TBA[Fe] in both cases. More specifically a decrease in intensity of the bands corresponding to the CO ligands of the catalyst was observed (Figures 18 and 19), indicating that a decarbonylation of the iron complex took place under both conditions developed for the thermal cyclopropanation of aryl alkenes and 1,3-enynes. Moreover, the presence of 4-nitroanisole accelerated this process, thus explaining the increased reactivity observed during the investigation of the thermal cyclopropanation of 1,3-enynes (Section 2.2.2). -0,15 -0,05 0,05 0,15 0,25 0,35 0,45 0,55 0,65 0,75 1000120014001600180020002200 A . U . Wavenumber (cm-1) 00:21:41 16:35:07 Fe-CO Fe-CO EDA EDA cyclopropane 7 69 Figure 18: Impact of 4-nitroanisole on the band intensity evolution of the CO ligands of TBA[Fe] in the presence of EDA in 1,2-DCE at 40 °C over time Figure 19: In situ IR spectroscopic analysis of TBA[Fe] in the presence of EDA at 40 °C -0,05 0 0,05 0,1 0,15 0,2 0,25 0,3 00:00:00 03:36:00 07:12:00 10:48:00 14:24:00 18:00:00 21:36:00 A . U . Time Fe-CO (1885 cm-1) + nitroanisole Fe-CO (1999 cm-1) + nitroanisole Fe-CO (1885 cm-1) Fe-CO (1999 cm-1) Fe-CO Fe-NO 70 Furthermore, a comparative experiment confirmed the influence of 4-nitroanisole on the reaction rate. The thermal formation of cyclopropane 190 was monitored by in situ IR spectroscopy (Figure 20) under different sets of conditions; (1) standard reaction conditions for the thermal cyclopropanation of 1,3-enynes, (2) addition of 4-nitroanisole 4 hours after the reaction start, (3) standard reaction conditions for the thermal cyclopropanation of aryl alkenes (absence of 4-nitroanisole). The rate of cyclopropane formation increased drastically in the presence of 4-nitroanisole (experiment 1 vs experiment 3) while adding 4-nitroanisole after a few hours resulted in an increase of cyclopropane formation almost immediately (experiment 2). The dents in the curves corresponding to experiments 2 and 3 were due to the refilling of liquid nitrogen used in the spectrometer cooling system. 71 Figure 20: Evolution of peak intensities of cyclopropane 191 over time in the presence or absence of 4- nitroanisole All of the conducted in situ IR experiments allowed us to postulate that decarbonylation of TBA[Fe] in the presence of ethyl diazoacetate under thermal or photochemical activation was the activating step in the iron-catalyzed cyclopropanation of aryl alkenes and 1,3-enynes. Additionally, the observation that only double bonds conjugated with an aromatic system or a triple bond were efficiently cyclopropanated (Sections 2.2.1.3 and 2.2.2.3) suggested a probable coordination of the iron center the adjacent aromatic unit or triple bond prior to the cyclopropanation step. We were curious to see whether TBA[Fe] could also coordinate to the distal triple bond of a 1,6-enyne and promote the subsequent cyclopropanation of the terminal olefin. Unfortunately, submitting 1,6-enyne 235 to the reaction conditions did not lead to any conversion, even at elevated temperatures, the starting material completely being recovered in each case (Scheme 41). -0,1 0,4 0,9 1,4 1,9 2,4 2,9 3,4 3,9 4,4 00:00:00 03:36:00 07:12:00 10:48:00 14:24:00 18:00:00 21:36:00 A . U . Reaction time product exp.1 product exp.2 product exp.3 addition of 4-nitroanisole after 4 hours renewal of liquid nitrogen cooling 72 Scheme 41: Cyclopropanation attempt on 1,6-enyne 235 Combining our findings in the in situ IR experiments with the effects observed in the reaction scope (Sections 2.2.1.3 and 2.2.2.3, and Scheme 41), we proposed the following mechanisms (Figures 21 and 22). 73 Figure 21: Mechanistic proposal for the TBA[Fe]-catalyzed cyclopropanation of aryl alkenes under thermal or photochemical activation Upon light irradiation, the [Fe(CO)3NO]-anion I adopts a distorted trigonal-bipyramidal configuration in the T1-state, liberating an open binding site (Figure 21). The reactive iron- 74 carbene species III is formed after reaction of Fe-species II with ethyl diazoacetate and decarbonylation. At 40 °C, iron-carbene species III is produced via thermal decarbonylation of tetrahedral carbonyl nitrosyl ferrate I in the presence of ethyl diazoacetate. As aliphatic alkenes as well as enones were not tolerated (Section 2.2.1, Figure 13, substrates 186, 187 and 189), the iron center most likely coordinates to the aromatic system of A to give intermediate IV. Metallacyclobutanes trans-V and cis-V are formed after [2+2]-cycloaddition, and after reductive elimination and addition of another molecule of ethyl diazoacetate active species III is regenerated and the desired cyclopropanes trans-B and cis-B are obtained. The diastereoselectivity of the reaction could be rationalized by the steric interactions between the aromatic ring and the incoming metal-carbene species (favoring the formation of the trans-cyclopropane) prevailing over coordination of the metal center to the aromatic ring (which would favor the cis-cyclopropane). When the olefin bears another substituent in the α-position (Section 2.2.1.3, Table 3, entries 13 to 15), a drop in trans-selectivity is observed, more pronounced in the case of an cyclopropyl substituent (entry 15), probably due to a situation in which the metal-carbene species is coordinated to the aromatic unit and avoids steric interactions with the bulkier substituent. The presence of a directing group in IV could justify the increase of the trans-selectivity in products 173 and 179 (Section 2.2.1.3, Table 3, entries 10 and 16). In the same fashion, the drop of diastereoselectivity observed in the cyclopropanation of 158 and 159 (entries 11 and 12) could be explained by unfavorable steric interactions. Moreover, the fact that internal alkenes were unreactive under the reaction conditions points into the direction of non-favorable interactions between the metal-carbene species and the double bond in the transition state. 75 Figure 22: Mechanistic proposal for the TBA[Fe]-catalyzed cyclopropanation of 1,3-enynes under thermal or photochemical activation In the presence of 4-nitroanisole, the thermal decarbonylation is accelerated by the reaction of I with the nitro group (Figure 22). Upon use of 0.5 equivalent of nitrobenzene 76 as additive in the thermal cyclopropanation of 192, nitrosobenzene as well as aniline were detected by GC-analysis, corroborating this hypothesis. The formation of the 16-electron iron-carbene species III under photochemical conditions is following the previously described pathway. In the same approach, the iron center probably coordinates to the alkyne moiety in a 2- or 4-fashion to give intermediate IV. [2+2]-cycloaddition and reductive elimination then provide cyclopropane B. The competition between steric interactions between the alkyne moiety and the incoming metal-carbene species and coordination of alkyne to the iron-carbene being less pronounced than in the case of aryl alkyne, the desired cyclopropanes are formed with a lessened trans-selectivity. Alkenes bearing an additional substituent of moderate size in the α-position (Section 2.2.2.3, Table 10, entries 8 and 9) lead to a minor decrease in trans:cis selectivity. A bulkier tert-butyl substituent (entry 12) resulted however in the exclusive formation of the corresponding cis-cyclopropane, reflecting a possible coordination of the metal-carbene species to the alkyne moiety to minimize steric interactions with the tert-butyl group. 2.3. Conclusion In this section we were able to demonstrate that the nucleophilic iron complex Bu4N[Fe(CO)3(NO)] efficiently catalyzes the cyclopropanation of aryl olefins as well as 1,3-enynes in good to excellent yields with a preference for the formation of trans- cyclopropanes (Scheme 42). Scheme 42: TBA[Fe]-catalyzed cyclopropanation of olefins and 1,3-enynes 77 A variety of functional groups are tolerated and the reaction exhibits good chemoselectivity. No competing X-H insertion or cyclopropenation reactions were observed during the course of our studies, non-conjugated double bonds seem to remain unaffected, and in the case of aliphatic enynes no isomerization within the π-bond system was observed. In general, photochemical conditions provide the propargyl cyclopropanes in higher yields while thermal conditions give superior results when aryl olefins were employed. As opposed to a number of previously established systems, the diazo compound did not require to be added slowly. The catalyst can be activated thermally under mild conditions or under light irradiation, providing the first example of an iron- catalyzed photochemical cyclopropanation of olefins and 1,3-enynes with ethyl diazoacetate. In situ IR-ATR spectroscopy studies as well as GC analyses under both sets of conditions revealed that the reaction proceeds through decarbonylation of the ferrate anion to liberate an additional coordination site required for the approach of the conjugated olefin (Scheme 43). Moreover, the use of sub-stoichiometric amounts of 4- nitroanisole in the thermal cyclopropanation of 1,3-enynes allowed for an enhancement of the catalytic activity by accelerating the decarbonylation step. Scheme 43: Activation of TBA[Fe] under thermal or photochemical conditions Finally, the propargyl cyclopropanes thus obtained could be efficiently derivatized to furnish interesting building blocks without affecting the cyclopropane moiety. 78 3. Silver-Catalyzed Oxidative Ring Expansion of Propargyl Cyclopropanes. 3.1. Purpose of this Research Most of the donor-acceptor cyclopropane transformations require the presence of two electron-withdrawing groups on the acceptor moiety, or an additional electron- withdrawing group on the substrate to enhance its activity and allow for the chelation of a Lewis-acid for the reaction to proceed (Section 1.3). After developing an iron-based system for the cyclopropanation of 1,3-enynes (Section 2.2.2), we were interested in the synthetic application of propargyl cyclopropanes possessing only one electron- withdrawing group on the acceptor moiety, making use of both the cyclopropane and the triple bond functionality, and came across an unexpected result during our preliminary investigations. Application of a method described by the group of Szabó for the fluorinative ring-opening of non-activated cyclopropanes[146] on propargyl cyclopropane cis-191 did not result on the formation of the expected linear product, but of cyclobutenyl ketone 237 (Scheme 44). Scheme 44: Preliminary result on the formation of cyclobutene 237 Such a ring expansion of propargyl cyclopropanes to furnish cyclobutenes has been scarcely investigated in the past,[124,147,148] with only a few reports of oxidative ring expansion of non-activated propargyl cyclopropanes being found in the literature.[125,149,150] Therefore, we set to design a novel oxidative ring expansion of donor- acceptor propargyl cyclopropanes that would furnish a convenient and rapid access to cyclobutenyl ketones bearing an additional ester functionality. Moreover, owing to the high synthetic value of cyclobutenyl derivatives (Section 1.4), we were eager to determine 79 whether this silver-catalyzed process could allow for the formation of chiral cyclobutenyl ketones when chiral propargyl cyclopropanes were employed as starting materials. 3.2. Results and Discussion 3.2.1. Optimization of the Silver-Catalyzed Oxidative Ring Expansion of Propargyl Cyclopropanes We started our investigation with a screening of different catalysts, employing (R,S)- 191 as model substrate (Table 12). Table 12: Catalyst screening Entry[a] Catalyst Yield[b] 1 AgBF4 42 % 2[c] [Fe(CO)(NO)(PPh3)2]BF4 traces 3[c] CuI 0 % 4[c] (PPh3)AuCl 0 % 5 AgPF6 34 % 6 AgF 0 % 7 CF3COOAg 0 % 8 AgOTf 35 % 9 AgSbF6 40 % 10 AgNO3 0 % 11 AgBArF 0 % 12 Ag2O 0 % 80 Entry[a] Catalyst Yield[b] 13[c] HBF4 decomposition [a]All reactions were performed on 0.25 mmol scale at room temperature under a nitrogen atmosphere for 3 h, shielded from light; [b]Isolated yield; [c]Not shielded from light. The reaction proceeded with only a few silver-based catalysts (entries 1, 5, 8 and 9), while no product or only traces were detected when Fe-, Cu- or Au-based complexes were used (entries 2−4). Silver salts bearing strongly coordinating anions such as F-, NO3 - and CF3COO- (entries 6, 7 and 10) did not lead to any product formation, while the presence of weakly bound counterions, excepted BArF - (entry 11), had a positive impact on the reaction outcome (entries 1, 5, 8 and 9), with AgBF4 providing desired cyclobutenyl ketone 237 in the most satisfying yield. Importantly, AgBF4 had to be kept under nitrogen and in dry conditions to avoid any moisture-induced degradation of the catalyst and thus achieve reproducible yields. No reaction was observed when 20 mol% of silver oxide was employed (entry 12), already excluding the possibility that this could be the active species in the catalysis. Moreover, we could postulate that the reaction might not be catalyzed by HBF4 generated in situ as the use of this strong Brønsted acid alone did not lead to any product formation (entry 13). Table 13: Solvent screening Entry[a] Solvent Yield[b] 1 CDCl3 42 % 2 DCM 29 % 3 CHCl3 0 % 4 MeCN 0 % 81 Entry[a] Solvent Yield[b] 5 toluene 0 % 6 THF 0 % 7 DMF 0 % 8 1,2-DCE 37 % 9 MeOH 0 % 10 1,4-dioxane 0 % 11 water 0 % [a]All reactions were performed on 0.25 mmol scale at room temperature under a nitrogen atmosphere for 3 h, shielded from light; [b]Isolated yield. A screening of solvents revealed that the reaction took place in a few chlorinated solvents only (Table 13, entries 1, 2 and 8). Interestingly, while the best yield was obtained in CDCl3, the use of CHCl3 did not lead to any conversion (entry 1 vs entry 3). We then proceeded with the optimization of the other reaction parameters (Table 14). Table 14: Optimization of the reaction conditions Entry[a] PhI(OAc)2 H2O Temperature Time Yield[b] 1[c] 1 eq. 1.1 eq. r.t. 3 h 42 %[d] 2[c] 0.5 eq. 1.1 eq. r.t. 3 h 13 % 3[c] 1.5 eq. 1.1 eq. r.t. 3 h 30 % 4[c] 2 eq. 1.1 eq. r.t. 3 h 40 % 5[c] 3 eq. 1.1 eq. r.t. 3 h 60 %[d] 6[c] 3 eq. 3.1 eq. r.t. 3 h 46 % 7[c] 3 eq. 6 eq. r.t. 3 h 5 % 8[c],[e] 3 eq. 1.1 eq. r.t. 3 h 0 % 82 Entry[a] PhI(OAc)2 H2O Temperature Time Yield[b] 9[c],[f] 3 eq. 1.1 eq. r.t. 3 h 0 % 10[c],[g] 3 eq. 1.1 eq. r.t. 3 h 0 % 11 3 eq. 1.1 eq. r.t. 3 h 60 %[d] 12 3 eq. 1.1 eq. 0 °C 3 h 0 % 13 3 eq. 1.1 eq. 40 °C 3 h 33 % 14[h] 3 eq. 1.1 eq. r.t. 3 h 51 %[d] 15[h] 3 eq. 1.1 eq. r.t. 4 h 64 %[d] (0 %[i]) 16[h] 3 eq. 1.1 eq. r.t. 5 h 38 %[d] 17[h] - 1.1 eq. r.t. 4 h 0 % 18[h] 3 eq. 0.45 eq. r.t. 4 h 20 % [a]All reactions were performed on 0.25 mmol scale at room temperature under a nitrogen atmosphere; [b]Yield determined by 1H NMR integration using mesitylene as internal standard; [c]Shielded from light; [d]Isolated yield; [e]PhI(OCOCF3)2 was used instead of PhI(OAC)2; [f]DMP was used instead of PhI(OAC)2; [g]NBS was used instead of PhI(OAC)2; [h]With 10 mol% AgBF4; [i]In the absence of AgBF4. Increasing the amount of (diacetoxyiodo)benzene from 1 to 3 equivalents led to the formation of 237 in 60 % yield (entry 5), while increasing the amount of water did not have a positive impact on the outcome of the reaction (entries 6 and 7). The use of other oxidizing agents was unsuccessful, and only starting material was recovered in the presence of PhI(OCOCF3)2, DMP or NBS (entries 8−10). As the yield was identical in the presence or absence of light (entry 5 vs entry 11), we proceeded further without shielding the reaction mixture from light. Reducing the catalyst loading to 10 mol% and extending the reaction time to 4 hours led to cyclobutenyl ketone 237 in a satisfying yield of 64 % (entry 15). Running the reaction on a longer period of time was not beneficial as the product was recovered in a lower yield, hinting at a possible product degradation under the developed conditions (entry 16). Finally, no cyclobutenyl ketone was formed in the absence of PhI(OAc)2 (entry 17), and lessening the amount of water from 1.1 to 0.45 equivalents resulted in a significant drop of the reaction yield (entry 15 vs entry 18). 83 3.2.2. Propargyl Cyclopropane Synthesis Unfortunately, as the catalytic system elaborated with TBA[Fe] for the cyclopropanation of 1,3-enynes (Section 2.2.2) led predominantly to the formation of the corresponding trans-cyclopropanes as a racemic mixture, we could not employ this method to access the desired cis-cyclopropanes in satisfying yields and enantiomeric purity. Thus, we turned our attention to other suitable systems and synthesized cobalt(II)- salen complex 34 previously developed by Katsuki et al.[38], starting from (R)-BINOL 238 and following literature-known procedures (Scheme 45).[38,151,152] Scheme 45: Synthesis of Co(II)-salen complex 34 84 Pleasingly, the use of complex 34 led to the formation of the cyclopropanes in almost exclusive cis-conformation, high enantioselectivity and good to excellent yields, according to the additional information provided by Hongdong Yuan (Table 15). Table 15: Synthesis of the cis-propargyl cyclopropanes[a] Entry Substrate Product Yield (%) e.e. (%) 1 88 94 2 68 n.d.[b] 3 quant. n.d.[b] 4 94 94[c] 85 Entry Substrate Product Yield (%) e.e. (%) 5 quant. 94[c] 6 93 94[c] 7 64 95[c] 8 99 94[c] 9 quant. n.d.[b] 86 Entry Substrate Product Yield (%) e.e. (%) 10 81 95[c] 11 71 n.d.[b] 12 84 95[c] 13 68 n.d.[b] 14 50 n.d.[b] [a]All reactions were performed under dry conditions nitrogen atmosphere, yields of isolated products are reported, the e.e. values were determined by chiral HPLC; [b]investigations to determine the e.e. values are currently performed by Hongdong Yuan; [c]e.e. values were measured by Hongdong Yuan on substrates he re-synthesized. The absolute configurations of propargyl cyclopropanes (R,S)-212 and 252 were unambiguously confirmed by X-Ray diffraction analysis (Figure 23 and Section 5). 87 Figure 23: X-Ray structures of (R,S)-212 and 252 3.2.3. Substrate Scope of the Silver-Catalyzed Oxidative Ring Expansion of Propargyl Cyclopropanes With the desired substrates and the optimized conditions in hand, we next examined the scope of the silver-catalyzed oxidative ring expansion of propargyl cyclopropanes (Table 16). Table 16: Scope of the silver-catalyzed ring expansion of propargyl cyclopropanes[a] Entry Substrate Product Time Yield (%) e.e. (%) 1 5 h 61 90 (94) (R,S)-212 252 88 Entry Substrate Product Time Yield (%) e.e. (%) 2 No conversion, 92 % of starting material recovered 24 h n.d. n.d. 3[b] Product degradation 3.5 h n.d. n.d. 4 0.5 h 85 92 (94) 5 5.5 h 82 (48[c]) 94 (94) 6 9.5 h 59 (33[d]) 94 (94) 89 Entry Substrate Product Time Yield (%) e.e. (%) 7 4.5 h 77 93 (95) 8 1 h 78 n.d.[e] (94) 9 No conversion, 90 % of starting material recovered 24 h n.d. n.d. 10 1 h 92 n.d.[e] (95) 11 No conversion, 70 % of starting material recovered 22 h n.d. n.d. 12 5.5 h 60 95 (95) 90 Entry Substrate Product Time Yield (%) e.e. (%) 13 4 h 68 n.d.[e] 14 3.5 h 72 95 [a]All reactions were performed on 0.50 mmol scale under a nitrogen atmosphere, yields of isolated products are reported, e.e. values were determined by chiral HPLC, e.e. values of the corresponding starting materials are indicated in parentheses; [b]with 1 eq. of PhI(OAc)2; [c]8 h reaction time; [d]24 h reaction time; [e]investigations to determine the e.e. values are currently performed by Hongdong Yuan. The desired cyclobutenyl ketones were obtained from the corresponding propargyl cyclopropanes in good yields and almost complete retention of the chiral information. Thus far, only a slight erosion of e.e. values were observed in products 255, 256 and 259. Propargyl cyclopropanes bearing an aryl substituent with an electron donating- or withdrawing group on the aromatic unit were well tolerated (entries 1, 4−8 and 10), and more sterically hindered propargyl cyclopropane 252 furnished product 261 in excellent yield (entry 10). However, independently of the electron-donating or -withdrawing character of the corresponding functional group, the presence of a nitrogen atom in the substrate completely inhibited the reaction, even for extended reaction times (entries 2, 3, 9 and 11). No reaction was observed when substrates presenting a nitro or cyano group in the para position of the aryl substituent, or a pyridine moiety, were submitted to the reaction conditions, and the corresponding starting materials were almost fully recovered (entries 2, 9 and 11). Amines did not seem to be compatible with the developed reaction conditions, as complete decomposition of (R,S)-215 was observed, even after lowering the amount of PhI(OAc)2 from 3 to 1 equivalent (entry 3). Substrates possessing a thiophene substituent (entry 12) or an alkyl chain (entries 13 and 14) smoothly reacted to 91 give cyclobutenyl ketones 262, 237 and 263 in good yields. It is important to note that the reaction had to be carefully monitored as the yield seemed to decrease after an extended reaction time (Section 3.2.1 and entries 5 and 6). The absolute configuration of cyclobutenyl ketone 258 was unambiguously determined by X-Ray diffraction analysis (Figure 24 and Section 5). Figure 24: X-Ray structure of 258 Upon submitting an equimolar mixture of cis- and trans-cyclopropane 191 to our developed conditions, we observed full conversion of the cis-diastereomer to product 237 while trans-191 was almost completely recovered (Scheme 46). Cyclobutenyl ketone 237 was obtained in the same yield as when (R,S)-191 was employed as sole substrate (Table 16, entry 13) hinting at a possible diastereoselective character of this silver-catalyzed process. 258 92 Scheme 46: Comparison experiment To further evaluate the stability of the formed cyclobutenyl ketones, we submitted product 237 to the reaction conditions (Scheme 47). Scheme 47: Stability experiment After 4 hours, only 48 % of the starting material was recovered, and no other product could be detected or isolated, confirming that a degradation process of the cyclobutenyl ketones took place during the catalytic process. One hypothesis could be that HBF4 formed in situ could take part in the degradation process as we observed not only a decrease of the reaction yield for prolonged reaction times but also complete degradation of the starting material upon using this acid as catalyst during the optimization of the