Azaheterocycles through Pd(II)- catalyzed formal cycloadditions involving C-H activation

ESCUELA DE DOCTORADO INTERNACIONAL DE LA USC Xandro Vidal Pereira Tesis doctoral Azaheterocycles through Pd(II)- catalyzed formal cycloadditions involving C–H activation Santiago de Compostela, 2022 Programa de doctorado en Ciencia y Tecnología Química TESIS DE DOCTORADO AZAHETEROCYCLES THROUGH Pd(II)–CATALYZED FORMAL CYCLOADDITIONS INVOLVING C–H ACTIVATION Xandro Vidal Pereira ESCUELA DE DOCTORADO INTERNACIONAL DE LA UNIVERSIDAD DE SANTIAGO DE COMPOSTELA PROGRAMA DE DOCTORADO EN CIENCIA Y TECNOLOGÍA QUÍMICA SANTIAGO DE COMPOSTELA AÑO 2022 DECLARACIÓN DEL AUTOR DE LA TESIS AZAHETEROCYCLES THROUGH Pd(II)–CATALYZED FORMAL CYCLOADDITIONS INVOLVING C–H ACTIVATION D. Xandro Vidal Pereira Presento mi tesis, siguiendo el procedimiento adecuado al Reglamento, y declaro que: 1) La tesis abarca los resultados de la elaboración de mi trabajo. 2) En su caso, en la tesis se hace referencia a las colaboraciones que tuvo este trabajo. 3) La tesis es la versión definitiva presentada para su defensa y coincide con la versión enviada en formato electrónico. 4) Confirmo que la tesis no incurre en ningún tipo de plagio de otros autores ni de trabajos presentados por mí para la obtención de otros títulos. En Santiago de Compostela, 27 de enero de 2022 Firmado Xandro Vidal Pereira AUTORIZACIÓN DEL DIRECTOR / TUTOR DE LA TESIS Azaheterocycles through Pd(II)-catalyzed formal cycloadditions involving C–H activation D. José Luis Mascareñas Cid y D. Moisés Gulías Costa En condición de: Tutor y director En condición de: Director INFORMAN: Que la presente tesis, se corresponde con el trabajo realizado por D. Xandro Vidal Pereira, bajo mi dirección/tutorización, y a utorizo su presentación, considerando que reúne l os r equisitos exigidos en el R eglamento de Estudios de Doctorado de la USC, y que como director de esta no incurre en las causas de abstención establecidas en la Ley 40/2015. De acuerdo con lo indicado en el Reglamento de Estudios de Doctorado, declara también que la presente tesis doctoral es idónea para ser defendida en base a la modalidad de Monográfica con reproducción de publicaciones, en los que la participación del doctorando fue decisiva para su elaboración y las publicaciones se ajustan al Plan de Investigación. En Santiago de Compostela, 28 de enero de 2022 El modo de dar una vez en el clavo es dar cien veces en la herradura -Miguel de Unamuno Table of contents 15 Agradecimientos ........................................................................................................................ 9 Table of contents ...................................................................................................................... 13 Abbreviations and acronyms ................................................................................................. 19 Chapter I: Introduction ............................................................................................................ 23 1- Organic synthesis: building molecules for life .................................................................. 25 1.1 Introduction .............................................................................................................. 25 1.2 Modern organic synthesis ........................................................................................ 26 2- Organometallic catalysis: a key tool in synthetic chemistry ............................................ 27 2.1 Introduction .............................................................................................................. 27 2.2 Catalysis: when fewer is better ................................................................................. 27 2.3 Transition-metal catalyzed reactions: cycloadditions .............................................. 28 2.4 Transition-metal catalyzed reactions: cross-coupling .............................................. 30 3- Organometallic catalysis triggered by C–H activation: initial developments ................. 32 4- Palladium: a noble metal that waived the field of catalytic C–H functionalizations ...... 36 4.1 Introduction .............................................................................................................. 36 4.2 Mechanisms of palladium-catalyzed C−H acvaons. The introducon of amino acids as ligands ............................................................................................................... 36 4.3 Types of reactions based on Pd-catalyzed C–H activation ....................................... 41 4.3.1 C–H functionalizations ................................................................................... 41 4.3.2 Formal cycloadditions involving the activation of C−H bonds ....................... 48 4.4 Current challenges and future outlook ..................................................................... 51 General objectives ................................................................................................................... 53 Chapter II: Synthesis of tetrahydroisoquinoline skeletons via enantioselective formal cycloadditions of benzyltriflamides with allenes ................................................................. 57 1- Introduction ....................................................................................................................... 59 1.2 Classical methods for the synthesis of optically active tetrahydroisoquinolines...... 59 1.2.1 Picted–Spengler cyclization ........................................................................... 59 1.2.2 Bischler−Napieralski cyclization/reduction ................................................... 60 1.2.3 Pomeranz−Fritsch−Bobbi synthesis ............................................................ 61 1.3 Synthesis of tetrahydroisoquinoline skeletons relying on Pd-catalyzed C–H activations ...................................................................................................................... 62 1.4 Palladium-catalyzed enantioselective C−H funconalizaon of benzylamine derivatives ...................................................................................................................... 63 2- Objectives .......................................................................................................................... 66 Table of contents 16 3- Results and discussion ....................................................................................................... 68 3.1 Preliminary studies to identify the best reaction conditions .................................... 68 3.2 Scope of the annulation ........................................................................................... 70 3.3 Asymmetric annulations .......................................................................................... 74 3.4 Mechanistic proposal ............................................................................................... 77 4- Conclusions ........................................................................................................................ 79 Chapter III: Assembly of azaheterocycles by Pd(II)-catalyzed cycloadditions involving the activation of C(sp3)–H bonds ............................................................................................ 81 1- Introduction ....................................................................................................................... 83 1.1 Challenges in the activation of C(sp3)–H bonds ........................................................ 83 1.2 Palladium-catalyzed functionalization of benzylic methyl groups ........................... 84 1.3 Palladium-catalyzed benzylic C(sp3)–H functionalization of o-methylaniline and omethylbenzylamine precursors ....................................................................................... 86 1.4 Formal cycloadditions involving Pd-catalyzed C(sp3)–H activations ........................ 88 1.4.1 Introduction ..................................................................................................... 88 1.4.2 (n+1) cycloadditions ......................................................................................... 89 1.4.3 (n+2) cycloadditions ......................................................................................... 92 2- Objectives .......................................................................................................................... 94 3- Results and discussion ...................................................................................................... 96 3.1 Formal (4+2) cycloaddition between o-methylanilines and allenes: initial assays and optimization ................................................................................................................... 96 3.2 Scope of the (4+2) cycloaddition between o-methylanilides and allenes ............... 102 3.3 Mechanistic experiments ........................................................................................ 106 3.3.1 Deuterium labeling experiments .................................................................... 106 3.3.2 Experiments with an optically active, chiral allene ........................................ 108 3.3.3 Mechanistic hypothesis .................................................................................. 110 3.4 Formal (5+2) cycloaddition between o-methylbenzyltriflamides and allenes: initial assays ........................................................................................................................... 111 3.5 Scope of the (5+2) cycloaddition between o-methylbenzylamides and allenes ..... 113 3.6 Preliminary tests on a (5+2) enantioselective cycloaddition based on a kinetic resolution strategy ....................................................................................................... 115 3.7 Derivatization of the cycloadducts ......................................................................... 116 4- Conclusions ...................................................................................................................... 118 Addendum: Preliminary studies on Pd-catalyzed cyclization of o-methylbenzyl amines to isoindolines involving C(sp3)–H activation ..................................................................... 121 1- Introduction ..................................................................................................................... 123 1.1 Features of Pd(II)/Pd(IV) based catalytic cycles...................................................... 123 Table of contents 17 1.2 Synthesis of indole-type skeletons through Pd(II)/Pd(IV) catalysis ........................ 124 2- Objectives ........................................................................................................................ 127 3- Results and discussion .................................................................................................... 128 4- Conclusions ...................................................................................................................... 132 General conclusions ............................................................................................................... 133 Resumo da tese doutoral ..................................................................................................... 137 Experimental Section ............................................................................................................ 147 Selected spectra ..................................................................................................................... 219 List of publications ................................................................................................................. 287 Abbreviations and acronyms Abbreviations and acronyms 21 Ac Acetate Ad Adamantyl Ala Alanine APAO N-acyl-protected aminomethyl oxazoline APAQ N-acyl-protected aminoethyl quinoline APCI Atmospheric pressure chemical ionization BDE Bond dissociation energy BINAP 2,2′-bis(diphenylphosphino)-1,1′- binaphthyl BINOL 1,1′-Bi-2-naphthol Bn Benzyl Boc tert-Butyloxycarbonyl BQ p-Benzoquinone brs Broad singlet Bz Benzoyl Cat Catalytic amount CMD Concerted metalationdeprotonation cod 1,5-Cyclooctadiene Cp cyclopentadienyl Cy Cyclohexyl d Doublet dba Dibenzylideneacetone DCE 1,2-Dichloroethane DCM Dichloromethane de Diasteroisomeric excess DEAD Diethylazodicarboxylate DEPT Distortionless Enhancement by polarization transfer DG Directing group DIAD Diisopropylazodicarboxylate DMAP N,N-Dimethylaminopyridine DMF N,N-Dimethyl formamide DMSO Dimethyl sulfoxide DOPA Dihydroxyphenylalanine dppp 1,4-Bis(diphenylphosphino) propane ee Enantiomeric excess equiv Equivalent er Enantiomeric ratio ESI Electrospray Et Ethyl Fmoc Fluorenylmethyloxycarbonyl Gly Glycine hfacac Hexafluoroacetylacetone HFIP Hexafluoroisopropanol HOMO Highest occupied molecular orbital HRMS High resolution mass spectroscopy HSQC Heteronuclear single quantum correlation iPr Isopropyl J Coupling constant KIE Kinetic isotopic effect Leu Leucine LUMO Lowest unoccupied molecular orbital m Multiplet Me Methyl Meas. Measured MPAA Mono-protected amino acid Abbreviations and acronyms 22 MPAAM Mono N-protected aminoethyl amine MPAThio Mono N-protected aminoethyl thioether Ms Mesyl Naph Naphtyl nBu n-Butyl NFSI N-fluorobenzenesulfonimide nHex n-Hexyl NMR Nuclear magnetic resonance nOe Nuclear Overhauser effect Ns 4-Nitrobenzenesulfonyl PG Protecting group Ph Phenyl Phe Phenylalanine Phth Phthaloyl pin Pinacolate PIP Pyridyl isopropylamine group Piv 2,2-Dimethylpropionate Pro Propyl q Quadruplet rr Regioisomeric ratio rt Room temperature s Singlet SIPr 1,3-Bis(2,6-diisopropylphenyl)-4,5- dihydro-1H-imidazol-3-ium-2-ide SN2 Bimolecular nucleophilic substitution t Triplet tAmOH 2-Methyl-2-butanol TBHP tert-Butyl hydrogen peroxide TBS tert-Butyldimethylsilyl tBu tert-Butyl TCE Trichloroethylene Tf Trifluoromethylsulfonyl TFA Trifluoroacetic acid THF Tetrahydrofuran THIQ Tetrahydroisoquinoline THQ Tetrahydroquinoline TM Transition metal TMEDA N,N,N’,N’- Tetramethylethylenediamine TMS Trimethylsilyl Tol Toluene TS Transition state Ts 4-Methylbenzenesulfonyl Val Valine Chapter I Introduction Chapter I 31 The synthetic applications of these processes encouraged organic chemists to research to broad the scope of these transformations. One of the key developments was the employment of ligands with different steric and electronic properties. The resulting modified catalysts made possible to perform cross-coupling transformations under milder conditions and with lower catalyst loadings. For example, Heck demonstrated that, by adding phosphines to the reaction media, the range of reactive alkenes could be expanded (Scheme 5).31 Scheme 5. Use of phosphines as ligands to improve the Heck reaction. Playing with ligands, it was possible to perform cross-coupling reactions which generate heteroatom bonds, instead of C–C bonds. Hartwig-Buchwald amination is probably one of the most important reactions in this context.32 It has been used in numerous synthetic processes, for example, in the Novartis route for the synthesis of Imatinib, a medication used to treat cancer (Scheme 6).33 Scheme 6. Last step of the Novartis route for the synthesis of Imatinib. Even though cross-couplings have proved to be very powerful tools for synthetic chemists, there are still some inherent limitations. Particularly, the need of prefunctionalized substrates such aryl halides, pseudohalides and organometallic reagents, which requires of additional synthetic steps to install the corresponding functional groups, with its subsequent waste of stoichiometric reactants. In the pursuit of greater atom and step economy, the dream of any synthetic chemist is the invention of other methodologies to form C–C or C–X bonds without the need of prefunctionalization. And at this point, it is where C−H activation has taken the stage. 31 Dieck, H. A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 1133. 32 Dorel, R.; Grugel, C. P.; Haydl, A. M. Angew. Chem. Int. Ed. 2019, 58, 17118. 33 O. Loiseleur, D. Kaufmann, S. Abel, H. M. Buerger, M. Meisenbach, B. Schmitz and G. Sedelmeier, World Pat., 03066613, 2003. Chapter I 32 3- Organometallic catalysis triggered by C–H activation: initial developments Carbon-hydrogen bonds have been generally considered “inert”. In fact, one of the old names of alkanes, “paraffines”, came from Latin parum affinis, which means “without affinity”. By having a look at bond dissociation energies (BDE), the strength of C–H bonds is evident. Whereas the weakly polarized C–H bond of methane presents a BDE of 105 kcal mol-1, its brominated counterpart, the more polarized C–Br bond of bromomethane, has a lower BDE of 70.3 kcal mol-1.34 Despite the challenge of its inertness, the activation of C–H bonds is a major research topic in modern synthetic chemistry. The ubiquity of this type of bonds in organic molecules makes this field very attractive to transform widely-available hydrocarbon feedstocks. However, this ubiquity is a double-edge sword. The little difference of energies among the several C−H bonds of organic molecules makes very difficult to control selectivity. In fact, classic reactions with alkanes, based on radical (autoxidation, halogenation) or carbene chemistry are characterized by a lack of selectivity. This is due to the fact that these reactions are based on very reactive species that are able to overcome the inherent inertness of alkanes, but that give rise to the formation of many products due to their indiscriminate attack to different C–H bonds.35 Therefore, the development of novel procedures to selectively activate carbon-hydrogen bonds represents a challenging issue in the field of synthetic chemistry. In the 1960’s, during the boom of organometallic chemistry, several research groups started to study the activation of carbon-hydrogen bonds by the employment of transition-metals, with the objective of creating organometallic complexes from hydrocarbons through the processed that was called “C–H activation”. The first examples in this field can be traced back to the work of Kleiman and Dubech (Scheme 7)36 in 1963, describing the cyclometalation of aromatic compounds with a Ni(0) complex, and the work of Chatt37 on 1965, on the addition of C−H bonds of naphthalene to Ru(0) complexes. Scheme 7. First example of stoichiometric C−H activation by Kleiman and Dubech. 34 Y. R. Luo, Comprehensive Handbook of Chemical Bond Energies, CRC Press, Boca Raton, 2007. 35 Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879. 36 Kleiman, J. P.; Dubeck, M.; J. Am. Chem. Soc. 1963, 85, 1544. 37 Chatt, J.; Davidson, J. M. J. Chem. Soc. 1965, 843. Chapter I 33 Palladium soon took protagonism as one of the mosts active metals in C–H activation. In 1965, Verberg38 published a method of oxidative coupling of aromatic compounds with palladium salts. A key discovery was the catalytic arylation of alkenes reported by Fujiwara and Moritani in 1969 by the employment of palladium catalysts (Scheme 8).39 Scheme 8. Fujiwara-Moritani reaction. It is important to notice that, even though this reaction proceeds through a very similar mechanism that the Mizoroki-Heck reaction (vide supra), the oxidative addition of the Ar–X bond to a Pd(0) complex is substituted by the C−H activation of the Ar–H bond with a Pd(II) catalyst, which overcomes one of the main disadvantages of cross-coupling reactions: the need of a prefunctionalized substrate. Curiously, the Heck reaction was published three years after the Fujiwara-Moritani reaction. In 1969, the first transition-metal C(sp3)−H bond activation was discovered. Shilov40 reported that K2PtCl4 catalyze the H–D exchange of methane with heavy water at room temperature. The group later developed a method to catalytically convert methane to methanol. It was called the Shilov system (Scheme 9).41 The need to use stoichiometric platinum as oxidant was its mayor drawback. However, it is, even today, one of the few catalytic systems that allows selective alkane functionalizations under mild conditions.42 Scheme 9. Shilov system to convert methane into methanol. 38 van Helden, R.; Verberg, G. Recl. Trav. Chim. Pays-Bas 1965, 84, 1263. 39 Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166. 40 Gol’dshleger, N. F.; Tyabin, M. B.; Shilov, A. E.; Shteinman, A. A. Zh. Fiz. Khim. 1969, 43, 2174. 41 (a) Gol'dshleger, N. F.; Es'kova, V. V.; Shilov, A. E.; Shteinman, A. A. Zh. Fiz. Khim. 1972, 46, 1353. (b) Crabtree, R. H. J. Chem. Soc. Dalt. Trans. 2001, 17, 2437. 42 Goldman, A. S.; Goldberg, K. I. Organometallic C–H Bond Activation: An Introduction. In ACS Symposium Series Vol. 885, 2004. Chapter I 34 The next breakthrough had to wait nearly a decade until, in 1982, Bergman43 and Graham44 independently published a photochemical C−H activation of alkanes with an iridium complex (Scheme 10). Scheme 10. C–H activation by Bergman et al. (left) and Graham et al. (right). It was not until 1993 that the field experimented a new boost, with the outstanding discovery by Murai and co-workers of a ruthenium-catalyzed selective ortho-directed C−H functionalization of aryl ketones (Scheme 11).45 The use of a carbonyl as directing group for the metal complex was key in the success of the reaction. This development revigorated the field, which is still in relentless ascension. Scheme 11. Ruthenium-catalyzed C−H functionalization of aryl ketones by Murai. At this point, it is important to mention that the term C−H functionalization includes any transformation that converts a C−H bond into a C−FG bond (FG ≠ H) via C−H activation. The work of Murai can be considered as the spark that ignited the C−H activation field using metal catalysis. Since its publication, the number of references of “C−H activation” has experienced an exponential grow,46 evidencing the importance of this topic in contemporary organic chemistry. The vast majority of the publications rely on the activation of C(sp2)–H bonds, due to the fact that this type of bond is easier to cleave (see section 1 of Chapter III for further explanation), even though the field of C(sp3 )–H activation has been growing in recent years. 43 Janowicz, A. H.; Bergman, R. G. J. Am. Chem. Soc. 1982, 104, 352. 44 Hoyano, J. K.; Graham, W. A. G. J. Am. Chem. Soc. 1982, 104, 3723. 45 Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; N. Chatani, N. Nature 1993, 366, 529. 46 Source: Scifinder, by searching “C–H activation” as keyword (searched 2022-01-05) there were 31 references in 1993 and 760 in 2021. Chapter I 35 Asymmetric functionalizations have also been developed by taking advantage of the employment of chiral ligands. One example is the work of Shibata in the enantioselective iridium-catalyzed C(sp3)–H alkylation of ɣ-butyrolactam for the synthesis of ɣ-amino acids, with the enantioselectivity induced by a chiral phosphine. The presence of the pyridine directing group in the substrate is key for the reaction (Scheme 12).47 Scheme 12. Iridium-catalyzed C(sp3)−H alkylation of ɣ-butyrolactam by Shibata. As can be deduced from the above reactions, the use of directing groups seems critical to allow the C−H activation chemistry.48 These moieties can control site-selectivity by approximating the reactive metal center to the desired C−H bond (Scheme 13), and accelerate the reactions by decreasing the entropic cost of C−H activation process. Scheme 13. Site selective controlled by the employment of a directing group. TM = transition metal. In fact, it was thanks to a ketone acting as a chelation-assisted directing group that Murai could achieve that important milestone in C−H activation chemistry that ignited the spark of this field (vide supra). During these two last decades, several directing groups have been employed to functionalize C−H bonds,48 some of which are depicted in Figure 2. Figure 2. Common directing groups, with indication (in red) of the C–H bond that is activated. Most directing groups are employed to functionalize aryl C−H bonds in ortho position, like Murai’s work (vide supra), but there is an increasing effort to develop novel strategies that allow meta49 and para50 functionalizations in aromatic systems. 47 Tahara, Y. K.; Michino, M.; Ito, M.; Kanyiva, K. S.; Shibata, T. Chem. Commun. 2015, 51, 16660. 48 Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107. 49 Xu, H. J.; Kang, Y. S.; Shi, H.; Zhang, P.; Chen, Y. K.; Zhang, B.; Liu, Z. Q.; Zhao, J.; Sun, W. Y.; Yu, J. Q.; Lu, Y. J. Am. Chem. Soc. 2019, 141, 76. 50 (a) Bag, S.; Patra, T.; Modak, A.; Deb, A.; Maity, S.; Dutta, U.; Dey, A.; Kancherla, R.; Maji, A.; Hazra, A.; Bera, M.; Maiti, D. J. Am. Chem. Soc. 2015, 137, 11888. (b) Li, M.; Shang, M.; Xu, H.; Wang, X.; Dai, H. X.; Yu, J. Q. Org. Lett. 2019, 21, 540. Chapter I 36 4- Palladium: a noble metal that waived the field of catalytic C–H functionalizations 4.1 Introduction Palladium, named after the Greek goddess Pallas Athenea, is one of the most used transitionmetals in organic chemistry. From cross-coupling reactions (vide supra) to the Tsuji-Trost reaction,51 palladium reagents have played a critical role in the development of novel organic transformations. Regarding the C−H activation field, palladium catalysts are particularly attractive for several reasons. First, there is a relatively low barrier between the oxidation states of 0 and +2 corresponding to the d10 and d8 configuration, which favors reversibility. As a consequence, oxidative insertions and reductive eliminations occur rapidly, leading to faster catalytic cycles. Second, the inherent square planar geometries of palladium complexes offer more versatility than linear geometries, characteristic of gold complexes, but are also relatively simple and sterically accessible, and easier to control than octahedral geometries where fac and mer stereoisomerism may appear. Palladium also shows a good affinity for electron donating ligands and unsaturated moieties, which further favors reactivity.52 4.2 Mechanisms of palladium-catalyzed C−H acvaons. The introduction of amino acids as ligands As stated in the previous section, the employment of directing groups is essential to boost reactivity and control selectivity in C−H functionalization reactions (vide supra). After coordination to these groups, the palladium complex can effectively perform the required C–H activation, usually through concerted metalation-deprotonation (CMD) processes (Scheme 14). In this mechanism, the palladium weakens the C−H bond, while a base, generally coordinated to the metal, abstracts the proton, all occurring in a concerted manner.53 The base is generally a carboxylate, like the acetate of Pd(OAc)2. Scheme 14. Scheme of a CMD mechanism for a Pd(II) complex. The ligands coordinated to the palladium center can modify the electronic properties and steric environment of the metal, and thus the performance of the catalyst in C–H activation reactions. Depending on the type of catalytic cycle that is present in the reaction, some ligands are 51 (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387. (b) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292. 52 (a) Hegedus, L. S. Transition metals in the synthesis of complex organic molecules University Science Books, 1994. (b) Crabtree, R. H. The organometallic chemistry of the transition metals. Wiley-VCH, 2014. 53 Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118. Chapter I 37 preferred over the others.54 For example, in Pd(II)/Pd(0) catalytic cycles, pyridines can be used as monodentate ligands for the reaction. These ligands are not only capable of tuning the electronics of the catalyst, but also of driving the formation of active monomeric catalytic species.55 The idea of employing chiral ligands in C–H activation reactions is very appealing as a way to introduce asymmetry in organic molecules. As early as in 1979, Sokolov hypothesized that a chiral carboxylate acting as a monodentate ligand could induce enantioselectivity during the C−H activation step (Figure 3, mechanism A). With this idea, his group developed the first stoichiometric asymmetric cyclopalladation by the employment of a N-acyl--amino acid as a chiral carboxylate.56 However, this mechanism, later studied by Richards,57 was inconsistent with some data reported by Yu’s group years later, such as the fact that C2-symmetric amino acids or diprotected amino acids give racemic mixtures. In 2008, Yu reported the first catalytic enantioselective C−H acvaon mediated by monoprotected amino acids (MPAA), a series of amino acids where the amine is monoprotected with an acyl group.58 He proposed in this publication an alternative mechanism for the C–H activation (Figure 3, mechanism B), with the amino acid coordinate in a bidentate fashion to the metal center, and with an external base activating the C−H bond. In this model, the nitrogen would coordinate as a neutral donor ligand. The problem with this hypothesis is that the N–H bond is more acidic than the C−H bond, thus the external base should deprotonate the N–H before attacking the C−H bond. Yu and Musaev discussed in 2012 a modification in the mechanism (Figure 3, mechanism C),59 in which the N–H deprotonation would occur first, generating an anionic palladium. This mechanism was supported by computational studies. However, some experimental data were still inconsistent. The employment of electron withdrawing protecting groups in the amine suppresses the reactivity in some particular cases. The mechanism C suggests exactly the opposite, as the inductive effect may stabilize the anionic palladium complex. Therefore, Houk, Yu and Musaev proposed an alternative mechanism (Figure 3, mechanism D),60 in which the external base is substituted with an inner-sphere C−H cleavage performed by the amidate group of the amino acid, in an overall ligand-assist CMD mechanism. This model is more consistent with all the reactivity and selectivity data reported to date, and it is generally proposed for Pdcatalyzed reactions using MPAAs as ligands. 54 Engle, K.M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927. 55 Cendón, B.; Font, M.; Mascareñas, J. L.; Gulıas, M. ACS Catal. 2020, 10, 3425. 56 Sokolov, V. I.; Troitskaya, L. L.; Reutov, O. A J. Organomet. Chem. 1979, 182, 537. 57 Günay, M. E.; Ilyashenko, G.; Richards, C. J. Tetrahedron Asymmetry 2010, 21, 2782. 58 Shi, B. F.; Maugel, N.; Zhang, Y. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 4882. 59 Musaev, D. G.; Kaledin, A.; Shi, B. F.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 1690. 60 (a) Cheng, G. J.; Yang, Y. F.; Liu, P.; Chen, P.; Sun, T. Y.; Li, G.; Zhang, X.; Houk, K. N.; Yu, J.-Q.; Wu, Y. D. J. Am. Chem. Soc. 2014, 136, 894. (b) Cheng, G. J.; Chen, P.; Sun, T. Y.; Zhang, X.; Yu, J.-Q.; Wu, Y. D. Chem. Eur. J. 2015, 21, 11180. Chapter I 38 Figure 3. Transition-state structures proposed for the Pd-catalyzed C−H acvaon assisted by MPAAs. MPAAs ligands have demonstrated to improve yields and broaden the scope of C–H functionalization reactions. 61 One example is the Pd(II)-catalyzed C–H olefination of phenylacetic acids reported by Yu and co-workers and depicted in Scheme 15, where the employment of Boc-Val-OH resulted in an increase in the reaction rate and in the efficiency of the reaction.62 The yield of the reaction increased from 12% to 90% when using a MPAA ligand, and kinetic studies determined that there is a 36-fold increase in the reaction rate in the ligandassisted olefination. Scheme 15. Ligand acceleration in the Pd(II)-catalyzed C–H olefination of phenylacetic acids reported by Yu and co-workers. The reactivity enhancement can be explaining considering several aspects contemplated in mechanism D:61a  The basicity of the carbonyl group of the amidate is higher compared to acetate.  A less steric hindrance environment for coordination of the directing group due to the smaller bite angle of the MPAA compared to two acetate ligands.  The favorable coplanar orientation of the N-acyl carbonyl group and the C−H bond, due to the planar structure of the bidentate MPAA and the square planar geometry of the palladium (II) center.  The stabilization of active monomeric palladium species in solution.  For this particular reaction, a change in the reaction mechanism, from electrophilic palladation to ligand-assisted CMD. 61 Selected reviews of mono-protected amino acid as ligands in Pd-catalyzed C-H activation: (a) Engle, K. M. Pure Appl. Chem. 2016, 88, 119. (b) Shao, Q.; Wu, K.; Zhuang, Z.; Qian, S.; Yu, J.-Q. Acc. Chem. Res. 2020, 53, 833–851. 62 (a) Wang, D. H.; Engle, K. M., Shi, B. F.; Yu. J.-Q. Science, 2010, 327, 315. (b) Engle, K. M.; Wang, D. H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137. Chapter I 39 An additional, important advantage of MPAAs is that they are chiral, and thefore can have enantio-inducting effects, especially if mechanism D is operating. The chelating ligand creates a semirigid framework that can differentiate the two diastereomeric transition states, as it is depicted in Scheme 16.61b Scheme 16. Stereomodel for bidentate internal amidate MPAA enantioselective C−H acvaon. The model is illustrated with a D-MPAA. The side chain of the amino acid (R2) is placed in an axial position due to the steric repulsion with the N-acyl protecting group (R1). Therefore, steric interactions of R2 with the R group of the substrate help to differentiate between the two diastereomeric transition states. The election of proper R1 and R2 moieties is crucial for achieving a good enantioselectivity. Besides, interactions with the directing group can also influence the relative energies of the transition states. Mechanistic studies of the behavior of mono-protected amino acids in palladium-catalyzed C−H activation reactions have shed a light on the influence of each structural feature of the ligand in these types of reactions. The conclusions are summarized in Figure 4. Figure 4. Structural features of MPAAs and its influence in C−H acvaon reacons. Chapter I 40 The employment of MPAAs as both promoters and chiral inductors has been very successful in different types of metal-catalyzed reactions, from remote C−H funconalizaons to late stage postfunctionalizations.61 However, it is usually needed to screen for the more appropriate MPAA for each reaction. Therefore, the discovery of a more general set of ligands that could be successfully employed in any type of palladium-catalyzed C−H functionalization would be extremely relevant. Yu’s group has also designed a new generation of ligands which preserve the key features of the MPAAs, but replace the carboxylate moiety for an L type ligand, preserving a bidentate coordination (Figure 5). Each ligand needs to be optimized for different types of C−H acvaon reacons. N-acyl-protected aminomethyl oxazoline (APAO) ligands induce high enantioselectivity in C−H desymmetrizaons of prochiral methyl groups in isobutyramides.63 N-acyl-protected aminoethyl quinoline (APAQ) ligands have been employed in enantioselective arylation of methylene C(sp3)−H bonds.64 Mono N-protected aminoethyl amine (MPAAM) ligands have demonstrated to be useful in enantioselective C−H arylaon of cyclopropanecarboxylic and 2-aminoisobutyric acids.65 Finally, mono N-protected aminoethyl thioether (MPAThio) ligands enable C−H olefinaon of simple free carboxylic acids.66 Figure 5. New generation of ligands inspired by MPAA mechanistic understanding. 63 Wu, Q. F.; Shen, P. X.; He, J.; Wang, X. B.; Zhang, F.; Shao, Q.; Zhu, R. Y.; Mapelli, C.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Science 2017, 355, 499. 64 Chen, G.; Gong, W.; Zhuang, Z.; Andrä, M. S.; Chen, Y. Q.; Hong, X.; Yang, Y. F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Science 2016, 353, 1023. 65 Shen, P. X.; Hu, L.; Shao, Q.; Hong, K.; Yu, J.-Q. J. Am. Chem. Soc. 2018, 140, 6545. 66 Zhuang, Z.; Yu, C. Bin; Chen, G.; Wu, Q. F.; Hsiao, Y.; Joe, C. L.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q. J. Am. Chem. Soc. 2018, 140, 10363. Chapter I 47 Other halogens can also be introduced using Pd-catalyzed C−H activation reactions.84 For instance, Yu developed in 2017 a β‑C(sp3)−H iodination of ketones using a removable directing group auxiliary that works as an L,X ligand (Scheme 25).85 After the palladacycle is formed, the iodination takes places through a Pd(II)/Pd(IV) mechanism, employing molecular iodine as oxidant, in a similar fashion to the acetoxylation reactions reported above (vide supra). Scheme 25. Pd-catalyzed β ‑ C(sp3)−H iodination of ketones reported by Yu and co-workers. The intermediate which likely undergoes reductive elimination of the C–I bond is depicted in Figure 7. After the formation of the iodinated product, the oxime directing group can be easily removed to obtain the β-iodinated ketone. Figure 7. Proposed intermediate of the catalytic cycle. 84 Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116, 8003. 85 Zhu, R. Y.; Liu, L. Y.; Yu, J.-Q. J. Am. Chem. Soc. 2017, 139, 12394. Chapter I 48 4.3.2 Formal cycloadditions involving the activation of C−H bonds 4.3.2.1 Introduction As it explained in previous sections, the use of directing groups tends to be mandatory in many transition-metal mediated C−H functionalization processes, including palladium-catalyzed reactions. In most of the cases, the directing group is only used as a coordinating motif to achieve the C−H functionalization, so it is not usually needed in the final structure, and it has to be removed afterwards. Thus, it is somewhat contradictory to employ C−H activation reactions as a way to pursue total atom and step economy, when the introduction and subsequent removal of structural motifs is often mandatory for this methodology. Additional strategies, like the employment of transient directing groups that are only present in the C−H functionalization step86, avoid these extra actions, but they only can be implemented in certain cases. Another alternative consists of engineering reactions in which the directing group could be part of the product, something that is feasible in formal cycloaddition processes. Classical metalcatalyzed cycloadditions involve the formation of metalacyclic intermediates via oxidative cyclometalations (Scheme 26a). Assembling related metalacycles using C–H activations could provide an alternative, step economical way to build cyclic products from acyclic starting materials in an atom economical manner. This strategy provides a new, different approach for the synthesis of cyclic molecules, particularly heterocyclic rings, which are a common motif in bioactive products (Scheme 26b). 87 Scheme 26. Comparison between classic transition-metal catalyzed cycloadditions and C−H activationbased cycloadditions. Most of the C−H activation-based formal cycloadditions rely on the same mechanistic framework, namely C−H activation, migratory insertion and reductive elimination. An illustrative example for a general Pd-catalyzed C(sp2)–H activation-based cycloaddition with alkenes is depicted in Scheme 27.88 The mechanism starts with the formation of the palladacycle via C−H acvaon assisted by the directing group. Then, the coupling partner, in this case an alkene, coordinates to the palladium center and undergoes a migratory insertion to form a larger palladacycle, that suffers a reductive elimination to form the product. The Pd(0) is reoxidized to Pd(II) with the aid of an oxidant. It is 86 Gandeepan, P.; Ackermann, L. Chem 2018, 4, 199. 87 (a) Majumdar, K. C.; Chattopadyay, S. K. Heterocycles in natural product synthesis Wiley-VCH, 2011. (b) Lamberth, C.; Dinges, J. Bioactive heterocyclic compound classes: Pharmaceuticals Wiley-VCH, 2012. 88 For further information about Pd-catalyzed C–H activation-based cycloadditions, among other metals: Gulías, M.; Mascareñas, J. L. Angew. Chem. Int. Ed. 2016, 55, 1100. Chapter I 49 important to mention that, if there are available hydrogens at the β position, an undesired βhydride elimination could take place after the migratory insertion. Scheme 27. General mechanism for a Pd-catalyzed cycloaddition with alkenes via C(sp2)–H activation. In the following sections, examples of different palladium-catalyzed cycloadditions engaging C(sp2)−H acvaon will be depicted. Only a few examples of formal cycloadditions entailing C(sp3)−H acvaons have been reported, and they will be covered in section 1.4 of Chapter III. 4.3.2.2 (n+1) cycloadditions In these types of formal cycloadditions, the coupling partner provides one carbon to the final ring. The most common reagent for this purpose is carbon monoxide. A representative example of this chemistry is the work of Shi and collaborators, describing the Pd(II)-catalyzed carbonylation of 2-arylphenols (formal (5+1) annulation).89 Mechanistic studies suggested that the C–H activation goes through an electrophilic cyclopalladation rather than a CMD. After this step, a Pd-carbonyl intermediate is formed. In a same way that the aforementioned general mechanism, this intermediate evolves by migratory insertion of the CO group followed by reductive elimination to afford the lactone-derived cycloadducts. The resulting Pd0 species is reoxidized to PdII by a combination of Cu(OAc)2 and oxygen from the air atmosphere (Scheme 28). 89 Luo, S.; Luo, F.-X.; Zhang, X.-S.; Shi, Z.-J. Angew. Chem. Int. Ed. 2013, 125, 10792. Chapter I 50 Scheme 28. Pd(II)-catalyzed (5+1) carbonylation of 2-arylphenols developed by Shi and co-workers, and key intermediate. 4.3.2.3 (n+2) cycloadditions In these reactions, the unsaturated coupling partners are 2-carbon donors, which usually coordinate well to the metal center through their π-bonds. A variety of methodologies based on these types of formal annulations have been described, especially using rhodium catalysis.90 Palladium catalysts have been scarcely reported. Our research group has published several formal (4+2) cycloadditions,91 e.g., the annulation between triflyl protected vinylanilines and allenes to give benzazepine skeletons (Scheme 29).91a Allenes are especially valuable as partners owing to their intrinsic reactivity and the viability of generating π-allyl intermediates that stabilize metalacycles and favor reductive elimination over β-hydride elimination. Besides, they are not as coordinating as alkynes, avoiding the saturation of the metal coordination sphere to give nonactive complexes. Scheme 29. Pd(II)-catalyzed (4+2) cycloaddition of vinylanilides and allenes reported by Gulías, Mascareñas and collaborators. 4.3.2.4 (n+n+n) cycloadditions Multicomponent cycloadditions are very interesting transformations as they can lead to a rapid increase in complexity in a single step. However, they are not as common as other types of C−H activation-based cycloadditions. Examples of these kind of transformations employing palladium complexes as catalysts are the (3+2+1) annulation reported by Wu92, and the (3+2+2) annulation reported by Wang (Scheme 30).93 90 Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212. 91 (a) Casanova, N.; Del Rio, K. P.; García-Fandiño, R.; Mascareñas, J. L.; Gulías, M. ACS Catal. 2016, 6, 3349. (b) Cendón, B.; Casanova, N.; Comanescu, C. C.; García-Fandiño, R.; Seoane, A.; Gulías, M.; Mascareñas, J. L Org. Lett. 2017, 19, 1674. (c) González, J. M.; Cendón, B.; Mascareñas, J. L.; Gulías, M. J. Am. Chem. Soc. 2021, 143, 3747. 92 Chen, J.; Natte, K.; Spannenberg, A.; Neumann, H.; Beller, M.; Wu, X. F. Chem. Eur. J. 2014, 20, 14189. 93 Wang, L.; Huang, J.; Peng, S.; Liu, H.; Jiang, X.; Wang, J. Angew. Chem. Int. Ed. 2013, 52, 1768. Chapter I 51 Scheme 30. Pd(II)-catalyzed (3+2+2) cycloaddition of isatin derivatives and alkynes developed by Wang and co-workers, and intermediate prior to C–H activation. The mechanism proposed for this reaction starts with an initial tandem amination of two alkyne moieties, followed by a C−H activation step and a reductive elimination. With this methodology, it is possible to build these interesting scaffolds in a single step from simple and readily available starting materials. Even though classic palladium-catalyzed cycloadditions of unsaturated precursors are still predominant, it is a matter of time that palladium-catalyzed C−H activation-based cycloadditions become a common method for the synthesis of cycles and heterocycles in organic synthesis. 4.4 Current challenges and future outlook With the global concern of climate change and other environmental challenges, it is now more important than ever to develop synthetic methodologies that follow the green chemistry precepts. The principles of atom and step economy should guide many of the future developments in synthetic chemistry. In this context, the metal-mediated C–H activation field, by avoiding the need of functionalized precursors, will provide some of the most relevant solutions. However, there are still important challenges to be solved, for instance, the requirement of stoichiometric amounts of inorganic oxidants to regenerate the metal catalysts. There is a notable interest in substituting the inorganic oxidants of C–H activation reactions for organic oxidants or, ultimately, by electricity.94 Another problem is the need to have directing groups, which are not relevant beyond their role as activating moiety. Additionally, as chirality is inherent to most of the bioactive molecules in nature, asymmetric methods that enable the synthesis of enantiopure compounds are highly desirable to avoid complex, costly enantiomeric resolutions that introduce extra steps in the overall procedure. Even though there have been important contributions in the field of enantioselective C–H functionalization, this area is yet starting to be developed. Another current challenge is the functionalization of C(sp3)–H bonds. This field is still underdeveloped, due to the inherent inertness of these types of bonds, which hampers its selective activation. Related to this, the field of formal cycloadditions based on the activation of C(sp3)–H bonds is still in its complete infancy, and only a few methods have been reported, none of them being enantioselective (see Chapter III). 94 Jiao, K. J.; Xing, Y. K.; Yang, Q. L.; Qiu, H.; Mei, T. S. Acc. Chem. Res. 2020, 53, 300. General objectives General objectives 55 General objectives Considering all the precedents and current challenges in the field of palladium-catalyzed C–H activation, discussed in the Chapter I, we have focused on the development of novel methodologies based on this area of research. Specifically, we have focused on the following objectives:  Development of novel formal cycloadditions based on palladium-catalyzed C–H activation: among all the reactions reported in the field of palladium-catalyzed C–H activation, formal cycloadditions are still underdeveloped. These types of reactions are especially useful for the assembly of azaheterocycles, whose synthesis is not straightforward using classic metal-catalyzed formal-cycloadditions. Our research group has published several formal (4+2) cycloadditions using allenes as coupling partners,91 and therefore this previous experience could be particularly useful for the accomplishment of this objective.  Exploring the asymmetric version of the aforementioned formal cycloadditions: heterocycles in nature often present several stereocenters due to the inherent chirality of life. Precedents in the employment of chiral ligands, like mono-protected amino acids, has demonstrated the possibility of performing asymmetric C–H activation reactions based on palladium catalysis. Therefore, it is of high interest to explore the use of chiral ligands to induce enantioselectivity in the novel formal cycloadditions based on C–H activation.  Development of novel transformations based on the activation of C(sp3)–H bonds: the activation of C(sp3)–H presents important challenges compared with the activation of C(sp2)–H bonds. In fact, palladium-catalyzed formal cycloadditions based on this type of activation are scarce, none of them being enantioselective. Therefore, development of novel methodologies, like formal cycloadditions or cyclizations, is of high interest as an elegant, efficient way to access cyclic structures like azaheterocycles. Chapter II: Introduction 63 The methodology is clever, but in some cases dialkenylation side products resulting from a double C–H activation of the precursor are obtained. Furthermore, the synthesis of the products in an asymmetric fashion relies on the use of chiral precursors. In 2014, the group of Nicolás published a formal (4+2) cycloaddition of α-disubstituted benzylamines and phenylethylamines with allenes (Scheme 36), a method that allows a direct assembly of the azaheterocyclic skeletons and is based on a Pd-catalyzed C–H activation.106 Scheme 35. Pd(II)-catalyzed formal (4+2) annulation of benzylamines and phenylethylamines with allenes reported by Nicolás and co-workers. While the strategy is very attractive, the reaction presents important limitations. First, the protocol only works with substrates bearing two substituents at the α-position of the amine to prevent benzylic oxidation. Second, the methodology is limited to the use of electron-poor primary allenes. Third, the resulting tetrahydroisoquinolines and benzazepines were obtained as regio- and stereoisomeric mixtures. And last but not least, the method is racemic, and therefore chiral THIQ cannot be obtained. In this context, performing asymmetric C–H activations of benzylamine precursors can open interesting opportunities. 1.4 Palladium-catalyzed enantioselective C−H functionalization of benzylamine derivatives The generation of asymmetry in C–H activation reactions has been an area of increasingly intensive research during the last decade.107 Several strategies can be used in order to make enantioenriched products using this chemistry. When in a racemic mixture, one of the enantiomers is selectively recognized by a chiral catalyst, we can achieve a kinetic resolution process. Alternatively, when there are symmetry elements in the molecule prior to the C−H activation, and the reaction results in the loss of one or more of them, we can promote desymmetrization processes. Both strategies have been employed for palladium-catalyzed C–H functionalizations of benzylamines. These types of substrates present an amino functionality that acts as a directing group, placing the palladium close to the desired C–H bond, often located in ortho position. However, the employment of substrates with unprotected amino groups usually limits the reactivity, in part because of the formation of highly stable cyclometalated intermediates, that are less reactive in subsequent functionalization steps. Indeed, amines are known to form stable, 106 Rodríguez, A.; Albert, J.; Ariza, X.; Garcia, J.; Granell, J.; Farràs, J.; La Mela, A.; Nicolás, E. J. Org. Chem. 2014, 79, 9578. 107 Newton, C. G.; Wang, S. G.; Oliveira, C. C.; Cramer, N. Chem. Rev. 2017, 117, 8908. Chapter II: Introduction 64 unreactive bis(amine)-Pd(II) species.108 Besides, free amines are susceptible to oxidative degradation through β-hydride elimination to give imines, and N-substitution reactions toward electrophiles. Additionally, amines coordinated to transition-metal catalysts have a strong donor effect that decreases the electrophilicity of the metal, thus, hampering the C−H activation based on electrophilic addition or CMD mechanisms. One strategy to address these problems consists of using electron-poor protecting groups that withdraw charge from the nitrogen, making it less reactive towards degradation and N- substitution reactions. However, these groups may also decrease the coordination ability of the amine to the catalyst. Therefore, they are usually combined with a base, that deprotonates the remaining hydrogen of the amine group in order to ease the coordination with the metal center. Besides, the base could also participate in the C−H activation step by triggering the CMD mechanism.109 In 2013, the Yu´s group disclosed the first palladium-catalyzed enantioselective Cؘ–H functionalization of benzylamides. They published a desymmetrization based on the ortho C–H iodination of triflyl-protected diarylmethylamines. Bz-Leu-OH was employed as chiral ligand, allowing the formation of the iodinated diarylmethylamines with ees up to 99% (Scheme 36).110 Pd(OAc)2(10 mol%) Bz-Leu-OH (40 mol%) CsOAc (3 equiv), I2(3 equiv) 12 examples 51-85% yield ee up to 99% NHTf H H Ar Ar NHTf H I Ar Ar Na2CO3(3 equiv), DMSO (15 equiv) tAmOH, 30 ºC, 48 h Scheme 36. Pd(II)-catalyzed desymmetric C–H iodination of diarylmethylamines reported by Yu and coworkers. One year later, the same group published a kinetic resolution of α-substituted benzyltriflamides under similar reaction conditions.111 The desymmetrizing ortho C–H arylation of diarylmethylamines with organoborons was described by the same group in 2015.112 In this case, they use a nosyl protecting group, which is easier to remove than the triflate, and Fmoc-Leu- NHOMe as chiral ligand (Scheme 37). One year later, they published the kinetic resolution of αsubstituted benzylnosylamides employing similar reaction conditions.113 108 Zhuang, Z.; Yu, J.-Q. J. Am. Chem. Soc. 2020, 142, 12015. 109 Engle, K. M.; Mei, T.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. 110 Chu, L.; Wang, X. C.; Moore, C. E.; Rheingold, A. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 16344. 111 Chu L.; Xiao, K.-J.; Yu, J.-Q. Science 2014, 346, 451. 112 Laforteza, B. N.; Chan, K. S. L.; Yu, J.-Q. Angew. Chem. Int. Ed. 2015, 54, 11143. 113 Xiao, K. J.; Chu, L.; Chen, G.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 7796. Chapter II: Introduction 65 Scheme 37. Pd(II)-catalyzed desymmetric C–H arylation of diarylmethylamines disclosed by Yu and coworkers. In 2019, after we published the results of our work, included in this thesis (vide infra), the group of Xu reported the desymmetrizing C–H carbonylation of benzyltosylamides to make enantioenriched isoindolinones. Boc-protected valine was employed as chiral ligand, and the reaction was performed by using a balloon with a mixture of carbon monoxide and oxygen (Scheme 38). Scheme 38. Pd(II)-catalyzed desymmetric C–H carbonylation of benzyltosylamides reported by Xu and coworkers. Chapter II: Objectives 66 2- Objectives Considering these precedents, and the need to develop practical, enantioselective entries to THIQs skeletons, we proposed as one of the main objectives of this doctoral thesis the development of a (4+2) formal cycloaddition between benzylamines and unsaturated twocarbon partners, mediated by a Pd-catalyzed C–H activation process (Scheme 39a). While we might explore different unsaturated partners, the precedents of the group on the use of allenes in other related cycloadditions91 led us to select these types of reactants as primary choices. Allenes might be advantageous over alkenes in terms of reactivity (migratory insertion), as well as because of the resulting π-allyl intermediates (Scheme 40) might easily undergo the required reductive elimination. We also intended to explore the viability of extending the annulation to alkenylamide precursors, which would lead to piperidine and azepine skeletons (Scheme 39b). Scheme 39. General objective of the (4+2) formal cycloaddition between benzylamines or alkenylamines and allenes. The proposed reactions should proceed though the general mechanism indicated below (Scheme 40). First, a C–H activation step would produce the metalacycle I, which could then react with the unsaturated partner through a migratory insertion step. When using allenes, this would produce π-allylic palladium species II that upon reductive elimination should yield the desired product. Chapter II: Objectives 67 Scheme 40. General mechanistic proposal of the (4+2) formal cycloaddition between benzyl-or alkenylamides and allenes. The strategy should allow the development of asymmetric variants, by using chiral palladium ligands. This would be an important advantage over other classical methods for the asymmetric synthesis of THIQs, as they often rely on the employment of chiral auxiliaries that have to be attached and removed. Particularly attractive is the possibility of implementing desymmetrizing cycloadditions as those indicated in Scheme 41. A chiral ligand coordinated to the palladium during the C–H activation step should favor the formation of one palladacycle over the other. Scheme 41. General objective of the desymmetrizing (4+2) formal cycloaddition between diarylbenzylamines and allenes. Chapter II: Results and discussion 68 3- Results and discussion 3.1 Preliminary studies to identify the best reaction conditions To begin our research, we decided to use benzyltriflamide 1a as model substrate. We selected the triflyl protecting group because it notably increases the acidity of the N–H bond, which should facilitate the formation of the Pd–N bond, while the palladium remains electrophilic enough to promote C–H activation. Benzyltriflamide 1a was readily synthesized by treatment of benzylamine with triflic anhydride in the presence of Et3N. As cycloaddition partners we focused on allenes, owing to the previous results in the group with other type of annulations.91 In particular, the initial assays were performed with the commercially available vinilidenecyclohexane 2a. We decided to employ Pd(OAc)2 as catalyst, Cu(OAc)2·H2O as oxidant for the catalyst and cesium carbonate as base, as it could help both the N–H deprotonation of the triflamide and the C–H activation step. The reaction was performed under air atmosphere as there are no oxygen- or moisture-sensitive reactants. In fact, oxygen could help to reoxidize the copper acetate. Using tAmOH as solvent, at 80 °C the expected product 3aa was obtained in a modest 15% yield, after 16 hours. It is worth to highlight that only one regioisomer was observed, which demonstrate the selectivity of this transformation. This regioselectivity may be related with the formation of a π-allyl intermediate (see section 3.4 for a mechanistic proposal). The reaction was carried out with 2 equivalents of benzyltriflamide 1a. However, full conversion of both 1a and allene 2a was observed. We detected significant amounts of benzaldehyde as an undesired side-product, presumably as a result of some benzylic oxidation and hydrolysis of the corresponding imine in the work-up conditions. Besides, allenes tend to decompose or polymerize in presence of transition-metals. After this initial result, we decided to make a screening of different conditions (Table 1). The reaction works in different solvents, being toluene the most suitable in terms of yield (25% at 90 °C, entry 5). Chapter II: Results and discussion 69 Table 1. Screening of solvents. Entry Solvent Temp. Yieldb 1 tAmyOH 80 °C 15% 2 Dioxane 80 °C 23% 3 DCE 80 °C 24% 4 CH3CN 80 °C 9% 5 Toluene 90 °C 25% a Conditions: 0.333 mmol 1a, 0.167 mmol of allene 2a, 2 mL of solvent. c Yields calculated by using an internal standard. Then, we started to test the effect of adding external ligands, in particular mono-protected amino acids (MPAA ligands) as they could facilitate C–H activation reactions (see section 4.2 of Chapter I), and might also allow asymmetric processes. These results are summarized in Table 2. The use of Boc-protected amino acids, or derivatives with methoxyamide groups, as ligands allowed to increase the yield (entries 1-4). But the important change came by using 2,6-F,F-Bz- Leu-OH as ligand, which allowed to obtain the cycloadduct 3aa in an 85% yield (entry 5). The reason for using this benzoate with two fluorides in ortho positions is to avoid internal C–H activations in the ligand. The addition of 15 equivalents of DMSO allowed to further rise the yield to 95% (entry 6). The reason behind the positive effect of this additive on the reaction is not clear; some studies114 suggest that DMSO can prevent the aggregation of palladium black via S– bound coordination to Pd(0) species, thus easing the reoxidation process. It may also act as a co-solvent, helping to solubilize salts in non-polar solvents like toluene. Besides, it could also have a positive effect on the enantioselectivity of asymmetric processes as well, by sequestering the small amount of free Pd(II) species not coordinated to the chiral ligand, thus inhibiting the racemic reaction.110 The amount of copper acetate can be decreased to 50 mol% without significantly affecting the yield (entry 7). Besides, it was discovered that the reaction can be performed with full conversion in only 40 minutes without compromising the yield (entry 8). In the absence of DMSO, under these conditions, the yield decreased to 31% (after 40 minutes, entry 9). 114 Diao, T.; White, P.; Guzei, I.; Stahl, S. S. Inorg. Chem. 2012, 51, 11898. Chapter II: Results and discussion 70 Table 2. Screening of mono-protected amino acids. Entry Ligand (40 mol%) Yieldb 1 Boc-Ala-OH 58% 2 Boc-Val-OH 69% 3 Boc-Leu-NHOMe 37% 4 Boc-Phe-NHOMe 31% 5 2,6-F,F-Bz-Leu-OH 85% 6c 2,6-F,F-Bz-Leu-OH 95%d 7c 2,6-F,F-Bz-Leu-OH 86%d,e 8c 2,6-F,F-Bz-Leu-OH 95%f 9 2,6-F,F-Bz-Leu-OH 31%f a Conditions: 0.333 mmol 1a, 0.167 mmol of allene 2a, 2 mL of solvent. b Yields calculated by using an internal standard. c 15 equiv of DMSO added d Isolated yield based on 2a. e 0.5 equiv. of Cu(OAc)2·H2O. f Reaction performed during 40 minutes. As an additional test, acetylmethyl- and nosylprotected benzylamines were submitted to the optimized reaction conditions, but the formation of the expected cycloadduct was not observed. Again, full conversion of both the protected benzylamine and the allene was observed, likely due to the same decomposition pathways previously observed with benzyltrilamide 1a. These results evidenced the key role of the triflyl protecting group in the cycloaddition. Other coupling partners were tested for the reaction. Diphenylacetylene was essentially unreactive, whereas with benzyl acrylate or styrene, we observed low conversions of the alkenes and traces of olefination products. These results highlight the relevance of using allenes as coupling partners for the cycloaddition. 3.2 Scope of the annulation With the optimized conditions in our hands, we studied the scope of the reaction. For that purpose, we synthesized several allenes bearing different substitution patterns, following previously reported synthetic procedures. The 1,1-disubstituted allenes 2b (5- vinylidenenonane) and 2c ((4-methylpenta-1,2-dien-3-yl)benzene) were synthesized from their corresponding propargylic alcohols in a two-step procedure that involves the tosylation of the Chapter II: Results and discussion 71 alcohol and the subsequent SN2’ reaction of the tosylate with the corresponding alkylmagnesium bromide and Cu(I) (Scheme 42a).115 1,3-disubstituted allene 2d (1,3- diphenylpropa-1,2-diene) was synthesized from phenylacetylene and benzaldehyde, using a zinc-catalyzed process (Scheme 42b).116 1,3-disubstituted allene 2e (buta-1,2-dien-1-ylbenzene) and trisubstituted allenes 2g ((3-methylbuta-1,2-dien-1-yl)benzene) and 2h ((3-methylhepta- 1,2-dien-1-yl)benzene) were synthesized from their corresponding propargylic alcohols in a twostep procedure that involves the acetylation of the alcohol and the subsequent SN2’ reaction of the acetoxylate with the corresponding alkylmagnesium bromide and Cu(I) (Scheme 42c).117 Allene 2f ((1,2-propadienyl)cyclohexane) was commercially available. Scheme 42. Synthetic procedures for the allenes 2a-2h. The results of the annulations with all these allenes are indicated in Scheme 43. As shown, 1,1- disubstituted allenes other than 2a, like 2b or 2c, were good reactions partners, affording the corresponding cycloadducts in 85% and 86% yield, respectively. The reaction also tolerates 1,3- disubstituted allenes, like 2d and 2e, providing the tetrahydroisoquinolines 3ad and 3ae as single stereo- and regioisomers (80% yield and 74% yield respectively). The explanation of this selectivity may be related with the steric hindrance of the phenyl group, which favors one of the possible conformations of the π-allyl intermediate over the other (see section 3.4 for the proposed mechanism). Monosubstituted allenes, like 2f, can also engage in the cycloaddition, leading to the formation of the corresponding product 3af in a 85% yield, albeit as a 1.1:1 mixture of E:Z steroisomers. Notably, trisubstituted allenes, like 2g and 2h, afford the corresponding cycloadducts as a single stereo- and regioisomer (80% yield and 90% yield respectively). Overall, the reaction presents a good scope with respect to the allenyl partner. 115 Kippo, T.; Fukuyama, T.; Ryu, I. Org. Lett. 2011, 13, 3864. 116 Zhao, Z.; Racicot, L.; Murphy, G. K. Angew. Chem. Int. Ed. 2017, 56, 11620. 117 Ting, C.-H.; Hsu, Y.-L.; Liu, R.-S., Chem. Commun. 2012, 48, 6577. Chapter II: Results and discussion 72 a Conditions: 0.333 mmol of amide 1a, 0.167 mmol of allenes 2, 2 mL toluene, 15 equiv DMSO, under air, 16 h. Isolated yields based on 2. E:Z and regioisomeric ratios are >20:1, unless otherwise noted. b Inseparable isomers. Regioisomeric ratio determined by crude 1H NMR. Scheme 43. Scope of the (4+2) cycloaddition between benzyltriflamides and allenes. In general, reactions initiated by the activation of C–H bonds in aromatic precursors tend to be much easier than those requiring the activation of alkenyl C–H bonds. Nonetheless, given our good results in the annulation, we wondered whether we could perform similar formal cycloadditions using alkenyl instead of aryl precursors. There are relatively few reports on palladium-catalyzed activation of olefinic C–H bonds, presumably because alkenes could engage in secondary reactions like additions or oxidations.118 The extension of our annulation to alkenyl substrates is challenging, but very attractive, as it would allow the formation of highly interesting piperidine and eventually azepine products in a single step. For evaluating the reaction, several alkenyltriflamides were synthesized using either a triflation reaction from their corresponding free amines or a Mitsunobu reaction from their corresponding alcohols (Scheme 44). 118 For recent examples of Pd-catalyzed C–H functionalization of olefins, see: (a) Schreib, B. S.; Carreira, E. M. J. Am. Chem. Soc. 2019, 141, 8758. (b) Liu, M.; Yang, P.; Karunananda, M. K.; Wang, Y.; Liu, P.; Engle, K. M. J. Am. Chem. Soc. 2018, 140, 5805. (c) Luo, Y.-C.; Yang, C.; Qiu, S.-Q.; Liang, Q.-J.; Xu, Y.-H.; Loh, T.- P. ACS Catal. 2019, 9, 4271. 79 4- Conclusions In conclusion, we have developed a methodology that allows a straightforward access to highly valuable tetrahydroisoquinoline (THIQ) skeletons through a formal (4+2) cycloaddition between benzyl triflamides and allenes. We have optimized the reaction conditions so that it is possible to obtain excellent yields of the cycloadducts. The reaction presents excellent levels of chemo- and regioselectivity. We successfully demonstrated the possibility of extending the methodology to triflamides bearing alkenyl instead of aryl pendants to afford tetrahydropyridine skeletons. In these reactions, the presence of a substituent in the most internal position of the alkene is necessary to avoid decomposition of the substrate. Furthermore, we reported one example of a rare formal (5+2) cycloaddition of homoallylamines, to give an azepine skeleton (Scheme 51). Scheme 51. Pd-catalyzed formal cycloaddition between benzyl- and alkenyltriflamides and allenes. Moreover, this methodology can be used to promote asymmetric processes. A desymmetrization of prochiral diarylmethylamines allows to obtain enantioenriched tetrahydroisoquinolines with enantiomeric ratios up to 98:2. This represents the first palladiumcatalyzed annulative C–H activation/desymmetrization process that has been reported. Thus, it is an important addition to the portfolio of catalytic asymmetric methods (Scheme 52). We also demonstrate the viability of a kinetic resolution process which can increase the scope of products in a significant manner. Scheme 52. Desymmetrizing Pd-catalyzed (4+2) formal cycloaddition between diarylmethyltriflamides and allenes. Chapter III Assembly of azaheterocycles by Pd(II)-catalyzed cycloadditions involving the activation of C(sp3)-H bonds This chapter includes work published in Organic Letters as: Vidal, X.;a Mascareñas, J. L.;a Gulías, M.a Org. Lett. 2021, 23 , 5323. a Centro Singular de Investigacion en Química Bioloxica e Materiais Moleculares (CIQUS) and Departamento de Química Organica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain DOI: 10.1021/acs.orglett.1c01594, Open Access article (ACS AutorChoice) Chapter III: Introduction 83 1- Introduction 1.1 Challenges in the activation of C(sp3)–H bonds As it has been stated in the introduction of this manuscript, the topic of metal-mediated C–H activation has become a well-stablished field of research, with hundreds of articles published every year. However, most of them are still based on the activation of C(sp2)–H bonds, as these types of bonds are easier to break than those found in their full-saturated counterparts. The reasons beyond the difficulties in activating C(sp3)–H bonds include: a high bond dissociation energy (BDE), lack of ‘‘active’’ orbitals (HOMO or LUMO) to interact with transition metal catalytic centers, the lower strength of the resulting C–M bonds, and the difficulties to control the regioselectivity (Figure 11a).121 As in the case of the activation of C(sp2)–H bonds, the most employed strategy to overcome these limitations is the use of directing groups,122 although indirect activations by other C(sp2)–M bonds generated from oxidative additions to C–X functionalities, has also been exploited (vide infra, Scheme 53). An interesting exception to this limitation can be found in allylic systems. In this special case, the adjacent olefin can coordinate the metal center and facilitate the C–H activation. Besides, the presence of the double bond also decreases the BDE of the C–H bond (88 kcal mol-1 versus 105 kcal mol-1 of methane).34 The subsequent reactivity of the system will be analogous to that of πallyl intermediates obtained using the Tsuji-Trost reaction.51 Benzylic C(sp3)–H bonds, despite the structural similarity, do not show the same reactivity than their allylic counterparts, in part because the π-cloud of the double bound located in the vicinal position is participating in the aromaticity of the benzene ring. However, the benzylic position is also benefiting from the decrease in the BDE due to the presence of a double bond (Figure 11b). Figure 11. Comparisons among different types of C–H activation. The activation of allylic and benzylic positions is thus a very interesting strategy to overcome the challenges of cleaving C(sp3)–H bonds. Between both of them, the activation and functionalization of benzylic methyl groups is especially appealing due to the accessibility of the precursors and the possibility of obtaining important products. 121 Li, H.; Li, B. J.; Shi, Z. J. Catal. Sci. Technol. 2011, 1, 191. 122 Xie, J.; Chengjian, Z. Transition Metal-Catalyzed, Directing Group-Assisted C(sp3)–H Bond Functionalization. In Sustainable C(sp3)–H Bond Functionalization, Springer, 2016. Chapter III: Introduction 84 1.2 Palladium-catalyzed functionalization of benzylic methyl groups The first example of palladium-catalyzed benzylic C(sp3)–H activations was reported in 2000 by Catellani and co-workers.123 They discovered a method for the construction of cyclopentene rings by activating benzylic methyl groups in the presence of norbornene. The reaction was initiated by the oxidative addition of the C–I bond to the Pd(0) catalyst, followed by migratory insertion of norbornene. Then, a C(sp3)–H activation of the benzylic methyl group and a subsequent reductive elimination led to the formation of the product in a 65% yield (Scheme 53). Scheme 53. Pd(0)-catalyzed benzylic C(sp3)–H functionalization of o,o’-dimethyliodobenzene with norbornene for the construction of cyclopentene rings reported by Catellani and co-workers. In 2004, Sanford and co-workers published the first example of a palladium-catalyzed acetoxylation of benzylic C–H bonds.75 They employed quinolines as substrates, which exhibit an intrinsic directing group, affording the acetoxylated products with excellent levels of regio- and chemoselectivity (Scheme 54). The reaction proceeds through a Pd(II)/Pd(IV) catalytic cycle, in a similar manner to that of other aforementioned acetoxylation reactions with PdI(OAc2) (see section 4.3.1.3 of Chapter I). Scheme 54. Pd(II)-catalyzed C(sp3)–H acetoxylation of benzylic bonds directed by quinolines reported by Sanford and co-workers. The Sanford´s group explored further these quinoline-type precursors. The following year they reported the C(sp3)–H arylation of 8-methylquinoline derivatives with hypervalent iodine(III) arylating reagents.124 Mechanistic experiments evidenced an unusual Pd(II)/Pd(IV) catalytic cycle involving a bimetallic intermediate.125 The same year, in 2006, Sanford and co-workers also published the C(sp3)–H fluorination of the same substrates with electrophilic N-fluoropyridinium reagents, further promoted by microwave radiation (Scheme 55).126 123 Catellani, M.; Motti, E.; Ghelli, S. Chem. Commun. 2000, 20, 2003. 124 Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. 125 Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234. 126 Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134. Chapter III: Introduction 85 Scheme 55. Pd(II)-catalyzed benzylic C(sp3)–H functionalizations of 8-methylquinoline derivatives reported by Sanford and co-workers. This system has also been explored by other research groups. Daugulis and Shabashov disclosed in 2005 a benzylic C(sp3)–H arylation of 8-methylquinolines complementary to Sanford’s work, employing aryl iodides as coupling partners.127 In 2012, the group of Muñiz published the C(sp3)– H oxidate amidation of the same substrates. 128 The use of NSFI as oxidant played a key role for the reductive C–N bond formation (Scheme 56). Yu´s group also reported some examples of benzylic C(sp3)–H alkylation of 8-methylquinolines as part of a larger study about the functionalization of sp2 and sp3 C–H bonds.129 Scheme 56. Pd(II)-catalyzed benzylic C(sp3)–H functionalizations of 8-methylquinoline derivatives developed by Daugulis, Shabashov, Muñiz and co-workers. There have been reports on benzylic C(sp3)–H functionalizations where the heteroatom-based directing group is placed in the same aromatic ring that bears the activated benzylic position. In 2008, Fagnou and co-workers published a palladium-catalyzed site-selective arylation of benzylic C(sp3)–H bonds of azine and diazine N-oxide substrates.130 The choice of a proper base was key for achieving the desired selectivity. Two years later, Huang´s group reported a novel protocol for the functionalization of 2-methylsubstituted azaheterocycles with N-sulfonyl aldimines.131 The proposed mechanism proceeds through a nucleophilic addition of the benzylic position over the coupling partner (Scheme 57). 127 Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. 128 Iglesias, Á.; Álvarez, R.; De-Lera, Á. R.; Muñiz, K. Angew. Chem. Int. Ed. 2012, 51, 2225. 129 Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634. 130 Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266. 131 Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2010, 132, 3650. Chapter III: Introduction 86 Scheme 57. Pd(II)-catalyzed benzylic addition of C(sp3)–H bonds to N-sulfonyl aldimines developed by Huang and co-workers, and key intermediate. 1.3 Palladium-catalyzed benzylic C(sp3)–H functionalization of o-methylaniline and omethylbenzylamine precursors A particular case of Pd-catalyzed benzylic C(sp3)–H functionalizations is the activation of methyl groups located in the ortho position of anilines or benzylamines. The challenges of employing free amines as directing groups were previously discussed (see section 1.4 of Chapter II). Therefore, it is not surprising that all the methodologies related to this particular activation employ appropriately protected amines. The first example of benzylic C(sp3)–H functionalization of aniline type of precursors was published in 2012 by Takemoto and co-workers.132 They describe the Pd(0)-catalyzed construction of oxindole skeletons from carbamoyl chloride precursors. The employment of Ad2PBu as palladium ligand and PivNHOH as an additive under a CO atmosphere allowed to achieve the chemoselective C(sp3)–H activation over competitive C(sp2)–H activation (Scheme 58). The process starts by oxidative addition of Pd(0) to the C–Cl bond, followed by the activation of the benzylic hydrogen. Scheme 58. Pd(0)-catalyzed chemoselective C(sp3)–H activation of carbamoyl protected o-methylanilines reported by Takemoto and co-workers. The same year, the group of Zhang disclosed a benzylic C(sp3)–H arylation/oxidation of omethylanilines equipped with a bidentate chelating group, employing aryl iodides as coupling partner and molecular oxygen as oxidant (Scheme 59).133 Substrates equipped with monodentate directing groups failed to react, which confirms the key role of the chelating system. This methodology was further established by Zhang and Huang, when they concurrently reported the C–H acetoxylation of the same substrates.134 132 Tsukano, C.; Okuno, M.; Takemoto, Y. Angew. Chem. Int. Ed. 2012, 51, 2763. 133 Xie, Y.; Yang, Y.; Huang, L.; Zhang, X.; Zhang, Y. Org. Lett. 2012, 14, 1238. 134 (a) Ju, L.; Yao, J.; Wu, Z.; Liu, Z.; Zhang, Y. J. Org. Chem. 2013, 78, 10821. (b) Cheng, T.; Yin, W.; Zhang, Y.; Zhang, Y.; Huang, Y. Org. Biomol. Chem. 2014, 12, 1405. Chapter III: Introduction 87 Pd(OAc)2(10 mol%) Ar2–I (4 equiv) O NH N H Ar1 O NH N O Ar1 Ar2 22 examples 41-88% yield AgOAc (4 equiv) O2balloon xylene, 130 ºC, 24 h Scheme 59. Pd(II)-catalyzed C(sp3)–H arylation/oxidation of o-methylanilides assisted by a chelating directing group reported by Zhang and co-workers. In 2014, Yu and co-workers reported an example of benzylic C(sp3)–H arylation of triflylprotected o-methylanilines with organoboron reagents, as part of a larger study on aminedirected C(sp3)–H activation of aliphatic chains.135 The amide moiety was used as directing group by itself, and MPAA ligands were also employed to promote the reactivity (Scheme 60). In 2019, the group of Babu published the C–H arylation and acetoxylation of o-methylanilines using 5- methylisoxazole-3-carboxamide as directing group, which can be easily removed afterwards.136 Scheme 60. Pd(II)-catalyzed C(sp3)–H arylation of triflyl protected o-methylanilines with organoboron reagents reported by Yu and co-workers. Regarding the Pd-catalyzed benzylic C(sp3)–H activation of o-methylbenzylamines, there are very few reports. Chen and co-workers disclosed in 2012 the intramolecular amination of a single o-methylbenzylamine derivative as part of a larger research on the synthesis of azaheterocycles through intramolecular amination of C(sp2)–H and C(sp3)–H bonds.137 The amine group was equipped with a bidentate chelating group. Two years later, Zhao, Yao and coworkers published a similar protocol with the same substrate, but assisted by an oxalyl amide auxiliary, also as part of a larger piece of research (Scheme 61).138 135 Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.; Yu, J.-Q. Nat. Chem. 2014, 6, 146. 136 Singh, P.; Dalal, A.; Babu, S. A. Asian J. Org. Chem. 2019, 8, 877. 137 He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3. 138 Wang, C.; Chen, C.; Zhang, J.; Han, J.; Wang, Q.; Guo, K.; Liu, P.; Guan, M.; Yao, Y.; Zhao, Y. Angew. Chem. Int. Ed. 2014, 53, 9884. Chapter III: Introduction 88 Scheme 61. Pd(II)-catalyzed intramolecular C(sp3)–H amination of o-methylbenzylamines assisted by chelating directing groups reported by Chen, Zhao, Yao and co-workers. 1.4 Formal cycloadditions involving Pd-catalyzed C(sp3)–H activations 1.4.1 Introduction The importance of cycloadditions in the context of atom and step economy for the synthesis of cyclic products has been already commented in Chapter I. Several examples of formal cycloadditions based on palladium-catalyzed C(sp2)–H activations have been reviewed in section 4.3.2 of that chapter. It is worth to highlight that despite the high relevance of this transformation, the number of reports entailing annulation processes through metal-catalyzed C(sp3)–H activations is very limited.139 There are several reasons for this shortage (Scheme 62). In the first place, the aforementioned difficulty of activating C(sp3)–H bonds. Second, the competition of β-hydride elimination side processes, either after the C(sp3)–H activation or the migratory insertion of the unsaturated partners. In fact, there are several methodologies that take advantage of this undesired pathway, relying in a sequence of functionalization/cyclization reactions (mostly alkenylation/Michael-addition).140 Third, reductive eliminations from sp3 carbons are slower and more difficult than from sp2 carbons, owing to the absence of coordinating π-bonds.141 Furthermore, the absence of a π-cloud on the substrates makes the approximation of the substrate to the catalyst more difficult. In fact, the metal center could be inactivated by coordinative saturation with the unsaturated coupling partner. 139For further information about Pd-catalyzed C(sp3)−H acvaon-based cycloadditions, among other metals: Font, M.; Gulías, M.; Mascareñas, J.L. Angew. Chem. Int. Ed. 2021, Accepted article, DOI: 10.1002/anie.202112848. 140 (a) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. (b) Ghosh, K. K.; Uttry, A.; Mondal, A.; Ghiringhelli, F.; Wedi, P.; van Gemmeren, M. Angew. Chem. Int. Ed. 2020, 59, 12848. (c) Calleja, J.; Pla, D.; Gorman, T. W.; Domingo, V.; Haffemayer, B.; Gaunt, M. J. Nat. Chem. 2015, 7, 1009. 141 Yu, Z. X.; Cheong, P. H. Y.; Liu, P.; Legault, C. Y.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 2378. Chapter III: Objectives 95 Scheme 70. General objective of the formal (5+2) cycloaddition between o-methylbenzylamines and allenes. These methodologies would represent a substantial addition to the scarce set of cycloadditions based on the activation of C(sp3)–H bonds, allowing the straightforward construction of highly valuable tetrahydroquinoline and tetrahydro-2-benzazepine scaffolds from readily available starting materials. Chapter III: Results and discussion 96 3- Results and discussion 3.1 Formal (4+2) cycloaddition between o-methylanilines and allenes: initial assays and optimization For the initial screening we selected 1,1,1-trifluoro-N-(o-tolyl)methanesulfonamide 4a as model substrate. Again, we decided to use the triflyl protecting group for the same reason that in our previous project: increasing the acidity of the N–H bond without compromising the electrophilicity of the palladium, that will be coordinated by the nitrogen atom. Substrate 4a was synthetized from commercially available o-methylaniline, by reaction with triflic anhydride in the presence of triethylamine. As initial coupling cycloaddition partner, we decided to select the 1,1,-disubstituted allene 5- vinylidenenonane (2b). We started by testing the reaction conditions optimized in our previous project: Pd(OAc)2 as catalyst, 2,6-F,F-Bz-Leu-OH as mono-protected amino acid (MPAA) ligand, Cu(OAc)2·H2O as oxidant, cesium carbonate as base, toluene as solvent and DMSO as additive. Again, the reaction was performed under air atmosphere, as there are no oxygen-sensitive reactants and oxygen can further help in closing the catalyst cycle. Gratifyingly, the expected product 5ab was obtained in a 45% yield, after heating at 105 °C for 16 hours. Complete conversions were observed in both the allene and the starting anilide. As comented in Chapter II, allenes tend to decompose or polymerize in the presence of transition-metals. A control experiment in which only the substrate 4a was heated at 105 °C in toluene in presence of Cs2CO3 revealed that the base can partially decompose the anilide. This result led us to employ an excess of anilide in the ensuing experiments. With the initial promising result, we performed a thorough screening of conditions. First, we started by testing several natural amino acid ligands bearing different protecting groups. The reaction results, indicated in Table 3, confirm that the acetyl protecting group is the one leading to the best results (entries 10-14). In every case, complete conversion of both the allene and the starting anilide was observed, presumably due to decomposition in the reaction media. Among all the side chains of the amino acids, valine led to the best yield (60%, entry 10). Valine amino acids featuring Boc, pivaloyl or propionyl protecting groups gave worse yields than when protected with acetyl, suggesting that large protecting groups in the nitrogen atom of the amino acid hamper the reaction. However, a formyl group, which is smaller than acetyl, also gave a low yield. This might be explained in terms of the lower basicity of the amidate carbonyl of the formyl-protected amino acid. Nonetheless, it is very difficult to interpret the effect of the protecting group or the side chain of the ligands in the reactivity of the system. Chapter III: Results and discussion 97 Table 3. Screening of amino acid ligands. Entry Ligand Yieldb Entry Ligand Yieldb 1 2,6-F,F,-Bz-Leu-OH 45% 8 Pro-Val-OH 52% 2 Boc-Val-OH 25% 9 Formyl-Val-OH 37% 3 Boc-Gly-OH 10% 10 Ac-Val-OH 60% 4 Boc-Cyclohexylglycine-OH 30% 11 Ac-Leu-OH 55% 5 Boc-Leu-NHOMe 18% 12 Ac-Ala-OH 55% 6 Fmoc-Leu-OH 10% 13 Ac-Phe-OH 35% 7 Piv-Val-OH <5% 14 Ac-Gly-OH 42% a Conditions: 0.333 mmol 4a, 0.167 mmol of allene 2b, 15 equiv of DMSO, 2 mL of toluene, under air, 16 h. b Yields calculated based on 2b. Calculated by using 1,3,5-trimethoxybenzene as 1H NMR internal standard. Once Ac-Val-OH was selected as the best amino acid ligand for the reaction, we explored the effect of the oxidant. The results are summarized in Table 4. The yield dropped dramatically when no oxidant was employed (entry 1). Copper acetate cannot be used in substoichiometric amounts without compromising the yield (entry 2). It was observed that performing the reaction under a O2 atmosphere slightly increases the yield for the substoichiometric test (entry 3), evidencing that there is an underlying reoxidation mechanism based on molecular oxygen. Other oxidants, like p-benzoquinone (BQ), silver salts or potassium persulfate gave worse results (entries 4-7) in terms of yield. After the screening, it was determined that the initial conditions were the most suitable for obtaining the best yields. Chapter III: Results and discussion 98 Table 4. Screening of oxidants. Entry oxidant Yieldb 1 - 7% 2 Cu(OAc)2·H2O (0.5 equiv) 37% 3 Cu(OAc)2·H2O (0.5 equiv) 47%c 4 BQ (2 equiv) 4% 5 Ag2CO3 (1.5 equiv) 8% 6 Ag2PO4 (1.5 equiv) 24% 7 K2S2O8 (2 equiv) 27% a Conditions: 0.333 mmol 4a, 0.167 mmol of allene 2b, 15 equiv of DMSO, 2 mL of toluene, under air, 16 h. b Yields calculated based on 2b. Calculated by using 1,3,5-trimethoxybenzene as 1H NMR internal standard. c Reaction performed under O2 atmosphere. We then evaluated the effect of different bases in the reaction. The results are described in Table 5. The reaction does not work without base (entry 1). It was observed that the use of substoichiometric amounts of cesium carbonate decreased the yield (entry 2). With different carbonate bases we observed that the larger the size of the cation, the better the yield (entries 3-5). The role of the cation is going to be discussed later during the mechanistic proposal (section 3.3.3). Potassium phosphate was also effective for the reaction, leading to similar yields than cesium carbonate (entry 6). However, cesium acetate was not as effective, probably because of the less basicity of the acetate group compared to phosphate or carbonate groups (entry 7). It is important to highlight that in all the experiments with different bases we observed complete conversion of the starting material, demonstrating that the decomposition is not only caused by cesium carbonate, but by other inorganic bases. Chapter III: Results and discussion 99 Table 5. Screening of bases. Entry base Yieldb 1 - <5% 2 Cs2CO3 (0.5 equiv) 49% 3 Li2CO3 (2 equiv) <5% 4 Na2CO3 (1.5 equiv) 31% 5 K2CO3 (1.5 equiv) 53% 6 K3PO4 (1.5 equiv) 58% 7 CsOAc (1 equiv) 38% a Conditions: 0.333 mmol 4a, 0.167 mmol of allene 2b, 15 equiv of DMSO, 2 mL of toluene, under air, 16 h. b Yields calculated based on 2b. Calculated by using 1,3,5-trimethoxybenzene as 1H NMR internal standard. We next studied the effect of the solvents. The results are illustrated in Table 6. The reaction worked in most of the solvents so far tested, albeit with lower yields than in toluene. The best result was obtained with 2-methyl THF, with a 58% yield (entry 8), very close to the 60% with toluene. 2-Methyl THF is environmentally friendly, as it is obtained from furfural, an agriculture byproduct, and therefore it is a very convenient solvent for the reaction from a sustainability perspective.148 148 Leal Silva, J. F.; Mariano, A. P.; Maciel Filho, R. Biomass and Bioenergy 2018, 119, 492. Chapter III: Results and discussion 100 Table 6. Screening of solvents. Entry Solvent Yieldb 1 Trifluorotoluene 42% 2d Hexafluorobenzene 32% 3 p-Xylene 49% 4 Dioxane 38% 5d Acetonitrile 28% 6d DCE <5% 7d THF 53%c 8d 2-methyl THF 58%c a Conditions: 0.333 mmol 4a, 0.167 mmol of allene 2b, 15 equiv of DMSO, 2 mL of solvent, under air, 16 h. b Yields calculated based on 2b. Calculated by using 1,3,5-trimethoxybenzene as 1H NMR internal standard. c Isolated yield based on a 2b. d Reaction performed in sealed tube. By using 2-methyl THF as solvent, it is possible to decrease the temperature to 85 °C without compromising the yield (entry 1, Table 7), which enables to perform the reaction without employing a sealed tube. Additionally, as 2-methyl THF is more polar than toluene, salts like copper acetate or cesium carbonate are more soluble. This may explain why it is possible to decrease the amount of oxidant and base to 1 equivalent each, even observing a slight increase in the yield (entry 2). The reaction was tested without DMSO, and it was evidenced that the effect of the additive is not as important as in apolar solvents like toluene (entry 3). However, its absence led to a slight decrease in the yield, so it was still used for the optimization. We found that equimolar amounts of both substrates 4a and 2b led to lower yields (entry 4), as when using excess of allene (entry 5). The reason behind these results is the decomposition of both the allene and the anilide in the reaction media, with the latter being more labile. Therefore, we decided to keep the excess of anilide and we performed a slow addition of the allene over the reaction media in 1 hour. That experiment gave a boost in the yield up to 71% (entry 6). Chapter III: Results and discussion 101 Table 7. Tests using 2-methyl THF as solvent. Entry mmol 4a mmol 2b equiv Cu(OAc)2·H2O equiv Cs2CO3 Yieldb 1 0.333 0.167 2 1.5 54%c 2 0.333 0.167 1 1 61%c 3d 0.333 0.167 1 1 56% 4 0.167 0.167 1 1 56% 5 0.167 0.333 1 1 55% 6e 0.333 0.167 1 1 71%c a Conditions: 40 mol% of Ac-Val-OH, 15 equiv of DMSO, 2 mL of 2-methyl THF, under air, 16 h. b Yields calculated based on 2b. Calculated by using 1,3,5-trimethoxybenzene as 1H NMR internal standard. c Isolated yield based on a 2b. d Without DMSO. e Slow addition over 1 h of 0.167 mmol of allene 2b in 1.5 mL of 2-methyl THF to the reaction instead of mixing it before heating. The reaction did not proceed in absence of palladium acetate, whereas the use of 5 mol% instead of 10 mol% led to incomplete conversion and 23% yield. The reaction was also tested using several protecting groups in the amine moiety, employing conditions of entry 10 of Table 3 (toluene, 105 °C, Method A) or entry 2 of Table 7 (2-methyl THF, 85 °C, Method B) for experimental simplicity. The results are depicted in Scheme 71. Among all tested, triflate was still the most adequate for the transformations, followed by mesyl, probably because of their structure similarity. Scheme 71. Screening of different protecting groups for the amine. Chapter III: Results and discussion 102 3.2 Scope of the (4+2) cycloaddition between o-methylanilides and allenes Using the optimized conditions, we explored the scope of the reaction. For that purpose, we synthesized allenes bearing different substitution patterns, following previously reported synthetic procedures. The synthesis of allenes 2a-2h were described in the previous chapter (section 3.2). Allene 2i (nona-4,5-diene) was made from trans-4-octene in a two-step procedure which involves a cyclopropanation with bromoform and a second step of elimination using methyllithium as base (Scheme 72a).115 Allene 2j (penta-1,2-diene-1,5-diyldibenzene) was synthesized from 3-phenylpropanal and phenylacetylene following also a two-step procedure (Scheme 72b). The first step was the reaction of the aldehyde with p-tosyhidrazine to form a hydrazone derivative that was reacted with phenylacetylene in a copper-catalyzed process.149 Allene 2k (1-(propa-1,2-dien-1-yl)-4-(trifluoromethyl)benzene) was synthesized from 4-ethynyl- α,α,α-trifluorotoluene following a standard Crabbé reaction with formaldehyde (Scheme 72c).150 Meanwhile, allene 2l (2-methyldeca-2,3-diene) was synthesized from 2-methyl-3-butyn-2-ol in a one-pot procedure that involves mesylation of 2-methylbut-3-yn-2-ol and then a SN2’ reaction with hexylmagnesium bromide and copper(I) (Scheme 72d).151 Scheme 72. Synthetic procedures for the allenes 2i-2l. 149 Ghosh, C.; Nagtilak, P. J.; Kapur, M. Org. Lett. 2019, 21, 3237. 150 Kuang, J.; Shengming, M. J. Org. Chem. 2009, 74, 1763. 151 Ahmar, M.; Barieux, J.-J.; Cazes, B.; Gore, J. Tetrahedron 1987, 43, 513. Chapter III: Results and discussion 103 We also prepared o-methylanilides featuring different electronic and steric characteristics. All of them were synthesized from their corresponding free amines through the same triflation procedure applied for the model substrate. Most of them were commercially available, except for 3-methyl-[1,1'-biphenyl]-4-amine (precursor of 4g) and 3,5-dimethyl-[1,1'-biphenyl]-4-amine (precursor of 4n), which were synthesized from their corresponding 4-bromoanilines through a Suzuki coupling with phenylboronic acid;152 and 3-methylnaphthalen-2-amine (precursor of 4p), which was synthesized from 2-amino-3-naphtoic acid by reduction with Red-Al® (Scheme 73).153 Scheme 73. Synthetic procedures for the o-methylanilides 4a-4p. We were happy to observe that the annulation works using different types of allenes. The results are summarized in Scheme 74. 1,1,-disubstituted allenes like commercially available vinylidenecyclohexane 2a gave the expected product with 61% yield. Symmetrical 1,3- disubstituted allenes such as 2i also led to good yields (61%). Gratifyingly, non-symmetrical 1,3- disubstituted allenes 2e and 2j afforded the expected cycloadducts with excellent regio- and stereoselectivities and good yields (66% and 76% respectively). As it was commented in section 3.2 of Chapter II, the preferential formation of the regioisomer depicted in the Scheme 74 is associated to a thermodynamic effect, with the double bond conjugated with the phenyl ring. Monosubstituted allenes, like 2f and 2k, can also engage in the reaction, albeit leading to mixtures of E:Z isomers. In the case of product 5ak the selectivity was good but the yield was low, probably as a result of the instability of the allene partner under the reaction conditions. Notably, trisubstituted allenes also led to the tetrahydroquinoline products, and therefore cycloadducts 5ag, 5ah and 5al equipped with quaternary centers were obtained in moderate to good yields (42%-73%). 152 J. Liu, R. Ma, F. Bi, F. Zhang, C. Hu, H. Venter, S. J. Semple, S. Ma, Bioorganic and Medicinal Chemistry Letters 2018, 1825. 153 G. Q. Li, H. Gao, C. Keene, M. Devonas, D. H. Ess, L. Kürti, J. Am. Chem. Soc. 2013, 135, 7414. Chapter III: Results and discussion 104 a Conditions: 0.333 mmol of 4a, 0.167 mmol of allene 2, 2.5 mL of Me-THF, 15 equiv DMSO, under air, 16 h. Slow addition over 1 h of allene in 1.5 mL of 2-methyl THF to the reaction instead of mixing it before heating. Regioisomeric ratios >20:1 and E/Z ratios >20:1, unless otherwise stated. Structure of the major product shown. Isolated yields based on 2. b Yield after a gram-scale experiment. Scheme 74. Scope of the (4+2) cycloaddition regarding the allene coupling partner. In the same way indicated in the previous chapter, the use of allenes as 2-carbon partners was key for the success of the cycloaddition. Alkynes, like diphenylacetylene, were unreactive and no conversion was observed. This might be due to the higher coordination ability of alkynes, which can lead to the saturation of the metal coordination sphere to give nonactive complexes. Alkenes, such as ethyl acrylate, failed to give annulation products, providing just traces of olefination products, resulted from migratory insertion/β-hydride elimination processes (see section 1.4). The next step was to evaluate how substitution in the aryl ring of the o-methylanilide affected the reaction. The results are illustrated in Scheme 75. Substitution in ortho position to the methyl group is tolerated, as well as the presence of diverse functional groups, like methoxy (4b), halogen (4c) or trifluoromethyl (4d). The corresponding products 5bb, 5cb and 5db were obtained in 69%, 50% and 34% yield respectively. Ortho-methylanilides bearing substituents in meta position to the methyl group, such as phenyl, methoxy or halogens, can also engage in the reaction, affording the cycloadducts in moderate yields (5eb-5ib, 16-73% yield). Chapter III: Results and discussion 111 Nevertheless, an outer-sphere mechanism cannot be ruled out, although in that situation we might have observed products arising from β-hydride elimination side pathways, which were not detected (Scheme 81). Experiments using chiral allene were inconclusive to settle the actual mechanism of reductive elimination, as the allene partially racemizes under the reaction conditions. Scheme 81. Alternative outer-sphere mechanism for the ring-closing step. 3.4 Formal (5+2) cycloaddition between o-methylbenzyltriflamides and allenes: initial assays At this stage, we wondered whether this methodology could be extended to more challenging o-methylbenzyltriflamides as annulation precursors. In these substrates, the directing group is one bond further apart from the methyl substituent, and therefore the C(sp3)–H activation is not warranted. However, this cycloaddition would be of high interest, as it would allow to assemble synthetically relevant seven-membered heterocycles in a novel type of formal (5+2) annulation. One important issue that needs to be taken into account is that the methodology may require the employment of ortho disubstituted benzyltriflamides in order to avoid the competitive activation of the C(sp2)–H bond of the aromatic ring. We first performed a brief re-screening of reaction conditions for the (5+2) cycloaddition starting from the optimized conditions of the (4+2) cycloaddition. For that purpose, we synthesized the 2,6-dimethylbenzyltriflamide 6a from commercially available 2,6- dimethylbenzylamine and triflic anhydride, using triethylamine as base. The remaining ortho position was blocked to prevent the C(sp2)–H activation of the aryl ring (vide infra). The results of the annulation experiments are summarized in Table 9. Using the optimized conditions for the (4+2) cycloaddition, the reaction gave low yield (entry 1, 29% yield). Complete conversion of the allene was observed after 16 hours. However, remaining substrate 6a was detected, even though its exact conversion was not measured. In toluene at 105 °C, the yield boosted to 60%. The efficiency of these conditions might be explained in terms of the structural similarity of the substrate 6a with the benzyltriflamides employed in the previous project (see Chapter II). Other amino acid ligands were tested for the reaction, but none of them enhanced Chapter III: Results and discussion 112 the yield (entries 3-6). During these assays, a side product coming from the ring closure of substrate 6a was detected, meaning that the amide substrate might evolve by other undesired pathways in which the allene is not involved. However, the presence of unreacted 6a suggested that this side reaction is slower than the decomposition of the allene, and therefore excess of the benzyltriflamides was not needed. This was evidenced when the reaction was performed using almost equimolar amounts of the reacting partners (entry 7), and especially with 2 equivalents of allene (entry 8), that allowed to increase the yield up to 86%. Table 9. Screening of conditions for the (5+2) cycloaddition. Entry Ligand Solvent Temp. Yieldb 1c Ac-Val-OH 2-methyl THF 85 °C 29%d 2 Ac-Val-OH Toluene 105 °C 60%d 3 Ac-Ala-OH Toluene 105 °C 58% 4 Ac-Leu-OH Toluene 105 °C 58% 5 Ac-Gly-OH Toluene 105 °C 47% 6 Formyl-Val-OH Toluene 105 °C 54% 7e Ac-Val-OH Toluene 105 °C 58%d 8f Ac-Val-OH Toluene 105 °C 86%d a Conditions: 0.333 mmol 6a, 0.167 mmol of allene 2b, 15 equiv of DMSO, 2 mL of solvent, under air, 16 h. b Yields calculated based on 2b. Calculated by using 1,3,5-trimethoxybenzene as 1H NMR internal standard. c 1 equiv of Cu(OAc)2·H2O and 1 equiv of Cs2CO3. Slow addition over 1 h of 0.167 mmol of allene 2b in 1.5 mL of 2-methyl THF to the reaction instead of mixing it before heating. d Isolated yield. e 0.167 mmol 6a, 0.184 mmol of allene 2b. f 0.167 mmol 6a, 0.333 mmol of allene 2b. Chapter III: Results and discussion 113 3.5 Scope of the (5+2) cycloaddition between o-methylbenzylamides and allenes With the optimized conditions in our hand, we explored the scope of the cycloaddition. We synthesized several o-methylbenzyltriflamides bearing different substitution patterns. Most of them were made from their corresponding free amines using a standard triflation procedure. The starting free amines were commercially available or synthesized from their corresponding nitriles and subsequent reduction of the imine following previously reported procedures. 119,156 However, 6c and 6d were synthesized from their corresponding alcohols using a Mitsunobu reaction (Scheme 82). Scheme 82. Synthetic procedures for the o-methylbenzyltriflamides 6a-6g. We then assayed the cycloaddition with different allenes. The results are illustrated in Scheme 83. The reaction works in a very efficient manner, and even leads to better yields than the homologous anilides. Interesting tetrahydro-2-benzazepines cycloadducts (7bb-7db) were obtained in good to excellent yields (71%-90% yield), evidencing the tolerance to functional groups like fluorine or methoxy. Substitution in α-position to the amino group is also tolerated (7eb and 7fb, 71% and 68% respectively). Other allenes, like trisubstituted allene 2g, can also engage in the cycloaddition, affording the tetrahydro-2-benzazepine 7cg in a 61% yield. 156 S. Levinger, S, R. Nair, A. Hassner, Beilstein J. Org. Chem. 2008, 4, 1. Chapter III: Results and discussion 114 Me nBu nBu NTf F nBu nBu NTf Me NHTf NTf R2 R3 + Ar Ar R4 7bb, 75% 7eb, 87%b 7cb, 90% OMe nBu nBu NTf 7db, 71% Me nBu nBu NTf MeO OMe Ph NTf Me Me 7cg, 61% X X R1 Et 6b-f 2b or 2g 7 R1 R5 Me Pd(OAc)2(10 mol%) Ac-Val-OH (40 mol%) Me nBu nBu NTf 7fb, 68%b,c Me Me 2 equiv · R4 R5 R3 R2Cu(OAc)2·H2O (2 equiv) Cs2CO3(1.5 equiv) toluene/DMSO, 105 °C, 16 h a Conditions: 0.167 mmol of amides 6, 0.333 mmol of allenes 2, 2 mL of toluene, 15 equiv DMSO, under air, 16 h. Regioisomeric ratios >20:1 and E/Z ratios >20:1, unless otherwise stated. Isolated yields based on 6. b Racemic Ac-Val- OH was used. c 0.167 mmol of amide 6f, 0.167 mmol of allene 2b. Scheme 83. Scope of the (5+2) cycloaddition between o-methylbenzylamines and allenes. As an additional test, the o-methylbenzyltriflamide 6g, that lacks on substitution in the ortho position, was assayed under optimized reaction conditions with racemic Ac-Val-OH and allene 2b (Scheme 92). As expected, the formation of the cycloadduct 7gb was not observed, whereas the product 8, result of the C(sp2)–H activation of the aryl ring, was isolated in an 89% yield. This demonstrates the importance of the disubstitution at the ortho position of the benzyltriflamide to prevent the more favorable C(sp2)–H activation, and points out an important future challenge, promoting the preferential activation of the methyl group over the aryl C–H bond. Scheme 84. Test with the monomethylated benzyltriflamide 6g. Chapter III: Results and discussion 115 3.6 Preliminary tests on a (5+2) enantioselective cycloaddition based on a kinetic resolution strategy With the above examples demonstrating the viability of employing α-substituted omethylbenzyltriflamides, we envisioned the possibility of developing an enantioselective version of the cycloaddition. For that purpose, we subjected the o-methylbenzyltriflamide 6e to a brief screening of conditions, as illustrated in Table 10. The use of Ac-Val-OH led to a very poor enantioselectivity at 70 °C, affording the cycloadduct 7eb with only a 59:41 enantiomeric ratio (entry 1). When the amino acid was protected with a larger group, like Boc, the result was slightly better (73:21 er, entry 2), while with the Boc-protected amino methyl ester of phenylalanine (Boc-Phe-NHOMe), the enantiomeric ratios increased to 83:17 (entry 3). It is important to highlight the strong influence of the temperature in the kinetic resolution. At 70 °C and employing Boc-Leu-NHOMe as ligand, the product was obtained in only an 8% yield with an 88:12 er (entry 4). However, increasing the temperature in 10 °C, the yield boosted up to 48%, but the er decreased to 78:22. Table 10. Preliminary tests for the kinetic resolution of 6e. Entry Ligand (mol%) Temp. Time Yieldb Conversionb er 7eb er rec. 6e 1 Ac-Val-OH (40) 70 °C 4 h 17% not meas. 59:41 not meas. 2 Boc-Val-OH (40) 70 °C 24 h 38% not meas. 73:21 not meas. 3 Boc-Phe-NHOMe (15) 70 °C 48 h 33% 42% 83:17 69:31 4 Boc-Leu-NHOMe (15) 70 °C 48 h 8% 34% 88:12 52:48 5 Boc-Leu-NHOMe (15) 80 °C 48 h 48% 57% 78:22 82:18 a Conditions: 0.1 mmol of amide 6e, 0.1 mmol of allene 2b, 2 mL of toluene, under air. b Isolated yields, conversion based on recovered 6e. o-Methylbenzyltriflamide 6f was also tested in this reaction using mono-protected amino methyl ester ligands. The results are summarized in Table 11. At 70 °C, both Boc-Phe-NHOMe and Boc- Leu-NHOMe ligands gave similar results (entries 1-2, 38-42% yield, 86:14-88:12 er). By decreasing the temperature 10 °C, the cycloadduct 7fb was obtained with a promising 90:10 enantiomeric ratio, albeit with a moderate 20% yield (entry 3). Chapter III: Results and discussion 116 Table 11. Preliminary tests for the kinetic resolution of 6f. Entry Ligand (mol%) Temp. Time Yieldb Conversionb er 7fa er rec. 6f 1 Boc-Phe-NHOMe (15) 70 °C 48 h 38% 43% 86:14 75:25 2c Boc-Leu-NHOMe (15) 70 °C 72 h 42% 59% 88:12 78:22 3d Boc-Leu-NHOMe (15) 60 °C 72 h 20% 21% 90:10 60:40 a Conditions: 0.1 mmol of amide 6f, 0.1 mmol of allene 2b, 2 mL of toluene, under air. b Isolated yields, conversion based on recovered 6f. c 7fb: [α]D 19.8 = -19.3 (c 1.0, CH2Cl2); recovered 6f: [α]D 19.8 = -10.3 (c 1.0, CH2Cl2) d 0.2 mmol of allene 2b. These preliminary results confirm that it is possible to generate optically active tetrahydro-2- benzazepine skeletons by employing the novel (5+2) cycloaddition, and warrant further studies to optimize the process. 3.7 Derivatization of the cycloadducts The products obtained in the cycloaddition are susceptible of synthetic manipulation. For instance, the exocyclic double bond in product 7cg was successfully hydrogenated with H2 over Pd/C to give a fully saturated tetrahydro-2-benzazepine skeleton (9) in a 73% yield. The structure of compound 9 was determined by X-ray diffraction analysis. Moreover, the triflyl protecting group can be removed by treatment with Red-Al©, affording the unprotected tetrahydro-2- benzazepine 10 in 76% yield (Scheme 85). Removal of the methoxy group of 6 was also attempted using a hydrogenation procedure reported by Hartwig with Ni(0).157 This would be very interesting, as methoxy group could be employed as a temporary moiety to block the oposition of the o-methylbenzyltriflamide. However, no reactivity was observed, and therefore the starting material was recovered. 157 Sergeev, A. G.; Hartwig, J.F. Science, 2011, 332, 439 Chapter III: Results and discussion 117 Scheme 85. Synthetic manipulation of compound 7cg. Hydrogenation of the quaternary double bond of product 5aa was tested using a balloon of hydrogen (1 atm) over Pd/C. However, there was no reaction, and the starting material was recovered (Scheme 86a). It is possible that increasing the hydrogen pressure we could achieve the desired reactivity but it was not tested. We also tried to break the double bond of 5aj with an ozonolysis reaction using dimethylsulfide or triphenylphosphine as reductants. However, only decomposition of the starting material was observed in both assays (Scheme 86b), probably due to an excessive fragmentation of the molecule. Scheme 86. Unsuccessful derivatization assays. Chapter III: Conclusions 118 4- Conclusions In conclusion, we have developed a palladium-catalyzed formal (4+2) cycloaddition between ortho-methyl anilides and allenes, relying on the activation of a benzylic C(sp3)–H bond. This methodology allows the straightforward assembly of highly substituted tetrahydroquinoline skeletons. After a thorough screening of reaction conditions, we were able to obtain good reaction yields. The cycloaddition presents good levels of chemo- and regioselectivity, and tolerates different substitution patterns in both the anilide and the allene coupling partner (Scheme 87). This reaction is one of the first examples of cycloadditions based on benzylic C(sp3)–H activation. Scheme 87. Palladium-catalyzed formal (4+2) cycloaddition between o-methylanilides and allenes. Some mechanistic tests have been performed in order to unravel more information about the mechanism. Kinetic isotope effect experiments manifested that the C(sp3)–H activation is the turnover-limiting step of the catalytic cycle. Experiments employing chiral allenes resulted in partially-racemized cycloadducts, which reinforces the hypothesis that the reaction involves πallyl intermediates. Moreover, this methodology has been applied to more challenging o-methylbenzyl triflamide substrates, in an unprecedented example of formal (5+2) cycloaddition. Tetrahydro-2- benzazepine skeletons can be assembled through this annulation, as demonstrated by the examples reported in the scope, with yields up to 90% (Scheme 88). Besides, the cycloadducts obtained with this methodology can be synthetically manipulated, as demonstrated with the hydrogenation of product 7cg, and the subsequent deprotection of the amino group. Chapter III: Conclusions 119 Furthermore, in a preliminary study, it has been demonstrated that optically active tetrahydro- 2-benzazepines can be synthesized through a kinetic resolution strategy from racemic αsubstituted o-methylbenzyltriflamides, affording the corresponding enantioenriched cycloadducts in enantiomeric ratios up to 90:10. Scheme 88. Palladium-catalyzed formal (5+2) cycloaddition between o-methylbenzyltriflamides and allenes. Addendum: Objectives 127 2- Objectives Considering the advantages of Pd(II)/Pd(IV) catalytic cycles to cope with difficult reductive eliminations, and taking into account the precedents for the synthesis of indole-type skeletons by the employment of these types of catalytic cycles, we envisioned that a cyclization strategy via C(sp3)–H activation of o-methylbenzylamines could be feasible. Additionally, the isolation of a small proportion of isoindolines in the cycloaddition experiments indicated in section 3.4 of Chapter III further supported the viability of this transformation. The development of this method would allow to build isoindoline skeletons in a quite straightforward manner. Moreover, if chiral ligands, like mono-protected amino acids, were employed for the C–H activation step, an asymmetric version of the cyclization might also be developed (Scheme 95). The election of the proper oxidant to form Pd(IV) intermediates would be crucial for the success of the intramolecular amination. Scheme 95. General objective: intramolecular amination of o-methylbenzylamines. Addendum: Results and discusion 128 3- Results and discussion In collaboration with Dr. Marc Font, a thorough investigation of reaction conditions for the cyclization of o-methylbenzylamines was performed. For the screening, 2,6- dimethylbenzyltriflamide 6a, which was synthesized for the project described in Chapter III, was selected as the model substrate. The election of an ortho disubstituted benzyltriflamides is not casual, as it can prevent undesired resting states involving the formation of palladacycles after the C(sp2)–H activation of the aryl ring, which may make the optimization more difficult. To begin our research, preliminary tests were performed by using the optimized conditions for the (5+2) cycloaddition, with the aim of determining the best oxidant for the reaction. The results are summarized in Table 12. By using (diacetoxyiodo)benzene, a very common oxidant in Pd(IV)/Pd(IV) catalysis, the product 11 was detected, but only in traces (entry 1). The conversion of the starting material is 22%, being 2,6-dimethylbenzaldehyde (12) the major product of the reaction, presumably as a result of benzylic oxidation and hydrolysis of the corresponding imine in the work-up. By employing another one-electron oxidant, cerium sulfate (entry 2), the reaction did not improve in terms of yield. The use Cu(OAc)2, the standard oxidant for Pd(II)/Pd(0) catalysis, did not allow to increase the yield either (entry 3). However, in combination with p-benzoquinone (BQ), which is known to ease kinetically difficult reductive elimination steps,164 the reaction yield rose to 13% (entry 4). The conversion of the starting material (86%) is very high, very likely because the copper salt is promoting side reactions (benzylic oxidations). Modifications in the loadings of both oxidants did not make significative differences in the yield (entries 5-6). Besides, BQ by itself cannot promote the reaction, affording the product in traces (entry 7). The combination of BQ with other copper salts (entry 8) or (diacetoxyiodo)benzene (entry 9) did not lead to better results. 164 Salazar, C. A.; Flesch, K. N.; Haines, B. E.; Zhou, P. S.; Musaev, D. G.; Stahl, S. S. Science, 2020, 370, 1454. Addendum: Results and discussion 129 Table 12. Screening of oxidants for the cyclization. Entry Oxidant (equiv) Conversion Yield (11)b 1 PhI(OAc)2 (2) 22% 2% 2 Ce(SO4)2 (2) 65% 3% 3 Cu(OAc)2 (2) 75% 5% 4 Cu(OAc)2·H2O (2) / BQ (1) 86% 13% 5 Cu(OAc)2·H2O (2) / BQ (0.5) 81% 8% 6 Cu(OAc)2·H2O (1) / BQ (0.5) 79% 11% 7 BQ (2) 56% 1% 8 Cu(acac)2 (2)/ BQ (1) 89% 5% 9 PhI(OAc)2 (2)/BQ (1) 21% <1% a Conditions: 0.1 mmol 6a, 40 mol% of Ac-Val-OH, 15 equiv of DMSO, 2 mL of toluene, under air, 16 h. b Yields calculated based on 6a. Calculated by using 2.4-dichlorobenzotrifluoride as 19F NMR internal standard. After selecting the combination of copper acetate and BQ as the best oxidants for the reaction, a screening of different ligands was performed. The results are described in Table 13. Other acetyl-protected amino acids, as well as propionyl-protected amino acids, gave similar results (entries 1-2). The rest of the amino-acids tested as ligands gave even worse results (entries 3-6), evidencing the importance of the ligand for the cyclization. Addendum: Results and discusion 130 Table 13. Screening of ligands for the cyclization. Entry Ligand Conversion Yield (11)b 1 Ac-Leu-OH 89% 11% 2 Pro-Val-OH 82% 12% 3 2,6-F,F-Bz-Leu-OH 77% 5% 4 Fmoc-Leu-OH 80% 7% 5 Boc-Phe-OH 57% 5% 6c Boc-Phe-NHOMed 82% 10% a Conditions: 0.1 mmol 6a, 40 mol% of ligand, 15 equiv of DMSO, 2 mL of toluene, under air, 16 h. b Yields calculated based on 6a. Calculated by using 2.4-dichlorobenzotrifluoride as 19F NMR internal standard. c Reaction performed by Dr. Marc Font. d 15 mol% of ligand. Some control tests were carried out in order to figure out the effect of the different components. The reaction does not work without catalyst, and neither without a base. Besides, acetyl and nosyl protecting groups for the benzylamine were also tested. Unfortunately, the formation of the cyclic product was not detected, and only benzylic oxidation of the starting material was observed. The lack of efficiency in the cyclization reaction may be related with a kinetically challenging reductive elimination step, with the difficulty of carrying out the required oxidation from Pd(II) to Pd(IV). Besides, there is a significant decomposition of the starting material because of the benzylic oxidation. In order to avoid this oxidation problem, we assayed the reaction with substrate 6e using different oxidants. The results are illustrated in Table 14. Unfortunately, the product 13 was not obtained, and only low amounts of 2,4,6-trimethylbenzaldehyde (14) were detected as a result of some benzylic oxidation of the starting material (entries 1-2). However, by using the nosyl-protected benzyltriflamide 6e’, the product 13’ is obtained in a 10% yield. Notably, the conversions are low, evidencing that α-substituted benzyltriflamides are more stable towards benzylic oxidation, but the cyclization is still difficult. The use of other oxidants, like Selectfluor© or PhI(OAc)2 did not lead to better results (entries 4-5). Addendum: Results and discussion 131 Table 14. Screening of conditions for the cyclization using α-substituted benzyltriflamide 6e. Entry Substrate Oxidant (equiv) Conversion Yield (8)b 1c 6e Cu(OAc)2·H2O (2) / BQ (1) 21% 0% 2c, d 6e Ag2CO3 (1) / BQ (1) 20% 0% 3c 6e’ Cu(OAc)2·H2O (1) / BQ (1) 15% 10% 4c 6e’ Selectfluor (1.5) 0% 0% 5c 6e’ PhI(OAc)2 (1.5) 0% 0% a Conditions: 0.1 mmol 6e, 40 mol% of Ac-Val-OH, 15 equiv of DMSO, 2 mL of toluene, under air, 16 h. b Yields calculated based on 6e. Calculated by using 2.4-dichlorobenzotrifluoride as 19F NMR internal standard. c Reaction performed by Dr. Marc Font. d Reaction performed without Cs2CO3. Overall, performing this cyclization is represents an important challenge that needs to be further addressed. Addendum: Conclusions 132 4- Conclusions In conclusion, we have made a preliminary study of reaction conditions to promote the cyclization of o-methylbenzyltriflamides to isoindolines. The results suggests that the selection of a proper oxidant is key, but the efficiency of the reaction is low. We are not yet sure which is the key problem that hampers the process, and further research is clearly needed. Reductive elimination involving sp3 carbons is more difficult, especially when the nitrogen is attached to electron withdrawing groups. It is probable that the lack of success is associated to the formation of Pd(IV) species and the reductive elimination step. General conclusions General conclusions 135 As general conclusions of this doctoral thesis: 1. We have developed a palladium-catalyzed formal (4+2) cycloaddition between benzyltriflamides and allenes that allows the synthesis of highly valuable tetrahydroisoquinolines skeletons in excellent yields and selectivities. We managed to extend the reaction to alkenyltriflamides to synthesize tetrahydropyridine and azepine skeletons. We have developed an asymmetric version of the reaction: a desymmetrization of diarybenzyltriflamides that affords enantioenriched tetrahydroisoquinolines in high yields and enantioselectivities. This represents the first palladium-catalyzed annulative C–H activation/desymmetrization process that has been reported. 2. We have developed a palladium-catalyzed formal (4+2) cycloaddition between omethylanilides and allenes based on a C(sp3)–H activation. This methodology makes possible to synthesize tetrahydroquinoline skeletons in good yields from trivial starting materials. Several mechanistic assays have been performed in order to unravel more information about the reaction mechanism. 3. We have developed a palladium-catalyzed formal (5+2) cycloaddition between omethylbenzyltriflamides and allenes based on a C(sp3)–H activation. This methodology allows the synthesis of tetrahydro-2-benzoazepines in good yields. We have demonstrated the viability of an asymmetric version of the reaction with a preliminary exploration of different chiral ligands. Additionally, we have synthetically manipulated the annulation products. 4. We have performed some preliminary assays on a potential palladium-catalyzed cyclization of o-methylbenzyltriflamides, presumably based on Pd(II)/Pd(IV) catalytic cycles. The reaction is viable, but the yields are very low. Resumo da tese doutoral 143 metilbencilaminas substituídas na posición α respecto da amina, esta reacción podería facerse de forma asimétrica utilizando ligandos quirais, como aminoácidos mono-protexidos. Comézase describindo os ensaios iniciais e a optimización da primeira cicloadición formal descrita neste capítulo: a cicloadición formal (4+2) entre o-metilanilidas e alenos. Para iso, sintetízase a o-metilanilina protexida cun triflato e avalíase a súa reacción co aleno 5- vinilidenonano. Durante a optimización, descóbrese que o uso de ligandos de tipo aminoácido mono-protexido mellora a reactividade. Establécese o acetato de cobre como o mellor oxidante para a reacción, e o carbonato de cesio como a mellor base, atopándose neste último caso que o tamaño do catión da base e determinante para o funcionamento da cicloadición. Ademais, a reacción funciona en 2-metiltetrahidrofurano, que é un disolvente verde, é dicir, que provén dunha fonte sustentable, en concreto o furfural, un subproduto da agricultura. Finalmente, coa adición lenta do aleno sobre a reacción, conséguese un rendemento do 71%. Outros grupos protectores para a amina resultan menos eficaces que o triflato. Unha vez descritas as condicións optimizadas, demóstrase a viabilidade da reacción utilizando alenos con diferentes patróns de substitución. Para iso, sintetízanse unha serie de alenos e avalíanse na anulación. A reacción resulta compatible con outros alenos 1,1-disustituidos, 1,3- disustituidos, monosustituidos e trisustituidos, dando nalgúns casos mesturas de isómeros E/Z. A maiores, avalíanse na cicloadición o-metilanilidas con diferentes patróns de substitución e grupos funcionais. A reacción demostra ser compatible cunha variedade de substituíntes en orto, meta e para, así como grupos funcionais como halóxenos, metoxilos ou mesmo ésteres. A tendencia xeral parece indicar que a presenza de grupos electrodadores no anel mellora a reactividade. En seguinte lugar, descríbense unha serie de experimentos mecanísticos que teñen como obxectivo desvelar algunhas incógnitas sobre o mecanismo da cicloadición formal. En primeiro lugar, realízase un experimento de incorporación de deuterio, que suxire que a etapa de activación da ligazón C–H é irreversible. Posteriormente, realízanse dous experimentos para medir o efecto isotópico cinético utilizando o análogo deuterado na posición bencílica da ometilanilina triflada. En concreto, un experimento de competición e outro paralelo. Tras a análise dos resultados, inférese que existe un efecto isotópico cinético primario, o que parece indicar que a activación C–H é a etapa limitante do ciclo catalítico. A continuación, realizáronse experimentos utilizando un aleno quiral, nos que se pretendía manter a quiralidade do aleno no producto final, co obxectivo de construir cicloaductos enantioenriquecidos. Con todo, estes experimentos non resultan concluíntes ao descubrirse que este aleno racemiza nas condicións de reacción. Con todos estes experimentos mecanísticos, proponse un mecanismo de reacción para a cicloadición formal (4+2), que resulta similar ao descrito no capítulo anterior. Resumo da tese doutoral 144 A continuación, descríbese a segunda reacción descrita neste capítulo: a cicloadición formal (5+2) entre o-metilbencilaminas e alenos. En primeiro lugar, sintetízase a o-dimetilbencilamina protexida con triflato e descríbese a reoptimización partindo das condicións de reacción da cicloadición formal (4+2). Neste caso, o tolueno e o mellor disolvente para a reacción, e o uso de exceso de aleno fronte a anilida permite aumentar o rendemento de forma notable. A continuación, avalíase o alcance da cicloadición con outras o-metilbencilaminas. A reacción demostra tolerancia a grupos funcionais tales como flúor ou metoxi, así como substitución na posición α respecto da amina. Avalíase de forma preliminar a posibilidade de realizar unha versión asimétrica da cicloadición. Os resultados utilizando diversos aminoácidos monoprotexidos como ligandos quirais, en concreto aminoácidos nos que o grupo carboxilo e substituído por un grupo amino metil éster, indican que si é posible realizar unha resolución cinética de o-metilbencilaminas, chegando a obter proporcións enantioméricas no cicloaducto de 90:10. Finalmente, avalíase a posibilidade de manipular sintéticamente os produtos obtidos en ambas as cicloadiciones formais. Demóstrase que un cicloaducto proveniente da cicloadición formal (5+2) pode ser hidroxenado para obter unha tetrahidro-2-benzoazepina triflada totalmente saturada. Ademais, este mesmo triflato pode ser eliminado para obter a tetrahidro-2- benzoazepina sen protexer. Con todo, a manipulación sintética dos produtos provenientes da cicloadición formal (4+2), como por exemplo a ozonólise ou a hidroxenación, non resulta frutífera. As conclusións deste capítulo é que se desenvolveron dúas reaccións de activación C(sp3)–H catalizadas por paladio: unha cicloadición formal (4+2) entre o-metilanilidas e alenos e unha cicloadición formal (5+2) entre o-metilbenciltriflamidas e alenos. Realizouse unha optimización das condicións de reacción e avaliouse o seu alcance e limitacións. Tamén se realizaron estudos mecanísticos para desvelar información sobre o seu mecanismo. Ademais, desenvolveuse un estudo preliminar da versión asimétrica da cicloadición formal (5+2), demostrando a súa viabilidade. Finalmente, realizáronse experimentos de manipulación sintética dos cicloaductos obtidos nas reaccións. Estas reaccións constitúen dúas dos escasos exemplos de cicloadiciones formais baseadas na activación de ligazóns C(sp3)–H. Anexo- Ciclación de o-metilbencilaminas cara a isoindolinas catalizada por paladio e que implica activación C(sp3)–H Neste anexo descríbense os resultados preliminares da ciclación de o-metilbencilaminas baseada na activación de ligazóns C(sp3)–H. Resumo da tese doutoral 145 En primeiro lugar, introdúcense brevemente as características dos ciclos catalíticos Pd(II)/Pd(IV). Coméntase o seu esquema xeral e as súas vantaxes respecto doutros ciclos catalíticos de paladio, tales como a súa resistencia a procesos de eliminación de β-hidruro, a súa facilidade para sufrir procesos de eliminación reductora ou a súa tolerancia á presenza de osíxeno na reacción. A continuación, descríbese unha serie de síntese de esqueletos de tipo indol mediante o uso de activación C–H catalizada por ciclos catalíticos Pd(II)/Pd(IV). Destácase que o uso deste tipo de catálisis facilita a etapa de eliminación reductora para xerar ciclos de 5 membros, que aínda que resultan complicados de sintetizar debido á tension anular, son de interese pola súa presencia en moléculas bioactivas. Tras esta breve introdución, preséntase o obxectivo deste anexo: a síntese de esqueletos de tipo isoindolina mediante unha reacción de ciclación de o-metilbencilaminas baseada en activación C–H mediada por ciclos catalíticos de Pd(II)/Pd(IV). Destácase que no caso de utilizar ometilbencilaminas substituídas na posición β respecto da amina, poderíase desenvolver tamén a versión asimétrica da ciclación co uso de ligandos quirais, de modo análogo ao que ocorría coa cicloadición formal (5+2) do capítulo anterior. NHPG [Pd] ligando quiral R Ar isoindolina quiral (se R H) Ar NPG R H oxidante A continuación, descríbense os resultados preliminares obtidos en colaboración co Dr. Marc Font. Os experimentos realizados coa o-dimethylbenciltriflamida usando oxidantes típicos dos ciclos catalíticos de Pd(II)/Pd(IV) non lograron rendementos superiores ao 3%. O uso de acetato de cobre como oxidante, máis relacionado con ciclos Pd(II)/Pd(0), aumentou o rendemento da reacción até o 13% ao usarse en combinación con benzoquinona, aínda que tamén levou a conversións case totais da sustancia de partida, evidenciando a oxidación bencílica mediada por cobre que se detectou con anterioridade neste tipo de substratos durante os capítulos II e III. A avaliación de diferentes tipos de aminoácidos mono-protexidos como promotores da reacción non permitiu mellorar o rendemento. Finalmente, probouse un substrato con substitución en α, que dificultaba a oxidación de devandita posición. Aínda que as conversións reducíronse, tan só se obtivo o produto esperado cando se utilizou nosilo como grupo protector da amina en lugar de triflato.A conclusión deste anexo é que a elección do oxidante adecuado resulta clave para obter mellores rendementos, xa que a etapa de eliminación reductora parece a etapa limitante da reacción. Os resultados preliminares resultan insuficientes para determinar a viabilidade da reacción, polo que é necesaria unha maior exploración nas condicións de reacción, sobre todo mediante o uso de oxidantes típicos de ciclos catalíticos de Pd(II)/Pd(IV). Conclusión xeral Como conclusión xeral, nesta tese doutoral descríbense varios procesos de cicloadición formal catalizados por paladio e baseados en activación de ligazóns C–H, ben de natureza sp2 ou sp3, dando lugar a diferentes azaheterociclos, sendo algúns deles ópticamente activos. Experimental Section Experimental section 149 1- General experimental procedures Reactions were conducted in dry solvents under argon atmosphere unless otherwise stated. Dry solvents were obtained from Aldrich and used without further purification. Pd(OAc)2 (98%) [3375-31-3] was obtained from Strem. All other chemicals, were purchased from Aldrich and used without further purification. All the amino acids ligands (except 2,6-F,F-Bz-Leu-OH) were commercially available. They were purchased from Aldrich and used without further purification. The abbreviation “rt” refers to reactions carried out at a temperature between 21-25 °C. Reaction mixtures were stirred using Teflon-coated magnetic stir bars. High reaction temperatures were maintained using Thermowatch-controlled heating blocks. Thin-layer chromatography (TLC) was performed on silica gel plates and components were visualized by observation under UV light, and/or by treating the plates with p-anisaldehyde, ninhydrin, phosphomolybdic or potassium permanganate solutions, followed by heating. Flash chromatography was carried out on silica gel. Dryings were performed with anhydrous Na2SO4. Concentration refers to the removal of volatile solvents via distillation using a Büchi rotary evaporator followed by high vacuum. All palladium-catalyzed reactions were carried out without particular precautions to extrude moisture or oxygen. 1H-NMR spectra were recorded at room temperature on a Varian 300 MHz or 500 MHz spectrometer in CDCl3 [using CDCl3 (for 1H, δ = 7.26) as internal standard]. 19F-NMR (282 MHz) spectra were recorded at room temperature on a Varian 300 MHz or 500 MHz spectrometer in CDCl3. 13C NMR spectra were recorded at room temperature on a Varian spectrometer in CDCl3 [using CDCl3 (for 13C, δ = 77.160) as internal standard]. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, brs = broad singlet. Carbon types and structure assignments were determined from DEPT-NMR and two-dimensional experiments (HSQC and NOESY). NMR spectra were analyzed using MestReNova© NMR data processing software (www.mestrelab.com). Mass spectra were acquired using electrospray ionization (ESI, ion polarity positive) or atmospheric pressure chemical ionization (APCI) and were recorded at the CACTUS facility of the University of Santiago de Compostela on Bruker micrOTOF. Melting points were measured on a Büchi Melting Point B- 560 apparatus. Enantiomeric ratios (er) were determined on an Agilent HPLC 1100 Series or on a Jasco SFC 4000 series using commercially available chiral columns. All racemic products were prepared under the same procedure than the chiral products but with the employment of a racemic amino acid. X-ray crystallographic analysis was done at the CACTUS facility of the University of Santiago de Compostela. The measurements were performed with a Bruker D8 Venture Photon III-14 using a microfocus sealed tube as diffraction source. Amounts of isolated products are indicated independently of the scale used. Experimental section: Chapter II 150 2- Chapter II: Synthesis of tetrahydroisoquinoline skeletons via enantioselective formal cycloadditions of benzyltriflamides with allenes 2.1 General procedure for the synthesis of diarylbenzylamines 1h, 1i and 1j Following a previously reported procedure,119 to a solution of arylmagnesium bromide (1.25 equiv) in THF (0.2 M) was added the nitrile (1 equiv) at room temperature, with the resulting mixture being refluxed for 4 h. After cool, anhydrous MeOH (1 equiv) was added (vigorous reaction) and the reaction stirred for 1 h at rt. Then, LiAlH4 (2 equiv) was added, and the reaction was stirred overnight at rt. After that, the reaction was quenched with the careful addition of water. The aqueous layer was extracted with diethyl ether three times. The combined organic phases were washed with aqueous NaHCO3 (sat.) and dried over Na2SO4. The crude was used in the next step without further purification. 2.2 General procedure for the synthesis of triflyl-protected benzylamines and alkenylamines from the precursor amines, exemplified for 1a To a solution of benzylamine (2 mL, 18.31 mmol) in dichloromethane (36.6 mL) under argon atmosphere was added triethylamine (2.55 mL, 18.31 mmol) at -12 °C. After the solution was stirred 5 minutes at that temperature, trifluoromethanesulfonic anhydride (3.23 mL, 19.22 mmol) was added dropwise. The reaction was stirred for 1 h at that temperature before being quenched with water. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic phase was washed with brine and then dried over Na2SO4. Evaporation and column chromatography on silica gel (hexanes:diethylether; 80:20) afforded N-benzyl-1,1,1-trifluoromethanesulfonamide (1a) as a white solid (3.97g, 91% yield). Mp: 43-44 °C. 1H NMR (300 MHz, CDCl3) δ 7.34 – 7.18 (m, 5H), 5.10 (brs, 1H), 4.33 (d, J = 5.8 Hz, 2H). 19F NMR (282 MHz, CDCl3) δ -77.64. 13C NMR (75 MHz, CDCl3) δ 135.3 (C), 129.2 (CH), 128.8 (CH), 128.0 (CH), 119.8 (q, J = 320.9 Hz, C), 48.3 (CH2). HRMS [APCI]: m/z calculated for C8H7F3NO2S [M+H]+: 238.0144, found 238.0145. Experimental section: Chapter II 151 N-allyl-1,1,1-trifluoromethanesulfonamide (1d) (1.35 g, 82% yield), obtained as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 5.96 – 5.78 (m, 1H), 5.39 – 5.23 (m, 2H), 4.89 (brs, 1H), 3.92 (d, J = 5.8 Hz, 2H). 19F NMR (282 MHz, CDCl3) δ -77.90. 13C NMR (75 MHz, CDCl3) δ 132.1 (CH), 119.8 (q, J = 321.1 Hz, C), 119.1 (CH2), 46.8 (CH2). HRMS [ESI]: m/z calculated for C4H7F3NO2S [M+H]+: 190.0150, found 190.0148. N-(2-(cyclohex-1-en-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide (1e) (433 mg, 84% yield), obtained as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 5.46 (brs, 1H), 5.03 (brs, 1H), 3.28 (q, J = 6.3 Hz, 2H), 2.14 (t, J = 13.5 Hz, 2H), 2.06 – 1.97 (m, 2H), 1.93 – 1.83 (m, 2H), 1.70 – 1.49 (m, 4H). 19F NMR (282 MHz, CDCl3) δ -78.00. 13C NMR (75 MHz, CDCl3) δ 132.8 (C), 125.7 (CH), 119.8 (q, J = 321.2 Hz, C), 42.1 (CH2), 38.2 (CH2), 27.7 (CH2), 25.2 (CH2), 22.7 (CH2), 22.2 (CH2). HRMS [ESI]: m/z calculated for C9H15F3NO2S [M+H]+: 258.0770, found 258.0769. 1,1,1-trifluoro-N-(1-phenylpropyl)methanesulfonamide (1f) (836 mg, 84% yield), obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.34 – 7.19 (m, 3H), 7.19 – 7.12 (m, 2H), 5.50 (d, J = 8.8 Hz, 1H), 4.40 (q, J = 7.7 Hz, 1H), 1.91 – 1.70 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 19F NMR (282 MHz, CDCl3) δ - 78.03. 13C NMR (75 MHz, CDCl3) δ 140.2 (C), 129.1 (CH), 128.4 (CH), 126.3 (CH), 120.0 (d, J = 320.9 Hz, C), 61.6 (CH), 31.0 (CH2), 10.6 (CH3). HRMS [ESI]: m/z calculated for C10H12F3NNaO2S [M+Na]+: 290.0433, found 290.0433. Data in agreement with those reported in literature.165 N-benzhydryl-1,1,1-trifluoromethanesulfonamide (1g) (1.62 g, 63% yield), obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.31 – 7.11 (m, 10H), 5.77 (d, J = 8.9 Hz, 1H), 5.68 (d, J = 9.0 Hz, 1H). 19F NMR (282 MHz, CDCl3) δ -77.31. 13C NMR (75 MHz, CDCl3) δ 139.7 (C), 129.1 (CH), 128.4 (CH), 127.3 (CH), 119.5 (q, J = 321.1 Hz, CF3) 62.5 (CH). HRMS [ESI]: m/z calculated for C14H12F3NNaO2S [M+Na]+: 338.0443, found 338.0440. Data in agreement with those reported in literature.110 N-(di-o-tolylmethyl)-1,1,1-trifluoromethanesulfonamide (1h) (2.60 g, 80% yield), obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.17 – 7.02 (m, 8H), 6.09 (d, J = 8.2 Hz, 1H), 5.27 (d, J = 8.2 Hz, 1H), 2.21 (s, 6H). 19F NMR (282 MHz, CDCl3) δ -77.42. 13C NMR (75 MHz, CDCl3) δ 137.2 (C), 136.0 (C), 131.2 (CH), 128.5 (CH), 127.0 (CH), 126.5 (CH, 119.4 (q, J = 321.2 Hz, C), 56.7 (CH), 19.1 (CH3). HRMS [ESI]: m/z calculated for C16H16F3NNaO2S [M+Na]+: 366.0746, found 336.0749. Data in agreement with those reported in literature.165 165 Miyamoto, K.; Hoque, M. M.; Ogasa, S. J. Org. Chem. 2012, 77, 8317. Experimental section: Chapter II 152 N-(di-p-tolylmethyl)-1,1,1-trifluoromethanesulfonamide (1i) (1.95 g, 70% yield), obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.09 – 6.97 (m, 8H), 5.75 – 5.54 (m, 2H), 2.22 (s, 6H). 19F NMR (282 MHz, CDCl3) δ -77.69. 13C NMR (75 MHz, CDCl3) δ 138.2 (C), 137.1 (C), 129.7 (CH), 127.1 (CH), 119.6 (d, J = 321.0 Hz, C), 62.2 (CH), 21.2 (CH3). HRMS [ESI]: m/z calculated for C16H16F3NNaO2S [M+Na]+: 366.0746, found 336.0743. Data in agreement with those reported in literature.165 N-(bis(4-chlorophenyl)methyl)-1,1,1-trifluoromethanesulfonamide (1j) (2.92 g, 74% yield), obtained as a white solid. Mp: 105-107 °C. 1H NMR (300 MHz, CDCl3) δ 7.31 – 7.24 (m, 4H), 7.12 – 7.04 (m, 4H), 5.73 (d, J = 8.8 Hz, 1H), 5.64 (d, J = 8.9 Hz, 1H). 19F NMR (282 MHz, CDCl3) δ -77.64. 13C NMR (75 MHz, CDCl3) δ 137.7 (C), 134.8 (C), 129.5 (CH), 128.6 (CH), 119.5 (q, J = 321.0 Hz, C), 61.4 (CH). HRMS [ESI]: m/z calculated for C14H10Cl2F3NNaO2S [M+Na]+: 405.9654, found 405.9656. N-(bis(4-methoxyphenyl)methyl)-1,1,1-trifluoromethanesulfonamide (1k) (302 mg, 24% yield), obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.09 – 7.02 (m, 4H), 6.81 – 6.73 (m, 4H), 5.69 (s, 2H), 3.70 (s, 6H). 19F NMR (282 MHz, CDCl3) δ -77.90. 13C NMR (75 MHz, CDCl3) δ 159.5 (C), 132.2 (C), 128.5 (CH), 119.6 (d, J = 321.1 Hz, C), 114.4 (C), 61.67 (C), 55.5 (CH3). HRMS [ESI]: m/z calculated for C16H16F3NNaO4S [M+Na]+: 398.0644, found 398.0641. Data in agreement with those reported in literature.165 N-(bis(3-methoxyphenyl)methyl)-1,1,1-trifluoromethanesulfonamide (1l) (325 mg, 84% yield), obtained as a white solid. Mp: 86-87 °C. 1H NMR (300 MHz, CDCl3) δ 7.20 – 7.11 (m, 3H), 6.78 – 6.65 (m, 5H), 6.00 (d, J = 9.0 Hz, 1H), 5.68 (d, J = 8.8 Hz, 1H), 3.63 (s, 6H). 19F NMR (282 MHz, CDCl3) δ -77.82. 13C NMR (75 MHz, CDCl3) δ 160.0 (C), 141.2 (C), 130.1 (CH), 119.6 (d, J = 321.1 Hz), 119.6 (CH), 113.6 (CH), 113.2 (CH), 62.3 (CH), 55.4 (CH3). HRMS [ESI]: m/z calculated for C16H17F3NO4S [M+H]+: 376.0825, found 376.0825. NHTf Me Me 1i Selected spectra: Chapter III 255 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 256 1 H NMR (500 MHz, CDCl3) DEPT-135 1 3 C NMR (126 MHz, CDCl3) Selected spectra: Chapter III 257 HSQC spectrum (CDCl3) Selected spectra: Chapter III 258 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 259 5cb N Tf n Bu nBu Cl 1 H NMR (500 MHz, CDCl3) DEPT-135 1 3 C NMR (126 MHz, CDCl3) Selected spectra: Chapter III 260 1 H NMR (500 MHz, CDCl3) DEPT-135 1 3 C NMR (126 MHz, CDCl3) 5db N Tf n Bu nBu CF3 Selected spectra: Chapter III 261 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 262 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 263 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 264 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 271 1 H NMR (500 MHz, CDCl3) DEPT-135 1 3 C NMR (126 MHz, CDCl3) Selected spectra: Chapter III 272 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 273 1 H NMR (500 MHz, CDCl3) DEPT-135 1 3 C NMR (126 MHz, CDCl3) Selected spectra: Chapter III 274 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 275 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 276 7cb NTf OMe n Bu nBu 1 H NMR (500 MHz, CDCl3) DEPT-135 1 3 C NMR (126 MHz, CDCl3) Selected spectra: Chapter III 277 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 278 7eb NTf Me n Bu nBu Me Et T = 50 °C 1 H NMR (500 MHz, CDCl3) DEPT-135 1 3 C NMR (126 MHz, CDCl3) Selected spectra: Chapter III 279 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) Selected spectra: Chapter III 280 1 H NMR (300 MHz, CDCl3) DEPT-135 1 3 C NMR (75 MHz, CDCl3) List of publications List of publications 289 Title Palladium - Catalyzed, Enantioselective Formal Cycloaddition between Benzyltriflamides and Allenes: Straightforward Access to Enantioenriched Isoquinolines Authors Xandro Vidal, José Luis Mascareñas and Moisés Gulías Year 201 9 Journal Journal of the American Chemical Society ( JACS ) Volume, pages… 141 , 1862 - 1866 Impact Factor 14. 695 PhD student contribution All the experimental data (yields and enantiomeric ratios) and synthesis and characterization of all the compounds. Copyright Open - access article (ACS AutorChoice article with CC - BY - NC - ND ) Title Assembly of Tetrahydroquinolines and 2 - Benzazepines by Pd - Catalyzed Cycloadditions Involving the Activation of C(sp3)–H Bonds Authors Xandro Vidal, José Luis Mascareñas and Moisés Gulías Year 20 21 Journal Organic Letters Volume, pages… 23, 5323 - 5328 Impact Factor 6.005 PhD student contribution All the experimental data (yields and enantiomeric ratios) and synthesis and characterization of all the compounds. Copyright Open - access article (ACS AutorChoice article with CC - BY ) Don’t regret anything you do because in the end it makes you who you are -Closer To The Edge, 30STM During this PhD thesis we have developed several palladiumcatalyzed formal cycloadditions involving the activation of both C(sp²)–H and C(sp³)–H bonds, using allenes as cycloaddition partners. These transformations allow to access highly valuable azaheterocyclic skeletons from simple starting materials in good yields. Moreover, asymmetric versions of these reactions have also been developed, making possible to achieve the corresponding cycloadducts with high enantioselectivities.