Rh(III)-catalyzed annulations based on C-H activation. Sustainable synthesis of carbo- and heterocycles

Centro Singular de investigación en Química Biológica y Materiales Moleculares Rh(III)-catalyzed annulations based on C-H activation. Sustainable synthesis of carboand heterocycles. Memoria que, para optar al grado de Doctor en Química por la Universidad de Santiago de Compostela, presenta Andrés Seoane Fernández Santiago de Compostela, abril 2016 D. JOSÉ LUIS MASCAREÑAS CID, CATEDRÁTICO DEL DEPARTAMENTO DE QUÍMICA ORGÁNICA DE LA UNIVERSIDAD DE SANTIAGO DE COMPOSTELA Y D. MOISÉS GULÍAS COSTA, PROFESOR AYUDANTE DOCTOR DEL DEPARTAMENTO DE QUÍMICA ORGÁNICA DE LA UNIVERSIDAD DE SANTIAGO DE COMPOSTELA, Fdo.: José Luis Mascareñas Cid Fdo.: Moisés Gulías Costa CERTIFICAN: Que la memoria adjunta, titulada Rh(III)- catalyzed annulations based on C-H activation. Sustainable synthesis of carboand heterocycles, que para optar al grado de Doctor en química presenta Don Andrés Seoane Fernández, ha sido realizada bajo nuestra dirección en los laboratorios del Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS) de la Universidad de Santiago de Compostela. Considerando que constituye trabajo de tesis, autorizamos su presentación en la Universidad de Santiago de Compostela. Y para que así conste, se expide el presente certificado en Santiago de Compostela, a 28 de abril de 2016. -We’ll Never Survive. - Nonsense. You’re only saying that because no one ever has. William Goldman, The Princess Bride. Aknowledgements. En primer lugar me gustaría agradecer a mis directores de tesis, José Luis y el Moisés por haber confiado en mí dándome la oportunidad de dedicar casi 5 años a un proyecto apasionante dentro de un grupo increíble. Esta tesis ha llegado a buen puerto gracias a su apoyo y enseñanzas, que han permitido que el mindundi que entró, salga con más conocimiento, confianza y cariño por la química. Espero haber hecho justicia a la confianza depositada que depositaron en mí. También me gustaría agradecer a mi familia el apoyo que me han dado. A mi madre por facilitarme la decisión sobre el camino que a seguir; a mi hermano, que, pese a ser más joven, es un gran ejemplo y que, además me ayudó enormemente a ejercitar el cerebro mientras encontraba nuevas maneras de meterme con él y a mi padre que, ya desde pequeño, aguantaba mis incansables preguntas alentando mi curiosidad y encendiendo en mí la chispa de la ciencia. Agradezco también a Susana que aprovechó esa chispa y la avivó gracias a unas clases que siempre me maravillaron y también a Mar, que me que consiguió que la química se convirtiese en mi primera opción y sin la cual no estaría escribiendo esto. Y, por supuesto, al grupo del Prof. Ricardo Alonso con el que me inicié en el mundo investigación. Tampoco puedo dejar atrás a mis compañeros del grupo que consiguieron que el desarrollo de esta tesis, que a muchos les parece un camino interminable y lleno de obstáculos, se convirtiera en una experiencia excepcional que repetiría sin dudar. Primero, a los que me recibieron el primer año haciéndome sentir como en casa: A Helio, que estaba riéndose siempre de fondo; a Luci y su infinita paciencia; Isaac, bueno, una coma más; a Lara, por las frases lapidarias y a Cris, por ser de las pocas que recuerda lo tímido que puedo llegar a ser. Mateo, muchas gracias por poderme hacerme sentir orgulloso de la locura. Además quiero agradecer María Rey, que además de aligerarnos trabajo me mostró cómo disfruta a pesar de cada segundo de la vida sea un infierno y que las personas normales también leen cómics. No me puedo olvidar de Fernando, Paloma, Marisel, Sergio, Marta que fueron de gran ayuda durante, al menos, gran parte de estos años. Noe, muchísimas gracias, no sólo por los proyectos compartidos si no por ser un ejemplo y por lo mucho que me enseñaste, no sólo en sobre química si no sobre cómo se puede sobrevivir en este mundo con una sonrisa en la cara. En segundo lugar, a los que llegaron detrás: Ronald, siempre dispuesto a aportar un dato sobre lo que sea; Noelia 2, con la que he compartido proyecto en la mayor parte de ésta tesis y por lo que me siento enormemente agradecido. Muchas gracias también a Iván, porque el laboratorio sin él habría sido enormemente aburrido; David, que fue mi primer pupilo y con el que aprendí mucho; Jaime, que desgraciadamente para los demás, entiende el humor de una forma muy parecida a la mía. Agradecer también a Felipe, un gran Compañero y a Cagiao, que siempre tiene tiempo para apuntarse a un plan. No me puedo olvidar (aunque casi lo haya hecho) de Cezar y Xabi con los que compartí el último proyecto de la tesis. Aunque por falta de espacio no les puedo dedicar las palabras que se merecen, también me gustaría agradecer a Jéssica, Natalia, Suso, Soraya, María Tomás, Rebeca, Paolo, Miguel, Tasneem, Jose, Jorge, Sandra y demás compañeros de edificio. Esta tesis también habría sido imposible sin la estimable ayuda de Ramón y Mentxa y el resto de técnicos de la USC que han hecho una parte crucial del trabajo presentado aquí. Me alegro también de poder haber completado esta etapa de mi vida manteniendo relación con algunos compañeros a los que conocí allá por primero de carrera. Iria… casi 10 años desde que empezamos y siempre un apoyo con el que contar y a Tito y María, descubrimiento tardío pero enormemente relevante en los años de doctorado. Me gustaría agradecer también a la Fundación Barrié por darme la oportunidad de realizar una estancia predoctoral en el grupo del Prof. Rueping. I would also like to acknowledge Prof. Rueping for giving me the chance of doing a research stay in his group and to Ele, Laura, Thomas, Patricia, Aleksandra, Quentin, Anthony and Roman for treating mi so well and making me miss Aachen. A pesar de todo el apoyo recibido en el grupo, esta tesis habría sido más difícil sin todos aquellos que me permitieron desconectar al salir del laboratorio. Fundamentalmente el grupo Montoto/Ex San Agustinos: Viri, Ada, Pot, Wences, Colo, Judoka, Ildara, Javi, Soso, Kar y María que convirtieron la mayoría de los martes y muchos otros días en una experiencia digna de ser vivida y llena de zorcilla. A Colo le agradezco nuevamente por aguantarme como compañero de piso durante la mayor parte de éstos años y por las eternas divagaciones sobre el mundo en general y la ciencia en particular. También agradezco a todas las personas que no he podido nombrar, ya sea por falta de espacio o por un olvido imperdonable. Espero que perdonéis la omisión. Y por último a todo aquel que lea algo de esta memoria, aunque sea un párrafo, gracias por hacer que todo el trabajo que hay detrás no caiga en el olvido. A mi familia y amigos. Abbreviations and acronyms. vi TFA Trifluoroacetic acid TFAc Trifluoroacetyl THF Tetrahydrofuran TMEDA N,N,N’,N’- tetramethylethylenediamine TMS Trimethylsilyl TS Transition state Ts 4-Methylbenzenesulfonyl . CHAPTER I: Introduction. Introduction. 3 1Organic Synthesis: Applications and challenges. 1.1 Introduction. Defined as “The branch of science concerned with the substances of which matter is composed, the investigation of their properties and reactions, and the use of such reactions to form new substances”,1 Chemistry is, arguably, one of the disciplines that have contributed the most to the well-being of mankind. Since the discovery of the fire until age of plastics, humans have modified molecules at their wish for their own benefit. By doing so, the art of creating and breaking chemical bonds has evolved, allowing us to advance as society to become what we currently are. This is the reason why the study of chemistry is of vital importance to pave the road towards a better world. Among the many branches of chemistry, Organic Synthesis has gained its privileged place by its own merits. Its quest started on the beginning of the XIX century, when chemists found out that there was no need of any “vital force” in order to create naturally occurring molecules. The success of Organic Synthesis as main area of chemistry arises from the fact that, starting from a relatively small variety of “bricks” (fundamentally C, H, O, N, P, S and halogens) allows the obtention of a virtually infinite number of structures with varying properties. By using this tool we are able; not only to mimic nature, but to create our own molecules that, diverging from our environment, possess uses in medicine, biology, cosmetics, food industry and much more. In fact, from the moment we wake up to when we go to sleep, almost every object we lay our eyes on has been created or modified by using Organic Chemistry to make our existence easier. One of the basic needs of the modern society and, specifically, chemical industry is the availability of relatively big amounts of diverse natural or synthetic molecules with divergent properties, which can be studied and used to solve problems encountered in our daily lives. To be able to obtain such quantities, it is mandatory to discover methods for the synthesis and isolation of these products. Moreover, organic compounds present high diversity and structural complexity, which leads to the necessity of highly selective transformations that can incorporate different motifs in the presence of various functional groups. During the past centuries, synthetic chemists have discovered and developed new methods that have been used to synthesize extremely complex molecules.2 1 "Chemistry, n." OED Online. Oxford University Press, December 2015. 2 (a) Nicoulaou, K. C.; Sorensen, E. J. Classics in total synthesis: Targets, strategies, methods Ed. WileyVCH, 1996. (b) Nicoulaou, K. C.; Sorensen, E. J. Classics in total synthesis II: More targets, strategies, methods Ed. Wiley-VCH, 2003. (c) Nicoulaou, K. C.; Chen, J. S. Classics in total synthesis III: Further targets, strategies, methods Ed. Wiley-VCH, 2011. Introduction. 4 Fig 1. Example of classic total syntheses and their number of steps and total yield. Despite these achievements are certainly impressing, they are somehow stained because, until not so long ago, chemists only purchased the synthesis of a complex molecule without stopping too much to evaluate the details of its obtention. Nowadays this vision has changed towards the quest for short and efficient synthesis.3 1.2. Requirements for modern Organic Chemistry. As it has been mentioned before, Organic Synthesis has moved from the purchase of the synthesis of a given molecule to focus on the route needed for achieving that goal. This new vision has given rise to several new concepts:4 Atom economy, which is the efficiency of a chemical transformation in terms of the maximizing the incorporation of the atoms present in the reactants into the final product;5 redox economy meaning the use as few redox steps as possible in the synthetic conquest of a target compound;6 step economy, that refers to the minimization of transformations performed in an synthesis;7 pot economy meaning the use the minimum amount of workups and purification steps as possible8 and green chemistry which 3 Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657. 4 Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010. 5(a)Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259. (c) Wender, P. A. Tetrahedron 2013, 69, 7529. 6 Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chemie - Int. Ed. 2009, 48, 2854. 7(a)Wender, P. A.; Croatt,M. P.; Witulski, B. Tetrahedron 2006, 62,7505. (b)Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40. (c) Wender, P. A.; Miller, B. L. Nature 2009, 460,197. 8 Hayashi, Y. Chem. Sci. 2016, 7, 866. Introduction. 5 includes, but is not limited to, minimization of waste and the use of toxic or hazardous chemicals9. 2– Organometallic Chemistry: The hammer in the reaction development toolbox. One way of lowering the amount of steps needed for a total synthesis is the use of new reactions leading to different disconnections. In order to fulfill this goal, it is needed to find novel reactivities that do not suffer the limitations associated to carbon-based Organic Chemistry. This is why, from the late XIX century, chemists have been working with metals to expand the amount of transformations available. During the dawn of the so-called organometallic chemistry, the scientific community paid much of their attention into main group metals such as Li, Mg or B10. However, from the half of the XX century, the development of reactions catalyzed with metals such as Pd, Ni, Rh or Ru among other has given rise of a very productive era of transition metal-catalyzed chemistry, widening the scope of transformations available for the Synthetic Chemist. The main advantages of employing these reagents stem from their rich coordination chemistry and the possibility of changing their oxidation states, which result in mechanistic pathways with lower activation energies. 11 While organometallic stoichiometric reactions have been used from the very beginning of this chemistry, it was soon realized that translating it into synthetically useful contexts would require developing catalytic transformations.12 In this way, with small amounts of organometallic precursor it is possible to transform large amounts of reactants. 2.2. Transition metal-catalyzed cycloadditions. One of the fields in which transition metal catalysis has proven particularly useful is in the cycloaddition chemistry. According to the IUPAC gold book, cycloadditions are reactions in which two or more unsaturated molecules (or parts of the same molecule) are combined with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity.13 The most representative example of this kind of transformations is the Diels-Alder, a (4+2) reaction between a diene and a dienophile that generates cyclohexenes with a hundred percent atom economy.14 9 Anastas P.T.; Warner, J.C. Green chemistry: Theory and practice, Ed. Oxford university press, 1998. 10 Astruc, D. Organometallic chemistry and catalysis, Springer-Verlag, 2007. 11 (a) Hegedus, L.S. Transition metals in the synthesis of complex organic molecules, Ed. University Science of books, 1994. (b) Crabtree, R.H. The organometallic chemistry of transition metals, Ed. Wiley, 2001. 12 Sabatier, P. Catalysis in organic chemistry, D. Van Nostrand Company, 1922. 13 McNaught, A. D.; Wilkinson, A. IUPAC. compendium of chemical terminology 2nd Ed. (The “gold” book), Oxford, 1997. XML on-line corrected version: http://goldbook.iupac.org (2006-) created by Nic, M.; Jirat, J.; Kosata, B. updates compiled by Jenkins, A. 14 Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460, 98. Introduction. 6 Scheme 1. Model of the Diels-Alder reaction. These cycloadditions, work under the limitations of Woodward and Hoffmann rules, which result on the need of specific substitution so the frontier orbitals could overlap keeping orbital symmetry during the process.15 These structural requirements limit the scope of these reactions to specific substrates that are appropriately matched from the electronic point of view. One way of improving the scope of cycloadditions consists on the use of light or Lewis acids as promoters, although, they only work with substrates with strategically located substituents.16 Transition metals can be used to circumvent these limitations since they operate via different mechanisms, resulting in reactions that could not be obtained by any other means17 such as in this example by the group of Paul Wender, where they perform a Nickelcatalyzed (4+4) cycloaddition, otherwise forbidden under thermal conditions.18 Scheme 2. Paul Wender’s Nickel-catalyzed (4+4) cycloaddition. The use of transition metal complexes as promoters in this chemistry allows, not only to perform classically forbidden transformations, but also to do it under milder conditions and, in some cases, achieving highly enantioselective transformations such as demonstrated in our research group with allenamides and gold catalysis.19 Scheme 3. Enantioselective gold (I) catalyzed (4+2) cycloaddition. 15 (a) Woodward, R.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87, 395. (b) Woodward, R.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87, 2046. (c) Woodward, R.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87, 2511. 16 Carruthers, W. Cycloaddition reactions in organic synthesis, Pergamon press, 1990. Kobayashi, S.; Jørgensen, K. A. Cycloaddition reactions in organic synthesis, Ed. Wiley-VCH, 2001. 17 Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. 18 Wender, P. A.; Ihle, N. C. J. Am.. Chem. Soc. 1986, 8, 4678. 19 Francos, J.; Grande-Carmona, F.; Faustino, H.; Iglesias-Sigüenza, J.; Díez, E.; Alonso, I.; Fernández, R.; Lassaletta, J. M.; López, F.; Mascareñas, J. L. J. Am. Chem. Soc. 2012, 134, 14322. Introduction. 7 Another advantage of the use of transition metals as catalysts, is that it is also possible to perform multicomponent annulations in a single step, as can be seen in a recent example from our research group.20 Scheme 4. Rh (I)-catalyzed (3+2+2) cycloaddition. Most of these transition metal catalyzed cycloadditions involve the generation of metallacycles resulting from the oxidation of the metal centre and a subsequent reductive elimination to regenerate the active catalyst as can be seen in this other example from our research group.21 Scheme 5. (2+2) cycloaddition occurring via metallacycle. This type of metal-catalyzed annulations are extremely attractive and have led to many important discoveries in the last decades. However, since these reactions rely on the transformation of pi into sigma bonds, they require the presence of functionalized, unsaturated precursors and therefore, in many cases, the preparation of the precursors involve a relatively large number of steps. 2.3. Cross coupling reactions. While metal-catalyzed cycloadditions like those shown above are extremely important reactions, transition metal catalysis has been also extensively used for many other transformations, prominently cross coupling reactions. The Mizoroki-Heck reaction is one elegant example of this approach22 which led Richard F. Heck to be awarded with the Nobel Prize in Chemistry in the year 2010.23 20 Araya, M.; Gulías, M.; Fernández, I.; Bhargava, G.; Castedo, L.; Mascareñas, J. L.; López, F. Chem. Eur. J. 2014, 20, 10255. 21 Gulías, M.; Collado, A.; Trillo, B.; López, F.; Oñate, E.; Esteruelas, M. A.; Mascareñas, J. L. J. Am. Chem. Soc. 2011, 133, 7660. 22 (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581 (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320. 23 http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2010/ Introduction. 8 Scheme 6. The Heck reaction. One of the advantages of the use of transition metals is the possibility to tune their reactivity by adding different ligands to improve the properties of the metallic centre.11a For instance, Heck demonstrated that the range of reactive alkenes of his reaction could be expanded by adding phosphines to the reaction media.24 Scheme 7. Use of phosphines as ligands to improve the Heck reaction. From the second half of the XX century, cross coupling reactions have been gaining relevance for the construction of molecules, being nowadays widely used in industry.25 Indeed, the well-known couplings developed by Suzuki and Negishi, which were also awarded with the Nobel Prize in chemistry in 2010, can be considered among the most relevant metalcatalyzed reactions discovered so far. Scheme 8. Metal-catalyzed cross coupling reaction. The mechanism of these reactions often starts with an oxidative addition of the metal to the C-X bond (being X a halogen or pseudohalogen) followed by the transmetallation with another metal-containing species (such as a borate in the case of the Suzuki coupling or zincate in the case of a Negishi coupling). A final reductive elimination joins the two hydrocarbons and regenerates the catalyst.26 24 Dieck, H. A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 1133. 25 (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177. (b) Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H. Transition metal catalysis in the pharmaceutical industry Ed. John Wiley and sons, 2012. 26 (a) De Mejiere, A.; Diederich, F. Metal-catalyzed cross coupling reactions Ed. Wiley-VCH, 2004. Introduction. 9 Scheme 9. Classic mechanistic explanation of Pd catalyzed cross-couplings. After the initial discovery of such processes, the scientific community demonstrated that the coupling reactions could be carried out using other organometallic compounds (such as magnesium in the Kumada coupling,27 tin in the Stille coupling28 or silicon in the Hiyama coupling29) and remarkably reducing the catalyst loadings; therefore, turning them into a tool which has been used in uncountable synthetic applications.30 In addition to the above reactions, the Sonogashira coupling provides an excellent way of attaching alkynes to different substrates. For instance, Thomas and co-workers at Abbot demonstrated the utility of this transformation in the kilogram-scale synthesis of 1, an intermediate of Fenleuton a 5lipoxigenase inhibitor.31 Scheme 10. Kilogram synthesis of Fenleuton intermediate 1. While the above reactions were designed for the construction of carbon-carbon bonds, it is also possible to make carbon-nitrogen bonds using the well-known Buchwald-Hartwig amination,32 or introduce other heteroatoms such as sulfur or oxygen33 starting from 27 (a) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc. Chem. Commun. 1972, No. 3, 144a. (b) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374. 28 Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. 29 Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. 30 Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chemie. Int. Ed. 2005, 44, 4442. 31 Thomas, A. V.; Patel, H. H.; Reif, L. A.; Chemburkar, S. R.; Sawick, D. P.; Shelat, B.; Balmer, M. K.; Patel, R. R. Org. ProcessRes.Dev. 1997, 1, 294. 32 Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. Introduction. 16 Fig 2. Diversity of directing groups. While in most cases the directing groups have been used for functionalizing aryl C-H bonds in ortho positions, there have been also elegant approaches that allow meta52 or even para53 functionalizations. 3.3 Mechanisms for C-H activation.54 C-H functionalization reactions may operate under different activation modes that are strongly dependant on the choice of the metal catalyst and the different additives employed. The different reaction pathways can be summarized into the following categories: 3.3.1 Oxidative addition. Oxidative addition reactions usually occur with low-valent, electron-rich transition metals and they are facilitated when they are coordinatively unsaturated. In this mechanism, the metal “inserts” into the C-H bond, raising its oxidation state by two units.37d Scheme 23. Mechanism of an oxidative addition into a C-H bond. This mechanism of activation is the one proposed in this work by Hartwig where they achieve the meta-selective borylation of anilines.55 52 Phipps, R. J.; Gaunt, M. J. Science, 2009, 323, 1953. 53 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. 54 For reviews on the different modes of C-H activation see: (a) Labinger, J. a; Bercaw, J. E. Nature 2002, 417, 507. (b) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118. (c) Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010, 110, 749. (d) Editor, G.; Mcgrady, J.; Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-bahamonde, A. I.; Balcells, D.; Moles, P.; Blakemore, J. D.; Raynaud, C.; Brudvig, G. W.; Crabtree, R. H.; Eisenstein, O.; Trans, D. Dalt. Trans. 2009, 5820. 37d Bergman, R. G. Nature 2007, 446, 391. 55 Larsen, M. A.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4287. Introduction. 17 Scheme 24. Example of C-H activation via oxidative addition. In this reaction an initial dissociation of cyclooctadiene ligand from the Ir (I) complex unsaturates the metal centre, which allows the oxidative addition into the C-H bond to generate an Ir (III) intermediate. This species evolves upon reductive elimination leading to the borylated picoline and the reduced catalyst, which undergoes transmetallation to reenter the cycle. 3.3.2 Sigma bond metathesis. A different way of achieving metallation of C-H bonds, mainly promoted by early transition metals with d0 configuration like scandium, lanthanides or actinides and, in some cases, other metals such as Ru,56 relies on a concerted exchange of a metal-ligand sigma bond with one carbon-hydrogen bond of an incoming substrate in a formal [2σ + 2σ] transition state structure.57 Scheme 25. Mechanism of the σ bond metathesis. The group of Hou reported a rare earth-based C-H addition of pyridines to olefins that proceeded via sigma bond metathesis. The mechanism starts with an initial C-H activation followed migratory insertion generating a metallacyclic intermediate II which reacts with another molecule of pyridine by a second metathesis that regenerates the catalyst and delivers the proton to the C-M bond.58 56 Hartwig, J. F.; Bhandari, S.; Rablen, P. R. J. Am. Chem. Soc. 1994, 116, 1839. 57 Waterman, R. Organometallics 2013, 32, 7249. 55a Labinger, J. a; Bercaw, J. E. Nature 2002, 417, 507. 58 Guan, B. T.; Hou, Z. J. Am. Chem. Soc. 2011, 133, 18086. Introduction. 18 Scheme 26. Example of C-H activation via σ bond metathesis. 3.3.3 Electrophilic substitution. When the metal is in a higher oxidation state and the substrate is relatively electron-rich, another metallation mode can take place. In this case, the nucleophilic hydrocarbon attacks the metal generating a delocalized cationic species (Wheland intermediate, in the case of an aromatic system) that now loses the acidic proton generating the metallated intermediate.55a Scheme 27. Mechanism of the electrophilic metallation. This mechanism is invoked in the arylation of naphthalene performed by the group of Melanie Sanford.59 The observation of a KIE value of 1.0 ± 0.1 was interpreted in terms of the cleavage of the carbon-hydrogen bond not being involved in the turnover-limiting step. This result is consistent with an electrophilic palladation followed by a fast cleavage of the acidic C-H bond from the Wheland intermediate. 59 Hickman, A. J.; Sanford, M. S. ACS Catal. 2011, 1, 170. Introduction. 19 Scheme 28. Pd-catalyzed arylation of naphthalene. 3.3.4 Concerted metallation-deprotonation (CMD). Closely related to the electrophilic substitution mechanism is the CMD process. Both mechanisms have been often mistaken and, in fact, CMD was proposed in order to justify some experimental data that electrophilic substitution could not fully explain. In the latter, the metal centre weakens the C-H bond while a base, generally coordinated to the metal, abstracts the proton in a concerted manifold. 55b,60 Scheme 29. Mechanism of the CMD. Recently, the group of Larrosa, described this mode of activation in his Ru (II)- catalyzed arylation of fluoroarenes with aryl halides. In their publication they also study this pathway by DFT calculations, which helped them to propose a mechanism. Their hypothesis starts with the in situ formation of the cationic species I which undergoes the CMD into the fluoroarene leading to complex II. This intermediate arylruthenium species undergoes a 55b Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118 60 Ackermann, L. Chem. Rev. 2011, 111, 1315. Introduction. 20 formal oxidative addition/reductive elimination step with the aryl halide and complex III, which, after halide abstraction regenerates I closing the cycle.61 Scheme 30. Ru-catalyzed arylation of fluoroarenes. 3.4. Rhodium (III)-catalyzed C-H functionalizations. In comparison to the widely used nickel, platinum and palladium catalysts; Rhodium presents exciting divergent properties for catalytic processes involving C-H activations.62 In particular, Rhodium has the ability to switch easily between oxidation states such as Rh (III) and Rh (IV) or even Rh (V) which opens a window for new reactivities. It also allows different coordination geometries, providing versatility in terms of ligand variability.63 A pioneering example on the use of Rh (III) to activate C-H bonds was demonstrated by Maitlis in 1987, presumably operating via σ bond metathesis,64 and, later by Davies employing a pentamethylcyclopentadienyl Rhodium dimer.65 61 Simonetti, M.; Perry, G. J. P.; Cambeiro, X. C.; Juliá, F.; Arokianathar, J. N.; Larrosa, I. J. Am. Chem. Soc. 2016, 138, 3596. 62 Evans, A. Modern Rhodium-catalyzed organic reactions, Ed. Wiley-VCH, 2005. 63 Housecroft, C. E.; Sharpe, A. G. Inorganic chemistry 2º Ed. Ed. Pearson Prentice Hall, 2006. 64 Kisenyi, J.M.; Sunley, G. J.; Cabeza, J. A.; Smith, A. J.; Adams, H.; Salt, N. J.; Maitlis, P. M. J. Chem. Soc., Dalton Trans., 1987, 2459. 65 Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton, S. T.; Russell, D. R. Dalt. Trans. 2003, 2, 4132. Introduction. 21 Scheme 31. First example of C-H activation by [Cp*RhCl2]2. Following the pioneering work of Miura, which demonstrated that a Cp*Rh complex could be an efficient catalyst for C-H functionalization,66 many other examples have been reported in the literature.67 For instance, the group of Glorius developed an olefination of acetilanilides using styrenes and a silver salt to activate the Rhodium (III) catalyst by abstracting a chlorine atom from the active catalytic complex.68 Scheme 32. Rh (III)-catalyzed C-H olefination. The most widely employed precatalyst in this chemistry is [Cp*RhCl2]2 which dissociates in presence of external ligands or additives to form the active monomers that perform the C-H activation step. The presence of the Cp* ligand appears to be crucial for the reactivity which can be explained in terms of the stabilization of the high oxidation states of the rhodium.69 After the metallation of the organic substrate, the complex adopts a characteristic piano stool configuration as shown in Figure 3 where phenylpyridine is activated and one of the chlorine atoms has been replaced by iodine to facilitate crystallization.70 66 Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. 67 (a) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212. (b) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. 68 Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982. 69 Maitlis, P. M. Acc. Chem. Res. 1978, 11, 301. 70 Luo, C. Z.; Gandeepan, P.; Jayakumar, J.; Parthasarathy, K.; Chang, Y. W.; Cheng, C. H. Chem. Eur. J. 2013, 19, 14181. Introduction. 22 Fig 3. Crystal structure of the Cp*Rh(ppy)I complex. The mode of C-H bond activation by Cp*Rh (III) complexes, particularly for arenes, has been mainly described as concerted metallation-deprotonation.71 4–Annulations based on C-H activation, an interesting match. 4.2. General overview. As it has been explained before, one of the most prominent ways of performing successful CH functionalizations consists on the employment of directing groups.40 However, despite the considerable advantages of using such groups for achieving selectivity, there is still one major drawback, which is that, in most of the cases, the directing group is only used as coordinating motif and it is not needed in the final structure. This means that additional steps are needed for the inclusion of such moiety in the backbone and for its subsequent elimination after the reaction. The use of transient directing groups avoids the extra steps needed for their elimination72 but they still generate waste and present low atom economy. However, given the fact that some directing groups can form metallacyciclic species after the C-H activation, it is possible to envision the use of such intermediates for similar transformations than those arising from already formed metallacycles, as the cycloadditions seen before. In this way, at least some atoms of the directing group will become part of the final cycle and therefore, it is not wasted. In addition, this approach provides a very appealing way of making reactive metallacycles that does not require the presence of unsaturations in the parent substrate. These reactions would imply an important increase in the molecular complexity and could become a very interesting and atom economical alternative to build cyclic molecules. This methodology would also open a door for a straightforward access to a wide range of heterocycles, which are very common skeletons present in countless naturally occurring 40 Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107. 71 Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics 2009, 28, 3492. 72 Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle, K. M.; Yu, J.-Q. Nature 2015, 519, 334. Introduction. 23 and/or biologically active products73, as well as molecules relevant for materials science such as OLEDS.74 While one could be tempted to include this approach to cyclic skeletons among the category of formal cycloadditions, the name oxidative annulation might be more suitable, owing to the oxidation state of the final product in comparison with the starting materials and the IUPAC gold book definition of annulation: “A transformation involving fusion of a new ring to a molecule via two new bonds”.13 Scheme 33. Oxidative annulations in contrast with cycloaddition and directed C-H functionalization. 4.2. General mechanistic aspects of oxidative annulations. The most common mechanism of these transformations involves the formation of the metallacyclic species which, after migratory insertion into an unsaturated partner generates a new metallacycle that, upon reductive elimination leads to the final molecule. The metal complex (usually from Pd, Rh, Ru or Ir) normally needs an additional reoxidation step in order to complete the catalytic cycle. 13 McNaught, A. D.; Wilkinson, A. IUPAC. compendium of chemical terminology 2nd Ed. (The “gold” book), Oxford, 1997. XML on-line corrected version: http://goldbook.iupac.org (2006-) created by Nic, M.; Jirat, J.; Kosata, B. updates compiled by Jenkins, A. 73 (a) Majumdar, K. C.; Chattopadyay, S. K. Heterocycles in natural product synthesis Ed. Wiley-VCH, 2011. (b) Lamberth, C.; Dinges, J. Bioactive heterocyclic compound classes: Pharmaceuticals Ed. Wiley-VCH, 2012. 74 Chen, D.; Su, S.-J.; Cao, Y. J. Mater. Chem. C 2014, 2, 9565. Introduction. 24 Scheme 34. General mechanism of oxidative annulations. There is also the possibility that the directing group is not included in the final cycle if two consecutive C-H activations occur however in this latter case, the utility of the directing group would be just as auxiliary. 4.3. Some examples of oxidative annulations. Oxidative annulations can be sorted according to different criteria. Herein we have chosen a classification based on the number of atoms provided by the unsaturated reaction partner. We have selected only a few representative examples among the vast number of reactions that have been described in recent years.75 4.3.1 (n+1) oxidative annulations. In these reactions, the coupling partner acts as a one-carbon surrogate. The most common reagent for this purpose is carbon monoxide. An example of the use of this gas is sown in scheme 35.76 Scheme 35. (3+1) Oxidative annulations of aliphatic amines with CO. A key element for the success of this reaction is the use of highly hindered amines unable to form inactive palladium diamine species. In the same communication the authors describe the isolation of a trimeric palladium complex formed prior to the carbonylation, after the CH activation. It is also possible to use other molecules to act as one-atom donors such as diazo compounds, since they can generate carbenes by the loss of a nitrogen molecule such as can be seen in the 75 Gulías, M.; Mascareñas, J. L. Angew. Chem. Int. Ed. 2016, in Press. 76 McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129. Introduction. 25 following example involving a Rh (III)-catalyzed reaction between imidamides and diazocompounds for the synthesis of indoles.77 Scheme 36. Oxidative annulations of imidamides to diazocompounds. In this case, the last step of the reaction involves a migratory insertion instead of the more standard reductive elimination so the reaction can be carried out in the absence of external oxidants. Scheme 37. (4+1) Oxidative annulations of imidamides with diazocompounds. 4.3.2 (n+2) oxidative annulations. In these transformations, the reaction partners are usually compounds featuring double or triple carbon-carbon bonds. Frequently, these transformations present a higher catalytic turnover when using rhodium (III) instead of palladium, probably due to the easier insertion of alkynes.68a The seminal work of Miura in oxidative annulations of benzoic67 acids opened the door for these reactions usually performed with the standard Rh (III) complexes although it has been later shown that it is possible to use other transition metals such as Ru78 or Co.79 77 Qi, Z.; Yu, S.; Li, X. Org. Lett. 2016, 18, 700. 68a Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212. 67 Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. 78 (a) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177. (b) Deponti, M.; Kozhushkov, S. I.; Yufit, D. S.; Ackermann, L. Org. Biomol. Chem. 2013, 142. Chapter II. 33 1– C-H functionalization of benzamides. 1.1 C-H functionalization of benzamides. Benzamides, owing to the presence of an amide directing group, are able to participate in a wide range of C-H functionalization reactions. In fact, a great variety of transformations has been described using different metal complexes to introduce diverse functional groups.40 For instance, Sukbok Chang and co-workers developed an iridium-catalyzed ortho-amination of benzamides. In their communication, they report the formation of a 5-membered metallacycle coordinated to the azide which would form a nitrene intermediate that, upon reductive elimination, generates the amidated product.85 Scheme 45. Ir (III)-catalyzed C-H amidation of benzamides. Also, the group of Prof. Jin-Quan Yu has demonstrated the importance of an appropriate choice of the directing group by using an electronically tuned pentafluorophenyl benzamide to carry out several Palladium catalyzed reactions.86 One example of this directing group is the palladium-catalyzed borylation of arenes.87 40 Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107. 85 Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang, S. J. Am. Chem. Soc. 2013, 135, 12861. 86 (a) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. (b) Yoo, E. J.; Ma, S.; Mei, T.; Chan, K. S. L.; Yu, J. J. Am. Chem. Soc. 2011, 133, 7652. (c) He, J.; Shigenari, T.; Yu, J.-Q. Angew. Chemie Int. Ed. 2015, 54, 6545. 87 Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 134. Chapter II. 34 Scheme 46. C-H borylation of pentafluorophenyl benzamides. For these reactions they report the use of the very electron poor pentafluorophenyl benzamide as critical for the success of the reactions. Probably due to the delocalization of the negative charge which makes it behave more as an L ligand while still keeping its coordinating abilities.88 Rhodium catalysis has been predominantly used with this motif. An elegant example reported by Glorius and coworkers describe the Rhodium-catalyzed cross dehydrogenative coupling of benzamides and simple arenes with hexabromobenzene as additive.89 Although crucial for the success of the reaction, the role of the additive is still unclear. However, it was suggested that it acts as an oxidant. This is due to the fact that pentafluorobenzene was isolated from the reaction mixture, probably arising from an oxidative addition of the reduced Rh (I) catalyst to the Ar-Br bond followed by protodemetallation. It is also supposed to be somehow favoring the undirected C-H activation of the simple arene. Scheme 47. Rh (III)-catalyzed C-H cross dehydrogenative coupling of benzamides with arenes. Amide-directed C-H functionalizations can be also applied to vinylic substrates. For instance, the group of Glorius was also able to carry out a similar arylation to the above one, but using acrylamides instead of benzamides.90 Scheme 48. Rh (III)-catalyzed C-H cross dehydrogenative coupling of acrylamides with arenes. 88 Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J. Q. Angew. Chemie. Int. Ed. 2011, 50, 9081. 89 Wencel-Delord, J.; Nimphius, C.; Wang, H.; Glorius, F. Angew. Chemie - Int. Ed. 2012, 51, 13001. 90 Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F. Chem. Asian J. 2012, 7, 1208. Chapter II. 35 1.2 Oxidative annulation of benzamides. The first report of the use of benzamides in Rh(III) catalyzed C-H functionalizations was, in fact an oxidative annulation. It was reported by the group of Fagnou as an extension for their work on the synthesis of indoles.91 Inspired by Yu’s work,92 they used benzhydroxamic acid derivatives and, interestingly, they found out that the N-O bond was cleaved after the reaction, presumably by oxidative addition of the reduced Rh (I) into the N-O bond followed by ligand exchange. This side reaction allowed them to get rid of the copper oxidant needed to recover the catalyst. Scheme 49. Rh (III)-catalyzed oxidative annulation of benzhydroxamic acid derivatives. They further developed their work by establishing calculations on the mechanism, tuning the internal oxidant and significantly expanding the scope including terminal alkynes and olefins as coupling partners.93 Scheme 50. Rh (III)-catalyzed oxidative annulation of pivaloyl substituted benzhydroxamic acids. The inclusion of an internal oxidant has been widely used since this work, not only cleaving the N-O bond as in this case, but also switching the connection to release the R-NH94 or using N-N bonds.95 91 Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. 92 Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058. 93 Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449. 94 Zhang, Z.; Jiang, H.; Huang, Y. ACS Catal. 2015, 6999. 95 Liu, B.; Song, C.; Sun, C.; Zhou, S.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 16625. Chapter II. 36 Shortly after, the group of Miura96 and the group of Hyster and Rovis published an extension of this work where they managed to carry out the reaction without the need of the N-O bond.97 Scheme 51. Rovis’ Rh (III)-catalyzed oxidative annulation of benzamides with alkynes. After extensive mechanistic studies, they established a mechanistic hypothesis. Their proposal involves the formation of the active catalytic species98 by ligand exchange of the chlorides with the acetates and a subsequent N-H cleavage leading to intermediate I. A CMD step would deliver the metallacycle II that can undergo migratory insertion into the alkyne followed by reductive elimination yielding the isoquinoline. The reduced catalyst is then reoxidized by the copper acetate. Scheme 52. (4+2) oxidative annulations of benzamides with alkynes. Inspired on Fagnou’s work on the annulation of benzamides and alkenes, the group of Cramer sought for an enantioselective version of such coupling. Since the Cp* is essential for 96 Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett. 2010, 39, 744. 97 Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565. 98 The ligand exchange between chlorines and acetates is detected by UV/Vis in: Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics 2009, 28, 3492. Chapter II. 37 the reactivity and the other three positions have to be available for different mechanistic steps, there is no possibility of adding any chiral ligand to obtain enantioselectivity. To solve this problem they introduced the use of chiral cyclopentadienes that shield one face of the benzamide favoring one orientation of the alkene.99 Scheme 53. Rh (III)-catalyzed enantioselective oxidative annulation of benzhydroxamic derivatives. At the same time, the groups of Rovis and Ward published an alternative version for achieving enantioselective annulations by engineering an artificial metallozyme based on biotin-streptavidin interactions leading to yields up to 95% and enantiomeric excesses up to 86%.100 Scheme 54. Streptavidin/Rh (III)-catalyzed enantioselective oxidative annulation of benzhydroxamic acid derivatives. Acrylamides also undergo oxidative annulations under transition-metal catalysis. For instance, Ackermann and co-workers described an oxidative annulation of acrylamides for the synthesis of 2-pyridones using a ruthenium complex.101 Scheme 55. Rh (III)-catalyzed oxidative annulation of benzamides with alkynes. 99 Ye, B.; Cramer, N. Science. 2012, 338, 504. 100 Hyster, T. K.; Ward, T. R.; Rovis, T. Science. 2012, 338, 501. 101 Ackermann, L.; Lygin, A. V; Hofmann, N. Org. Lett. 2011, 13, 3278. Chapter II. 38 These annulations of benzamides and acrylamides were further studied by the groups of Fagnou, Miura and Rovis as well as others. becoming a powerful and robust transformation.102 102 For more reports on the oxidative annulation of benzamides see: (a) Ya Du, T. K. H.; Rovis, T. Chem. Commun. 2011, 47, 12074. (b) Cui, S.; Zhang, Y.; Wu, Q. Chem. Sci., 2013, 4, 3421. (c) Cui, S.; Zhang, Y.; Wu, Q. Chem. Sci., 2013, 4, 3912. (d) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364. (e) Huckins, J. R.; Bercot, E. A.; Thiel, O. R.; Hwang, T.; Bio, M. M. J. Am. Chem. Soc. 2013, 135, 14492. (f) Shi, Z.; Grohmann, C.; Glorius, F. Angew. Chemie. Int. Ed. 2013, 52, 5393. (g) Yu, D.; Azambuja, F. De; Glorius, F. Angew. Chemie. Int. Ed. 2014, 53, 2754. (h) Yu, D.-G.; de Azambuja, F.; Gensch, T.; Daniliuc, C. G.; Glorius, F. Angew. Chemie Int. Ed. 2014, 53, 1. (i) Peng, X.; Wang, W.; Jiang, C.; Sun, D.; Xu, Z.; Tung, C.-H. Org. Lett. 2014, 16, 5354. Chapter II. 39 2– Objectives When we started our work in this research area, the reports in the oxidative annulations of benzamides were scarce and limited to the initial reports of Rovis, Miura and Fagnou. Therefore we considered that there were many aspects in this chemistry that would deserve further attention. Among others, we considered the possibility of achieving intramolecular annulations, given that this would provide a nice way to obtain relatively complex polycycles from very simple starting materials in an atom economical manner. Following these thoughts we considered the development of a fully intramolecular oxidative annulation leading to tricyclic isoquinolines. Scheme 56. General objective. This type of tricyclic cores is present in a wide range of biologically relevant products, such as the ones shown in the figure and therefore, a practical access to these structures was considered worthy. Fig 4. Natural products presenting a tricyclic isoquinoline core. Although, this adaptation from inter to intramolecular reactions might seem obvious, a more careful analysis on the basis of the proposed mechanism revealed that it could be not so trivial. According to the hypothetical mechanism, consisting of a migratory insertion of the alkyne into the C-Rh bond of the resulting species from the C-H activation, this step would generate a bridged bicyclic intermediate such as I, that seems to be quite strained and, hence, Chapter II. 40 might not be formed. Alternatively, the reaction could take place by migratory insertion into the Rh-H bond, which would produce a much more comfortable species II.103 Scheme 57. Possible intermediates after the migratory insertion. On these bases there were a number of interesting challenges to be pursued:  Study the effect of the intramolecularity, including changes on the reactivity and regioselectivity.  Easily access to biologically relevant tricyclic isoquinolines  Study the mechanistic pathway through experimental and computational calculations. 103 These two possibilites are described in: Li, B.; Feng, H.; Xu, S.; Wang, B. Chem. Eur. J. 2011, 17, 12573. Chapter II. 41 3– Results and discussion. 3.1 Optimization of the reaction conditions. To study the viability of the reaction we synthesized the model substrate 10. The preparation of this alkyne-tethered benzamide was achieved by an initial Boc protection of benzamide followed by a Mitsunobu type reaction with pentynol and deprotection. This sequence led to the terminal alkyne-tethered benzamide 9. A final Sonogashira coupling with iodobenzene provided 10 in a 17% overall yield without major optimization. Scheme 58. Synthesis of model substrate 10. With the model substrate in hand we screened several reaction conditions, varying the solvent and the catalytic system. The results of these experiments are summarized in Table 1. Chapter II. 48 we synthesized the benzamide 10-D5 as described in scheme 58. We then run the reactions in separate vessels under the optimized conditions taking aliquots every 5 minutes which were quenched by diluting with dichloromethane and filtered through a florisil pad. NMR analysis of the amount of isoquinoline present at each aliquot allowed calculating a KIE value of 2.5. This is consistent with a moderate influence of the C-H cleavage in the reaction rate, which is in agreement with the energetic profile resulting from the computational studies. Scheme 66. Study of the KIE 3.3 Further studies on the intramolecular oxidative annulation of anilides. At this point of the research, we were curious about the possibility of extending the intramolecularity in oxidative annulations to other precursors like anilides, as this would lead to interesting polycyclic indoles. As commented in the introduction, Fagnou and coworkers had previously developed a brilliant method for the obtention of indoles by a rhodium-catalyzed intramolecular oxidative annulation between acetamides and alkynes (scheme 40). 81 However, intramolecular versions had not been studied and, hence, we decided to make the precursors 38 (scheme 68) to check their reactivity. y = 5E-05x - 0,0161 y = 5E-05x - 0,0116 y = 2E-05x - 0,0067 y = 2E-05x - 0,005 0 0,01 0,02 0,03 0,04 0,05 0,06 0 500 1000 1500 2000 2500 3000 Ammount of product (mmol) Time (s) Measurement of the KIE 10-run1 10-run2 10-D5-run1 10-D5-run2 81 (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474. (b) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326. Chapter II. 49 Scheme 67. Synthesis of indoles by oxidative annulation. The synthesis of the alkyne tethered anilide 18a was done by the condensation of aniline with 5-pentynoic acid followed by a Sonogashira coupling to yield the internal alkyne. Scheme 68. Synthesis of anilide 18a. Treatment of the anilide 18a under the same conditions described by Fagnou for the intermolecular cases failed on yielding even traces of the tricyclic indole, either with or without the silver salt and the a complex mixture or starting material was recovered respectively. Although at the beginning we were a little surprised by this result, a close look into the hypothetical intermediate resulting from the C-H activation (III), allows inferring that it would not be easy for the alkyne to come close to the C-Rh bond and, thereby, undergo the required migratory insertion step. So species III is likely a death intermediate unable to further evolve which hampers the catalytic cycle. Scheme 69. Failed intramolecular version of the annulation of anilide 28a. We also synthesized and tested the naphthaleneacetamide 18b, which was easily assembled by an analogous procedure as stated before. Remarkably, in this case we did observe reactivity but, instead of forming the indole resulting from a (3+2) annulation, we observed the (4+2) adduct 19 in the absence of the chlorine scavenger while with the addition of the silver salt, decomposition of the starting material was observed. The formation of tetracycle Chapter II. 50 19 can rationalized assuming that the 5-membered rhodacycle IV resulting from the activation of the C8-H bond, can evolve to the product by N-metallation and reductive elimination. Scheme 70. Intramolecular (4+2) oxidative annulation of naphthaleneacetamide 18b. Interestingly, a competition experiment between naphthaleneacetamide 18b and an external alkyne in presence of a sliver salt, led to the preferential formation of the indole 20 in a 25% yield. This result confirms the viability of activating the C-H bond at the position 8 of the naphthalene, most probably in a reversible manner. Scheme 71. Competition between interand intramolecular annulations of naphthaleneacetamide 18b. Overall, the above results confirm that a direct translation of intramolecular oxidative annulations to intramolecular settings is not obvious and different factors can significantly affect the reaction outcome. 3.4 Partially intramolecular oxidative annulation of benzhydroxamic derivatives. During our investigations, and just before we submitted our work for publication, the group of Park described an interesting strategy to control the regioselectivity of the annulation. Their idea was based on connecting the alkyne tether to the benzamide using a cleavable NO bond. Although the reaction mechanism could be considered intramolecular, the required cleavage of the N-O bond to regenerate the catalyst leads to products similar to those obtained in intermolecular annulations.111 111 Xu, X.; Liu, Y.; Park, C. Angew. Chem. Int. Ed. 2012, 51, 9372. Chapter II. 51 Scheme 72. Rh (III)-catalyzed semi-intramolecular oxidative annulation of benzhydroxamic acid derivatives. Chapter II. 53 4– Conclusions. In conclusion we have developed a fully intramolecular version of the oxidative annulation of benzamides and alkynes and demonstrated that it presents a wide scope to make a great variety of tricycles and that, this chemistry can be extended to more challenging acrylamides. Scheme 73. Oxidative annulation of acryl and benzamides. Our mechanistic studies provide evidences pointing that the migratory insertion into the RhN bond is more favorable than the insertion into the Rh-C bond, most probably because of geometric reasons. Similar intermolecular processes prefer to proceed through carbometallation instead of aminometallations. Scheme 74. Rh-C vs. Rh-N insertion. We have also demonstrated how, in the case of anilides, tethering the two reactive moieties can shut down the reactivity, while in naphthaleneacetamides that have other available C-H bonds to be activated, the intramolecular annulation is possible, in this case leading to products which arise from formal (4+2) annulations.112 Scheme 75. Oxidative annulation of naphthaleneacetamides. 112 This work was done in collaboration with Dr. Noelia Quiñones and published in: Quiñones, N.; Seoane, A.; García-Fandiño, R.; Mascareñas, J. L.; Gulías, M. Chem. Sci. 2013, 4, 2874. CHAPTER III: Assembly of benzoxepines and coumarins by oxidative annulations of ovinylphenols. Chapter III. 57 1– Introduction. 1.1 Relevance of the phenolic core: Benzoxepines and coumarins. The phenolic skeleton is widely spread in a huge variety of natural products and derivatives, either in its free form or protected as cyclic or acyclic ethers or esters. Many phenolcontaining products show highly relevant biological properties113 and therefore, the development of synthetic access to these derivatives is a very appealing goal.114 Scheme 76. Naturally occurring phenols. Among all the products with phenolic frameworks, benzoxepines and coumarins stand out for their interesting properties. The former, have proven to have antiplasmodial, antimycobacterium and anticancer activities as well as other others.115 On the other hand, coumarins are a versatile scaffold for organic synthesis and present a wide range of interesting properties, which result in their use in very different fields with varying purpose such as fluorescence probes or anticancer and anticoagulant drugs.116 These properties make benzoxepines and coumarins quite interesting synthetic targets. 117 113 Gomes, C. A.; Girão Da Cruz, T. G.; Andrade, J. L.; Milhazes, N.; Borges, F.; Marques, M. P. M. J. Med. Chem. 2003, 46, 5395. 114 (a) Tyman, J. H. P Synthetic and natural phenols. Ed. Elsevier, 1996. (b) Rappaport, Z.The chemistry of phenols. Ed. Wiley Interscience, 2003. 115(a) Sprogøe, K.; Manniche, S.; Larsen, O.; Christophersen, C. Tetrahedron 2005, 61, 8718. (b) Narita, K.; Nakamura, K.; Abe, Y.; Katoh, T. Eur. J. Org. Chem. 2011, 4985. 116 For the synthesis and biological properties of coumarins see: (a) Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem. 2005, 12, 887. (b) Musa, M. A.; Cooperwood, J. S.; Khan, M. O. F. Curr. Med. Chem. 2008, 15, 2664. Wagner, B. D. Molecules 2009, 14, 210. 117 For the synthesis of oxepines see: Snyder, N. L.; Haines, H. M.; Peczuh, M. W. Tetrahedron 2006, 62, 9301. Chapter III. 64 Scheme 90. Oxidative carbonylation of o-vinylphenols. In 2013, Iwasawa reported a related carbonylation using CO2 instead of CO, while being able to lower the gas pressure to 1 atm. In this work they describe the Palladium-catalyzed C-H activation of the olefin one unit of vinylphenol followed by coordination by a second molecule of vinylphenol. The reversible nucleophilic carboxylation of the metallacycle leads to palladacyle II which reacts with another molecule of vinylphenol and base to afford the coumarin with the regeneration of the cyclometallated intermediate I. 131 Scheme 91. Oxidative carbonylation of o-vinylphenols. 131 Sasano, K.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2013, 135, 10954. Chapter III. 65 From the above discussion it seems clear that, readily available phenols and derivatives can be transformed into a variety of products, including several oxacycles, using catalytic processes involving C-H activations, generally directed by the phenolic OH group. However, the number of transformations is still limited, and many challenges related with synthetic and mechanistic aspects of these transformations remain to be approached. Chapter III. 67 2– Objectives. Considering the precedents on the C-H functionalization of phenols, it was uncertain for us which would be the reactivity of o-vinylphenols in the presence of an alkyne when treated under conditions that promote C-H activations. As indicated in scheme 92, vinylphenols contain several potentially cleavable carbon-hydrogen bonds and depending on the process, different possible annulation products could be formed. 120,123,132 In particular, and taking into account the precedent of carbonylation reactions, we were particularly attracted by the possibility of activating the terminal C-H bonds and in this way, gaining access to benzoxepines, which had not been obtained using this chemistry. In principle we envisioned to investigate the performance of these substrates in presence of Rh (III) catalysts since they had proven their utility in other annulations with alkynes. Scheme 92. General objective. Alternatively, the use of carbon monoxide as reaction partner might provide an attractive, atom economical and mild entry to coumarins. Scheme 93. Synthesis of coumarins. 120 Miura, M.; Tsuda, T.; Satoh, T.; Nomura, M. Chem. Lett. 1997, 11, 1103. 123 Kuram, M. R.; Bhanuchandra, M.; Sahoo, A. K. Angew. Chemie. Int. Ed. 2013, 52, 4607. 132 Hu, J.; Hirao, H.; Li, Y.; Zhou, J. Angew. Chemie. Int. Ed. 2013, 52, 8676. Chapter III. 69 3– Results and discussion. 3.1 Optimization of the reaction conditions. To study the viability of the reaction, we synthesized model the substrate 23a by a Wittig reaction from commercially available salicylaldehyde in 96% yield. Scheme 94. Synthesis of model substrate 23a. With the model substrate in hand we started to explore its performance under different conditions with diphenylacetylene as reaction partner. As shown in table 2, using Rh catalysis we observed the formation of the benzoxepin product. The reaction works in a variety of solvents (entries 1,4, 5) being acetonitrile the one that gives better yield rising from 51 to 91% even reducing the amount of copper (entry 6). It is also possible to reduce the equivalents of alkyne oxidant to 1.5, which even allowed to slightly increase the yield to an excellent 96% (entry 7). Decreasing the amount of Copper acetate to 10 mol% the reaction is slower and the yield drops to an 87% (entry 8). Other metals failed to yield the oxepin, either due to lack of conversion with an iridium Cp* complex (entry 2) or decomposition of the vinylphenol with a Ru catalyst (entry 3). We also confirmed that the rhodium is crucial for the reaction since its omission leads to no conversion of the starting materials. Table 2. Screening of the reaction conditions Entry Catalyst 38a (equiv) Solvent T (°C) Yield (%)b 1 [Cp*RhCl2]2 2 Toluene 100 52 2 [Cp*IrCl2]2 2 Toluene 100 0c 3 [Ru(p-cymene)Cl2]2 2 Toluene 100 Tracesd 4 [Cp*RhCl2]2 2 DMF 100 72 5 [Cp*RhCl2]2 2 t-AmOH 100 83 6 [Cp*RhCl2]2 2 CH3CN 85 91e 7 [Cp*RhCl2]2 1.5 CH3CN 85 97e 8 [Cp*RhCl2]2 1.5 CH3CN 85 87f 9 none 1.5 CH3CN 85 0c a Reaction conditions: 32a (0.33 mmol), catalyst (2.5 mol %), Cu(OAc)2·H2O (2.1 equiv), solvent (2 mL). b Isolated yield. c Recovery of the starting materials. d Complex mixture. e 0.5 equiv of Cu(OAc)2·H2O/air balloon were used. f 0.1 equiv of Cu(OAc)2·H2O/air balloon were used, 16h. Chapter III. 70 3.2 Substrate scope. With the optimized conditions in hand, we proceeded to study the scope of the reaction with regard to the alkyne. Symmetrical alkynes bearing electron-rich or electron-poor substituents efficiently participate in the reaction leading to the desired oxepines in good yields (25ab and 25ac), alkynes bearing aliphatic substituents can also be used, although the yield drops to about 50% (25ad and 25ae). It is also possible to use alkynes with silyloxy substituents as well with esters or free hydroxyl groups (25af, 25ah and 25ai). Interestingly unsymmetrical alkynes afford the corresponding products with selectivities up to 14:1 (25ag). a Reaction conditions: 23 (0.33 mmol), 29 (1.5 equiv), [Cp*RhCl2]2 (2.5 mol%), Cu(OAc)2·H2O (0.5 equiv), CH3CN (2 mL), 85°C. b Isolated yields based on 29. Scheme 95. Scope of the alkynes. To examine the scope with respect to the phenols, we synthesized several hydroxystyrenes using the same procedure shown in scheme 94.133 As disclosed above, reaction tolerates different electronically biased aromatic rings with substitution at different positions. When electron-donating groups are placed at the para position of the hydroxyl, the expected oxepines are obtained in good to excellent yields (25ba-25da). The same scenario happens for electron-withdrawing substituents (25ea-25ga). The ortho position of the phenol can also be substituted with no changes in the reactivity. Moreover, the reaction is also unaffected by substitution at the para position of the double bond leading to products (25ha-25ka) in good to excellent yields. However, when the internal position of the alkene is substituted with a methyl group the oxepin is obtained in low yields in favor of two different byproducts 133 In collaboration with Noelia Casanova Chapter III. 71 (25na). Interestingly the reaction is not efficient when there is substitution at the ortho position of the olefin or at the double bond leading to an 8% yield and a complex mixture of products respectively (25ma, 25oa). a Reaction conditions: 23 (0.33 mmol), 29 (1.5 equiv), [Cp*RhCl2]2 (2.5 mol%), Cu(OAc)2·H2O (0.5 equiv), CH3CN (2 mL), 85°C. b Isolated yields based on 29. c Complex mixture. d Isolated with two different byproducts. Scheme 96. Scope of the o-vinylphenols. The structure of the products was unambiguously confirmed by X-Ray diffraction of oxepine 25aa as seen below. Fig 5. Structure of 25aa obtained by X-Ray diffractometry. To elucidate the regiochemistry of the products arisen from when unsymmetrical alkynes where used, we carried out nOe experiments between the aliphatic side chain of the alkyne and the hydrogen at C4, as exemplified below. Chapter III. 72 Fig 6. Determination of the regiochemistry of 25ag by nOe. In summary, we have described a new and attractive method of making a variety of benzoxepines from trivial starting material. 3.3 (5+1) annulation towards coumarins. After the good results of the (5+2) annulation, we wondered whether it was possible to use carbon monoxide as coupling partner in order to obtain coumarins. Gratifyingly, when ovinylphenol was treated under the reaction conditions in an atmosphere of carbon monoxide and 1.2 equivalents of copper acetate, the corresponding coumarin was obtained (28a). The reaction also works efficiently with electron-poor or electron-rich substituents (28b and 28c). Interestingly, in contrast to the annulations to alkynes, the carbonylation tolerates substitution at the internal position and therefore, coumarin 28d can be isolated in an 84% yield. a Reaction conditions: 27 (0.5 mmol), [Cp*RhCl2]2 (2.5 mol%), Cu(OAc)2·H2O (1.2 equiv), CH3CN (2 mL), 85°C. overnight. Fig 7. Scope of the carbonylation. 3.4 Mechanistic investigations. In an effort to obtain mechanistic information about this transformation, we carried out several experiments. First of all we performed a competition between phenols 23a and 23f. When both are mixed together, the electron poor 23f reacts preferentially leading to an 8:1 mixture of both oxepines. Chapter III. 73 Scheme 97. Competition between 25aa and 25fa. However, when the reactions are carried out in separate vessels the formation of 25aa is faster. This divergence can be explained in terms of an irreversible formation of a phenoxideRh complex that should be easier for more acidic protons while, further steps could be favorable for more electron-rich substrates. Scheme 98. Reaction yields after 10 min of reaction of 25aa and 25fa. We also measured the relative reaction rates between standard vinylphenol and an electronpoor counterpart, with a trifluoromethyl substituent para to the olefin. Like in the previous 25aa 25fa Chapter IV. 81 1– Precedents. 1.1 Isolation of the spirocycle. As commented before, while working on the annulation of o-vinylphenols and alkynes, we observed that, when a methyl substituent was located at the internal position of the double bond only a 15% of the benzoxepin was observed in favor of two different byproducts. Isolation of those products allowed us to characterize the as the dearomatized spirocycle 31aa and the azulenone 32aa. Scheme 105. Different products arising from the oxidative annulation of alkenylphenols with alkynes. This unexpected and intriguing reactivity prompted us to further investigate this transformation to further optimize it and understand the mechanism. 1.2 Dearomatization of phenols. Although energetically unfavorable, the dearomatization of aromatic rings is a powerful way of obtaining new structures with increased molecular complexity form simple planar structures.137 In particular, phenols are common substrates for these transformations since the lone pair of the heteroatom allows for an easier breaking of the aromaticity.138 An example of this approach is the synthesis of the core of Ryanodine by Deslongchamps in 1969.139 Scheme 106. Synthetic approach towards Ryanodine. Among the many ways of inducing the dearomatization of phenols, the oxidation to quinones140 and the generation of quinone methides141 stand out for their versatility and 137(a) Mander, L. N. Synlett 1991, 134. (b) Roche, S. P.; Porco, J. A. Angew. Chemie. Int. Ed. 2011, 50, 4068. 138 Quideau, S.; Pouységu, L.; Deffïeux, D. Synlett 2008, No. 4, 467. 139 Berney, D.; Deslongchamps, P. Can. J. Chem. 1969, 47, 515. 140 Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383. Chapter IV. 82 numerous products have been synthesized by using these methodologies. An example can be seen in the total synthesis of Elisaebthin A by the group of Mulzer in 2003.142 Their procedure involves the generation of a highly reactive dearomatized quinone that undergoes a fast intramolecular Diels-Alder cycloaddition to produce the core of the natural product. Scheme 107. Key step in the total synthesis of Elisabethin A. The use of ortho quinone methides is exemplified in the total synthesis of (±)-Alboatrin by Baldwin and co-workers which also involves a Diels-Alder cyclization although in this case, the quinone is the diene instead of the dienophile.143 Other methods for the dearomatization of phenols rely on photoisomerizations, oxidations or acid or base-mediated elimination.138 Scheme 108. Key step in the total synthesis of (±)-Alboatrin. 141 Van de Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367. Toteva, M. M.; Richard, J. P. Adv. Phys. Org. Chem. 2011, 45, 39 138 (a) Mander, L. N. Synlett 1991, 134. (b) Roche, S. P.; Porco, J. A. Angew. Chemie. Int. Ed. 2011, 50, 4068. 142 Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc. 2003, 125, 4680. 143 Rodriguez, R.; Adlington, R. M.; Moses, J. E.; Cowley, A.; Baldwin, J. E. Org. Lett. 2004, 6, 3617. Chapter IV. 83 In addition to the aforementioned methods, transition metals can also promote reactions that involve the dearomatization of phenolic derivatives.144 In 2011, Buchwald and co-workers developed an arylative dearomatization catalyzed by Pd (0). They also demonstrated that the reaction could be performed in an enantioselective manner by using chiral phosphines.145 Scheme 109. Pd(0)-catalyzed dearomatizing arylation of phenols. Later, while we were working in the synthesis of the oxepines and coumarins, Luan and coworkers published a Ru(II)-catalyzed dearomatizing oxidative annulation of naphthols with alkynes. Although no explanation is given, in the same communication they report that, when phenols are used instead of naphthols, the reaction delivers less than a 5% of the spirocyle146 Scheme 110. Ru(II)-catalyzed dearomatizing annulation of naphthols. Their mechanistic hypothesis starts with the formation of the active catalytic species followed by a hydroxyl directed C-H activation. A migratory insertion of the alkyne leads to the eight-membered metallacycle II which, to release the strain, evolves through keto tautomerization towards the ruthenacyle III. A final reductive elimination yields the spirocyle and the reduced catalyst which is further reoxidized by the copper acetate. 144 For selected examples see (a) Wiegand, S.; Schafer, H. J. Tetrahedron 1995, 51, 5341. (b) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu, M.; Hamada, Y. Org. Lett. 2010, 12, 5020. (c) Wu, Q.; Liu, W.; Zhuo, C.; Rong, Z.; Ye, K.; You, S. Angew. Chem. Int. Ed. 2011, 50, 4455. 145 Rousseaux, S.; García-Fortanet, J.; Del Aguila Sanchez, M. A.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 9282. 146 Nan, J.; Zuo, Z.; Luo, L.; Bai, L.; Zheng, H.; Yuan, Y.; Liu, J.; Luan, X.; Wang, Y. J. Am. Chem. Soc. 2013, 135, 17306. Chapter IV. 84 Scheme 111. Mechanistic hypothesis. 1.3 Hydroxyl-directed synthesis of spirocycles by oxidative annulation. A related example was developed at the group of Lam by using ruthenium catalysis and 1,3 diketones that act as masked enols.147 Scheme 112. Ru(II)-catalyzed dearomatizing annulation of designed diketones. The proposed mechanism starts with a keto-enol tautomerization and hydroxyl-directed C-H activation to give intermediate I. This ruthenacyle evolves via migratory insertion leading to the oxa-π-allylruthenium, which can also be depicted as the Cor Obound forms. Finally a C-C reductive elimination affords the spirodiketone and the reduced Ruthenium catalyst. Copper acetate may oxidize the Ru (0) to Ru (II) which is reincorporated into the catalytic cycle 147 Chidipudi, S. R.; Khan, I.; Lam, H. W. Angew. Chem. Int. Ed. 2012, 51, 12115. Chapter IV. 85 Scheme 113. Mechanistic hypothesis. The same group reported an interesting catalyst-dependant divergent reactivity. Using slightly different substrates, they were able to assemble tricyclic chromenes with ruthenium while a palladium-carbene based catalyst afforded the previously described spirocycles. In their communication, the authors were unable to clarify the reason behind this catalystdependant divergence.148 Scheme 114. Divergent oxidative annulation of specific diketones. The group of Wang also reported a palladium-catalyzed (2+2+1) annulation between hydroxycoumarins and alkynes leading to spirocyclopentadienechroman-2-4,diones. In their report they explain the reaction in terms of the activation of the olefinic C-H bond of the coumarin followed by two consecutive migratory insertions leading to intermediate I which, after a cyclopalladation driven by the conversion of the enol into a ketone, yields the sixmembered intermediate III. This intermediate undergoes reductive elimination releasing the 148 Dooley, J. D.; Reddy Chidipudi, S.; Lam, H. W. J. Am. Chem. Soc. 2013, 135, 10829. Chapter IV. 86 spirocycle and reoxidation of the catalyst to reinitiate the cycle.149 This methodology was later applied by Luan using naphthols as the one-atom component.150 Scheme 115. (2+2+1) oxidative annulation for the synthesis of spirocycles. 1.3 Spirocycles as a synthetic goal. Spirocyclic compounds are relevant,151 not only due to their unique structural properties which have been used in order to build chiral ligands, 152 but also because of their presence in several natural products. 153 In particular, spiro[5.4]nonane systems are quite common in many terpenes of natural origin. This is why methods leading to them are of high interest.154 Scheme 116. Naturally occurring products and chiral ligand containing spirocycles. 149 Peng, S.; Gao, T.; Sun, S.; Peng, Y.; Wu, M. Adv. Synth. Catal. 2014, 356, 319. 150 Gu, S.; Luo, L.; Liu, J.; Bai, L.; Zheng, H. Org. Lett. 2014, No. Ii, 10. 151 (a) Krapcho, P. A. Synthesis. 1974, 383. (b) Sannigrahi, M. Tetrahedron 1999, 55, 9907. 152 Ding, K.; Han, Z.; Wang, Z. Chem. Asian. J. 2009, 4, 32. 153 Rios, R. Chem. Soc. Rev 2012, 41, 1060. 154 Quasdorf, K. W.; Overman, L. E. Nature 2014, 516, 181. Chapter IV. 87 2– Objectives. Considering the precedents shown above, we aimed to further study dearomatizing (3+2) oxidative annulation of o-alkenylphenols with alkynes, trying to enhance the selectivity of the process towards the formation of the spirocycle. Scheme 117. Objective. We also wanted to investigate the mechanistic pathway and the reason why the substituent of the olefin changes the reactivity towards the spirocycle. Finally, we also need to provide an explanation for the formation of the azulenone 32aa. Chapter IV. 89 3– Results and discussion. 3.1 Optimization of the reaction conditions. To accomplish our goals we started with the synthesis of alkenylphenol 27a as described earlier. Scheme 118. Synthesis of model substrate 47a. With the model substrate in hand, we explored its reactivity against diphenylacetylene under different conditions in order to improve the selectivity of the transformation. The results of this screening are summarized in the table below. Table 3. Screening of the reaction conditions. Yield (%)b Entry Catalyst Solvent T (°C) 50 53aa 54aa 1 [Cp*RhCl2]2 CH3CN 85 15 51 25 2 [Cp*RhCl2]2 t-AmOH 100 12 18 15 3 [Cp*RhCl2]22 Toluene 100 8 19 17 4 [Cp*RhCl2]2 CH3CN rt 44 4 5 [Cp*RhCl2]2 CH3CN 40 97c Traces 6 [Cp*RhCl2]2 CH3CN 40 91d 8 7 [Ru(p-cymene)Cl2]2 CH3CN 40 15 5e 8 Pd(OAc)2 CH3CN 40 <10 -e 9 none CH3CN 85 - - -f a Reaction conditions: 27a (0.33 mmol), catalyst (2.5 mol %), alkyne (1.5 equiv), Cu(OAc)2·H2O (0.5 equiv), solvent (2 mL), air balloon. b Isolated yield. c In 2h. d 0.1 equiv of Cu(OAc)2·H2O/air balloon were used, 16h. e Decomposition of the alkenylphenol. b Starting materials were recovered. As seen above, the reaction works productively in acetonitrile, and leads to lower overall yields when other solvents are used (entries 1-3). The reaction also works at room temperature although the yield drops to a 44% but, in this case, no benzoxepin is formed (entry 4). When the reaction is carried out at 40 °C and stopped after two hours, only the spirocycle 53aa is formed with traces of the azulenone 54aa (entry 5). It is even possible to lower the amount of copper oxidant to 10 mol % by increasing the reaction time without diminishing the overall yield, although a slightly higher proportion of the azulenone is Chapter IV. 96 This interconversion between spirocycle and azuleneone can be explain in terms of the formation of a zwitterionic species and the subsequent ring-opening of the resulting tricycle.158 Scheme 131. Formation of the azulenone. 158 (a) a [1,5] sigmatropic rearrangement or a radical-based mechanism are also plausible: Spangler, C. W. Chem. Rev. 1976, 76, 187. (b) For a recent, related rearrangement see: Li, X.-Y.; Yang, Y.-F.; Peng, X.- R.; Li, M.-M.; Li, L.-Q.; Deng, X.; Qin, H.-B.; Liu, J.-Q.; Qiu, M.-H. Org. Lett. 2014, 16, 2196. Chapter IV. 97 4Conclusions. In conclusion we have developed a mild formal (3+2) annulation between o-vinylphenols and alkynes promoted by rhodium (III) catalysis that provides structurally interesting spirocycles. This transformation conveys a cleavage of the O-H and a C-H bond, and the dearomatization of the phenolic ring. The reaction takes place with excellent chemo and regioselectivity generating chirality form simple, plain structures. Scheme 132. Oxidative annulation of o-vinylphenol. Scheme 133. Divergence of outcomes depending on the substitution. Our studies also suggest that from readily available substrates, namely o-alkenylphenols and alkynes it is possible to obtain relevant and structurally unrelated products such as azulenones.159 Scheme 134. Synthesis of azulenones form o-alkenylphenols. 159 These results were published in: Seoane, A.; Casanova, N.; Quiñones, N.; Mascareñas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 7607. CHAPTER V: Oxidative annulations of oalkenylanilines. Chapter V. 101 1– Introduction After developing the annulation chemistry of o-alkenylphenols, we wondered whether it was possible to translate their chemistry to nitrogen-containing molecules. The motivations behind this goal rely on the prevalence of nitrogen atoms in drugs and bioactive compounds. In fact, if we could to replicate the same (5+2) annulation performed with phenols to anilines we would be able to access to benzazepines, a common motif in several pharmaceuticals and natural products.160 Scheme 135. Biologically active and naturally occurring [1] benzazepines. 1.2 Reactivity of o-alkenylanilines. Unlike previously described o-vinylphenols, which where scarcely used in the literature, there are several precedents for the use of o-alkenylanilines in synthesis. Their use started with the pioneering work of Dewar and Dietz where they treated them with boron trichloride which allowed the isolation of a cyclic compound isosteric to naphthalene.161 Scheme 136. Synthesis of the naphthalene isostere. Later, Hegedus and co-workers described that treatment of alkenylanilines, either free or tosyl protected, under Palladium catalysis afforded indoles by cyclization. Their mechanistic hypothesis starts with the coordination of the palladium to the olefin and nucleophilic attack 160 Shah, J. H.; Hindupur, R. M.; Pati, H. N. Curr. Bioact. Compd. 2015, 11, 170. 161 Dewar, M. J. S.; Dietz, R. J. Chem. Soc. 1959, 2728. Chapter V. 102 by the nitrogen. Finally, a β-hydride elimination and reoxidation of the catalyst close the cycle and yields the indoles in a moderate yield.162 Scheme 137. Palladium-catalyzed cyclization of o-alkenylanilines. The group of Larock improved the catalytic system by using Palladium acetate and oxygen as oxidant. With those conditions, they were able to expand the scope to different amines albeit in lower yields. Interestingly, when having a methyl at the inner position of the double bond, the reaction can be performed at lower temperatures and the 3-methylene-2,3dihydroindole 34 is obtained instead of the expected indole.163 Scheme 138. Larock’s synthesis of indoles. Following this work, other metals164 were used to carry out this synthesis. Photocatalytic165 and even metal-free conditions166 were also developed by different research groups. Larock and co-workers also designed a method for synthesizing dihydroquinolinones by using the same tosylanilides and vinylic (pseudo)halides in a formal (5+1) annulation.167 162 (a) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800. (b) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657. 163 Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584. 164 (a) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054. (b) Liwosz, T. W.; Chemler, S. R. Chem. Eur. J. 2013, 19, 12771. (c) Youn, S. W.; Ko, T. Y.; Jang, M. J.; Jang, S. S. Adv. Synth. Catal. 2015, 357, 227. 165 Maity, S.; Zheng, N. Angew. Chemie. Int. Ed. 2012, 51, 9562. 166 Jang, Y. H.; Youn, S. W. Org. Lett. 2014, 16, 3720. 167 (a) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584. (b) Larock, R. C.; Pace, P.; Yang, H. Tetrahedron Lett. 1998, 39, 2515. Chapter V. 103 Scheme 139. Larock’s formal (5+1) annulation. Their mechanistic explanation consists of an initial reduction of palladium acetate and oxidative addition to the aryl (pseudo)halide. Subsequent migratory insertion and β-hydride elimination lead to the diene II. From this intermediate, the palladium migrates to the outer olefin, which undergoes a migratory insertion leading to π-allyl V. This species suffers a nucleophilic attack from the amine releasing the product and the reduced catalyst, which is now able to reenter the cycle by adding onto the C-X bond. Scheme 140. Mechanistic hypothesis. The group of Takemoto employed an oxidative addition to direct the palladium C-H activation in the synthesis of indolinones. Their mechanistic hypothesis starts with the oxidative addition of the Pd (0) into the C-CN bond on the anilide which is followed by the Chapter V. 104 migratory insertion of the alkenyl unit. A final reductive elimination affords the indolinone and releases the active catalyst.168 Scheme 141. Palladium-catalyzed synthesis of indolinones. In 2010, Buchwald and co-workers also took advantage of an oxidative addition-directed strategy to synthesize several nitrogen-containing heterocycles. They were able to control the selectivity of the C-H activation by the use of different phosphines. In their communication, they also explained the formation of the dibenzazepine 35 in terms of a palladium-induced dearomatization/rearomatization mechanism.169 168 Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. Tetrahedron 2007, 63, 2978. 169 Tsvelikhovsky, D.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14048. Chapter V. 105 Scheme 142. Divergent synthesis of heterocycles from (N-aryl)vinylanilines. You et al. developed an interesting work on the allylation of vinylanilines by using Ir (I) catalysis and allylic carbonates. They were also able to couple the allylation with an intramolecular amination for the synthesis of dihydrobenzazepines.170 Scheme 143. Ir(I)-catalyzed allylation and tandem allylation-cyclization of o-vinylanilines with allylic carbonates. 170 (a) He, H.; Liu, W. B.; Dai, L. X.; You, S. L. J. Am. Chem. Soc. 2009, 131, 8346. (b) He, H.; Liu, W. B.; Dai, L. X.; You, S. L. Angew. Chemie. Int. Ed. 2010, 49, 1496. (c) (d) Ye, K.-Y.; Dai, L.-X.; You, S.-L. Asian J. Org. Chem. 2013, 2, 244. Chapter V. 112 Fig 8. X-Ray structure of naphthylamides 39aa and 39aa’. 3.2 Optimization of the reaction conditions. Once established that the triflate group was providing the appropriate electronics for the reactivity, we started to investigate the best conditions to achieve this unusual transformation. Table 5. Screening of catalyst.a Entry Catalyst Yield 61aa (%)b Yield 61aa’ (%)b 1 [Cp*RhCl2]2 28 16 2 RhCl3· xH2O 0 0c 3 Rh(PPh3)3Cl Traces Tracesc 4 [Cp*IrCl2]2 0 0c 5 [(p-cymene) RuCl2]2 0 0c 6 Pd(OAc)2 0 0c a Reaction conditions: 37a (0.33 mmol), 29a (1 equiv), catalyst (5 mol %), Cu(OAc)2·H2O (1 equiv), acetonitrile (2 mL). b Isolated yield. c Starting material was mostly recovered. We started by identifying the appropriate precatalyst for this transformation. To do so, we tested several metal complexes with only [Cp*RhCl2]2 leading to appreciable conversions (entry 1). From the other precatalysts screened, Ir and Ru complexes as well as RhCl3· xH2O did not lead to any product and starting materials were mostly recovered (entries 2, 4, 5). Wilkinson’s catalyst worked slightly better providing traces of the cycloadducts along with starting material, while palladium acetate led to the decomposition of the anilide and a complex mixture of products. Chapter V. 113 Table 6. Screening of conditions.a Entry Solvent Catalyst Additive (equiv) Yield 39aa (%)b Yield 39aa’ (%)b 1 Toluene [Cp*RhCl2]2 - 32 12 2 EtOH [Cp*RhCl2]2 - 32 14 3 TFE [Cp*RhCl2]2 - 18 7 4 AcOH [Cp*RhCl2]2 - 0 0 5 t-AmOH [Cp*RhCl2]2 - 30 16 6c,d DMF [Cp*RhCl2]2 - 35 17 7c DMF [Cp*RhCl2]2 - Traces Traces 8 Dioxane [Cp*RhCl2]2 - 60 19 9 Dioxane [CptBuRhCl2]2 - 21 9 10 Dioxane [CpiPrRhCl2]2 - 38 29 11 Dioxane [Cp*RhCl2]2 AcOH (2) 57 20 12 Dioxane [Cp*RhCl2]2 PivOH (2) 56 21 13 Dioxane [Cp*RhCl2]2 CsOAc (2) 35 17 14 Dioxane [Cp*RhCl2]2 CsOPiv (2) 56 23 15 Dioxane [Cp*RhCl2]2 AgSbF6 (0.2) 0 0 16e Dioxane [Cp*RhCl2]2 19 5 17 f Dioxane [Cp*RhCl2]2 57 24 18 f Dioxane 0 0 a Reaction conditions: 37a (0.33 mmol), 29a (1 equiv), catalyst (5 mol %), Cu(OAc)2·H2O (1 equiv), additive, solvent (2 mL). b Isolated yield. c Reaction performed at 110 °C, starting material was recovered. d AgOAc (1 equiv) was used instead of Copper acetate. e Reaction performed at 60 °C. f 0.5 equiv of Copper acetate were used. After finding the best catalyst for the transformation, we tested different solvents and additives to further improve the reaction. Among the screened solvents, the best one proved to be dioxane leading to a 79% overall yield in a 3:1 ratio of regioisomers (entry 8) under this conditions, the replacement of the Cp*Rh precatalyst with the analogous CptBu and CpiPr led to lower yields (entries 9, 10). Also, the addition of either acids or bases did not affect the performance of the reaction (entries 11-14) while the use of a silver salt as chlorine scavenger afforded the decomposition of the anilide. Lowering the temperature to 60 °C resulted in the overall yield dropping to a 24% (entry 16) and reducing the amount of copper acetate to 0.5 equivalents does not affect the reaction (entry 17). Finally we confirmed the requirement of the catalyst since, in its absence, starting materials are mostly recovered (entry 18) We next sought to check the requirement of the oxidant by omitting them from the reaction. To our surprise the reaction could be carried out even in the absence of copper salts as shown below. Chapter V. 114 Table 7. Control experiments.a Entry Base (equiv) Yield 39aa (%)b Yield 39aa’ (%)b Observations 1 Cu(OAc)2 (0.5) 57 24 2 CsOAc (2) 57 15 3 CsOAc (1) 54 16 4 CsOAc (1) 56 15 Under Ar atmosphere 5 NaOAc (2) 57 16 6 NaOAc (0.5) 53 15 7 CsCO3 0 0 Recovery of starting material 8 AcOH 0 0 Recovery of starting material 9 CsOAc (2) 0 0 No Rh, recovery of starting material a Reaction conditions: 37a (0.33 mmol), 29a (1 equiv), [Cp*RhCl2]2 (5 mol %), Base, Dioxane (2 mL). b Isolated yield. When copper was omitted from the reaction media and cesium acetate was used as base, the reaction still took place catalytically affording the corresponding naphthylamides in similar yield to the one obtained with copper (entries 1, 2). To rule out the possibility that oxygen was acting out as an oxidant, we carried out the reaction with a careful extrusion of air in deoxygenated dioxane, obtaining the same result as before. Sodium acetate was used due to its lower hygroscopicity and, even in a catalytic way, reproduced the previous results (entries 4, 5). Neither cesium carbonate nor acetic acid were able to promote the reaction (entries 6, 7). Finally, when no rhodium catalyst is used under these new conditions, no conversion is observed and the starting material is recovered. We finally tried the reaction in THF under the copper-free conditions which allowed us to reduce the temperature and still observe a slightly improvement of the yield. These conditions were the ones considered as optimal for the study of the scope. Scheme 150. “Copper free” oxidative annulation with alkenylanilides. Chapter V. 115 3.3 Substrate scope. For studying the scope of the reaction we synthesized different anilides. The synthetic route used was as follows: When the 2’-aminoacetophenones were available, a Wittig reaction followed by triflation afforded the corresponding annulation precursor. When the ketone was not commercial we synthesized it by the addition of a Grignard to the corresponding benzonitrile. Scheme 151. Synthesis of the triflylanilides. When submitted to the optimized conditions, differently substituted alkynes undergo the oxidative annulation with the model anilide to obtain the corresponding naphthylamides. Electron-rich and electron-poor diarylacetylenes are well tolerated affording the corresponding regioisomers (39ab and 39ac). Interestingly, unsymmetrical aliphatic and aromatic alkynes provide only two of the four possible regioisomers, this preference, probably taking place during the migratory insertion, is similar to the one observed for the annulations with phenols in the previous chapters (39ai and 39ag). Aliphatic alkynes participate in the reaction showing higher regioisomeric ratios, all of them above 10:1 (39ad and 39ae). Despite the lack of copper in the reaction, which might react with terminal alkynes, alkynes with a hydrogen substituent led to no conversion after 16h and the starting materials were mostly recovered (39al). Chapter V. 116 a Reaction conditions: 39a (0.33 mmol), 29 (1 equiv), [Cp*RhCl2]2 (5 mol %), CsOAc (0.5 equiv), THF (2 mL). b Isolated yield. c Starting material was recovered. Scheme 152. Scope of the alkynes. Regarding the anilides, the reaction requires substitution at the internal position of the olefin since, when o-vinylanilide was submitted to the reaction conditions, no progress was observed and starting material was mostly recovered (39bd). Mechanistically interesting, when an isopropyl group is replacing the methyl of the alkene, no product is observed instead, we could isolate the isomerized (42) in a 47% while when the substituent is an aryl motif, regardless of its electronic nature, the naphthylamides are isolated in 66-90% yield (39dd–39fd). If there is a methyl at the terminal position of the alkene, whether cis or trans the reaction does not proceed at all and starting material is recovered (39gd). Same scenario is observed when 2-phenylanilide is used. When the hydrogen at the para position of the amide is replaced by a methyl group, the resulting naphthylamide is isolated in a 72% yield (39id). Concerning the para position of the double bond, a methyl group affords a satisfactory yield of 59% (39jd) and the strongly electron-withdrawing trifluoromethyl also yields 39kd in a 61% yield although the regioisomeric proportion drops to 5:1. In all of the cases 4-octyne was used as the coupling partner due to the easier identification of the products and the obtention of higher regioisomeric ratios. Chapter V. 117 Reaction conditions: 37 (0.33 mmol), 29d (1 equiv), [Cp*RhCl2]2 (5 mol %), CsOAc (0.5 equiv), THF (2 mL). b Isolated yield. c Starting material was recovered. Scheme 153. Scope of the anilides. 3.4 Mechanistic hypothesis. Although still more studies have to be made in order to establish a plausible mechanism, our current working model consists of the formation of the active catalytic species by cleavage of the rhodium dimer and ligand exchange with the acetates. Another ligand exchange with the NH group followed by the C-H activation would lead to metallacycle I which, upon migratory insertion of the alkyne and subsequent protodemetallation, delivers the open alkenylrhodium complex II. A second protodemetallation affords the diene III which can be coordinated to a Rh (III) species. This intermediate may undergo a nitrogen-mediated nucleophilic attack to the rhodium affording imine IV which, after β-hydride elimination yields spirocycle V. Rearrangement of this species might lead to both naphthylamines depending on which bond migrates178. The rhodium hydride complex can now react with the acetic acid formed in the reaction releasing hydrogen and regenerating the catalyst.179 178 A similar rearrangement has been described in a Palladium-mediated stoichiometric reaction regarding N,N-dimethylated o-phenylanilines: Dupont, J.; Pfeffer, M.; Theurel, L.; Rotveel, M. A.; De Cian, A.; Fischer, J. New J. Chem. 1991, 15, 551. 179 This protonation of hydrides is described for Manganese in He, R.; Huang, Z. T.; Zheng, Q. Y.; Wang, C. Angew. Chemie. Int. Ed. 2014, 53, 4950. Chapter V. 118 Scheme 154. Mechanistic hypothesis. Other mechanisms could also be operating. Another possibility is the protodemetallation of spirocycle IV that may release the catalyst and dihydronaphthylamides VI and VII which, in presence of the oxygen during the workup, rapidly oxidize to the naphthylamides. Scheme 155. Alternative mechanistic hypothesis. A third possibility is a mechanism analogous to the one of the obtention of spirocycles with phenols (see in scheme 129 the previous chapter) leading directly to V which rearrangement affords the naphthylamines. The reduced complex could be regenerated via oxidative Chapter V. 119 addition to the acetic acid and protonation of the Rhodium hydride as seen in the first mechanism. Scheme 156. Oxidation of Rh(I) by copper acetate. Chapter V. 121 4Conclusions In conclusion, we have developed an unprecedented Rh (III)-catalyzed (4+2) oxidative annulation between triflyl-protected ortho-alkenyl anilides to afford naphthylamines. The reaction requires appropriate substitution at the nitrogen and leads to the formation of different regioisomers arising from an apparent 1,2 migration of the alkenyl unit prior to the annulation. We have also proven that this transformation occurs even in the absence of oxygen or copper salts and sodium acetate alone is able to accomplish this task. Finally, we have proposed different plausible mechanistic pathways for the reaction, although more experiments have to be done in order to distinguish among those possibilities. Chapter VI. 128 chromatography hexanes:ethyl acetate 1:3) to obtain the corresponding arene 10a (112 mg, 80%). N-(5-Phenylpent-4-yn-1-yl)benzamide (10): white solid. 1H NMR (300 MHz, CDCl3) δ 7.86 – 7.60 (m, 2H), 7.51 – 7.13 (m, 8H), 6.53 (br s, 1H), 3.57 (dd, J = 12.6, 6.4 Hz, 2H), 2.48 (t, J = 6.7 Hz, 2H), 1.99 – 1.77 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.5 (C), 134.5 (C), 131.5 (CH), 131.3 (CH), 128.5 (CH), 128.2 (CH), 127.8 (CH), 126.8 (CH), 123.4 (C), 89.2 (C), 81.6 (C), 39.7 (CH2), 28.2 (CH2), 17.5 (CH2).LRMS (m/z, I) 263 (87), 262 (43) 235 (27) HRMS calculated for C18H17NO 263.1310, found 263.1318. 4-Methoxy-N-(5-phenylpent-4-yn-1-yl)benzamide (10b): yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.74 – 7.54 (m, 2H), 7.42 – 7.09 (m, 5H), 6.83 – 6.66 (m, 2H), 6.51 (br s, 1H), 3.73 (s, 3H), 3.53 (dt, J = 13.9, 6.9 Hz, 2H), 2.46 (t, J = 6.8 Hz, 2H), 1.92 – 1.80 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.2 (C), 162.1 (C), 131.7 (CH), 128.8 (CH), 128.4 (CH), 127.9 (CH), 126.9 (C), 123.6 (C), 113.72 (CH), 89.5 (C), 81.7 (C), 55.4 (CH3), 39.8 (CH2), 28.4 (CH2), 17.6 (CH2). LRMS (m/z, I) 293 (16), 292 (25), 291 (291), 277 (4). N-(5-Phenylpent-4-yn-1-yl)-4-(trifluoromethyl)benzamide (10c): yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.40 – 7.22 (m, 5H), 6.90 (br s, 1H), 3.65 (dd, J = 12.5, 6.3 Hz, 2H), 2.55 (t, J = 6.7 Hz, 2H), 2.08 – 1.83 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.4 (C), 137.9 (C), 133.1 (q, J = 32.8 Hz, C), 131.6 (CH), 128.4 (CH), 128.1 (CH), 127.5 (CH), 125.6 (q, J = 3.5 Hz, CH), 123.4 (C), 120.1 (q, J = 272.4 Hz, C), 89.4 (C), 81.9 (C), 40.2 (CH2), 28.1 (CH2), 17.7 (CH2). LRMS (m/z, I) 331 (74), 330 (27), 312 (13), 302 (23), 277 (15). HRMS calculated for C19H16NOF3 331.1184, found 331.1187 4-Bromo-N-(5-phenylpent-4-yn-1-yl)benzamide (10d): white solid. 1H NMR (300 MHz, CDCl3) δ 7.66 – 7.06 (m, 8H), 6.80 (br s, 1H), 3.53 (dd, J = 12.5, 6.3 Hz, 2H), 2.46 (t, J = 6.7 Hz, 2H), 2.03 – 1.64 (m, 2H). 13C NMR (75 MHz, CDCl3) δδ 166.7 (C), 133.5 (C), 131.7 (CH), 131.6 (CH), 128.6 (CH), 128.4 (CH), 128.0 (CH), 126.1 (C), 123.4 (C), 89.4 (C), 81.8 (C), 40.0 (CH2), 28.2(CH2), 17.6 (CH2).LRMS (m/z, I) 341 (28), 313 (9). HRMS calculated for C18H16NOBr 341.0415, found 341.0428. Chapter VI. 129 3-methyl-N-(5-phenylpent-4-yn-1-yl)benzamide (10e): white solid. 1H NMR (300 MHz, CDCl3) δ 7.60 – 7.47 (m, 1H), 7.40 – 7.30 (m, J = 6.7, 3.1 Hz, 1H), 7.30 – 7.17 (m, 2H), 6.49 (s, 1H), 3.63 (dd, J = 12.6, 6.4 Hz, 1H), 2.54 (t, J = 6.8 Hz, 1H), 2.30 (s, 1H), 2.01 – 1.86 (m, J = 6.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 167.9 (C), 138.5 (C), 134.7 (C), 132.2 (CH), 131.7 (CH), 128.4 (CH), 128.4 (CH), 127.9 (CH), 127.7 (CH), 124.0 (CH), 123.6 (C), 89.4 (C), 81.7 (C), 39.8 (CH2), 28.4 (CH2), 21.3 (CH3), 17.6 (CH2). 3-methoxy-N-(5-phenylpent-4-yn-1-yl)benzamide (10f): white solid . 1H NMR (300 MHz, CDCl3) δ 7.40 – 7.30 (m, 3H), 7.30 – 7.15 (m, 5H), 7.02 – 6.95 (m, 1H), 6.61 (s, 1H), 3.79 (s, 3H), 3.62 (dd, J = 12.6, 6.5 Hz, 2H), 2.53 (t, J = 6.8 Hz, 2H), 1.99 – 1.86 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6 (C), 159.9 (C), 136.2 (C), 131.7 (CH), 129.6 (CH), 128.3 (CH), 127.9 (CH), 123.6 (C), 118.7 (CH), 117.7 (CH), 112.4 (CH), 89.3 (C), 81.7 (C), 55.5 (CH3), 39.8 (CH2), 28.4 (CH2), 17.5 (CH2). N-(5-Phenylpent-4-yn-1-yl)-1-naphthamide (10g): white solid. 1H NMR (300 MHz, CDCl3) δ 8.34 – 8.13 (m, 1H), 7.90 – 7.69 (m, 2H), 7.61 – 7.11 (m, 9H), 6.60 (br s, 1H), 3.59 (dd, J = 12.6, 6.4 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 2.00 – 1.75 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 170.1 (C), 134.9 (C), 134.0 (C), 131.9 (CH), 130.8 (CH), 130.5 (C), 128.7 (CH), 128.2 (CH), 127.4 (CH), 126.8 (CH), 125.8 (CH), 125.3 (CH), 125.1 (CH),124.0 (C), 89.6 (C), 82.0 (C), 39.9 (CH2), 28.8(CH2), 17.8 (CH2). LRMS (m/z, I) 313 (57), 312 (90), 285 (40). N-(5-(o-Tolyl)pent-4-yn-1-yl)benzamide (10h): brown oil. 1H NMR (300 MHz, CDCl3) δ 7.77 – 7.52 (m, 2H), 7.48 – 6.89 (m, 8H), 6.53 (br s, 1H), 3.58 (dd, J = 12.5, 6.7 Hz, 2H), 2.61 – 2.40 (m, 2H), 2.32 (s, 3H), 1.97 – 1.77 (m 2H). 13C NMR (75 MHz, CDCl3) δ 167.7 (C), 140.1 (C), 134.6 (C), 132.0 (CH), 131.5 (CH), 129.5 (CH), 128.6 (CH), 127.9 (CH), 127.0 (CH), 125.6 (CH), 123.3 (C), 93.2 (C), 80.6 (C), 39.8 (CH2), 28.6 (CH2), 20.9 (CH3), 17.7 (CH2). LRMS (m/z, I) 277 (59), 259 (28). HRMS calculated for C19H19NO 277.1467, found 277.1455. Chapter VI. 130 N-(5-(3,5-Dimethylphenyl)pent-4-yn-1-yl)benzamide (10i): brown solid. 1H NMR (300 MHz, CDCl3) δ 7.66 (dd, J = 7.9, 6.7 Hz, 2H), 7.42 – 7.32 (m, 1H), 7.31 – 7.20 (m, 2H), 6.92 (s, 2H), 6.84 (s, 1H), 6.59 (brs, 1H), 3.56 (dd, J = 12.6, 6.3 Hz, 2H), 2.46 (dd, J = 8.4, 5.0 Hz, 2H), 2.18 (s, 3H), 1.92 – 1.78 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 168.0 (C), 138.3 (C), 135.1 (C), 131.8 (CH), 130.3 (CH), 129.8 (CH), 129.0 (CH), 127.4 (CH), 123.6 (C), 89.0 (C), 82.5 (C), 40.3 (CH2), 28.8 (CH3), 21.6 (CH2), 18.1 (CH2). LRMS (m/z, I) 291 (55), 263 (20). HRMS calculated for C20H21NO 291.1623, found 291.1622. N-(5-(p-Tolyl)pent-4-yn-1-yl)benzamide (10j): brown solid. 1H NMR (300 MHz, CDCl3) 7.66 (dd, J = 6.2, 5.2 Hz, 2H), 7.37 (dd, J = 10.6, 4.1 Hz, 1H), 7.31 – 7.16 (m, 4H), 7.00 (d, J = 8.0 Hz, 2H), 6.54 (brs, 1H), 3.56 (q, J = 6.3 Hz, 2H), 2.53 – 2.39 (m, 2H), 2.26 (s, 3H), 1.95 – 1.78 (m, 2H).13C NMR (75 MHz, CDCl3) δ 168.1 (C), 138.4 (C), 135.1 (C), 132.0 (CH), 131.9 (CH), 129.6 (CH), 129.0 (CH), 127.4 (CH), 120.9 (C), 89.0 (C), 82.3 (C), 40.3 (CH2), 28.8 (CH2), 22.0 (CH3), 18.0 (CH2). LRMS (m/z, I) 277 (33), 262 (6) 249 (6) HRMS calculated for C19H19NO 277.1467, found 277.1455. N-(5-(4-Methoxyphenyl)pent-4-yn-1-yl)benzamide (10k): brown solid. 1H NMR (300 MHz, CDCl3) δ 7.68 (dd, J = 8.3, 1.2 Hz, 2H), 7.47 – 7.11 (m, 5H), 6.82 – 6.67 (m, 2H), 6.56 (brs, 1H), 3.69 (d, J = 23.8 Hz, 3H), 3.55 (dt, J = 22.2, 10.9 Hz, 2H), 2.48 (dd, J = 12.6, 6.0 Hz, 2H), 2.03 – 1.77 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6 (C), 159.3 (C), 134.7 (C), 133.1 (CH), 131.7 (C), 131.5 (CH), 128.6 (CH), 127.0 (CH), 114.0 (CH), 87.8 (C), 81.5 (C), 55.4 (CH3), 39.9 (CH2), 28.4 (CH2), 17.6 (CH2). LRMS (m/z, I) 293 (45), 262 (6). HRMS calculated for C19H19NO2 293.1416, found 293.1420. N-(5-(Naphthalen-1-yl)pent-4-yn-1-yl)benzamide (10l): brown solid. 1H NMR (300 MHz, CDCl3) δ 8.24 (dd, J = 7.9, 1.1 Hz, 1H), 7.96 – 7.00 (m, 11H), 6.64 (brs, 1H), 3.72 – 3.46 (m, 2H), 2.56 (dt, J = 31.6, 6.8 Hz, 2H), 2.15 – 1.80 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.7 (C),134.5 (C), 133.4 (C), 133.2 (C), 131.4 (CH), 130.3 (CH), 128.5 (CH), 128.3 (CH), 127.0 (CH), 126.8 (CH), 126.5 (CH), 126.4 (CH), 126.2 (CH), 125.3 (CH), 121.2 (C), 94.4 (C), 79.7 (C), 39.9 (CH2), 28.6(CH2), 17.9(CH2). LRMS (m/z, I) 313 (47), 262 (7). HRMS calculated for C22H19NO 313.1467, found 313.1470. Chapter VI. 131 N-(5-(4-(Trifluoromethyl)phenyl)pent-4-yn-1-yl)benzamide (10m): white solid. 1H NMR (300 MHz, CDCl3) δ 7.87 – 7.04 (m, 9H), 6.85 (s, 1H), 3.52 (dd, J = 12.7, 6.7 Hz, 2H), 2.44 (t, J = 6.9 Hz, 2H), 2.00 – 1.70 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.8 (C), 134.5 (C), 131.8 (CH), 131.4 (CH), 129.4 (q, J = 32.6 Hz, C), 128.5 (CH), 127.5 (C), 127.0 (CH), 125.2 (q, J = 3.8 Hz, CH), 124.0 (q, J = 272.3 Hz, C), 92.1 (C), 80.3 (C), 39.6 (CH2), 28.3 (CH2), 17.4 (CH2). LRMS (m/z, I) 331 (44), 330 (33), 303 (8), 262 (9). HRMS calculated for C19H16NOF3 331.1184, found 331.1182. N-(Hex-4-yn-1-yl)benzamide (10o)180: white solid. 1H NMR (300 MHz, CDCl3) δ 7.88 – 7.65 (m, 2H), 7.55 – 7.30 (m, 3H), 6.55 (d, J = 35.7 Hz, 1H), 3.56 (dd, J = 12.6, 6.5 Hz, 2H), 2.37 – 2.13 (m, 2H), 1.85-1.70 (m, 5H). 13C NMR (75 MHz, CDCl3) δ 167.5(C), 134.7(C), 131.3 (CH), 128.5 (CH), 126.9 (CH), 78.4 (C), 76.6 (C), 39.7 (CH2), 28.3 (CH3), 16.7 (CH2), 3.5(CH2). LRMS (m/z, I) 201 (24), 200 (93) 173 (38). HRMS calculated for C13H15NO201.1154, found 201.1114. N-(6-Phenylhex-5-yn-1-yl)benzamide (10p): white solid. 1H NMR (300 MHz, CDCl3) δ 7.76 – 7.61 (m, 2H), 7.53 – 7.01 (m, 8H), 6.48 (br s, 1H), 3.39 (dt, J = 6.7, 3.8 Hz, 2H), 2.35 (dd, J = 9.3, 4.2 Hz, 2H), 1.80 – 1.44 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 167.7 (C), 134.8 (C), 131.7 (CH), 131.5 (CH), 128.7 (CH), 128.3 (CH), 127.8 (CH), 127.0 (CH), 123.9 (C), 89.8 (C), 81.3 (C), 39.7 (CH2), 29.0 (CH2), 26.2 (CH2), 19.2 (CH2). LRMS (m/z, I) 277 (32), 261 (50), 249 (12). HRMS calculated for C19H17NO 275.1310, found 275.1312 N-(7-Phenylhept-6-yn-1-yl)benzamide (10q): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.79 – 7.54 (m, 2H), 7.47 – 7.22 (m, 5H), 7.23 – 7.12 (m, 3H), 6.31 (br s, 1H), 3.47 – 3.26 (m, 2H), 2.34 (t, J = 6.7 Hz, 2H), 1.70 – 1.36 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 167.7 (C), 134.9 (C), 131.6 (CH), 131.4 (CH), 128.6 (CH), 128.3 (CH), 127.6 (CH), 126.9 (CH), 124.0 (C), 90.0 (C), 80.1(C), 40.0 (CH2), 29.3 (CH2), 28.4 (CH2), 26.2 (CH2), 19.4 (CH2). LRMS (m/z, I) 291 (36), 277 (16). HRMS calculated for C20H19NO 291.1623, found 291.1624. 180 This substrate was prepared using 4-hexyn-1-ol as starting material for the Mitsunobu reaction following the general procedure for the synthesis of benzamides. Chapter VI. 132 2.2 Procedure for the synthesis of alkynylbenzamides (14a-14d), exemplified for 14a. Acryloyl chloride (0.2 mL, 2.4 mmol) was stirred in CH2Cl2 (10 mL) with triethylamine (0.46 mL, 0.36 mmol) at rt for 10 min. Addition of commercial available 4-pentynamine (200 mg, 2.40 mmol) was followed by stirring for 5 h. The CH2Cl2 was removed in vacuo, and the remaining residue was dissolved in ethyl acetate. The solution was washed with 10% HCl and brine, dried over magnesium sulfate and filtered. The solvent was removed and the product was purified by column chromatography (hexanes:EtOAc; 1:1) to afford N-(pent-4yn-1-yl)acrylamide (13) (208 mg, 63%). In a Schlenk flask containing Pd(PPh3)4 (87 mg, 5 mol %) and CuI (14 mg, 5 mol%) at rt, N- (pent-4-yn-1-yl)acrylamide (206 mg, 1.5 mmol) and Et3N (10 mL) were added with stirring. Then iodobenzene (0.16 mL, 1 equiv.) was added and the mixture was heated to 60 ºC. After 5 hours the solvent was removed and the product was purified by column chromatography (hexanes:ethyl acetate; 1:1) to afford the product 14a (262 mg, 82%). N-(5-Phenylpent-4-yn-1-yl)acrylamide (14a): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.42 – 7.21 (m, 5H), 6.48 (s, 1H), 6.25 (d, J = 17.0 Hz, 1H), 6.11 (dd, J = 17.0, 10 Hz, 1H), 5.57 (d, J = 10.0 Hz, 1H), 3.47 (q, J = 6.4 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 1.83 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 165.7 (C), 131.4 (CH), 130.8 (CH), 128.1 (CH), 127.6 (CH), 126.1 (CH2), 123.5 (C), 88.9 (C), 81.3 (C), 38.8 (CH2), 28.2 (CH2), 17.0 (CH2). LRMS (m/z, I) 157 (50), 140 (69). N-(5-Phenylpent-4-yn-1-yl)methacrylamide (14b): yellow solid 1H NMR (300 MHz, CDCl3) δ 7.44 – 7.34 (m, 2H), 7.33 – 7.22 (m, 3H), 6.14 (s, 1H), 5.71 – 5.64 (m, 1H), 5.33 – 5.26 (m, 1H), 3.49 (dd, J = 12.7, 6.7 Hz, 2H), 2.49 (t, J = 6.9 Hz, 2H), 1.99 – 1.92 (m, 3H), 1.86 (p, J = 6.9 Hz, 2H).13C NMR (75 MHz, CDCl3) δ 168.5 (C), 140.1 (C), 131.5 (CH), 128.2 (CH), 127.8 (CH), 123.5 (C), 119.3 (CH2), 89.0 (C), 81.5 (C), 39.1 (CH2), 28.2 (CH2), 18.6 (CH3), 17.3 (CH2). LRMS (m/z, I) 212 (7), 199 (40). HRMS calculated for C15H17NO 227.1310, found 227.1312. Chapter VI. 133 N-(5-Phenylpent-4-yn-1-yl)cyclohex-1-enecarboxamide (14d): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.41 – 7.34 (m, 2H), 7.31 – 7.24 (m, 3H), 6.66 – 6.54 (m, 1H), 6.03 (s, 1H), 3.49 (dd, J = 12.6, 6.5 Hz, 2H), 2.49 (t, J = 6.8 Hz, 2H), 2.23 – 2.16 (m, 2H), 2.08 (dd, J = 6.1, 2.4 Hz, 2H), 1.85 (p, J = 6.7 Hz, 2H), 1.67 – 1.50 (m, 4H).13C NMR (75 MHz, CDCl3) δ 168.6 (C), 133.3 (CH), 133.1 (C), 131.5 (CH), 128.2 (CH), 127.7 (CH), 123.5 (C), 89.2 (C), 81.5 (C), 39.1 (CH2), 28.3 (CH2), 25.3 (CH2), 24.3 (CH2), 22.1 (CH2), 21.5 (CH2), 17.4 (CH2). LRMS (m/z, I) 250 (11), 239 (30). 2.3 Procedure for synthesis of hexynamides 18a and 18b, exemplified for 18b. To a solution of hex-5-ynoic acid (1.1 mL, 10 mmol) in CH2Cl2 (50 mL) at room temperature under argon were added dimethylaminopyridine (DMAP, 12 mg, 0.10 mmol), N,N'- Dicyclohexylcarbodiimide (DCC, 2.06 g, 10 mmol) and naphthalen-1-amine (1.43 g, 10.0 mmol). The mixture was stirred 10 min. at this temperature and then heated at reflux for 5 hours. CH2Cl2 (20 ml) was added and the precipitate filtered off. The resulting homogeneous solution was washed with 10% HCl (20 ml) and saturated NaHCO3 (20 ml). The solvent was evaporated and the crude product purified by flash chromatography (Hexanes:EtOAc; 3:1) to give N-(naphthalen-1-yl)hex-5-ynamide (1.28 g, 54 %) as a white solid. In a Schlenk flask containing Pd(PPh3)4 (232 mg, 5 mol %) and CuI (37 mg, 5 mol%), N- (naphthalen-1-yl)hex-5-ynamide (744 mg, 4 mmol) and Et3N (20 mL) were stirred at room temperature. Then iodobenzene (0.43 mL, 1 equiv.) was added and the mixture was heated to 60 ºC. After 5 hours the solvent was removed and the crude product was purified by column chromatography (hexanes:diethylether; 1:1) to afford the product 18b (511 mg, 59%). N,6-Diphenylhex-5-ynamide (18a): 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.60 – 7.21 (m, 9H), 7.16 – 6.96 (m, 1H), 2.68 – 2.41 (m, 4H), 2.09 – 1.95 (m, 2H).13C NMR (75 MHz, CDCl3) δ 170.8 (C), 137.9 (C), 131.5 (CH), 128.9 (CH), 128.2 (CH), 127.7 (CH), 124.1 (CH), 123.6 (C), 119.9 (CH), 88.9 (C), 81.6 (C), 36.2(CH2), 24.2 (CH2), 18.8 (CH2).LRMS (m/z, I) 220 (18), 159 (34). HRMS calculated for C18H17NO 263.1310, found 263.1309. Chapter VI. 134 N-(Naphthalen-1-yl)-6-phenylhex-5-ynamide (18b): 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.89 – 7.79 (m, 2H), 7.71 (dd, J = 33.9, 7.8 Hz, 2H), 7.53 – 7.21 (m, 8H), 2.59 (t, J = 7.2 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 2.07 – 1.95 (m, 2H).13C NMR (75 MHz, CDCl3) δ 171.5 (C), 133.9 (C), 132.2 (C), 131.5 (CH), 128.4 (CH), 128.2 (CH), 127.7 (CH), 127.4 (C), 126.0 (CH), 125.8 (CH), 125.4 (CH), 123.6 (C), 121.3 (CH), 121.0 (CH), 89.0 (C), 81.7 (C), 35.8 (CH2), 24.4 (CH2), 18.7 (CH2). LRMS (m/z, I) 183 (19), 128 (27). HRMS calculated for C27H19NO 313.1467, found 313.1465. 2.4 Procedure for catalytic reactions of alkynylbenzamides 11a-11q. In a Schlenk flask equipped with a stir bar were added 10 (0.25 mmol), [Cp*RhCl2]2 (3.9 mg, 2.5% mol) and Cu(OAc)2 (91 mg, 0.52 mmol) without any particular precautions to extrude oxygen or moisture. t-AmOH (2.0 mL) was then added and the flask sealed and placed in a pre-heated (110 °C) block. The reaction was stirred for 16 hours, cooled to room temperature and checked by TLC. The solvent was removed in vacuo and the remaining residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate) to afford the corresponding product 11. 10-Phenyl-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11a): white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (ddd, J = 7.9, 1.5, 0.5 Hz, 1H), 7.58 – 7.34 (m, 5H), 7.34 – 7.22 (m, 3H), 4.31 – 4.20 (m, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.14 (dt, J = 14.8, 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 161.0 (C), 141.2 (C), 138.0 (C), 136.3 (C), 131.8 (CH), 130.5 (CH), 128.6 (CH), 127.5 (CH), 127.3 (CH), 125.5 (CH), 124.9 (C), 124.2 (CH), 113.6 (C), 48.5 (CH2), 31.0 (CH2), 21.8 (CH2) .LRMS (m/z, I) 261 (100), 260 (75) HRMS calculated for C18H15NO 261.1154, found 275.1160. 8-Methoxy-10-phenyl-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11b): brown solid. 1H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 8.9 Hz, 1H), 7.66 – 7.12 (m, 6H), 7.04 – 6.82 (m, 1H), 6.55 (d, J = 2.5 Hz, 1H), 4.28 – 4.02 (m, 2H), 3.63 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 2.04 (dt, J = 14.9, 7.5 Hz, 2H).13C NMR (75 MHz, CDCl3) δ 162.6 (C), 160.9 (C), 142.1 (C), 140.3 (C), 136.5 (C), 130.6 (CH), 129.5 (CH), 128.8 (CH), 127.6 (CH), 119.1 (C), 114.5 (CH), Chapter VI. 135 113.4 (C), 106.0 (CH), 55.3 (CH3), 48.4 (CH2), 31.2 (CH2), 21.9 (CH2).LRMS (m/z, I) 291 (100), 277 (30). LRMS (m/z, I) 341 (28), 313 (9), 212 (38). HRMS calculated for C19H17NO2 291.1259, found 291.1266 10-Phenyl-8-(trifluoromethyl)-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11c): green solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J = 8.4 Hz, 1H), 7.63 – 7.31 (m, 5H), 7.31 – 7.15 (m, 2H), 4.23 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.25 – 2.03 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 160.3 (C), 143.2 (C), 138.1 (C), 135.3 (C), 133.53 (q, J = 32.1 Hz, C), 130.4 (CH), 129.1 (CH), 128.6 (CH), 128.1 (CH), 127.0 (C), 123.9 (q, J = 273.0 Hz, C), 121.6 (q, J = 3.4 Hz, CH), 113.6 (C), 48.8 (CH2) , 31.3 (CH2), 21.8 (CH2). LRMS (m/z, I) 329 ([M] 100), 328 (38) HRMS calculated for C19H14NOF3 329.1027, found 329.1019. 8-Bromo-10-phenyl-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11d): green solid 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J = 8.6 Hz, 1H), 7.32 (ddd, J = 46.4, 25.7, 6.7 Hz, 7H), 4.16 (t, J = 7.2 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.29 – 1.92 (m, 2H).13C NMR (75 MHz, CDCl3) δ 160.6 (C), 143.0 (C), 139.7 (C), 135.6 (C), 130.5 (CH), 129.3 (CH), 129.0 (CH), 128.9 (CH), 127.9 (CH), 127.4 (C), 126.8 (CH), 123.7 (C), 112.8 (C), 48.7 (CH2), 31.3 (CH2), 21.8 (CH2).LRMS (m/z, I) 341 (28), 313 (9), 212 (38) HRMS calculated for C18H14NOBr 339.0259, found 339.0259. 7-methyl-10-phenyl-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11e): yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.53 – 7.22 (m, 6H), 7.18 (d, J = 8.3 Hz, 1H), 4.30 – 4.22 (m, 2H), 2.92 (t, J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.20 – 2.07 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 161.1 (C), 140.4 (C), 136.6 (C), 135.9 (C), 135.7 (C), 133.5 (CH), 130.7 (CH), 128.8 (CH), 127.5 (CH), 127.1 (CH), 125.0 (C), 124.3 (CH), 113.7 (CH), 48.6 (CH2), 31.03 (CH2), 22.1 (CH2), 21.3 (CH3). 7-methoxy-10-phenyl-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11f): yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 2.7 Hz, 1H), 7.58 – 7.33 (m, 3H), 7.33 – 7.10 (m, 4H), 4.32 – 4.23 (m, 2H), 3.93 (s, 3H), 2.92 (t, J = 7.6 Hz, 2H), 2.21 – 2.09 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 160.7 (C), 157.9 (C), 138.8 (C), 136.4 (C), 132.2 (C), 130.5 (CH), 128.6 (CH), 127.4 (C), 126.1 (C), 125.9 (CH), 122.3 (CH), 113.7 (C), 107.1 (CH), 55.6 (CH3), 48.6 (CH2), 30.7 (CH2), 22.0 (CH2). Chapter VI. 136 9-methoxy-10-phenyl-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11f’): yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.13 (dd, J = 8.1, 1.0 Hz, 1H), 7.47 – 7.12 (m, 6H), 6.97 (dd, J = 7.8, 0.7 Hz, 1H), 4.37 – 4.11 (m, 2H), 3.35 (s, 3H), 2.79 (t, J = 7.7 Hz, 2H), 2.22 – 1.98 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 160.8 (C), 155.9 (C), 141.9 (C), 141.0 (C), 129.5 (CH), 128.5 (C), 127.5 (CH), 126.9 (C), 126.3 (CH), 126.2 (CH), 120.0 (CH), 114.1 (CH), 112.1 (C), 55.9 (CH3), 48.9 (CH2), 31.6 (CH2), 21.7 (CH2). Assignment of regioisomers by 1H-NMR The two regioisomers were assigned based on the coupling constants. As expected, in the 1HNMR spectrum of 11f, Ha appears as a doublet (d) with a small Jac = 2.7 Hz characteristic of this long distant couplings. Meanwhile, in the 1H-NMR spectrum of 11f’, Ha is a double of doublets (dd) with a Jab = 8.1 Hz and a small Jac = 1 Hz, which are also characteristic of these couplings. 7-Phenyl-9,10-dihydrobenzo[h]pyrrolo[1,2-b]isoquinolin-12(8H)-one (11g): yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.25 (d, J = 8.7 Hz, 1H), 8.02 – 6.98 (m, 10H), 4.44 – 4.13 (m, 2H), 2.84 (td, J = 7.7, 2.5 Hz, 2H), 2.25 – 1.88 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 161.6 (C), 143.2 (C), 139.5 (C), 136.8 (C), 133.1 (CH), 132.3 (C), 131.7 (C), 130.9 (CH), 128.8 (CH), 128.2 (CH), 128.0 (CH), 127.6 (CH), 127.4 (CH), 126.0 (CH), 122.8 (CH), 117.9 (C), 114.2 (C), 49.5 (CH2), 31.6 (CH2), 21.4 (CH2). LRMS (m/z, I) 313(57), 312 (89), 285 (40) HRMS calculated for C22H17NO311.1309, found 311.1310 10-(o-Tolyl)-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11h): pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.54 – 8.38 (m, 1H), 7.71 – 7.20 (m, 5H), 7.16 (d, J = 7.0 Hz, 1H), 6.99 (dd, J = 8.1, 0.9 Hz, 1H), 4.38 – 4.17 (m, 2H), 2.98 – 2.60 (m, 2H), 2.28 – 2.06 (m, 2H), 2.04 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.4 (C), 141.2 (C), 138.1 (C), 137.8 (C), 135.6 (C), 132.1 (CH), 131.0 (CH), 130.4 (CH), 128.2 (CH), 127.6 (CH), 126.4 (CH), 125.7 (CH), 125.0 (C), 124.2 (CH), 113.0 (C), 48.6 (CH2), 30.8 (CH2), 21.9 (CH2), 19.8 (CH3). LRMS (m/z, I) 275 (100), 260 (3), 246 (7). HRMS calculated for C19H17NO275.1310, found 275.1316. Chapter VI. 137 10-(3,5-Dimethylphenyl)-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11i): yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 8.0 Hz, 1H), 7.72 – 7.11 (m, 3H), 6.93 (d, J = 21.7 Hz, 1H), 6.84 (s, 2H), 4.35 – 4.08 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.54 – 2.17 (m, 6H), 2.07 (dt, J = 15.2, 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 161.2 (C), 141.1 (C), 138.3 (2xC), 136.2 (C), 131.9 (CH), 130.7 (C), 129.2 (CH), 128.3 (2xCH), 127.4 (CH), 125.6 (CH), 125.0 (C), 124.5 (CH), 114.1 (C), 48.6 (CH2), 31.2 (CH2), 22.0 (CH2), 21.5 (CH3).LRMS (m/z, I) 289 (100), 274 (7). HRMS calculated for C20H19NO289.1467, found 289.1467. 10-(Naphthalen-1-yl)-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11j): brown oil. 1H NMR (300 MHz, CDCl3) δ 8.58 – 8.47 (m, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.63 – 7.32 (m, 7H), 6.98 – 6.88 (m, 1H), 4.42 – 4.24 (m, 2H), 2.94 – 2.78 (m, 1H), 2.63 (ddd, J = 17.0, 8.2, 6.8 Hz, 1H), 2.23 – 2.03 (m, 2H).13C NMR (75 MHz, CDCl3) δ 161.9 (C), 142.8 (C), 139.2 (C), 134.4 (C), 134.2 (C), 133.2 (C), 132.5 (CH), 129.2 (CH), 129.0 (CH), 128.9 (CH), 127.9 (CH), 126.9 (CH), 126.6(CH), 126.3 (CH), 126.2 (CH), 126.1 (CH), 125.3 (C), 125.1 (CH), 111.9 (C), 49.1 (CH2), 31.3 (CH2), 22.2 (CH2). LRMS (m/z, I) 311 (100) 282 (5) HRMS calculated for C22H17NO311.1310, found 275.1310 10-(p-Tolyl)-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11k): yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 7.9 Hz, 1H), 7.48 – 7.27 (m, 3H), 7.21 (dd, J = 8.1, 4.3 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 4.19 (t, J = 7.2 Hz, 2H), 2.85 (t, J = 7.6 Hz, 2H), 2.35 (s, 3H), 2.13-1.98 (m 2H). 13C NMR (75 MHz, CDCl3) δ 161.2 (C), 141.3 (C), 138.4 (C), 137.3 (C), 133.4 (C), 131.9 (CH), 130.5 (CH), 129.5 (CH), 127.5 (CH), 125.6 (CH), 125.1 (C), 124.4 (CH), 113.8 (C), 48.6 (CH2), 31.2 (CH2), 22.0 (CH2), 21.4 (CH3).LRMS (m/z, I) 275 (100), 261 (24) HRMS calculated for C19H17NO275.1310, found 275.1304. 10-(4-Methoxyphenyl)-2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (11l): yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.40 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 – 7.09 (m, 5H), 7.03 – 6.88 (m, 2H), 4.29 – 4.12 (m, 2H), 3.80 (s, 3H), 2.86 (t, J = 7.6 Hz, 2H), 2.07 (dt, J = 15.3, 7.6 Hz, 2H).13C NMR (75 MHz, CDCl3) δ 161.2 (C), 159.1 (C), 141.5 (C), 138.5 (C), 131.9 (CH), 131.7 (CH), 128.5 (C), 127.5 (CH), 125.6 (CH), 125.0 (C), 124.4 (CH), 114.2 (CH), 113.42 (C), 55.4 (CH3), 48.6 (CH2), 31.2 (CH2), 22.0 (CH2). LRMS (m/z, I) 275 (100), 261 (24) HRMS calculated for C19H17NO2 291.1250, found 291.1260. Chapter VI. 240 135.5 (C), 135.4 (C), 128.6 (CH), 128.5 (CH), 128.3 (CH), 127.8 (CH), 127.3 (CH), 126.8 (CH), 126.3 (CH), 75.9 (C), 13.2 (CH3). HRMS (m/z, ESI) calculated for C23H18ClO [M+H]+ 345.1047 found, 345.1041. confirmed by XR-analysis. CCDC 995496 contains the crystallographic data of 31ka, which can be obtained via www.ccdc.cam.ac.uk/data_request/cif. 8-chloro-2-ethyl-4-methyl-1-phenylspiro[4,5]deca-1,3,7,9-tetraen-6-one (31kg): 73% yield, yellow oil. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.30 – 7.19 (m, 3H), 7.10 – 7.06 (m, 2H), 6.49 – 6.45 (m, 1H), 6.43 – 6.40 (m, 2H), 6.01 – 5.97 (m, 1H), 2.47 (q, J = 7.3 Hz, 2H), 1.76 (d, J = 1.6 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 194.7 (C), 152.9 (C), 149.5 (C), 144.9 (C), 143.1 (CH), 139.9 (C), 135.5 (CH), 135.4 (C), 128.4 (CH), 128.0 (CH), 127.0 (CH), 126.7 (CH), 125.9 (CH), 75.2 (C), 21.7 (CH2), 13.8 (CH3), 13.1 (CH3). HRMS (m/z, ESI) calculated for C19H18ClO [M+H]+ 297.1036 found, 297.1041. Assignment of the regiochemistry The major regioisomer was assigned based on the HMBC, HSQC, COSY experiments, as well as by the observation of nOe between the CH2OH chain and the hydrogen of the C3. 5-methyl-2,3-diphenyl-5´, 6´, 7´, 8´-tetrahydro-1´H-spiro[cyclopenta[2,4]diene-1,2naphthalen]1´-one (31ma): 78% yield, Yellow oil. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.39 – 7.34 (m, 2H), ), 7.28 (t, J = 2.2 Hz, 1H), 7.27 – 7.25 (m, 2H), 7.16 – 7.11 (m, 3H), 7.07 – 7.02 (m, 2H), 6.57 (q, J = 1.4 Hz, 1H), 6.28 (d, J = 9.3 Hz, 1H), 5.92 (d, J = 9.3 Hz, 1H), 2.47 – 2.33 (m, 4H), 1.81 (d, J = 1.5 Hz, 3H), 1.71 (dt, J = 11.5, 4.6 Hz, 4H). 13C NMR (75 MHz, CDCl3) δ(ppm): 196.2 (C), 150.7 (C), 146.1 (C), 144.9 (C), 141.6 (C), 136.6 (CH), 136.2 (C), 135.9 (C), 134.7 (CH), 133.6 (C), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.4 (CH), 127.3 (CH), 126.8 (CH), 76.0 (C), 30.8 (CH2), 22.1 (CH2), 22.0 (CH2), 13.2 (CH3). LRMS (CI) (m/z, I): 346 (69), 344 (69), 173 (100). 4,8,9-Trimethyl-1,2-diphenylspiro[4,5] deca-1,3,7,9-tetraen-6-one (31na): 77% yield, yellow solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.37 – 7.28 (m, 2H), 7.24 (ddd, J = 6.5, 3.7, 1.1 Hz, 3H), 7.16 – 7.07 (m, 3H), 7.07 – 7.00 (m, 2H), 6.59 – 6.51 (m, 1H), 6.15 (s, 1H), 5.76 (s, 1H), 2.13 (s, 3H), 2.03 (d, J = 1.0 Hz, 3H), 1.81 – 1.78 (m, 3H). 13C NMR (75 MHz, CDCl3) δ(ppm):197.1 (C), 157.3 (C), 146.3 (C), 145.0 (C), 141.6 (C), 136.1 (C), 136 (CH), 135.9 (C), 134.8 (CH), 132.4 (C), 128.6 (CH), 128.4 (CH), 128.2 (CH), 127.4 (CH), 127 (CH), 126.8 (CH), 21.7 (CH3), Chapter VI. 241 19.2 (CH3), 13.2 (CH3). LRMS (CI) (m/z, I): 339 (60), 338 (39), 275 (71), 257 (100), 246 (86), 149 (91). HRMS calculated for C25H23O: 339.1749, found, 339.1749. 4.5 Procedure B for the Rh-catalyzed annulations. To a solution of [Cp*RhCl2]2 (5.2 mg, 2.5 mol%) and Cu(OAc)2·H2O (33 mg, 0.5 equiv, 0.165 mmol) in CH3CN (2 mL) under air atmosphere was added the alkyne 2 (0.333 mmol) followed by the addition of corresponding ortho-vinylphenols 27 (0.50 mmol, 1.5 equiv). The reaction flask was sealed with a rubber septum and an air atmosphere was injected in the flask with a balloon and a needle. The reaction was heated at 60 °C, stirred until completion followed by TLC and then cooled to room temperature. The solvents were removed in vacuo and the remaining residue was purified by flash column chromatography on silica gel to afford the corresponding spirocycles 31. 1,2,4-triphenylspiro[4,5]deca-1,3,7,9-tetraen-6-one (31ca): 92% yield, orange solid. 1H NMR (300 MHz, CDCl3) δ(ppm):7.51 (s, 1H), 7.36 – 7.32 (m, 6H), 7.28 – 7.18 (m, 7H), 7.17 – 7.09 (m, 3H), 6.53 (dd, J = 9.2, 6.0 Hz, 1H), 6.33 (d, J = 9.9 Hz, 1H), 6.28 – 6.23 (m, 1H). 13C NMR (75 MHz, CDCl3) δ(ppm): 196.5(C), 148.2(C), 145.7(C), 143.1(CH), 142.3(C), 141.5(CH), 135(C), 134.9(C), 134.1(CH), 133.6(C), 129.4(CH), 129.2(CH), 128.8(CH), 128.5(CH), 128.3(CH), 128.1(CH), 127.7(CH), 127.7(CH), 125.7(CH), 123.2(CH), 75.5(C). HRMS (m/z, ESI) calculated for C28H21O [M+H]+ 373.1587 found, 373.1577. 4-(4-methoxyphenyl)-1,2-diphenylspiro[4.5]deca-1,3,7,9-tetraen-6-one (31da): 70% yield, brown foam. 1H NMR (300 MHz, CD2Cl2) δ 7.35 – 7.15 (m, 11H), 7.14 – 7.06 (m, 3H), 6.89 – 6.80 (m, 2H), 6.48 (dd, J = 9.0, 6.0 Hz, 1H), 6.27 – 6.17 (m, 2H), 3.78 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ 196.8 (C), 159.8 (C), 148.6 (C), 146.3 (C), 143.6 (CH), 142.1 (CH), 141.9 (C), 135.7 (C), 135.6 (C), 132.5 (CH), 129.8 (CH), 129.5 (CH), 128.9 (CH), 128.8 (CH), 128.5 (CH), 128.1 (CH), 128.0 (CH), 127.4 (CH), 127.1 (C), 123.6 (CH), 114.7 (CH), 75.9 (C), 55.8 (CH3). LRMS (CI) (m/z, I): 403 (49), 271 (50), 228 (100). HRMS calculated for C29H23O2 403.1698, found 403.1712 Chapter VI. 242 1,2-diphenyl-4-(4-(trifluoromethyl)phenyl)spiro[4.5]deca-1,3,7,9-tetraen-6-one (31ea): 98% yield, brown foam. 1H NMR (300 MHz, CDCl3) δ 7.62 – 7.51 (m, 3H), 7.39 (d, J = 8.2 Hz, 2H), 7.36 – 7.16 (m, 8H), 7.16 – 7.07 (m, 3H), 6.52 (dd, J = 9.2, 6.0 Hz, 1H), 6.34 – 6.28 (m, 1H), 6.24 – 6.18 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 196.0 (C), 146.5 (C), 145.6 (C), 143.7 (C), 143.2 (CH), 140.8 (CH), 136.8 (C), 136.5 (CH), 134.6 (C), 134.5 (C), 129.21 (CH), 129.19 (CH), 128.5 (CH), 128.4 (CH), 128.2 (CH), 127.9 (CH), 125.7 (CH), 124.2 (q, J = 271.8 Hz, C) 123.6 (CH), 75.3 (C). LRMS (CI) (m/z, I): 440 (100), 421 (50), 412 (58). HRMS calculated for C29H20OF3 441.1480, found 441.1466. 8-bromo -4-methyl-1,2-diphenylspiro[4,5] deca-1,3,7,9-tetraen-6-one (31ha): 67% yield, red oil. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.32 – 7.22 (m, 4H), 7.17 – 7.13 (m, 4H), 7.11 (d, J = 2.7 Hz, 1H), 7.04 – 7.01 (m, 2H), 6.58 (t, J = 1.6 Hz, 1H), 6.30 (d, J = 2.6 Hz, 1H), 6.15 (d, J = 10.1 Hz, 1H), 1.86 (d, J = 1.6 Hz, 3H).13C NMR (75 MHz, CDCl3) δ (ppm):194.9 (C), 146.7 (CH), 145.7 (C), 145.0 (C), 140.4 (C), 139.6 (CH), 135.7 (CH), 135.4 (C), 135.2 (C), 130.0 (CH), 128.5 (CH), 128.5 (CH), 128.3 (CH), 127.8 (CH), 127.3 (CH), 114.5 (C), 78.7 (C), 13.4 (CH3). HRMS (m/z, ESI) calculated for C23H18BrO [M+H]+ 389.0536 found, 389.0551. 1,2-triphenylazulen-7-bromo-4(3aH)-one (32ha):188 18% yield, red solid. 1H NMR (300 MHz, CDCl3) δ(ppm): 7.41 – 7.35 (m, 2H), 7.30 (dd, J = 2.9, 2.3 Hz, 2H), 7.27 – 7.24 (m, 3H), 7.20 (d, J = 0.7 Hz, 1H), 7.15 – 7.08 (m, 4H), 7.00 – 6.94 (m, 1H), 5.68 (d, J = 12.9 Hz, 1H), 1.46 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 197.8 (C), 151.2 (C), 145.8 (C), 143.9 (CH), 140.8 (CH), 139.4 (C), 134.5 (C), 133.9 (C), 133.8 (CH), 130.4 (CH), 128.8 (CH), 128.4(CH), 128.3 (CH), 128.2 (CH), 127.8 (CH), 122.2 (CH), 117.1 (C), 67.6 (C), 24.3 (CH3). LRMS (CI) (m/z, I): 390 (52), 311 (68), 310 (100). calculated for C23H18BrO [M+H]+ 389.0536 found, 389.0530. The structure of this compound was further confirmed by XR-anaylysis. CCDC 995497 contains the crystallographic data of 5ha, which can be obtained via www.ccdc.cam.ac.uk/data_request/cif. 188This compound was isolated as minor product in the reaction of xx and xx following general procedure B. Chapter VI. 243 4.6 Mechanistic experiments. 4.1 KIE measurements. To a solution of [Cp*RhCl2]2 (4.5 mg, 2.5 mol%) and Cu(OAc)2·H2O (29 mg, 0.146 mmol, 0.5 equiv) and diphenylacetylene (52 mg, 0,293 mmol) in MeCN (1 mL) under air atmosphere was added a equimolar solution of 27 and 27-d2 (0.386 mmol each) in MeCN (1 mL). This solution was prepared by mixing 75 mg of 31 and 99 mg of 31-d2 (88% deuterated). The reaction mixture was heated at 40 °C. After 45 minutes the reaction was poured in to Et2O (10mL), the solvents were evaporated in vacuo and the remaining residue was purified by flash column chromatography on silica gel to remove the remaining starting material. The residue was analyzed by H NMR. The KIE value (approx 2.3) was obtained by integrating the H3 of the spiro 31 and the H9 of the spiro 31 and 31-d. The conversion (approx 10%) was determined based on the starting material (27) recovered. 4.1 Deuterium exchange (without alkyne). To a solution of [Cp*RhCl2]2 (5.2 mg, 2.5 mol%) and Cu(OAc)2·H2O (33 mg, 0.5 equiv, 0.165 mmol) in CH3CN (1.7 mL) under air atmosphere was added 2-(prop-1-en-2-yl)phenol 27a H3 H9 Chapter VI. 244 (0.50 mmol, 1.5 equiv) and D2O (0.3 mL). The reaction was sealed with a rubber septum and an air atmosphere was injected in the flask with a balloon and a needle. The reaction was heated at 40 °C, stirred for 4 h and then cooled to room temperature. The solvents were removed in vacuo and the remaining residue was purified by flash column chromatography on silica gel to give 27a and 27a-dn (26 mg, 39% recovery). 30% deuteration on both olefinic protons based on 1H-NMR.189 1) 1-H-NMR of starting material 27a 2) 1H-NMR of the starting material 27a-dn -recovered (30% deuteration) 189No deuteration was observed in absence of the either the rhodium catalyst or copper acetate. Chapter VI. 245 4.2 Deuterium exchange (with alkyne). To a solution of [Cp*RhCl2]2 (5.2 mg, 2.5 mol%) and Cu(OAc)2·H2O (33 mg, 0.5 equiv, 0.165 mmol) in CH3CN (1.7 mL) under air atmosphere was added diphenylacetylene (59 mg, 1 equiv, 0.333 mmol) followed by the addition of 2-(prop-1-en-2-yl)phenol 27a (0.50 mmol, 1.5 equiv) and D2O (0.3 mL). The reaction was sealed with a rubber septum and an air atmosphere was injected in the flask with a balloon and a needle. The reaction was heated at 40 °C, stirred for 4 h and then cooled to room temperature. The solvents were removed in vacuo and the remaining residue was purified by flash column chromatography on silica gel to afford the 4-methyl-1,2-diphenylspiro[4.5]deca-1,3,7,9-tetraen-6-one 31aa (12 mg, 11%), diphenylacetylene 29a (49 mg, 83% recovered) and 2-(prop-1-en-2-yl)phenol 27a (44 mg, 66% recovered). 3) 1-H-NMR of product 31aa recovered 4) 1H-NMR of 27a-recovered Chapter VI. 246 4.3 Competition between alkynes 29b and 29c. To a solution of [Cp*RhCl2]2 (4.6 mg, 2.5 mol%) and Cu(OAc)2·H2O (30 mg, 0.150 mmol, 0.5 equiv) and alkynes 29b (143 mg, 2 equiv, 0.6 mmol) and 29c (189 mg, 2 equiv, 0.6mmol) in MeCN (2 mL) under air atmosphere was added 2-(prop-1-en-2-yl)phenol (27a) (40 mg, 1 equiv, 0,3 mmol). The reaction was sealed with a rubber septum and an air atmosphere was injected in the flask with a balloon and a needle. The reaction was heated at 40 °C and stirred at that temperature. After 2h, the resulting mixture was filtered through silica, washing with diethylether; the solvents were evaporated in vacuo and the residue was analyzed by 1H NMR in CDCl3 indicating ~ 1:7 mixture of 31ab:31ac and a conversion of approx 35%, based on the amount of starting materials recovered. 4.4 Stoichiometric experiment. To a solution of [Cp*RhCl2]2 (50 mg, 0.5 equiv) in CH3CN (1 mL) under air atmosphere was added diphenylacetylene (29 mg, 1 equiv, 0.162mmol) followed by the addition of 2-(prop-1en-2-yl)phenol 27a (22 mg, 1 equiv. 0.162 mmol). The reaction was sealed with a rubber septum and an air atmosphere was injected in the flask with a balloon and a needle. The solution was stirred for 45 min at 40 °C and no conversion was observed through TLC, after that, CsOAc (62 mg, 2 equiv) was added and the mixture stirred 1h. The solvents were removed in vacuo and the remaining residue was purified by flash column chromatography on silica gel to afford the 4-methyl-1,2-diphenylspiro[4.5]deca-1,3,7,9-tetraen-6-one 31aa (43 mg, 86%). Chapter VI. 247 A similar experiment was carried out using Et3N (41 µL, 2 equiv) instead of CsOAc to afford the 4-methyl-1,2-diphenylspiro[4.5]deca-1,3,7,9-tetraen-6-one 31aa (32 mg, 64%) after 5h of reaction. 4.7 Thermal rearrangement. A solution of 31aa (31 mg, 0.10 mmol) or 32aa (31 mg, 0.10 mmol) in CH3CN (2 mL) was refluxed for 12h. The solvents were removed in vacuo and the product was isolated in quantitative yield without further manipulation. Analysis of the 1H-NMR shows aprox. 1:1 mixture of 31aa and 32aa. Chapter VI. 249 5CHAPTER V: Oxidative annulations of o -alkenylanilines 5.1 General considerations All non commercial vinylanilines were synthesized from the corresponding ketone via Wittig reaction, if the ketone was not available, then an addition of the corresponding Grignard reagent was done to the appropriately substituted 2-aminobenzonitrile.190 Boc191, acetyl, tosyl, isopropyl173, trifluoroacetyl192 and nosyl193 protected o-alkenylanilines were synthesized as previously described in the literature. All spectral data recorded was in agreement with those in the corresponding communication. 5.2 Procedure for the synthesis of triflyl protected o-alkenylanilides (37a37k) exemplified for 37a. To a solution of o-isopropenylaniline (1 mL, 7.34 mmol) in dichloromethane (25 mL) under Ar atmosphere was added triethylamine (1.228 ml, 1.2 equiv) at 0 ⁰C. Then trifluoromethanesulfonic anhydride (1.489 ml, 1.2 equiv) was added dropwise. The reaction was stirred at 0 °C for 1.5 hours and quenched with saturated NH4Cl aqueous solution. The resulting mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. Evaporation of the solvent followed by purification column flash chromatography on silica gel (hexanes:diethylether; 8:2) affording 1,1,1-trifluoro-N-(2-(prop-1-en-2yl)phenyl)methanesulfonamide (37a), (1.84g, 94%), as a white solid upon freezing. 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 7.9 Hz, 1H), 7.25 – 7.09 (m, 4H), 5.36 (dd, J = 2.7, 1.2 Hz, 1H), 4.92 (s, 1H), 2.00 (d, J = 1.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 142.2 (C), 135.9 (C), 130.8 (C), 128.7 (CH), 128.6 (CH), 126.4 (CH), 121.1 (CH), 119.9 (q, J = 323.4 Hz, C), 118.1 (CH2), 24.5 (CH3). 1,1,1-trifluoro-N-(2-vinylphenyl)methanesulfonamide (37b): 59% yield, pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.49 – 7.37 (m, 1H), 7.35 – 7.10 (m, 3H), 6.79 (dd, J = 17.3, 11.1 Hz, 1H), 6.59 (brs, 1H), 5.63 (d, J = 17.4 Hz, 1H), 5.37 (d, J = 11.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 134.4 (C), 131.1 (CH), 130.8 (C), 129.2 (CH), 190 Jana, S.; Ashokan, A.; Kumar, S.; Verma, A.; Kumar, S. Org. Biomol. Chem. 2015, 13, 8411. 191 Kobayashi, K.; Fukamachi, S.; Nakamura, D.; Morikawa, O.; Konishi, H. Heterocycles 2007, 75, 95. 173 Ferguson, J.; Zeng, F.; Alwis, N.; Alper, H. Org. Lett. 2013, 15, 1998. 192 Kobayashi, K.; Miyamoto, K.; Morikawa, O.; Konishi, H. Bull. Chem. Soc. Jpn. 2005, 78, 886. 193 Liwosz, T. W.; Chemler, S. R. Synlett 2015, 26, 335. Chapter VI. 256 N-(8-(4-chlorophenyl)-5,6-dipropylnaphthalen-1-yl)-1,1,1-trifluoromethanesulfonamide (39ed) major regioisomer: 90% yield 4:1 mixture of inseparable regioisomers, brown solid. 1H NMR (300 MHz, CDCl3) δ 7.75 (dd, J = 8.5, 0.9 Hz, 1H), 7.44 – 7.01 (m, 9H), 3.38 – 3.23 (m, 2H), 2.82 – 2.64 (m, 2H), 1.62 (dd, J = 15.4, 7.6 Hz, 2H), 1.48 (dd, J = 16.3, 7.5 Hz, 2H), 1.07 – 0.91 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 141.0 (C), 139.5 (C), 137.9 (C), 134.2 (C), 133.7 (C), 133.5 (C), 131.7 (CH), 131.1 (CH), 129.9 (C), 129.1 (CH), 128.7 (CH), 128.3 (CH), 128.2 (CH), 124.1 (CH), 119.9 (q, J = 323.6 Hz, C), 36.9 (CH2), 31.8 (CH2), 25.6 (CH2), 25.0 (CH2), 14.4 (CH3), 14.1 (CH3). LRMS (EI) (m/z, EI): 471 (19), 469 (50), 338 (34), 336 (100). HRMS calculated for C23H23NO2 F3SCl: 469.1090 found, 469.1080. N-(5,6-dipropyl-8-(p-tolyl)naphthalen-1-yl)-1,1,1-trifluoromethanesulfonamide (39fd): 90% yield, brown solid. 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J = 8.4, 1.3 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.30 – 7.19 (m, 6H), 7.08 (brs, 1H), 3.39 – 3.29 (m, 2H), 2.82 – 2.73 (m, 2H), 1.74 – 1.60 (m, 2H), 1.60 – 1.45 (m, 2H), 1.07 (t, J = 7.3 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 141.04 (C), 139.2 (C), 138.1 (C), 137.3 (C), 133.8 (C), 133.5 (C), 131.1 (CH), 130.3 (CH), 129.8 (C), 129.5 (CH), 129.2 (CH), 128.6 (C), 127.9 (CH), 123.8 (CH), 119.9 (q, J = 323.7 Hz, C), 36.9 (CH2), 31.8 (CH2), 25.7 (CH2), 25.0 (CH2), 21.3 (CH3), 14.4 (CH3), 14.1 (CH3). LRMS (m/z, EI): 449 (53), 316 (100). HRMS calculated for C24H26NO2F3S: 449.1636 found, 449.1654. N-(2,8-dimethyl-5,6-dipropylnaphthalen-1-yl)-1,1,1-trifluoromethanesulfonamide (39hd) major regioisomer: 60% yield <13:1 mixture of inseparable regioisomers, brown solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.13 (s, 1H), 6.87 (brs, 1H), 3.35 (t, J = 7.5 Hz, 2H), 2.83 – 2.70 (m, 2H), 2.61 (s, 6H), 1.76 – 1.60 (m, 2H), 1.36 – 1.20 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 140.8 (C), 137.5 (C), 132.8 (C), 132.7 (C), 131.7 (C), 131.2 (C), 130.4 (CH), 127.0 (CH), 126.8 (CH), 125.7 (C), 119.48 (q, J = 323.0 Hz, C), 37.3 (CH2), 31.5 (CH2), 24.9 (CH2), 24.6 (CH2), 19.8 (CH2), 19.7 (CH2), 14.3 (CH3), 14.2 (CH3). LRMS (m/z, EI): 387 (23), 254 (100). HRMS calculated for C19H24NO2F3S: 387.1480 found, 387.1486. N-(4,8-dimethyl-5,6-dipropylnaphthalen-1-yl)-1,1,1-trifluoromethanesulfonamide (39id) major regioisomer: 72% yield >15:1 mixture of inseparable regioisomers, brown solid. 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 8.3 Hz, 2H), 7.03 (brs, 1H), 3.36 – 3.23 (m, 2H), 2.86 (s, J = 7.6 Hz, 3H), 2.83 (s, 3H), 2.80 – 2.70 (m, 2H), 1.67 (dq, J = 14.9, 7.4 Hz, 2H), 1.44 (dq, J = 15.0, 7.4 Hz, 2H), 1.11 – 0.92 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 140.5 (C), 138.4 (C), 135.3 (C), 133.7 (CH), 133.6 (C), 132.9 (C), 131.7 (C), 127.6 (CH), 127.1 (C), Chapter VI. 257 126.8 (CH), 119.8 (q, J = 324.0 Hz, C), 36.6 (CH), 32.2 (CH2), 26.4 (CH2), 26.1 (CH3), 24.8 (CH2), 24.8 (CH2), 14.3 (CH3), 14.1 (CH3). LRMS (m/z, EI): 387 (34), 254 (100). HRMS calculated for C19H24NO2F3S: 387.1480 found, 387.1486 . N-(3,8-dimethyl-5,6-dipropylnaphthalen-1-yl)-1,1,1-trifluoromethanesulfonamide (39jd) major regioisomer: 59% yield >10:1 mixture of inseparable regioisomers, brown solid. 1H NMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.35 (s, 1H), 7.17 (s, 1H), 7.03 (brs, 1H), 3.34 – 3.23 (m, 2H), 2.78 – 2.70 (m, 2H), 2.61 (s, 3H), 2.50 (s, 3H), 1.75 – 1.41 (m, 4H), 1.16 – 0.97 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 140.1 (C), 134.5 (C), 133.6 (C), 132.1 (C), 132.0 (C), 131.1 (CH), 129.4 (CH), 128.7 (C), 127.6 (C), 126.2 (CH), 119.91 (q, J = 323.7 Hz, C), 36.7(CH2), 31.6 (CH2), 25.7(CH2), 25.0 (CH2), 21.2 (CH2), 20.3 (CH2), 14.4 (CH3), 14.0 (CH3). LRMS (m/z, EI): 387 (45), 254 (100). HRMS calculated for C19H24NO2 F3S: 387.1480 found, 387.1478 . N-(3,8-dimethyl-5,6-dipropylnaphthalen-1-yl)-1,1,1-trifluoromethanesulfonamide (39kd) major regioisomer: 61% yield 5:1 mixture of inseparable regioisomers, brown solid. 1H NMR (300 MHz, CDCl3) δ 8.22 (s, J = 0.8 Hz, 1H), 7.59 (s, 1H), 7.24 (s, 1H), 7.13 (brs, 1H), 3.33 – 3.16 (m, 2H), 2.78 – 2.66 (m, 2H), 2.62 (d, J = 9.6 Hz, 3H), 1.70 – 1.51 (m, 2H), 1.49 – 1.34 (m, 2H), 1.08 – 0.90 (m, 6H).13C NMR (75 MHz, CDCl3) δ 140.1 (C), 134.5 (C), 133.6 (C), 132.1 (C), 132.0 (C), 131.1 (CH), 129.4 (CH), 128.7 (C), 127.6 (C), 126.2 (CH), 119.91 (q, J = 323.7 Hz, C), 36.7(CH2), 31.6 (CH2), 25.7(CH2), 25.0 (CH2), 21.2 (CH2), 20.3 (CH2), 14.4 (CH3), 14.0 (CH3). LRMS (m/z, EI): 441 (43), 308 (100). HRMS calculated for C19H21NO2 F6S: 441.1197 found, 442.1199 Chapter VII. 259 CHAPTER VII: Selected spectra Chapter VII. 261 1. Selected spectra from chapter II. Chapter VII. 262 Chapter VII. 263 Chapter VII. 264 Chapter VII. 265 Chapter VII. 272 Chapter VII. 273 Chapter VII. 274 Chapter VII. 275 4. Selected spectra from chapter V. Chapter VII. 276 Chapter VII. 277 Chapter VII. 278 Chapter VII. 279 Chapter VII. 280 ANNEX I: Resumen Annex I. 288 una reorganización del espirociclo. De hecho, se propone que existe un equilibrio entre ambos productos en condiciones de reacción ya que, la disolución y calentamiento de cualquiera de los dos por separado, da lugar a una mezcla de espirociclo y azulenona. Para explicar dicho equilibrio se echa mano de la formación de un intermedio tricíclico zwitteriónico consistente en dos anillos de seis y cinco miembros fusionados formando un ciclopropano. Anelación oxidativa de o-alquenilanilinas. El último capítulo de la tesis se centra en trasladar la química de alquenilfenoles a alquenilanilinas ya que una gran parte de los productos farmacológicos de interés, poseen algún átomo de nitrógeno en su estructura. En primer lugar, se busca identificar un sustituyente apropiado para el átomo de nitrógeno que aporte los requerimientos estéricos y electrónicos necesarios para que la reacción tenga lugar. Entre los diversos grupos probados, se observa que los electroatractores son más propensos a reaccionar de forma productiva. Sin embargo, en lugar de las benzazepinas o espirominas esperados, se obtiene una mezcla de naftilaminas regioisoméricas. Estos dos isómeros provienen de una cicloadición formal (4+2) entre el aminoestireno y el alquino y otra cicloadición formal (4+2) entre ambos sustratos pero con una migración formal 1,2 del alqueno previa a la anelación. Una posterior optimización de las condiciones permite llegar a rendimientos globales superiores al ochenta por ciento. Concretamente, cuando se usan 5 mol% de precatalizador de rodio en dioxano a reflujo con un equivalente de cobre como oxidante. Sorpresivamente, se demuestra que aunque el catalizador es, previsiblemente, imprescindible para que la reacción ocurra, no lo es así el oxidante de cobre ya que, su sustitución por acetato de sodio sigue dando lugar a una mezcla similar de naftilaminas en rendimientos comparables. Se demuestra, además, que la transformación también puede ser llevada a cabo en condiciones más suaves como THF a reflujo sin disminución apreciable del rendimiento global. Al igual que en capítulos anteriores, se estudia el efecto de la sustitución en la reactividad obteniéndose que, con respecto al anillo, tanto sustituyentes dadores como atractores son Annex I. 289 aceptados. En el caso de los alquinos empleados se encuentran diferencias significativas entre los sustituidos con grupos arilo o alquilo ya que estos últimos, generalmente, dan lugar a mezclas de regiosómeros más favorables hacia la anelación sin migración formal. También se describe cómo la reacción es incapaz de producirse cuando no hay sustitución en la posición interna del doble enlace o cuando la hay en la externa. Asimismo se comenta que la reacción falla cuando se usan 2-fenilanilinas en lugar de 2-alquenilanilinas. Por último describen un resultado interesante cuando se usan olefinas sustituidas con un grupo isopropilo, que es la isomerización del doble enlace hacia el isopropilo generando la olefina trisustituida. En este caso no se han realizado estudios mecanísticos pero sí se proponen varias hipótesis capaces de explicar cómo se producen ambos isómeros (para lo cual se postula la formación de una espiroimina intermedia) y cómo la reacción puede suceder en ausencia de un oxidante “clásico” como el aire o el cobre: - La primera explicación consiste en la hidroarilación del alquino catalizada por rodio (III) y la posterior formación del espirociclo mediada por el mismo complejo de rodio y completada con una β-eliminación de hidruro. La protonación del hidruro de rodio generado daría lugar a hidrógeno gas y a la recuperación del complejo catalíticamente activo. - En segundo lugar se propone la formación de las dihidronaftilaminas a partir del dihidroespirociclo las cuales, al entrar en contacto con el oxígeno en la elaboración, se oxidan dando lugar a las naftilaminas correspondientes. - Por último se postula que la reacción sigue un ciclo análogo a los propuestos para los alquenilfenoles y la oxidación del complejo de rodio (I), formado en la etapa de eliminación reductora, por adición oxidante al ácido acético, formado en el paso de activación C-H, y protonación del hidruro de rodio generado como en el caso anterior. Conclusión general. Como conclusión general, en esta tesis se describen varios procesos de anelación oxidativa catalizados por rodio (III) dando lugar a diferentes productos y realizando experimentos mecanísticos para elucidar los caminos que siguen las reacciones.