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Synthesis of Cyclopropylboronates and Allylic Alcohols Via Copper -Catalyzed Borylation Reactions

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Synthesis of Cyclopropylboronates and Allylic Alcohols Via Copper -Catalyzed Borylation Reactions Synthesis of Cyclopropylboronates and Allylic Alcohols via Copper -Catalyzed Borylation Reactions Laura Amenós Núñez Doctoral Thesis Supervised by Dr. Mariola Tortosa Departamento de Química Orgánica Universidad Autónoma de Madrid Madrid, Noviembre, 2017 A Javi. Por todo. This Doctoral Thesis has been developed in the Organic Chemistry Department at Universidad Autónoma de Madrid, under supervision of Dr. Mariola Tortosa Manzanares. The financial support for this work has been obtained from the European Research Council (ERC-337776) and MINECO (CTQ2012-35957). Esta Tesis Doctoral ha sido realizada en el Departamento de Química Orgánica de la Universidad Autónoma de Madrid, bajo la dirección de la Doctora Mariola Tortosa Manzanares. Este trabajo ha sido financiado por el ‘European Research Council’ (ERC -337776) , así como por MINECO (CTQ2012 -35957). Acknowledgements _________________________________________________________________________ Después de todo el tiempo y esfuerzo que conlleva una tesis, creo que una de las cosas más importantes es el cariño y apoyo de la gente que te rodea, por eso quiero agradecer a todos los que han compartido conmigo esta etapa de mi vida de algún modo. En primer lugar quiero empezar agradeciendo a mis dos pilares en el mundo de la química, a Antonio por acogerme en mis primeros pasos de aprendizaje y por tener siempre la puerta abierta para ayudar en lo que fuese y a Mariola por darme la oportunidad de desarrollar una tesis doctoral en este grupo en el que ha sido un placer trabajar, sin duda. Empezando por el principio de los tiempos, quería agradecer a mis compañeros de carrera Toni , Cristian y Jordi por acompañarme en esos años, pero sobre todo a Cristina por haber sido un apoyo muy importante en esa etapa y porque lo sigue siendo, aunque este tiempo en la distancia. D’altra banda, li he d’agrair moltíssim al Toni Moragas per ensenyar- me a treballar en un laboratori de veritat, perquè que no ens enganyin durant la carrera no se n’aprèn. Moltes gràcies per la teva paciència, per transmetre’m la teva passió per la investigació i sobretot pel teu suport, perquè vas estar en els moments que més et vaig necessitar. Mi paso por el ICIQ estuvo también marcado por personas a quien quiero dar las gracias, a Ruth por todos los descansos y meriendas, a Pili por contagiarme de su energía, a Tania por desprender felicidad y Ana , mi asturiana preferida, por dejarse arrastrar hacia las tradiciones catalanas y por hacerme sentir que no pasa el tiempo cuando nos vemos. Llegando a Madrid, a mi familia, porque dicen que los amigos son la familia que se escoge y vosotros lo habéis sido. Llegué sin nada, ni nadie y me lo llevo TODO! Son muchas vivencias compartidas, risas, anécdotas, cenas, palentinos, escapadas y como no, algún que otro llanto; pero todas dignas de recordar. Porque sin duda lo mejor de esta tesis ha sido conocer a todas esta gente. Gracias a Fran , Edu , Sara Morales y Sandra por todos los buenos momentos compartidos en la cuarta planta durante los primeros meses. A la primera persona con la que hablé en el laboratorio y la que ha resultado ser la más importante, Cristina , nunca me imaginé que conectaríamos tanto, gracias por todo, pero sobre todo gracias por enseñarme que hay veces que la distancia no importa. A Aurora , otra de las grandes, mi primera compañera de vitrina y de batalla, gracias por estar siempre ahí codo con codo. A Mer por su preocupación y por su gran apoyo en mis peores momentos. A Gema por tener siempre historias que contar para amenizar las comidas. A Alex , el segundo de abordo, por estar siempre ahí para tirar de nosotros cuando la cosa se tuerce y recordarnos que la química es muy ‘caprichosa’. A Manu , porque lo importante no es como se empieza sino como se acaba. A Carlos , por ser un gran compañero y estar siempre dispuesto a ayudarme. A mis extremeños, a Víctor Tena por compartir tanto y a Alfredo por aguantarme estos últimos meses; gracias a los dos por ser como sois, Acknowledgements _________________________________________________________________ porque os habéis convertido en personas muy importantes para mí y quiero que esto no cambie por muchas vueltas que dé la vida. A Ana Arroyo , por sufrirme, porque lo de enseñar nunca fue lo mío y tú me lo pusiste muy fácil. A Víctor Martín , por enseñarme que todas las buenas amistades empiezan con un ‘tú antes me caías mal’. Also, I want to thank to Tim for all his advices, it was a great pleasure to work next to you. A Ana Pereira , por traer su alegría sureña, gracias por significar tanto en tan poco tiempo. A Laura Trulli , por ser una persona con tanta ‘essenza’, me encantas. Al Miquel , per portar-me una mica de Catalunya al laboratori i per contagiar el seu bon rotllo a tothom. A Víctor García , el niño, por no saber nunca por donde nos iba a salir y por regalarnos siempre una sonrisa. A Fabio , Mario y Sergio por ser grandes compañeros aun habiendo coincido poco. Y a Jaime y Yago porque siempre saben cómo arrancarte una carcajada cuando te cruzas con ellos. A los de siempre, a Chris por no necesitar mucho para entendernos. A Ana por conseguir retomar lo que se quedó en el aire. A Gemma por su alegría contagiosa. Y a Diana por seguir entendiéndonos por mucho que pase el tiempo. A los amigos de Javi. ¡Qué digo! A MIS amigos, a Joan y Araceli por todos los buenos momentos. A Óscar , por su sincera amistad. Al Miquel per estar sempre disposat a tot. Y a Cris y Carol por todo el cariño que me transmiten día a día. A les nenes, a la Myriam pel seu etern somriure. A la Maria Pérez per ser tan natural. A la Maria Riera pel seu humor tan especial. A la Núria per contagiar-nos la seva vitalitat. I a l’ Anna , que ara més que mai val per dos, per fer el que calgui perquè ens retrobem totes. A Marta , por venir. No hi ha paraules per agrair-te tot el que hem viscut, perquè res hagués estat igual sense tu a Madrid. Gràcies pels moments de plorar de riure, per les abraçades, per la complicitat, gràcies per absolutament TOT! Y es que algunas veces la familia se hace corta y se le añade alguien que no tiene la misma sangre, pero lo parece. A Pili y a Francisco por todo el apoyo incondicional que siempre he recibido por su parte. A Soraya y Dani por todos los buenos momentos compartidos pero sobretodo por haber traído al mundo a Dani y a Martina , quienes dan luz a nuestros días nublados. A MIS PADRES por su paciencia, por su apoyo, por haberme enseñado tanto y por haberme ayudado a ser la persona que he llegado a ser, porque sin ellos nada de esto hubiese sido posible. GRACIAS POR TODO! Y por último, a Javi por creer en mí, por darme fuerza, por aguantarme y por estar siempre ahí. Porque la distancia que nos ha separado durante cuatro años, nos ha unido más si cabe. Cada día tengo más claro que eres la persona con quien quiero compartir el resto de mi vida, porque solo tú sabes cómo sacar siempre lo mejor de mí. ¡TE QUIERO! TABLE OF CONTENTS Abbreviations SUMMARY …………………………………………………… 1 RESUMEN ……………………………………………….......... 5 1. INTRODUCTION 1.1. General Overview ……………………………….…..……. 11 1.2. Boronic Acids and Derivatives ………………….….….… 14 1.3. Copper-Catalyzed Borylation Reactions ………..….…… 20 1.3.1. Copper-Catalyzed Borylation of Alkynes ……...………...……. 25 1.3.2. Copper-Catalyzed Borylation of Alkene .……………………… 30 1.3.3. Copper-Catalyzed Borylation of α,β-Unsaturated compounds .. 33 1.3.4. Copper-Catalyzed Borylation of Dienes, Enynes, and Allenes … 36 1.3.5. Copper-Catalyzed Borylation of Aldehydes and Imines ……..... 40 1.3.6. Copper-Catalyzed Borylation of Allylic and Propargylic Electrophiles …………….………………………………….………… 43 2. SYNTHESIS OF CYCLOPROPYLBORONATES BY COPPER-CATALYZED DESYMMETRIZATION OF CYCLOPROPENES 2.1. Background ………………………………………….......... 49 2.1.1. Importance of Cyclopropanes in Organic Chemistry …...…….. 49 2.1.2. Enantioselective Desymmetrization of Cyclopropenes …….…. 52 2.1.3. Synthesis of Cyclopropylboronates …………………...……..... 59 2.1.3.1. Diastereoselective Synthesis of Cyclopropylboronates …….. 60 2.1.3.2. Asymmetric Synthesis of Cyclopropylboronates …………… 65 2.2. Synthesis of Cyclopropylboronates through Copper- Catalyzed Desymmetrization of Cyclopropenes …………..... 71 2.2.1. Copper(I)-Catalyzed Borylation ………………………………. 71 2.2.1.1. Introduction and Objectives ………………………………… 71 2.2.1.2. Synthesis of a Model Substrate ……………………………... 72 2.2.1.3. Copper-Catalyzed Borylation of Cyclopropenes Using non- Chiral Ligands: Screening of Conditions ……………………………. 73 2.2.1.4. Copper-Catalyzed Borylation of Cyclopropenes Using Chiral Ligands: Screening of Conditions …………………...………………. 75 2.2.1.5. Scope of the Reaction ……………………………………….. 81 2.2.1.6. Mechanistic Proposal ……………………………………….. 86 2.2.1.7. Proposed Transition-State Models for the Copper-Catalyzed Hydroboration of Cyclopropenes ……………………………………. 87 2.2.2. Copper(I)-Catalyzed Aminoboration ………………………..... 89 2.2.2.1. Introduction and Objectives ………………………………… 89 2.2.2.2. Synthesis of Starting Materials ………………………..……. 91 2.2.2.3. Copper-Catalyzed Aminoboration of Cyclopropenes: Screening of conditions ……………………………………………… 92 2.2.2.4. Scope of the Reaction ………………………………..……… 95 2.2.2.5. Mechanistic Proposal ……………………………………….. 98 2.2.3. Conclusions …………………………………………...………. 99 2.2.4. Conclusiones ………………………………………………….. 100 2.3. Supplementary data ……………………………..………. 101 2.3.1. General Experimental Details ……………………..………….. 101 2.3.2. Synthesis of Starting Materials …………..………..………….. 103 2.3.2.1. General Procedure for the Synthesis of Dibromocyclopropanes, II-2 ……………………..………………….. 103 2.3.2.2. General Procedure for the Synthesis of 3,3-Disubstituted Cyclopropenes, II-4 …………………………….....……..………….. 108 2.3.2.3. Synthesis of (1-methylcycloprop-2-en-1-yl-2,3-d2)benzene, II-4j ………………………………………………………………….
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