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Catalytic Methods to Convert Allylic Substrates Through Hydride and Proton Shifts

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Catalytic Methods to Convert Allylic Substrates Through Hydride and Proton Shifts Samuel Martinez-Erro Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts Transition Metal-Catalyzed and Organocatalyzed Approaches Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts Hydride and Proton through Substrates Allylic to Convert Methods Catalytic Samuel Martinez-Erro Samuel Martinez-Erro Samuel was born in Pamplona, Spain. In 2015, he started his PhD at Stockholm University supervised by Prof. Belén Martín-Matute. He has expertise in Organic Synthesis, Metal and Organocatalysis and Mechanistic studies. ISBN 978-91-7797-903-6 Department of Organic Chemistry Doctoral Thesis in Organic Chemistry at Stockholm University, Sweden 2019 Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts Transition Metal-Catalyzed and Organocatalyzed Approaches Samuel Martinez-Erro Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry at Stockholm University to be publicly defended on Friday 6 December 2019 at 10.00 in Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B. Abstract The present thesis describes the development of new catalytic protocols to transform allylic substrates into a wide variety of versatile carbonyl and vinyl organic compounds. All procedures that are described in this work have in common the existence of one or more hydrogen shifts as key steps in the mechanism of the reactions. The thesis is divided into two mayor sections depending on the strategy employed, metal catalysis or organocatalysis. The introductory chapter (Chapter 1) starts with an overview of the different types of catalysis and the importance of allylic substrates in organic chemistry. The chapter continues with an extensive description of the isomerization of allylic alcohols and finishes with a short introduction about hypervalent iodine chemistry. The goals of the thesis are also depicted at the end of this chapter. Chapters 2, 3 and 4 embody the use of iridium catalysis as an effective tool to synthesize α-functionalized carbonyl compounds selectively as single constitutional isomers from allylic alcohols. The first two chapters of this section describe the employment of several electrophiles to trap enolate derivatives formed from the corresponding allylic alcohols. Chapter 2 shows the development of two new protocols for the preparation of challenging α-iodinated carbonyl compounds. In chapter 3, the synthesis of α-aminooxy and α-hydroxyketones is investigated by employing an N-oxoammonium salt as electrophilic agent. Chapter 4 describes the development of an umpolung strategy that allows the synthesis of α- functionalized carbonyls through the reaction of two formal nucleophiles: enolate derivatives and alcohols. Mechanistic investigations performed in this section point to the presence of an iridium-catalyzed hydride shift operating in the reaction pathways. The last three chapters (5, 6 and 7) describe the development of metal-free methods for the conversion of allylic substrates into valuable products by means of base catalysis. Chapter 5 and 6 depict the stereospecific isomerization of a large scope of allylic alcohols, ethers and halides. A simple guanidine-type base, TBD (1,5,7-triazabicyclo[4.4.0]dec-5- ene), is an effective catalyst to isomerize allylic substrates with excellent levels of transfer of chirality. The mechanism of this transformation is studied in detail experimentally and computationally and it is suggested to involve a [1,3]- proton shift through the formation of a tight ion-pair. Chapter 7 shows that base-catalysis allows the isomerization of conjugated polyenyl alcohols and ethers which has been proved to be challenging with metal–catalysis. Experimental and computational investigations in this last chapter suggests that the mechanism may proceed through a series of iterative [1,3]-proton shifts or “base-walk”. Keywords: Allylic substrates, Iridium catalysis, Base catalysis, Method development, Isomerization, Hydride shift, Proton shift, Mechanistic studies. Stockholm 2019 http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-175359 ISBN 978-91-7797-903-6 ISBN 978-91-7797-904-3 Department of Organic Chemistry Stockholm University, 106 91 Stockholm CATALYTIC METHODS TO CONVERT ALLYLIC SUBSTRATES THROUGH HYDRIDE AND PROTON SHIFTS Samuel Martinez-Erro Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts Transition Metal-Catalyzed and Organocatalyzed Approaches Samuel Martinez-Erro ©Samuel Martinez-Erro, Stockholm University 2019 ISBN print 978-91-7797-903-6 ISBN PDF 978-91-7797-904-3 Cover image: "In a far away land called Organic Synthesis" by Silvia Martínez Erro designed using resources from freepik.com Printed in Sweden by Universitetsservice US-AB, Stockholm 2019 To those who made it possible “When life gets you down, do you wanna know what you´ve gotta do? Just keep swimming!” Dory, Finding Nemo Abstract The present thesis describes the development of new catalytic protocols to transform allylic substrates into a wide variety of versatile carbonyl and vinyl organic compounds. All procedures that are described in this work have in common the existence of one or more hydrogen shifts as key steps in the mechanism of the reactions. The thesis is divided into two major sections depending on the strategy employed, metal catalysis or organocatalysis. The introductory chapter (Chapter 1) starts with an overview of the different types of catalysis and the importance of allylic substrates in organic chemistry. The chapter continues with an extensive description of the isomerization of allylic alcohols and finishes with a short introduction about hypervalent iodine chemistry. The goals of the thesis are also depicted at the end of this chapter. Chapters 2, 3 and 4 embody the use of iridium catalysis as an effective tool to synthesize a-functionalized carbonyl compounds selectively as single constitutional isomers from allylic alcohols. The first two chapters of this section describe the employment of several electrophiles to trap enolate derivatives formed from the corresponding allylic alcohols. Chapter 2 shows the development of two new protocols for the preparation of challenging a-iodinated carbonyl compounds. In chapter 3, the synthesis of a-aminooxy and a-hydroxyketones is investigated by employing an N-oxoammonium salt as electrophilic agent. Chapter 4 describes the development of an umpolung strategy that allows the synthesis of a-functionalized carbonyls through the reaction of two formal nucleophiles: enolate derivatives and alcohols. Mechanistic investigations performed in this section point to the presence of an iridium-catalyzed hydride shift operating in the reaction pathways. The last three chapters (5, 6 and 7) describe the development of metal-free methods for the conversion of allylic substrates into valuable products by means of base catalysis. Chapter 5 and 6 depict the stereospecific isomerization of a large scope of allylic alcohols, ethers and halides. A simple guanidine-type base, TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), is an effective catalyst to isomerize allylic substrates with excellent levels of transfer of chirality. The mechanism of this transformation is studied in detail experimentally and computationally and it is suggested to involve a [1,3]-proton shift through the formation of a tight ion-pair. Chapter 7 shows that base-catalysis allows the isomerization of conjugated polyenyl alcohols and ethers which has been proved to be challenging with metal–catalysis. Experimental and computational investigations in this last chapter suggests that the mechanism may proceed through a series of iterative [1,3]-proton shifts or “base-walk”. i Populärvetenskaplig sammanfattning Organiska molekyler har många viktiga användningar i det moderna samhället. Från läkemedel och jordbrukskemikalier till sensorer, bränslen eller hushållsprodukter. Deras existens i vår vardag är enorm. En stor utmaning för kemister är att skapa metoder för att få tillgång till organiska molekyler på ett effektivt och selektivt sätt. Numera är det viktigare än någonsin att dessa metoder är hållbara och har minimal påverkan på miljön. Av dessa skäl är det extremt viktig att forskningen syftar till att utveckla nya effektiva och miljövänliga reaktioner för att få tillgång till viktiga organiska molekyler. I detta sammanhang presenteras i denna doktorsavhandling flera projekt som syftar till att söka nya metoder för syntes av användbara molekyler inom organisk kemi. Det övergripande målet är att utveckla effektiva och selektiva metoder med olika katalysatorer och använda vanligt förekommande allyliska substrat som råmaterial. Den första delen av denna avhandling handlar om användningen av iridiumkatalys som ett effektivt verktyg för selektiv syntes av a-funktionaliserade karbonylföreningar. Lättillgängliga allyliska alkoholer omvandlas effektivt till en mängd olika funktionaliserade aldehyder och ketoner som är extremt mångsidiga föreningar i organisk syntes. Därefter handlar den andra delen om upptäckten av nya metallfria reaktioner vilka utnyttjar baskatalys. Allyliska substrat såsom allyliska alkoholer, etrar och halogenider omvandlas till relevanta molekyler under milda reaktionsbetingelser och med användning av en enkel bas som katalysator. Reaktionsvägen har alltid studerats och undersökts i alla projekt genom denna avhandling. Att få en djup förståelse av reaktionsmekanismen möjliggör att metoden i framtiden förbättras och utvecklas på ett bättre och mer effektivt
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