Direct functionalization of heterocyclic and non-heterocyclic arenes

L’application des métaux de transition à la fonctionnalisation directe a ouvert la voie à une nouvelle classe de réactions pour la formation de liens carbone-carbone. De par l'omniprésence des liaisons C–H, l’introduction de nouvelles fonctionnalités chimiques par voie directe et pré-activation minimale s’impose comme une stratégie de synthèse très attrayante. Ainsi, il est envisageable de préparer de manière rapide et efficace des supports complexes menant à des molécules complexes, qui pourraient être utiles dans divers domaines de la chimie. L'objectif principal de la présente thèse vise la fonctionnalisation directe des arènes hétérocycliques et non hétérocycliques et, plus précisément, les techniques d’arylation. Dans un premier temps, nous allons aborder le thème de l’arylation directe tout en mettant l’accent sur les pyridines (Chapitre 1). Ces molécules sont à la base d'une multitude de composés biologiquement actifs et jouent un rôle important dans le domaine des sciences des matériaux, de l’agrochimie et de la synthèse des produits naturels. Dans un deuxième temps, nous discuterons de nos travaux sur l’arylation directe catalysé par un complex de palladium sur des ylures de N-iminopyridinium en soulignant la dérivatisation du sel de pyridinium après une phénylation sp2 (Chapitre 2). L’étude de ce procédé nous a permis de mettre en lumière plusieurs découvertes importantes, que nous expliquerons en détails une à une : l’arylation benzylique directe lorsque des ylures N-iminopyridinium substituées avec un groupement alkyl à la position 2 sont utilisés comme partenaires dans la réaction; les allylations Tsuji-Trost catalysée par un complex de palladium; et l’alkylation directe et sans métal via une catalyse par transfert de phase. Plusieurs défis restent à relever pour le développement de procédés directs utilisant des métaux de transition peu coûteux, d’autant plus que la synthèse par transformation directe des pyridines 2-alcényles, lesquelles sont pertinentes sur le plan pharmacologique, n’a pas encore été rapportée à ce jour. Avec cette problématique en tête, nous avons réussi à mettre au point une alcénylation directe catalysé par un complex de cuivre sur des ylures de N-iminopyridinium. Nous discuterons également d’une nouvelle méthode pour la préparation des iodures de vinyle utilisés dans les couplages. Ces réactions sont non seulement remarquablement chimiosélectives, mais sont aussi applicables à plusieurs substrats (Chapitre 3). En optimisant ce procédé direct, nous avons découvert une façon unique de synthétiser les pyrazolo[1,5-a]pyridines 2-substituées (Chapitre 4). Le mécanisme global met en jeu une séquence tandem de fonctionnalisation-cyclisation directe et un procédé direct en cascade, qui n’avais jamais été rapporté. Cela simplifie ansi la synthèse autrement compliquée de ces substrats en y apportant une solution à un problème de longue date. Dans les deux derniers chapitres, nous examinerons en détail les techniques d’arylation directe qui n'impliquent pas les partenaires de couplage hétérocycliques. Entre autres, au Chapitre 5, nous soulignerons notre découverte d’un umpolung dirigé et catalysé par un complexe de palladium du benzène et de quelques autres dérivés arènes. Il s’agit là du premier cas de fonctionnalisation directe dans laquelle le groupe directeur se trouve sur le partenaire halogène et il s’ajoute à la courte liste d’exemples connus dans la littérature rapportant une arylation directe du benzène. Finalement, au Chapitre 6, nous passerons en revue une nouvelle arylation directe catalysée au fer, qui se veut un procédé peu coûteux, durable et présentant une économie d’atomes. Nous discutons des substrats possibles ainsi des études mécanistiques réalisés.The application of transition metals towards direct functionalization processes has exposed an opportunistic new class of carbon-carbon bond forming reactions. Given the undeniable ubiquity of C–H bonds, the possibility of introducing functionality through direct means with minimal preactivation is an irresistible strategy in synthesis. As such one can envision rapidly and efficiently building up complex scaffolds towards complex molecules of interest in a plethora of chemical fields. The focus of this thesis is on the direct functionalization of heterocyclic and non-heterocyclic arenes, focusing on arylation technologies. First, the topic of direct arylation will be introduced, with special emphasis being on pyridines (Chapter 1). These molecules comprise the backbone of a myriad of biologically active compounds, and are also relevant in material sciences, agrochemicals, and natural products synthesis. This will be followed by a discussion of work on the palladium-catalyzed direct arylation of N-iminopyridinium ylides with accent on the derivatization of the pyridinium following the sp2 phenylation (Chapter 2). The exploration of this process led to the discovery of direct benzylic arylation when 2-alkyl N¬-iminopyridinium ylides are employed as reacting partners, in addition to palladium-catalyzed Tsuji-Trost allylations, and metal-free direct alkylation via phase transfer catalysis. All of these findings will be discussed in detail. There remains a significant challenge in developing direct processes utilizing inexpensive transition metals. Furthermore, the synthesis of pharmacologically relevant 2-alkenyl pyridines through direct transformations had not yet been reported. We focused on these challenges and developed a copper-catalyzed direct alkenylation of N-iminopyridinium ylides. A novel method to prepare the vinyl iodide coupling partners will also be discussed. The scopes of these reactions are quite large and remarkably chemoselective (Chapter 3). Through the optimization of this direct process we uncovered an unique means of synthesizing 2-substituted pyrazolo[1,5-a]pyridines (Chapter 4). The global process involved a tandem direct functionalization/cyclization sequence, and may be the first account of a direct process used in a cascade. This work also solves an important problem, as the synthesis of these substrates through alternate means is not straightforward. The last two chapters will detail direct arylation technologies that do not involve heterocyclic coupling partners. Chapter 5 will highlight our uncovering of a palladium-catalyzed, directed, umpolung arylation of benzene and other arene derivatives. This was the first account of a direct functionalization whereby the directing group is situated on the pseudo electrophile. Also, it adds to the few examples of direct benzene arylation exisiting in the literature. Finally, a discussion of an atom economical, inexpensive, sustainable iron-catalyzed direct arylation process will be presented with special emphasis on substrate scope and mechanistic investigations (Chapter 6)

A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

Ladder polyether natural products are a class of natural products denoted by their high functional-group density and large number of well-defined stereocenters. They comprise the toxic component of harmful algal blooms (HABs), having significant negative economic and environmental ramifications. However, their mode of action, namely blocking various cellular ion channels, also denotes their promise as potential anticancer agents. Understanding their potential mode of biosynthesis will not only help with developing ways to limit the damage of HABs, but would also facilitate the synthesis of a range of analogs with interesting biological activity. 1,3-Dioxan-5-ol substrates display remarkable ‘enhanced template effects’ in water-promoted epoxide cyclization processes en route to the synthesis of these ladder polyether natural products. In many cases, they provide near complete endo-to-exo selectivity in the cyclization of epoxy alcohols, thereby strongly favoring the formation of tetrahydropyran (THP) over tetrahydrofuran (THF) rings. The effects of various Brønsted and Lewis acidic and basic conditions are explored to demonstrate the superior selectivity of the template over the previously reported THP-based epoxy alcohols. In addition, the consideration of other synthetic routes are also considered with the goal of gaining rapid access to a plethora of potential starting materials applicable towards the synthesis of ladder polyethers. Finally, cascade sequences with polyepoxides are investigated, further demonstrating the versatility of this new reaction template.National Institute of General Medical Sciences (U.S.) (Grant GM72566)Natural Sciences and Engineering Research Council of CanadaFonds québécois de la recherche sur la nature et les technologie

α-Amino bicycloalkylation through organophotoredox catalysis †

Bridged bicycloalkanes such as bicyclo[1.1.1]pentanes (BCPs) and bicyclo[3.1.1]heptanes (BCHeps) are important motifs in contemporary drug design due to their potential to act as bioisosteres of disubstituted benzene rings, often resulting in compounds with improved physicochemical and pharmacokinetic properties. Access to such motifs with proximal nitrogen atoms (i.e. α-amino/amido bicycloalkanes) is highly desirable for drug discovery applications, but their synthesis is challenging. Here we report an approach to α-amino BCPs and BCHeps through the visible-light enabled addition of α-amino radicals to the interbridgehead C–C bonds of [1.1.1] and [3.1.1]propellane respectively. The reaction proceeds under exceptionally mild conditions and displays broad substrate scope, providing access to an array of medicinally-relevant BCP and BCHep products. Experimental and computational mechanistic studies provide evidence for a radical chain pathway which depends critically on the stability of the α-amino radical, as well as effective catalyst turnover

The Pandora multi-algorithm approach to automated pattern recognition of cosmic-ray muon and neutrino events in the MicroBooNE detector.

The development and operation of liquid-argon time-projection chambers for neutrino physics has created a need for new approaches to pattern recognition in order to fully exploit the imaging capabilities offered by this technology. Whereas the human brain can excel at identifying features in the recorded events, it is a significant challenge to develop an automated, algorithmic solution. The Pandora Software Development Kit provides functionality to aid the design and implementation of pattern-recognition algorithms. It promotes the use of a multi-algorithm approach to pattern recognition, in which individual algorithms each address a specific task in a particular topology. Many tens of algorithms then carefully build up a picture of the event and, together, provide a robust automated pattern-recognition solution. This paper describes details of the chain of over one hundred Pandora algorithms and tools used to reconstruct cosmic-ray muon and neutrino events in the MicroBooNE detector. Metrics that assess the current pattern-recognition performance are presented for simulated MicroBooNE events, using a selection of final-state event topologies

Convolutional Neural Networks Applied to Neutrino Events in a Liquid Argon Time Projection Chamber

We present several studies of convolutional neural networks applied to data coming from the MicroBooNE detector, a liquid argon time projection chamber (LArTPC). The algorithms studied include the classification of single particle images, the localization of single particle and neutrino interactions in an image, and the detection of a simulated neutrino event overlaid with cosmic ray backgrounds taken from real detector data. These studies demonstrate the potential of convolutional neural networks for particle identification or event detection on simulated neutrino interactions. We also address technical issues that arise when applying this technique to data from a large LArTPC at or near ground level

The Pandora multi-algorithm approach to automated pattern recognition of cosmic-ray muon and neutrino events in the MicroBooNE detector

The development and operation of Liquid-Argon Time-Projection Chambers for neutrino physics has created a need for new approaches to pattern recognition in order to fully exploit the imaging capabilities offered by this technology. Whereas the human brain can excel at identifying features in the recorded events, it is a significant challenge to develop an automated, algorithmic solution. The Pandora Software Development Kit provides functionality to aid the design and implementation of pattern-recognition algorithms. It promotes the use of a multi-algorithm approach to pattern recognition, in which individual algorithms each address a specific task in a particular topology. Many tens of algorithms then carefully build up a picture of the event and, together, provide a robust automated pattern-recognition solution. This paper describes details of the chain of over one hundred Pandora algorithms and tools used to reconstruct cosmic-ray muon and neutrino events in the MicroBooNE detector. Metrics that assess the current pattern-recognition performance are presented for simulated MicroBooNE events, using a selection of final-state event topologies.Comment: Preprint to be submitted to The European Physical Journal

Determination of muon momentum in the MicroBooNE LArTPC using an improved model of multiple Coulomb scattering

We discuss a technique for measuring a charged particle's momentum by means of multiple Coulomb scattering (MCS) in the MicroBooNE liquid argon time projection chamber (LArTPC). This method does not require the full particle ionization track to be contained inside of the detector volume as other track momentum reconstruction methods do (range-based momentum reconstruction and calorimetric momentum reconstruction). We motivate use of this technique, describe a tuning of the underlying phenomenological formula, quantify its performance on fully contained beam-neutrino-induced muon tracks both in simulation and in data, and quantify its performance on exiting muon tracks in simulation. Using simulation, we have shown that the standard Highland formula should be re-tuned specifically for scattering in liquid argon, which significantly improves the bias and resolution of the momentum measurement. With the tuned formula, we find agreement between data and simulation for contained tracks, with a small bias in the momentum reconstruction and with resolutions that vary as a function of track length, improving from about 10% for the shortest (one meter long) tracks to 5% for longer (several meter) tracks. For simulated exiting muons with at least one meter of track contained, we find a similarly small bias, and a resolution which is less than 15% for muons with momentum below 2 GeV/c. Above 2 GeV/c, results are given as a first estimate of the MCS momentum measurement capabilities of MicroBooNE for high momentum exiting tracks

Design and construction of the MicroBooNE Cosmic Ray Tagger system

The MicroBooNE detector utilizes a liquid argon time projection chamber (LArTPC) with an 85 t active mass to study neutrino interactions along the Booster Neutrino Beam (BNB) at Fermilab. With a deployment location near ground level, the detector records many cosmic muon tracks in each beam-related detector trigger that can be misidentified as signals of interest. To reduce these cosmogenic backgrounds, we have designed and constructed a TPC-external Cosmic Ray Tagger (CRT). This sub-system was developed by the Laboratory for High Energy Physics (LHEP), Albert Einstein center for fundamental physics, University of Bern. The system utilizes plastic scintillation modules to provide precise time and position information for TPC-traversing particles. Successful matching of TPC tracks and CRT data will allow us to reduce cosmogenic background and better characterize the light collection system and LArTPC data using cosmic muons. In this paper we describe the design and installation of the MicroBooNE CRT system and provide an overview of a series of tests done to verify the proper operation of the system and its components during installation, commissioning, and physics data-taking

Noise Characterization and Filtering in the MicroBooNE Liquid Argon TPC

The low-noise operation of readout electronics in a liquid argon time projection chamber (LArTPC) is critical to properly extract the distribution of ionization charge deposited on the wire planes of the TPC, especially for the induction planes. This paper describes the characteristics and mitigation of the observed noise in the MicroBooNE detector. The MicroBooNE's single-phase LArTPC comprises two induction planes and one collection sense wire plane with a total of 8256 wires. Current induced on each TPC wire is amplified and shaped by custom low-power, low-noise ASICs immersed in the liquid argon. The digitization of the signal waveform occurs outside the cryostat. Using data from the first year of MicroBooNE operations, several excess noise sources in the TPC were identified and mitigated. The residual equivalent noise charge (ENC) after noise filtering varies with wire length and is found to be below 400 electrons for the longest wires (4.7 m). The response is consistent with the cold electronics design expectations and is found to be stable with time and uniform over the functioning channels. This noise level is significantly lower than previous experiments utilizing warm front-end electronics.Comment: 36 pages, 20 figure

Ionization Electron Signal Processing in Single Phase LArTPCs II. Data/Simulation Comparison and Performance in MicroBooNE

The single-phase liquid argon time projection chamber (LArTPC) provides a large amount of detailed information in the form of fine-grained drifted ionization charge from particle traces. To fully utilize this information, the deposited charge must be accurately extracted from the raw digitized waveforms via a robust signal processing chain. Enabled by the ultra-low noise levels associated with cryogenic electronics in the MicroBooNE detector, the precise extraction of ionization charge from the induction wire planes in a single-phase LArTPC is qualitatively demonstrated on MicroBooNE data with event display images, and quantitatively demonstrated via waveform-level and track-level metrics. Improved performance of induction plane calorimetry is demonstrated through the agreement of extracted ionization charge measurements across different wire planes for various event topologies. In addition to the comprehensive waveform-level comparison of data and simulation, a calibration of the cryogenic electronics response is presented and solutions to various MicroBooNE-specific TPC issues are discussed. This work presents an important improvement in LArTPC signal processing, the foundation of reconstruction and therefore physics analyses in MicroBooNE.Comment: 54 pages, 36 figures; the first part of this work can be found at arXiv:1802.0870