DOCSLIB.ORG

4-Π Photocyclisation: a New Route to Functionalised Four-Membered Rings

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
4-Π Photocyclisation: a New Route to Functionalised Four-Membered Rings 4- Photocyclisation: A New Route to Functionalised Four-Membered Rings Thomas Britten This dissertation is submitted for the degree of Doctor of Philosophy April 2019 School of Chemistry Dedicated to Elsie Daisy Alice Moore (1916-2018) and Karin Dixon Wilkins (1962-2015) i Declaration This thesis has not been submitted in support of an application for another degree at this or any other university. It is the result of my own work and includes nothing that is the outcome of work done in collaboration except where specifically indicated. Many of the ideas in this thesis were the product of discussion with my supervisor Dr Susannah Coote. Thomas K. Britten MChem Lancaster University, UK ii Abstract The work disclosed within this thesis describes the use of photochemistry to develop efficient and scalable methodology to access functionalised four-membered rings. Chapter 2 examines the synthesis and synthetic potential of 1,2-dihydropyridazines. The feasibility of the current literature syntheses of 1,2-dihydropyrdazines on multigram scales has been investigated, which has resulted in the development of a novel, scalable route to unsubstituted 1,2-dihydropyridazines. Currently, the synthesis is not amenable to the synthesis of substituted 1,2-dihydropyridazines. 1,2-Dihydropyridazines are precursors to interesting molecular scaffolds through double bond transformations, however in some cases the isolated product was not the expected product. Chapter 3 investigates the optimisation and scale up of the 4-π photocyclisation of 1,2- dihydropyridazines using commercially available batch and flow photoreactors. The use of a batch photoreactor gave better yields, purity and productivity for the synthesis of bicyclic 1,2- diazetidines compared to the flow photoreactor. The photophysical properties of 1,2- dihydropyridazines have been studied and the data has provided guidance for optimisation and rationale for the observed results. Chapter 4 explores the stability and synthetic potential of bicyclic 1,2-diazetidines to access functionalised 1,2-diazetidines, cyclobutenes and other products that were not expected at the outset of the project. Attempts to access cyclobutenes (through N-N cleavage) were unsuccessful due to a facile 4-π electrocyclic ring opening, whereas it was possible to synthesis a range of novel monocyclic functionalised 1,2-diazetidines. Chapter 5 provides overall conclusions, as well as a comparison of the synthesised compounds to Lipinski’s “rule of five” and lead-like space using open access software and ideas for future work Chapters 6 and 7 will provide the experimental details and characterisation of novel compounds that have been reported in this thesis. The appendix gives details on the X-ray crystal structures and differential scanning calorimetry traces for a select few examples. iii Acknowledgements Firstly, I would like to thank my supervisor Dr Susannah Coote for all her help, support and guidance throughout my PhD. In the same manner, I would like to thank my industry supervisor Dr Paul Kemmitt for your support, input into the project and making me feel welcome when I completed my placement at AstraZeneca. A special thank you my second supervisor Dr Mike Coogan, Dr Nicholas Evans, as well as my appraisal panel members Dr Vilius Franckevicius and Dr Verena Görtz. In addition, I would like to thank Lancaster University and AstraZeneca for funding my PhD project, as well as the Society of Chemical Industry (SCI) for a scholarship to support my studies. The most important thanks must go to my partner, Izzy, who has been unbelievably supportive, understanding, motivating and patient over the last 3.5 years. You took a leap of faith moving here, much like me, but you have been truly fantastic and now we can move forward into an exciting future. Thank you to my family (Sally, Russell, Nan, Emily, Jamie, Jack, Archie, James, Catherine, Edison, Brenda, Louise) for your unwavering support, not only throughout my PhD but throughout my entire academic career thus far. Thank you to my fantastic pets (Peanut, Cashew, Duchess and Poppy) for helping to take my mind off my PhD and providing a rare cuddle, though I am not thankful for all the rabbit fur that has gotten everywhere! Thank you to my boys from university (Dipen, Rob, Josh, Jack, Kam, Ross, Baines, Pete) for helping me to get through my PhD and I apologise that I have not seen some of you all that much. Finally, I would like to thank everybody here in the Chemistry Department at Lancaster University for helping to create a great working environment and I will miss you all. I would like to personally thank Henry, Mark, Josh, Charlie, James, Bette, Abbie, Patch, Callum, Miles, Gillian, Eleanor, Vassilis, Dhruv, Ross, Ben, Olivia, Izaak, Stuart, Weronika, Bara, Chloe, Pip, Jack, Craig and Sapphire for making my PhD enjoyable and providing some fantastic memories. iv Contents 1. Chapter 1: Introduction 1 1.1 The Growing Interest In sp3-Rich Compounds 2 1.2 Project Aims and Objectives 6 1.3 The Synthesis of 1,2-Diazetidines 7 1.3.1 Synthesis of 1,2-Diazetidines via [2+2] Cycloaddition 7 1.3.2 Other Methods to Synthesise 1,2-Diazetidines 12 1.3.2.1 Synthesis of 1,2-Diazetidine 12 1.3.2.2 Synthesis of 3-Substituted-1,2-Diazetidines 14 1.3.2.3 Synthesis of Other Substituted-1,2-Diazetidines 15 1.3.2.4 Peripheral Functionalisation of 1,2-Diazetidines 17 1.4 The Thermal Stability of Substituted Cyclobutenes 19 1.4.1 Torquoselectivity – Theory 20 1.4.2 Torquoselectivity – Experimental Evidence 23 1.5 Conclusions 30 2. Chapter 2: Synthesis and Reactions of 1,2-Dihydropyridazines 32 2.1 Introduction 33 2.1.1 Synthetic Approaches to 1,2-Dihydropyridazines 33 2.1.2 Conformational Studies 42 2.1.3 Conclusions 43 2.2 Aims 43 2.3 Results and Discussion 44 2.3.1 Synthesis of 1,2-Dihydropyridazines Through Literature Procedures 44 2.3.1.1 Synthesis of 1,2,3,6-Tetrahydropyridazines 44 2.3.1.2 Synthesis of 1,2-Dihydropyridazines from Tetrahydropyridazines 46 2.3.1.3 Synthesis of 1,2-Dihydropyridazines from 2-Pyrones 48 2.3.2 Novel Synthesis of 1,2-Dihydropyridazines from O-Substituted Dienes 49 2.3.2.1 Diene Synthesis 49 2.3.2.2 Diels-Alder Optimisation 51 2.3.2.3 Synthesis of 1,2-Dihydropyridazines 52 2.3.2.4 Scope 57 2.3.2.4.1 Synthesis of Hydrazines 58 2.3.2.4.2 Synthesis of Azo Compounds 59 2.3.2.4.3 Diels-Alder Reactions 62 2.3.2.4.4 Palladium-Catalysed Elimination Reactions 64 2.3.3 Variable-Temperature NMR of 1,2-Dihydropyridazines 66 2.3.4 Reactions of 1,2-Dihydropyridazines 71 2.4 Conclusions 77 3. Chapter 3: Photochemistry of 1,2-Dihydropyridazines 79 3.1 Introduction 80 v 3.1.1 4-π Photocyclisation of 1,2-Dihydropyridazines 80 3.1.2 Organometallic Complexes with Azo Compounds 81 3.1.3 Cyclobutadiene and Azo Compounds 82 3.1.4 Photochemistry of Other 1,2-Dihydropyridazines 85 3.1.5 Conclusions 89 3.2 Aims 90 3.3 Results and Discussion 90 3.3.1 Ultraviolet-Visible (UV-Vis) of 1,2-Dihydropyridazine 9b 90 3.3.2 Optimisation in a Batch Photoreactor 93 3.3.3 Optimisation in a Flow Photoreactor 105 3.4 Conclusions 109 4. Chapter 4: Reactions of Bicyclic 1,2-Diazetidines 110 4.1 Introduction 111 4.1.1 Derivatisation of Bicyclic 1,2-Diazetidines 111 4.1.2 Conclusions 114 4.2 Aims 114 4.3 Results and Discussion 115 4.3.1 Thermal Stability of Bicyclic 1,2-Diazetidines 115 4.3.2 Synthesis of Functionalised 1,2-Diazetidines 121 4.3.3 Synthesis of Functionalised Cyclobutenes 126 4.4 Conclusions 132 5. Chapter 5: Conclusions and Future Work 133 5.1 Conclusions 134 5.1.1 Synthesis and Reactions of 1,2-Dihydropyridazines 134 5.1.2 Synthesis and Reactions of Bicyclic 1,2-Diazetidines 136 5.2 Future Work 138 6. Chapter 6: Experimental 142 6.1 General Information 143 6.2 General Procedures 144 6.3 Synthetic Procedures 148 7. Chapter 7: References 205 8. Chapter 8: Appendix 224 7.1 X-Ray Data 225 7.2 Differential Scanning Calorimetry (DSC) Traces 238 vi List of Abbreviations and Acronyms A absorbance Ac acetyl ADMET absorption, distribution, metabolism, excretion and toxicity AIBN 2,2’-azobis(2-methylpropionitrile) Aq aqueous Ar unspecified aryl group APCI atmospheric pressure chemical ionization ATR attenuated total reflection BBN 9-borabicyclo[3.3.1]nonane Bn benzyl Boc tert-butyloxycarbonyl bp boiling point br broad Bu butyl Bz benzoyl c concentration C centigrade CAN cerium ammonium nitrate COSY correlation spectroscopy Cy cyclohexane d doublet D dimensional DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBAD di-tert-butyl azodicarboxylate DBB di-tert-butylbiphenyl DBU 1,8-diazabicycloundec-7-ene DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DMAD dimethyl azodicarboxylate DMAP 4-dimethylaminopyridine vii DME 1,2-dimethoxyethane DMEDA 1,2-dimethylethylenediamine DMF dimethylformamide DMSO dimethyl sulfoxide DPAD diphenyl azodicarboxylate dppp 1,3-bis(diphenylphosphino)propane DSC differential scanning calorimetry EDG electron donating group ee enantiomeric excess Eq equivalents ESI electrospray ionization Et ethyl FTIR fourier transform infrared h Planck’s constant (6.626 x 10−34 Js) HMBC heteronuclear multiple-bond coherence HMDS bis(trimethylsilyl)amine HOMO highest occupied molecular orbital HRMS high resolution mass spectrometry hr(s) hour(s) HSQC heteronuclear single quantum coherence Hz hertz i iso IBDA iodobenzene diacetate IBX 2-iodoxybenzoic acid IR infrared ISC intersystem crossing IT ion trap J coupling constant l path length LED light-emitting diode LLAMA lead-likeness and
Load more

Recommended publications
  • Selective Syntheses of Difluoromethylene Compounds Via Difluorocarbene Catalyses
    Selective Syntheses of Difluoromethylene Compounds via Difluorocarbene Catalyses 著者 青野 竜也 内容記述 この博士論文は全文公表に適さないやむを得ない事 由があり要約のみを公表していましたが、解消した ため、2017年10月2日に全文を公表しました。 year 2016 その他のタイトル ジフルオロカルベンを用いた触媒反応によるジフル オロメチレン化合物の選択的合成 学位授与大学 筑波大学 (University of Tsukuba) 学位授与年度 2015 報告番号 12102甲第7642号 URL http://hdl.handle.net/2241/00144162 Selective Syntheses of Difluoromethylene Compounds via Difluorocarbene Catalyses Tatsuya Aono February 2016 Selective Syntheses of Difluoromethylene Compounds via Difluorocarbene Catalyses Tatsuya Aono Doctoral Program in Chemistry Submitted to the Graduate School of Pure and Applied Sciences in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Science at the University of Tsukuba Contents Chapter 1 General Introduction 1 Chapter 2 O-Selective Difluoromethylation of Amides with Free Difluorocarbene 20 2.1. Introduction 21 2.2. Synthesis of Difluoromethyl Imidates 24 2.3. Mechanistic Considerations on O-Selective Difluoromethylation of Amides 31 2.4. Conclusion 33 2.5. Experimental Section 34 2.6. Reference 38 Chapter 3 Regioselective Syntheses of gem-Difluorocyclopentanone Derivatives with Transition Metal Difluorocarbene Complexes 39 3.1. Introduction 40 3.2. Domino Difluorocyclopropanation/Ring Expansion with Nickel Difluorocarbene Complex 45 3.3. [4 + 1] Cycloaddition with Copper Difluorocarbene Complex 58 3.4. Conclusion 66 3.5. Experimental Section 67 3.6. Reference 101 Chapter 4 Conclusion 104 List of Publications 105 Acknowledgement 106 Chapter 1 1. General Introduction Organofluorine compounds often exhibit unique properties and behaviors in comparison with nonfluorinated parent compounds, playing important roles as pharmaceuticals and agrochemicals. Because of the high bond dissociation energy of C–F bonds, organofluorine compounds are resistant to heat and chemicals, and stable to metabolism. In addition, organofluorine compounds have high lipophilicity.
    [Show full text]
  • Cyclobutene Photochemistry. Steric Effects on the Photochemical Ring Opening of Alkylcyclobutenes
    1688 J. Am. Chem. SOC.1995,117, 1688-1694 Cyclobutene Photochemistry. Steric Effects on the Photochemical Ring Opening of Alkylcyclobutenes William J. Leigh* and J. Albert0 Postigo Contribution ffom the Department of Chemistry, McMaster University, Hamilton, Ontario, Canada US4Ml Received August 19, 1994@ Abstract: Quantum yields for photochemical ring opening and cycloreversion in hydrocarbon solution have been determined for the direct photolysis (214 nm) of six 1,2-dimethylcyclobutenederivatives which contain methyl groups at C3 and C4 in numbers varying from zero to four. As the hydrogens on C& of the parent compound (1,2- dimethylcyclobutene)are replaced with increasing numbers of methyl groups, the total quantum yield for ring opening increases to a maximum of -0.3 and then decreases with further methyl substitution. The quantum yields for ring opening (&tal) of hexamethylcyclobutene and 1,2-dimethylcyclobuteneare nearly the same, and the lowest in the series. The maximum occurs with trans- 1,2,3,4-tetramethylcyclobutene;q5tod for the cis-isomer is significantly lower, but both yield an approximate 1:l mixture of formally allowed and forbidden diene isomers. A similar trend is observed in the relative quantum yields for ring opening and cycloreversion throughout the series. The results are interpreted in terms of a combination of bond strength and steric effects on the efficiency of the ring-opening process. Increasing methyl substitution causes an increase in @total through the first three members of the series owing to progressive weakening of the C3-C4 bond. Compounds containing cis-dimethyl substitution exhibit substantially reduced quantum yields for ring opening, relative to what would be expected based on bond strength effects alone.
    [Show full text]
  • Cyclobutene Photochemistry. Identification of the Excited States Responsible for the Ring-Opening and Cycloreversion Reactions of Alkylcyclobutenes
    J. Am. Chem. SOC.1991, 113,4993-4999 4993 Cyclobutene Photochemistry. Identification of the Excited States Responsible for the Ring-Opening and Cycloreversion Reactions of Alkylcyclobutenes W. J. Leigh,*?" K. Zheng,= N. Nguyen, N. H. Werstiuk, and J. Ma" Contribution from the Department of Chemistry, McMaster University, Hamilton, Ontario, Canada US4Ml. Received November 28, 1990. Revised Manuscript Received March 7, 1991 Abstract: Two substituted bicyclic cyclobutene derivatives-7-methyl- and 7-(trifluoromethyl)bicyclo[4.2.0]oct-7-enehave been prepared. Gas- and solution-phase UV absorption and He1 UV photoelectron spectra have been recorded for the two compounds as well as for the parent hydrocarbon bicyclo[4.2.0]oct-7-ene. The gas-phase spectra suggest that the a,R(3s) state is the lowest energy state in bicyclo[4.2.0]octene and the 7-methyl derivative but is raised to higher energies than the *,A* state in the 7-trifluoromethylderivative. Direct photolysis of the three compounds in hydrocarbon solution with monochromatic far-UV (1 93 and 214 nm) light leads to competitive ring opening to the corresponding cis,cis- and cis,trans-l,3-cyclooctadiene derivatives, as well as fragmentation to cyclohexene and alkyne in all three cases. Product quantum yields (193-nm excitation) have been measured for both substituted derivatives relative to those for the parent compound. The quantum yields of fragmentation products are highest for the methyl- and unsubstituted compounds, suggesting that these products arise from a Rydberg-like excited state. In contrast, ring opening is most efficient for the trifluoromethyl-substituted compound, although the diene distributions obtained from the reaction do not vary throughout the series.
    [Show full text]
  • Durham E-Theses
    Durham E-Theses Halogenated diazines and triazines Wood, D. E. How to cite: Wood, D. E. (1978) Halogenated diazines and triazines, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/8324/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk UNIVERSITY OF Du'RKAM A THESIS entitled HALOGENATED DIAZINES AND TRIAZINES Submitted by D E. WOOD (Grey), B Sc (London) The copyright of this thesis rests with the author No quotation from it should be published without his prior written consent and information derived from it should be acknowledged A candidate for the degree of Doctor of Philosophy 19 78 sr i i > j J To my MoLhcr and FaLhcr WLLII Lh.inks for .ill LhaL Lhey have done ACKNOWLEDGEMLNTS I would like LO express my thanks Lo Professor R D Chambers i under whose guidance this research was undertaken, for considerable encouragement, advice and discussion Thanks are due to Dr R S Matthews for his expert advice with n in r.
    [Show full text]
  • Triprismane (CH)6
    Triprismane (CH)6 Ein DaMocles Projekt von • Heiko Hofmann • Nina Hundertmark • Fatema Rad • Regina Sander Contents Introduction…………………………………………...page 1 Chemical and physical informations………………...page 2 Stability………………………………………………..page 3 Preparation……………………………………………page 4 - 6 Research and Development…………………………..page 7 - 8 References……………………………………………..page 9 Introduction Triprismane is the smallest and probably most famous member of a class of extraordinary and interesting polyhederanes, the [n]-prismanes. The smallest member of this hydrocarbon family was proposed by Ladenburg in 1869 as structure for benzene, and more than a century ago, the existence of triprimane became part of a discussion about cage compounds. Formally these cage compounds consist of an even number of methine units positioned at the corners of a regular prism. It's very high symmetry and their complex structure makes them not only difficult to preparate, but also highly strained. The conservation of orbital symmetry, publicised by Woodward and Hoffmann, is the most important facet about the durableness of triprismane and its thermodynamic stability. In 1965 Woodward won the nobel prize of chemistry for these rules. Seite 1 von 9 1.) Chemical and physical informations [3]-prismane [4]-prismane [5]-prismane [6]-prismane (ΔHf = 1338,9 kJ/mol) (ΔHf = 719,7 kJ/mol) (ΔHf = 602,5 kJ/mol) (ΔHf = 686,2 kJ/mol) ΔHf(Benzol) = 961,9 kJ/mol) These interpretations have been predicted by MM2 calculations as they are also used by programmes like ChemDraw. Empirical formula C6H6 CAS RN (Registry 650-42-0 N°) Name: IUPAC: teracylo[2.2.0.02,6.03,5]-hexane prismane, [3]-prismane, triprismane, ladenburg-Benzene.
    [Show full text]
  • An Indicator of Triplet State Baird-Aromaticity
    inorganics Article The Silacyclobutene Ring: An Indicator of Triplet State Baird-Aromaticity Rabia Ayub 1,2, Kjell Jorner 1,2 ID and Henrik Ottosson 1,2,* 1 Department of Chemistry—BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden; [email protected] (R.A.); [email protected] (K.J.) 2 Department of Chemistry-Ångström Laboratory Uppsala University, Box 523, SE-751 20 Uppsala, Sweden * Correspondence: [email protected]; Tel.: +46-18-4717476 Received: 23 October 2017; Accepted: 11 December 2017; Published: 15 December 2017 Abstract: Baird’s rule tells that the electron counts for aromaticity and antiaromaticity in the first ππ* triplet and singlet excited states (T1 and S1) are opposite to those in the ground state (S0). Our hypothesis is that a silacyclobutene (SCB) ring fused with a [4n]annulene will remain closed in the T1 state so as to retain T1 aromaticity of the annulene while it will ring-open when fused to a [4n + 2]annulene in order to alleviate T1 antiaromaticity. This feature should allow the SCB ring to function as an indicator for triplet state aromaticity. Quantum chemical calculations of energy and (anti)aromaticity changes along the reaction paths in the T1 state support our hypothesis. The SCB ring should indicate T1 aromaticity of [4n]annulenes by being photoinert except when fused to cyclobutadiene, where it ring-opens due to ring-strain relief. Keywords: Baird’s rule; computational chemistry; excited state aromaticity; Photostability 1. Introduction Baird showed in 1972 that the rules for aromaticity and antiaromaticity of annulenes are reversed in the lowest ππ* triplet state (T1) when compared to Hückel’s rule for the electronic ground state (S0)[1–3].
    [Show full text]
  • 1 Abietic Acid R Abrasive Silica for Polishing DR Acenaphthene M (LC
    1 abietic acid R abrasive silica for polishing DR acenaphthene M (LC) acenaphthene quinone R acenaphthylene R acetal (see 1,1-diethoxyethane) acetaldehyde M (FC) acetaldehyde-d (CH3CDO) R acetaldehyde dimethyl acetal CH acetaldoxime R acetamide M (LC) acetamidinium chloride R acetamidoacrylic acid 2- NB acetamidobenzaldehyde p- R acetamidobenzenesulfonyl chloride 4- R acetamidodeoxythioglucopyranose triacetate 2- -2- -1- -β-D- 3,4,6- AB acetamidomethylthiazole 2- -4- PB acetanilide M (LC) acetazolamide R acetdimethylamide see dimethylacetamide, N,N- acethydrazide R acetic acid M (solv) acetic anhydride M (FC) acetmethylamide see methylacetamide, N- acetoacetamide R acetoacetanilide R acetoacetic acid, lithium salt R acetobromoglucose -α-D- NB acetohydroxamic acid R acetoin R acetol (hydroxyacetone) R acetonaphthalide (α)R acetone M (solv) acetone ,A.R. M (solv) acetone-d6 RM acetone cyanohydrin R acetonedicarboxylic acid ,dimethyl ester R acetonedicarboxylic acid -1,3- R acetone dimethyl acetal see dimethoxypropane 2,2- acetonitrile M (solv) acetonitrile-d3 RM acetonylacetone see hexanedione 2,5- acetonylbenzylhydroxycoumarin (3-(α- -4- R acetophenone M (LC) acetophenone oxime R acetophenone trimethylsilyl enol ether see phenyltrimethylsilyl... acetoxyacetone (oxopropyl acetate 2-) R acetoxybenzoic acid 4- DS acetoxynaphthoic acid 6- -2- R 2 acetylacetaldehyde dimethylacetal R acetylacetone (pentanedione -2,4-) M (C) acetylbenzonitrile p- R acetylbiphenyl 4- see phenylacetophenone, p- acetyl bromide M (FC) acetylbromothiophene 2- -5-
    [Show full text]
  • Novel Approaches Towards the Discovery of Tumor-Selective Histone Deacetylase Inhibitors
    Novel Approaches Towards The Discovery of Tumor-Selective Histone Deacetylase Inhibitors A Dissertation Presented to The Academic Faculty By Idris Raji In Partial Fulfilment of the Requirements for the Degree Doctor of Philosophy in Chemistry School of Chemistry and Biochemistry Georgia Institute of Technology, Atlanta GA 30332 December 2016 COPYRIGHT 2016 © IDRIS RAJI Novel Approaches Towards The Discovery of Tumor-Selective Histone Deacetylase Inhibitors Committee members: Dr. Adegboyega K. Oyelere, Advisor Dr. Andreas Bommarius School of Chemistry and Biochemistry School of Chemical and Biomolecular Georgia Institute of Technology Engineering Georgia Institute of Technology Dr. M. G. Finn School of Chemistry and Biochemistry Dr. Ravi Bellamkonda Georgia Institute of Technology Pratt’s school of Engineering Duke University Dr. Stefan France School of Chemistry and Biochemistry Georgia Institute of Technology Date Approved: November 4th, 2016 To my mother, Mrs. Jolade Raji AKNOWLEDGEMENTS I have been very fortunate to have met and interact with people who have positively influenced my life since arriving at Georgia Tech for graduate studies. I will be forever grateful to my advisor, Dr. Adegboyega K. Oyelere, for giving me the opportunity to learn in his lab. I joined his lab with minimal research experience, but he has helped to tremendously enrich my knowledge base and instill a level of confidence in me that was previously nonexistent. I am very grateful for his patience, guidance, availability to discuss research progress and the countless recommendation letters he wrote on my behalf. I am greatly indebted to my thesis committee members Dr. M G Finn, Dr. Stefan France, Dr. Ravi Bellamkonda, and Dr.
    [Show full text]
  • International Nonproprietary Names for Pharmaceutical Substances (INN)
    WHO Drug Information, Vol. 29, No. 4, 2015 Proposed INN: List 114 International Nonproprietary Names for Pharmaceutical Substances (INN) Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–109) and Recommended (1–70) International Nonproprietary Names can be found in Cumulative List No. 15, 2013 (available in CD-ROM only). The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs. Dénominations communes internationales des Substances pharmaceutiques (DCI) Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0058872 A1 Crew Et Al
    US 2016.0058872A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0058872 A1 Crew et al. (43) Pub. Date: Mar. 3, 2016 (54) IMIDE-BASED MODULATORS OF A613 L/426 (2006.01) PROTEOLYSIS AND ASSOCATED METHODS A 6LX3 L/505 (2006.01) OF USE A613 L/454 (2006.01) A613 L/55 (2006.01) (71) Applicant: Arvinas, Inc., New Haven, CT (US) C07D40 L/4 (2006.01) A6II 45/06 (2006.01) (72) Inventors: Andrew P. Crew, Guilford, CT (US); (52) U.S. Cl. Craig Crews, New Haven, CT (US), CPC ............ A61K 47/481 (2013.01); C07D401/14 Hanging Dong, Madison, CT (US); Jing (2013.01); C07D 495/14 (2013.01); C07D Wang, Milford, CT (US); Yimin Qian, 417/14 (2013.01); A61K 45/06 (2013.01); Plainsboro, NJ (US); Kam Siu Milford, A6 IK3I/505 (2013.01); A61 K3I/454 CT (US); Meizhong Jin, East Northport, (2013.01); A61 K3I/551 (2013.01); A61 K NY (US) 3 1/426 (2013.01) (21) Appl. No.: 14/792,414 (57) ABSTRACT (22) Filed: Jul. 6, 2015 The description relates to imide-based compounds, including Related U.S. Application Data bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially (63) Continuation-in-part of application No. 14/686.640, inhibitors of a variety of polypeptides and other proteins filed on Apr. 14, 2015. which are degraded and/or otherwise inhibited by bifunc (60) Provisional application No. 61/979,351, filed on Apr. tional compounds according to the present invention. In par 14, 2014, provisional application No.
    [Show full text]
  • United States Patent Office Patented July 1, 1969
    3,453,337 United States Patent Office Patented July 1, 1969 1. 2 3,453,337 FLUORINATION OF HALOGENATED The presence in the reaction mixture of the two fluo ORGANIC COMPOUNDS rides, or the complex fluoride enables better yields of Royston Henry Bennett and David Walter Cottrell, Ayon highly fluorinated products to be obtained under less mouth, England, assignors to Imperial Smelting Cor severe reaction condions, markedly increases the amount poration (N.S.C.) Limited, London, England, a British of fluorination reagent reacted under otherwise similar company conditions and enables the fluorination reaction to be No brawing. Filed Feb. 19, 1965, Ser. No. 434,128 carried out (for the same yield of product) at a lower Claims priority, application Great Britain, Feb. 26, 1964, temperature with the consequent use of less costly ma 7,932/64 terials and techniques of reactor construction. The pres Int, C. C07c 25/04 10 ence of the fluorides enables the vapor phase reaction U.S. C. 260-650 2 Claims to be carried out (for the same yields) at lower pressure This invention relates to the fluorination of organic than the pressure involved in the reactions using only halogen compounds and more especially to a process the alkali metal fluorides as proposed hitherto. The fur for the production of highly fluorinated aromatic com ther possibility of using a continuous flow apparatus such pounds by the replacement of higher halogen atoms in 15 as a fluidised reactor will be apparent to those familiar halogeno-aromatic compounds by fluorine atoms. with the art. The presence of the two fluorides or com Aromatic halogenocarbons containing carbon and halo plex fluoride enables a lower temperature to be em gen atoms only can be reacted with alkali fluorides ployed than was hitherto believed to be necessary, with under various conditions to give yields of halofluoro a consequent reduction in the extent of thermal degrada aromatic compounds.
    [Show full text]
  • Dulaneyspr15.Pdf (409.1Kb)
    Adventures in Organophosphorus Chemistry James W. Dulaney, III (Faculty Mentor: David E. Lewis) Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54702-4004 Background Challenges with the Mitsunobu reaction What is required in a replacement to make the reaction Azodicarboxylates, an important component of the re- “green”? Organophosphorus compounds have been an increasingly important part of organic synthesis since the discovery action, are very hazardous: of the Arbuzov rearrangement in 1905. In the century that followed this discovery, the applications of phosphorus- O Green? based reagents in synthesis has grown to incorporate the Wittig and Horner-Wadsworth-Emmons reactions for OEt • They are highly explosive (especially diethyl azodi- N alkene formation, as well as the Mitsunobu inversion reaction, which is used to convert alcohols to a wide range carboxylate). N Green reactions are run under more environmentally sustainable conditions with a view to of products with inversion of configuration. O minimizing environmental impact: • They are highly toxic (especially diethyl azodicar- OEt boxylate). diethyl azodicarboxylate • They are highly regulated. (DEAD) • Wherever possible, renewable sources are used • Wherever possible, hazardous materials are eliminated completely or replaced by The Wittig reaction Ph Ph Ph BuLi Ph less hazardous materials P R P R Regulations have been put into place by the DOT that O Ph Ph O-i-Pr • Wherever possibler, catalytic reactions are used Reaction between an ylide and an aldehyde or ketone to give an alkene. make azodicarboxylic esters even more difficult to ob- N • Hazardous waste is minimized wherever possible (e.g. organic solvents can be re- Reaction gives mainly the Z isomer with aldehydes O tain and use.
    [Show full text]