Mitsunobu Reaction
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October 1, 2020 Webinar
Phosphorus Specialties: the cornerstone of synthesis for pharmaceutical applications Eamonn Conrad, Ph.D., Global BD Manager Dino Amoroso, Ph.D., NA Account Manager William Stibbs, Ph.D. Senior BD Manager Overview • Solvay Phosphorus Specialties, Strem Chemicals Inc. Partnership • Chemistry for the Manufacture of Phosphine Ligands • Applications in Pharmaceutical Catalysis • Applications in Life Sciences • Summary and Questions *Solvay partners with Strem Chemicals for sample distribution page 2 Phosphorus Specialties Strem Chemicals, Inc. Solvay partners with Strem Chemicals for sample distribution! Established in 1964 More than 55 years of experience in manufacturing and handling high quality inorganics and organometallics 5,000+ specialty chemicals available Laboratory Chemicals for R&D cGMP Products Manufactured in Kilo-lab Suites High Pressure Materials Custom Synthesis Projects Customers include: Corporate Headquarters Academic, industrial and government R&D laboratories Corporate Headquarters European Headquarters Commercial scale businesses in the pharmaceutical, Newburyport, MA USA Strasbourg, France microelectronics, chemical & petrochemical industries Phosphorus Specialties Samples available from Strem Who We Are Phosphorus Specialties Mining Solutions Polymer Additives Putting our science to work for customers to develop differentiated products and technologies Dedicated on-site technical service and applications expertise to support our customers’ needs Deep customer relationships and ongoing collaborations to solve demanding -
Phosphine-Catalyzed Additions of Nucleophiles and Electrophiles to Α
PHOSPHINE-CATALYZED ADDITIONS OF NUCLEOPHILES AND ELECTROPHILES TO α,β–UNSATURATED CARBONYL COMPOUNDS Reported by Michael Scott Bultman November 4, 2004 INTRODUCTION Organophosphorous compounds are becoming increasingly important in organic synthesis. Phosphines serve as precursors to phosphonium ylides in the Wittig reaction,1 and as nucleophilic triggers in the Mitsunobu2 and Staudinger3 reactions. In these processes, the phosphine is stoichiometrically consumed and converted into a phosphine oxide. Phosphines are also commonly used as ligands for transition metal-catalyzed reactions, to modulate reactivity and stereocontrol.4 On the other hand, the use of phosphines as nucleophilic catalysts for organic reactions has only gained attention in the last ten years. First reported by Rauhut and Currier in 1963,5 phosphine catalysis has since been reinvestigated after the phosphine ligands in some transition-metal-catalyzed reactions were found to be better catalysts than the metal/phosphine complexes alone!6 Phosphines are well suited for catalyzing the addition of both nucleophiles and electrophiles to electron deficient alkenes, alkynes, and allenes. Activation of these α,β-unsaturated carbonyl systems with the phosphine enables the formation of new bonds at the α-, β-, and γ-positions. This report will highlight these different modes of addition to α,β-unsaturated carbonyl systems under phosphine catalysis that allow for the formation of a wide array of products from a single class of substrates. GENERAL REACTIVITY OF PHOSPHINES Key characteristics required for successful nucleophilic catalysis lie in the balance of leaving group ability, nucleophilicity, and ease of ylid formation. Increasing leaving group ability can often be + correlated with decreasing basicity. -
Guidelines for Pyrophoric Materials
Guidelines for Pyrophoric Materials Definition and Hazards Pyrophoric materials are substances that ignite instantly upon exposure to air, moisture in the air, oxygen or water. Other common hazards include corrosivity, teratogenicity, and organic peroxide formation, along with damage to the liver, kidneys, and central nervous system. Examples include metal hydrides, finely divided metal powders, nonmetal hydride and alkyl compounds, white phosphorus, alloys of reactive materials and organometallic compounds, including alkylithiums. Additional pyrophoric materials are listed in Appendix A. Failure to follow proper handling techniques could result in serious injury or death. Controlling the Hazards . If possible, use safer chemical alternatives. A “dry run” of the experiment should be performed using low-hazard materials, such as water or solvent, as appropriate. Limit the amount purchased and the amount stored. Do not accumulate unneeded pyrophoric materials. BEFORE working with pyrophoric materials, read the MSDS sheets. The MSDS must be reviewed before using an unfamiliar chemical and periodically as a reminder. A Standard Operating Procedure (SOP) should be prepared and reviewed for each process involving pyrophoric materials. In lab training should be completed and documented. If possible, use the “buddy system”. Working alone with pyrophorics is strongly discouraged. All glassware used for pyrophorics should be oven-dried and free of moisture. Review the location of the safety shower, eyewash, telephone, and fire extinguisher. Keep an appropriate fire extinguisher or extinguishing material close at hand. Additional controls when handling liquid pyrophoric materials . Secure pyrophoric reagent bottle to stand. Secure the syringe so if the plunger blows out of the body of the syringe the contents will not splash anyone. -
Bond Formation Reactions to Phosphorus Using an Electrophilic Phosphinidene Complex
BOND FORMATION REACTIONS TO PHOSPHORUS USING AN ELECTROPHILIC PHOSPHINIDENE COMPLEX A Thesis Submitted to the Faculty of Graduate Studies and Research In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy in Chemistry University of Regina By Kandasamy Vaheesar Regina, Saskatchewan September, 2013 Copyright 2013: K. Vaheesar UNIVERSITY OF REGINA FACULTY OF GRADUATE STUDIES AND RESEARCH SUPERVISORY AND EXAMINING COMMITTEE Kandasamy Vaheesar, candidate for the degree of Doctor of Philosophy in Chemistry, has presented a thesis titled, Bond Formation Reactions to Phosphorus Using an Electrophilic Phosphinidene Complex, in an oral examination held on August 28, 2013. The following committee members have found the thesis acceptable in form and content, and that the candidate demonstrated satisfactory knowledge of the subject material. External Examiner: *Dr. Stephen Foley, University of Saskatchewan Supervisor: Dr. Brian Sterenberg, Department of Chemistry/Biochemistry Committee Member: Dr. Mauricio Barbi, Department of Physics Committee Member: Dr. Allan East, Department of Chemistry/Biochemistry Committee Member: Dr. R. Scott Murphy, Department of Chemistry/Biochemistry Chair of Defense: Dr. Dongyan Blachford, Faculty of Graduate Studies & Research *Participated via Video Conference ABSTRACT Electrophilic phosphinidene complexes play a central role in organophosphorus chemistry. The chemistry of transient phosphinidene complexes has been well studied, but stable, cationic phosphinidene complexes are not as well understood. Therefore the i + 5 reactivity of a cationic phosphinidene complex [CpFe(CO)2{PN Pr2}] (Cp = η - cyclopentadienyl, iPr = isopropyl), toward bond activation, cycloaddition and nucleophilic addition has been examined. i + The complex [CpFe(CO)2{PN Pr2}] reacts with primary, secondary, and tertiary i + silanes to form the silyl phosphine complexes [CpFe(CO)2{P(H)(SiR3)N Pr2}] (SiR3 = SiPhH2, SiPh2H, Si(C2H5)3), in which the phosphinidene has inserted into the Si-H bond. -
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. -
Working with Hazardous Chemicals
A Publication of Reliable Methods for the Preparation of Organic Compounds Working with Hazardous Chemicals The procedures in Organic Syntheses are intended for use only by persons with proper training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at http://www.nap.edu/catalog.php?record_id=12654). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices. In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red “Caution Notes” within a procedure. It is important to recognize that the absence of a caution note does not imply that no significant hazards are associated with the chemicals involved in that procedure. Prior to performing a reaction, a thorough risk assessment should be carried out that includes a review of the potential hazards associated with each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices. The procedures described in Organic Syntheses are provided as published and are conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein. -
Advanced Studies on the Synthesis of Organophosphorus Compounds
ALMA MATER STUDIORUM UNIVERSITÀ DI BOLOGNA DOTTORATO DI RICERCA IN SCIENZE CHIMICHE (XIX° ciclo) Area 03 Scienze Chimiche-CHIM/06 Chimica Organica Dipartimento di Chimica Organica “A. Mangini” Coordinatore: Chiar.mo Prof. Vincenzo Balzani Advanced Studies on the Synthesis of Organophosphorus Compounds Dissertazione Finale Presentata da: Relatore: Dott. ssa Marzia Mazzacurati Prof. Graziano Baccolini Co-relatore: Dott.ssa Carla Boga INDEX Index: Keywords…………………………………………………………….………….VII Chapter 1…………………………………………………………………………..3 GENERAL INTRODUCTION ON PHOSPHORUS CHEMISTRY 1.1 Organophosphorus Chemistry………………………………………………….4 1.1.1 Phosphines………………………………………………………………..5 1.1.2 Phosphonates……………………………………………………………..6 1.1.3 Phosphites………………………………………………………………...7 1.2 Uses of Organophosphorus Compounds………………………………………..7 1.2.1 Agricultural Application………………………………………………….8 1.2.2 Catalysis……………………………………………………………..…....9 1.2.3 Organophosphorus Conpounds in Medicine…………………………….11 1.2.4 Phosphorus in Biological Compounds…………………………………..12 1.3 References……………………………………………………………………..15 Chapter 2…………………………………………………………………………17 THE HYPERCOORDINATE STATES OF PHOSPHORUS 2.1 The 5-Coordinate State of Phosphorus……………………………………….17 2.2 Pentacoordinated structures and their non rigid character…………………….18 2.3 Permutational isomerization…………………………………………………..19 2.3.1 Berry pseudorotation……………………………………………………20 2.3.2 Turnstile rotation………………………………………………………..21 2.4 The 6-Coordinate State of Phosphorus……………………………………….22 2.5 References…………………………………………………………………......24 I Chapter -
Improved Processes for the Preparation of 1-Aryl-5-Alkyl Pyrazole Compounds
(19) TZZ¥__Z_T (11) EP 3 184 510 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 28.06.2017 Bulletin 2017/26 C07D 231/18 (2006.01) (21) Application number: 16199220.1 (22) Date of filing: 22.04.2013 (84) Designated Contracting States: • LEE, Hyoung, Ik AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Cary, NC 27519 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • ZHAN, Xinxi PL PT RO RS SE SI SK SM TR BDA, Beijing 100176 (CN) Designated Extension States: • LABROSSE, Jean-Robert BA ME F-34160 Saint Hilaire De Beauvoir (FR) • MULHAUSER, Michel (30) Priority: 20.04.2012 US 201261635969 P F-69370 Saint Didier au Mont d’Or (FR) (62) Document number(s) of the earlier application(s) in (74) Representative: D Young & Co LLP accordance with Art. 76 EPC: 120 Holborn 13720198.4 / 2 852 577 London EC1N 2DY (GB) (71) Applicant: Merial, Inc. Remarks: Georgia 30096 (US) •This application was filed on 16-11-2016 as a divisional application to the application mentioned (72) Inventors: under INID code 62. • MENG, Charles, Q •Claims filed after the date of filing of the Grayson, GA 30017 (US) application/dateof receipt of the divisional application • LE HIR DE FALLOIS, Loic, Patrick (Rule 68(4) EPC). Atlanta, Georgia 30305 (US) (54) IMPROVED PROCESSES FOR THE PREPARATION OF 1-ARYL-5-ALKYL PYRAZOLE COMPOUNDS (57) Provided are improved processes for the preparation of 1-aryl pyrazole compounds of formula (I) and (IB): which are substituted at the 5-position of the pyrazole ring with a carbon-linked functional group. -
Organic Synthesis Using Carbon Dioxide As Phosgene-Free Carbonyl Reagent*
Pure Appl. Chem., Vol. 84, No. 3, pp. 581–602, 2012. http://dx.doi.org/10.1351/PAC-CON-11-05-04 © 2011 IUPAC, Publication date (Web): 1 September 2011 Organic synthesis using carbon dioxide as phosgene-free carbonyl reagent* An-Hua Liu, Yu-Nong Li, and Liang-Nian He‡ State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China Abstract:CO2 is very attractive as a typical renewable feedstock for manufacturing com- modity chemicals, fuel, and materials since it is an abundant, nontoxic, nonflammable, and easily available C1 resource. The development of greener chemical methodologies for replac- ing the utility of hazardous and environmentally undesirable phosgene largely relies on ingenious activation and incorporation of CO2 into valuable compounds, which is of para- mount importance from a standpoint of green chemistry and sustainable development. Great efforts have been devoted to constructing C–C, C–O, and C–N bond on the basis of CO2 acti- vation through molecular catalysis owing to its kinetic and thermodynamic stability. The aim of this article is to demonstrate the versatile use of CO2 in organic synthesis as the alterna- tive carbonyl source of phosgene, with the main focus on utilization of CO2 as phosgene replacement for the synthesis of value-added compounds such as cyclic carbonates, oxa - zolidinones, ureas, isocyanates, and polymers, affording greener pathways for future chemi- cal processes. Keywords: atom economy; aziridines; carbon dioxide; carbonylation; catalysis; green chemistry; ionic liquids; organic carbonate; phosgene-free process; urea. INTRODUCTION CO2 as an abundant, nontoxic, easily available, and typical renewable C1 source as well as an impor- tant “greenhouse” gas has been drawing more and more attention in line with the need for development of green chemistry and a sustainable society. -
Diethyl Azodicarboxylate, Conventionally Abbreviated As DEAD and Sometimes As DEADCAT, Is an Organic Compound with the Structural Formula
DBU • 1,5-Diazabicyclo[5.4.0]undec-7-ene, or more commonly DBU, is a chemical compound and belongs to the class of amidine compounds. • It is used in organic synthesis as a catalyst, a complexing ligand, and a non-nucleophilic base. • . It is also used as a curing agent for epoxy. • It is used in fullerene purification with trimethylbenzene (it reacts with C 70 and higher fullerenes, but not to C 60 fullerenes) • It is also used as a catalyst in polyurethane production. • It has a strong catalyst effect for the reactions of alicyclic and aliphatic isocyanates. • It also exhibited its dual character (base and nucleophile) in the synthesis of aryl- and styryl-terminal acetylenes. DEAD • Diethyl azodicarboxylate, conventionally abbreviated as DEAD and sometimes as DEADCAT, is an organic compound with the structural formula CH3CH2O2CN=NCO2CH2CH3. Its molecular structure consists of a central azo functional group, RN=NR, flanked by two ethyl ester groups. • It is an oxidising agent • This orange-red liquid is a valuable reagent but also quite dangerous and explodes upon heating. • Therefore, commercial shipment of pure diethyl azodicarboxylate is prohibited in the United States and is carried out either in solution or on polystyrene particles. • DEAD is an aza-dienophile and an efficient dehydrogenating agent, converting alcohols to aldehydes, thiols to disulfides and hydrazo groups to azo groups; it is also a good electron acceptor. • DEAD dissolves in most common organic solvents, such as toluene, chloroform, ethanol, tetrahydrofuran and dichloromethane but has low solubility in water or carbon tetrachloride; the solubility in water is higher for the related azo compound dimethyl azodicarboxylate. -
New Boron–Hydrogen Insertion Reactions of Ligated Boranes By
New Boron–Hydrogen Insertion Reactions of Ligated Boranes by Thomas H. Allen B.S. Chemistry, Magna Cum Laude, Ohio Northern University, 2012 Submitted to the Graduate Faculty of the Kenneth P. Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2018 UNIVERSITY OF PITTSBURGH KENNETH P. DIETRICH SCHOOL OF ARTS AND SCIENCES This dissertation was presented by Thomas H. Allen It was defended on July 17, 2018 and approved by Sruti Shiva, Associate Professor, Department of Pharmacology and Chemical Biology W. Seth Horne, Associate Professor, Department of Chemistry Kay M. Brummond, Professor, Department of Chemistry Committee Chair: Dennis P. Curran, Distinguished Service Professor and Bayer Professor, Department of Chemistry ii Copyright © by Thomas H. Allen 2018 iii New Boron–Hydrogen Insertion Reactions of Ligated Boranes Thomas H. Allen, PhD University of Pittsburgh, 2018 Chemical transformations of ligated borane complexes, including N-heterocyclic carbene boranes, are demonstrated. Chapter 1 begins with an introduction of Lewis base borane complexes, rhodium carbene chemistry, and B–H insertion of ligated boranes. The second part of Chapter 1 describes the insertion of rhodium carbenes, previously demonstrated with NHC- boranes, into the B–H bonds of other ligated boranes. Stable ligated α-boryl esters were isolated. A series of competitive B–H insertion experiments are described that were used to develop a relative reactivity profile of ligated boranes toward rhodium-catalyzed B–H insertion. The enantioselective B–H insertion of NHC-boranes with chiral dirhodium catalysts was also investigated. Finally, the synthesis and application of two chiral bridged dirhodium catalysts is described. -
Pyrophoric Handling Procedure
Pyrophoric Handling Procedure Carnegie Mellon Environmental Health & Safety 5000 Forbes Avenue FMS Building, 3rd Floor Pittsburgh, PA 15213 412-268‐8182 www.cmu.edu.ehs October 2019 TABLE OF CONTENTS Introduction ........................................................................................................................................3 Examples of Pyrophoric/Water Reactive Materials ...........................................................................3 Hazards ..............................................................................................................................................3 Controlling the Hazards .....................................................................................................................3 Personal Protective Equipment (PPE) ...............................................................................................4 Eye Protection ........................................................................................................................4 Skin Protection .......................................................................................................................4 Eyewash/Safety Showers .......................................................................................................4 Fume Hood.............................................................................................................................4 Glove (dry) box ......................................................................................................................5