OLEFIN METATHESIS APPLICATION GUIDE WITH BONUS METATHESIS QUICK REFERENCE GUIDE INCLUDED FOREWORD The metathesis experts at Materia have assembled this guide to help chemists who are interested in applying olefin metathesis in their own synthetic routes. It starts by discussing some general reaction parameters and practical considerations for running routine olefin metathesis reactions. It then covers some more challenging metathesis reactions with examples from academic, pharmaceutical, and specialty chemical laboratories that illustrate some of the elegant solutions that have been developed. DISCLAIMER: This document and the information contained herein, are intended to be used solely as a general guideline and for information purposes only. Actual results may vary. Use of, or reliance on, this document or any product referred to herein shall be at user’s own risk. 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MATERIA, MATERIA Logo, and GRUBBS CATALYST are trademarks or registered trademarks of Materia, Inc CONTENTS About Materia and the Authors 3 Getting Started With Metathesis 4 Synthesis Of Medium-Sized Rings 7 Macrocyclic Ring-Closing Metathesis 8 Sterically Demanding Ring-Closing Metathesis 9 Cross Metathesis of Electron-Deficient Olefins 10 Trisubstituted Linear Olefins 11 ® www.materia-inc.com | allthingsmetathesis.com 2 ABOUT MATERIA Adam Johns earned his Ph.D. in 2006 with John Hartwig at Yale and joined Materia in Materia is the provider of high performance 2012 after stints at Dow Chemical and Halcyon catalysts and resins that leading companies Molecular and a visiting professor appointment worldwide use to invent new products, at Claremont McKenna College. enhance industrial processes, and capitalize on their highest-value opportunities. Dick Pederson earned his Ph.D. with Chi-Huey Wong at Texas A&M in 1989 and joined Materia The history of Materia began in the in 2000 after developing metathesis routes to laboratories of Caltech over twenty years insect pheromones at his own company. ago when Professor Robert H. Grubbs synthesized the world’s first broadly applicable, John Phillips earned his Ph.D. in 2005 with user-friendly olefin metathesis catalyst. The Laura Kiessling followed by post-doctoral technology is one of the most important studies with Brian Stoltz at Caltech and John breakthroughs in modern chemistry, enabling Montgomery at University of Michigan, joining significant industrial and commercial Materia in 2010. developments across a broad range of markets. Diana Stoianova earned her Ph.D at the In partnership with Caltech and Dr. Grubbs, University of Zurich in 1995 followed by Materia continues to advance the Grubbs post-doctoral studies with Al Meyers at Colorado Catalyst® technology and the advanced State University and Paul Hanson at the materials based on this technology to solve University of Kansas, joining Materia in 2001. complex global and business challenges, driving major economic and environmental Ba Tran earned his Ph.D. with Daniel Mindiola benefits. Materia’s exclusive Grubbs Catalyst® at Indiana University in 2012, followed by products are the world’s leading olefin post-doctoral studies with John Hartwig at metathesis catalysts. Berkeley, joining Materia in 2014. Philip Wheeler earned his Ph.D. with Tom Rovis at Colorado State University in 2013, joining ABOUT THE AUTHORS Materia in 2015 after two years at Sigma-Aldrich. Prof. Bob Grubbs is the Victor and Elizabeth Atkins Professor of Chemistry at the California Institute of Technology and shared the 2005 Nobel Prize in Chemistry with Prof. Richard Schrock and Prof. Yves Chauvin for their contributions towards “the development of the metathesis reaction in organic synthesis.” Top, left to right: Adam Johns, Philip Wheeler, Diana Stoianova. Bottom, left to right: Dick Pederson, Prof. Bob Grubbs, John Phillips. Not pictured: Ba Tran ® www.materia-inc.com | allthingsmetathesis.com 3 cases, using more catalyst may lead to unwanted side reactions. Even for challenging reactions, loadings GETTING STARTED less than 1 mol% can be effective given the careful choice of other reaction parameters, which will be WITH METATHESIS covered below. METATHESIS REACTION TYPES SOLVENT SELECTION There are three main classes of metathesis reactions, two of which are utilized regularly for small molecule organic synthesis. Ring-closing metathesis is an intramolecular reaction of an acyclic diene to form a ring (Fig. 1), while cross metathesis brings two olefins together in an intermolecular reaction to give an olefin product bearing substituents from each of the starting olefins (Fig. 2). metathesis catalyst + Figure 1. Ring-closing metathesis (RCM) The list of preferred solvents for olefin metathesis metathesis reactions includes hydrocarbon solvents such as catalyst toluene and heptanes, chlorinated solvents such as + methylene chloride, esters such as ethyl acetate, and Figure 2. Cross metathesis (CM) peroxide-resistant ethers such as TBME. Ethereal solvents themselves do not cause issues, but the peroxides that can form in ethereal solvents can GENERAL REACTION SET-UP react with the ruthenium center and cause catalyst 1. Deoxygenated solvents and reaction mixtures are decomposition. When using any peroxide-forming recommended for optimal results. If necessary, solvent, be sure to use solvent that has been stored degas the solvent before use. with BHT as an inhibitor,1 and check for peroxides 2. In a dry, inert reaction vessel with a stir bar, dissolve before use. your substrate(s) in the solvent of choice. 3. Weigh the catalyst (open to the air is fine) and add it While there are many examples of olefin metathesis in to the reaction mixture either as a solid or a solution the presence of protic solvents, a primary alcohol can in the reaction solvent. react with the ruthenium complex to form ruthenium 4. Heat the reaction to the desired temperature and hydrides, which are not effective olefin metathesis monitor until complete. catalysts, but are effective olefin isomerization catalysts (see Preventing Olefin Isomerization). In general, highly coordinating solvents such as DMF or CATALYST SELECTION AND LOADING pyridine will interfere with the catalytic activity of the If you are running a metathesis reaction for the first ruthenium complex. At high pH, water (e.g. hydroxide) time, consider using Hoveyda-Grubbs Catalyst® 2nd can also alter the ruthenium complex such that it is no Generation (C627). This catalyst typically displays longer active. similar activity to Grubbs Catalyst® 2nd Generation (C848) but initiates at a lower temperature (<23 °C) and is more stable to storage and handling. In metathesis reactions TEMPERATURE Most Grubbs Catalyst® Products will initiate on an olefin involving sterically encumbered olefins, it may be necessary substrate between 23 and 40 °C, but some reactions to use a more specialized catalyst such as C571 or C711 may require additional heat to achieve suitable rates. (see Sterically Demanding Ring Closing Metathesis and The formation of trisubstituted olefins (see Trisubstituted Trisubstituted Linear Olefins). Linear Olefins), and macrocyclizations (see Macrocyclic Ring-Closing Metathesis) may require temperatures As long as reaction conditions are chosen carefully, as high as 100 °C for conversion to be complete high loadings of catalyst are not necessary. In some within hours. ® www.materia-inc.com | allthingsmetathesis.com 4 the double bonds in either the substrate or the metathesis CONCENTRATION product. This typically occurs because the catalyst has When choosing reaction concentration, keep in mind decomposed to a ruthenium hydride species. The most that intermolecular reactions such as cross common way for this to happen is by reaction metatheses should be run as concentrated as possible, of the ruthenium complex with a primary alcohol, and macrocyclizations should be run as dilute as is present in either the substrate or the solvent.4 Users practical. Ring-closing metathesis reactions forming should be aware of this possibility when running a 5 or 6 membered rings can be run at concentrations metathesis reaction in a primary alcohol solvent. approaching 1 M or greater. C848 mol (5 %) + O , O O OTHER CONSIDERATIONS CD2Cl2 40 °C Aside from careful selection of the basic reaction no additive: <5% 95% parameters, there are several other precautions that with 10 mol % 1,4-benzoquinone: >95% none none should be taken to ensure maximal reaction efficiency. with 10 mol % AcOH: >95% Figure 4. Preventing olefin isomerization EXCLUSION OF OXYGEN The Grubbs group and others have reported the Although Grubbs Catalyst® Products are air and moisture addition of a mild oxidant such as a 1,4-benzoquinone derivative or a mild acid such as acetic acid to suppress stable as solids, they are less stable to oxygen while in 5 solution. For this reason,