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Green Chemistry Green Chemistry PAPER View Article Online View Journal | View Issue Comparative performance evaluation and systematic † Cite this: Green Chem., 2013, 15, 1880 screening of solvents in a range of Grignard reactions Asha Kadam,a Mylinh Nguyen,a Michael Kopach,b Paul Richardson,c Fabrice Gallou,d Zhao-Kui Wane and Wei Zhang*a The solvent effect on the Grignard reaction of benzyl, aryl and heteroaromatic substrates has been sys- tematically evaluated based on reaction efficiency, ease of subsequent work-up, safety and greenness. Received 14th April 2013, 2-Methyltetrahydrofuran (2-MeTHF), which can be derived from renewable resources, had at least an equal Accepted 3rd May 2013 if not a superior overall process most notably in suppressing the Wurtz coupling by-product from the DOI: 10.1039/c3gc40702k benzyl Grignard reactions. It is therefore a recommended alternative solvent to Et2O and THF for the www.rsc.org/greenchem preparation of most Grignard reagents and their subsequent reactions. Creative Commons Attribution 3.0 Unported Licence. 1 Introduction evaluate solvents for Grignard reactions. In 2011, the Zhang group at UMass Boston was awarded a grant from GCIPR to The American Chemical Society’s Green Chemistry Institute carry out this targeted research and development. Preliminary Pharmaceutical Roundtable (GCIPR) was developed in 2005 to results of these R&D efforts were presented at the 16th Annual encourage the integration of green chemistry and engineering Green Chemistry and Engineering Conference.1 Herein we into the pharmaceutical industry and to promote sustainable report the full set of results, which includes explorations of manufacturing. GCIPR presently has 16 member companies benzyl, aryl and heteroaromatic Grignard reactions. including contract research/manufacturing organizations, generic pharmaceuticals, and related companies. In 2009, 1.1 Background of the Grignard reaction This article is licensed under a GCIPR identified that a preponderance of commonly used Victor Grignard and Paul Sabatier received the Nobel Prize in organometallic reagents was supplied in solvents lacking 1912 for the discovery of what was later called the Grignard greenness from an environmental and process safety perspec- reaction.2 The classic Grignard reaction is an organometallic Open Access Article. Published on 03 maí 2013. Downloaded 26.9.2021 02:16:29. tive. Unfortunately, the solvent used for the organometallic reaction in which alkyl- or aryl-magnesium halides (Grignard reagent biases a process towards a less green position from the reagents) add to carbonyl groups of aldehydes and ketones to outset of development. Frequently these sub-optimal solvents generate a new carbon–carbon bond. In addition to the broad persist through the development lifecycle all the way through applications on a research scale, Grignard reactions have also to commercial manufacturing. To address these issues, a been adapted to a large scale and are the pivotal steps in the GCIPR team was assembled with the objective to catalyse sup- manufacture of numerous complex molecules. From a pliers to provide organometallic reagents in the greenest poss- pharmaceutical perspective, the Grignard reaction has been ible solvent. In 2010, feedback was received from several employed as a key step in numerous syntheses such as that of organometallic reagent suppliers that the strongest impact tramadol,3 ravuconazole,4 naproxen,5 ibuprofen,6 aprepitant,7 could be realized by conducting independent research and droloxifene,8 and tamoxifen9 (Fig. 1). For each molecule shown publishing the findings with head to head performance com- in Fig. 1, the bond prepared by the Grignard reaction is parisons between different solvents. Based on this feedback, highlighted. the GCIPR developed a research grant to systematically Despite significant utility, Grignard reactions present chal- lenges particularly on scaling-up. From a safety standpoint, the initiation step is often hard to control, and is strongly aDepartment of Chemistry, University of Massachusetts Boston, Boston, Massachusetts 02125, USA. E-mail: [email protected] exothermic as is the subsequent Grignard reaction. In some bEli Lilly and Company, Indianapolis, Indiana 46285, USA instances research scale chemistry has been recently carried cPfizer-La Jolla, 10777 Science Center Drive, La Jolla, California 92122, USA out using continuous flow methods to alleviate the exotherm d Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland hazards of the Grignard reaction.10 Furthermore, the solvents e Pfizer-Cambridge, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, typically employed such as Et O and THF have low boiling USA 2 †Electronic supplementary information (ESI) available. See DOI: 10.1039/ points, and are capable of forming peroxides, which are both c3gc40702k hazardous as well as detrimental to the reaction. In addition, 1880 | Green Chem., 2013, 15, 1880–1888 This journal is © The Royal Society of Chemistry 2013 View Article Online Green Chemistry Paper equilibrium. THF and in particular Et2O are not optimal sol- vents for scale-up work due to their potential for peroxide for- mation, as well as physical hazards such as their low boiling points and flashpoints. An ideal alternative solvent would present an improved reaction profile, and allow for an opera- tionally simpler work-up. From an environmental standpoint, the optimal solvent would also be one with a better safety profile, and ideally available from renewable sources.13 Aycock14 has presented initial data showing the promising nature of 2-MeTHF for Grignard reactions, and Clarke15 has employed Grignard reagents of significantly enhanced concen- trations (up to 5 M) in cross-coupling chemistry using this solvent. 2-MeTHF can be derived from a renewable source,16 is more stable to acids and bases than THF, is less prone to per- oxide formation, and is immiscible with water thus enabling an easier phase-split for work-up.17 Cyclopentylmethyl ether (CPME), which can be produced directly from cyclopentene, Fig. 1 Pharmaceutical syntheses featuring the Grignard reaction. has also been promoted as a potential alternative solvent for Grignard reactions.18 CPME is resistant to peroxide formation, the reactions typically use the reactive Grignard metal, and the and like 2-MeTHF it is more easily dried than typical ethereal product profile is often complicated by the symmetrical homo solvents due to formation of an azeotrope with water. Merck (Wurtz) coupling by-product and the proteo by-product result- recently reported the results of oral toxicity studies for 19 Creative Commons Attribution 3.0 Unported Licence. ing from direct reduction of the substrate or unfavourable 2-MeTHF and CPME. For both these solvents the results were water ingress into the reaction. The amounts of oxygen and negative for genotoxicity and mutagenicity which should assist moisture intake are also key parameters impacting both the in favourable long-term ICH classifications. Although widely success of the initial reagent formation and subsequent pro- promoted as greener solvents, only a handful of Grignard cesses of Grignard reactions. Numerous methods have been reagents are available in 2-MeTHF or CPME. Despite the initial devised to initiate sluggish Grignard reactions.11 All these promising results demonstrated for 2-MeTHF and CPME, to derive from the common theme of weakening the passivation the best of our knowledge, no systematic and unbiased evalu- layer of magnesium oxide, thereby exposing highly reactive ation of solvent performance of a range of solvents has been magnesium to the organic halide. reported in the literature. For the purpose of comparison, This article is licensed under a other solvents such as diethoxymethane (DEM),20 toluene, and diglyme are also included in our study (Table 1). 1.2 Selection of substrates and solvents for Grignard Open Access Article. Published on 03 maí 2013. Downloaded 26.9.2021 02:16:29. reactions Because of the broad use in the pharmaceutical and fine chemicals industry, benzyl, aryl and heteroaromatic halides 2 Results and discussion were identified as the representative substrates to systemati- cally evaluate the solvent effect for the Grignard reactions. The The approach used in this study was to evaluate Grignard reac- reaction solvent is the key component in the formation of the tions of the selected substrates in the seven solvents shown in Grignard reagent and reaction. From a process standpoint, the Table 1. The Grignard reagents were generated by reacting the solvent typically represents the largest fraction of the process alkyl- or aryl-halides with commercial grade magnesium turn- mass12 and as such its judicious selection for work-up, safety, ings. The in situ generated Grignard reagents were allowed to cost and reaction profile is critical. Numerous Grignard react with the electrophile. In the solvent screening reactions, reagents are available commercially, and as previously men- the reaction mixtures were analysed by GC-MS or LC-MS to tioned the vast majority of these are offered either as THF or determine the ratio of the product and by-products. Gram- Et2O solutions. The use of commercially prepared Grignard scale reactions were then conducted under optimized con- solutions provides an advantage for the synthetic chemist in ditions in selected solvents to examine the ease of product iso- that the hazardous initiation step is removed. However, it lation and determine the yield. Other than solvents, key causes problems
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