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Preparation and Reactions of Polyfunctional Magnesium and Zinc Organometallics in Organic Synthesis

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Preparation and Reactions of Polyfunctional Magnesium and Zinc Organometallics in Organic Synthesis Chemical Science View Article Online PERSPECTIVE View Journal | View Issue Preparation and reactions of polyfunctional magnesium and zinc organometallics in organic Cite this: Chem. Sci.,2021,12,6011 † All publication charges for this article synthesis have been paid for by the Royal Society of Chemistry Alexander Kremsmair, Johannes H. Harenberg, Kuno Schwarzer,¨ Andreas Hess and Paul Knochel * Polyfunctional organometallics of magnesium and zinc are readily prepared from organic halides via a direct metal insertion in the presence of LiCl or a Br/Mg-exchange using iPrMgCl$LiCl (turbo-Grignard) or related reagents. Alternatively, such functionalized organometallics are prepared by metalations with TMP-bases Received 3rd February 2021 (TMP ¼ 2,2,6,6-tetramethylpiperidyl). The scope of these methods is described as well as applications in Accepted 9th March 2021 new Co- or Fe-catalyzed cross-couplings or aminations. It is shown that the use of a continous flow DOI: 10.1039/d1sc00685a set-up considerably expands the field of applications of these methods and further allows the rsc.li/chemical-science preparation of highly reactive organosodium reagents. Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 1. Introduction Although, some innovative chemistry of lithium, sodium and potassium will be presented considering some remarkable The compatibility of functional groups with a carbon–metal properties of these species, the main part of this article will bond in an organometallic reagent is essential for broad concern the preparation and reactivity of polyfunctional Mg synthetic applications in modern organic synthesis. In this and Zn reagents. The behaviour of aryl- and heteroaryl perspective article, we will show that Mg and Zn organome- organometallics will be especially emphasized because of their tallics are unique for combining an excellent functional group importance in material, agrochemical and pharmaceutical This article is licensed under a tolerance with a high reactivity toward various classes of research. We will also show that continuous ow set-ups electrophiles. Furthermore, magnesium and zinc derivatives involving such organometallic reactions further expands the arenon-toxicandthemoderatepriceofthesetwoelements application scope, especially by allowing some new Barbier- Open Access Article. Published on 16 2021. Downloaded 2021/9/27 13:20:57. makes them ideal candidates for industrial applications. type procedures. Department of Chemistry, Ludwig-Maximilans-Universitat¨ Munchen,¨ † In memory of Victor Snieckus. Butenandtstraße 5-13, 81377 Munchen,¨ Germany. E-mail: paul.knochel@cup. uni-muenchen.de Alexander Kremsmair was born Johannes H. Harenberg was in 1994 in Linz a. d. Donau born in Berlin (Germany) in (Austria). Aer nishing his 1992. Aer his undergraduate high school diploma, he studied studies at the Ludwig-Max- chemistry at the Ludwig-Max- imilians-Universitat¨ (Munich) imilians-Universitat¨ in Munich he joined the research group of andjoinedthegroupofProf. Professor Paul Knochel for his Paul Knochel for his Master Master's thesis and started his thesis in 2018, where he stayed PhD in the same group in 2019. to pursue his PhD. His research His current research work is focuses on the preparation of focused on the application of new chiral secondary alkylme- alkali organometallic species in tal reagents for asymmetric continuous ow. synthesis and the regioselective metalation of sensitive heterocycles. © 2021 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2021,12,6011–6019 | 6011 View Article Online Chemical Science Perspective 2. Preparation of polyfunctional Zn and Mg organometallics 2.1 Direct reaction of magnesium or zinc with organic halides The carbon–zinc bond is a covalent carbon–metal bond with moderate intrinsic reactivity. Metallic zinc is a weaker reducing agent compared to magnesium, and therefore a mixed metal synthesis using magnesium dust in the presence of LiCl and ZnCl2 is an advantageous procedure for the preparation of aryl and heteroaryl zinc reagents bearing sensitive functional groups.1 Under these conditions, methyl 4-bromobenzoate (1) underwent a smooth conversion to the corresponding zinc reagent within 3 h at 25 C (see Scheme 1). The addition of LiCl was essential for removing the organ- ometallic species on the metal surface by forming a mixed magnesium–lithium complex of the type RMgX$LiCl.2 Fast Scheme 1 Magnesium and zinc insertions to functionalized (hetero) magnesium insertion rates were observed with electron- aryl halides mediated by LiCl and indium salts. decient substrates like electron-poor aromatics or heterocy- clic chlorides such as 2.1 The direct zinc insertion may require the addition of a Lewis-acid catalyst whose role is to facilitate these conditions, a sensitive functional group like an acetyl electron transfer steps from the metal surface to the organic group which is prone to enolization, like in 4-iodoacetophenone Creative Commons Attribution-NonCommercial 3.0 Unported Licence. halide. Thus, in the presence of In(acac) (3 mol%), 2-bromo-1- 3 (4), was perfectly tolerated. The mild conditions required for chloro-4-(triuoromethyl)-benzene (3) was converted to the these insertion reactions are also compatible with the presence corresponding zinc reagent at 50 C within 2 h.3 The use of of acidic NH-groups.5 Thus, the iodo-indole derivative 5 was 4 a polar co-solvent such as DMPU proved to be helpful. Under converted to the corresponding zinc reagent at 25 C.6 In the presence of a palladium catalyst (2 mol% Pd(OAc)2; 4 mol% SPhos), a Negishi cross-coupling with an N-heterocyclic iodide Kuno Schwarzer¨ was born in 1992 in Innichen (Italy). Aer his readily took place at 25 C. Secondary alkyl iodides usually react undergraduate studies at the faster in these direct insertion reactions. Thus, cis-iodo-pyrrole This article is licensed under a Ludwig-Maximilians-Universitat¨ in Munich he joined the group of Paul Knochel was born in 1955 in Prof. Paul Knochel for his Strasbourg (France). He studied Open Access Article. Published on 16 2021. Downloaded 2021/9/27 13:20:57. Master's thesis and started his at the University of Strasbourg PhD thesis in the same group in (France) and did his PhD at the 2017. His research focuses on the ETH-Zurich¨ (D. Seebach). He reaction of [1.1.1]propellane with spent four years at the University organometallic reagents and the Pierre and Marie Curie in Paris metalation of nitrogen- (J.-F. Normant) and one year at containing heterocycles with Princeton University (M. F. Sem- TMP-bases. melhack). In 1987, he became Professor at the University of Andreas Hess was born in 1995 in Michigan. In 1992, he moved to Landshut (Germany). Aer his Philipps-University at Marburg undergraduate studies at the (Germany). In 1999, he then moved to the Chemistry Department of Ludwig-Maximilians-Universitat¨ Ludwig-Maximilians-University in Munich (Germany). His research (Munich) he joined the research interests include the development of novel organometallic reagents group of Professor Paul Knochel and methods for use in organic synthesis, asymmetric catalysis, and for his Master's thesis and started natural product synthesis. Prof. Knochel has received many his PhD in the same group in distinguished prizes including the Berthelot medal of the Academie 2020. His research focuses on the des Sciences (Paris), the IUPAC Thieme prize, the Otto–Bayer-prize, regioselective magnesiation of the Leibniz-prize, the Arthur C. Cope scholar award, Karl-Ziegler- nitrogen-containing heterocycles prize, the Nagoya Gold Medal, the H. C. Brown award, and Paul and arenes. Karrer gold medal. He is member of the Acad´emie des Sciences, the Bavarian Academy of Science and the German Academy of Sciences Leopodina. He is author of over 900 publications. 6012 | Chem. Sci.,2021,12,6011–6019 © 2021 The Author(s). Published by the Royal Society of Chemistry View Article Online Perspective Chemical Science 6, which was readily available from trans-2-aminocyclohexanol, underwent a zinc insertion within 10 min at 25 C leading to a cis, trans-mixture of zinc reagent 7. This loss of stereochem- istry is characteristic for Mg or Zn insertions which proceed through radical intermediates. However, in the presence of a palladium catalyst, a diastereoselective cross-coupling7 took place leading exclusively to the trans-cyclohexane derivative 8 (84%; 99% ee; dr >99 : 1; see Scheme 2).6 Scheme 3 Br/Mg-Exchange on functionalized aryl bromides using the 2.2 The halogen/metal exchange turbo-Grignard reagent (9). The halogen/lithium exchange (Hal ¼ I, Br) is a fast reaction, independently discovered in 1939 by Gilman and Wittig.8 In tetramethylpiperidine, TMP-H), it was possible to prepare comparison, the halogen/magnesium-exchange is a much a series of metallic amides complexed with LiCl slower reaction, which had only found applications in the (TMPMgCl$LiCl, TMP2Mg$2LiCl, TMPZnCl$LiCl and TMP2- preparation of some heterocyclic Grignard reagents9 and Zn$2LiCl) with high solubility in THF (1.2–1.4 M) and excep- magnesium carbenoids.10 However, by using organomagnesium tional kinetic basicity.19 The preparation of polyfunctional halides complexed by LiCl such as iPrMgCl$LiCl (9, turbo- magnesium reagents became now possible from halide-free Grignard reagent) fast I/Mg- and Br/Mg-exchanges took place precursors. Thus, the highly functionalized arene 12 was producing functionalized aryl and heteroaryl magnesium magnesiated with TMPMgCl$LiCl at À20 Cleadingtoan
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