A novel manganese-catalyzed C-H activation methodology for selective hydrogen isotope exchange of benzaldehydes is presented. Using D2O as a cheap and convenient source of deuterium, the reaction proceeds with excellent functional group tolerance. Highortho-selectivity is achieved in the presence of catalytic amounts of specific amines, whichin situform a transient directing group. © The Royal Society of Chemistry 2021

Beller, Matthias

Kopf, Sara

Neumann, Helfried

English

Repositorium für Naturwissenschaften und Technik

This journal is©The Royal Society of Chemistry 2021 Chem. Commun., 2021, 57, 1137--1140 | 1137Cite this:Chem. Commun., 2021,57, 1137Manganese-catalyzed selective C–H activationand deuteration by means of a catalytic transientdirecting group strategy†Sara Kopf, Helfried Neumann * and Matthias Beller *A novel manganese-catalyzed C–H activation methodology forselective hydrogen isotope exchange of benzaldehydes is presented.Using D2O as a cheap and convenient source of deuterium, thereaction proceeds with excellent functional group tolerance. Highortho-selectivity is achieved in the presence of catalytic amounts ofspecific amines, which in situ form a transient directing group.Not only since the first deuterated drug was accepted by the U.S.Food and Drug Administration (FDA) in 2017, an increasinginterest in the development of methodologies for the selectivelate-stage incorporation of deuterium into organic molecules hasmanifested itself within the field of organic synthesis.1 As aresult, the current toolbox for labeling reactions comprises anumber of established techniques for diverse substrates. As anexample, deuteration of arenes predominantly relies on iridium-catalyzed hydrogen isotope exchange (HIE) (Scheme 1a). Here,the most important representative, the NHC-ligated Kerrcatalyst, affects deuteration under deuterium gas atmosphereortho to a number of pre-installed directing groups, includingN-heterocycles, carbonyl groups and sulfur-containing functionalgroups.2 Most recently, base metal-catalyzed methodologies haveexpanded the field by presenting new selectivity concepts basedon steric and/or electronic control. In this context, the deuterationof the least sterically hindered positions in arenes and hetareneshas been achieved under catalysis with iron pincer complexes(Scheme 1b),3 whereas a diamine nickel complex preferentiallyenabled HIE on electron-deficient positions of pyridinederivatives.4 However, the precision of a directed approach hasso far been unmet by alternative strategies. In this respect, thedevelopment of metal catalyzed directed HIE methodologies,5combining inexpensive and available metals with predictableselectivity, is desirable.Among the different earth-abundant 3d metals, manganeseis a most promising candidate, haven proven its efficacy forcatalytic directed C(sp2)–H functionalization reactions byenabling a plethora of transformations.6 Moreover, althoughmanganese-catalyzed deuteration of arenes has only been scar-cely investigated yet,7 some mechanistic investigations alreadyhint at the potential success of such an endeavor.8 However,despite these advances, manganese-catalyzed C–H activation isstill limited to substrates comprising nitrogen-containingdirecting groups9 and thus often demands additional syntheticsteps. For instance, a recently disclosed allylation reaction ofarenes required the pre-formation of an imine as a directinggroup, which subsequently needed to be hydrolyzed in aseparate step.10 A methodology that allows this imine formationto occur in situ with a catalytic amount of amine and thus reducestime and waste would certainly be more appealing. Interestingly,such a transient directing group strategy has been utilized innoble metal catalysis,11 but has thus far not been applied to eithermanganese-catalyzed C–H activation or directed HIE. We believedthat both fields could be merged thus report herein on the firstScheme 1 Selectivity control of deuteration methodologies.Leibniz-Institut für Katalyse, Albert-Einstein-Straße 29a, Rostock 18059, Germany.E-mail: matthias.beller@catalysis.de† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0cc07675aReceived 23rd November 2020,Accepted 18th December 2020DOI: 10.1039/d0cc07675arsc.li/chemcommChemCommCOMMUNICATIONOpen Access Article. Published on 07 January 2021. Downloaded on 3/29/2022 7:25:46 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article OnlineView Journal  | View Issue1138 | Chem. Commun., 2021, 57, 1137--1140 This journal is©The Royal Society of Chemistry 2021manganese-catalyzed ortho-selective C–H deuteration of aromaticaldehydes through transient formation of a catalytic directinggroup (Scheme 1c). We started our investigations by studying thedeuteration of para-anisaldehyde under typical conditions forbase-assisted manganese-catalyzed C–H activation. More specifically,we used 5 mol%12 manganese pentacarbonyl bromide along withD2O as the cheapest source of deuterium in the presence of catalyticamounts of different amines (Scheme 2).Firstly, in the absence of amine additives, no deuterationwas observed, confirming that the aldehyde moiety is not afeasible directing group for such C–H activation. Furthermore,established transient directing groups such as anilines andglycine11 could not afford any deuteration either. Surprisingly,the addition of 20 mol% of benzylamine to the reaction mixtureenabled selective deuteration in the ortho positions of thealdehyde with a deuterium incorporation of 66% (A3). Theuse of sterically more hindered 1-phenylethylamine led to adrop in deuterium incorporation whereas substituents on thearomatic ring did not have a major influence on the reactivity(A5 and A6). A slightly increased deuteration was observedwith aliphatic amines such as n-butylamine (A7) so that bothbenzylic and aliphatic amines can be considered efficientcatalytic additives for transient directing group formation.Notably, the deuterium incorporation can be simply increasedby re-submitting the isolated, partially deuterated compound tothe reaction conditions (Table 1, entry 1). Interestingly, thereaction does not benefit from elevated temperature (120 1C)but works equally well at 80 1C (Table 1, entries 2–4). Finally, inthe absence of a manganese catalyst, no deuteration took place(Table 1, entry 5).Having gained insights into the influence of various para-meters on the deuteration efficiency, we moved on to explorethe substrate scope of this novel deuteration methodology. Forthis purpose, we conducted reactions at a temperature of 100 1Cto ensure that less reactive substrates are also deuteratedefficiently. To our delight, a variety of benzaldehyde derivativesproved to be amenable substrates, being selectively deuteratedin ortho position without any side product formation(Scheme 3). In this context, halogenated benzaldehydes provedto be particularly viable substrates and did not undergo com-peting deuterodehalogenation (2–7 and 17).13 Only remainingamounts of the intermediary imine or the volatility of thesubstrates sometimes slightly impacted the recovery of thealdehyde. Further, substituents in ortho, meta and para posi-tions as well as multi-substituted benzaldehydes are all welltolerated while guidance by Lewis-basic substituents isobserved in the presence of two non-identical ortho positions,overriding potential steric effects (14, 16, 20).14Strongly electron-deficient benzaldehydes comprising nitro orcyano substituents (19–23) required slightly modified reactionconditions: due to the increased stability of the intermediaryimine,15 a switch from base to acid catalysis facilitated turnoverof the catalytic amine, thus yielding the corresponding aldehydeswith high deuterium incorporation even at a low catalyst loadingof 2.5 mol%. Similarly, good results were achieved with hetero-cyclic aldehydes (24–28), demonstrating the broad applicability ofthis methodology. Only substrates containing heteroatoms ina-position to the aldehyde moiety as well as pyridine derivativesappeared to form unreactive manganese complexes instead.Notably, chromone derivative 28 undergoes formyl deuterationadditionally, presumably aided by coordination of the proximalketo group.To test the functional group compatibility of this reactionbeyond the groups already mentioned in the text and high-lighted in Scheme 3, further deuteration experiments wereconducted in the presence of equimolar amounts of a terminalolefin, a boronic acid, a sulfonamide, and phenol. All theseadditives were well-tolerated and did not affect the deuteriumincorporation in the aldehyde substrate. On the other hand,hydroxy-substituted aldehydes as well as substrates comprisingterminal alkynes were not deuterated.From a synthetic point of view it is interesting that thereaction is selective for aldehydes, leaving aromatic ketonesuntouched despite their ability to form ketimines. Moreover,other carbonyl groups which had previously been employed asScheme 2 Mn-catalyzed o-deuteration of p-anisaldehyde in thepresence of catalytic amine additives for the in situ formation of transientdirecting groups. Scale: 0.5 mmol 1. Deuterium incorporation was deter-mined by 1H NMR through the decrease of the doublet at 7.81 ppm whilereferencing on the protons in meta position.Table 1 Mn-catalyzed o-deuteration of p-anisaldehyde undervarious conditionsEntry Variation D [%]1 1-d2 (73% D) instead of 1 882 120 1C 793 80 1C 764 60 1C 495 No [Mn] 0Scale: 0.5 mmol 1. Deuterium incorporation was determined by1H NMR through the decrease of the doublet at 7.81 ppm whilereferencing on the protons in meta position.Communication ChemCommOpen Access Article. Published on 07 January 2021. Downloaded on 3/29/2022 7:25:46 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article OnlineThis journal is©The Royal Society of Chemistry 2021 Chem. Commun., 2021, 57, 1137--1140 | 1139directing groups for manganese catalyzed C–H functionalization16did not induce ortho-deuteration under our conditions, whereasheterocyclic directing groups could potentially enable additionaldeuteration patterns in more complex substrates.While a variety of methods exists for the labeling of arenes(vide supra), the deuteration of olefinic substrates is much lessdeveloped.17 Notably, current methodologies for the labeling ofa,b-unsaturated carbonyl compounds either exchange all olefinicprotons alike or are slightly selective for the b position.17c,e, fLikewise, a previously reported manganese-catalyzed olefinicC–H activation also led to exclusive functionalization inb position.18 In this context, we explored the deuteration ofa,b-unsaturated aldehydes and ketones. Indeed, as shown inScheme 4, labelling proceeded smoothly with high selectivity forthe a-position. While this work was in progress, an amine-mediateda-selective deuteration of a,b-unsaturated aldehydes andketones was published.19 Accordingly, substrates 29–31 canScheme 3 Mn-catalyzed o-deuteration of various benzaldehyde derivatives. Scale: 0.5 mmol. Deuterium incorporation was determined by 1H NMR byreferencing on the formyl proton and/or protons in m or p positions and is indicated in square brackets (red). Percentage values below the structures refer toisolated yields. a BnNH2 instead ofnBuNH2.b 50 mol% p-chlorobenzoic acid instead of 1 eq. NaOAc. c 2.5 mol% Mn(CO)5Br.d 72 h. e 8 h. f 10 mol% Mn(CO)5Br.Scheme 4 a-Deuteration of a,b-unsaturated aldehydes and ketones.Scale: 0.5 mmol. Deuterium incorporation was determined by 1H NMR.ChemComm CommunicationOpen Access Article. Published on 07 January 2021. Downloaded on 3/29/2022 7:25:46 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Online1140 | Chem. Commun., 2021, 57, 1137--1140 This journal is©The Royal Society of Chemistry 2021be also deuterated in the absence of the manganese catalyst,whereby the amine acts as a nucleophilic catalyst rather than atransient directing group.In conclusion, we describe a new base metal-catalyzed ortho-selective deuteration methodology using the most practicallabelling reagent (D2O). This convenient alternative to currentiridium-catalyzed directed hydrogen isotope exchange reac-tions shows broad scope of (hetero)aromatic aldehydes andversatile functional group compatibility. Moreover, we haveintroduced the transient directing group concept to the fieldof manganese-catalyzed C(sp2)–H activation which willundoubtedly improve the step economy of future transforma-tions by alleviating the need for pre-installed directing groups.We acknowledge the financial support from the EuropeanUnion (Flow Chemistry for Isotope Exchange, FLIX, 862179),the BMBF and the State of Mecklenburg–Western Pommerania.We thank the analytical team of LIKAT for their kind support.Conflicts of interestThere are no conflicts to declare.Notes and references1 (a) J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid, Angew. Chem., Int.Ed., 2018, 57, 1758; (b) J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid,Angew. Chem., Int. Ed., 2018, 57, 3022.2 (a) J. A. Brown, A. R. Cochrane, R. Irvine, W. J. Kerr, B. Mondal,J. A. Parkinson, L. C. Paterson, M. Reid, T. Tuttle, S. Andersson andG. N. Nilsson, Adv. Synth. Catal., 2014, 356, 3551; (b) W. J. Kerr,M. Reid and T. Tuttle, ACS Catal., 2015, 5, 402; (c) M. Valero,T. Kruissink, J. Blass, R. Weck, S. Güssregen, A. T. Plowright andV. Derdau, Angew. Chem., Int. Ed., 2020, 59, 5626; (d) W. J. Kerr,G. J. Knox, M. Reid, T. Tuttle, J. Bergare and R. A. Bragg, ACS Catal.,2020, 10, 11120.3 (a) R. P. Yu, D. Hesk, N. Rivera, I. Pelczer and P. J. Chirik,Nature, 2016, 529, 195; (b) J. Corpas, P. Viereck and P. J. Chirik,ACS Catal., 2020, 10, 8640; (c) S. Garhwal, A. Kaushansky,N. Fridman, L. J. W. Shimon and G. de Ruiter, J. Am. Chem. Soc.,2020, 142, 17131.4 (a) H. Yang, C. Zarate, W. N. Palmer, N. Rivera, D. Hesk and P. J. Chirik,ACS Catal., 2018, 8, 10210; (b) C. Zarate, H. Yang, M. J. Bezdek, D. Heskand P. J. Chirik, J. Am. Chem. Soc., 2019, 141, 5034.5 J. Zhang, S. Zhang, T. Gogula and H. Zou, ACS Catal., 2020, 10, 7486.6 (a) W. Liu and L. Ackermann, ACS Catal., 2016, 6, 3743;(b) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz andL. Ackermann, Chem. Rev., 2019, 119, 2192; (c) R. Cano, K. Mackeyand G. P. McGlacken, Catal. Sci. Technol., 2018, 8, 1251.7 There is a report on manganese catalyzed aliphatic HIE, though:S. Kar, A. Goeppert, R. Sen, J. Kothandaraman and G. K. S. Prakash,Green Chem., 2018, 20, 2706.8 (a) B. Zhou, P. Ma, H. Chen and C. Wang, Chem. Commun., 2014,50, 14558; (b) S. Wu, Q. Yang, Q. Hu, Y. Wang, L. Chen, H. Zhang,L. Wu and J. Li, Org. Chem. Front., 2018, 5, 2852; (c) C. Zhu,R. Kuniyil and L. Ackermann, Angew. Chem., Int. Ed., 2019, 58,5338.9 A few exceptions exist but need bimetallic C–H activation systems:(a) S. Sueki, Z. Wang and Y. Kuninobu, Org. Lett., 2016, 18, 304;(b) B. Zhou, Y. Hu, T. Liu and C. Wang, Nat. Commun., 2017, 8, 1169;(c) Y. Hu, B. Zhou, H. Chen and C. Wang, Angew. Chem., Int. Ed.,2018, 57, 12071; (d) X. Kong and B. Xu, Org. Lett., 2018, 20, 4495;(e) S. Ali, J. Huo and C. Wang, Org. Lett., 2019, 21, 6961.10 W. Liu, S. C. Richter, Y. Zhang and L. Ackermann, Angew. Chem., Int.Ed., 2016, 55, 7747.11 (a) P. Gandeepan and L. Ackermann, Chemistry, 2018, 4, 199;(b) S. John-Campbell and J. A. Bull, Org. Biomol. Chem., 2018,16, 4582; (c) B. Niu, K. Yang, B. Lawrence and H. Ge, ChemSusChem,2019, 12, 2955; (d) J. I. Higham and J. A. Bull, Org. Biomol. Chem.,2020, 18, 7291.12 Catalyst loadings of 10 mol% are most common for manganese-catalyzed C–H activation procedures. Cf. ref. 7, 8b, e.13 Recent examples of deuterodehalogenation: (a) Z.-Z. Zhou,J.-H. Zhao, X.-Y. Guo, X.-M. Chen and Y.-M. Liang, Org. Chem. Front.,2019, 6, 1649; (b) J. J. Gair, R. L. Grey, S. Giroux and M. A. Brodney,Org. Lett., 2019, 21, 2482; (c) M. Kuriyama, G. Yano, H. Kiba,T. Morimoto, K. Yamamoto, Y. Demizu and O. Onomura,Org. Process Res. Dev., 2019, 23, 1552.14 This effect has previously been observed in manganese catalyzedC–H activation: cf. ref. 9 and D. Zell, U. Dhawa, V. Müller, M. Bursch,S. Grimme and L. Ackermann, ACS Catal., 2017, 7, 4209.15 R. W. Layer, Chem. Rev., 1963, 63, 489.16 T. S. Amide, T. Yoshida, H. H. A. Mamari, L. Ilies and E. Nakamura,Org. Lett., 2017, 19, 5458; ester: ref. 8a.17 Examples for olefinic deuteration: (a) S. K. S. Tse, P. Xue, Z. Lin andG. Jia, Adv. Synth. Catal., 2010, 352, 1512; (b) A. Di Giuseppe,R. Castarlenas, J. J. Pérez-Torrente, F. L. Lahoz, V. Polo andL. A. Oro, Angew. Chem., Int. Ed., 2011, 50, 3938; (c) W. J. Kerr,R. J. Mudd, L. C. Paterson and J. A. Brown, Chem. – Eur. J., 2014,20, 14604; (d) M. Hatano, T. Nishimura and H. Yorimitsu, Org. Lett.,2016, 18, 3674; (e) A. L. Garreau, H. Zhou and M. C. Young, Org. Lett.,2019, 21, 7044; ( f ) A. Bechtold and L. Ackermann, ChemCatChem,2019, 11, 435.18 B. Zhou, Y. Hu and C. Wang, Angew. Chem., Int. Ed., 2015, 54, 13659.19 V. G. Landge, K. K. Shrestha, A. J. Grant and M. C. Young, Org. Lett.,2020, 22, 9745.Communication ChemCommOpen Access Article. Published on 07 January 2021. Downloaded on 3/29/2022 7:25:46 AM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Online

Manganese-catalyzed selective C–H activation and deuteration by means of a catalytic transient directing group strategy

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Manganese-catalyzed selective C–H activation and deuteration by means of a catalytic transient directing group strategy

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