Mild, Selective Ru‐Catalyzed Deuteration Using D2O as a Deuterium Source
AbstractA method for the selective deuteration of polyfunctional organic molecules using catalytic amounts of [RuCl2(PPh3)3] and D2O as a deuterium source is presented. Through variation of additives like CuI, KOH, and various amounts of zinc powder, orthogonal chemoselectivities in the deuteration process are observed. Mechanistic investigation indicates the presence of different, defined Ru‐complexes under the given specific conditions.
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<p>P. Eisele, F. Ullwer, S. Scholz, B. Plietker, Chem. Eur. J.
2019, 25, 16550.</p><p>The exchange of hydrogen atoms for their isotopes deuterium or tritium is a common method for studies on biosynthesis but also metabolism.1 Moreover, the position selective deuteration is a mean to mask notoriously reactive C−H bonds against a fast oxidative metabolic degradation.2 The use of the kinetic isotope effect leads to a reduction of reactivity and hence to an improved bioavailabiltiy/‐stability of a pharmacophore in living organisms.3 On the other hand, the isotope effect can provide important insights into mechanistic issues.1, 4 There is thus much interest in the development of chemoselective deuteration methods.5 Often, the incorporation of deuterium or tritium occurs when using D2 or T2 gas, which is not unproblematic because of the hazard potential of these gases.6 The use of D2O (or T2O) for deuteration seems more feasible against this background.7</p><p>In the course of total syntheses and studies on possible metabolic degradation products, we needed a viable method for selective deuteration. Some time ago, we reported that the readily available Ru complex [RuCl2(PPh3)3] (1) catalyzes orthogonal‐chemoselective reductions of multifunctional substrates by using zinc and stoichiometric amounts of water in the presence of different cocatalysts.8 While the addition of CuI as a cocatalyst allows the selective reduction of alkynes to alkenes in the presence of carbonyl groups, the exchange of the cocatalyst reverses the sequence of reactivity. Alkynes are not reduced, and carbonyl groups are selectively converted into the corresponding alcohols.8 Based on these results and motivated by our search for a workable deuteration method, we initiated a research project in which we sought to exploit the cocatalyst‐dependent chemoselectivity trends of the Ru–Zn–H2O system for the development of selective isotope labeling. Herein we report the first results of this study, in which we demonstrate the selective deuteration of different polyfunctional organic substrates. NMR spectroscopic investigations were used to identify the in situ formed Ru catalysts 2–4 (Figure 1).</p><p>Additive‐dependent chemoselective Ru‐catalyzed deuterations.</p><p>The study presented here was based on in‐depth NMR spectroscopic studies on the influence of the additives KOH and CuI on the preacatalyst activation. The quintessence of this extensive work is summarized in Scheme 1. Consequently, the Ru−H species [RuHI(PPh3)3] (2) is formed in the presence of an excess of zinc in H2O using CuI as an additive starting from precatalyst [RuCl2(PPh3)3] (1) [Eq. (1), Scheme 1]. In contrast, the presence of KOH and zinc as an additive yields the Ru "superhydride" complex [Ru(H2)H2(PPh3)3] (3) [Eq. (3), Scheme 1]. In the absence of zinc, the Ru–OH complex 4 is formed from 1 in the presence of catalytic amounts of KOH [Eq. (2), Scheme 1]. These spectroscopic results provide a direct explanation for the observed chemoselectivities. For example, the activity of the structurally similar complex [RuHCl(PPh3)3] in the chemoselective reduction of olefins in the presence of carbonyl groups has been described in the literature.9 On the contrary, complex 3 is one of the most active Ru catalysts in the reduction of carbonyl groups and quasi inert to olefin/alkyne reductions.10</p><p>Activation of the precatalyst [RuCl2(PPh3)3] (1) through additives.</p><p>With these results in hand, the activation of D2O under the established conditions was studied by the reduction of diarylalkynes 5–7 and acetophenone derivatives 11–13 (Scheme 2). By addition of CuI, the Z‐bis‐deuterated olefins 8–10 could be isolated in good yields of 86 % at a deuteration degree of 85 %. Another 14 % corresponded to the E‐bis‐deuterated olefin; interestingly, the degree of deuteration on both olefinic carbon atoms was identical at about 85 %. Mixed H–D‐substituted olefins were undetectable. After a longer reaction time only E‐configured olefins 8–10 could be detected; a change in the degree of deuteration or overreduction was not observed [reaction conditions (A), Eq. (1), Scheme 2]. Upon addition of KOD [reaction conditions (B), Eq. (2), Scheme 2], no conversion was observed, whereas ketones 11–13, upon addition of catalytic amounts of KOD, reacted cleanly to give the corresponding alcohols 14–16 [Eq. (3), Scheme 2]. The H–D exchange at the acidic α‐carbon atom occurs as a KOD‐catalyzed background reaction, and the addition of [RuCl2(PPh3)3] 1 was not necessary under these conditions. In the presence of CuI as an additive, however, no reduction of the carbonyl group and no deuteration at the α‐carbon atom was observed. Interestingly, under these conditions a selective deuteration of the two ortho‐carbon atoms in the aromatic moiety ketones 17–19 was observed [Eq. (4), Scheme 2].</p><p>Additive‐directed chemoselective reductive deuteration of carbonyl compounds and alkynes. [a] 16 h reaction time.</p><p>Carbonyl groups are able to direct the ortho‐selective C−H activation through coordination of Ru catalysts. Since the groundbreaking work of Murai,11 a large number of Ru complexes have been developed that enable ortho‐C−H activation by a wide variety of directing groups under redox‐neutral7, 12 and oxidative13 conditions. The simple H–D exchange is formally a redox‐neutral transformation, which raises the question of the necessity of zinc as a reducing agent in such processes. To obtain a better overview of the scope of ortho‐deuteration, different catalyst‐directing groups were subsequently investigated with regard to their reactivity (Table 1). In fact, using catalytic amounts of [RuCl2(PPh3)3] (1) and KOD in the absence of stoichiometric amounts of zinc (conditions (C)) an efficient ortho‐selective C(sp2)–H–D exchange was possible. The use of catalytic amounts of [RuCl2(PPh3)3] (1) and CuI (conditions (A)), on the other hand, provided the expected deuterated aromatics only when using zinc.</p><p>Ru‐catalyzed ortho‐deuteration of aromatics by using D2O as d‐surrogate after 16 h.[a,b]</p><p>Entry</p><p>Product</p><p>Entry</p><p>Product</p><p></p><p>Ru‐cat./KOD/D2O</p><p>Ru‐cat./CuI/Zn/D2O</p><p></p><p>Ru‐cat./KOD/D2O</p><p>Ru‐cat./CuI/Zn/D2O</p><p>1</p><p></p><p>20</p><p></p><p>20</p><p>7</p><p></p><p>27</p><p></p><p>28</p><p>2</p><p></p><p>21</p><p></p><p>21</p><p>8</p><p></p><p>29</p><p></p><p>30</p><p>3</p><p></p><p>22</p><p></p><p>22</p><p>9</p><p></p><p>31</p><p></p><p>32</p><p>4</p><p></p><p>23</p><p></p><p>23</p><p>10[c]</p><p></p><p>33</p><p></p><p>33</p><p>5</p><p></p><p>24</p><p></p><p>24</p><p>11</p><p>no reaction</p><p></p><p></p><p>34</p><p>6</p><p></p><p>25</p><p></p><p>26</p><p>12[e]</p><p></p><p>35</p><p>no reaction</p><p>[a] Conditions (A): substrate [0.5 mmol], [RuCl2(PPh3)3] [0.0125 mmol, 2.5 mol %], CuI [0.05 mmol, 10 mol‐%], zinc [1 mmol], D2O [4 mmol], dioxane [1 mL], 80 °C, 16 h. [b] Conditions (C): substrate [0.5 mmol], [RuCl2(PPh3)3] [0.0125 mmol, 2.5 mol %], KOD [0.125 mmol, 25 mol %], D2O [4 mmol], dioxane [1 mL], 80 °C, 16 h. [c] 62 h reaction time. [d] in [D8]THF. [e] in the presence of zinc powder.</p><p>Depending on the additive, significant differences in the deuteration were observed. While the ortho‐deuteration of C(sp2)−H bonds using catalytic amounts of KOD was highly selective, catalytic depletion of CuI led both to C(sp2)−H‐ and C (sp3)−H bond deuteration plus in some cases ring opening of the directing group, for example, oxazolidines. Since C(sp3)−H‐deuteration of benzoic acid propylamide 33 with the addition of both KOD and CuI led to almost identical results (entry 10, Table 1), we assume that C(sp3)−H‐deuteration occurs prior to the opening of the oxazolidinone. Importantly, no dehalogenation reactions were observed under either reaction conditions.14 Control experiments indicated that upon using CuI or KOD in the presence of stoichiometric amounts of zinc in situ generation of D2 from D2O is likely.15 However, since the ortho‐selective H–D exchange occurs with addition of catalytic amounts of KOD even without zinc, a direct deuteration from D2O can be assumed under these conditions.</p><p>With these results in hand, we turned to the deuteration of more complex substrates (Table 2). Both p‐ and m‐alkynylpyridyl‐substituted aromatics 36 and 37 were tested under the established conditions (entries 1 and 2, Table 2). The use of catalytic amounts of KOD both in the presence and absence of zinc occurred with no reduction of the CC triple bond but selective CH deuteration in the ortho‐position to the pyridyl substituent. In the presence of catalytic amounts of CuI, a semireduction of the alkynes to the olefins 41 and 42 plus ortho‐deuteration was observed. The initially formed cis‐configured olefins rearrange with longer reaction times into the trans‐products. Starting from arylalkynyl aryl ketones 38 and 39, only deuteration of the carbonyl‐bound methyl group was observed in the presence of catalytic amounts of KOD. Interestingly, no ortho‐deuterations were detected (entries 3 and 4, Table 2). In analogy to substrates 36 and 37, the use of catalytic amounts of CuI and stoichiometric amounts of zinc led to a selective semireduction of alkynes 38 and 39 plus ortho‐deuteration to give the corresponding olefins 43 and 44. The substitution pattern of the starting materials 36–39 had a significant impact on the ortho‐deuteration process. While in para‐substituted substrates 36 and 38 both ortho‐positions were equally deuterated (entries 1 and 3, Table 2), only the position ortho to the catalyst‐directing group was deuterated for meta‐substituted arylalkynes 37 and 39. Both electronic as well as steric effects might account for this finding (entries 2 and 4, Table 2).</p><p>Additive‐directed Ru‐catalyzed deuteration of polyfunctional substrates after 62 h reaction time.[a,b]</p><p>Entry</p><p>Substrate</p><p>Product</p><p></p><p></p><p>Ru‐cat./KOD/D2O</p><p>Ru‐cat./CuI/Zn/D2O</p><p>1</p><p></p><p>36</p><p></p><p>36</p><p></p><p>41</p><p>2</p><p></p><p>37</p><p></p><p>37</p><p></p><p>42</p><p>3</p><p></p><p>38</p><p></p><p>38</p><p></p><p>43</p><p>4</p><p></p><p>39</p><p></p><p>39</p><p></p><p>44</p><p>5[c]</p><p></p><p>40</p><p></p><p>40</p><p></p><p>40</p><p>[a] Condition (A): substrate [0.5 mmol], [RuCl2(PPh3)3] [0.0125 mmol, 2.5 mol %], CuI [0.05 mmol, 10 mol %], zinc [1 mmol], D2O [4 mmol], dioxane [1 mL], 80 °C, 62 h. [b] Condition (C): substrate [0.5 mmol], RuCl2(PPh3)3 [0.0125 mmol, 2.5 mol %], KOD [0.125 mmol, 25 mol %], D2O [4 mmol], dioxane [1 mL], 80 °C, 62 h. [c] 16 h reaction time.</p><p>Finally, we tested both methods on complex drugs such as piribedil 45 or boscalid 46. Fortunately, it was shown that both reaction conditions are also applicable to the selective deuteration of polyfunctional materials such as 45 and 46 [Eqs. (1)–(4), Scheme 3].</p><p>Additive‐directed Ru‐catalyzed deuteration of piribedil 45 and boscalid 46.</p><p>Thus, in the presence of catalytic amounts of CuI (conditions (A), Scheme 3), a selective deuteration of the methylene group of the piperazine ring is observed [Eq. (1), Scheme 3]. The pyrimidine substituent obviously acts as a directing group. While under these conditions the pyrimidine ring is inert, we observed partial deuteration of the pyrimidine ring upon addition of catalytic amounts of KOD in addition to the H–D exchange at the methylene group of the piperazine [Eq. (2), Scheme 3]. It was found that by increasing the reaction time or by repeatedly reacting the deuterated product, higher degrees of deuteration can be obtained.15</p><p>The selectivity difference of our protocols is particularly evident in the reaction of boscalid 46 [Eqs. (3) and (4), Scheme 3]. Apparently, the carboxylic acid amide group at position 3 of the pyridine ring acts as a catalyst‐directing group, and in the presence of CuI directs the deuteration to the ortho‐positions of the pyridine ring [Eq. (3), Scheme 3]. In contrast, under KOD/ Zn conditions, the 6‐position of the pyridine ring is selectively deuterated [Eq. (4), Scheme 3]. In both cases, a partial Cl–D exchange is observed on the activated heteroaromatic moiety. In contrast, the second C−Cl bond in the unactivated aromatic remains unreactive under either conditions.</p><p>Herein, we present a preparatively simple method for the deuteration of functional organic molecules under mild conditions. Depending on the additive, the precatalyst [RuCl2(PPh3)3] 1 is converted into different defined Ru complexes 2–4 by using either CuI (cat.)/Zn, or KOD (cat.) or KOD (cat.)/Zn. Each of these complexes shows a different selectivity in H–D exchange reactions. D2O is used as the common deuterium source in all cases. When using zinc as an additive, the formation of D2 gas could be experimentally proven. Future work will aim to improve the present protocols, for example, through systematic variation of ligands, in order to amplify the selectivity trends.</p><!><p>The authors declare no conflict of interest.</p><!><p>As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.</p><p>Supplementary</p><p>Click here for additional data file.</p>