Half-Sandwich Ruthenium Carbene Complexes ... - ACS Publications

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Half-Sandwich Ruthenium Carbene Complexes Link transHydrogenation and gem-Hydrogenation of Internal Alkynes Alexandre Guthertz, Markus Leutzsch, Lawrence M. Wolf,† Puneet Gupta, Stephan M. Rummelt, Richard Goddard, Christophe Farès, Walter Thiel, and Alois Fürstner* Max-Planck-Institut für Kohlenforschung, Mülheim/Ruhr 45470, Germany S Supporting Information *

ABSTRACT: The hydrogenation of internal alkynes with [Cp*Ru]-based catalysts is distinguished by an unorthodox stereochemical course in that E-alkenes are formed by transdelivery of the two H atoms of H2. A combined experimental and computational study now provides a comprehensive mechanistic picture: a metallacyclopropene (η2-vinyl complex) is primarily formed, which either evolves into the E-alkene via a concerted process or reacts to give a half-sandwich ruthenium carbene; in this case, one of the C atoms of the starting alkyne is converted into a methylene group. This transformation represents a formal gem-hydrogenation of a π-bond, which has hardly any precedent. The barriers for trans-hydrogenation and gem-hydrogenation are similar: whereas DFT predicts a preference for trans-hydrogenation, CCSD(T) finds gem-hydrogenation slightly more facile. The carbene, once formed, will bind a second H2 molecule and evolve to the desired E-alkene, a positional alkene isomer or the corresponding alkane; this associative pathway explains why double bond isomerization and overreduction compete with trans-hydrogenation. The computed scenario concurs with para-hydrogen-induced polarization transfer (PHIP) NMR data, which confirm direct trans-delivery of H2, the formation of carbene intermediates by gem-hydrogenation, and their evolution into product and side products alike. Propargylic −OR (R = H, Me) groups exert a strong directing and stabilizing effect, such that several carbene intermediates could be isolated and characterized by X-ray diffraction. The gathered information spurred significant preparative advances: specifically, highly selective trans-hydrogenations of propargylic alcohols are reported, which are compatible with many other reducible functional groups. Moreover, the ability to generate metal carbenes by gemhydrogenation paved the way for noncanonical hydrogenative cyclopropanations, ring expansions, and cycloadditions.

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INTRODUCTION Canonical hydrogenations of π-bonds with the aid of transition metal catalysts, as long as they do not involve transfer of H•, are under frontier orbital control.1−3 As a consequence, they invariably proceed via suprafacial delivery of the two hydrogen atoms of H2 to the substrate. In view of this stringent synselective course, it is unsurprising that a considerable number of heterogeneous as well as homogeneous catalysts is known that allow internal alkynes to be semihydrogenated with formation of the corresponding (Z)-alkenes; among them, Lindlar hydrogenation is arguably the most popular protocol.4−6 Although the individual methods greatly differ in efficiency and practicality as well as in their bias to saturate the olefin products initially formed, the stereoselectivity is generally excellent. If over-reduction prevails or other reducible sites are endangered under hydrogenation conditions, alternative stoichiometric procedures are available to the practitioner that also allow alkynes to be transformed into (Z)-olefins with appreciable selectivity.7,8 The situation is much less comfortable when it comes to the semireduction of internal alkynes to the corresponding (E)© XXXX American Chemical Society

alkenes. The classical arsenal is basically limited to dissolving metal reductions;9 other reagents capable of transferring electrons to triple bonds such as Cr(+2) have occasionally been used for the same purpose.10 Moreover, LiAlH4 or related metal hydrides allow propargyl alcohols (and very few other substrates)11 to be converted to the corresponding Econfigured allylic alcohols.12−14 The use of alkali metals in liquid ammonia or of highly reactive aluminum hydrides, however, drastically limits the scope of these methods because applications to compounds containing other reducible and/or base-sensitive functionality are precluded. A few methods for formal trans-hydrogenation (or transfer hydrogenations) of alkynes are known.15,16 In mechanistic terms, however, these reactions commence with a canonical cisreduction followed by Z → E isomerization; for this latter step to proceed well, the double bond usually has to carry at least one aryl substituent or must be significantly polarized. Therefore, none of the methods falling into this category Received: January 18, 2018 Published: February 11, 2018 A

DOI: 10.1021/jacs.8b00665 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

Scheme 1. Alkyne trans-Hydrogenation and Competing Isomerization En Route to Brefeldin A

shows any decent scope when it comes to the semireduction of ordinary dialkylalkynes. The arguably best current alternative is an indirect procedure in which the alkyne is first subjected to a ruthenium-catalyzed trans-hydrosilylation, as originally described by Trost and coworkers,15,17,18 followed by desilylation of the resulting alkenylsilane with the help of a mild fluoride source.17,19 For its excellent selectivity profile and broad scope, this two-step protocol was rapidly embraced by the synthetic community;20,21 it finds its limitations when it comes to the transhydrosilylation of sterically hindered substrates or compounds comprising conjugated π-systems such as 1,3-enynes; products sensitive to fluoride are typically also beyond reach.22 Our laboratory has recently demonstrated that transhydrosilylation is by no means a singularity but only one of several possible incarnations of an unorthodox but certainly more general mechanism. The underlying concept has been successfully translated into widely applicable trans-hydroboration,23 trans-hydrogermylation,24,25 and trans-hydrostannation reactions.24,26,27 These transformations are distinguished by excellent chemo- and stereoselectivity and can be controlled in regiochemical terms in many cases,24,27 as witnessed by a growing number of applications to natural product synthesis.28,29 Moreover, direct trans-hydrogenation of internal alkynes has been accomplished, which truly violates the paradigm of suprafacial delivery of H2 that had been reigning catalytic hydrogenation ever since its inception.30 Thus, cationic as well as neutral [Cp*Ru]-based complexes allow triple bonds to be semihydrogenated to the corresponding Ealkenes with impeccable trans-selectivity; there is no indication whatsoever that the net outcome might be the result of classical cis-reduction followed by Z → E isomerization of the primary product; dialkyl alkynes are hence adequate if not even the preferred substrates.31 In mechanistic terms, this method is different from the procedures mentioned above:16 it represents a true stereochemical complement to the classical Lindlarhydrogenation and constitutes a potentially attractive alternative to dissolving metal reductions, in particular when it comes to applications to functionalized substrates.32 These aspects are illustrated by a total synthesis of brefeldin A, a macrolide of fungal origin that selectively targets the Golgi apparatus of eukaryotic cells (Scheme 1).33 Specifically, cycloalkyne 1 formed by ring-closing alkyne metathesis34 was hydrogenated on a gram scale to give product 2 with an E:Z ratio approaching the limits of detection (>99:1). The reducible enoate, the lactone, and the silyl ether passed uncompromised; this ensemble of functional groups would certainly not subsist under Birch conditions, had an alkali metal in liquid ammonia been used as the reducing agent. These virtues notwithstanding, the brefeldin case also illustrates the currently most prominent shortcoming of this emerging methodology: with [Cp*Ru(cod)Cl] as the precatalyst, substantial over-reduction was noticed, whereas the use of [Cp*Ru(MeCN)3]PF6 led to partial positional isomerization of the disubstituted double bond to the trisubstituted position at the ring junction (3a) or endocyclic to the five-membered ring (3b). Therefore, the desired product 2 was isolated only in 56% yield.33 Similar issues have been noticed with a number of model compounds.30 Interestingly, these studies suggested that overreduction and isomerization are not primarily caused by secondary processes in which the product alkene reacts further with the catalyst. If substantial amounts of such byproducts are formed, as in the brefeldin case, they seem to be largely

generated in situ. To clarify this opaque yet important aspect, we embarked into a combined experimental/theoretical study of this unconventional alkyne trans-hydrogenation reaction, which led to a fairly concise picture. During this investigation, it also became clear that its noncanonical mechanism provides additional opportunities beyond hydrogenation, as outlined in the following summary of our work in this field.35

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RESULTS AND DISCUSSION NMR Spectroscopy. Preliminary NMR investigations that made use of the remarkable sensitivity of para-hydrogen (pH2)-induced polarization transfer (PHIP)36−39 had shown that the (E)-alkene formed by semihydrogenation of a representative alkyne such as 4a exhibits PHIP-enhanced olefinic signals in the 1H NMR spectra (Figure 1). This result proves that the H atoms of H2 are transferred in a pairwise manner to the substrate.35 Surprisingly, PHIP-enhanced signals were also observed in the aliphatic region of the spectra, which fade away once full conversion is reached. These resonances showed large negative scalar coupling constants of −15 to −19 Hz (or even larger, see below), suggestive of the presence of geminally coupled diastereotopic methylene protons. Furthermore, it was observed that RO− substituents (R = H, Me) next to the triple bond increase the lifetime of these transient species;35 actually, substrates of type 8 bearing two stabilizing groups furnished intermediates with a sufficiently long lifetime to allow for full characterization by conventional NMR (Figures 2 and 3). The data, not least the signature high frequency signals in the 13C NMR spectra, left no doubt about the carbene nature of these intermediates. This assignment was confirmed when we managed to grow crystals of complex 9b suitable for X-ray diffraction.35 The structure in the solid state showed the presence of a piano-stool ruthenium carbene unit and revealed how the neighboring −OR groups exert their stabilizing influence: the −OMe group engages in a donor/acceptor interaction with the Lewis-acidic metal center, whereas the −OH substituent entertains a hydrogen bond with the −Cl ligand on ruthenium.40 The fact that an alkyne is transformed into a carbene upon hydrogenation is remarkable in conceptual terms. In a formal B


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Figure 3. Excerpt of the 1H/13C HMBC spectrum of the reaction mixture formed upon hydrogenation of 8a (R = H) with p-H2 using [Cp*Ru(cod)Cl] as the catalyst showing the cross peaks between the gem-hydrogen atoms and the low-field carbene resonance of 9a.

Table 1. Effect of Propargylic Heteroatom Substituents on the Carbene Distribution As Determined by NMR Figure 1. Hydrogenation of 4a with p-H2 catalyzed by [Cp*RuCl] primarily affords three products showing hyperpolarized antiphase signals; whereas the vicinal coupling of the olefinic protons of 5a is positive, the coupling constants of the geminal protons of the transient carbene intermediates 6a and 7a have a negative sign.

substrate

R1

R2

[Ru]

6:7a

4a

H

Me

4b

Me

Me

4c 4d 4e

H Me H

Et Ph tBu

4f

Me

tBu

[Cp*Ru(cod)Cl] [Cp*Ru(MeCN)3]PF6 [Cp*Ru(cod)Cl] [Cp*Ru(MeCN)3]PF6 [Cp*Ru(cod)Cl] [Cp*RuCl]4 [Cp*Ru(cod)Cl] [Cp*Ru(MeCN)3]PF6 [Cp*RuCl]4

1:10 2:3 1:99 1:14 5:2 1:3b 99:1 1:1 c

a

PHIP data, unless stated otherwise. bDetermined by standard 1H NMR. cNo carbene formation observed; see text.

−OH···Cl interaction synergizes with the steric repulsion between the bulky Cp* ligand and the lateral tert-butyl group (see Figure 7). The corresponding methyl ether 4f was the only substrate of this series that failed to undergo hydrogenation; formation neither of the corresponding E-alkene nor of any intermediate (alkyne π-complex, carbene) was observed, likely for steric reasons. Although unsurprising in view of the bulk of the ancillary Cp* ligand on the catalyst, this outcome indicates that the current methodology finds a limitation when it comes to reductions of substrates that are overcrowded on either alkyne terminus. An additional series of NMR experiments was meant to clarify whether neighboring −OR substituents are mandatory to engender formation of carbene species. NMR-monitoring of the hydrogenation of unfunctionalized substrates such as 2pentyne or 3-hexyne with p-H2 showed rapid formation of the corresponding E-alkenes but did not allow any carbene intermediate to be observed; it could not be decided experimentally, however, whether such an intermediate is not formed or if it is simply too short-lived to be detected.44 Yet, the computational data outlined below leave no doubt that unfunctionalized substrates are equally capable of forming metal carbenes in the first place by gem-hydrogen delivery.

Figure 2. Spectral features of a set of ruthenium carbenes 9 prepared by gem-hydrogenation of substrates of type 8.

sense, the triple bond behaves as a 1,2-dicarbene synthon:41 one “carbene” center is intercepted by the [Cp*Ru] fragment, whereas the vicinal “carbene” site oxidatively inserts into the H−H bond. The resulting net geminal hydrogenation has hardly any precedent in the literature.42 While largely unknown for carbon, geminal hydrogen delivery is the prototypical reactivity mode of transition metal centers when exposed to H2.43 The results compiled in Table 1 provide further insights into the directing effect exerted by propargylic substituents. It is evident that (i) a propargylic −OMe group is a more effective guide than the corresponding free alcohol, (ii) carbenes derived from a neutral [Cp*RuCl] fragment are more responsive than their congeners derived from the cationic precatalyst [Cp*Ru(MeCN)3]PF6, and (iii) the directing effect exerted by a chelating substituent may be reinforced or counterbalanced by steric factors. The selective formation of compound 6e from 4e and [Cp*Ru(cod)Cl], for example, suggests that an attractive C


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Journal of the American Chemical Society Hydrogenations of ynoates and ynones with p-H2 definitely involve transient carbene intermediates; a representative example is shown in Figure 4. In this case, the 2J coupling

Scheme 2. Assessing the Stabilizing Effect of Propargylic −OR Groups (R = H, Me)

Figure 4. gem-Hydrogenation of ynones leads to carbene chelate complexes of type 10 distinguished by a particularly large 2J coupling constant; this distinctive spectral feature is shown for R1 = Me, R2 = C6H13; for further details, see the Supporting Information.

stable that its congener 12b (R = H): for 12a to react further, the mixture had to be stirred at 70 °C in 1,2-dichloroethane as the solvent for 18 h, which led to the saturated compound 15 as the only product. In contrast, formation of 12b (R = H) and further evolution into the E-alkene 14 could not be decoupled even at ambient temperature. This comparison shows that a propargyl ether exerts a stronger stabilizing effect onto the emerging carbene than does a propargyl alcohol or a ketone carbonyl group. Decomplexation of the catalyst from product 14 was found to be slow enough such that adduct 13 primarily formed could be detected and even isolated in pure form (Figure 5). This

constant is remarkably large (−24.3 Hz): this conspicuous spectral feature indicates the presence of a five-membered ring,45 which in turn implies that the metal carbene resides distal to the carbonyl and the oxygen atom is ligated to ruthenium (10A); this positioning follows and enhances the natural polarization of the 2-decyne-4-one substrate. Although one might expect that chelation to a Lewis-acidic metal center favors enolization of the carbonyl, the recorded PHIP data rule out that ynoate- or ynone-derived carbenes have ground-state structures of type 10B, for which small 4J coupling constants are expected; moreover, the OPSY spectra lack any signals that could be attributed to an “enol” substructure (for details, see the Supporting Information).46 Qualitatively, the data outlined above leave no doubt about the intervention of ruthenium carbenes generated by formal gem-hydrogenation. The concentration of such intermediates in solution, however, is almost certainly highly variable and strongly substrate-dependent. Because the intensities of signals with and without PHIP-effect cannot be directly compared, an accurate quantitative assessment was not possible in most cases reported herein. Moreover, the recorded spectra represent only snapshots, which depend on the currently unknown rate of carbene formation/consumption relative to the NMR time scale. These caveats notwithstanding, it is of note that the antiphase signal intensities observed in routine 1H NMR spectra were lower than the ordinary proton signals of substrate and/or product in a number of cases; if so, the concentration of the metal carbene transiently formed must be very small. The hydrogenation of 2-decyne-4-one leading to carbene 10A is representative (for details, see the Supporting Information). Yet, we also noted the other extreme marked by ruthenium carbenes such as 6e, 7d, or 12a, which enjoy efficient stabilization by lateral heteroatom substituents within a sterically favorable microenvironment; these complexes were formed almost quantitatively as judged by 1H and 13C NMR (see the Supporting Information). Substrates 11a,b were designed to compare the steering effect exerted by a carbonyl and a propargylic −OR substituent (Scheme 2). For either substrate, the highly regioselective formation of a carbene intermediate of type 12 was observed by NMR, in which the [Cp*Ru = C] unit resides distal to the −OR group but vicinal to the ketone; this conclusion was confirmed by crystallographic means (see Figure 9). The regioselective course is noteworthy as it shows that the directing capability of a −OR group outweighs the effect exerted by a ketone. 12a (R = Me) proved considerably more

Figure 5. Structure of the alkene complex 13 in the solid state; the two independent molecules present in the unit cell are mutually linked via intermolecular −OH···Cl−Ru H-bonds (see the Supporting Information); only the olefinic and −OH protons are shown for clarity.

observation was unexpected because a recent investigation on the mechanistically related trans-hydrostannation of alkynes had shown that product release from the active catalyst is extremely facile even at low temperature.27 In complex 13, it is the alcohol oxygen rather than the carbonyl that coordinates onto the Lewis-acidic ruthenium center and, in doing so, helps to keep the olefinic ligand in place; the −OH proton engages in tight intermolecular hydrogen bonding (2.17/2.28 Å) to the Cl atom of the second independent molecule present in the unit cell. Moreover, the low-lying π*-orbital of the enone favors electron back-donation from the metal center, as manifest in the notably elongated C4−C5 alkene unit (av. 1.408(4) Å).47 Relevance of the Carbene Intermediates for Catalysis. Collectively, the data outlined above show that heteroatom substituents in proximity to the triple bond to be hydrogenated steer the regiochemical course of carbene formation and massively impact their lifetime. This raised the crucial question D


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Journal of the American Chemical Society as to whether metastable carbenes such as 6, 7, 9, 10, or 12 have any relevance for alkyne trans-hydrogenations or if they are nothing but unreactive sinks off the catalytic cycle. To clarify this critically important aspect, a 2D 1H-OPSYEXSY experiment48,49 was carried out in which compound 4b (R = Me) was hydrogenated with p-H2 using [Cp*Ru(cod)Cl] as the precatalyst (Figure 6).50 Because of the high sensitivity of

Figure 7. Structure of one of two independent carbene complexes 6e present in the unit cell; only the H atoms delivered by gem-hydrogen transfer are shown; for the strong hydrogen bond (ca. 2.40 Å) between the −OH group and the −Cl of a neighboring molecule in the crystal, see the Supporting Information.

Figure 6. Relevant strips of the 2D 1H-OPSY-EXSY spectrum (CD2Cl2, 298 K, ppm) showing cross peaks that link carbene 7b formed by hydrogenation of 4b (R = Me) with p-H2 in the presence of [Cp*Ru(cod)Cl] with the E-alkene 5b, the positional alkene isomer 16, the over-reduced product 17, as well as H2.

this hyperpolarization method, the exchange experiment unmistakably showed that the characteristic methylene signals of the carbene 7b generated in situ has cross peaks with resonances of the desired E-alkene product 5b,51 the positional isomer 16, the saturated compound 17, as well as free hydrogen in solution. Importantly, this result proves that carbene 7b is linked to product and side-products alike; it is therefore on the productive cycle (or at least connected to it), yet also seems to be a gateway to the undesirable over-reduction product and alkene isomer. Carbene Structures in the Solid State. NMR suggested that carbene complexes 6e, 7d, and 12a are generated almost quantitatively and might be sufficiently stable to allow for isolation in pure form. After considerable experimentation, we indeed managed to grow single crystals of these sensitive species suitable for X-ray diffraction. The structure of 6e in the solid state (Figure 7) is comparable to the structure of complex 9b previously communicated,35 even though it comprises only a single stabilizing −OH substituent. The carbene resides adjacent to the tertiary alcohol, which engages directly with the Ru atom as evident from the short O1−Ru1 distance (2.234(3) Å) to give a complex with a formal 18e count. In the crystal, the −OH group entertains an additional strong hydrogen-bonding interaction with the chloride of a neighboring molecule (ca. 2.40 Å).40 The structural features of complexes 7d and 12a are also informative (Figures 8 and 9). In line with the notion that methyl ethers exert a strong directing effect, the donor/ acceptor interaction O1−Ru1 (2.217(1) Å in 7d; 2.187(3) Å in 12a) is shorter that the corresponding contact of the free alcohol in 6e (av. 2.234(3) Å), which is part of a fourmembered ring. The lengths of the carbene units in 6e (av. 1.892(2) Å), 7d (1.906(2) Å), 9b (av. 1.889(7) Å),35 and 12a (C1−Ru1 1.897(4) Å) are all similar. Although they are slightly longer

Figure 8. Structure of complex 7d in the solid state; only the H atoms delivered by gem-hydrogen transfer are shown.

Figure 9. Structure of the carbene 12a in the solid state; only the H atoms delivered by gem-hydrogen transfer are shown.

than the RuCHPh bond of prototype Grubbs carbenes (1.79−1.85 Å),52,53 backbonding from the metal into the carbene LUMO is likely significant. This notion is corroborated by the fact that the phenyl ring in 7d is not coplanar with the carbene unit (Ru1−C1−C10−C15 39.8°); this feature distinguishes the ruthenium carbenes discussed herein from related gold or rhodium carbene complexes, in which overlap of E


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Journal of the American Chemical Society the “empty” carbene p-orbital with the π-bonds of the flanking aryl rings rather than dπ → pπ back-bonding is the prime stabilizing factor.54 The torsional angle O2−C10−C1−Ru1 of −95.5° in complex 12a implies little orbital overlap between the electrophilic carbene center and the equally electrophilic ketone C atom in the solid state. Whether or not this electronic decoupling persists in solution needs further scrutiny: we note that the 13C NMR resonance of the carbene center in 12a (δC = 295.5 ppm) is shifted to lower frequency as compared to the resonances in the sister compounds 6e (δC = 306.3 ppm), 7d (δC = 305.2 ppm), and 9b (δC = 340.9 ppm);35 because the adjacent ketone is markedly deshielded (δC = 223 ppm), some mutual influence between these sites in solution is likely. DFT Study Using a Model Substrate. A detailed computational study was carried out for the sake of a better understanding of the mechanism of this unorthodox transhydrogenation reaction in general, the origins of the high stereoselectivity, and the role of the carbene intermediates. To this end, free energy profiles were computed at the M06/def2TZVP level for all putative reaction pathways including those leading to olefin isomerization or over-reduction (see the Supporting Information for details). As the results have previously been communicated,35 only the major findings are briefly summarized herein. According to DFT, the reaction commences by formation of a ruthenium complex A1 loaded with 2-butyne as the model substrate and H2 (Scheme 3). In A1, H2 is bound via its σ-

therefore almost certainly irreversible. The computed pathway to the Z-alkene, although viable, has a barrier that is higher by 3.4 kcal mol−1 (not shown in Scheme 3),35 which concords with the generally excellent experimental E/Z-ratios. A particularly striking computational result with important ramifications is the observation that the reaction pathway bifurcates at the stage of the ruthenacyclopropene E1 (Scheme 4): this intermediate can not only convert into the desired EScheme 4. Free Energy Profile Bifurcates at the Metallacyclopropene Stage between Direct trans-Reduction and Formation of a Ruthenium Carbene

Scheme 3. Free Energy Profile for the trans-Hydrogenation of 2-Butyne with Complex [Cp*Ru(cod)Cl] alkene E2 by a concerted mechanism, but can also evolve into a ruthenium carbene C2 via a transition state that is computed at the chosen level of theory to be only 1.2 kcal mol−1 higher in energy. Because carbene formation is not only facile but also strongly exergonic, it is reasonable that intermediates of this type are observable by PHIP NMR or even stable enough for isolation in favorable cases. Moreover, the DFT results ascertain that both H atoms of the newly formed methylene group in C2 derive from the same H2 molecule (“gemhydrogenation”), which is mandatory for the PHIP effect to be operative.36,37 Hence, the overall computational scenario is in excellent agreement with the experimental data. The fate of carbene C2 turns out to be largely selectivity determining (Scheme 5). The unimolecular reverse reaction to E1 is high in energy; yet, C2 is a 16e species that can bind an extra ligand, which might lower the barriers. In fact, DFT suggests that coordination of a second molecule of H2 opens a favorable outlet. Details apart, this associative mechanism leads to the desired product E-2-butene, the isomeric product 1butene (D4), and fully saturated butane (B2).35 All of these reaction channels have fairly low barriers of similar magnitude; the actual product spectrum depends on steric parameters, which determine the side from which H2 approaches the [Cp*RuC] unit.35 Experimental Scrutiny. The conclusions drawn from the DFT-studies are in excellent accord with the available experimental results. The fact that the 2D 1H-OPSY-EXSY experiment linked the carbene 7b to product 5b, the positional isomer 16, and the fully saturated product 17 (Figure 6) corresponds perfectly to the computed scenario; yet, congruence between predicted and observed product distribu-

bond;55,56 this computational result nicely accords with early experimental observations, which had shown that the structurally well-defined σ-complex [Cp*Ru(H−H)(cod)]OTf57 is a competent trans-hydrogenation catalyst.30 A1 converts into metallacyclopropene (η2-vinyl complex) E1;58 this key intermediate evolves via the fairly low-lying stereochemistry-determining transition state TSE1−E2 (ΔΔG⧧ = 5.1 kcal mol−1, relative to E1) into the desired E-2-butene (E2). The product-forming step is exergonic by 33.6 kcal mol−1 and F


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DFT Study Using a Functionalized Substrate. Because an associative mechanism largely determines the fate of a 16ecarbene species of type C2, it is obvious why its 18e analogues 6e, 7d, 9b, and 12 are kinetically rather stable even under H2 atmosphere. As long as the necessary coordination site at ruthenium is blocked by the −OR substituent, uptake of H2 is prevented, and hence the computed low-energy pathways are basically shut off. To put intuition on a firmer basis, the reaction of substrate 8b with [Cp*Ru(cod)Cl] and H2 was computed at the same level of theory (Scheme 6). As expected, the propargylic substituents alter the free energy landscape to a significant extent: Specifically, the barrier to ruthenacyclopropene formation (A1 → E1) is lowered by no less than 8 kcal mol−1, largely due to hydrogen bonding between the −OH group and the [Ru−Cl] unit. Moreover, conversion of E1 into carbene C2 is now preferred over concerted E-alkene formation by 2.6 kcal mol−1. Again, the stabilizing effect of the lateral substituents is significant as decomplexation of the −OMe group from the ruthenium center of C2 with formation of C2′ entails a 6.5 kcal mol−1 enthalpic penalty. Suffice it to say that the computed structural features of C2 nicely reproduce the crystal structure of this complex (9b)35 and hence lend further credence to the computed scenario. These results showcase that functional groups in the vicinity of the triple bond exert a massive influence on the reaction coordinate. For 8b as the substrate, the ruthenium carbene 9b ( C2) actually represents a thermodynamic sink, which explains why we managed to isolate this species. While the appreciable influence of the chemical microenvironment on the stability of the reaction intermediates evident from this example has implications for the scope of trans-hydrogenation in general, it also opens new vistas for harnessing genuine carbene chemistry. Exploratory studies along these lines are outlined below. Coupled Cluster Study Using 2-Butyne as the Model Substrate. The DFT-computed barriers for the pathways leading from the key metallacyclopropene E1 to the E-alkene E2 and the ruthenium carbene C2 are small but selectivitydetermining. Generally speaking, DFT energy differences of a few kcal mol−1 have to be met with caution. We therefore decided to perform more accurate single-point coupled cluster calculations at the DFT-optimized geometries to achieve chemical accuracy (1 kcal mol−1) for the computed relative energies. More specifically, we employed the domain-based pair natural orbital coupled cluster method with single and double excitations, DLPNO-CCSD, and with a perturbational estimate of the triples contributions, DLPNO-CCSD(T).59 The computational details and the numerical results are fully documented in the Supporting Information. The CCSD and CCSD(T) results are generally close to each other (see the Supporting Information). Hence, we focus here on the comparison between the DFT and our most accurate CCSD(T) free energy profiles for the pathways leading from the reactants to E2 and C2 (Scheme 7). Overall, the two profiles shown in Figure 7 are qualitatively similar, and in most cases the relative energies from DFT and CCSD(T) differ by less than 2 kcal mol−1. As compared to DFT, CCSD(T) gives notably higher energies for the loaded complex A1 and for the products E2 and C2 (higher by up to 5 kcal mol−1). More significant from a mechanistic point of view is that CCSD(T) eliminates the slight kinetic preference for direct E-alkene formation (E1 → E2) over carbene generation

Scheme 5. An Associative Mechanism Links the Ruthenium Carbene to the Side Products

tion does not prove that the pathway is associative in nature as suggested by DFT. Under the proviso that the calculations capture the essence of the transformations downstream of carbene C2 correctly (Scheme 5), H2 has first to be coordinated but will get released again en route to the desired product E2 and the isomerized alkene D4; H2 hence serves as a “catalyst” in that it features as a reagent and as a product alike. Under this premise, the EXSY spectra should also have a cross peak between carbene 7b and the “product” H2; Figure 6 shows that this is indeed the case. To further strengthen the argument, we subjected the deuterated substrate [D3]-4b to the same reaction conditions. Formation of the isomeric alkene [D2]-16 by the proposed associative mechanism mandates association of H−H but release of H−D (Figure 10). This product was unambiguously

Figure 10. Formation of H−D during the hydrogenation of [D3]-4b is indicative of an associative mechanism downstream from the carbene intermediate [D3]-7b.

identified in the 1H NMR spectra by virtue of its characteristic coupling pattern. Alternative sources of H−D, for example, via C−D bond activation, are deemed improbable. Hence, the available NMR data nicely validate the computed scenario in all regards: they not only confirm the overall product spectrum but also speak for an associative character of the steps downstream of C2. G


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Journal of the American Chemical Society Scheme 6. Computed Pathway of the Reduction of the Functionalized Alkyne 8ba

a

Free energies relative to 8b, kcal mol−1.

Scheme 7. Overlay of the DFT and CCSD(T) Free Energy Profiles for the Reactions Yielding the E-Alkene (E2) and the Carbene Complex C2

(E1 → C2) that DFT had predicted, with the difference in the relevant transition state energies changing from −2.0 to +0.5 kcal mol−1 (Scheme 7). At the same time, CCSD(T) lowers the barrier for reversion of carbene C2 to E1 while increasing the relative energies of all intermediates downstream to C2 by typically 2−3 kcal mol−1 (see Figures S2 and S3). For the H2 associative pathways that lead to the side products by olefin isomerization or over-reduction, the DFT and CCSD(T) results are again qualitatively similar, with only minor deviations in the computed relative free energies (see the Supporting Information). In summary, it is gratifying that the gross mechanistic picture remains unchanged when going from the DFT to the more accurate CCSD(T) level. However, the overlay shown in Scheme 7 also indicates that the selectivity-determining factors are very subtle and that great care is needed when trying to predict product distributions computationally. In the present case, the more accurate coupled cluster calculations suggest that the carbene C2 is even more easily accessible than anticipated from the DFT calculations. This reinforces the conclusion that it is a key intermediate, which plays an important mechanistic role. Preparative Implications: trans-Hydrogenation of Functionalized Propargylic Alcohols. The spectroscopic,

crystallographic, and computational study outlined above suggested that propargyl alcohol derivatives might be good candidates for trans-hydrogenation: the −OH group should block the coordination site necessary for secondary H2 binding and hence increase the chance that the carbene reverts to the metallacyclopropene and evolves from there on to the desired E-alkene. In any case, this class of compounds had previously not been studied. Although amenable to LiAlH4 (or Red-Al) reduction, this standard method cannot be applied whenever the substrate bears additional reducible functionality. With the hope to fill this methodological gap, we investigated the trans-hydrogenation of a representative set of propargyl alcohol derivatives (Scheme 8). Although aromatic rings can block the active [Cp*Ru] catalyst by η6-coordination,31 this deleterious effect is offset by the assistance that the hydroxy group does provide in binding of the metal fragment to the triple bond.27 In line with this notion, tert-propargyl alcohol derivatives with aryl substituents were found to react smoothly in the presence of [Cp*RuCl]4 (1−2 mol %) in CH2Cl2; in most cases, the trans-hydrogenation proceeded at ambient temperature at only 1 bar H2 pressure. Substrates with aliphatic rather than aromatic substituents on the triple bond reacted similarly well but tend to require higher temperatures for good selectivity as reached with 1,2-dichloroethane (instead of H


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Journal of the American Chemical Society Scheme 8. trans-Hydrogenation of Propargyl Alcohol Derivatives and Related Substratesa

applications of this venerable transformation to murraol (41),62 a secondary metabolite originally isolated from leaves of Murraya exotica (Rutaceae), gave very modest results as reported by two different laboratories (28−40%).63 We were therefore pleased to learn that a sequence of Sonogashira coupling followed by trans-hydrogenation was clearly more effective (Scheme 9). The isomeric product E-suberenol (43) Scheme 9. Preparation of Murraol (41) and E-Suberenol (43)a

a

Reagents and conditions: (a) I2, KI, aq NH3; (b) MeI, K2CO3, acetone, 24% (over both steps); (c) 2-methyl-but-3-yn-2-ol, [(Ph3P)2PdCl2] cat., CuI, PPh3, Et3N, DMF, 88%; (d) H2 (1 bar), [Cp*RuCl]4 (2 mol %), CH2Cl2, 81% (E-alkene/alkane = 89:11); (e) NaOMe, MeOH, 65 °C; (f) I2, KI, aq NH3, then Ph2O, 190 °C, 24% (overall); (g) 2-methyl-but-3-yn-2-ol, [(Ph3P)2PdCl2] cat., CuI, PPh3, Et3N, DMF, 81%; (h) H2 (1 bar), [Cp*RuCl]4 (2 mol %), CH2Cl2, 84%.

a

(a) Unless stated otherwise, the reactions were carried out in CH2Cl2 at room temperature. (b) In 1,2-dichloroethane at 70 °C.

was equally well accessible in good overall yield. This particular coumarin derivative was isolated from different plants and is found as an ingredient in various beverages.64 The excellent chemoselectivity of the reaction opened an efficient approach to compound 47, which is an odoriferous constituent of sun-cured tobacco (Scheme 10).65 Allylic

CH2Cl2) as the solvent. In general, tert-propargyl alcohols gave the best results. Although the selectivity for trans-reduction was equally high for their sec- and primary congeners, redox isomerization with formation of enones is a competing process, lowering the yield; this reaction is induced by the same type of ruthenium catalysts.60,61 Because amides, sulfonamides, and carbamates exert a steering effect similar to that of −OH groups,24 it is unsurprising that formation of compound 29 was also effective. The trans-hydrogenation proved compatible with many (reducible) functional groups, including aldehyde, ketone, acetal, ether, ester, enoate, alkene, nitrile, sulfonamide, and aryl bromide; even a nitro substituent passed uncompromised. A particularly striking feature is the ability to distinguish between the propargylic triple bond and a silylated alkyne unit, which remained unchanged (31); such chemoselectivity is difficult to accomplish in ordinary hydrogenation reactions. Albeit not reducible itself, an aniline derivative could act as a potential ligand to ruthenium, yet did not interfere with the reaction (25). Reactivity was basically lost when the −OH group was blocked in form of a methyl ether (37) as this change likely renders the carbene intermediate too stable (compare complexes 7d, 12a). Other limitations were encountered with the primary homopropargyl alcohol 36 or in cases in which the catalyst might get trapped by a competing binding site or via chelation, as is the case when the nitrile or an ordinary alkene is placed ortho to the triple bond (38, 39). Applications. The 3-hydroxy-3-methyl-1-butenyl group is a biogenetic modification of the prenyl residue present in innumerous natural products. Although this moiety can a priori be introduced in one step by a Heck reaction, previous

Scheme 10. Preparation of an Odoriferous Tobacco Constituenta

a

Reagents and conditions: (a) ethylene glycol, p-TsOH cat., benzene, 80 °C, 55%; (b) SeO2, tBuOOH, CH2Cl2, 0 °C, 51%; (c) NBS, PPh3, CH2Cl2, −30 °C, 74%; (d) 2-methyl-3-butyne-2-ol, nBuLi, CuI, THF, −30 °C, 69%; (e) p-TsOH cat., acetone, H2O, 62%; (f) H2 (1 bar), [Cp*RuCl]4 (2 mol %), 1,2-dichloroethane, 70 °C, 60%.

oxidation of the acetal derived from 44 followed by bromination of the resulting alcohol furnished product 45 in readiness for copper-mediated coupling with the dianion derived from 2-methyl-3-butyn-2-ol. Provided the reaction was carried out at −30 °C, competing SN2′ substitution was largely suppressed. Acetal cleavage furnished enyne 46, which underwent clean trans-hydrogenation at 70 °C. As expected on the basis of the model studies outlined above, only the triple I


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to the complexes of type 7 outlined above. Ynone 57 also reacted well to give the cyclopropyl ketone 58 as the major product. From the conceptual viewpoint, this example is significant as it shows that ynones can serve as stable surrogates for α-diazo ketones, which had found numerous applications in synthesis in the past.70−72 This equivalence forecasts ample opportunity for further studies in this field.73,74 The case of the N-tethered enyne 59 is also noteworthy: on treatment with [Cp*RuI]4 at 70 °C, appreciable amounts of cyclopropane 60 were formed (in addition to 9% of the expected trans-hydrogenation product). Importantly, the use of complex 6275 changed the regiochemical course of cyclization in that it led to cyclopropane 61 as the major product. We tentatively ascribe this catalyst control over the pathway of hydrogenative cyclopropanation to the more bulky and more electron-rich cyclopentadienyl ligand in 62, which favors carbene formation distal to the equally bulky tertiary alcohol site on steric grounds. Even though it is certainly much more challenging to outperform hydrogenation by C−C-bond formation in intermolecular settings, the fully characterized carbene 12a reacted with ethylene (1 bar). Cyclopropane 64 was only the minor product (12%, NMR), but the formation of alkenes 65 (60%, NMR) and 66 (28%, NMR) suggests the intervention of a metallacyclobutane of type 63 (Scheme 12). Although this aspect needs further scrutiny, the outcome is reminiscent of certain enyne metathesis reactions with ethylene as partner,

bond got reduced to give the target compound 47, whereas neither the alkene nor the ketone function was affected under the chosen conditions. Scheme 11 shows the formation of product 53 corresponding to the head piece of fostriecin, which had served as a prominent Scheme 11. Application of trans-Hydrogenation to a Fostriecin Model Compounda

a

Reagents and conditions: (a) NaIO4, CH2Cl2, H2O; (b) 49, nBuLi, THF, 55% (over both steps); (c) acryloyl chloride, iPr2NEt, CH2Cl2, 91%; (d) HGII (3 × 2 mol %), 1,2-dichloroethane, 70 °C, 48%; (e) TBAF, HOAc, THF, 62%; (f) H2 (1 bar), [Cp*RuCl]4 (2 mol %), 1,2dichloroethane, 40 °C, 61%.

Scheme 12. Hydrogenative Cyclopropanation

target in the past.66 Addition of 50 to freshly prepared aldehyde 49 followed by acylation of the resulting secondary alcohol with acryloyl chloride set the stage for the closure of the δ-lactone ring by RCM and subsequent removal of the TES-ether with buffered TBAF.67 The quite acid-sensitive product 52 was then trans-hydrogenated to give 53 as a fostriecin model, without touching the equally reducible enoate entity. To properly assess this outcome, we refer to a recent literature report that described the failure of all attempts to semireduce the triple bond of the very closely related substrate 54 unless the lactone was first treated with Dibal-H and the resulting hemiketal converted into the corresponding isopropyl glycoside.68 Harnessing Genuine Carbene Reactivity. Our experimental and computational data show that properly placed substituents in vicinity to the triple bond to be hydrogenated instigate formation of metastable ruthenium carbenes in the first place; it requires binding and activation of a second H2 molecule for such intermediates to re-enter the catalytic cycle resulting in hydrogenation. We conjectured that it might be possible to outperform this step, even under an H2 atmosphere, by kinetically favorably (intramolecular) processes and, in doing so, harness prototypical metal carbene chemistry. To this end, however, it is necessary to explore the innate reactivity of piano-stool cyclopentadienyl ruthenium carbene complexes, which has been studied in the past not nearly as extensively as that of other ruthenium carbene species.69 In a first foray, enyne 55 was hydrogenated under standard conditions. We were pleased to find that the cyclopropyl derivative 56 was formed in excellent yield, evidently via formation and interception of a ruthenium carbene analogous J


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carbene isomer can emerge from this substrate, which condenses with unreacted 75 to give the furan derivative 76; in contrast to the previous examples, THF rather than CH2Cl2 was the solvent of choice, as it largely suppressed competing [2+2+2] cyclotrimerization of the substrate.

which afforded cyclopropanes as byproducts when [Cp*Ru]based catalysts were employed.76 Formation of a cyclopropane via metal-catalyzed hydrogenation of an enyne is a highly unorthodox and perhaps even counterintuitive transformation; to the best of our knowledge, it is without precedent in the literature. While an attempt at extending this reactivity pattern to CH-insertion into an acetal has so far been unsuccessful but mainly led to over-reduction of substrate 67 with formation of product 68, prototypical carbene reactivity could be harnessed in the form of 1,2-alkyl shift reactions.77,78 Specifically, substrates 70 and 73 were chosen as they are expected to lead to the formation of a single carbene isomer such as 71, residing proximal to the −OH and distal to the −OMe substituent. We conjectured that a strain-driven ring expansion might compete with activation of a second H2 molecule and hence outperform trans-reduction and/or overreduction of the substrate. The peripheral −OH····Cl hydrogen-bonding array could provide further assistance, as it facilitates the necessary proton transfer during or after the rearrangement. In fact, the reactions were very clean, affording the corresponding ketones 72 and 74 in essentially quantitative assay yields (Scheme 13); the volatility of 72, however, led to

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CONCLUSION A combined experimental and computational approach allowed a concise scenario of ruthenium-catalyzed alkyne trans-hydrogenation to be drawn. The reaction differs from basically all other known procedures for the reduction of triple bonds to Ealkenes in that it does not involve formation of a Z-alkene in the first place followed by isomerization to the thermodynamically more stable E-isomer; rather, the two H-atoms are truly delivered in a trans-fashion via a metallacyclopropene (η2-vinyl complex) as the key intermediate. It is shown that propargyl alcohols are excellent substrates that have not been investigated before; many reducible functional groups proved compatible with catalytic trans-hydrogenation that would not subsist under more conventional conditions. Olefin isomerization and over-reduction are the most serious side reactions that compete with trans-hydrogenation. These transformations largely derive from piano-stool Cp*Ru-carbene species, the formation of which competes with the productive evolution of the ruthenacyclopropene to the E-alkene. From the conceptual viewpoint, however, this hydrogenative entry into metal carbenes is remarkable as it mandates delivery of both H-atoms of H2 to the same C-atom of the substrate; such geminal hydrogenations of ordinary organic compounds are largely unprecedented. This novel entry into carbenes opens new opportunities for reaction development as illustrated by unorthodox hydrogenative cyclopropanation, hydrogenative ring expansion, and hydrogenative [3+2] cycloaddition reactions. These transformations deserve further study in their own right and insinuate that yet other creative ways of harnessing genuine carbene reactivity via hydrogenation of unsaturated substrates might await discovery.

Scheme 13. Hydrogenative 1,2-Alkyl Shift Reactions and Attempted C−H Insertion

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b00665. Experimental section including characterization data, NMR spectra of new compounds, and supporting crystallographic information (PDF) Computational section including methodological details, energy tables, and additional energy profiles (PDF) X-ray crystallographic data for compounds 6e, 7d, 12a, 13 (CIF)

some loss during isolation, whereas 74 was indeed obtained in excellent yield. Just like the hydrogenative cyclopropanation, these hydrogenative ring expansion reactions seem to be the first of their kind. Finally, hydrogenative carbene formation followed by a formal [3+2] cycloaddition was accomplished using acetylene dicarboxylate 75 (Scheme 14). For symmetry reasons, a single

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AUTHOR INFORMATION

Corresponding Author

*[email protected]

Scheme 14. Hydrogenative [3+2] Cycloaddition

ORCID

Markus Leutzsch: 0000-0001-8171-9399 Richard Goddard: 0000-0003-0357-3173 Christophe Farès: 0000-0001-6709-5057 Walter Thiel: 0000-0001-6780-0350 Alois Fürstner: 0000-0003-0098-3417 K


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Journal of the American Chemical Society Present Address

(b) Dieter, R. K. Sci. Synth. 2006, 8, 43. (c) Kaiser, E. M. Synthesis 1972, 1972, 391. (d) Brandsma, L.; Nieuwenhuizen, W. F.; Zwikker, J. W.; Mäeorg, U. Eur. J. Org. Chem. 1999, 1999, 775. (e) Kovárǒ vá, I.; Streinz, L. Synth. Commun. 1993, 23, 2397. (10) (a) Castro, C. E.; Stephens, R. D. J. Am. Chem. Soc. 1964, 86, 4358. (b) Smith, A. B.; Levenberg, P. A.; Suits, J. Z. Synthesis 1986, 1986, 184. (c) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117, 8106. (11) Homopropargyl alcohols and ω-alkynols: (a) Rossi, R.; Carpita, A. Synthesis 1977, 1977, 561. Thioalkynes: (b) Hojo, M.; Masuda, R.; Takagi, S. Synthesis 1978, 1978, 284. Chloroalkynes: (c) Zweifel, G.; Lewis, W.; On, H. P. J. Am. Chem. Soc. 1979, 101, 5101. Alkynylamines: (d) Eisch, J. J.; Gopal, H.; Rhee, S.-G. J. Org. Chem. 1975, 40, 2064. Alkynylsilanes (stannanes, germanes, phosphines): (e) Eisch, J. J.; Foxton, M. W. J. Org. Chem. 1971, 36, 3520. (f) Kinoshita, H.; Yaguchi, K.; Tohjima, T.; Hirai, N.; Miura, K. Tetrahedron Lett. 2016, 57, 2039. (12) Saito, S. Sci. Synth. 2004, 7, 86. (13) For pioneering studies, see: (a) Slaugh, L. H. Tetrahedron 1966, 22, 1741. (b) Zweifel, G.; Steele, R. B. J. Am. Chem. Soc. 1967, 89, 5085. (c) Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 4245. (d) Molloy, B. B.; Hauser, K. L. Chem. Commun. 1968, 1017. (e) Grant, B.; Djerassi, C. J. Org. Chem. 1974, 39, 968. (f) Chan, K.-K.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem. 1978, 43, 3435. (g) Blunt, J. W.; Hartshorn, M. P.; Munro, M. H. G.; Soong, L. T.; Thompson, R. S.; Vaughan, J. J. Chem. Soc., Chem. Commun. 1980, 820. (14) For optimization and recent advances, see the following for leading references and literature cited therein: (a) Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595. (b) Jones, T. K.; Denmark, S. E. Org. Synth. 1986, 64, 182. (c) Igawa, K.; Tomooka, K. Angew. Chem., Int. Ed. 2006, 45, 232. (d) Houpis, I. N. Top. Organomet. Chem. 2011, 42, 103. (e) Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785. (15) The term trans-hydrogenation (boration, silylation, germylation, stannation) of an alkyne as used herein denotes a reaction in which the H and the E-unit (E = H, BR2, SiR3, GeR3, SnR3) end up trans to each other. For the formalism of nomenclature, however, the resulting products are correctly termed Z-configured for E = SiR3, GeR3, SnR3, but E-configured for E = H, BR2. (16) (a) Abley, P.; McQuillin, F. J. J. Chem. Soc. D 1969, 1503. (b) Tani, K.; Iseki, A.; Yamagata, T. Chem. Commun. 1999, 1821. (c) Yoshida, T.; Youngs, W. J.; Sakaeda, T.; Ueda, T.; Otsuka, S.; Ibers, J. A. J. Am. Chem. Soc. 1983, 105, 6273. (d) Shirakawa, E.; Otsuka, H.; Hayashi, T. Chem. Commun. 2005, 5885. (e) Cho, C. S.; Kim, D. T.; Shim, S. C. Bull. Korean Chem. Soc. 2009, 30, 1931. (f) Luo, F.; Pan, C.; Wang, W.; Ye, Z.; Cheng, J. Tetrahedron 2010, 66, 1399. (g) Shen, R.; Chen, T.; Zhao, Y.; Qiu, R.; Zhou, Y.; Yin, S.; Wang, X.; Goto, M.; Han, L.-B. J. Am. Chem. Soc. 2011, 133, 17037. (h) Li, J.; Hua, R. Chem. - Eur. J. 2011, 17, 8462. (i) Srimani, D.; Diskin-Posner, Y.; BenDavid, Y.; Milstein, D. Angew. Chem., Int. Ed. 2013, 52, 14131. (j) Chen, T.; Xiao, J.; Zhou, Y.; Yin, S.; Han, L.-B. J. Organomet. Chem. 2014, 749, 51. (k) Chen, T.; Xiao, J.; Zhou, Y.; Yin, S.; Han, L.-B. J. Organomet. Chem. 2014, 749, 51. (l) Richmond, E.; Moran, J. J. Org. Chem. 2015, 80, 6922. (m) Liu, Y.; Hu, L.; Chen, H.; Du, H. Chem. Eur. J. 2015, 21, 3495. (n) Karunananda, M. K.; Mankad, N. P. J. Am. Chem. Soc. 2015, 137, 14598. (o) Higashida, K.; Mashima, K. Chem. Lett. 2016, 45, 866. (p) Kusy, R.; Grela, K. Org. Lett. 2016, 18, 6196. (q) Tokmic, K.; Fout, A. R. J. Am. Chem. Soc. 2016, 138, 13700. (r) Neumann, K. T.; Klimczyk, S.; Burhardt, M. N.; Bang-Andersen, B.; Skrydstrup, T.; Lindhardt, A. T. ACS Catal. 2016, 6, 4710. (s) Karunananda, M.- K.; Mankad, N. P. Organometallics 2017, 36, 220. (t) Fu, S.; Chen, N.-Y.; Liu, X.; Shao, Z.; Luo, S.-P.; Liu, Q. J. Am. Chem. Soc. 2016, 138, 8588. (u) Furukawa, S.; Komatsu, T. ACS Catal. 2016, 6, 2121. (17) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726. (b) Trost, B. M.; Ball, Z. T.; Jöge, T. J. Am. Chem. Soc. 2002, 124, 7922. (c) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644. (18) For the first application to propargylic alcohols, see: Trost, B. M.; Ball, Z. T.; Jöge, T. Angew. Chem., Int. Ed. 2003, 42, 3415.

†

Department of Chemistry, University of Massachusetts− Lowell, 1 University Avenue, Lowell, Massachusetts 01854, United States. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Generous financial support by the MPG is gratefully acknowledged. We thank K. Radkowski, Dr. B. Sundararaju, and Dr. M. Fuchs for the initial work on trans-hydrogenation and the analytical departments of our Institute for excellent support.

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