Cleavage of NâH Bond of Ammonia via MetalâLigand Cooperation

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

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Cleavage of N−H Bond of Ammonia via Metal−Ligand Cooperation Enables Rational Design of a Conceptually New Noyori−Ikariya Catalyst Pavel A. Dub,*,† Asuka Matsunami, Shigeki Kuwata, and Yoshihito Kayaki* Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, 2-12-1-E4-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan

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S Supporting Information *

ABSTRACT: The asymmetric transfer hydrogenation (ATH) of ketones/imines with Noyori−Ikariya catalyst represents an important reaction in both academia and fine chemical industry. The method allows for the preparation of chiral secondary alcohols/amines with very good to excellent optical purities. Remarkably, the same chiral Noyori−Ikariya complex is also a precatalyst for a wide range of other chemo- and stereoselective reductive and oxidative transformations. Among them are enantioselective sulfonamidation of acrylates (intramolecular aza-Michael reaction) and carboxylation of indoles with CO2. Development of these catalytic reactions has been inspired by the realized cleavage of the N−H bond of sulfonamides and indoles by the 16e− amido derivative of the 18e− precatalyst via metal−ligand cooperation (MLC). This paper summarizes our efforts to investigate N−H bond cleavage of gaseous ammonia in solution via MLC and reports the serendipitous discovery of a new class of chiral tridentate κ3[N,N′,N″] Ru and Ir metallacycles, derivatives of the famous M−FsDPEN catalysts (M = Ru, Ir). The protonation of these metallacycles by strong acids containing weakly coordinating (chiral) anions generates ionic complexes, which were identified as conceptually novel Noyori−Ikariya precatalysts. For example, the ATH of aromatic ketones with some of these complexes proceeds with up to 99% ee.

1. INTRODUCTION The asymmetric transfer hydrogenation (ATH) of ketones and imines with chiral molecular catalysts is understood to be a powerful, practical, and versatile tool to access chiral alcohols and amines in organic synthesis because of its excellent selectivity, operational simplicity, and wide substrate scope.1 The method serves as a “green chemistry” compatible alternative to hydrogenation as hydrogen sources are typically selected from renewable resources such as propan-2-ol, HCO2Na/H2O, or azeotropic mixtures of HCO2H−NEt3. Among the various chiral catalysts reported, the most notable are the Noyori−Ikariya complexes (Figure 1). The first generation of these complexes (Figure 1B) was developed in the mid 1990s by Noyori and Ikariya,3 as well as independently by Mashima and Tani for M = Ir and Rh.4 The second “tethered” generation represented by various precatalysts (Figure 1C)5 was developed after the discovery of the first example by Wills in 2005,5ae,ag including the commercially available Ts−DENEB complex developed by Takasago International Corp.5b,j,s which has found considerable use in several industrial applications.6 Good to excellent product enantiopurities, stabilities including robustness toward air/water, and high turnover efficiencies allowed both generations of these precatalysts to be successfully applied in numerous industrial settings.2,5j,k,s,6c,d,7 Despite the large number of developed catalysts, significant efforts have been continuously paid to © XXXX American Chemical Society

develop novel complexes of this type. In particular, enhanced enantioselectivity and/or more robust precatalysts are needed for “challenging” substrates and large-scale applications.2 In this work, we report discovery of the conceptually novel Noyori−Ikariya molecular precatalysts composed of a chiral 18e− organometallic cation and a tunable (chiral) organic or inorganic anion, including the syntheses of the corresponding complexes, their characterizations, and catalytic efficiencies (Figure 1D).8 The results presented in this paper were obtained serendipitously and originated from the investigation of the ability to cleave the N−H bond of ammonia via MLC based on the platform of classical Noyori−Ikariya 16e− amido complexes 1−5 as shown in Scheme 1.9 Ammonia is one of the world’s most produced chemicals.10 However, its application in processes involving transition metals is limited.11 Cleavage of the N−H bond of ammonia is much rarer than for many other “inert” small molecules11b and is typically12 based on oxidative addition13 as shown in Scheme 1(b) as is seen for different mononuclear14 or multinuclear15 organometallic complexes. In several cases, this transformation may be a key step for catalytic addition to olefins, arylation of ammonia with aryl halides, and more.11a,16 Milstein’s,17 Ozawa’s,18 Roesler’s,19 Chirik’s,20 and our group21 have demonstrated the Received: December 5, 2018

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DOI: 10.1021/jacs.8b12961 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

Figure 1. ATH of ketones and imines with Noyori−Ikariya precatalysts (A) and an example of a large-scale ATH by Actelion Pharmaceuticals (Aa).2 Representative examples of complexes belonging to first (B) and second “tethered” (C) generations of the Noyori−Ikariya precatalysts and a novel family of “ionic” precatalysts reported in this work (D). Major diastereomer of the precatalyst is shown. The absolute configurations could be relative.

Scheme 1. Left: Cleavage of the N−H Bond of Ammonia Based on (a) MLC and (b) Oxidative Addition and Right: Complexes Used in This Work to Investigate Scenario (A) Within the Initial Purpose of This Work

amido complex 122 reversibly cleaves the H−H bond of hydrogen,22,23 O−H bond of water24 or secondary alcohols,22 C−H bond of several 1,3-dicarbonyl compounds,25 and N−H bond of sulfonamides as shown at the top of Scheme 2.26 Such realizations resulted in a series of practical enantioselective catalytic reactions with 1 or its derivatives and the aforementioned or similar substrates.27 These results prompted us to investigate the reactions between 1 as well as its derivatives 2−3 with ammonia in CD2Cl2 over a wide temperature range, probed by NMR spectroscopy. In all three cases (see Supporting Information), however, the equilibria was highly shifted toward

possibility to cleave the N−H bond of ammonia based on the MLC. Here we summarize our efforts to investigate N−H bond cleavage of ammonia via MLC based on complexes 1−5 and provide a detailed description on how the conceptually novel Noyori−Ikariya catalysts were discovered.

2. RESULTS AND DISCUSSION 2.1. Reactions of Complexes 1−3 with Ammonia in Dichloromethane. 2.1.1. Variable-Temperature (VT) NMR Study. Thanks to the combination of a Lewis acid and Lewis base within a single molecule, the well-defined 16e− chiral Ru B


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reversibly from violet to deep purple upon cooling to −80 °C, whereas for 2−ammonia the color was yellow at room temperature, consistent with the highest value of the equilibrium constant. No characteristic high-field 1H NMR peaks due to the M−NH2 hydrogens (ca. −2 ppm)28 for the putative amido Ru or Ir complexes were observed. 2.1.2. DFT Studies in Continuum Dichloromethane. The DFT analysis of the reaction between complexes 1−3 and ammonia was initiated in order to probe the feasibility of the N−H bond cleavage of ammonia via MLC, to obtain insights into the configurational and conformational effects, and to rationalize the NMR experiments. All the calculations were carried out on unabridged chiral models of the complexes in continuum dichloromethane using the SMD solvation model29 in order to introduce a nonspecific solvation. The corresponding free energy thermodynamics diagram is presented in Figure 2. The following conclusions can be made: (1) in agreement with the NMR studies, all the equilibria are shifted toward starting materials; (2) formation of R-configured diastereomers is computed to be energetically more feasible, except for the lessstable δ-conformer of complex 1b; (3) λ-configuration of the five-membered NN ring is computed to be more favorable for the R-configured diastereomers, whereas δ-configuration is either less favorable, isoenergetic, or slightly more favorable for the S-configured diastereomers depending on the identity of the complex; (4) formation of amido M−NH2 complexes 1b−3b is less favorable than ammine complexes M ← NH3 1a−3a; however, 1b−3b seem to be kinetically accessible, ∼6−10 kcal·mol−1. 2.2. Reactions of FsDPEN Complexes 4 and 5 with Ammonia in Dichloromethane and Isolation of Metallacycles 6 and 7. 2.2.1. VT NMR Study in Dichloromethane-d2. Computed kinetic accessibility of M−NH2 complexes 1b−3b encouraged us to investigate the reactions of ammonia with the 16e− bifunctional amido complexes 4−5 bearing the intramolecular

Scheme 2. Established Reactivity for Complex 1 towards NuH as Well as the Equilibrium Observed by NMR between Amido Complexes 1−3 and Ammonia in This Work

the starting materials as shown at the bottom of Scheme 2. The ammine complexes 1a−3a were directly identified from the spectra based on a combination of 1H, 13C{1H}, and 2D 1H−1H gCOSY NMR coupled with the density functional theory gauge including atomic orbital (DFT GIAO) chemical shift calculations (see SI, Figures S3−S8). The available estimated equilibrium constant has the order of ∼10−1 M−1 for 1−ammonia at 193 K, 2−ammonia at 273 K, and 3−ammonia at 213 K, respectively. Notably for the 1−ammonia system bearing the smallest equilibrium constant, the color of the solution changed

Figure 2. Free energy thermodynamics profile for the reaction between complexes 1−3 with ammonia computed at the ωB97X-D/def2-TZVP/ SMD(dichloromethane) level of theory. Abbreviations: δ = delta and λ = lambda configuration of the five-membered NN ring, respectively. (R) or (S) are absolute configurations on the metal atom based on enhanced Cahn−Ingold−Prelog rules. The energies are calibrated relative to the δ conformer of the five-membered NN ring of each complex, in accordance to the solid-state X-ray data.22 C


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Scheme 3. Reported Reactions of 16e− Bifunctional Amido Complexes 4 and 5 Bearing an Intramolecular Trapping (S,S)FsDPEN Ligand with Water and Identified Reactivity Towards Ammonia in This Work in CD2Cl2 by NMR, 25 to −80 °C

(17% formation of a new product displaying four 1:1:1:1 multiplet resonances (−143.4, −160.4, −165.9, and −185.7) in the 19F NMR spectrum was monitored within 5 min after mixing the reagents. The reaction is time-dependent and further requires a stoichiometric amount of KOH for a net formation of this product, ∼3 h. The κ 3[N,N′,N″] cyclometalated tetrafluorophenylamido product 6 can be further isolated as an air-stable complex in 85−95% yield as described below in Section 2.3, characterized by elemental analysis, HRESI-MS, multinuclear NMR, IR, and X-ray diffraction, as shown in Figure 3.30 The absolute configuration on the metal atom is SRu based on enhanced Cahn−Ingold−Prelog rules,31 and the reaction is therefore diastereoselective. In the next step, the same reaction was studied by NMR in a wide temperature range. When the argon atmosphere of the violet 2.6 × 10−2 M solution of 4 in CD2Cl2 was replaced with dry ammonia via a freeze−pump−thaw cycle at −80 °C, the color also immediately changed to yellow, and formation of an equilibrium mixture of complex 4 and a new product, most likely (vide infra, computational analysis) an ammine complex 4a (Scheme 3), was monitored by NMR spectroscopy as shown in Figure S9(b). The complex 4a displayed five 1:1:1:1:1 19F NMR resonances due to hindered rotation of the pentafluorophenyl ring at low temperatures. At −80 °C the ratio of 4a:4 was 97:3 (in equilibrium with 33 equiv of NH3 present in the solution from 1H NMR). At −40 °C, the concentration of the intermediate 4a decreased to 70%, and the concentration of starting material 4 increased to 26% as shown in Figure S9(f). When the temperature was decreased again to −80 °C the spectra were fully recovered, except for a small amount of the unidentified byproduct D


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Figure 5. 19F NMR (376.2 MHz; CD2Cl2): (a) spectrum of 5 at 25 °C; (b) replacement of argon atmosphere in (a) with dry ammonia via a freeze−pump−thaw cycle at 25 °C; (c) same as (b) in 24 h; (d) spectrum (c) at −80 °C.

present in less than 6% abundance (green dots on Figure 5(b)−(c)). The resonances in the position of the starting material were significantly broadened and shifted (yellow dots on Figure 5(b)). This averaged single set of three signals at 25 °C gave two sets of five signals at −80 °C, giving loose cross-peaks in the corresponding 19F−19F phase-sensitive 2D NOESY spectrum (see SI, Figure S10). Based on a similar reaction with water24b and computational studies (vide infra), this observation was assigned to the equilibration of two diastereomers of 5a in a 6:4 ratio (5aR:5aS) as shown in Scheme 4, either of which exhibits hindered rotation of the perfluorophenyl ring. The perfect diastereoselectivity in formation of 7 implies that only the major 5aR diastereomer is convertible to the azametallacycle in a retention mode. In summary, NMR studies of the reactions between 4 and 5 with ammonia revealed stepwise and time-dependent formation of the metallacyclic complexes 6 and 7, respectively, via observable intermediates 4a and 5a. No high-field 1H NMR peaks were observed across the temperature range, suggesting that similar to reactions between 1−3 and ammonia discussed in the previous section amido M−NH2 complexes 4b and 5b are not observed in detectable amounts by NMR. However,

Figure 3. X-ray structures of the compounds 6·(CH2Cl2)0.25 and 7·CH2ClCH2Cl.30 The solvent molecules and noncritical H atoms are omitted. Ellipsoids are drawn at the 30% probability level. Selected bond distances (Å) for 7·CH 2ClCH2Cl: Ir1−N1 = 2.118(5), Ir1−N2 = 2.106(5), Ir1−N3 = 2.081(5), and Ir1−CNThmb = 1.784(3).

Figure 4. van’t Hoff plot of the equilibrium between Ru amido complex 4, ammonia, and the ammine complex 4a. Trendline, equation, and R-squared value are presented on the chart. E


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Journal of the American Chemical Society Scheme 4. Equilibration of Two Diastereomers of 5a Observed by NMR

Figure 6. Free energy profile for the reaction of Ru complex 4 and one molecule of NH3 computed at the B3LYP/SDD(Ru)/6-31G*(C,H,N,O,S,F)/ C-PCM(CH2Cl2) level of theory.

leading to the experimentally observed diastereomer 6S starts with the formation of hydrogen-bonded adduct Re-face 4R·NH3. The second step is coordination of an ammonia molecule and the formation of an ammine complex 4aR (ΔG°298 K = −1.7 kcal·mol−1). During this step, the planar geometry around the initial 16e− complex are transformed into a distorted octahedral configuration of the 18e− complex. The overall transformation is characterized by an activation barrier (ΔΔG⧧298 K) of 7.4 kcal·mol−1. The third step involves a thermodynamically unfavorable N−H bond cleavage of ammonia via MLC and the formation of amido complex 4bR (ΔΔG°298 K = 5.8 kcal·mol−1). This step is characterized by an activation barrier (ΔΔG⧧298 K) of 9.4 kcal·mol−1. Alternatively, the transformations 4aR → 4bR may occur via a “proton shuttle” generated by an explicit NH3 molecule. The corresponding sixmembered pericyclic two-bond33 synchronous33,34 concerted transition state TS2R···NH3 was found to be ∼8 kcal·mol−1 uphill in energy as compared to TS2R (Figure 7).

formation of 6 and 7 suggests their existence on the potential energy surface (PES) and kinetic accessibility. 2.2.2. DFT Studies in Continuum Dichloromethane. The DFT analysis of the reaction between complexes 4−5 and ammonia was performed in order to corroborate the NMR experiments and understand the mechanism of diastereoselective formation of 6 and 7. The computational studies were initiated by a proper conformational search. Similar to the complexes described in section 2.1.2., it was noted in the present calculations that conformers having a puckered-ring λ-conformation of the fivemembered NN ring, i.e. where C−H protons are located in axial (aa) positions,32 were found typically more stable than conformers with a δ-ring. This is in agreement with the X-ray data in the solid state for complexes 6 and 7. The energy profile for the reaction 4−NH3 leading to two diastereomers of 6 is shown in Figure 6. All energies (free ΔG°298 K or electronic ΔE in kcal·mol−1) were calibrated relative to the most stable (E-scale) δ-puckered-ring conformer of the 16e− amido complex 4. The five-step reaction F


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in the form of the 4aR diastereomer. Taking into account the accuracy in energy calculations by DFT,34 the calculated thermodynamic parameters for the reactions 4 + NH3 = 4aR, ΔH° = −7.4 kcal·mol−1, and ΔS° = −42 e.u. are reasonable comparable to the experimental values determined by the NMR experiment described above (ΔH° = −5.5 ± 0.3 kcal·mol−1 and ΔS° = −21.6 ± 1.3 e.u.). The computed profile for the reaction 5−NH3 was found to be very similar and is presented in the SI; the activation barrier leading to the experimentally observed Ir complex 7S is ∼2 kcal·mol−1 higher than the one leading to Ru complex 6S, also qualitatively consistent with experimental observations. In summary, DFT analysis nicely explains the origin of diastereoselectivity and supports our assessment that the multistep reactions between 16e− amido complexes and ammonia take place via a step in which the N−H bond is cleaved via MLC. 2.3. Practical Synthesis of Chiral Metallacycles 6 and 7 and Novel Ruthenacycle 10. We found that, more conveniently, metallacycles 6 and 7 could be prepared by the reaction of easily available dimers [RuCl2(η6-hmb)]2 or [Cp*IrCl2]2 with 2 equiv of (S,S)-FsDPEN ligand in the presence of KOH and ammonia in dry dichloromethane or NaNH2 in dry THF, respectively (Scheme 5). The Ru complex 6 could be also prepared by using 18e− chlorido precursor 8, the synthesis and characterization of which is also reported in this paper (see SI). In the course of this work, the p-cymene complex 10 was also prepared from complex 9 and fully characterized, the latter of which is commercially available from Takasago International Corp. Complexes 8, 9, and 10 were analyzed by single-crystal X-ray diffraction studies, revealing the corresponding structures in the Supporting Information. The X-ray structure of 10 is similar to 6·(CH2Cl2)0.25 (cf. Figure S2). 2.4. Reactions of Amidoiridium Complex 5 with Ammonia and Primary Amines. Isolation of N-Methyl(fluorinated arylamido) Complex 11 from the Reaction with MeNH2. Taking into account the high kinetic stability of Ir complex 5 toward moisture,24b the reactions between 5 and ammonia as well as five different commercially available primary amines were studied in dichloromethane at 25 °C by highresolution electrospray ionization mass spectrometry (HRESI-MS) (Scheme 6). The analysis of the reaction mixtures confirmed the formation of the corresponding κ3[N,N′,N″] metallacycles in a mixture with other products, likely intermediates leading to its formation as described in previous sections. Furthermore, the N-methyl(fluorinated arylamido) complex 11 was independently isolated in 71% yield from the reaction of [Cp*IrCl2]2, 2 equiv of

Figure 7. Comparison of ammonia N−H bond cleavage via MLC alone (right) and in the presence of one explicit NH3 molecule (left) computed at the B3LYP/SDD(Ru)/6-31G*(C,H,N,O,S,F)/C-PCM(CH2Cl2) level of theory. Noncritical H atoms are omitted for clarity for the optimized geometries of the transition states.

The fourth step of the reaction is irreversible amidometalation via SNAr through Meisenheimer-type transition states TS3R to afford protonated [6SH]+F−. Finally, its deprotonation by external KOH or NH3 present in the reaction affords 6S (the reaction [6SH]+F− → 6S + HF is thermodynamically unfavorable, ΔΔG°298 K = 11.6 kcal·mol−1). Formation of 6R takes place via a similar sequence of steps, except all the intermediates are placed ∼5 kcal·mol−1 higher on the free energy profile, according to the intrinsic reaction coordinate calculations, and TS3S affords hydrogen-bonded adduct 6R·HF. Diastereomer 6R is not only thermodynamically but also kinetically unfavorable. Therefore, the S-stereochemistry on the metal atom of the resulting 6 is determined kinetically by the relative stabilities of the corresponding Meisenheimer-type transition states TS3S and TS3R. DFT calculations also suggest that prior to the irreversible cyclometalation the reaction between 4 and NH3 should produce largely species 4a in equilibrium with the starting compounds, in agreement with the NMR experiment. The same calculations also suggest that 4a exists largely (almost exclusively) Scheme 5. Practical Synthesis of Metallacycles 6, 7, and 10

G


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Journal of the American Chemical Society Scheme 6. Reactions between 5 and Ammonia or Primary Amines Studied by the HRESI-MSa

Experimental and calculated (in brackets) peaks (m/z) correspond to the protonated cation [M + H]+ of each κ3[N,N′,N″] metallacycle under studies (less-intensive [M + Na]+ and [M + K]+ peaks were also observed, see SI). In each case the reagent was stirred for at least for 24 h prior to measurements.

a

Table 1. Asymmetric Transfer Hydrogenation of α-Hydroxyacetophenone in a Formic Acid/Triethylamine Mixture Catalyzed by Various Chiral Ru(II) and Ir(III) Complexes

entry

cat.

% conv.a

% yielda

% eeb

1 2 3 4 5 6 7 8

9 12 5 10 7 13 6c 14c

100 100 59 100 41 31 ∼0.3 2

92 92 50 91 35 13 ∼0.3 2

93 95 81 93 64 n.d. 60 30

a Determined by NMR (internal standard). bDetermined by HPLC analysis. cSubstrate = PhC(O)CH3: the yield is determined by using balance of the material present.

H


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Journal of the American Chemical Society Table 2. Asymmetric Transfer Hydrogenation of αSubstituted Acetophenones in a Formic Acid−Triethylamine Mixture Catalyzed by Chiral Ru(II) Complex 10

entry

R1

R2

% conv.a

yielda

% eeb

1 2 3 4

H H OCH3 F

OH H H H

100 83 42 75

91 72 40 65

93(R) 98(S) 96(S) 93(S)

Scheme 7. Reactions of 6, 7 or 10 with strong acids HA (1 equiv) in CH2Cl2 leading to isolable complexes [6H]+BF4−, [6H]+OTf−, [7H]+BF4−, [10H]+BF4−, [10H]+OTf−, and 15

a

Determined by NMR (internal standard). bDetermined by HPLC analysis.

the (S,S)-FsDPEN ligand, and an excess of MeNH2 (2.0 M in THF) in the presence of powdered potassium hydroxide following the prescribed procedure, (see SI). It was characterized by NMR, IR, and X-ray diffraction analysis, and the structure of 11 is found to be analogous to 7·CH2ClCH2Cl (see SI). In conclusion to this section, the reactions leading to ruthenaand iridacycles described in this work can be potentially expanded to a broad range of primary amines and can be used, for example, as a novel immobilization strategy for the Noyori− Ikariya catalyst.5ah,35 2.5. Asymmetric Transfer Hydrogenation of Aromatic Ketones Using the Metallacycles 6, 7, and 10: Importance of Proton-Responsive Nature of the Aromatic Amino Nitrogen Atom. Taking into account previous reports of effective catalytic systems employing the FsDPEN ligand for the asymmetric transfer hydrogenation of prochiral aromatic ketones in academic5a,36 and industrial settings,6b,7,37 the catalytic efficiencies of classical M-FsDPEN (M = Ru, Ir) complexes 9, 12, and 5, as well as its azametallacyclic derivatives 10 and 7 reported in this work, were compared.38 α-Hydroxyacetophenone was chosen as a model substrate, and the asymmetric reduction was performed using an azeotrope of HCOOH and NEt3 in the presence of a series of Ru and Ir complexes with a substrate/catalyst (S/C) ratio of 200 at 30 °C for 24 h; the results are presented in Table 1. Commercially available chlorido(amine)−Ru complex 9 as well as its 16e− derivative amido complex 12 are found to be excellent precursors for the reaction to provide the final product with the same very good ∼94% ee (runs 1−2). The Ir complex 5 provides the final product with a lower yield and a poor enantioselectivity of ∼81% (run 3). It is worth noting that almost comparable yields and ee’s were provided by the reaction using the azametallacycles 10 and 7 (runs 1−3 vs runs 4−5). Conversely, the related oxaruthenacycle 13, which is accessible from the FsDPEN−amido complex with water,24b proved to be inefficient for the reaction (run 6).39 This suggests the importance of the proton-responsive nature of the aromatic amino nitrogen atom in 10 in particular. Table 2 further supports that 10 is an efficient precatalyst for a number of α-substituted

Figure 8. X-ray structures (30% probability level of thermal ellipsoids) of [10H]+BF4−(CH2Cl2)0.3330 and 15. Selected bond distances (Å) for 15: Ru1−N1 = 2.096(11)/2.099(11), Ru1−N2 = 2.186(11)/ 2.145(12), Ru1−CNTcym = 1.662(6)/1.665(6). I


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Figure 9. Section plots of the 19F (376.2 MHz, 25 °C) NMR spectra of the isolated complexes [6H]+BF4−, [10H]+BF4−, [7H]+BF4−, [6H]+OTf−, [10H]+OTf−, 17, and 15 in CD2Cl2 placed in descending order.

Scheme 8. Stoichiometric Reactions (a)−(c) Studied by 19F NMR

[6H]+BF4−, [6H]+OTf−, [10H]+BF4−, [10H]+OTf−, and redcolored [7H]+BF4− respectively, as shown in Scheme 7. The products [6H] + BF 4 − , [6H] + OTf − , [7H] + BF 4 − , [10H]+BF4−, and [10H]+OTf− were isolated in quantitative yields and characterized by HRESI-MS, multinuclear NMR in solution, and combustion elemental analysis whenever possible (see SI), as well as single-crystal X-ray diffraction for [10H]+BF4− as shown in Figure 8. Interestingly, the reaction of 10 with Et2OH+Cl− having a strong coordinating anion (Cl−) afforded orange air-stable complex 15 (Scheme 7), which was also characterized by elemental analysis, HRESI-MS, multinuclear NMR, and X-ray crystallography (Figure 8). This complex can be viewed as a functionalized analogue of complex 9, where one ortho-F atom on the pentafluorinated DPEN was substituted with an NH2 group. For convenience, 19F NMR charts of isolated complexes [6H]+BF4−, [6H]+OTf−, [10H]+BF4−, [10H]+OTf−, [7H]+BF4−, 15, and 17 (vide supra) in CD2Cl2 are compared

acetophenones, providing the final products with very good to excellent ee’s. Precatalysts 6, 7, and 10 are 18e−-saturated complexes, and one may anticipate that a coordination vacancy is further required for the catalytic reaction to proceed, i.e., in order to generate a hydrido complex, to the active catalytic species.40 To confirm that this vacancy is generated via probable dissociation of the functionalized FsDPEN arm, complexes 6, 7, and 10 were treated with a range of inorganic and organic Brønsted acids. 2.6. Reaction of Complexes 6, 7, and 10 with Brønsted Acids in Dichloromethane. Isolation of [6H] + A − , [7H]+BF4−, [10H]+A− (A = BF4, OTf), and Complexes 15 (A = Cl) and 17 (A = (S)-(+)-1,1′-Binaphthyl-2,2′-diyl Hydrogenphosphate Anion ≡ (S)-BNP). Aerobic reaction of 6, 7, or 10 with strong acids HA (1 equiv) bearing weakly coordinating anions (A = BF4 or OTf) in dichloromethane at room temperature afforded air-stable yellow-colored ionic complexes J


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Figure 10. (A) van’t Hoff plot of the equilibrium between 17A and 17B in CDCl3 solution. Trendline, equation, and R-squared value are presented on the chart. This gives ΔH° = 4.3 ± 0.1 kcal·mol−1 and ΔS° = 10.6 ± 0.3 e.u. (B) Proposed identity of two coordination isomers (17A and 17B) of the complex 17. (C) Optimized geometries and energies of 17A and 17B computed at the B3LYP/SDD(Ru)/6-31G*(C,H,N,O,S,F)/C-PCM(CH2Cl2) level of theory. Noncritical H atoms are omitted for clarity.

separately in Figure 9. The 19F NMR chemical shifts can be well predicted by DFT NMR GIAO chemical shift calculations, and a full peak assignment is available in the Supporting Information. The 19F NMR spectroscopy provides a convenient tool to monitor the reactions involving all metallacycles reported in this work. Addition of ∼1.5 equiv of AgOTf to the solution of 15 in CD2Cl2 resulted in precipitation of presumably AgCl and formation of [10H]+OTf− based on 19F NMR analysis (Figure S19) as shown in Scheme 8(a).

The experiment (a) in Scheme 8 confirms that the weakly coordinating nature of the A-anion is important toward the exclusive formation of the κ3[N,N′,N″]-protonated metallacycle form in solution. Interestingly, whereas no reaction occurs upon dissolution of 10 in CD3CN, complex [10H]+OTf− undergoes transformation under the same conditions, leading to a new product, presumably 16 based on a decoordinated pentafluorinated arm and coordinated solvent CD3CN molecule characterized in situ by 19F NMR (multiplets at δ/ppm: −136.3, −156.0, −162.7, and −177.2) in CD3CN (Scheme 8(b)−(c)). K


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Table 3. Comparison of Catalytic Efficiencies of Classical p-Cymene-Based Ru−FsDPEN Complex 9 and Its Metallacycle 10 and [10H]+BF4− in Asymmetric Transfer Hydrogenation of Aromatic Ketones

entry

substrate

cat.

additive

S/C

% yielda

% eeb

1 2 3 4 5 6 7 8 9 10

A A B C A C A B C Cd

9 9 9 9 10 10 [10H]+BF4− [10H]+BF4− [10H]+BF4− [10H]+BF4−

-

200 1000 200 200 200 200 200 200 200 1000

91 22 85 >99 83 100 74 65 100 26

97(S) 97(S) 98(S) 94(R) 98(S) 93(R) 98(S) >99(S) 96(R) 88(R)

a

Determined by NMR, the yield is determined by using balance of the material present. bDetermined by HPLC analysis. dIn air.

catalytic activities. Nevertheless, one may speculate that the use of the ionic precatalyst complex [10H]+A− or similar complex could potentially benefit the reaction in at least two ways: (1) it could arguably be more stable than classical 18e− chlorido precatalyst (at least for storage) due to its ionic nature and (b) the possibility to easily tune the nature of the A− anion, including the ability to choose among chiral anions. It is presently unknown if the chiral anion could affect the final ee value of the catalytic reaction, and in-depth studies justify a separate investigation. Since a hydride complex 18 is considered to be an important intermediate in the catalytic reaction1a,41 for the classical p-cymene-based Ru−FsDPEN complex 9 in Scheme 9, one may expect at least two active species 19/[19H]+A− in the catalytic reaction pool with [10H]+A− (Scheme 9). Complexes 19 and [19H]+A− are expected to be in equilibrium, and providing that ATH may be performed in solvents of different polarity and coordination abilities, solvent effects could arguably affect the final ee value. Indeed, the origin of the enantioselectivity with the Noyori−Ikariya catalyst lies on the compromise of C−H···π attractions and lone-pair SO2/π repulsions.41 One may speculate therefore that having a chiral A-anion in close proximity to the SO2 catalyst group could add novel properties to the Noyori−Ikariya catalyst, and as was noticed, a detailed investigation of this is warranted in the future.

Reaction of 10 with 1 equiv of chiral acid (S)-BNPH bearing an anion of medium coordination ability in dichloromethane, where (S)-BNPH is chiral (S)-(+)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, afforded complex 17. At room temperature, 17 exists as an equilibrium mixture of two coordination isomers 17A (19F NMR: multiplets at δ/ppm −134.6 (d, 3JF−F = 22 Hz), −149.9 (brs), −152.8 (brs), −155.1 (brs); 31P{1H} NMR: δ 5.0 ppm) and 17B (19F NMR: multiplets at δ/ppm −138.6 (d, 3JF−F = 22 Hz), −158.1 (vt, J = 15 Hz), −164.4 (brs), −168.5 (brs); 31P{1H} NMR: δ 11.2 ppm) in a ratio of 7:3, respectively. At −80 °C the equilibrium is fully shifted toward 17A. The equilibrium between 17A and 17B is characterized by ΔH° = 4.3 ± 0.1 kcal·mol−1 and ΔS° = 10.6 ± 0.3 e.u. from the van’t Hoff method based on variable-temperature 19F NMR data in CDCl3 as shown in Figure 10A. Based on the 19F NMR spectrum of 17, [6H]+BF4−, [10H]+BF4−, [7H]+BF4−, [6H]+OTf−, [10H]+OTf−, and 15 shown in Figure 9, the identity of 17A and 17B is assigned as shown in Figure 10B. The assignment is qualitatively supported by the DFT calculations (Figure 10C). 2.7. Comparison of Catalytic Efficiencies of Classical p-Cymene-Based Ru−FsDPEN Complex 9 and Its Metallacyclic Derivatives 10 and [10H]+BF4− in Asymmetric Transfer Hydrogenation of Aromatic Ketones. In the final step, the catalytic efficiencies of classical p-cymene-based Ru−FsDPEN complex 9 and its metallacycle 10 and [10H]+BF4− were compared in asymmetric transfer hydrogenation of three aromatic ketones (Table 3). The results shown in Table 3 reveal that complexes 9 and its derivatized metallacycle 10 and [10H]+BF4− show comparable

3. SUMMARY AND CONCLUSIONS The initial purpose of the present work was to investigate the possibility to cleave the N−H bond of ammonia via metal−ligand L


Article


of chiral tridentate κ3[N,N′,N″] ruthenium and iridium metallacycles as summarized in Scheme 10. Computational analysis explains the origin of diastereoselectivity and supports our assessment that the multistep reactions between 4 or 5 with ammonia take place via the N−H bond cleavage via metal−ligand cooperation following the C−F bond cleavage via SNAr. Although the C−F bond represents an example of inert functionalities in chemistry,42 some of these transformations occur already at −30 °C and also can be expanded to primary amines. The neutral Ru/Ir metallacycles prepared from ammonia were found to react with electrophiles, inter alia Brønsted acids bearing weakly noncoordinating anions to generate well-defined ionic ruthenium and iridium complexes which were identified as novel Noyori−Ikariya precatalysts. Two generations of the Noyori−Ikariya catalysts have had a powerful impact on chemical synthesis. Nevertheless, there are still many reactions where there would be benefits from the development of improved systems. The Ru complex [10H]+A− or similar analogues could potentially benefit the reaction in at least two ways: expected higher stability due to ionic nature of the complex and the possibility to easily tune the nature of A− anion including the ability to incorporate chiral anions. The combination of a chiral cation and anion has precedents in asymmetric catalysis43 including Ir complex of Xiao for asymmetric reductive amination.44 The catalysts developed in this work add to this list and could serve as a starting point toward new catalyst design relying on chiral counterion strategy that would be based on “H-bonded supramolecular charge-assisted complexes” rather than on “pure electrostatic ion pairs”.45

Scheme 9. Relevant Intermediate 18 for the ATH of Ketones for the Classical p-Cymene-Based Ru−FsDPEN Complex 9 Based on Presently Accumulated Data41 and Postulated Intermediates 19/[19H]+A− for the ATH of Ketones for the Precatalyst Complex [10H]+A− Developed in This Work

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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.8b12961.

cooperation based on the platform of the 16e− chiral amido complexes 1−5. In the case of compounds 1−3, only equilibria were observed between the starting materials and corresponding ammine M ← NH3 complexes 1a−3a. Computational analysis suggests that the amido M−NH2 complexes 1b−3b are too high in energy to be observed by the NMR but are kinetically accessible, ∼6−10 kcal·mol−1. In the case of 4 or 5 bearing intramolecular trapping chiral ligand (S,S)-FsDPEN,24b the reaction led to the diastereoselective formation of a new family

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Methods, syntheses, characterizations, NMR spectra/ charts, details of X-ray structural analysis, details of catalytic reaction experiments, computational details, Cartesian coordinates for all optimized compounds, tables of energy data, and other details (PDF) CIF files for compounds 7, 8, 9, 10, and 15 (CIF)

AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected]

Scheme 10. Discovery of a New Family of Chiral Tridentate κ3[N,N′,N″] Ruthenium and Iridium Metallacycles Described in This Worka

Their protonation leads towards the discovery of novel air-stable Noyori−Ikariya precatalysts (A− = weakly coordinating anion).

a

M


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Journal of the American Chemical Society ORCID

ant: Hydrogenation or Transfer Hydrogenation? Org. Process Res. Dev. 2013, 17, 1531−1539. (3) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. Ruthenium(II)-catalyzed asymmetric transfer hydrogenation of ketones using a formic acid-triethylamine mixture. J. Am. Chem. Soc. 1996, 118, 2521−2522. (b) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. Asymmetric transfer hydrogenation of imines. J. Am. Chem. Soc. 1996, 118, 4916−4917. (c) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.-i.; Ikariya, T.; Noyori, R. Amino alcohol effects on the Ruthenium(II)-catalysed asymmetric transfer hydrogenation of ketones in propan-2-ol. Chem. Commun. 1996, 233−234. (d) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. Asymmetric Transfer Hydrogenation of Aromatic Ketones Catalyzed by Chiral Ruthenium(II) Complexes. J. Am. Chem. Soc. 1995, 117, 7562−7563. (e) Murata, K.; Ikariya, T.; Noyori, R. New Chiral Rhodium and Iridium Complexes with Chiral Diamine Ligands for Asymmetric Transfer Hydrogenation of Aromatic Ketones. J. Org. Chem. 1999, 64, 2186−2187. (4) Mashima, K.; Abe, T.; Tani, K. Asymmetric Transfer Hydrogenation of Ketonic Substrates Catalyzed by (η5-C5Me5)MCl Complexes (M = Rh and Ir) of (1S,2S)-N-(p-Toluenesulfonyl)-1,2diphenylethylenediamine. Chem. Lett. 1998, 27, 1199−1200. (5) (a) Matsunami, A.; Ikeda, M.; Nakamura, H.; Yoshida, M.; Kuwata, S.; Kayaki, Y. Accessible Bifunctional Oxy-Tethered Ruthenium(II) Catalysts for Asymmetric Transfer Hydrogenation. Org. Lett. 2018, 20, 5213−5218. (b) Yuki, Y.; Touge, T.; Nara, H.; Matsumura, K.; Fujiwhara, M.; Kayaki, Y.; Ikariya, T. Selective Asymmetric Transfer Hydrogenation of α-Substituted Acetophenones with Bifunctional Oxo-Tethered Ruthenium(II) Catalysts. Adv. Synth. Catal. 2018, 360, 568−574. (c) Soni, R.; Jolley, K. E.; Gosiewska, S.; Clarkson, G. J.; Fang, Z.; Hall, T. H.; Treloar, B. N.; Knighton, R. C.; Wills, M. Synthesis of Enantiomerically Pure and Racemic BenzylTethered Ru(II)/TsDPEN Complexes by Direct Arene Substitution: Further Complexes and Applications. Organometallics 2018, 37, 48−64. (d) Cotman, A. E.; Modec, B.; Mohar, B. Stereoarrayed 2,3Disubstituted 1-Indanols via Ruthenium(II)-Catalyzed Dynamic Kinetic Resolution−Asymmetric Transfer Hydrogenation. Org. Lett. 2018, 20, 2921−2924. (e) Hodgkinson, R.; Jurčík, V.; Nedden, H.; Blackaby, A.; Wills, M. An alternative route to tethered Ru(II) transfer hydrogenation catalysts. Tetrahedron Lett. 2018, 59, 930−933. (f) Forshaw, S.; Matthews, A. J.; Brown, T. J.; Diorazio, L. J.; Williams, L.; Wills, M. Asymmetric Transfer Hydrogenation of 1,3Alkoxy/Aryloxy Propanones Using Tethered Arene/Ru(II)/TsDPEN Complexes. Org. Lett. 2017, 19, 2789−2792. (g) Zhang, X.; Jing, L.; Wei, L.; Zhang, F.; Yang, H. Semipermeable Organic−Inorganic Hybrid Microreactors for Highly Efficient and Size-Selective Asymmetric Catalysis. ACS Catal. 2017, 7, 6711−6718. (h) Jeran, M.; Cotman, A. E.; Stephan, M.; Mohar, B. Stereopure Functionalized Benzosultams via Ruthenium(II)-Catalyzed Dynamic Kinetic Resolution−Asymmetric Transfer Hydrogenation. Org. Lett. 2017, 19, 2042−2045. (i) Zheng, L.-S.; Llopis, Q.; Echeverria, P.-G.; Férard, C.; Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V. Asymmetric Transfer Hydrogenation of (Hetero)arylketones with Tethered Rh(III)−N-(p-Tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine Complexes: Scope and Limitations. J. Org. Chem. 2017, 82, 5607−5615. (j) Touge, T.; Nara, H.; Fujiwhara, M.; Kayaki, Y.; Ikariya, T. Efficient Access to Chiral Benzhydrols via Asymmetric Transfer Hydrogenation of Unsymmetrical Benzophenones with Bifunctional Oxo-Tethered Ruthenium Catalysts. J. Am. Chem. Soc. 2016, 138, 10084−10087. (k) Touge, T.; Arai, T. Asymmetric Hydrogenation of Unprotected Indoles Catalyzed by η6-Arene/N-Me-sulfonyldiamine−Ru(II) Complexes. J. Am. Chem. Soc. 2016, 138, 11299−11305. (l) Cotman, A. E.; Cahard, D.; Mohar, B. Stereoarrayed CF3-Substituted 1,3-Diols by Dynamic Kinetic Resolution: Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation. Angew. Chem., Int. Ed. 2016, 55, 5294−5298. (m) Lau, Y. Y.; Zhai, H.; Schafer, L. L. Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights To Realize the Enantioselective Synthesis of Piperazines. J. Org. Chem. 2016, 81, 8696−8709. (n) Rast, S.; Modec, B.; Stephan, M.; Mohar, B.; γ-Sultam-

Pavel A. Dub: 0000-0001-9750-6603 Shigeki Kuwata: 0000-0002-3165-9882 Yoshihito Kayaki: 0000-0002-4685-8833 Present Address †

Chemistry Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Dedicated to the memory of late Professor Takao Ikariya, Tokyo Institute of Technology, deceased on April 21, 2017. This work was supported via the award of a Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship for PAD (No. 10F00344) and largely performed in the years 2011−2013. This work was also financially supported by the Grant for Engineering Research from Mizuho Foundation for the Promotion of Sciences and JSPS KAKENHI Grant number JP18K19070 (SK). A.M. is grateful to JSPS for a Research Fellowship for Young Scientists (No. 17J09484). We also thank Takasago International Corporation for the generous gift of (S,S)-DPEN. Computations were performed by using the TSUBAME-2 supercomputer (Tokyo Institute of Technology).

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