Asymmetric Transfer Hydrogenation of Arylketones Catalyzed by Enantiopure Ruthenium(II)/Pybox Complexes Containing Achiral Phosphonite and Phosphinite Ligands

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Article Asymmetric Transfer Hydrogenation of Arylketones Catalyzed by Enantiopure Ruthenium(II)/Pybox Complexes Containing Achiral Phosphonite and Phosphinite Ligands

Miguel Claros, Eire de Julián, Joseﬁna Díez, Elena Lastra and M. Pilar Gamasa *

Departamento de Química Orgánica e Inorgánica-IUQOEM (Unidad Asociada al CSIC), Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Oviedo, E-33006 Oviedo, Principado de Asturias, Spain; [email protected] (M.C.); [email protected] (E.d.J.); [email protected] (J.D.); [email protected] (E.L.) * Correspondence: [email protected]; Fax: +34-985103446

Academic Editor: Rafael Chinchilla Received: 28 January 2020; Accepted: 18 February 2020; Published: 23 February 2020

i Abstract: A family of complexes of the formula trans-[RuCl2(L)(R-pybox)] (R-pybox = (S,S)- Pr-pybox, (R,R)-Ph-pybox, L = monodentate phosphonite, PPh(OR)2, and phosphinite, L = PPh2(OR), ligands) were screened in the catalytic asymmetric transfer hydrogenation of acetophenone, observing a strong inﬂuence of the nature of both the R-pybox substituents and the L ligand in the process. The best results were obtained with complex trans-[RuCl2{PPh2(OEt)}{(R,R)-Ph-pybox}] (2c), which provided high conversion and enantioselectivity (up to 96% enantiomeric excess, e.e.) for the reduction of a variety of aromatic ketones, aﬀording the (S)-benzylalcohols.

Keywords: asymmetric catalysis; transfer hydrogenation; alcohols; ruthenium; pybox; phosphonite ligands; phosphinite ligands

1. Introduction Asymmetric transfer hydrogenation (ATH) of prochiral ketones catalyzed by transition metal complexes, displaying well designed chiral ligands, is currently recognized as a powerful and versatile tool to access enantiopure alcohols [1–13]. In this area, it must be mentioned that the studies focused on the asymmetric transfer hydrogenation (ATH) of ketones using ruthenium(II) complexes bearing PPh3 and enantiopure C2 or C1 symmetry N,N,N-donor ligands with NH functionality (see Figure1A–E). Thus, the groups of Zhang [14] and Beller [15] described the use of in situ-generated ruthenium complexes, containing bis(oxazolinylmethyl)amine (ambox ligand) (Figure1A) [ 14] and pyridine(bis)imidazolines (pybim ligand) (Figure1B) [ 15], respectively. On the other hand, it has also been reported that isolated ruthenium complexes with C1-symmetry N,N,N donor ligands (Figure1C–E) [ 16–18] efficiently catalyze the asymmetric transfer hydrogenation of aryl ketones. In all of these examples, the presence of the NH functionality in the enantiopure ligand is a requisite for achieving high reactivity and enantioselectivity. We have also made some contributions in this field, particularly on the synthesis and catalytic activity of group 8 metal complexes based on enantiopure N,N,N-ligands, lacking the N-H functionality. In this context, we reported the complexes cis-[MCl2(L)(R-pybox)] (M = Ru, Os, L = phosphane) and trans-[MCl2(L)(R-pybox)] (M = Ru, L = phosphane, phosphite; M = Os, L = phosphite) and studied their catalytic activity toward the asymmetric transfer hydrogenation of aryl ketones. Interestingly, the efficiency of these catalysts depends not only on the metal and the chiral ligand but also on the nature of the auxiliary P-donor ligand [19,20]. Thus, we found that the reduction of different aryl ketones was best achieved using the combination of Ru(II)/(R,R)-Ph-pybox/phosphane (95%–99% conversion; up to

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95% e.e.) and Os(II)/(S,S)-iPr-pybox)/phosphite (96%–99% conversion; up to 94% e.e.). However, the corresponding phosphite ruthenium and phosphane osmium complexes led to lower enantiomeric excess. The influence of the P-donor ligand was also analyzed by Beller and col. using mixtures of 6 [RuCl2(η -C6H6)]/pybim and monodentate or bidentate phosphanes as the catalyst [15]. In the light of these findings, we found of interest to move to explore further combinations of ruthenium/osmium complexes with other phosphorous ligands with different electronic demand and steric requirement. Continuing our studies on the ATH of ketones using ruthenium(II) complexes, containing pybox derivatives as the chiral auxiliary and phosphane/phosphite as the achiral phosphorous ligand, we reported the ATH reaction of aryl ketones catalyzed by ruthenium complexes trans-[RuCl2(L){(S,S)- i Pr-pybox}] and trans-[RuCl2(L){(R,R)-Ph-pybox}], containing monodentate phosphonite (L = PPh(OR)2) and phosphinite (L = PPh2(OR)) ligands (Figure1F,G) [ 21]. Such ligands can be placed between phosphanesMolecules 2019, and24, x FOR phosphites PEER REVIEW in a donor-acceptor ligand scale. 2 of 9

Figure 1.1. SelectedSelected ruthenium(II)ruthenium(II) complexes,complexes, bearingbearing enantiopureenantiopure CC22 oror CC11 symmetrysymmetry NN,,NN,,NN-donor-donor ligands,ligands, usedused inin asymmetricasymmetric transfertransfer hydrogenationhydrogenation (ATH)(ATH) ofof ketonesketones (Examples(Examples correspondingcorresponding toto complexescomplexes AA––EE featurefeature thethe N-HN-H functionality;functionality; structuresstructures FF––GG lacklack thethe N-HN-H functionality).functionality). 2. Results and Discussion We have also made some contributions in this field, particularly on the synthesis and catalytic 2.1.activity Ruthenium(II) of group/R-pybox 8 metal Catalysts complexes1a–1c basedand 2a –on2c enantiopure N,N,N-ligands, lacking the N-H functionality. In this context, we reported the complexes cis-[MCl2(L)(R-pybox)] (M = Ru, Os, L = We explored the eﬀectiveness of ruthenium(II) complexes 1–2 (Figure1F,G), containing achiral phosphane) and trans-[MCl2(L)(R-pybox)] (M = Ru, L = phosphane, phosphite; M = Os, L = phosphite) phosphoniteand studied their (1a, 2a catalytic) and phosphinite activity toward (1b,c ,the2b ,asyc) ligandsmmetric [21 transfer], in the hydrogenation ATH reaction of aryl ketones. InInterestingly, accordance the with efficiency their C2 symmetricof these catalysts structure, depends complexes not only1–2 onshowed the metal a single and the set ofchiral signals ligand for but the 1 13 1 twoalso oxazolineon the nature fragments of the in auxiliary the H and P-donorC{ H} liga NMRnd [19,20]. spectra. Thus, Therefore, we found the chloro that the ligands reduction and the of Ldifferent/pyridine aryl ligands ketones adopted was best a trans-arrangement. achieved using the combination of Ru(II)/(R,R)-Ph-pybox/phosphane (95%–99%Moreover, conversion; this stereochemistry up to 95% e.e. had) and been Os(II)/( conﬁrmedS,S)- byiPr-pybox)/phosphite single-crystal X-ray (96%–99% analysis for conversion; complexes 1aupand to 2c94%. An e.e. ORTEP-type). However, view the ofcorresponding these complexes phosphit is showne ruthenium in Figure1 and(thermal phosphane ellipsoids osmium were complexes led to lower enantiomeric excess. The influence of the P-donor ligand was also analyzed by Beller and col. using mixtures of [RuCl2(η6-C6H6)]/pybim and monodentate or bidentate phosphanes as the catalyst [15]. In the light of these findings, we found of interest to move to explore further combinations of ruthenium/osmium complexes with other phosphorous ligands with different electronic demand and steric requirement. Continuing our studies on the ATH of ketones using ruthenium(II) complexes, containing pybox derivatives as the chiral auxiliary and phosphane/phosphite as the achiral phosphorous ligand, we reported the ATH reaction of aryl ketones catalyzed by ruthenium complexes trans-[RuCl2(L){(S,S)- iPr-pybox}] and trans-[RuCl2(L){(R,R)-Ph-pybox}], containing monodentate phosphonite (L = PPh(OR)2) and phosphinite (L = PPh2(OR)) ligands (Figure 1F,G) [21]. Such ligands can be placed between phosphanes and phosphites in a donor-acceptor ligand scale.

2. Results and Discussion

2.1. Ruthenium(II)/R-pybox Catalysts 1a–1c and 2a–2c

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We explored the effectiveness of ruthenium(II) complexes 1-2 (Figure 1F,G), containing achiral phosphonite (1a, 2a) and phosphinite (1b,c, 2b,c) ligands [21], in the ATH reaction of aryl ketones. In accordance with their C2 symmetric structure, complexes 1–2 showed a single set of signals for the two oxazoline fragments in the 1H and 13C{1H} NMR spectra. Therefore, the chloro ligands and the L/pyridine ligands adopted a trans-arrangement. Moreover, this stereochemistry had been confirmed by single-crystal X-ray analysis for complexes 1a and 2c. An ORTEP-type view of these complexes is shown in Figure 1 (thermal ellipsoids were shown at the 30% probability level, and hydrogen atoms were omitted for clarity), and selected bonding data are collected in the Table S1 (Supporting Information). Both structures exhibited a distorted octahedral geometry around the ruthenium atom, which was bonded to the three nitrogen atoms (R-pybox; R = iPr (1a), Ph (2c)), to the phosphorous atom (PPh(OMe)2 (1a), PPh2(OEt) (2c)), and to two chlorine atoms. The chlorine atoms were located in a Molecules 2020, 25, 990 3 of 9 trans disposition with Cl(1)-Ru(1)-Cl(2) angles of 171.60(6) (1a) and 173.25(5)° (2c). The N(2)–Ru(1)– P(1) angle was close to the linearity (178.3(2) (1a) and 177.76(15)° (2c)), and the Ru(1)–P(1) distances shownwere 2.2625(18) at the 30% (1a probability) and 2.2829(13) level, and (2c) hydrogen Å. The Ru(1)–N(1), atoms were Ru(1)–N(2), omitted for clarity),and Ru(1)–N(3) and selected distances, bonding as datawell areas the collected N–Ru(1)–N in the bond Table angles, S1 (Supporting fell in the Information). range observed for other related ruthenium(II) pybox complexesBoth structures [22,23] (see exhibited Table S1, a Supporting distorted octahedral Information). geometry around the ruthenium atom, which was bonded to the three nitrogen atoms (R-pybox; R = iPr (1a), Ph (2c)), to the phosphorous atom (PPh(OMe)2.2. Catalytic2 Asymmetric(1a), PPh2(OEt) Transfer (2c)), Hydrogenation and to two chlorine of Ketones atoms. The chlorine atoms were located in a transThen,disposition the above-reported with Cl(1)-Ru(1)-Cl(2) complexes angles were of tested 171.60(6) towards (1a) and the 173.25(5)ATH of acetophenone.◦ (2c). The N(2)–Ru(1)–P(1) Thus, Table angle1 summarizes was close the to conversion the linearity of (178.3(2)acetophenone (1a) and into 177.76(15) enriched◦ 1-phenylethanol(2c)), and the Ru(1)–P(1) using the distances ruthenium(II) were 2.2625(18)(S,S)-iPr-pybox) (1a) and (1) 2.2829(13)and (R,R)-Ph-pybox (2c) Å. The (2 Ru(1)–N(1),) catalysts. The Ru(1)–N(2), electronic and nature Ru(1)–N(3) and steric distances, demand as[24,25] well as(Tolman the N–Ru(1)–N electronic bondparameter angles, (TEP) fell inand the cone range an observedgles) of the for achiral other related auxiliary ruthenium(II) phosphonite pybox and complexesphosphinite [22 ligands,23] (see used Table in this S1, Supportingreport were Information). between those of the phosphane and phosphite ligands, already studied by us in the ATH of ketones [19]. 2.2. Catalytic Asymmetric Transfer Hydrogenation of Ketones In a typical experiment, the ruthenium catalyst precursor 1,2 (0.01 mmol, 0.2 mol%) was added to a solutionThen, the containing above-reported 5 mmol complexes of acetophenone were tested in 45 towards mL of 2-propanol the ATH of under acetophenone. an argon Thus,atmosphere, Table1 summarizesand the solution the conversionwas stirred ofinitially acetophenone for 15 min into at enriched 82 °C. After 1-phenylethanol this time, a solution using the of ruthenium(II)0.24 mmol of i (KOS,St)-BuPr-pybox) in 5 mL of (1 )2-propanol and (R,R)-Ph-pybox (ketone/catalyst/KO (2) catalysts.tBu The ratio electronic = 500:1:24) nature was andadded, steric and demand the resulting [24,25] (Tolmanmixture was electronic heated parameterfor 15 min and (TEP) then and monitore cone angles)d by gas of chromatography the achiral auxiliary using phosphonitea chromatograph and phosphinitewith a Supelco ligands β-DEX used 120 inchiral this capillary report were column between (90 min those of ofstirring the phosphane time was used and phosphitein some instances; ligands, alreadysee Table studied 1, entries by us2,6,8). in the ATH of ketones [19].

Table 1.1.Asymmetric Asymmetric Transfer Transfer Hydrogenation Hydrogenation of Acetophenone of Acetophenone Catalyzed Catalyzed by Ruthenium(II) by Ruthenium(II) Complexes 1aComplexes–c and 2a–c. 1a–c and 2a–c.

a a CatalystCatalyst TimeTime (min) (min) Conv.Conv. (%) a(%) e.e. (%)e.e. a(%) i 1 [RuCl2{PPh(OMe)2}( Pr-pybox)]i (1a) 15 63 16 (R) 1 [RuCl2{PPh(OMe)2}( Pr-pybox)] (1a) 15 63 16 (R) 2 2 90 90 9797 20 (R20) (R) i i 3 3 [RuCl[RuCl2{PPh2{PPh2(OMe)}(2(OMe)}(Pr-pybox)]Pr-pybox)] (1b ()1b ) 1515 9696 43 (R43) (R) i i 4 4 [RuCl[RuCl2{PPh2{PPh2(OEt)}(2(OEt)}(Pr-pybox)]Pr-pybox)] (1c ()1c ) 1515 9595 62 (R62) (R) 5 5[RuCl [RuCl2{PPh(OMe)2{PPh(OMe)2}(Ph-pybox)]2}(Ph-pybox)] (2a ()2a ) 1515 6767 5 (S)5 (S) S 6 6 90 90 9898 11 ( 11) (S) 7 [RuCl2{PPh2(OMe)}(Ph-pybox)] (2b) 15 48 46 (S) 7 8[RuCl2{PPh2(OMe)}(Ph-pybox)] (2b) 9015 9248 46 (S46) (S) 8 9 [RuCl2{PPh2(OEt)}(Ph-pybox)] (2c) 15 90 9592 63 (S46) (S) 9 [RuCl2{PPha Determined2(OEt)}(Ph-pybox)] by GC with a ( Supelco2c) β-DEX 120 chiral15 capillary column.95 63 (S) a Determined by GC with a Supelco β-DEX 120 chiral capillary column.

InFrom a typical the results experiment, displayed the rutheniumin Table 1, catalystseveral precursorfeatures worth1,2 (0.01 attention: mmol, 0.2i) All mol%) of the was complexes added to awere solution active containing towards 5the mmol asymmetric of acetophenone reduction in 45of mLacetophenone, of 2-propanol the under conversion an argon varying atmosphere, from and the solution was stirred initially for 15 min at 82 ◦C. After this time, a solution of 0.24 mmol of KOtBu in 5 mL of 2-propanol (ketone/catalyst/KOtBu ratio = 500:1:24) was added, and the resulting mixture was heated for 15 min and then monitored by gas chromatography using a chromatograph with a Supelco β-DEX 120 chiral capillary column (90 min of stirring time was used in some instances; see Table1, entries 2,6,8). From the results displayed in Table1, several features worth attention: i) All of the complexes were active towards the asymmetric reduction of acetophenone, the conversion varying from moderate (48%–67%, entries 1,5,7) to high (95%–96%, entries 3,4,9) after 15 min of reaction. ii) The efficiency of the catalyst depended greatly on the auxiliary achiral P-ligand (phosphonite vs. phosphinite). Thus, the phosphinite complexes 1b–c/2b–c were notably superior to the phosphonite complexes 1a/2a (entries 3,4,7,8,9 vs. 1,2,5,6). The values of asymmetric induction obtained were in accordance with the Tolman 1 electronic parameter (cm− ) and the cone angles (deg) of these achiral ligands [24,25]. iii) Complexes 1 Molecules 2020, 25, 990 4 of 9 and 2 were able to selectively convert acetophenone into (R)- and (S)-1-phenylethanol, respectively. Under these conditions tested, the chiral ligand did not significantly affect the efficiency of the reaction (iPr-pybox, entries 1–4; Ph-pybox, entries 5–9). Therefore, once the basic reaction conditions were defined, we carried out the optimization of the reduction of acetophenone using the complex [RuCl2{PPh2(OEt)}(Ph-pybox)] (2c) as catalyst (Table2). The following parameters were explored: i) Catalyst loading (entries 1–4): First of all, the amount of catalyst was varied in the range of 0.1–0.4 mol% (entries 1–4), starting from the basic reaction conditions (entry 1; ketone/KOtBu ratio of 500:24; 50 mL of 2-propanol). The highest e.e. value was obtained when 0.3 mol% of catalyst was employed (entry 3). Lower ratio of catalyst (0.2 and 0.1 mol%; entries 1–2) required longer reaction times and/or led to poorer enantiomeric excess, while a little decrease of the e.e. was observed with 0.4 mol% of catalyst (entry 4). ii) Concentration (entries 5, 6): Then, we studied the effect of the amount of 2-propanol and found a notable improvement of both conversion and enantioselectivity as the total amount of 2-propanol increased from 50 mL (entry 3) to 75 mL (entries 5, 6). iii) Base (entries 5–11): Taking the entries 5, 6 as the reference, some other bases were explored (entries 7–11). We found that KOtBu, NaOH, and NaOtBu behaved more efficiently than KOH and t Cs2CO3 (entries 5–9 vs. 10, 11). Among the former, the base NaO Bu seemed to be slightly superior (entries: 8, 9 vs. 5, 6). iv) Ketone/catalyst/NaOtBu ratio (entries 8, 12, 13): Decreasing the ratio of base from 500:1.5:24 (entry 8) to either 500:1.5:12 or 500:1.5:6 (entries 12, 13) resulted in a slightly higher e.e.

Table 2. Optimization of Reaction Conditions for Transfer Hydrogenation of Acetophenone Catalyzed a by Ruthenium Complex [RuCl2{PPh2(OEt)}(Ph-pybox)] (2c) .

Catalyst Loading iPrOH Time Conversion e.e. (%) Base Ketone/BaseRatio (mol %) (mL) (min) (%) b (S) b 1 0.2 50 KOtBu 500/24 15 95 63 2 0.1 50 KOtBu 500/24 30 79 67 3 0.3 50 KOtBu 500/24 15 91 70 4 0.4 50 KOtBu 500/24 15 93 66 5 0.3 75 KOtBu 500/24 5 91 87 6 0.3 75 KOtBu 500/24 15 97 83 7 0.3 75 NaOH 500/24 10 95 83 8 0.3 75 NaOtBu 500/24 5 97 89 9 0.3 75 NaOtBu 500/24 10 97 86 10 0.3 75 KOH 500/24 30 95 67 11 0.3 75 Cs2CO3 500/24 30 95 78 12 0.3 75 NaOtBu 500/12 5 96 92 13 0.3 75 NaOtBu 500/6 5 97 90 a b Reactions were carried out at 82 ◦C using 5 mmol of acetophenone. Determined by GC with a Supelco β-DEX 120 chiral capillary column.

Once the reduction of acetophenone was optimized using 2c as a catalyst [26], the ATH of a number of aryl ketones was studied, and the results are gathered in Table3. In most cases, the reaction required short reaction time (5–10 min) and took place with high conversion (around 90%) and excellent enantioselectivity (87%–96% e.e.). Thus, this pattern was observed for acetophenone, propiophenone, and 2-acetonaphthone (entries 1, 2 and 3), as well as for electron-rich 3- and 4-methoxyacetophenone (entries 4 and 5) (3000–4000 TOF) [27]. On the other hand, increasing the steric demand of the substrate, particularly that of the aryl group, had a great impact on the process in terms of both conversion and enantiomeric excess. Thus, although the reduction of 2-methoxyacetophenone (entries 6 and 7) was rather ineﬃcient, isobutyrophenone could be transformed into the alcohol with high enantiomeric excess and moderate (entry 8) or good conversion (entry 9). MoleculesMolecules 2019 2019,, 24, 24,, x,x x FORFOR FOR PEERPEER PEER REVIEWREVIEW REVIEW 5 5of of 9 9 Molecules 2019, 24, x FOR PEER REVIEW 5 of 9 termsterms ofof bothboth conversionconversion andand enantiomericenantiomeric excess.excess. Thus,Thus, althoughalthough thethe reductionreduction ofof 2-2- terms of both conversion and enantiomeric excess. Thus, although the reduction of 2- methoxyacetophenonemethoxyacetophenone (entries(entries 66 andand 7)7) waswas rathratherer inefficient,inefficient, isobutyrophenoneisobutyrophenone couldcould bebe methoxyacetophenone (entries 6 and 7) was rather inefficient, isobutyrophenone could be transformedtransformed intointo thethe alcoholalcohol withwith highhigh enantiomenantiomericeric excessexcess andand moderatemoderate (entry(entry 8)8) oror goodgood transformedMolecules 2020 , 25into, 990 the alcohol with high enantiomeric excess and moderate (entry 8) or good5 of 9 conversionconversion (entry (entry 9). 9). conversion (entry 9).

Table 3. Transfer Hydrogenation of Ketones Catalyzed by Complex [RuCl {PPh2 2 (OEt)}(Ph-pybox)]2 2 (2c) TableTable 3. 3. Transfer Transfer Hydrogenation Hydrogenation of of Ketones Ketones Catalyzed Catalyzed by by Complex Complex [RuCl [RuCl2 22{PPh{PPh2 22(OEt)}(Ph-pybox)](OEt)}(Ph-pybox)] Table 3. Transfer Hydrogenation of Ketones Catalyzed by Complex [RuCl2{PPh2(OEt)}(Ph-pybox)] Table 3. Transfer Hydrogenationa a.ofa. Ketones Catalyzed by Complex [RuCl2{PPh2(OEt)}(Ph-pybox)] (2c(under2c) )under under Optimized Optimized Optimized Conditions Conditions Conditions. a.a. ((2c)) underunder OptimizedOptimized ConditionsConditions a. (2c) under Optimized Conditions a.

TimeTime b c c KetoneKetone Time TOFTOF (h 1(h−1−)1 )b b ConversionConversion (%) (%) c c e.e.e.e.e.e. (%) (%)S ( S(S)c) c KetoneKetone TimeTime (min) TOFTOF (h −(h−)1) b ConversionConversion (%) (%) c e.e.(%) (%) ( ()S)c Ketone (min)(min) TOF (h−1) b Conversion (%) c e.e. (%) (S)c Ketone (min)(min) TOF (h ) Conversion (%) e.e. (%) (S) (min)

1 1 1 55 5 384038403840 96 96 96 92 92 92 1 5 3840 96 92

2 2 2 101010 304030403040 97 97 97 96 96 96 2 10 3040 97 96

3 3 3 55 5 384038403840 96 96 96 87 87 87 3 5 3840 96 87

4 4 5 5 39203920 98 98 90 90 4 4 55 39203920 98 98 90 90

5 5 5 5 34403440 86 86 89 89 5 5 55 34403440 86 86 89 89

6 6 4545 500 500 54 54 72 72 6 6 4545 500 500 54 54 72 72

7 7 9090 500500 7575 6868 7 7 9090 500500 7575 6868

8 8 1010 720 720 51 51 91 91 8 8 1010 720 720 51 51 91 91

9 9 6060 720 720 90 90 87 87 9 60 720 90 87 a9 a 9 6060 720 720 90 90 87 87 aa ReactionsReactions were were carried carried out out at at 82 82 °C °C using using 5 5 mmol mmol of of ketone ketone and and 2-propanol 2-propanol (75 (75 mL), mL), 0.015 0.015 mmol mmol (0.3 (0.3 a Reactions were carried out at 82 °C using 5 mmol of ketoneketone andand 2-propanol2-propanol (75(75 mL),mL), 0.0150.015 mmolmmol (0.3(0.3 a Reactionsa were carried out at 82 °C using 5 mmol of ketone and 2-propanol (75 mL), 0.015 mmol (0.3 Reactions were carried outt t at 82 ◦C using 5 mmol of ketone andt t 2-propanol (75b b mL), 0.015 mmol (0.3 mol %) molmol %) %) catalyst, catalyst, and and NaO NaOtBuBu (acetophenone/catalyst/NaO (acetophenone/catalyst/NaOtBuBu 500:1.5:12). 500:1.5:12). b CalculatedCalculated TOF TOF (turnover (turnover mol %) catalyst, andt NaOtBu (acetophenone/catalyst/NaOt tBub 500:1.5:12). b Calculated TOF (turnover molcatalyst, %) catalyst, and NaO andBu (acetophenoneNaO Bu (acetophenone/catalyst/NaOc c /catalyst/NaO Bu 500:1.5:12). BuCalculated 500:1.5:12). TOF (turnoverCalculated frequency) TOF (turnover values at t frequency)frequency)c values values at at t t= = 5 5 min. min. cc DeterminedDetermined by by GC GC with with a a Supelco Supelco β β-DEX-DEX 120 120 chiral chiral capillary capillary column. column. frequency)frequency) valuesvalues atat tt == 55 min.min. c Determined by GC with a Supelco β-DEX-DEX 120120 chiralchiral capillarycapillary column.column. frequency)= 5 min. Determined values at t by= 5 GC min. with c Determined a Supelco β-DEX by GC 120 with chiral a capillarySupelco column. β-DEX 120 chiral capillary column. ComplexesComplexes 1 1 and and 2 2 fulfilled fulfilled the the requirement requirement to to be be precursors precursors of of active active species species in in the the catalytic catalytic Complexes 1 andand 2 fulfilledfulfilled thethe requirementrequirement toto bebe precursorsprecursors ofof activeactive speciesspecies inin thethe catalyticcatalytic ComplexesComplexes 1 1andand 22 fulfilledfulfilled the the requirement requirement to to be be precursors precursors of of active activei i species species in in the the catalytic catalytic asymmetric transfer hydrogenation of ketones by hydrogen transfer from iiPrOH/base. Regarding the asymmetricasymmetric transfer transfer hydrogenation hydrogenation of of ketones ketones by by hydrogen hydrogen transfer transfer from from iPrOH/base. PrOH/base. Regarding Regarding the the asymmetricasymmetric transfer transfer hydrogenation hydrogenation of ofketones ketones by byhydrogen hydrogen transfer transfer from from iPrOH/base.iPrOH/base. Regarding Regarding the stereochemicalstereochemical outcome,outcome, thethe observedobserved resultsresults werewere inin accordanceaccordance withwith thethe establishedestablished reactionreaction stereochemicalthe stereochemical outcome, outcome, the observed the observed results results were were in inaccordance accordance with with the the established established reaction reaction pathwaypathway [28–31].[28–31]. Thus,Thus, thethe hydrogenhydrogen transfertransfer stepstep hadhad beenbeen proposedproposed toto occuroccur throughthrough aa four-four- pathwaypathway [28–31]. [28–31]. Thus,Thus, thethe hydrogen hydrogen transfer transfer step step had had been been proposed proposed to occur to through occur through a four-membered a four- memberedmembered cyclic cyclic transition transition state, state, involving involving the the me metal-hydridetal-hydride and and the the ketone. ketone. Such Such a a transition transition state state memberedcyclic transition cyclic transition state, involving state, involving the metal-hydride the metal-hydride and the and ketone. the ketone. Such a Such transition a transition state would state wouldwould result result from from i) i) chloride chloride extraction extraction and and meta metal lisopropoxide isopropoxide formation, formation, ii) ii) generation generation of of metal metal wouldresult fromresult i) from chloride i) chloride extraction extraction and metal and isopropoxide metal isopropoxide formation, formation, ii) generation ii) generation of metal hydride of metal by hydridehydride by by β β-elimination-elimination of of propanone propanone (an (an inner-sphere inner-sphere mechanism), mechanism), iii) iii) loss loss of of the the second second chloride chloride hydrideβ-elimination by β-elimination of propanone of propanone (an inner-sphere (an inner-sphere mechanism), mechanism), iii) loss of theiii) loss second of the chloride second to chloride generate toto generate generate a a 16-electron 16-electron metal metal hydride, hydride, iv) iv) coor coordinationdination of of metal metal hydride hydride and and ketone. ketone. Then, Then, the the toa generate 16-electron a 16-electron metal hydride, metal iv) hydride, coordination iv) coor ofdination metal hydride of metal and hydride ketone. and Then, ketone. the approach Then, the of approachapproach of of the the ketone ketone to to the the metal-hydride metal-hydride complex complex could could occur occur in in two two ways, ways, involving involving the the re re-face-face approachthe ketone of tothe the ketone metal-hydride to the metal-hydride complex could complex occur could in two occur ways, in involvingtwo ways, the involvingre-face orthesi re-face-face of oror si si-face-face of of the the ketone. ketone. Figure Figure 2 2 illustrates illustrates the the transition transition states states in in the the case case of of ( R(R,R,R)-pybox)-pybox complexes, complexes, orthe si-face ketone. of the Figure ketone.2 illustrates Figure 2 illustrates the transition the transition states in the states case in of the ( Rcase,R)-pybox of (R,R)-pybox complexes, complexes, showing showingshowing that that the the steric steric repulsions repulsions of of the the oxazoline- oxazoline- and and ketone-phenyl ketone-phenyl groups groups make make transition transition state state showingthat the stericthat the repulsions steric repulsions of the oxazoline- of the oxazoline- and ketone-phenyl and ketone-phenyl groups make groups transition make transition state A lower state in AA lowerlower inin energyenergy thanthan transitiontransition statestate B,B, providingproviding thethe (S)(S)-alcohols-alcohols preferentiallypreferentially [19,32].[19,32]. Aenergy lower than in transitionenergy than state transitionB, providing state the B, (S) -alcoholsproviding preferentially the (S)-alcohols [19,32 ].preferentially Conversely, the[19,32]. use of (S,S)-pybox complexes favored the formation of the corresponding (R)-alcohols.

Molecules 2019, 24, x FOR PEER REVIEW 6 of 9

Conversely,Molecules 2020, 25the, 990 use of (S,S)-pybox complexes favored the formation of the corresponding 6(R of)- 9 alcohols.

FigureFigure 2. ProposedProposed transition transition states states for for the the asymmetric asymmetric transfer transfer hydrogenation of aryl ketones.

3. Materials and Methods 3. Materials and Methods 3.1. General Comments 3.1. General Comments The reactions were performed under an atmosphere of dry argon using vacuum-line and standard The reactions were performed under an atmosphere of dry argon using vacuum-line and Schlenk techniques. The reagents were obtained from commercial suppliers and used without further standard Schlenk techniques. The reagents were obtained from commercial suppliers and used purification. Solvents were dried by standard methods and distilled under argon before use [19,21]. without further purification. Solvents were2 dried by standardi methods and distilled2 under argon The precursor complexes trans-[RuCl2(η -C2H4){(S,S)- Pr-pybox}] and trans-[RuCl2(η -C2H4){(R,R)- before use [19,21]. The precursor complexes trans-[RuCl2(η2-C2H4){(S,S)-iPr-pybox}] and trans- Ph-pybox}] [33,34] and the complexes 1–2 [21] were prepared by reported methods. The 1H, 13C{1H}, and [RuCl2(η2-C2H4){(R,R)-Ph-pybox}] [33,34] and the complexes 1-2 [21] were prepared by reported 31P{1H} NMR spectra of complexes 1a–c and 2a– c were reported in the Supplementary Materials [21]. methods. The 1H, 13C{1H}, and 31P{1H} NMR spectra of complexes 1a–c and 2a–c were reported in the Supplementary3.2. X-ray Crystal Materials Structure [21]. Determination of Complexes 1a 2CHCl and 2c 2.5CH Cl · 3 · 2 2 n 3.2. X-RaySuitable Crystal crystals Structure for X-ray Determination diffraction of analysis Complexes were 1a·2CHCl obtained3 and by slow2c·2.5CH diffusion2Cl2 of -hexane into a solution of the complexes in chloroform (1a) or dichloromethane (2c). The most relevant crystal and refinementSuitable data crystals are collected for X-ray in diffraction Table S2 in analysis the Supporting were obtained Information. by slow diffusion of n-hexane into a solutionThe di offf theraction complexes data of in both chloroform complexes (1a) were or dichloromethane recorded on an ( Oxford2c). The Di mostffraction relevant Xcalibur crystal Nova and refinement(Agilent, Santa data Clara, are collected CA, USA) in Tabl single-crystale S2 in the diSupportingffractometer, Information. using Cu-K α radiation (λ = 1.5418 Å). ImagesThe were diffraction collected data at aof 62 both mm complexes fixed crystal-detector were recorded distance, on an usingOxford the Diffraction oscillation Xcalibur method, Nova with (Agilent, Santa Clara, CA, USA) single-crystal diffractometer, using Cu-Kα radiation (λ = 1.5418 Å). 1◦ oscillation and variable exposure time per image (6.5–35 s (for 1a) and 30–110 s (for 2c)). The data Imagescollection were strategy collected was at calculated a 62 mm withfixed thecrystal-dete programctor CrysAlis distance, Pro using CCD [the35]. oscillation Data reduction method, and with cell 1°refinement oscillation were and performed variable exposure with the time program per image CrysAlis (6.5–35 Pro REDs (for [35 1a].) and Empirical 30–110 absorption s (for 2c)). correction The data collectionwas applied strategy using was the SCALE3calculated ABSPACK with the program algorithm, CrysAlis as implemented Pro CCD in[35]. the Data program reduction CrysAlis and cell Pro refinementRED [35]. were performed with the program CrysAlis Pro RED [35]. Empirical absorption correction was appliedThe software using packagethe SCALE3 WINGX ABSPACK [36] was algorithm, used for space-groupas implemented determination, in the program structure CrysAlis solution, Pro REDand refinement.[35]. The structures were solved by Patterson interpretation and phase expansion using The software package WINGX [36] was used for space-group determination, structure solution, DIRDIF [37]. In the crystals of 1a and 2c, 2CHCl3 (for 1a) or 2.5CH2Cl2 solvent molecules (for 2c) per unit andformula refinement. of the complex The structures were present. were solved For complex by Patterson2c also, interpretation other highly disordered and phase solvent expansion molecules using DIRDIFwere found, [37]. whichIn the crystals were impossible of 1a and to2c refine, 2CHCl using3 (for conventional 1a) or 2.5CH2 discrete-atomCl2 solvent molecules models. (for To resolve2c) per unitthese formula issues, theof the contribution complex ofwere solvent present. electron For complex density was 2c also, removed other by highly SQUEEZE disordered/PLATON solvent [38]. moleculesIsotropic least-squares were found, which refinement were impossible on F2 using to SHELXL2013 refine using conventional [39] was performed. discrete-atom During models. the final To resolvestages ofthese the refinements, issues, the all thecontribution positional parametersof solvent and electron the anisotropic density temperature was removed factors by of 2 SQUEEZE/PLATONall the non-H atoms were[38]. refined.Isotropic The least-squares H atoms were refinement geometrically on F placed,using SHELXL2013 riding on their [39] parent was performed.atoms with isotropicDuring displacementthe final stages parameters of the setrefi tonements, 1.2 times all the the Ueq positional of the atoms parameters to which theyand were the anisotropicattached (1.5 temperature for methyl factors groups). of all For the both non-H complexes, atoms were the maximumrefined. The residual H atoms electron were geometrically density was placed,located riding near heavy on their atoms. parent atoms with isotropic displacement parameters set to 1.2 times the Ueq of theThe atoms function to which minimized they were was attached [w(Fo2 (1.5Fc2 for)/w (methylFo2)]1/2 groups)., where w For= 1both/[σ2( complexes,Fo2) + (aP)2 the+ bP maximum] (a and b − residualvalues are electron collected density in the was Table located S2 in thenear Supporting heavy atoms. Information) with σ(Fo2) from counting statistics

Molecules 2020, 25, 990 7 of 9 and P = (Max (Fo2, 0) + 2Fc2)/3. Atomic scattering factors were taken from the International Tables for X-Ray Crystallography [40]. The crystallographic plots were made with PLATON [38]. CCDC 1,545,753 (1a 2CHCl ) and CCDC 1,545,754 (2c 2.5CH Cl ) contain the supplementary · 3 · 2 2 crystallographic data for this paper. These data could be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

3.3. General Procedure for Hydrogen Transfer Reactions The ruthenium catalyst precursor 1, 2 (0.01 mmol) was placed in a three-bottomed Schlenk ﬂask containing 5 mmol of ketone in 45 mL of 2-propanol under an argon atmosphere. The solution was heated at 82 ◦C for 15 min, and then a solution of 0.24 mmol of the base in 5 mL of 2-propanol was added, and the reaction mixture stirred for the time given in Tables1–3. The course of the reaction was monitored by gas chromatography using a chromatography Agilent Model HP-6890 equipped with a Supelco β-DEX 120 chiral capillary column. The enantiomeric ratio and the absolute conﬁguration of the major enantiomer were determined by GC (retention times) and optical rotations, respectively, and compared with literature values. The resulting alcohols and the starting ketones were, in all cases, the only products detected.

4. Conclusions The present study showed that complexes featuring the combination Ru(II)/R-pybox [(S,S)-iPr- pybox, (R,R)-Ph-pybox]/P-donor ligand (methoxy-phosphonites and methoxy- and ethoxy-phosphinites) were active catalysts toward the ATH reaction of arylketones. The best results were obtained using the complex trans-[RuCl2{PPh2(OEt)}{(R,R)-Ph-pybox}] (2c), providing (S)-benzylalcohols in high yield (87%–98 %) and enantioselectivity (up to 96 % e.e.). These results were in the range of those previously i described using the complexes cis- and trans-[RuCl2(L) {(R,R)-Ph-pybox}] (L = PPh3,P Pr3) and were superior to those obtained using the complexes with phosphite ligands trans-[RuCl2(L){(R,R)-Ph-pybox}] (L= P(OMe)3, P(OPh)3)). On the other hand, they confirmed that the nature of the achiral P-donor ligand did influence the efficiency of the catalyst. The values of asymmetric induction obtained were 1 in accordance with the Tolman electronic parameter (cm− ) and the cone angles (deg) of these achiral ligands. Moreover, this report illustrated the utility of chiral ligands, lacking the N-H functionality, thus complementing previous works of ATH processes based on chiral N-H ligands.

Supplementary Materials: The following are available online. GC spectra for all the reactions of the Tables1–3. Selected Bond Distances (Å) and Angles (deg) for Complexes 1a 2CHCl3 and 2c 2.5CH2Cl2 (Table S1). Crystal Data and Structure Refinement for Complexes 1a 2CHCl and 2c 2.5CH· Cl (Table· S2). · 3 · 2 2 Author Contributions: M.C., E.d.J., and M.P.G. conceived and designed the experiments. M.C. and E.d.J. performed the studies on the catalytic asymmetric transfer hydrogenation of ketones and synthesized the complexes employed in this work. M.C. prepared the single crystals, and J.D. conducted the X-ray analysis of complexes 1a and 2c. All authors have given approval to the final version of the manuscript. E.L. and M.P.G. provided supervision, financial support via projects and wrote the paper. Funding: This research was funded by the MICINN of Spain (CTQ2011-26481, CTQ2015-69583-R, and RTI2018- 094605-B-I00). Acknowledgments: E. de J. thanks the FICYT (Principado de Asturias, Spain) for the award of corresponding Ph.D. (BP12-158). Conflicts of Interest: The authors have declared that there is no conflict of interest.

References and Notes

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Sample Availability: Samples of the compounds are not available from the authors.

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