Efficient Acceptorless Dehydrogenation of Secondary Alcohols to Ketones mediated by a PNN-Ru(II) Catalyst

Zheng Wang,a,b,c Bing Pan,b Qingbin Liu,b,* Erlin Yue,a Gregory A. Solan,*,a,d Yanping Ma,a and Wen-Hua Sunb,c* a Key Laboratory of Engineering Plastics and Beijing National Laboratory for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. b College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, China. c University of Chinese Academy of Sciences, Beijing 100049, China d Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, UK. E-mail: gas8@leicester.ac.uk † Corresponding Authors: whsun@iccas.ac.cn; liuqingb@sina.com; Tel: +86-10-62557955


Introduction
The conversion of alcohols to carbonyl compounds can be regarded as one of the most important fundamental reactions in organic chemistry as evidenced by its extensive application in the synthesis of fine chemicals and pharmaceutical intermediates.Indeed, a raft of methods have been implemented over the years to accomplish this transformation. 1Traditionally, stoichiometric amounts of common oxidants are used, but these reactants tend not only to be hazardous or toxic but can generate large quantities of noxious byproducts. 2 In recent years, the development of transition-metalcatalyzed oxidation of alcohols using environmentally friendly oxidants such as O2, 3 H2O2 4 or acetone 5 offers an improved approach.However, from the viewpoint of atom economy and reaction safety, the direct dehydrogenation of an alcohol to form a carbonyl compound (e.g., a ketone or an aldehyde) without the need for an oxidant altogether, is an even more desirable and sustainable route as the only by-product is hydrogen. 6The first reports of complexes that were capable of mediating this green transformation were reported by Robinson in the 1970s and Cole-Hamilton in the 1980's, in which well-defined ruthenium(II) complexes of the type [Ru(OCOCF3)2(CO)(PPh3)2] 7 and [RuH2(N2)(PPh3)3] 8 were employed.In the intervening years, the concept of acceptorless alcohol dehydrogenation (AAD) 9 has rapidly grown in interest with not only ruthenium 11 but iridium 10 catalysts now capable of the promoting the reaction.While both heterogeneous 12 and homogeneous 6,10,11 processes have been developed, the catalytic efficiency of the homogeneous variant remains insufficiently high to merit its industrial application and hence needs to be improved.For example, the ruthenium-and iridium-based homogeneous catalysts reported so far tend to require relatively high catalyst loadings in the 0.1 − 5 mol% range to achieve satisfactory conversions.Nevertheless, recent developments using pincer complexes that can operate using metal−ligand cooperation (MLC) show great potential for improving these catalytic performances.3e, 13,14,15 In our previous work we have shown the ruthenium-hydride [fac-PNN]RuH(PPh3)(CO) (PNN = 8-(2-diphenylphosphinoethyl)amidotrihydroquinoline) (A) (Chart 1) to be an effective catalyst in the coupling cyclizations of γ-amino alcohols with secondary alcohols to give pyridine or quinoline derivatives.Indeed, this system has proved highly efficient and amenable to catalyst loadings of as low as 0.025 mol% to achieve satisfactory results in this multistep dehydrogenative pathway. 16Furthermore, A and its derivative [fac-PNHN]RuH(η 1 -BH4)(CO) (B) (PNHN = 8-(2-diphenylphosphinoethyl)aminootrihydroquinoline) (Chart 1) can also be applied to the catalytic hydrogenation of esters.Notably, when combined with 5 mol% of NaBH4, A or B can deliver high efficiencies for the hydrogenation of a wide range of esters under mild reaction conditions. 17his journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins for the acceptorless dehydrogenation of alcohols.In particular, C is shown to exhibit unprecedented efficiency in the acceptorless dehydrogenation of secondary alcohols to afford the corresponding ketones, with very low catalytic loadings required to achieve high conversions.We view these complexes as showing great potential for applications in atom-economic synthesis and the development of organic hydride hydrogen storage systems.Furthermore, we propose a mechanism for the catalyzed acceptorless dehydrogenation reactions that is based on various intermediates that have been characterized by EI-MS and NMR spectroscopy.Reaction of RuCl2(PPh3)3 with 8-(2-diphenylphosphinoethyl)aminotrihydroquinoline (PNHN) 16 in toluene at 100 ºC for 3 hours gave on work-up, [fac-PNHN]RuCl2(PPh3) (C), in good yield (Scheme 1).Complex C displays peaks in its ESI mass spectrum corresponding to a protonated molecular ion and a fragmentation peak attributable to a loss of chloride from the molecular ion.Unexpectedly, on standing in deuterated chloroform for four hours, C undergoes partial isomerization resulting in a mixture consisting of C and C' in a 72:28 ratio.The 31 P{ 1 H} NMR spectrum of C exhibits two mutually coupled doublets at δ 55.68 and δ 45.61 with a coupling constant of ca.28 Hz corresponding to a cis-arrangement of the phosphine donors.In C' a cis-arrangement of the phosphine donors is again apparent with the two doublets (each ca. 2 J(PP) = 28 Hz) in this case appearing at δ 48.12 and δ 43.16 (see SI). Crystals of the major isomer C suitable for a single-crystal X-ray diffraction study could be grown by slow diffusion of n-hexane into its solution in dichloromethane.The structure consists of a distorted octahedral geometry at ruthenium with the PNHN ligand adopting a facconfiguration with the triphenylphosphine molecule trans to the amine donor and the two chloride ligands mutually cis (Fig. 1, see SI).The borohydride derivative of C, [fac-PNHN]RuH(η 1 -BH4)(PPh3) (D), could be readily obtained by reacting complex C with NaBH4 in a toluene/ethanol mixture at 65 o C; the structure of D was confirmed by multinuclear NMR spectroscopy, MS and elemental analysis (see SI).
Please do not adjust margins Please do not adjust margins Typically, the catalytic screen was performed using an equimolar ratio of cycloheptanol to the t-BuOK base (5 mmol), using 0.025 mol% of the corresponding ruthenium complex in p-xylene at reflux for 24 hours.To our delight, all the ruthenium species were active with the conversion to cycloheptanone being 50% for A, 52% for B, 76% for C and 74% for D (Table 1, entries 1, 3, 4 and 6).In the absence of t-BuOK, the conversion dropped to 35% using D, while for B it lowered to 26% (Table 1, entries 2 and 5).In order to rule out any catalyst precursor effects on performance, RuH(CO)(PPh3)3 and RuCl2(PPh3)3 in the presence of 5 mmol t-BuOK, were independently evaluated under the same conditions; the conversion to cycloheptanone in these cases was 12 and 16%, respectively (Table 1, entries 7, 8).Overall, the best results were obtained using the PNN-ruthenium(II) complexes C and D. However, due to D being synthesized from C, coupled with the fact that D showed some instablity in solution, we choose C as our catalyst for subsequent studies.Secondly, with a view to establishing the most compatible base, the acceptorless dehydrogenation of cycloheptanol to cycloheptanone with C as catalyst was screened with four different types of bases, NaOH, K2CO3, CsCO3 and t-BuOK (Fig. 2, see SI, Table S1), in toluene at reflux.It was found that the type of base introduced had a significant effect on the conversion of cycloheptanol to cycloheptanone with t-BuOK the standout performer.When equivalent molar ratios of NaOH or K2CO3 were employed (5 mmol), the conversion observed after 24 hours is markedly less (23 and 39%, respectively) than that seen with t-BuOK (74%).With 2.5 mmol of CsCO3 (relatively expensive and toxic), 69% of cycloheptanone was produced after 24 hours.On increasing the temperature to reflux in p-xylene, the conversion using C/t-BuOK increased to 76% in 24 hours and 94% in 36 hours (see SI, Table S1).Notably in the absence of base and under the same reaction conditions using C as catalyst, only 5% of cycloheptanone was produced after 24 hours.Overall, carrying out the AAD in p-xylene at reflux using t-BuOK as the base proved the optimal operating conditions to deliver high conversions to cycloheptanone.
To explore the versatility of C, a broad range of secondary alcohols were selected for study in the AAD using the optimal conditions established (viz., alcohol: t-BuOK = 1:1, 0.025 mol% C in p-xylene at reflux); the results are compiled in Table 2.  b The conversion was determined by GC using dodecane as an internal standard.
It was found that for the cyclic alcohols, the smaller ring sizes (n ≤ 6) led to very low conversions, e.g., only 23% and 34% of cyclohexanone and cyclopentanone were obtained after 24 hours, respectively (Table 2, entries 1-2).By contrast, the larger cyclic alcohols (n ≥ 7) gave excellent conversions to the corresponding ketones, with cycloheptanone and cyclooctanone being obtained in 94% in 36 hours and 100% in 24 hours, respectively (entries 3-4).

Mechanistic and Characterization aspects
A proposed catalytic cycle for these AAD reactions that makes use of bifunctional metal-ligand cooperativity, 13j,k,19 is shown in Scheme 2. Firstly, C undergoes the loss of H + and Cl -, under the action of the strong base t-BuOK, forming amide M-1 along with KCl and t-BuOH.
Crabtree has previously noted that the NH of a pincer ligand needs to be deprotonated to form the active catalyst and we similarly propose a related step occurring during the conversion of C to M-1. 6 Subsequently, the hydroxyl group in the secondary alcohol adds across the Ru=N bond in M-1, to form intermediate M-2.The CHR1R2O hydrogen atom belonging to the coordinated alkoxide in M-2 transfers to the Ru center to generate hydride M-3 and ketone.
In the last step elimination of hydrogen gas from M-3 occurs reforming M-1.In order shed some light on this mechanism, we monitored the reaction of an equimolar ratio of C, t-BuOK and benzyl alcohol in CDCl3 at 45 ºC for 24 hours, by ESI-MS and 1 H NMR spectroscopy.In the ESI-MS peaks corresponding to C along with four different intermediates have been identified: 3 and SI).18a At the same time, the 1 H NMR spectrum was recorded after 1, 6 and 24 hours (see Fig. 3).Close examination of the spectra reveals the signal corresponding to the benzyl alcohol CH2 group at 4.72 ppm decreases in intensity with the time: at t = 0 h, peak area = 3.76; at t = 1 h, peak area = 3.57; at t = 6 h, peak area = 3.49; at t = 24 h, peak area = 3.14.Furthermore, after one hour a new peak at 5.32 ppm forms with a peak area of 0.25 which can be assigned to the benzyl alkoxide intermediate M-2''.After 6 hours, this peak area increases in intensity to 0.35 while a new peak at 10.5 ppm becomes visible which can be attributed to the formation of benzaldehyde.After 24 hours, the peak area at 5.32 ppm for M-2'' integrates to 0.31 which is similar in intensity to that observed after 6 hours.This would therefore suggest that an equilibrium is established between M-2" and benzyl alcohol.In summary, all this in-situ determined data firmly support the steps shown in the catalytic cycle in Scheme 2. Fig. 3. 1 H NMR (500 MHz, CDCl3) spectra of an equimolar ratio of C and benzyl alcohol recorded: 1. after sample dissolution, 2. with t-BuOK (1 eq.) at 45 ºC after 1 hour, 3. with t-BuOK (1 eq.) at 45 ºC after 6 hours, 4. with t-BuOK (1 eq.) at 45 ºC after 24 hours.

Conclusions
Four types of PNN-Ru(II) complexes, A -D, have been evaluated as catalysts in the acceptorless dehydrogenation of secondary alcohols to give ketones.Complex [fac-PNHN]RuCl2(PPh3) (C), in the presence of t-BuOK, proved the most suitable and was able to operate efficiently with a catalyst loading of just 0.025 mol%.Indeed, using C/t-BuOK as catalyst, seventeen different kinds of secondary alcohols could be dehydrogenated to give their corresponding ketones with yields in the range 21-100%; structural variations in the substrate greatly affect the catalyst performance.In addition, a mechanism for the PNN-Ru mediated dehydrogenation has been proposed that is supported by various intermediates that have been characterized by EI-MS and NMR spectroscopy.

General information.
All experiments with metal complexes and phosphine ligands were carried out under an atmosphere of nitrogen.All solvents were reagent grade or better and were used after being distilled under nitrogen.Most of the chemicals used in the catalytic reactions were re-purified according to standard procedures (e.g., vacuum distillation).All 1 H NMR (500 MHz), 13 C NMR (125 MHz) and 31 P NMR spectra were recorded on a Bruker AV-III (500 MHz) spectrometer.GC analyses were carried out on an Agilent 6820 instrument using an OV-1701 column.GC conditions: Injector Temp: 250 ºC; Detector Temp: 250 ºC; column temperature 150 ºC.ESI-MS analysis was performed on a 3200 QTRAP 1200 infinity series instrument using a column C18, acetonitrile: water = 70:30, flow rate = 1 mL / min, electronic energy = 50 eV, Q1MS scan range = 100~1000.

Catalytic study details.
Under an atmosphere of argon, a Schlenk vessel equipped with a stir bar, was loaded with the ruthenium complex (A -D) (1.25 × 10 -3 mmol) to be investigated, the corresponding alcohol (5 mmol) and the desired amount of base (NaOH, K2CO3, CsCO3, t-BuOK) (1 -5 mmol) in p-xylene (5 mL) (or toluene).The reaction was then stirred and heated to the desired oil-bath temperature (130 o C or 160 o C) with the reaction vessel open to the bubbler.After the specified reaction time (10 -48 h), the resultant solution was cooled to room temperature and the reaction mixture filtered through a plug of silica gel and then analyzed by GC using dodecane as an internal standard, 11c,e employing an OV-1701 column column on Agilent 6820 instrument.

X-ray Structure Determination
A single-crystal X-ray diffraction study of C was conducted on a Rigaku Sealed Tube CCD (Saturn 724+) diffractometer with graphitemonochromated Mo-Kα radiation (λ = 0.71073 Å) at 173(2) K. Cell parameters were obtained by global refinement of the positions of all collected reflections (see Table S3 in SI).Intensities were corrected for Lorentz and polarization effects and empirical absorption.The structures were solved by direct methods and refined by full-matrix least squares on F 2 .All non-hydrogen atoms were refined anisotropically and all hydrogen atoms were placed in calculated positions.Using the SHELXL-97 package, structural solution and refinement were performed. 20lease do not adjust margins Please do not adjust margins The ruthenium(II) complex, [fac-PNHN]RuCl2(PPh3) (C), in combination with t-BuOK proved an effective and versatile catalyst allowing aromatic-, aliphatic-and cycloalkyl-containing alcohols to be efficiently converted to their corresponding ketones with particularly high values of TON achievable.

Scheme 1 .
Scheme 1. Synthesis of PNN-ruthenium complexes C and D

Scheme 2 .
Scheme 2. Proposed mechanism for the acceptorless dehydrogenation of secondary alcohols catalyzed by C Graphical forTable of Contents Efficient Acceptorless Dehydrogenation of Secondary Alcohols to Ketones mediated by a PNN-Ru(II) Catalyst Zheng Wang, a,b,c Bing Pan, b Qingbin Liu,* ,b Erlin Yue, a Gregory A. Solan,* ,a,d Yanping Ma, a and Wen-Hua Sun* ,a,c a Key Laboratory of Engineering Plastics and Beijing National Laboratory for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.Email: whsun@iccas.ac.cn b College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, China.Email: liuqingb@sina.comc University of Chinese Academy of Sciences, Beijing 100049, China d Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, UK.E-mail: gas8@leicester.ac.uk
a OH O p -xylene at reflux A-D (0.025 mol%), 24 h

Table 2 .
Substrate scope in the acceptorless alcohol dehydrogenation by C. a This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins