Preparation of a Series of Supported Nonsymmetrical PNP‐Pincer Ligands and the Application in Ester Hydrogenation

Abstract In contrast to their symmetrical analogues, nonsymmetrical PNP‐type ligand motifs have been less investigated despite the modular pincer structure. However, the introduction of mixed phosphorus donor moieties provides access to a larger variety of PNP ligands. Herein, a facile solid‐phase synthesis approach towards a diverse PNP‐pincer ligand library of 14 members is reported. Contrary to often challenging workup procedures in solution‐phase, only simple workup steps are required. The corresponding supported ruthenium‐PNP catalysts are screened in ester hydrogenation. Usually, industrially applied heterogeneous catalysts require harsh conditions in this reaction (250–350 °C at 100–200 bar) often leading to reduced selectivities. Heterogenized reusable Ru‐PNP catalysts are capable of reducing esters and lactones selectively under mild conditions.


Introduction
Te rdentate pincer-type ligands have attracted tremendous attention for applications in ab road rangeo fc atalytic reactions since the pioneering work of Shaw and van Koten in the 1970s. [1] Given that the modular nature of pincer ligands allows for efficient fine-tuning of the electronic and steric properties, [2] symmetrical PNP pincer ligands, which feature a central N-donora nd two identical phosphorus moieties, have been studied extensively in the last two decades. Although nonsymmetrical PNP ligandsg ive accesst oasignificantly increasedn umber of potentiall igand structuresw ith unique stereo-electronic properties, reports remain fairly limited. [3] This can be attributed to the often more challengings ynthesis and troublesome purification procedures required for nonsymmetrical pincers opposed to simplified twofold-substitution protocols for ligandsw ith C 2v symmetry.I nc ase of representative chiral PNP pincers I-V,l igand desymmetrization was achieved through additional substituents in the aliphaticb ackbone as well as through mixed phosphorus-donorm oieties ( Figure 1). [4] To the best of our knowledge,l igands VI-IX reported by Kinoshitaetal. remain the sole examples of nonsymmetrical pyri-dine-based PNPl igands whichd iffer in the nature of the phosphines. [5] Structures VI-IX,c omposed of aP ( tBu) 2 group and a secondP -donor bearing alkyl anda ryl substituents,w ere prepared by successive deprotonation and mono-substitution of 2,6-lutidine using variouschlorophosphines.
Regardless of the advances in rational design of high-performance ligands, synthetic approaches through trial-and-error remain the most common methodologies for catalystoptimization. There is, however,s till al ack of efficient combinatorial methodse nabling the synthesis ands creening of large ligand libraries, especially for phosphorus-based multidentate ligands. [6] Although modulara pproaches towards symmetrical pyridine-based PNP pincer ligandsh ave been explored by Kirchner and co-workers, [7] facile synthetic protocols towards large combinatorial ligand libraries of nonsymmetricalP NP-type ligands remain elusive.
Solid-phase synthesis (SPS),o riginating from well-established polypeptide synthesis, offers an attractive alternative toolt owardsl igand libraries. [8] The main advantage of SPS over traditionals olution-phase approaches is the ease of purification, often requiring only as imple filtration step and allowing for   the use of al arge excess of reactants. [9] Systematic variation of substituents bound to the phosphine moieties enables the preparation of alarge combinatorial PNP ligand library through SPS. This facilitates the finetuning of ligand properties for catalyst optimization.
Moreover,c atalyst immobilizationo ni nsoluble supports combines the advantages of both worlds, that is, high activity, selectivity and tunability of homogeneous catalysts and the recoverability and recyclability of heterogeneous catalysts. [10] In particular, the recycling of these expensive and often toxic transition metals and ligands can be truly simplified.
Notwithstanding the widea pplicability of PNP pincer-based catalysts, approaches towards immobilization strategies remain fairly limited. Goni et al. reported on aR u-PONOP-type catalyst supported on as ilica poly(allylamine) composite through a two-stepM annich reaction yieldingt wo regioisomers covalently bound to the solid in both ortho-a nd meta-position of the central pyridine ring. [11] Similarly,aphosphine oxide PNP ligand was anchored onto mesoporous silica through aC u-catalyzed click reaction by Lo et al. [12] Upon reduction to the free supported phosphine, the corresponding Ir-PNP catalyst was applied in CO 2 hydrogenation. Wang et al. employed a" knitting" strategyb ya nchoring as olution-phase Ru-PNPc atalyst covalently to the structure of ap orouso rganic polymer fora pplication in dehydrogenation of formic acid. [13] As upported ionicliquid phase (SILP) strategy was chosen by the group of Kirchner for the immobilization of aF e-PNP catalysti ni onic liquids deposited on both silica [14] and polymer-based spherical activated carbon. [15] However,i na ll cases as inglep remade PNP ligand or complex is immobilized missing the opportunity for efficient ligand modification. This calls for am ore versatile and combinatorial methodology that allows for the facile synthesis of ad iverse PNP-ligand library.
Pincer ligands have contributed tremendously to environmentally benign, homogeneously catalyzed reductionse mploying molecular hydrogen asa na tom-economical reducing agent. [1d-f, 16] Particularly,c hallenging hydrogenations of carboxylic acids and their ester derivatives represent crucial transformations in organic synthesis for both laboratory scale as well as bulk and fine-chemical industry. [17] Common synthetic methods often rely on the use of stoichiometrica mounts of metal hydridess uch as LiAlH 4 and NaBH 4 , [18] whichi sa ccompanied by the hazard in handling as well as the generation of large amounts of inorganic waste. [19] In industrial applications, heterogeneousc atalysts require harsh reaction conditions (250-350 8Ca t1 00-200bar) often leading to side-product formation and limited functional-group tolerance. [20] Consequently, there has been as trong drive from both academia and industry to develop molecularly well-definedh omogeneous catalysts for selectivec atalytic hydrogenations under milder conditions (see representative examples in Figure 2).
Since Milstein's seminalw ork on the non-innocent pyridinebased PNN ligand in Ru-catalyzed ester hydrogenation( X), [21] a plethora of pincer-typec atalysts has been developed. In contrast to their nonsymmetrical PNNa nalogue, Ru-PNP catalysts (XI and XII)e mploying symmetrical PNP ligandse xhibited significantly less activity in this transformation. [21,22] This was asso-ciated with the lack of hemilability of one of the side arms due to two equally strong electron-donating phosphorusm oieties presenti nb oth ligands. As an alternative to the pyridine backbone, aliphatic PN(H)P ligandse mployed in catalysts such as Ru-MACHO( XIII)b ut also base-metal catalysts [1e-h] have demonstrated excellent performances in the reduction of esters. [23] Inspiredb yt he highly active Ru-SNS (XIV)a nd Ru-PNN (XV) ester hydrogenation catalysts developed by Gusev andc oworkers, [24] we recently reported on the first reusable resin-boundR u-PNN system (XVI)a pplicable in this reactionu nder very mild conditions (25 8C, 50 bar). [25] In this work, we demonstrate the first synthesis of asupported combinatorial library of nonsymmetrical pyridine-based PNP ligandsb yu sing af acile solid-phases ynthesis approach. Moreover,t he application of the corresponding heterogeneous Ru-PNP catalysts in the hydrogenation of variousl actones, mono-, and diesters is reported.
The systematic variation of R 2 and R 3 enables an efficient tuningo ft he steric and electronic properties of the phospho-  rus donor atom. Due to the presence of mono-a nd di-substituted product in the reaction mixture, only low to moderate yields of the desired mono-substituted phosphine-boranes were obtained. Alternatively,am ixture of mono-a nd disubstituted products was used in the next step because only the desired mono-substituted PN fragment reacts with the supported reactants whereas the unreacted disubstituted byproduct present in the supernatant solution can easily be filtered off.
After removal of the borane groups by treatment with a large excess of diethylamine at 50 8C, the resin-bound PNPpincer ligands L 1 -L 14 were obtained.I nt he presence of more bulky -PtBu 2 and -PAd 2 (Ad = adamantyl) groups,s everal replacements with fresh diethylamine as well as longer reaction times were required. Quantitative deprotection of both phosphine moieties was readily monitored by 31 PNMR, indicated by as ignificant highfield shift of all corresponding phosphorus signals. The representative synthesis of L 6 monitored by gelphase 31 PNMR is depicted in Figure 3.
All resin-bound PNP ligands were synthesized in high yields and purity.O nly simple filtration and washing steps were required for purification demonstrating the power of the solidphase synthesis approach. Finally,t he actual phosphorus loading was determined by elemental analysis.
Through systematic variationo ft he phosphine substituents R 1 ,R 2 ,a nd R 3 as well as by employing three different types of polymerics upports, ac ombinatorial library of 14 different sup-ported PNP pincerl igands was efficiently accessed through a solid-phase synthetic approach (Figure 4). In contrast to structurally similar homogeneous analogues, ligands L 1 -L 13 represent nonsymmetrical ligandsw hich have been rarely investigated in solution-phase. However,t he combinationo ft wo phosphorus moieties exhibiting different electronic and steric properties offers great potentialf or efficient catalystt uning. Amonga ll library members, only the nonsymmetrical solutionphase analogues of L 6 and L 7 as well as the nearly symmetrical ligand L 14 have been reported previously. [5,28] The 31 PNMR spectra for both reportede xamples are well in line with those obtained for their heterogenized equivalents.
In analogy to the synthesis in monophasics ystems, the resin-bound ligands were reacted with the rutheniump recursor [RuHCl(PPh 3 ) 3 CO] at 60 8Ci nT HF to afford the corresponding resin-bound Ru-PNPc omplexes C 1 -C 14 (Scheme 3). The progress of the reaction was monitored by 31 PNMR indicating full displacement of PPh 3 together with the quantitative disappearance of the free PNP ligand signals.
The gel-phase 31 PNMR spectra of complexes C 4 , C 6 , C 7 ,a nd C 9 -C 12 revealt wo new broad resonances occurring in a1 :1 ratio, whichc orrespond to both phosphine moieties coordinated to the ruthenium center. Due to the lack of solvent-dependent swelling properties of C 7 and C 10 immobilized on the Scheme2.Solid-phasesynthetic approach towards supported pyridine-based PNP-type pincerl igands L 1 -L 14 . higher cross-linked MF 4% resin, the signals appear significantly broadened compared with complexes immobilized on supports with 1% cross-linking. The representative synthesis of C 6 monitored by 31 PNMR is depicted in Figure 5.
The signalo ft he -PtBu 2 group is shiftedf rom d = 35.5 in L 6 to d = 91.2 ppm, whereas the resonance of the resin-bound -PPh moiety arises at d = 56.5 in C 6 in contrast to d = À13.9 ppm in the free ligand. The phosphine resonances in C 1 -C 3 and C 5 overlap leadingt oasingle broad peak whereas the gel-phase 31 PNMR spectraf or C 8 and C 13 reveal three broad signals. The latter can be attributed to the presenceo fa racemic -P(PhtBu) group in both complexes leadingt oad ifference of up to D11-15 ppm between the corresponding signals of the stereoisomers.D ue to significant peak broadening in the gel-phase NMR of C 14 ,t he immobilized complex was analyzed using solid-state NMR techniques. The 31 PMAS NMR spectrum shows two signals appearing in ar atio of 1:1a td = 78.9 and d = 65.1 ppm corresponding to the two chemically different phosphorus donora toms (Figure 6a). The chemical shifts of C 14 are in line with those obtained for the homogeneous Ru-PNPc ounterpart XVII reported by Arenas et al. (Figure 7). [28] Unfortunately,due to significant peak broadening commonly observed for polymer-bound complexes, coupling constants could not be determined in solid-state and gel-phase NMR. [13, 27a, 29] Amongt he broad signals belonging to the aromatic and aliphatic protonso fthe polymericbackbone, the hydride ligand of C 14 was observeda tadistinct shift of À13.85 ppm in the 1 HMAS NMR (Figure6b).
In the 13 CCP/MAS spectrumt he CO peak appears at d = 211.0 ppm. Characteristic pyridine signals at d = 162.1,1 45.5, and 120.1 ppm are overlapped by the aromatic signals belonging to the ligand phenyl group as well as to the support (Figure 6c). Resonances of tBu are observed at d = 35.0, 31.9, and 27.5 ppm. The signals corresponding to the methylene side-arms can be expected at 40.5 ppm but are overlapping with the peaks of the support. To gain additional evidence of the molecular structure of supported complex C 6 ,t he homogeneous Ru-P Ph NP tBu analogue 5 was prepared. Twod ifferent phosphorus donorm oieties bearing both Ph and tBu substituents are present in the nonsymmetrical PNP pincerl igand. These were introduced by reacting 1a with 1.0 equivalent of borane protected lithium di-Scheme3.Solid-phasesynthesis of resin-bound Ru-PNP complexes C 1 -C 14 .  Single crystalss uitable for X-ray crystallography were obtained by slow diffusion of n-pentanei nto as olution of 5 in CH 2 Cl 2 .A ss hown in Figure 8, the complex exhibits ad istorted octahedral geometry around the Ru II centerw ith trans-coordination of the CO ligand to the nitrogen atom of pyridine and the hydride trans to the chloride. Hence, am eridional coordination geometry of the PNP ligand aroundt he metal centeri s obtained as reported for symmetrical pyridine-based [RuHCl(PNP)CO] complexes. [30] The hydridel igand exhibitsad oublet of doublets in the 1 HNMR spectrum at d = À14.51 ppm (J HP = 17.1 and 20.5 Hz) as found in similar Ru-complexes. [28,31] The  . Selectedsolid-state (left) and solution-phaseN MR signals (right) of supported Ru-PNP complex C 14 and homogeneous analogue XVII. [28] Scheme4.Synthesis of homogeneous Ru-PNP complex 5.  (Figure 9, red spectrum).T hese resultsc ompare well to the 31 PNMR resonances at d = 91.2 and 56.5 ppm obtained for the correlating supported Ru-complex C 6 differing only in the methylene linker to the MF support (Figure 9, black spectrum). The CO stretching band in the FT-IR spectrum of 5 was observed at 1887cm À1 . Subsequently,t he supported combinatorial Ru-PNPl ibrary (C 1 -C 14 )w as screened in the hydrogenation of methyl benzoate (S 1 ). The catalytic reactions were performed under optimized conditions over 16 hours in THF at 80 8Ca nd 50 bar H 2 pressure. Furtherr eaction conditions are listed in Ta ble S1 (see the SupportingInformation).F or supported catalyst C 1 ,bearing phenylg roups on both phosphine moietieso ft he PNP ligand, 84 %c onversion and 92 %s electivity towards the desired benzyla lcohol (BzOH) were obtained (Table 1, entry 1). By changingt om ore electron-donating4 -MeOPh groups bound to the remote phosphine in C 2 ,a ni ncreasei nc atalyst activity (97 %) and selectivity (99 %) was observed compared with C 1 (Table 1, entry 2). Electron-withdrawing4 -ClPh groups in C 3 led to areduced activity of 69 %conversion and more transesterification to benzyl benzoate (BzBz, Table 1, entry 3). When changing to unsymmetrical ligands carrying aromatic substituents on the resin-bound phosphorus-donor and alkyl substituents on the remote phosphine, moderate activities were obtained for C 4 and C 5 (Table 1, entries 4a nd 5). With increasing steric demand in case of strong electron-donating tBu groups (C 6 )o r even more bulky adamantyl groups (C 9 ), excellent conversions were reached with full selectivity towards BzOH (Table 1, entries 6a nd 10). Opposed to the high activity and selectivity at room temperature for the reported resin-bound Ru-PNN system (XVI), [25] ar educed temperature of 60 8Cr esulted in lower conversion of 82 %i nc ase of C 6 (Table 1, entry 7). When applyingt he equivalent catalysts C 7 and C 10 immobilized on the higherc ross-linked resin MF 4%,r educed performances (64-65 %c onversion,8 3-84 %s electivity) compared with C 6 and C 9 immobilized on MF 1% were found (Table 1, entries 8 and 11 vs. 6a nd 10). This can be attributedt ot he lacko fs olvent dependentg el-like behavior of the higherc ross-linked polymer and the consequently reduced accessibility of the catalyticallyactive sites within the support.
Supported catalyst C 8 bearing both aP ha nd tBu substituent on the remote phosphine led to 89 %c onversion and 96 %s electivity (Table 1, entry 9). Hence, catalytic activityf or catalysts with R 1 = Ph rises with gradual increaseo fs teric bulk and electron-donating properties in the series C 1 < C 8 < C 6 .R eplacing R 1 = Ph by aC yg roup on the resin-boundp hosphorus donor led to slightly reduced performances for C 11 and C 12 compared with the correspondingc omplexes C 1 and C 6 (Table 1, entries 12 and1 3). Catalysts C 13 and C 14 supported on PS-resin with R 1 = tBu gave even less activity than their phenyl analogues C 6 and C 8 (Table 1, entries 14 and 15). Surprisingly, when the nonsymmetrical solution-phase complex 5 was applied under the same conditions,o nly 78 %c onversion was reached compared with 98 %o fi ts heterogenized counterpart C 6 (Table 1, entries 6a nd 16). This indicates that the support does not exert ad etrimentale ffect on the performancec ontrary to reports for many known immobilized catalysts.
Subsequently,t he substrate scope was determined employing the best-performing supported catalysts C 6 and C 9 in the  hydrogenation of monoesters S 1 -S 8 ,d iesters S 9 -S 10 ,a nd lactones S 11 -S 12 ( Figure 10). Although the aromatic ester ethyl benzoate (S 2 )w as hydrogenated with slightly reduced conver-sion and selectivity compared with S 1 ,b enzyl benzoate( S 3 ) provedtob em ore challenging (69 %c onversion).
When employing catalyst C 9 ,e ven less activity (44 %) was observed towards the formation of BzOH. Linear alkyl esters gave up to 84 %c onversion and 86 %s electivity to the primary alcohol in case of methyl hexanoate (S 4 )w hereas ethyl hexanoate (S 5 )a nd hexyl hexanoate (S 6 )a lso proved to be more challenging substrates. Again, better performances were achieved when using C 6 instead of C 9 .B ranched alkyl esters, such as methyli sovalerate (S 7 )a nd methyl cyclohexanoate (S 8 ), were converted more readily than their linear analoguesw ith 84 % conversion and 86 %s electivity for S 8 .A sr eported for the sup-portedR u-PNN catalyst XVI,n oc onversion was observed for diethyl succinate (S 9 ). [25] This could be attributed to ac helating coordination of the short-chain diester S 9 to the catalyst. When extending the carbon chain length by using dodecanedioate (S 10 ), 70 %o ft he diesterw as converted after 24 hy ielding the monohydrogenatedp roduct as the main product whereas only 11 %o ft he diol was formed. At 2.0 mol %c atalyst loading and 100 8C, excellent conversion of S 10 was obtained with 74 % selectivity towards the desired 1,12-dodecanediol. Finally, g-butyrolactone (S 11 )a nd biomass-derived g-valerolactone (S 12 ) were selectivelyc onverted into the corresponding diols underlining the versatility of the heterogenized Ru-PNP system.
Finally,t he recovery and recyclability of the supported Ru-PNP catalyst C 6 was investigated in the hydrogenation of S 1 ( Table 2). It was decidedt os hortent he reactiont ime from 16 to 2h to assess anye ffect on the catalyst performance as a consequence of catalyst deactivation.A fter each cycle, the supernatant solution was filtered off followed by addition of  The results show that the heterogenized catalystw as successfully recovered and reused up to at least 4t imes. In run 2 and 3, as mall decrease in activity of 4% together with as light drop in selectivity was observed compared with run 1. After run 5, the catalyst reached 33 %conversion and 68 %selectivity indicating some catalyst decomposition. This could be attributed to deterioration of the polymerics upport due to mechanical stirring leading to finely ground particles the supernatant solution.T he loss of activity cannotb ee xplained by Ru leaching, because the Ru content of the supernatant wasb elow the detection limit of 5ppm after tenfoldd ilution.T his indicates that no more than 10 %o ft he Ru content could be lost by leaching, less than the loss of activity duringt he recycle experiments. However, thesep reliminaryr esults demonstrate the potentialf or recovery andr ecycling of supported Ru-PNPc atalysts only requiring simple filtrations. Given that continuous flow processes in fixed-bed reactorso ffer the opportunity to recycle under constantc onditions without disruption of the catalytic system, these immobilized catalysts represent highly suitable candidates for application under flow conditions. [29b]

Conclusions
We developedt he first facile accesst oacombinatoriall ibrary of nonsymmetrical resin-bound PNP pincer-type ligands by employing as olid-phase synthesis approach. Systematic variation of phosphine substituents combinedw ith the use of three differentt ypes of polymerics upports led to al ibrary with 14 members (L 1 -L 14 ). The supported ligands were obtained in high purity only requiring minimal purifications teps opposed to typicallya rduous syntheticp rotocols for solution-phase analogues. The immobilized nonsymmetrical PNP ligandso ffer higher potential for efficient fine-tuning of stereo-electronic ligand properties compared with C 2v symmetrical ligands. The corresponding resin-bound Ru-PNP complexes C 1 -C 14 were successfully screened in the hydrogenation of methyl benzoate (S 1 )u nder mild conditions. Minor changes within the structure of the phosphine substituents had as ubstantial impact on catalyst performances underlining the necessity of catalyst screening. Ab road range of monoesters and long-chain diester S 10 were hydrogenated to the desired alcohols under mild conditions. Lactones, such as bioderived g-valerolactone (S 12 ), could be readily converted with high selectivities towards the corre-spondingd iols. Preliminary recycling experiments indicated facile recovery and reusability of the supported catalyst.

Experimental Section
Generalp rocedure for the synthesis of 1a-g To as olution of secondary phosphine-borane adduct (1.0 equiv) in dry THF at À78 8C, nBuLi (2.5 m in hexanes, 1.0 equiv) or sec-BuLi (1.4 m in cyclohexane, 1.0 equiv) in case of (adamantyl) 2 PH·BH 3 was added dropwise. The solution was stirred for 30 min at À78 8Ca nd subsequently warmed to room temperature and was left for an additional amount of time until full conversion was achieved according to 31 PNMR. 2,6-Bis(chloromethyl)pyridine (1.0 equiv) was dissolved in dry THF and cooled to À78 8C. Next, the freshly prepared lithium boranyl phosphanide solution (0.28 m,1 .0 equiv) in THF was added slowly.T he mixture was warmed up to room temperature overnight leading to ap ale-yellow solution. The solvent was removed under vacuum and the yellow residue was dissolved in CH 2 Cl 2 .T he organic phase was washed with water and brine and subsequently dried over MgSO 4 .A fter filtration, the solvent was removed under reduced pressure. The residue was purified through flash chromatography (9:1 hexanes/ethyl acetate) or as stated otherwise yielding awhite solid.
Step 3: Ar esin-bound PNP borane adduct 3a-n synthesized in the last step was swollen in 10 mL of diethyl amine and heated to 50 8Co vernight with occasional stirring to avoid mechanical abrasion of the resin. The reaction was monitored using gel-phase 31 PNMR and was allowed to react until full conversion was observed. Next, the mixture was cooled to room temperature and the supernatant was removed. The resin was washed with three portions of THF (10 mL) followed by three portions of Et 2 O( 10 mL) and dried in vacuo yielding ap ale yellow resin-bound PNP pincer ligand (L 1 -L 14 ). General procedure for the synthesis of resin-bound complexes C 1 -C 14 Ap reviously synthesized resin-bound PNP pincer ligand (L 1 -L 14 , % 80-170 mg, 1.0 equiv) and [Ru(HCl(PPh 3 ) 3 CO] (1.1 equiv) were weighed into aS chlenk tube. The mixture was suspended in THF (10 mL) and heated to 60 8Cu nder gentle stirring. The reaction mixture was left at 60 8Cw ith occasional stirring to avoid mechanical abrasion of the resin and the progress of the reaction was monitored by gel-phase 31 PNMR. Once full complexation of the resin-bound PNP ligand was observed, the mixture was cooled to room temperature and the supernatant was removed. The resinbound complex was washed with three portions of THF (10 mL), three portions of CH 2 Cl 2 (10 mL) followed by three portions of Et 2 O (10 mL). After drying in vacuo, ay ellow to brown resin-bound Ru-PNP complex (C 1 -C 14 )was obtained.
General procedure for Ru-catalyzed ester hydrogenation The hydrogenation experiments were performed in as tainless steel autoclave charged with an insert suitable for up to 12 reaction vessels (2 mL) including Te flon mini stir bars. Inside ag love box, ar eaction vessel was charged with ar esin-bound Ru-PNP complex C 1 -C 14 ( % 7mg, 5.0 mmol, 1.0 mol %). To the reaction vessel 0.5 mL of as tock solution of KOtBu (10 mol %) in THF was added and the mixture was stirred for 5minutes. Next, 0.5 mL of the substrates S 1 -S 12 (0.5 mmol) and the internal standard dodecane (50 mol %) dissolved in THF were added. Subsequently,t he autoclave was purged three times with 10 bar of argon gas and the insert loaded with reaction vessels was transferred into the autoclave. Next, the autoclave was purged three times with 10 bar of H 2 and then pressurized (30-50 bar) and heated to the desired temperature (40-100 8C). The reaction mixtures were gently stirred at 450 rpm for 16-24 hours. The autoclave was cooled to room temperature, depressurized and the conversion was determined by GC-FID.