[Ru(arene)(diamine)] catalysts in ionic liquids: recyclable catalytic systems for transfer hydrogenation

[Ru(arene)(diamine)] catalysts have been immobilized in a variety of ionic liquids for asymmetric transfer hydrogenation of acetophenone. Catalyst recycling is possible with several ionic liquids, and enantiomeric excess is well maintained


Introduction
Asymmetric transfer hydrogenation of prochiral ketones using either 2-propanol or formic acid as the hydrogen source has become an attractive method for the synthesis of chiral alcohols and amines. 1 [Ru(arene)(diamine)] complexes, such as the precatalyst 1 developed by Noyori et al., have shown a good reliability for high enantiomeric excesses on a variety of substrates. 2,3mmobilization of these catalysts for the purpose of catalyst recovery or straightforward product separation has attracted much attention. 4Concerning 1, many research groups have immobilized this complex with sometimes very favorable results for catalyst recycling. 5,6Thus 1 has been heterogenized on polystyrenes, 5a-b on dendritic supports, 5c-e or on silicas.5f,g It has been modified by addition of sulfonate functions for biphasic catalysis, 5h,i immobilized in a polydimethoxysilane membrane, 5j or in room temperature ionic liquids (RTILs). 6The most promising result for high turn-over number (TON) has been obtained by immobilization on a PEG support, albeit with an ee lower than with the other methods.RTILs are interesting alternatives to conventional organic solvents as has been shown by numerous reports. 7We are interested in the use of RTILs as solvents in applications as various as electrosynthesis 8a enzymatic catalysis, 8b metal oxide catalysis, 8c or organometallic catalysis.8d When the right RTIL is chosen for a given reaction, not only it can lead to enhanced yields or reaction rates, but also improves the results of the work-up, from product separation to catalyst recycling.Herein we wish to report the immobilization of catalyst 2 and of the catalyst derived from precatalyst 1, in a variety of RTILs (Figure 1) for asymmetric transfer hydrogenation of acetophenone, and the successful recycling of these systems.Figure 1.RTILs used in this study (bmim = 1-butyl-3-methylimidazolium, emim = 1-ethyl-3methylimidazolium, bpy = N-butylpyridinium, tmba = trimethylbutylammonium). 9-14

Results and Discussion
Transfer hydrogenation with catalyst 2 Use of 2 and related complexes for the asymmetric transfer hydrogenation of arylketones has been studied by Chung et al. 15 We started from their experimental conditions, and substituted RTILs as solvent for dichloromethane (DCM) in the reduction of acetophenone (Scheme 1, condition A). 16  (0.02 eq), RTIL (1L/eq), T=30°C.Conditions B: precatalyst 1 (0.005 eq), RTIL (0.75L/eq).

Transfer hydrogenation with precatalyst 1
With this successful recycling of catalyst 2 in hand, we have proceeded with a detailed study of the recycling of 1 when immobilized in a variety of RTILs.We started from Noyori's original conditions, and added RTILs as solvent in the reduction of acetophenone (Scheme 1, conditions B). 2c Table 2 shows the results obtained for this reduction in a variety of RTILs.] in particular, the catalytic system can be recycled three times and gives a total TON higher than 700, with an ee higher than 96% for the last run (entries 9-12).Instead of bulb-to-bulb distillation of the 1-phenylethanol produced, the catalytic system can also be recycled after liquid/liquid extraction.We have chosen [tmba][NTf 2 ] as immobilization solvent, on account of the preceding results obtained with this RTIL.Volatile organic solvents immiscible with [tmba][NTf 2 ] are few; we have retained three (the partition coefficients of 1-phenylethanol between these solvents and [tmba][NTf 2 ] are given in parentheses) † : water (0.15), heptane (0.35), t-butylmethylether (1.15).Based on these coefficients t-butylmethylether has been chosen for the extractions.The results (Table 2, entries 24-26) show a deactivation of the catalyst which parallels the deactivation observed with recycling by bulb-to-bulb distillation (Table 2, entries 14-16), but once again the ee is well preserved after the recycles.The low leaching of ruthenium during the extractions prompted us not to graft the catalyst on an ionic support.This grafting has been achieved by others but did not lead to a clear improvement. 6owever it would be interesting if one could immobilize an analogue of triethylamine, because large quantities of triethylamine are generally used in transfer hydrogenations when formic acid is the hydrogen donor, and they are lost during the recycling.For a catalysis taking place in [tmba][NTf 2 ], 14 and 15 seem to be promising candidates.The calculated pKa of these bases (respectiveley 10.5 and 10.6, at zero ionic strength) are similar to that of triethylamine (10.6). 17Accordingly, triethylamine has been substituted by bases 14 and 15 for transfer hydrogenation of acetophenone, but neither of them allowed the catalysis to occur.14 and 15 may lack basicity in the very ionic reaction medium.Studies employing 14 as a base in the Heck coupling did however demonstrate a similar reactivity as triethylamine.].In addition it has been reused four times with preservation of enantiomeric excess, and only a moderate decrease of activity.Catalyst 1 also allows efficient recycling when immobilized in certain RTILs.Thus we have shown that its immobilization in [tmba][NTf 2 ] allows three recycles and the reduction of acetophenone with a total TON higher than 700 and an ee of 96% in the last cycle.In comparison to catalyst 1 supported on insoluble polymers, in dendritic structures, or with sulfonate functional groups, 1 immobilized in [tmba][NTf 2 ] gives faster rates, a higher total TON and better ee's.5a-e,h,i The TON for immobilization in RTILs is slightly lower than with zeolite immobilization, 5f,g and really lower than with PEG immobilization, 5k,l but immobilization in RTILs allows the best enantioselectivity.

Experimental Section
General Procedures.All glassware was oven dried prior to use.Acetophenone was distilled and stored under an argon atmosphere and protected from light.Preparation of ionic liquids [bmim][PF6], 9 [emim][TfO], 10 [bmim][BF4], 11 [bmim][NTf2], 10 [emim][Br], 10 [emim][NTf2],10 [bpy][NTf2], 12 [tmba][NTf2], 13 [C14Hex3P][NTf2] 14 are reported in the references quoted.Gas liquid chromatography (GLC) was carried out on a Fisons 8130 gas chromatograph using N2 as carrier gas and a Chrompack CP-Chiralsil-Dex CB column (R enantiomer of 1-phenylethanol elutes first).Ruthenium leaching was measured by ICP.Typical procedure for the asymmetric transfer hydrogenation of acetophenone with catalyst 2 in a formic acid -triethylamine -RTIL mixture, and recycling of the catalytic system.18.4 mg (0.03 mmol) of [Ru(p-cymene)Cl 2 ] 2 and 12.4 mg (0.06 mmol) of (2S,4R)-4hydroxyprolinanilide ligand 13 are dissolved in 3 mL DCM, then transferred in a Schlenk tube containing 3 mL of a RTIL which has previously been dried under reduced pressure (10 -2 mm Hg) at 100°C for 2 hours.After the DCM has been eliminated (10 -2 mm Hg at 50°C for 30 min), the Schlenk tube is stirred at the temperature chosen for the reaction, and 1.56 g of a 5:2 mixture of formic acid and triethylamine (18 mmol of formic acid) is introduced.After 30 min (time necessary for the in situ formation of the catalyst), 350 µL (3 mmol) of acetophenone are added (initial moment for reaction monitoring).The reaction monitoring is carried out by filtration of an aliquot of the reaction medium on silica, and its analysis by GLC.Recycling of the catalytic system is done by bulb-to-bulb distillation of the product (10 -2 mm Hg at 60-70°C for 1 hour).The reactor is then reloaded with a 5:2 mixture of formic acid and triethylamine (1.56 g), and with acetophenone (350 µL).
ARKAT Typical procedure for asymmetric transfer hydrogenation of acetophenone with precatalyst 1 in a formic acid -triethylamine -RTIL mixture, and recycling of the catalytic system.12.7 mg (0.02 mmol) of precatalyst 1 are dissolved in 2.10 g of a 5:2 mixture of formic acid and triethylamine (24 mmol of formic acid), then transfered in a Schlenk tube containing 3 mL of RTIL which has previously been dried (10 -2 mm Hg at 100°C for 2 hours).The Schlenk tube is stirred at the chosen temperature and 470 µL (4 mmol) acetophenone are added (initial moment for the reaction monitoring).The reaction monitoring is done as mentioned above.The recycling of the catalytic system can be done by bulb-to-bulb distillation (as mentioned above).Alternatively it can be done by extraction of the product with ten times 3 mL t-butylmethylether, followed by drying of the RTIL under reduced pressure for 2 hours.The reactor is then reloaded with a mixture of formic acid and triethylamine (2.10 g) and with acetophenone (470 µL).

Table 1
the RTILs allowed for the recycling of the catalytic system by bulb-to-bulb distillation of the 1-phenylethanol produced.The reactor can then be reloaded for another reaction.Table1shows the results obtained for five consecutive cycles in [bmim][PF 6 ] (entries 4-8).Catalyst 2 retains a good activity and good ee's in this RTIL.After four recycles the observed ee has only diminished from 72 to 68%, and its TOF 1/2 * is still as high as 2.5, which compares favorably to the TOF 1/2 of 2.6 for the standard run in DCM (entry 1).

Table 1 .
Asymmetric transfer hydrogenation of acetophenone catalyzed by 2 (Scheme 1, conditions A) a R enantiomer.b Recycling of the supported catalyst is performed by bulb-to-bulb distillation of the product.

Table 2
employed in the asymmetric transfer hydrogenation of acetophenone, brings about accelerated catalysis when it is immobilized in [bmim][PF 6 nARKATConclusionsCatalyst 2,