Enantiopure fluorous 1,2-diaryl-1,2-diaminoethanes: synthesis and applications in asymmetric organometallic catalysis

The synthesis of a new enantiopure fluorous 1,2-diaryl-1,2-diaminoethane bearing two fluorous ponytails is described. The palladium-catalyzed reaction of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate in the presence of this ligand and its analogue bearing four fluorous ponytails gave the alkylated product with ee up to 44%. Their application as ligands in hydrogen transfer reactions associated with rhodium, iridium, or ruthenium in a two-phase system gave ee up to 39%, the catalyst being recycled without loss of enantioselectivity in the case of the ruthenium complex.


Introduction
Enantiopure 1,2-diamines, particularly those possessing C 2 -symmetry, and their derivatives, have found wide applications as chiral auxiliaries and ligands in asymmetric synthesis. 1,2Among the large variety of 1,2-diamine structures that have been synthesized and used as ligands in asymmetric catalysis, enantiomerically pure 1,2-diaryl-1,2-ethanediamines and their derivatives seem to be among the most studied, giving high enantioselectivities in a large number of metalcatalyzed enantioselective reactions.Intensive research has been devoted to the synthesis of such easily recoverable enantiopure 1,2-diaryl-1,2-ethanediamines.The hydrosolubilization of such ligands has been performed by attachment on the aromatic rings of hydrophilic substituents, such as phenolic hydroxy groups, 3 polyethylene glycol chains, 3,4 sulfonic acid 5 or phosphonic acid 6 functions.Heterogenization of these enantiopure diamines has also been performed by attachment to soluble or insoluble organic polymers, 4,7 or immobilization onto inorganic supports. 8Fluorous techniques have recently been introduced in asymmetric synthesis and are rapidly emerging as convenient alternatives for the recovery of chiral catalysts. 9ur group has recently described the synthesis of some enantiopure fluorous 1,2-diamines and diimines, and described their use as ligands in metal-catalyzed asymmetric transfer hydrogenation of ketones using the FBS (Fluorous Biphasic System) concept. 10We also described the preparation of a fluorous 1,2-diphenyl-1,2-ethanediamine bearing four fluorous ponytails. 11Herein we report the synthesis of a new fluorous 1,2-diphenyl-1,2-ethanediamine bearing only two fluorous ponytails, and the application of these two fluorous ligands in asymmetric transfer hydrogenation and asymmetric allylic alkylation.
In order to use these two substrates as ligands in asymmetric organometallic catalysis we measured their equilibrium distribution between FC-72, a fluorous solvent, and various non-fluorous solvents (Table 1).As expected, the fluorous diamine 1a, bearing two fluorous ponytails and with a fluorous content of 55%, is preferentially dissolved in the non-fluorous solvent, whatever the latter.Conversely, the fluorous diamine 1b, bearing four fluorous ponytails and a fluorous content of 62.2%, exhibited very good fluorophilicity, with partition coefficients of 10.36 and 2.23, respectively in the presence of acetonitrile or ethanol, allowing its probable use as a ligand in a two-phase system of fluorous solvent-non-fluorous solvent.The fluorous diamines 1a,b were tested as ligands in the allylic alkylation of 1,3-diphenyl-2propenyl acetate with dimethyl malonate catalyzed by Pd(0) (Tsuji-Trost alkylation).This reaction was first done at room temperature in THF, using the fluorous ligand 1 (6 mol.%) and [Pd(η 3 -C 3 H 5 )Cl] 2 (2.5 mol.%) in the presence of NaH as the base.The alkylated product was obtained in 28% and 32%, after two days, using ligands 1a and 1b, respectively, with 28 and 32% ee (Table 2, entries 1 and 2).However, performing this reaction at 50 °C afforded quantitatively the coupling product with 29 and 35% ee, respectively (Table 2, entries 2 and 4).All attempts to perform this alkylation reaction in a two-phase system of fluorous solvent/nonfluorous solvent failed.We next turned our attention to the catalytic hydrogen-transfer reduction.These fluorous diamines 1a-b, in association with [Rh(C 6 H 10 )Cl] 2 were successfully tested in the asymmetric reduction of acetophenone with isopropanol as the hydride source in the presence of PFMCH as the fluorous solvent at 70 °C (Table 3, entry 1 and 2).The reduction was almost quantitative after one hour using the two ligands, with ee up to 35% in the presence of ligand 1b.Since only ligand 1b could allow the recycling of the catalyst, all the following experiments were performed in the presence of 1b.It is to be noted that the recycling of the catalyst [Rh(C 6 H 10 )Cl] 2 /ligand 1b gave also a quantitative conversion after one hour, but with a lower enantioselectivity (22% ee) (Table 3, entry 2*).
The catalyst obtained by mixing [Ir(COD)Cl] 2 and ligand 1b afforded quantitatively the alcohol after one hour with ee up to 28.The recycling of this catalyst was also possible with the same activity; unfortunately the enantioselectivity dropped to 7% (Table 3, entries 3 and 3*).
Finally the complex [Ru(p-cymene))Cl] 2 associated with diamine 1b gave quantitatively the reduced product after three hours, with 33% ee; this catalyst allowed efficient recycling, 39% ee being obtained in this case (Table 3, entries 4 and 4*).

Conclusions
We describe here a quite general approach for the synthesis of enantiopure fluorous 1,2-diaryl-1,2-diaminoethanes, bearing some fluorous ponytails.These fluorous ligands have been used as ligands in the palladium-catalyzed alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate in tetrahydrofuran as the solvent, with ee up to 44% being obtained.These fluorous diamines have also been used in the reduction of acetophenone by hydrogen transfer associated with rhodium, iridium, or ruthenium complexes, with ee in the range of 26-35% .The use of a biphasic system i-PrOH-fluorous solvent allows recycling of the catalyst, with no decrease in enantioselectivity in the case of the ruthenium catalyst.

Experimental Section
General Procedures.Solvents were purified by standard methods and dried if necessary, except for perfluoromethylcyclohexane (PFMC), which was used as received.FC-72 (mixture of fluorous hexanes) and 4,4'-dimethoxybenzil (2) were commercially available, 1H,1Hperfluorooctan-1-yl nonafluorobutanesulfonate was prepared according to the literature.To a solution of the bis-carbamate (1R,2R)-5 (1.43 g, 2.26 mmol) in anhydrous DME (60 mL) maintained at 0 °C was added LiAlH 4 (0.86 g, 22.6 mmol) in portions.The reaction mixture was heated at 85 °C for 20 h, and the cooled to 0 °C.Water (4 mL) was added slowly at 0 °C, and then the mixture was heated at reflux for 30 min.The mixture was cooled to RT, and the white precipitate filtered using a pad of Celite and washed with THF (3x20 mL).Evaporation of the solvent under reduced pressure gave a residue that was diluted with Et 2 O (20 mL); a 1M solution of gaseous HCl (3.7 mL) in Et 2 O was then added.The mixture was stirred at RT for 10 min, and the solid obtained was filtered and washed with Et 2 O.The solid was suspended in Et 2 O and treated with an aqueous 1% NaOH solution until dissolution of the solid.The organic phase was separated, washed with H 2 O (2x5 mL), and dried (Na 2 SO 4 ).Evaporation of the solvent under reduced pressure gave the diamine 6 as a colorless solid (450 mg, 66%), which was washed with hexane and dried.Mp 118-120 °C (lit. 13mp 118-120 °C); [α] D 20 +36 (c 0.9, CHCl 3 ) (lit. 13 [α] D 20 +36.4 (c 1, CHCl 3 )); Determination of partition coefficients P. A 10 mL vial equipped with a magnetic stirrer was charged with the fluorous diamine 1 (50 mg), PFMC (2 mL) and the organic solvent (2 mL).The mixture was thermostatted at 25 °C and stirred vigorously for 4 h.A 1 mL sample was taken out of each phase, evaporated to dryness, and weighed on an analytical balance.The partition coefficient P was determined as the ratio between the weight of the fluorous phase residue and the weight of the organic phase residue.Alkylation of (±)-1,3-diphenyl-2-propenyl acetate.The catalyst was prepared in a Schlenk tube by stirring [Pd(η 3 -C 3 H 5 )Cl] 2 (45.6 mg, 12.5 µmol) and the fluorinated diamine (30 µmol) in degassed THF (1.5 mL) at R.T. for 1 h.1,3-Diphenyl-2-propenyl acetate (126 mg, 0.5 mmol) dissolved in THF (1.5 mL) was added and the solution stirred for a further 20 min, after which it was transferred under nitrogen into another Schlenk tube containing a solution of NaH (36 mg, 1.5 mmol) and dimethyl malonate (198 mg, 1.5 mmol) in THF (2 mL).The solution was stirred at the desired temperature for the time indicated in Table 2.The conversion was determined by GC using a Quadrex OV1 column (30 m x 0.25 mm) and the enantioselectivity by HPLC on a chiral stationary phase (column: Chiralpak AD; eluent hexane/i-PrOH 60:40).Hydrogen-transfer reduction of acetophenone.The catalyst was prepared in a Schlenk tube by stirring [Rh(C 6 H 10 )Cl] 2 (8.8 mg, 20 µmol), [Ir(COD)Cl] 2 (10.3 mg, 20 µmol), or [Ru(pcymene)Cl 2 ] 2 (12.2 mg, 20 µmol) and the fluorinated diamine 1 (40 µmol) in degassed PFMC (5 mL) at 70 °C for 3 h.To this solution, cooled to RT, was added a solution of acetophenone (48 mg, 0.4 mmol) and KOH (5.6 mg, 0.1 mmol) in i-PrOH (5 mL).The mixture was stirred at 70 °C.The conversion and enantiomeric excess were determined by GC analysis using a capillary Quadrex OV1 column (30 m x 0.25 mm) and a capillary Cyclodex-β column (30 m x 0.25 mm), respectively. 13

Table 1 .
Partition coefficients P (P = c fluorous phase /c organic solvent ) for fluorous diamines 1a-b between FC-72 and standard organic solvents a a In a 50:50 (v:v) mixture of FC-72/organic solvent at 25 °C.Determined gravimetrically (see Experimental Section).