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Enantiomerically Enriched 1,2-P,N-Bidentate Ferrocenyl Ligands for 1,3-Dipolar Cycloaddition and Transfer Hydrogenation Reactions

Novel complexes of 1,2-P,N-bidentate ferrocenyl ligands with AgOAc or with [RuCl2(PPh3)3] as catalysts have been studied in asymmetric synthesis. The catalytic activity of these systems have been studied in [3+2]-cycloaddition of azomethine ylides with olefins and the asymmetric transfer hydrogenation of ketones.


Introduction
Planar chiral 1,2-bidentate ferrocenyl ligands, as well as binaphthyls, bi(hetero)aryls, and spirobiindans, are widely spread in versatile reactions of asymmetric synthesis reactions [1]. They are connected with the ability, at low concentrations, of the catalyst to provide a high degree of enantioselectivity and high yield of target products. Such ligands are essential for the production of pharmaceuticals and natural products.
In our previous work, an efficient and straightforward route for the synthesis of planar chiral (hetaryl)ferrocenes P,N-ligands L1 (er > 99:1) and L2 (er > 99:1) (Figure 1) has been demonstrated [31]. The obtained (hetaryl)ferrocenes revealed high catalytic activity in the Pd-catalyzed Tsuji-Trost allylic allylic substitution [31]. In the present paper, the catalytic activity of chiral complexes based on the ligands L1 and L2 in the [3+2]-cycloaddition of azomethine ylides with olefins and the asymmetric transfer hydrogenation of ketones is demonstrated.

Results and Discussion
Asymmetric [3+2]-cycloaddition [32] represents one of the most efficient, straightforward, and atom-economical methods for the construction of optically active pyrrolidine derivatives with multiple stereocenters. After pioneering studies of asymmetric pyrrolidines synthesis [8,33], many efforts were directed to the development of synthetic approaches to novel chiral catalysts. Chiral pyrrolidines are present in many biologically active [34][35][36] and natural [37] compounds, and were recently often applied as organocatalysts [38][39][40][41][42][43][44]. For instance compound 1 demonstrates an antiviral activity against hepatitis C (as an inhibitor of RNA polymerase) [45,46], and α-kainic acid (2) has a neuroexcitatory effect [47]. (-)-Dysibetaine (3) is a neuroexcitotoxin which may bind to the glutamate receptors presented in the CNS of mice [48]. Hydroxyprolines 4 and 5 play an important role in the catabolism of collagen, and in the stabilization of protocollagens and glycoproteins in living systems [49]. Derivatives of pyrrolopyrans 6 [23] are known to be the analogues of natural monoterpenoids of the class of cyclopentanopyranes (iridoids), performing protective functions in the organism. Lactam 7 is thrombin inhibitor (Figure 2) [50].

Results and Discussion
Asymmetric [3+2]-cycloaddition [32] represents one of the most efficient, straightforward, and atom-economical methods for the construction of optically active pyrrolidine derivatives with multiple stereocenters. After pioneering studies of asymmetric pyrrolidines synthesis [8,33], many efforts were directed to the development of synthetic approaches to novel chiral catalysts. Chiral pyrrolidines are present in many biologically active [34][35][36] and natural [37] compounds, and were recently often applied as organocatalysts [38][39][40][41][42][43][44]. For instance compound 1 demonstrates an antiviral activity against hepatitis C (as an inhibitor of RNA polymerase) [45,46], and α-kainic acid (2) has a neuroexcitatory effect [47]. (-)-Dysibetaine (3) is a neuroexcitotoxin which may bind to the glutamate receptors presented in the CNS of mice [48]. Hydroxyprolines 4 and 5 play an important role in the catabolism of collagen, and in the stabilization of protocollagens and glycoproteins in living systems [49]. Derivatives of pyrrolopyrans 6 [23] are known to be the analogues of natural monoterpenoids of the class of cyclopentanopyranes (iridoids), performing protective functions in the organism. Lactam 7 is thrombin inhibitor (Figure 2) [50].
Molecules 2018, 23, x FOR PEER REVIEW 2 of 12 allylic substitution [31]. In the present paper, the catalytic activity of chiral complexes based on the ligands L1 and L2 in the [3+2]-cycloaddition of azomethine ylides with olefins and the asymmetric transfer hydrogenation of ketones is demonstrated.
A plausible mechanism is shown in Scheme 2. In the first step of the reaction, silver(I) is simultaneously coordinated by the bidentate chiral ligand L1 and the substrate 8 in a tetrahedral arrangement to form the catalytic complex A. Next step of deprotonation of complex A by triethylamine leads to the formation of the azomethine ylide, the active substrate for the cycloaddition. This active substrate then undergoes a cycloaddition with dienophile 9 to furnish the product 10a (Scheme 2). The dienophile attacks from the less-hindered side (above the plane), to avoid unfavorable steric interactions with the bulky diphenylphosphine group of the ligand [20].

Scheme 2.
A plausible mechanism of [3+2] cycloaddition of imino ester 8a and dienophile 9a. (8) and N-alkylmaleimide (9) catalyzed by the complex L1/AgOAc: a The enantiomeric ratio was determined by high-performance liquid chromatography (HPLC) on a Chiralpak AD. b The enantiomeric ratio was determined by HPLC on a Chiralcel OD-H. c The enantiomeric ratio was determined by supercritical fluid chromatography (SFC) on a Chiralcel OD-H. d Use of the L2/AgOAc complex.
A plausible mechanism is shown in Scheme 2. In the first step of the reaction, silver(I) is simultaneously coordinated by the bidentate chiral ligand L1 and the substrate 8 in a tetrahedral arrangement to form the catalytic complex A. Next step of deprotonation of complex A by triethylamine leads to the formation of the azomethine ylide, the active substrate for the cycloaddition. This active substrate then undergoes a cycloaddition with dienophile 9 to furnish the product 10a (Scheme 2). The dienophile attacks from the less-hindered side (above the plane), to avoid unfavorable steric interactions with the bulky diphenylphosphine group of the ligand [20]. Notably, using (RFc)-1-(quinolin-2-yl)-2-(α-(R)-diphenylphosphinoethyl)ferrocene L2, the product 10d was obtained in 55% yield as a racemate (er = 50:50) using the optimized reaction conditions (Scheme 1).
A plausible mechanism is shown in Scheme 2. In the first step of the reaction, silver(I) is simultaneously coordinated by the bidentate chiral ligand L1 and the substrate 8 in a tetrahedral arrangement to form the catalytic complex A. Next step of deprotonation of complex A by triethylamine leads to the formation of the azomethine ylide, the active substrate for the cycloaddition. This active substrate then undergoes a cycloaddition with dienophile 9 to furnish the product 10a (Scheme 2). The dienophile attacks from the less-hindered side (above the plane), to avoid unfavorable steric interactions with the bulky diphenylphosphine group of the ligand [20]. The structures of the cycloaddition products 10a-f have been confirmed by NMR spectroscopy, and the data corresponding well with the literature [53,54]. In addition, we carried out nuclear Overhauser effect spectroscopy (NOESY) experiments for compound 10a, to gain structural and stereochemical information. The NOESY experiment showed a NOE effect of the H-3 to H-3a, and H-1 to H-6a, enabling the determination of the stereochemistry of this compound as endo-product (Figure 3). Absolute configuration was determined by comparison with the literature data [54]. The enantiomeric ratio of the compounds was determined by high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) analysis.
Molecules 2018, 23, x FOR PEER REVIEW 5 of 12 The structures of the cycloaddition products 10a-f have been confirmed by NMR spectroscopy, and the data corresponding well with the literature [53,54]. In addition, we carried out nuclear Overhauser effect spectroscopy (NOESY) experiments for compound 10a, to gain structural and stereochemical information. The NOESY experiment showed a NOE effect of the H-3 to H-3a, and H-1 to H-6a, enabling the determination of the stereochemistry of this compound as endo-product ( Figure 3). Absolute configuration was determined by comparison with the literature data [54]. The enantiomeric ratio of the compounds was determined by high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) analysis. The asymmetric hydrogenation of double bonds is known to be of great importance in the synthesis of biologically active compounds and their precursors. For example, (S)-Duloxetine (11) is an antidepressant drug targeting the presynaptic cell and (R)-Fluoxetine (12) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class ( Figure 4) [55][56][57]. In particular, ferrocenyl chiral complexes [29,30,58,59] are utilized for the carbonyl group reduction. Next, we tried to examine the catalytic activity of planar chiral ferrocenyl ligands L1 and L2 applying the Ru-catalyzed transfer hydrogenation of ketones with acetophenone 13 as a model substrate (Scheme 3, Table 2). According to the standard procedure [29], the reaction was carried out in the presence of catalytic amounts of base and the active complex L1/RuCl2(PPh3)3 in degassed iPrOH. The reaction of  The asymmetric hydrogenation of double bonds is known to be of great importance in the synthesis of biologically active compounds and their precursors. For example, (S)-Duloxetine (11) is an antidepressant drug targeting the presynaptic cell and (R)-Fluoxetine (12) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class ( Figure 4) [55][56][57]. In particular, ferrocenyl chiral complexes [29,30,58,59] are utilized for the carbonyl group reduction. The structures of the cycloaddition products 10a-f have been confirmed by NMR spectroscopy, and the data corresponding well with the literature [53,54]. In addition, we carried out nuclear Overhauser effect spectroscopy (NOESY) experiments for compound 10a, to gain structural and stereochemical information. The NOESY experiment showed a NOE effect of the H-3 to H-3a, and H-1 to H-6a, enabling the determination of the stereochemistry of this compound as endo-product ( Figure 3). Absolute configuration was determined by comparison with the literature data [54]. The enantiomeric ratio of the compounds was determined by high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) analysis. The asymmetric hydrogenation of double bonds is known to be of great importance in the synthesis of biologically active compounds and their precursors. For example, (S)-Duloxetine (11) is an antidepressant drug targeting the presynaptic cell and (R)-Fluoxetine (12) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class ( Figure 4) [55][56][57]. In particular, ferrocenyl chiral complexes [29,30,58,59] are utilized for the carbonyl group reduction. Next, we tried to examine the catalytic activity of planar chiral ferrocenyl ligands L1 and L2 applying the Ru-catalyzed transfer hydrogenation of ketones with acetophenone 13 as a model substrate (Scheme 3, Table 2). According to the standard procedure [29], the reaction was carried out in the presence of catalytic amounts of base and the active complex L1/RuCl2(PPh3)3 in degassed iPrOH. The reaction of  Next, we tried to examine the catalytic activity of planar chiral ferrocenyl ligands L1 and L2 applying the Ru-catalyzed transfer hydrogenation of ketones with acetophenone 13 as a model substrate (Scheme 3, Table 2). The structures of the cycloaddition products 10a-f have been confirmed by NMR spectroscopy, and the data corresponding well with the literature [53,54]. In addition, we carried out nuclear Overhauser effect spectroscopy (NOESY) experiments for compound 10a, to gain structural and stereochemical information. The NOESY experiment showed a NOE effect of the H-3 to H-3a, and H-1 to H-6a, enabling the determination of the stereochemistry of this compound as endo-product ( Figure 3). Absolute configuration was determined by comparison with the literature data [54]. The enantiomeric ratio of the compounds was determined by high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) analysis. The asymmetric hydrogenation of double bonds is known to be of great importance in the synthesis of biologically active compounds and their precursors. For example, (S)-Duloxetine (11) is an antidepressant drug targeting the presynaptic cell and (R)-Fluoxetine (12) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class (Figure 4) [55][56][57]. In particular, ferrocenyl chiral complexes [29,30,58,59] are utilized for the carbonyl group reduction. Next, we tried to examine the catalytic activity of planar chiral ferrocenyl ligands L1 and L2 applying the Ru-catalyzed transfer hydrogenation of ketones with acetophenone 13 as a model substrate (Scheme 3, Table 2). According to the standard procedure [29], the reaction was carried out in the presence of catalytic amounts of base and the active complex L1/RuCl2(PPh3)3 in degassed iPrOH. The reaction of  1-0.3 ppm and 0.1-0.2 ppm, respectively. It should be noted that in the 31 P spectra of the complex, the signal is downfield shifted by 5.6 ppm relative to the initial ligand. According to the standard procedure [29], the reaction was carried out in the presence of catalytic amounts of base and the active complex L1/RuCl 2 (PPh 3 ) 3 in degassed iPrOH. The reaction of L1 with [RuCl 2 (PPh 3 ) 3 ] in toluene at room temperature for 10 min gave the desired red complex. The structure of complex L1/RuCl 2 (PPh 3 ) 3 has been confirmed by NMR spectroscopy HRMS and elemental analysis (see Supplementary Materials page S2, S22, figures S3, S5, S21, S23). The 1 H-NMR spectra point out that the proton signals of the ferrocene and heterocyclic moieties of the complex L1/RuCl 2 (PPh 3 ) 3 (3.9-5.4 and 7.4-7.9 ppm) in comparison to the initial ligand L1 (3.8-5.1 and 7.2-8.0 ppm) are downfield shifted by 0.1-0.3 ppm and 0.1-0.2 ppm, respectively. It should be noted that in the 31 P spectra of the complex, the signal is downfield shifted by 5.6 ppm relative to the initial ligand.
Asymmetric transfer hydrogenation of acetophenone 13 to (R)-1-phenylethanol 14 was carried out in the presence of 0.5 mol % of complex L1/RuCl 2 (PPh 3 ) 3 and 2 mol % t-BuOK. The reaction mixture was stirred under argon atmosphere for 20 h at room temperature. (R)-1-phenylethanol 14 was isolated by column chromatography on SiO 2 in 20% yield and with the selectivity of more than 99% (Table 2, entry 2). The asymmetric transfer hydrogenation conditions were optimized with respect to the type and amount of base and the reaction temperature ( Table 2).
The application of 4-dimethylaminopyridine (DMAP) and NaH as bases provided low yields of product 14 ( Table 2, entries 3 and 4). Furthermore, 14 was obtained in 2% yield after 72 h in the presence of 20 mol % using triethylamine as base (Table 2, entry 5). Next, we tried to increase the yield by heating to 80 • C ( Table 2, entry 6). At last, (R)-1-phenylethanol 14 in 98% yield was achieved by carrying out the reaction at 80 • C in the presence of 20 mol % t-BuOK (Table 2, entry 7). Reducing the loading of t-BuOK to 10 and 2 mol % resulted in a slight decrease in the product yield ( Table 2, entries 8 and 9). The selectivity of the process in all above cases with L1/RuCl 2 (PPh 3 ) 3 was more than 99%.  1 The enantiomeric ratio was determined by SFC on a Lux Amylose-2. 2 The product was isolated by column chromatography on SiO 2 . 3 The yield was determined by NMR spectroscopy.
Based on the above results, we conclude that the optimal conditions for this transformation are as follows: 20 mol % t-BuOK, 0.5 mol % ligand, 0.5 mol % RuCl 2 (PPh 3 ) 3 and 80 • C. In order to investigate the effect of the substituent on the yield and selectivity of the products, other ketones were used (Scheme 4). The asymmetric transfer hydrogenation of 2-butanone 13b led to the formation of products 14b in 50% yields. Next, we investigated the ability of using of asymmetric transfer hydrogenation for π-excess and π-deficient carbonyl compounds such as 2-acetylthiophene 13c and 2-acetylpyridine 13d (Scheme 4). (R)-1-(Thiophen-2-yl)ethan-1-ol 14c was isolated in trace amounts. This is interpreted by the instability of thiophene derivatives. As opposed to 2-acetylthiophene, the asymmetric transfer hydrogenation of π-deficient 2-acetylpyridine 13d led to the formation of products 14d in high yield and selectivity (Scheme 4).

General Procedure for the Synthesis of Products 10
Ligand L1 (6 mol %) and AgOAc (5 mol %) were dissolved in dichloromethane (1.0 mL) and the solution was stirred for 15 min at room temperature. Then, dipolarophile 9 (1.2 mmol), imine 8 (1 mmol) and Et3N (20 mol %) were added to the mixture and stirred at room temperature for 24 h. After evaporation under reduced pressure, the residue was purified through column chromatography on silica gel (hexane/ethyl acetate = 9/1) to give the pure products. The structures of products were known [53,54] and confirmed by NMR. The enantiomeric excesses of the products were determined by HPLC and SFC on chiral stationary phase.

General Information
All reactions were carried out under argon using standard Schlenk Techniques (Hofmann Glastechnik GmbH, Staudt, Germany). The 1 H-NMR (400 MHz), 13 C-NMR (100 MHz), 31 P-NMR (162 MHz) spectra were recorded on a NMR spectrometer (400 MHz). Chemical shifts are given in δ values (ppm) using tetramethylsilane (TMS) as internal standard and CDCl 3 as solvent. Electrospray mass spectra were recorded in positive mode with maXis impact high resolution Q-TOF mass spectrometer (Bruker Daltonics, Bremen, Germany) in 50-2500 Da mass range by direct infusion of sample solutions in methanol using kdScientific (KD Scientific Inc., Holliston, MA, USA) syringe pump at 120 µL/h flow rate. Modified instrument settings of a pre-installed method Direct_Infusion_100-1000 were used. Mass calibration was performed using ES-TOF G1969-85000 tuning mix (Agilent Technologies) by HPC method (High Precision Calibration standard procedure by Bruker). All data were collected and analyzed with Compass for oTof series 1.7/DataAnalysis 4.2 software package (Bruker, Germany). Analytical HPLC (Knauer, Berlin, Germany) and SFC (Waters Corporation, Milford, MA, USA) were performed using a chiral column. The angle of rotation was measured on a polarimeter Perkin-Elmer 343+ (PerkinElmer Instruments, Llantrisant, Wales, UK). The elemental analysis was carried out on a CHNS/O analyzer Perkin-Elmer (PerkinElmer Instruments, Norwalk, CT, USA). The course of the reactions was monitored by thin layer chromatography (TLC) on silica gel plates (Macherey-Nagel GmbH & Co, Düren, Germany). The column chromatography was performed on silica gel (silica gel 60, 0.035−0.070 mm, 220−440 mesh).

General Procedure for the Synthesis of Products 10
Ligand L1 (6 mol %) and AgOAc (5 mol %) were dissolved in dichloromethane (1.0 mL) and the solution was stirred for 15 min at room temperature. Then, dipolarophile 9 (1.2 mmol), imine 8 (1 mmol) and Et 3 N (20 mol %) were added to the mixture and stirred at room temperature for 24 h. After evaporation under reduced pressure, the residue was purified through column chromatography on silica gel (hexane/ethyl acetate = 9/1) to give the pure products. The structures of products were known [53,54] and confirmed by NMR. The enantiomeric excesses of the products were determined by HPLC and SFC on chiral stationary phase.

General Procedure for the Synthesis of Products 14
A solution of ketone (1 mmol) and a base (20 mol %) was added to a solution of complex L1/RuCl 2 (PPh 3 ) 3 (0.5 mol %) in degassed iPrOH (30 mL). The reaction mixture was stirred at 80 • C for 20 h, and the progress of the reaction was monitored by TLC. After evaporation under reduced pressure, the residue was purified through column chromatography on silica gel to yield pure product. The structures of products were known and were confirmed by NMR spectroscopy.

Conclusions
New Ag-and Ru-catalysts based on the planar chiral ferrocene P,N-ligands L1 and L2 have been obtained. The scope of activity of the complexes was demonstrated in two types of asymmetric reactions: [3+2]-cycloaddition of azomethine ylides with olefins and asymmetric transfer hydrogenation of carbonyl compounds. The catalytic activity of the ligands L1 and L2 has been shown to be comparable with the ones of previously described ligands in the presented transformations. Thus, the obtained complexes revealed high reactivity and good enantioselectivity and enabled to access to optically active pyrrolidine derivatives and products of reduction of multiple bonds under mild conditions. As the final step, we succeeded to apply the approach to the synthesis of potential biologically active compounds.