The efficient catalytic systems generated in situ from RuCl(2)(PPh(3))(3) and chiral ligands N,N-bis[2-(di-o-tolylphosphino)-benzyl]cyclohexane-1,2-diamine(2) were employed for asymmetric transfer hydrogenation of aromatic ketones, giving the corresponding optically active alcohols with high activities(up to 99% conversion) and excellent enantioselectivities(up to 96% e.e.) undcr mild conditions. The chiral ruthenium(II) complex (R,R)-3 has been prepared and characterized by NMR and X-ray crystallography.National Natural Science Foundation of China[20423002, 20703034]; Natural Science Foundation of Fujian Province of China[2008J0235]; Natural Science Foundation of Guangxi Province of China[0991016

Cheng, Zhi-bo

Dong, Zhen-rong

Gao, Jing-xing

Huang, Ke-lin（Guangxi Res Inst Chem Ind）

Li, Yan-yun

Sun, Guo-song（Guangxi Res Inst Chem Ind）

Yu, Shen-luan

高景星

Chemical Research in Chinese Universities

Xiamen University Institutional Repository

  CHEM. RES. CHINESE UNIVERSITIES 2011, 27(2), 170—173 ——————————— *Corresponding author. E-mail: cuihua@xmu.edu.cn Received March 15, 2010; accepted June 8, 2010. Supported by the National Natural Science Foundation of China(Nos.20423002, 20703034), the Natural Science Foundation of Fujian Province of China(No.2008J0235) and the Natural Science Foundation of Guangxi Province of China(No. 0991016).  Novel Chiral PNNP-Ru Complexes: Synthesis and Application in Asymmetric Transfer Hydrogenation of Ketones CHENG Zhi-bo1, YU Shen-luan1, LI Yan-yun1, DONG Zhen-rong1, SUN Guo-song2,  HUANG Ke-lin2 and GAO Jing-xing1* 1. State Key Laboratory of Physical Chemistry of Solid Surfaces, National Engineering Laboratory for Green Chemical Productions of Alcohols-Ethers-Esters, Department of Chemistry,  College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China; 2. Guangxi Research Institute of Chemical Industry, Nanning 530001, P. R. China  Abstract  The efficient catalytic systems generated in situ from RuCl2(PPh3)3 and chiral ligands N,N-bis[2-(di-o- tolylphosphino)-benzyl]cyclohexane-1,2-diamine(2) were employed for asymmetric transfer hydrogenation of aro-matic ketones, giving the corresponding optically active alcohols with high activities(up to 99% conversion) and ex-cellent enantioselectivities(up to 96% e.e.) under mild conditions. The chiral ruthenium(II) complex (R,R)-3 has been prepared and characterized by NMR and X-ray crystallography. Keywords  Chiral PNNP ligand; Ru complex; Asymmetric transfer hydrogenation; Aromatic ketone Article ID  1005-9040(2011)-02-170-04  1  Introduction The design and application of new chiral ligands leading to high activity and enantioselectivity in metal-catalyzed asymmetric catalysis is a topic of constantly ongoing re-searches. Over the past two decades, a large number of chiral mixed-P, N ligands have been synthesized and applied in cata-lytic asymmetric synthetic reactions[1―9]. Among these ligands, the chiral tetradentate PNNP-type ligands[10,11] have received considerable attention in view of their conformational rigidity, which is expected to provide a favorable combination during a catalytic cycle[12,13]. In 1996, we synthesized C2-symmetric chiral diimino- and diamino-diphosphine ligands[14]. Since then, a new class of chiral PNNP-type ligands has been synthesized and their cata-lytic performance for asymmetric hydrogenation has been stu-died in detail. Based on the PNNP ligands, their coordination chemistry with various metal centers, such as Ru(II), Rh(I), Ir(I), Co(II) and Fe(II), has been investigated[14―20]. The appli-cation has been extended from asymmetric transfer hydrogena-tion (ATH) of ketones[14―18,21―25] to oxidative kinetic resolu-tion of racemic second alcohols[26], asymmetric epoxidation[27], asymmetric cyclopropanation[28―32], hydrovinylation of sty-rene[19] and so on. The chiral PNNP ligands are so versatile that they have promoted us to further study the relationship between the structure and performance of the ligands. In our previous  studies, we have used different chiral 1,2-diamines to prepare a series of PNNP ligands[33]. However, another synthetic    improvement is to introduce different aromatic groups on the phosphine, which has seldom been reported. Mezzetti       et al.[30―32] synthesized the CF3-substituted PNNP ligands and employed them in the asymmetric cyclopropanation of olefins efficiently. Recently, we have used 2-(di-o-tolylphosphino)benzyl- dehyde, instead of o-(diphenylphosphino)benzaldehyde, to synthesize novel chiral tetradentate PNNP ligands N,N-bis[2- (di-o-tolylphosphino)-benzyl]cyclohexane-1,2-diimine(1) and N,N-bis[2-(di-o-tolylphosphino)-benzyl]cyclohexane-1,2-dia-  mine(2)(Fig.1). The catalytic performance of the ligands was investigated in the ATH of aromatic ketones with high chiral efficiency[34]. Herein we reported the synthesis of chiral PNNP- Ru complexes and their application in asymmetric transfer hydrogenation of ketones.       Fig.1  Chiral PNNP ligands (R, R)-1 and (R, R)-2 2  Experimental 2.1  General Methods All the experiments were carried out under nitrogen   atmosphere. The solvents were dried and purified according  to standard methods. NMR spectra were recorded on a Bruker AV 400 instrument. Mass spectra were recorded on a Finnigan No.2 CHENG Zhi-bo et al. 171  LCQ mass spectrometer. IR spectra were recorded on a Nicolet Avatar 360 FTIR spectrometer. All the melting points were measured on an X-4 digital melting point apparatus and were uncorrected. The conversions and e.e. values were determined by GC analysis with a CP-Chirasil-Dex CB column or HPLC using a chiralcel OD column. Optical rotations were measured with a Perkin-Elmer 341 polarimeter. X-Ray diffraction data were collected on a Bruker Smart Apex CCD diffractometer. 2.2  General Procedure for ATH of Ketones A solution of ligand (R,R)-2(4.3 mg, 0.006 mmol) and RuCl2(PPh3)3(4.8 mg, 0.005 mmol) in iPrOH(10 mL) was stirred for 20 min, KOH/iPrOH solution and aromatic ketone  (1 mmol) were then introduced, and the solution was stirred at the desired temperature for the required reaction time. The reaction mixture was then filtered through a pad of silica gel and analyzed by GC using a chiral CP-Chirasil-Dex CB column or HPLC using chiralcel OD column. 2.3  Synthesis of Chiral Ru Complex (R,R)-3 Complex (R,R)-3 was synthesized by the reaction of (R,R)-2(0.6 g, 0.8 mmol) and trans-Ru(DMSO)4Cl2(0.4 g, 0.8 mmol) in refluxing toluene(40 mL) for 13 h. The resulting orange-red solution was cooled to room temperature and the solvent was removed under vacuum to leave an orange-red residue. The solid was purified by column chromatography on silica with CH2Cl2/acetone(20:1, volume ratio) as an eluant to give an orange-yellow solid (R, R)-3(0.54 g, 73% yield). m. p. 228―234 °C, D = –13.3(c=0.1, CHCl3). IR(KBr), /cm−1: 3207, 3052, 3003, 2924, 2856, 1588, 1467, 1448, 1129, 1043, 1008, 963, 752, 716, 671. 1H NMR(CDCl3, 400 MHz), δ: 8.47―8.58(m, 1H), 7.81(s, 1H), 6.67―7.50(m, 22H), 5.72(s, 1H), 5.29(d, 1H, J=13.2 Hz), 4.29―4.48(m, 2H), 3.72(d, 2H, J=6.4 Hz), 3.31(m, 1H), 3.11―3.13(m, 2H), 2.58(d, 1H, J=9.2 Hz), 2.40(s, 6H), 2.08―2.17(m, 6H), 1.58(s, 6H), 1.46(d, 1H, J=9.6 Hz), 0.79―1.07(m, 4H). 31P NMR(CDCl3, 162 MHz), δ: 49.65 and –29.03. Complex (S,S)-3 was synthesized by the similar procedure. 2.4  X-Ray Crystallographic Study of (R,R)-3 Orange-yellow crystals of (R,R)-3 suitable for X-ray dif-fraction were grown from ethanol/toluene. Diffraction data were collected on a Bruker Smart Apex CCD diffractometer with graphite monochromated Mo Kα radiation at 296 K. The structure was solved by SHELXS-97 and refined by full-matrix least-quares with anisotropic thermal parameters for all of the nonhydrogen atoms. Hydrogen atoms were located from a dif-ference Fourier map. All the calculations were performed on a microcomputer via SHELXL-97 and SHELXS-97 pro-grams[35,36]. Crystal data for compound (R,R)-3(CCDC 730809 con-tains the supplementary crystallographic data for the structure of (R,R)-3. These data can be abtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif): monoclinic, a= 1.1701(3) nm, b= 1.4933(3) nm, c=2.8875(6) nm, V=5.0456(19) nm3, Z=10, ρcalcd.=1.272 g/cm3, T=273(2) K, R1=0.0476, wR2=0.1462 [I>2σ(I)], R1=0.0511, wR2=0.1490 for all data. 3  Results and Discussion 3.1  ATH of Propiophenone In the initial experiment, the ATH of propiophenone was chosen as a model reaction. The catalyst systems were gene- rated in situ by mixing ligand (R,R)-2 with metal complex in iPrOH under nitrogen atmosphere. Typical results are listed in Table 1. The trinuclear ruthenium cluster Ru3(CO)12 combined with ligand (R,R)-2 showed low activity(Table 1, Entry 1). While RuCl2(DMSO)4 was used, the activity was improved but the enantioselectivity was still unsatisfactory(Table 1, Entry 2). Notably, the catalytic system composed of RuCl2(PPh3)3/    (R,R)-2 gave the best result with a conversion of 97% and an  e.e. of 91%(Table 1, Entry 3). Although the activities were improved, low enantioselectivities were observed when Rh complexes were employed in the reactions(Table 1, Entries 4 and 5). The Ir complexes proceeded with very high activity and moderate enantioselectivities for 3 h at 30 °C(Table 1, Entries 6 and 7). Therefore, RuCl2(PPh3)3 was chosen as metallic pre-cursor for further study. Table 1  ATH of propiophenone with (R,R)-2 and metal complexes as catalyst precursorsa Entry Metal complex t/°C Time/h Conv.b(%) e.e.b(%) 1 Ru3(CO)12 45 5 11 65 2 RuCl2(DMSO)4 45 5 63 65 3 RuCl2(PPh3)3 45 3 97 91 4 RhCl(PPh3)3 45 5 92 18 5 [Rh(COD)Cl2]2 45 5 90 55 6 [IrCl(COD)]2 30 3 97 76 7 IrCl(COD)PPh3 30 3 90 60    reaction conditions: ketone, 0.5 mmol; iPrOH, 5 mL; propiophenone: [M]:ligand:KOH=100:1:1.2:4, molar ratio; b. conversion and e.e. were determined by GC analysis on a chiral CP-Chirasil-Dex CB column. The catalytic performance of (R,R)-1 was also tested in the ATH of propiophenone, coupled with RuCl2(PPh3)3, giving only a conversion of 78% with an e.e. of 61% over 12 h. The result is similar to our earlier studies[14], indicating that the NH functions in the ligands are responsible for the high activity and enantioselectivity. 3.2  ATH of Various Ketones The catalytic systems RuCl2(PPh3)3/ligand 2 have been investigated for the ATH of a diverse range of aromatic ketones in iPrOH. Typical results are listed in Table 2. A variety of aromatic ketones could be smoothly reduced to the corresponding chiral secondary alcohols under mild con-ditions. The activity and the enantioselectivity were highly dependent on the steric and electronic properties of ketones. With increasing the bulkiness of alkyl groups(methyl<ethyl< propyl), high conversion and excellent enantioselectivity were 172 CHEM. RES. CHINESE UNIVERSITIES Vol.27  obtained(Table 2, Entries 1―5). Notably, for cyclohexyl phenyl ketone, the corresponding chiral alcohols could be observed with a yield of 95% and an e.e. of 96%(Table 2, Entry 6). When the 1,1-diphenylacetone was used as substrate, the e.e. of the reaction dropped significantly(Table 2, Entry 7). The electronic properties and position of the groups in the ring substituent also affected the enantioselectivity of the reduction reaction. The ortho-methyl acetophenone was reduced with higher enanti-oselectivity but lower activity compared to the aromatic   ketones with chloride substituent in the meta or para position (Table 2, Entries 8―10). An analogous trend was found for the chloro-substituted acetophenone(Table 2, Entries 11―13). The ketones having an electron-withdrawing substituent, meta- or para-chloroacetophenone showed higher activity compared to Table 2  ATH of various ketones catalyzed by RuCl2(PPh3)3 /ligand(R,R)-2a Entry Substrate Time/h Conv.b(%) e.e.b(%) Config.c1 0.5 90 90 S 2 1 95 95 S 3d 1 94 93 R 4 2 95 93e S 5d 2 96 91 R 6e 4 95 96f S 7e  4 99 87f S 8 2 98 95 S 9 1 95 84 S 10 1 91 84 S 11 1 99 90 S 12 0.2 96 84 S 13 0.3 96 87 S 14 1 97 82 S a. Reaction conditions: ketone, 1 mmol; iPrOH, 10 mL; ketone: [M]:ligand:KOH=200:1:1.2:8, molar ratio; temp.: 45 °C; b. yield and e.e. were determined by GC analysis on a chiral CP-Chirasil-Dex CB column;  c. the configurations were determined by comparison of the retention time of the enantiomer on the GC traces with literature values; d. ligand (S,S)-2;  e. temp.: 60 °C; f. the e.e. values were determined on a chiralcel OD column (eluent, iPrOH: hexane=1:99, volume ratio). the methoxyl acetophenone containing electron-donating subs-tituent(Table 2, Entries 12―14). 3.3  Synthesis of Chiral Ruthenium Complex 3 The interaction of trans-Ru(DMSO)4Cl2 with (R,R)-2 in refluxing toluene gave chiral ruthenium(II) complex (R,R)-3 in good yield(73%) as an orange-yellow solid(Scheme 1). The  31P NMR spectrum of (R,R)-3 exhibits two signals at δ 49.65 and –29.03, indicating that only one phosphorous atom coordi-nated to the ruthenium center.            Scheme 1  Synthesis of complex (R,R)-3 The structure of (R,R)-3 was established by an X-ray dif-fraction study, which revealed a non-C2-symmetric configura-tion for the complex(Fig.2). The selected bond lengths and bond angles are listed in Table 3.           Fig.2  Structure of complex (R,R)-3 All hydrogen atoms are omitted for clarity. The solvent molecules are not given.  Table 3  Selected bond lengths(nm) and bond angles(°) Ru1―N1  0.2185(3)  Ru1―N2  0.2140(3) Ru1―P2  0.23389(11)  Ru1―Cl1  0.24329(11)Ru1―Cl2  0.24389(11)  Ru1―S1  0.22162(11)N2―Ru1―N1  80.63(12)  N2―Ru1―S1  88.07 N1―Ru1―S1  91.54(10)  N2―Ru1―P2  92.46(9) N1―Ru1―P2  168.33(9)  S1―Ru1―P2  97.65(4) N2―Ru1―Cl1  167.58(9)  N1―Ru1―Cl1  87.41(9) S1―Ru1―Cl1  95.63(5)  P2―Ru1―Cl1  98.77(4) N2―Ru1―Cl2  87.81(10)  N1―Ru1―Cl2  80.08(10) S1―Ru1―Cl2  171.17(4)  P2―Ru1―Cl2  90.33(4) Cl1―Ru1―Cl2  86.84(4)      Complex (S,S)-3 was synthesized by the similar procedure. In our previous study[14], the interaction of trans-RuCl2 (DMSO)4 with chiral PNNP ligand 4 gave a C2-symmetric  ruthenium(II) complex 5, in which two phosphino groups are coordinated and equivalent. The possible explanation is that in the complex (R,R)-3 the four tolyl groups create an unfavorable No.2 CHENG Zhi-bo et al. 173  steric clash, which lead to one of the P-pendants distorting away from the metal center and no coordinate to Ru atom. 3.4  ATH of Ketones Catalyzed by Chiral Ruthe-nium Complex (R,R)-3 The chiral ruthenium(II) complex (R,R)-3 was applied to the ATH of prochiral ketones. The catalytic performance exhi-bited high activity and lower enantioselectivity: acetophenone (70% e.e., 74% conversion), propiophenone(82% e.e., 98%  conversion), n-butyrophenone(75% e.e., 97% conversion), phenyl cyclohexyl ketone(75% e.e., 96% conversion) and 1,1-diphenylacetone(72% e.e., 99% conversion). The reason might be that the steric hindrance of the complex prevented the formation of an efficient chiral environment around the metal in the catalytic reaction, which is responsible for the chiral efficiency of chiral catalyst. 4  Conclusions In summary, we have synthesized the new chiral PNNP ligands (R,R)-1 and (R,R)-2 and investigated their application in the asymmetric transfer hydrogenation of ketones. The cata-lytic system generated from (R,R)-2 and RuCl2(PPh3)3 was employed to efficiently catalyze the asymmetric reduction of a variety of aromatic ketones with high activity(99% conversion) and excellent enantioselectivity(up to 96% e.e.) under mild conditions. The turnover frequency reached 960 h–1 at 45 °C. The PNNP-Ru complex (R,R)-3 bearing a non C2-symmetric structure was also synthesized and characterized. In order to reveal the exact reaction mechanism, isolation and characteri-zation of the catalytic active species is under further investiga-tion.  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Novel Chiral PNNP-Ru Complexes: Synthesis and Application in Asymmetric Transfer Hydrogenation of Ketones

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Novel Chiral PNNP-Ru Complexes: Synthesis and Application in Asymmetric Transfer Hydrogenation of Ketones

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