The Novel Application of Chiral -Ethylphenyl Amine Tartaric Acid Salts- Cyanosilylation of Prochiral Aldehydes

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1 The pen Catalysis Journal, 010,, pen Access The Novel Application of Chiral Ethylphenyl Amine Tartaric Acid Salts Cyanosilylation of Prochiral Aldehydes Luo Mei *,1, Zhang Jia ai, Yin ao, Sun Jie and u Ke Liang 1 efei University of Technology, Department of Chemical Engineering, efei, 0009,China University of Science and Technology, Department of Chemistry, efei, 0009,China Shanghai Institute of rganic Chemistry, Shanghai, 000, China Abstract: The ethylphenylamine tartaric acid salts were synthesized from R()/S() ethylphenylamine by reacting with (S,S)()/(R,R)() dihydrobutanedioic acid. They were used as the catalysts in cyanosilylation of prochiral aldehydes to give the corresponding cyanohydrin trimethylsilyl ethers in moderate conversion at room temperature. Keywords: ethylphenylamine tartaric acid salts, R()/S() ethylphenyl amine, (S,S)()/(R,R)() dihydrobutanedioic acid, cyanosilylation of prochiral aldehydes, cyanohydrin trimethylsilyl ethers. INTRDUCTIN Many chiral catalysts provide good catalysis for the cyanosilylation, including Al [1] TiN [], MgN complexes [], basic cinchona alkaloid [4] chiral oxazaborolidinium ions [5], thiourea catalysts [6], and chiral amino acid salts [7]. But the scope and limitation of this reaction often makes it difficult for large scale syntheses. For example, generally, asymmetric cyanosilylation must be conducted with very little acid or base. Furthermore, the yields for the cyanosilylation of prochiral ketones are less than for cyanosilylation of prochiral aldehydes. The reported asymmetric cyanosilylation reactions were all conducted with base catalysts or bifunctional catalysts which are not easily synthesized [8]. Metalligands as lewis acid catalysts have been used widely in organic reactions and polymerization [911]. owerever Brøsted acids catalysts have not been reported up to date. In this paper we report for the first time, a novel application of chiral (R)()/(S)() ethylphenyl amine, (S,S)()/(R,R)()dihydrobutanedioic acid salts, as well as well as several control experiments (with catalysts 1e1h). The experiments demonstrate that enantiomerically pure compounds are required because (R)()/(S)() ethylphenylamine(dl)dihydrobutanedioic acid and (±) ethylphenylamine (S,S)()/(R,R)()dihydrobutanedioic acid as the catalysts in this reaction do not produced the desired effect (Table ). Perhaps the reason has something to do with the quality of the catalyst, as catalysts are easily purified by crystallization, but catalyst s1e1h are not. Catalysts are the Brønsted acids, and they were synthesized from ethylphenylamine reacted with (S,S) ()/(R,R)()dihydrobutanedioic acid in methanol (Fig. 1). *Address correspondence to this author at the efei University of Technology, Department of Chemical Engineering, efei, 0009, China; Tel: , ; s: luomei@pku.edu.cn,lmhh5585@yahoo.cn In addition, the crystal structure of S() ethylphenylamine (R,R)() dihydrobutanedioic acid salt (Fig. ) was obtained. EXPERIMENTAL SECTIN General Procedures All cyanosilylation reactions were monitored by thin layer chromatography using 0.5 mm E. Mercksilica gel coated glass plates (60F54) using UV light to visualize the course of reaction. Flash column chromatography was performed using E. Merck siliga gel (60, particle size mm). Chemical conversion were obtained by 1 NMR, 1 MR, 1 and 1 C NMR spectra were obtained using a Bruker AM00, Bruker AM400 spectrometer. The following abbreviations were used to designate chemical shiftmutiplicities: s = singlet, d = doublet, t = triplet, m =multiplet, Infraredspectra were recorded on a Mattson Galaxy Series FTIR 000 Spectrometer. igh resolution mass spectra were obtained on Micro GCTMS, ptical rotations were measured on WZZ1 automatic polarimeter. The enantiomeric excess(ee) was determined by PLC analysis, PLC was performed on Beijing Chuangxin tonghang system consisting of the following :pump, UV, DAICEL CIRACEL D; mobile phase,hexane. R ()/S() ethylphenyl amine, (R,R)()/(S,S)(), dihydroxy butanedioic acid were bought from the Changzhou KeRuiDa corporation. R() ethylphenylamine[a] D 5 = 9.º(c=0.64, C ), S() ethylphenylamine[a] D 5 =9.º (c=0.68, C )and (R,R)(),dihydroxy butanedioic acid [a] D 5 =14.8º(c=1.58, ), (S,S)(),dihydroxy butanedioic acid [a] D 5 =15.0º(c=1.4, ), The srtucture was solved by direct methods and different Fourier map techniques by using Brucker SMART program, and refinement on F was performed by fullmatrix leastsquares methods with anistropic displacement parameters for all nonhydrogen atoms, all hydrogen atoms were found by difference Fourier map techniques by using SELXS X/ Bentham pen

2 88 The pen Catalysis Journal, 010, Volume Mei et al. C N C N C C C C N. C catalyst C C N. C catalyst 1c C N C C N. C catalyst 1e C N C N C N C N C N C C dl tartaric acid C C N. C catalyst 1b C C N. C catalyst C C N. C catalyst 1f R() Áethylphenylamine(dl), dihydroxybutanedioic acid salt catalyst 1g S() Áethylphenylamine(dl), dihydroxybutanedioic acid salt catalyst 1h Catalyst : R() Áethylphenylamine(R,R)(),dihydroxybutanedioic acid salt Catalyst 1b: R() Áethylphenyllamine(S,S)(),dihydroxybutanedioic acid salt Catalyst 1c: S() Áethylphenylamine(R,R)(),dihydroxybutanedioic acid salt Catalyst : S() Áethylphenylamine(S,S)(),dihydroxybutanedioic acid salt Catalyst 1e: () Áethylphenylamine(R,R)(),dihydroxybutanedioic acid salt Catalyst 1f: () Áethylphenylamine(S,S)(),dihydroxybutanedioic acid salt Fig. (1). Synthetic routes of the catalysts1h.

3 The Novel Application of Chiral Ethylphenyl Amine Tartaric Acid Salts The pen Catalysis Journal, 010, Volume 89 Fig. (). Crystal structure of 1c. program and refined isotropically in the riding mode with fixed thermal factors. The final cycle of refinement gave rise to R=0.01 R=0.0846, w=1/[\s^^(fo^^)(0.064p)^^ P] where P=(Fo^^Fc^^)/', s=1.0, ( / ) max =0.000 and ( / ) mean = ( / ) max =0.8, ( / ) min = The molecular graphics were drawn with the Brucker SELTXL program package [1, 1]. : Prepartion of R() Ethylphenyl Amine (R,R) (), 6.g of ()tartaric acid was dissolved in 90ml methanol, and 5g Raphenylethylamine was slowly added in a dry 50ml cone bottle, motionless above 4h, the single crystals were obtained.5g, 1% in yield melting point: 6668ºC, [a] 5 D = 1.9º (c=1.7,c ); 1 NMR (00Mz,CD D, 7 ), (ppm)= 7.8~7.(m, 5), 4.89(s, 5),4.4~4.(m, 1), 4.40 (s, ), 1.6~1.64(d, J=5.16,), 1 MR: 0.80(x), 5.7,74.0,17.69,10.04,10.4,19.89,177.07,IR:74,1 9,950,867,88,1710,1597,146,154,109,165,1089,99 6,90,898,81,754,706,669,5,577,5; RMS(EI): m/z(%): calcd for C 14 6 N : ; found: b: Prepartion of R() Ethylphenyl Amine (S,S) (), The same procedure described, [a] 5 D =1.6º(c=1.54, C ). 1c: Preparation of S() Ethylphenyl Amine (R,R)(), The same procedure described, [a] 5 D = 1.5º(c=1.6, C ). : Preparation of S() Ethylphenyl Amine (S,S) (), The same procedure described, [a] 5 D =1.1º(c=1.4, C ). 1e: Preparation of Ethylphenyl Amine (R,R)(), 6.g of ()tartaric acid was dissolved in 90ml methanol, and 5g aethylphenyl amine was slowly added in a dry 50ml cone bottle, motionless above 0.5h, concentrated in vacuo, recrystallized with hexane, white solid was obtained 4.5g, melting point:6668 ºC, [a] 5 D = 15.º(c=0.88, ). 1f: Prepartion of Ethylphenyl Amine(S,S)(), 6668 ºC, [a] 5 D =15.4º(c=1.0, ). 1g: Prepartion of R() Ethylphenyl Amine, 6466 ºC, [a] 5 D =16.9º(c=0.8, ). 1h: Preparation of S() Ethylphenyl Amine, 6870 ºC, [a] 5 D =14.8º(c=0.8, ). 1i: Preparation of R() (Trimethylsilyoxyl)Phenylacetonitrile 0.15g(0.55mmol) was dissolved in 5ml hexane, benzaldehyde 0.ml (1.98 mmol) and TMS (0.4 ml,.00mmol)were successively added at room temperature. After 40h, the reaction were quenched. and the mixture was exacted with dichloromethane (x10ml), the combined organic layers was dried over Na S 4,concentrated in vacuo, further purification was performed by silica gel (petroleum/dichloromethane 4/1). The title compound was obtained as a colorless oil, conversion =67 %, 1 NMR (00Mz, CDCl ) (m, 0.9 z, ), (m, ), 5.4 (s, 1),0.16 (s, 9). 1 C NMR (75 Mz, CDCl ) 16.1, 18.8(x), 16.(x), 119.1, 6.5, 0.9(x). RMS(EI): m/z(%):calcd for C NSi: 05.09; found: j: R()(FurylPhenyl)(Trimethylsilyloxy)Acetonitrile obtained as a colorless oil, conversion =78 %, 1 NMR (00Mz, CDCl ) (m, 0.9 z, ), (m, ), 5.4 (s, 1),0.16 (s, 9). 1 C NMR (75 Mz, CDCl ) 16.1, 18.8(x), 16.(x), 119.1, 6.5, 0.9(x). RMS(EI):M15/z calcd for C NSiF: , Found: k: R()(4Methoxyphenyl)(Trimethylsilyloxy)Acetonitrile obtained as a colorless oil, conversion =4%, 1 NMR (00Mz, CDCl ) (m, ), (m, ), 5.44(s, 1),.81(s,), 0.1(s, 9). 1 C NMR (75 Mz, CDCl ) 160.4,18.6,17.9,119.4,114.,6.4,55.,0.45(x), RMS(EI):calcd for C 1 17 N Si:5.109 Found: l: R()(4Methylphenyl)(Trimethylsilyloxy)Acetonitrile The same prcedure described 1e, the title compound was obtained as a colorless oil, conversion =%, 1 NMR (00Mz, CDCl ) (m, ), (m, ),

4 90 The pen Catalysis Journal, 010, Volume Mei et al. 5.(s, 1),.8(s,), 0.4(s, 9). 1 C NMR (75 Mz, CDCl) 19.,1.5,19.6,16.4,6.6,1.6,.6,1.,14.1, 0.(x) RMS(EI) calcd for C 1 17 NSi: , Found: m: ()(Trimethylsilyloxy)Pentanenitrile obtained as a colorless oil, conversion =77%, 1 NMR (00Mz, CDCl ) (t, J=0.04z, 1), (m, ), (m,), (m,), 0.17(s, 9). 1 C NMR (75 Mz, CDCl ) 10.0,61.,8.,16.8,1.,0.50(x). RMS (EI): m/z(%):calcd for C 8 17 NSi: ; found: RESULTS AND DISCUSSIN ur initial catalyst screening was done in TF solvent with a 8% mol catalyst () loading condition. It was found that catalyst showed relatively good reactivity (Table 1). The reason for catalyst loading at 8%mol is that it allowed the catalyst to be measured at a weight (0.15 g) that could be done accurately. In order to get higher conversion, we prolonged the reaction time. owever, after several experiments, we also found that according to the molar ratio of benzaldehyde/tms (1:1.5), even if the reaction time was prolonged to 5 days, the 1 NMR showed not much improvement in conversion. The reason is probably closely connected with the structure of the catalyst, and is more important if the catalyst is a brønsted acid. In fact, we were pleased to find that if ethylphenyl amine was used, the conversion was >99% within 4h. Table 1. Catalysts Effect a Table. Solvents Effect a TMS 8mol% catalyst RT,40h Catalyst Solvent Conv. % b TMS C Cl exane Ether Isopropanol Toluene C Cl exane Ether Isopropanol a Room temperature is around 100 C, b The conversion (%) was calculated by 1 NMR (CDCl ). Table. Cyanosilylation of Aldehydes Catalyzed by and a TMS 8mol% catalyst hexane, RT, 40h TMS TMS 8mol% catalyst TF, RT,40h TMS Entry Aldehyde Catalyst Conv.% b 1i 67 Catalyst Conv. % b 51 1b 1c e 0 1f 1g 19 1h 8 (R)()/ ethyl phenyl amine 6 (R,R)() dihydrobutane dioic acid 41 a The room temperature is around 100 C, b: The conversion (%) was given by 1 NMR 1j 1k 1l C F (CDCl ). C ptimization of the solvents effects such as in hexane, ether, toluene, isopropanol, dichloromethane with 8mol% catalyst and, the results are summarized in Table, and hexane was the solvent of best choice, which gave the yield 67%. 1m 77 a The room temperature is around 100 C, b The conversion (%) was given by 1 NMR (CDCl ).

5 The Novel Application of Chiral Ethylphenyl Amine Tartaric Acid Salts The pen Catalysis Journal, 010, Volume 91 Encouraged by the results achieved in the presence of 8 mol % catalyst in hexane at room temperature(around 10 0 C), the asymmetric cyanosilylation of aromatic aliphatic aldehydes was also investigated under the optimized reaction conditions. After screening, we obtained some results with moderate to excellent enantioselectivity as displayed in Table. The aromatic aldehydes and aliphatic aldehydes such as FPhC, 4C PhC, 4C PhC, and C 7 C afforded the corresponding trimethylsilyl ethers in 78%, 4%, %., and 77% conversion respectively. To further improve the conversion, we found that when the molar ratio of aldehyde to TMS was changed to 1:5, after days, the conversions were nearly all >99%. A probable reaction mechanism that can be proposed is that the proton acid can greatly active the C= bond, increasing the electronphilic reactivity of the carbon atom, which can then accept the nucleophilic attack of. CLUSINS In conclusion, the novel catalysts used in the cyanosilylation of prochiral aldehydes have been reported here for the first time with moderate yield and good enantioselectivity at room temperature. The use of these catalysts in other applications such as in Aldol reactions, the enry ions, and allylation reactions are all in progress. REFERENCES [1] (a) Midland, M.; Lee, P. B. Asymmetric synthesis of hydroxycarboxylic acids. J. rg. Chem. 1981, 46, 94. (b) Lang, T.; Li, D. Dynamic kinetic resolution via dualfunction catalysis of modified cinchona alkaloids: asymmetric synthesis of hydroxy carboxylic acids. J. Am. Chem. Soc. 00, 14, ; (c) Jenkins S S. The Preparation and some properties of the chloromandelic acids, their Metal esters. J. Am. Chem. Soc. 191, 5, 414. 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Jensen, XRay Structure Determination: a Practical Guide. MacMillan: New York, Received: ctober, 009 Revised: November 17, 009 Accepted: November 17, 009 Mei et al.; Licensee Bentham pen. This is an open access article licensed under the terms of the Creative Commons Attribution NonCommercial License ( which permits unrestricted, noncommercial use, distribution and reproduction in any medium, provided the work is properly cited.