Asymmetric Transfer Hydrogenation of 3-(Trifluoromethyl)quinolines

Transcription

1 PAPER 275 paper Asymmetric Transfer ydrogenation of 3-(Trifluoromethyl)quinolines Asymmetric Transfer ydrogenation Ran-ing Guo, a,b Zhang-Pei Chen, b Xian-Feng Cai, b Yong-Gui Zhou* b a Department of Chemistry, Dalian University of Technology, Dalian 602, P. R. of China b State Key Laboratory of Catalysis, Dalian Institute of Chemical ysics, Chinese Academy of Sciences, Dalian 6023, P. R. of China Fax +86(4)843792; ygzhou@dicp.ac.cn Received: ; Accepted after revision: Abstract: A chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation of 3-(trifluoromethyl)quinolines was successfully developed with up to 98% ee. The new method provides a direct and facile access to chiral 2,3-disubstituted,2,3,4-tetrahydroquinoline derivatives containing a stereogenic trifluoromethyl group. Key words: chiral phosphoric acid, transfer hydrogenation, quinolines, trifluoromethyl group R chiral heterocycles containing a stereogenic group asymmetric reduction challenges: resonance stability was difficult to destroy stereoselectivity was difficult to control R heteroaromatics bearing a group Enantiopure trifluoromethylated ( ) molecules have received increasing attention in the field of medicinal, agricultural, and material chemistry, mainly due to the enhanced metabolic stability, lipophilicity, bioavailability, and binding selectivity upon introduction of the group into parent molecules. 2 Especially, heterocycles containing a stereogenic group represent a major structural class of biologically active compounds. 3 In view of the ready availability and easy preparation of the heteroaromatic compounds bearing a group, 4 the asymmetric reduction of such compounds would provide an efficient and straightforward access to the corresponding chiral heterocycles containing a stereogenic group. owever, because of their resonance stability and the difficulty to control the stereoselectivity, there is little information available in literature on the asymmetric reduction of -substituted aromatics. Chiral phosphoric acids (CPAs) and derivatives, originally developed by Akiyama et al. 5 and Terada et al. 6 in 04, have emerged as an attractive and powerful tool in asymmetric catalysis. 7 The interest towards CPA-catalyzed asymmetric transfer hydrogenation (AT) was developed in 05, when Rueping et al. 8 and List et al. 9 independently reported the AT of ketimines. Over the last few years, much progress has been made in the CPA-catalyzed AT of C=C, C=, and C=O double bonds 0 as well as heteroaromatics with antzsch esters (E) 2 as the hydrogen source. As part of our ongoing research program toward the asymmetric reduction of aromatic compounds, 3 herein, we report the first CPA-catalyzed transfer hydrogenation of heteroaromatics bearing a group 3-(trifluoromethyl)quinolines 4 with up to 98% ee (Scheme ). SYTESIS 4, 46, Advanced online publication: X DOI: 0.055/s ; Art ID: SS-4-h0325-OP Georg Thieme Verlag Stuttgart ew York Scheme Retrosynthetic analysis of the asymmetric reduction of 3-(trifluoromethyl)quinolines Our studies began by using 2-phenyl-3-(trifluoromethyl)quinoline (a) as a model substrate. First, the reaction was carried out in toluene using CPA (S)-3a as the catalyst and E 2a as the hydrogen source at 25 C. The reaction proceeded smoothly to give the desired product 4a in 94% yield with 25% ee (Table, entry ). Encouraged by the promising result, the effect of the solvent was tested subsequently (Table, entries 2 5). The survey showed that the yield of 4a was uniformly good in most solvents, whereas the enantioselectivity exhibited a significant dependence upon the solvent identity and the best ee value was obtained when C 2 Cl 2 was employed (35% ee; entry 3). Further investigation on various commercially available CPAs showed that catalyst (S)-3d was the best choice (entries 6 8), which gave the target product 4a with the highest enantioselectivity (97% ee; entry 8). It is noteworthy that the steric bulk of the aryl moieties at the 3,3 -positions of CPA displayed a dramatic influence on the stereoselectivities, the sterically demanding catalyst (S)-3b, (S)-3c, and (S)-3d gave the product (2R,3S)-4a (entries 6 8) while the catalyst (S)-3a with the smaller phenyl group yielded the opposite enantiomer (2S,3R)-4a (entry 3). The reasons for the different stereoselectivities are elusive for the moment. Lastly, several dihydropyridines 2 were evaluated (entries 9 ). The ee value of 4a was improved to 98% by using 2d bearing acetyl group at 3,3 -position as the hydrogen source (entry ). Thus, the optimized reaction conditions are: CPA (S)- 3d (5 mol%), dihydropyridine 2d (2.4 equiv), C 2 Cl 2. aving established the optimized reaction conditions, a series of 3-(trifluoromethyl)quinolines were investigated, and the results are summarized in Table 2. For 2-aryl-substituted substrates, the reactions proceeded smoothly to deliver the corresponding products with high to excellent ee values and in high yields (93 98% ee, 89 96% yields;

2 2752 R.-. Guo et al. PAPER Table Evaluation of Reaction Parameters a a + R O 2 2a: R = OEt 2b: R = OMe 2c: R = Ot-Bu 2d: R = Me Ar (S)-3 (5 mol%) solvent, 25 C Entry Solvent 2 (S)-3 Yield (%) b ee (%) c toluene 2a 3a benzene 2a 3a 94 3 C 2 Cl 2 2a 3a d 4 CCl 3 2a 3a 97 3 d 5 ClC 2 C 2 Cl 2a 3a d 6 C 2 Cl 2 2a 3b C 2 Cl 2 2a 3c C 2 Cl 2 2a 3d C 2 Cl 2 2b 3d C 2 Cl 2 2c 3d <5 C 2 Cl 2 2d 3d O a Conditions: 2-enyl-3-(trifluoromethyl)quinoline (a; 0.0 mmol), dihydropyridine 2 (2.4 equiv), chiral phosphoric acid (S)-3 (5 mol%), solvent (3 ml), 25 C, h. b Isolated yield of 4a based on a. 5 c Determined by PLC analysis. d The opposite enantiomer was obtained. Table 2, entries 9). Both electron-donating and electron-withdrawing groups were tolerated under the standard reaction conditions. The hydrogenation of 6- methoxy-substituted substrate j gave the product 4j in 8% yield with good 84% ee (entry 0). This method was successfully applied to the 2-methylsubstituted substrate k, the desired product 4k was obtained with low diastereoselectivity (62:38) albeit with high ee values (Scheme 2). Scheme 2 Asymmetric transfer hydrogenation of 2-methyl-3-(trifluoromethyl)quinoline (k) R O P O O O Ar (S)-3 4a 3a: Ar = 3b: Ar = 9-phenanthryl [ 8 ] 3c: Ar = -naphthyl [ 8 ] 3d: Ar = 2,4,6-(i-Pr) 3 C 6 2 2d (2.4 equiv) (S)-3d (5 mol%) C 2 Cl 2, 35 C k 4k 74% yield, dr 62:38 93 and 86% ee Table 2 Asymmetric Transfer ydrogenation of 3-(Trifluoromethyl)quinolines a R R 2 2d (2.4 equiv) (S)-3d (5 mol%) C 2 Cl 2, C 4 Entry R, R 2 Temp ( C) Yield (%) b ee (%) c, (4a) 98 ( ) 2, 3-MeC (4b) 97 ( ) 3, 4-MeC (4c) 97 ( ) 4, 4-t-BuC (4d) 94 ( ) 5, 3-MeOC (4e) 97 ( ) 6, 4-MeOC (4f) 95 (2R,3S) 7, 4-ClC (4g) 97 ( ) 8, 4- C (4h) 97 ( ) 9, 2-naphthyl (4i) 93 ( ) 0 MeO, 35 8 (4j) 84 ( ) a Conditions: 3-(Trifluoromethyl)quinoline (0.0 mmol), dihydropyridine 2d (2.4 equiv), chiral phosphoric acid (S)-3d (5 mol%), C 2 - Cl 2 (3 ml), 8 48 h. b Isolated yields based on. 5 c Determined by PLC analysis. The 2-alkynyl-substituted 2-(phenylethynyl)-3-(trifluoromethyl)quinoline (m) could also be completely transformed while the conjugated C C triple bond was preserved. The corresponding products were obtained in high yield, poor diastereoselectivity, and high enantioselectivities (Scheme 3). 2d (2.4 equiv) CF 3 (S)-3d (5 mol%) + C 2 Cl 2, 35 C m trans-4m 47% yield, 92% ee Scheme 3 Asymmetric transfer hydrogenation of 3-(trifluoromethyl)quinoline m 6 After recrystallization from C 2 Cl 2 hexane, enantiomerically pure product 4f (>99% ee) was obtained as colorless crystals. Its absolute configuration was determined to be cis-(2r,3s) based on single crystal X-ray diffraction analysis 7 (Figure ). In conclusion, we have developed a chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation of 3- (trifluoromethyl)quinolines, with up to 98% ee. The different diastereoselectivities for the different substrates maybe attributed to the different electronic effect of aryl, alkyl, and alkynyl substituents. This method provides a direct and facile access to optically pure 2,3-disubstituted,2,3,4-tetrahydroquinoline derivatives containing a stereogenic group. otably, this is the first report on highly asymmetric reduction of -substituted aromat- R R 2 cis-4m 43% yield, 78% ee Synthesis 4, 46, Georg Thieme Verlag Stuttgart ew York

3 PAPER Asymmetric Transfer ydrogenation 2753 Figure Absolute configuration of the asymmetric transfer hydrogenation product 4f ics. Further work will be devoted to the application of the developed strategy. Commercially available reagents were used without further purification. Solvents were purified prior to use according to the standard methods., 3 C, and F MR spectra were recorded at r.t. in CD- Cl 3 on a 400 Mz instrument with TMS as internal standard. Enantiomeric excess was determined by PLC analysis, using chiral columns described below in detail. Optical rotations were measured by polarimeter. Flash column chromatography was performed on silica gel (0 300 mesh). Asymmetric Transfer ydrogenation of 3-(Trifluoromethyl)quinolines; General Procedure A mixture of the appropriate 3-(trifluoromethyl)quinoline (0.0 mmol), dihydropyridine 2d (46 mg, 0.24 mmol, 2.4 equiv), and chiral phosphoric acid (S)-3d (3.8 mg, mmol, 5 mol%) in C 2 Cl 2 (3 ml) was stirred under 2 for 8 48 h. After completion of reaction (TLC monitoring, eluent: hexane EtOAc, :), the solvent was removed under reduced pressure. Purification was performed by silica gel column chromatography eluting with hexane EtOAc (80: to :) to give the desired product (Table 2). The enantiomeric excesses were determined by chiral PLC. ( )-2-enyl-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4a) Yield: 26 mg (94%); 98% ee; colorless oil; R f = 0.70 (hexane EtOAc, :); [α] D 53. (c 0.52, C 2 Cl 2 ). PLC: Chiracel OD- column, 254 nm, 30 C, n-hexane i- PrO (70:30), flow = 0.7 ml/min, t R =.9 min (major) and 6.0 min. IR (film): 3060, 2928, 2859, 63, 495, 442, 388, 330, 275, 34, 030 cm. MR (400 Mz, CDCl 3 ): δ = (m, 5 ), (m, 2 ), 6.7 (td, J = 7.4,.0 z, ), 6.55 (d, J = 8.0 z, ), 4.8 (d, J = 3.9 z, ), 4.40 (s, ), (m, ), 2.93 (d, J = 9.0 z, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 43., 4.5, 29.5, 28.3, 27.9, 27.9, 27.5, 26.6 (q, J F,C = z), 7.5, 7.3, 3.7, 53.4 (q, 3 J F,C = 2.4 z), 42.2 (q, 2 J F,C = 26.3 z), 22.6 (q, 3 J F,C = 2.6 z). F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = 278. ([M + ] + ), 257.9, 238.0, 0.0. RMS (ESI): m/z [M + ] + calcd for C 6 4 F 3 : 278.5; found: ( )-2-(m-Tolyl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4b) Yield: 28 mg (96%); 97% ee; colorless oil; R f = 0.45 (hexane EtOAc, :); [α] D 66.6 (c 0.56, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 9.2 min (major) and 3.3 min. IR (film): 3022, 2927, 2863, 603, 494, 453, 386, 329, 274, 65, 34 cm. MR (400 Mz, CDCl 3 ): δ = 7.07 (t, J = 7.9 z, ), (m, 5 ), (m, ), 6.47 (d, J = 8.0 z, ), 4.69 (d, J = 3.7 z, ), 4.29 (s, ), (m, 3 ), 2.2 (s, 3 ). 3 C MR (00 Mz, CDCl 3 ): δ = 43., 4.5, 37.9, 30.8, 29.5, 28.7, 28.2, 27.9, 26.6 (q, J FC = z), 24.5, 7.4, 7.4, 3.7, 53.5 (q, 3 J F,C = 2.2 z), 42.2 (q, 2 J F,C = 26.3 z), 22.7 (q, 3 J F,C = 2.5 z), 2.5. F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 272.0, 252.0, 9.9. RMS (ESI): m/z [M + ] + calcd for C 7 7 F 3 : ; found: ( )-2-(p-Tolyl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4c) Yield: 26 mg (89%); 98% ee; colorless oil; R f = 0.45 (hexane EtOAc, :); [α] D 28. (c 0.54, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 8.9 min (major) and 3.2 min. IR (film): 3025, 2926, 2860, 608, 497, 44, 387, 328, 27, 6, 027 cm. MR (400 Mz, CDCl 3 ): δ = (m, 6 ), 6.70 (t, J = 7.4 z, ), 6.55 (d, J = 8.0 z, ), 4.79 (d, J = 3.8 z, ), 4.40 (s, ), (m, ), 2.93 (dd, J = 2.8, 5.9 z, 2 ), 2.3 (s, 3 ). 3 C MR (00 Mz, CDCl 3 ): δ = 42., 37.5, 36.6, 28.5, 28.0, 26.8, 26.4, 25.6 (q, J F,C = z), 6.4, 6.3, 2.6, 52. (q, 3 J F,C = 2.4 z), 4. (q, 2 J F,C = 26.3 z), 2.6 (q, 3 J F,C =2.4 z),.0. F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 272.0, 252.0, 9.9. RMS (ESI): m/z [M + ] + calcd for C 7 7 F 3 : ; found: ( )-2-(4-tert-Butylphenyl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4d) Yield: 3 mg (93%); 94% ee; white solid; mp C; R f = 0.35 (hexane EtOAc, :); [α] D 56.8 (c 0.62, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 7.6 min (major) and.3 min. IR (KBr): 3056, 2959, 2866, 65, 494, 427, 384, 327, 27, 23, 064 cm. MR (400 Mz, CDCl 3 ): δ = (m, 2 ), 7.4 (d, J = 8.4 z, 2 ), 7.06 (dd, J = 3.2, 7. z, 2 ), 6.70 (td, J =7.4,.0 z, ), 6.54 (d, J = 8.0 z, ), 4.78 (d, J = 3.7 z, ), 4.38 (s, ), (m, 3 ),.28 (s, 9 ). 3 C MR (00 Mz, CDCl 3 ): δ = 50.9, 43.2, 38.4, 29.5, 27.8, 27.2, 26.6 (q, J F,C = z), 25.2, 7.4, 7.4, 3.7, 53. (q, 3 J F,C = 2.4 z), 42.2 (q, 2 J F,C = 26.2 z), 34.5, 3.3, 22.7 (q, 3 J F,C = 2.5 z). F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 294.0, 278.0, 9.9. RMS (ESI): m/z [M + ] + calcd for C 23 F 3 : ; found: ( )-2-(3-Methoxyphenyl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4e) Yield: 29 mg (95%); 97% ee; white solid; mp C; R f =0.35 (hexane EtOAc, :); [α] D 54.5 (c 0.58, C 2 Cl 2 ). Georg Thieme Verlag Stuttgart ew York Synthesis 4, 46,

4 2754 R.-. Guo et al. PAPER (70:30), flow = 0.7 ml/min, t R = 0.8 min (major) and 7.5 min. IR (KBr): 3030, 2930, 2849, 606, 494, 45, 385, 327, 276, 63, 30, 094, 048 cm. MR (400 Mz, CDCl 3 ): δ = 7.8 (t, J = 7.9 z, ), 7.05 (dd, J = 3.7, 7.2 z, 2 ), (m, 3 ), 6.70 (td, J = 7.4,.0 z, ), 6.55 (d, J = 7.6 z, ), 4.77 (d, J = 3.7 z, ), 3.7 (s, 3 ), (m, ), 2.95 (dd, J = 0., 4.6 z, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 59.5, 43., 43.0, 29.5, 29.3, 27.9, 26.6 (q, J FC = z),.9, 7.6, 7.3, 3.7, 3.6, 3.0, 55., 53.4 (q, 3 J F,C = 2.4 z), 42.2 (q, 2 J F,C = 26.3 z), 22.7 (q, 3 J F,C = 2.5 z). F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 288.0, 267.9, 0.. RMS (ESI): m/z [M + ] + calcd for C 7 7 F 3 O: ; found: (2R,3S)-2-(4-Methoxyphenyl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4f) Yield: 28 mg (9%); 95% ee; white solid; mp C; R f =0.30 (hexane EtOAc, :); [α] D 4.4 (c 0.42, C 2 Cl 2, for >99% ee). (70:30), flow = 0.7 ml/min, t R =.0 min (major) and 6.7 min. IR (KBr): 2926, 2850, 67, 503, 386, 329, 26, 66,, 098, 026 cm. MR (400 Mz, CDCl 3 ): δ = 7.3 (d, J = 8.6 z, 2 ), 7.06 (dd, J = 4.2, 7.3 z, 2 ), 6.79 (d, J = 8.7 z, 2 ), 6.70 (t, J =7.4 z, ), 6.55 (d, J = 8.0 z, ), 4.77 (s, ), (s, ), 3.77 (s, 3 ), (m, ), 2.92 (d, J = 8.3 z, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 59.3, 43., 33.6, 29.5, 28.6, 27.9, 26.6 (q, J F,C = z), 7.4, 7.3, 3.7, 3.6, 55.2, 52.8 (q, 3 J F,C = 2.4 z), 42.2 (q, 2 J F,C = 42.2 z), 22.5 (q, 3 J F,C =2.5 z). F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 288.0, 0.0. RMS (ESI): m/z [M + ] + calcd for C 7 7 F 3 O: ; found: ( )-2-(4-Chlorophenyl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4g) Yield: 30 mg (96%); 97% ee; colorless oil; R f = 0.45 (hexane EtOAc, :); [α] D 52.7 (c 0.60, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 9.4 min (major) and 7.2 min. IR (film): 3058, 2928, 286, 602, 493, 399, 330, 274, 00, 03 cm. MR (400 Mz, CDCl 3 ): δ = (m, 2 ), 7.4 (d, J = 8.5 z, 2 ), 7.07 (dd, J = 6.3, 7.8 z, 2 ), 6.72 (td, J =7.4, 0.9 z, ), 6.56 (d, J = 8.0 z, ), 4.80 (d, J = 3.9 z, ), 4.39 (s, ), (m, ), (m, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 42.7, 40.0, 33.8, 29.6, 28.9, 28.5, 28.0, 26.5 (q, J F,C = z), 7.7, 7.0, 3.7, 52.8 (q, 3 J F,C = 2.5 z), 42. (q, 2 J F,C = 26.4 z), F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = 33.0 ([M + ] + ), 293.0, 273.0, 9.9. RMS (ESI): m/z [M + ] + calcd for C 6 4 ClF 3 : ; found: ( )-3-(Trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]-,2,3,4- tetrahydroquinoline (4h) Yield: 33 mg (96%); 97% ee; colorless oil; R f = 0.70 (hexane C 2 - Cl 2, 2:); [α] D 46.7 (c 0.66, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 8.6 min (major) and 8.7 min. IR (film): 2925, 2859, 623, 498, 425, 390, 329, 275, 64, 2, 066, 023 cm. MR (400 Mz, CDCl 3 ): δ = 7.52 (d, J = 8.2 z, 2 ), 7.34 (d, J = 8. z, 2 ), 7.09 (dd, J = 6.4, 7.9 z, 2 ), 6.74 (t, J =7.4 z, ), 6.58 (d, J = 8.0 z, ), 4.88 (d, J = 4.0 z, ), 4.0 (s, ), (m, ), (m, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 45.4, 42.5, 30.2 (q, 2 J F,C = 32.4 z), 29.6, 28., 27.9, 26.4 (q, J F,C = z), 25.3 (q, 3 J F,C = 3.7 z), 24.0 (q, J F,C = z), 7.9, 7.0, 3.8, 53. (q, 3 J F,C = 2.3 z), 42. (q, 2 J F,C = 26.7 z), 22.4 (q, 3 J F,C = 2.5 z). F MR (376 Mz, CDCl 3 ): δ = 62.6, MS (ESI): m/z = ([M + ] + ), 326.0, 306.0, 9.9. RMS (ESI): m/z [M + ] + calcd for C 7 4 F 6 : ; found: ( )-2-(aphthalen-2-yl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4i) Yield: 30 mg (92%); 93% ee; white solid; mp 0 2 C; R f = 0.35 (hexane EtOAc, :); [α] D (c 0.60, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 5. min (major) and.3 min. IR (KBr): 3050, 2924, 2855, 64, 494, 387, 332, 270, 60, 7 cm. MR (400 Mz, CDCl 3 ): δ = (m, ), (m, 2 ), 7.66 (s, ), (m, 2 ), 7.32 (dd, J = 8.6,.4 z, ), 7.09 (dd, J = 5.9, 7.7 z, 2 ), 6.74 (td, J = 7.4,.0 z, ), (m, ), 4.95 (d, J = 3.8 z, ), 4.36 (s, ), (m, ), (m, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 43., 39.0, 33., 33.0, 29.6, 28., 28.0, 28.0, 27.6, 26.6 (q, J FC = z), 26.5, 26.2, 26., 25.5, 7.6, 7.4, 3.7, 53.6 (q, 3 J F,C = 2.3 z), 42.3 (q, 2 J F,C = 26.3 z), 22.8 (q, 3 J F,C = 2.5 z). F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 308.0, 288.0, 0.0. RMS (ESI): m/z [M + ] + calcd for C 7 F 3 : ; found: ( )-6-Methoxy-2-phenyl-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4j) Yield: 25 mg (8%); 85% ee; colorless oil; R f = 0.5 (hexane C 2 - Cl 2 2:); [α] D 33.4 (c 0.50, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 9.3 min and 8.0 min (major). IR (film): 2926, 285, 66, 50, 435, 386, 26, 66,, 098, 025 cm. MR (400 Mz, CDCl 3 ): δ = (m, 3 ), (m, 2 ), 6.73 (dd, J = 8.6, 2.8 z, ), 6.67 (d, J = 2.8 z, ), 6.54 (d, J = 8.6 z, ), 4.79 (d, J = 3.9 z, ), 4.2 (s, ), 3.78 (s, 3 ), (m, ), (m, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 52.2, 4.8, 37.4, 28.5, 28.0, 27.6, 26.8 (q, J F,C = z) 8.6, 5.0, 4.8, 4.4, 56.0, 53.8 (q, 3 J F,C = 2.3 z), 42.4 (q, 2 J F,C = 26. z), 23.2 (q, 3 J F,C =2.7 z). F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 293.0, 288.0, Synthesis 4, 46, Georg Thieme Verlag Stuttgart ew York

5 PAPER Asymmetric Transfer ydrogenation 2755 RMS (ESI): m/z [M + ] + calcd for C 7 7 F 3 O: ; found: Methyl-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (4k) Yield: 6 mg (74%, inseparable mixture of two diastereoisomers); 62:38 dr; 93% and 86% ee; colorless oil; R f = 0.55 (hexane EtOAc, :). PLC (for 93% ee): Chiracel OD- column, 254 nm, 30 C, n-hexane i-pro (70:30), flow = 0.7 ml/min, t R = 6.6 min and 7.8 min (major). PLC (for 86% ee): Chiracel OD- column, 254 nm, 30 C, n-hexane i-pro (70:30), flow = 0.7 ml/min, t R = 6.9 min (major) and 8.9 min. IR (film): 2963, 2925, 2859, 628, 455, 395, 262, 095, 026 cm. MR (400 Mz, CDCl 3 ): δ = 6.93 (t, J = 6.9 z, 2 ), 6.59 (t, J = 7.2 z, ), 6.43 (d, J = 8.3 z, ), (m, 0.38 ), 3.58 (s, ), (m, ), (m, 2 ), (m, 0.38 ), (m, 0.62 ),.26 (d, J = 6.2 z,.89 ),.3 (d, J = 6.5 z,.4 ). 3 C MR (00 Mz, CDCl 3 ): δ = 43.5, 42.3, 29.5, 29.2, 27.5, 27.4, 27.2 (q, J F,C = 278. z), 27.0 (q, J F,C = z), 8.6, 7.9, 7.7, 7.3, 4.8, 4.0, 47.2 (q, 3 J F,C =2. z), 44.8 (q, 3 J F,C = 2.7 z), 43.6 (q, 2 J F,C = 25.2 z), 4. (q, 2 J F,C = 26.6 z), 26.6 (q, 3 J F,C = 3.4 z), 22.4 (q, 3 J F,C =2.9 z),.9 (q, 4 J F,C =.6 z), 7.4 (q, 4 J F,C =.4 z). F MR (376 Mz, CDCl 3 ): δ = 68.6, MS (ESI): m/z = 26.0 ([M + ] + ), 6.0, RMS (ESI): m/z [M + ] + calcd for C 3 F 3 : ; found: trans-2-(enylethynyl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (trans-4m) Yield: 4 mg (47%); 92% ee; colorless oil; R f = 0.70 (hexane EtOAc, :); [α] D 28.9 (c 0.28, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 7. min (major) and 8.0 min. IR (film): 3063, 2927, 2858, 2227, 602, 490, 435, 384, 300, 255, 6, 2 cm. MR (400 Mz, CDCl 3 ): δ = (m, 2 ), (m, 3 ), (m, 2 ), 6.67 (t, J = 7. z, ), 6.53 (d, J =7.8 z, ), 4.48 (d, J = 6.6 z, ), 4.00 (s, ), 3.6 (dd, J = 6.5, 5.8 z, ), (m, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 42., 3.7, 29., 28.6, 28.3, 27.4, 26.4 (q, J F,C = z), 22.3, 8.9, 8.4, 4.8, 87.2, 84.3, 43.4 (q, 3 J F,C = 3.0 z), 42.5 (q, 2 J F,C = 25.9 z), 25.0 (q, 3 J F,C = 2.6 z). F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 282.0, RMS (ESI): m/z [M + ] + calcd for C 8 5 F 3 : 302.5; found: cis-2-(enylethynyl)-3-(trifluoromethyl)-,2,3,4-tetrahydroquinoline (cis-4m) Yield: 3 mg (43%); 78% ee; white solid; mp C; R f =0.55 (hexane EtOAc, :); [α] D 85.8 (c 0.26, C 2 Cl 2 ). (70:30), flow = 0.7 ml/min, t R = 8.3 min (major) and 0.8 min. IR (KBr): 3063, 2925, 2858, 2224, 602, 488, 439, 388, 330, 264, 62, 00 cm. MR (400 Mz, CDCl 3 ): δ = 7.32 (dd, J = 7.5,.9 z, 2 ), (m, 3 ), 7.05 (dd, J = 7., 4.3 z, 2 ), 6.76 (t, J =7.2 z, ), (m, ), 4.69 (s, ), 3.35 (dd, J = 6.6, 4. z, ), (m, 2 ). 3 C MR (00 Mz, CDCl 3 ): δ = 4.6, 3.7, 29.5, 28.4, 28.2, 27.4, 26. (q, J F,C = z), 22.5,., 8.6, 5.6, 86.0, 84.9, 42.3 (q, 3 J F,C = 3.6 z), 4.8 (q, 2 J F,C = 27. z), 23.4 (q, 3 J F,C = 2. z). F MR (376 Mz, CDCl 3 ): δ = MS (ESI): m/z = ([M + ] + ), 282.0, RMS (ESI): m/z [M + ] + calcd for C 8 5 F 3 : 302.5; found: Acknowledgment We are grateful for the financial support from ational Science Foundation of China (992) and ational Basic Research Program (0CB833300). Supporting Information for this article is available online at /s SuportingInformationSuportingInformation References () (a) Ma, J.-A.; Cahard, D. Chem. Rev. 04, 04, 6. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 08, 37, 3. (c) Ma, J.-A.; Cahard, D. Chem. Rev. 08, 08, PR. (d) Cahard, D.; Xu, X.; Couve- Bonnaire, S.; Pannecoucke, X. Chem. Soc. Rev. 0, 39, 558. (e) Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 0, 352, (f) ie, J.; Guo,.-C.; Cahard, D.; Ma, J.-A. Chem. Rev.,, 455. (g) e,.-r.; uang, Y.-Y.; Verpoort, F. Acta Chim. Sin. 3, 7, 700. (2) (a) iyama, T. Organofluorine Compounds: Chemistry and Applications; Springer: ew York, 00. (b) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; Wiley: oboken, 00. (c) Müller, K.; Faeh, C.; Diederich, F. Science 07, 37, 88. (d) Furuya, T.; Kamlet, A. S.; Ritter, T. ature, 473, 470. (3) Petrov, V. A. Fluorinated eterocyclic Compounds: Synthesis, Chemistry, and Applications; Wiley: ew Jersey, 09. (4) For recent reviews, see: (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev.,, (b) Pan, F.; Shi, Z. Acta Chim. Sin. 2, 70, 679. (c) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem. Int. Ed. 2, 5, (d) Studer, A. Angew. Chem. Int. Ed. 2, 5, (e) Liu,.; Gu, Z.-.; Jiang, X.-F. Adv. Synth. Catal. 3, 355, 67. (f) Chu, L.; Qing, F.-L. Acc. Chem. Res. 4, 47, 53. (5) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 04, 43, 566. (6) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 04, 26, (7) For reviews, see: (a) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 09, 38,. (b) ie, J.; Zhang, G.-W.; Wang, L.; Zheng, D.-.; Zheng, Y.; Ma, J.-A. Eur. J. Org. Chem. 09, 345. (c) Terada, M. Synthesis 0, 29. (d) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev., 40, (e) Wu, X.; Li, M.; Gong, L. Acta Chim. Sin. 3, 7, 09. (8) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 05, 7, 378. (9) offmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed. 05, 44, Georg Thieme Verlag Stuttgart ew York Synthesis 4, 46,

6 2756 R.-. Guo et al. PAPER (0) For selected examples, see references 8, 9 and: (a) Storer, R. I.; Carrera, D. E.; i, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 06, 28, 84. (b) Mayer, S.; List, B. Angew. Chem. Int. Ed. 06, 45, 43. (c) offmann, S.; icoletti, M.; List, B. J. Am. Chem. Soc. 06, 28, (d) Martin,. J. A.; List, B. J. Am. Chem. Soc. 06, 28, (e) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 07, 29, (f) Kang, Q.; Zhao, Z.-A.; You, S.-L. Adv. Synth. Catal. 07, 349, 657. (g) Kang, Q.; Zhao, Z.-A.; You, S.-L. Org. Lett. 08, 0, 3. (h) Rueping, M.; Brinkmann, C.; Antonchick, A. P.; Atodiresei, I. Org. Lett. 0, 2, (i) Wakchaure, V..; Zhou, J.; ouffmann, S.; List, B. Angew. Chem. Int. Ed. 0, 49, 462. (j) enseler, A.; Kato, M.; Mori, K.; Akiyama, T. Angew. Chem. Int. Ed., 50, 880. (k) Zhang, Z.; Jain, P.; Antilla, J. C. Angew. Chem. Int. Ed., 50, 096. (l) Chen, Q.-A.; Chen, M.- W.; Yu, C.-B.; Shi, L.; Wang, D.-S.; Yang, Y.; Zhou, Y.-G. J. Am. Chem. Soc., 33, (m) Chen, M.-W.; Chen, Q.-A.; Duan, Y.; Ye, Z.-S.; Zhou, Y.-G. Chem. Commun. 2, 48, 698. (n) Yin, Q.; Wang, S.-G.; You, S.- L. Org. Lett. 3, 5, (o) Saito, K.; Kajiwara, Y.; Akiyama, T. Angew. Chem. Int. Ed. 3, 52, (p) Chen, Z.-P.; Chen, M.-W.; Guo, R.-.; Zhou, Y.-G. Org. Lett. 4, 6, 406. () (a) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem. Int. Ed. 06, 45, (b) Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem. Int. Ed. 08, 47, 759. (c) Rueping, M.; Theissmann, T.; Raja, S.; Bats, J. W. Adv. Synth. Catal. 08, 350, 00. (d) Rueping, M.; Theissmann, T. Chem. Sci. 0,, 473. (e) Rueping, M.; Tato, F.; Schoepke, F. R. Chem. Eur. J. 0, 6, (f) Rueping, M.; Koenigs, R. M. Chem. Commun., 47, 304. (g) Rueping, M.; Theissmann, T.; Stoeckel, M.; Antonchick, A. P. Org. Biomol. Chem., 9, (h) Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G.; Duan, Y.; Fan,.-J.; Yang, Y.; Zhang, Z. J. Am. Chem. Soc., 33, 626. (i) Chen, Q.-A.; Gao, K.; Duan, Y.; Ye, Z.-S.; Shi, L.; Yang, Y.; Zhou, Y.-G. J. Am. Chem. Soc. 2, 34, (j) Tu, X.-F.; Gong, L.-Z. Angew. Chem. Int. Ed. 2, 5, 346. (k) Cai, X.-F.; Chen, M.-W.; Ye, Z.-S.; Guo, R.-.; Shi, L.; Li, Y.-Q.; Zhou, Y.-G. Chem. Asian J. 3, 8, 38. (l) Stemper, J.; Isaac, K.; Pastor, J.; Frison, G.; Retailleau, P.; Voituriez, A.; Betzer, J.-F.; Marinetti, A. Adv. Synth. Catal. 3, 355, 363. (m) Wang, S.-G.; You, S.-L. Angew. Chem. Int. Ed. 4, 53, 24. (n) Cai, X.-F.; Guo, R.-.; Feng, G.-S.; Wu, B.; Zhou, Y.-G. Org. Lett. 4, 6, (2) For recent reviews on asymmetric reactions using E as hydrogen source, see: (a) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C. Acc. Chem. Res. 07, 40, 327. (b) You, S.-L. Chem. Asian J. 07, 2, 8. (c) Connon, S. J. Org. Biomol. Chem. 07, 5, (d) Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett 0, 852. (e) Rueping, M.; Dufour, J.; Schoepke, F. R. Green Chem., 3, 084. (f) Zheng, C.; You, S.-L. Chem. Soc. Rev. 2, 4, (3) For recent reviews, see: (a) Zhou, Y.-G. Acc. Chem. Res. 07, 40, 357. (b) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G. Chem. Rev. 2, 2, (c) Glorius, F. Org. Biomol. Chem. 05, 3, 47. (d) Chen, Q.-A.; Ye, Z.- S.; Duan, Y.; Zhou, Y.-G. Chem. Soc. Rev. 3, 42, 497. (e) Lu, S.-M.; an, X.-W.; Zhou, Y.-G. Chin. J. Org. Chem. 05, 25, 634. (4) For selected examples on asymmetric reduction of quinolines, see references a,b,i,j and: (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; an, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 03, 25, (b) Zhou,.; Li, Z.; Wang, Z.; Wang, T.; Xu, L.; e, Y.; Fan, Q.-.; Pan, J.; Gu, L.; Chan, A. S. C. Angew. Chem. Int. Ed. 08, 47, (c) Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J. Angew. Chem. Int. Ed. 09, 48, (d) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; e, Y.; Fan, Q.-.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. J. Am. Chem. Soc., 33, (5) The cis-isomers of products are formed in high selectivity and, unless otherwise stated, they are the only visible products. (6) The relative configuration are proposed by comparison of their coupling constants in MR spectra and also by analogy with the compound 4f. (7) CCDC contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at or from the Cambridge Crystallographic Data Centre, 2 Union Road, Cambridge CB2 EZ, UK; fax: +44(223)336033; deposit@ccdc.cam.ac.uk. Synthesis 4, 46, Georg Thieme Verlag Stuttgart ew York