English

• 1.   Introduction

  The enantioselective addition of carbon-based nucleophiles to organic carbonyl compounds provides the most straightforward strategy for the construction of optically active alcohols.^[1~5] The optically active diaryl alcohols bearing heteroaryl such as furyl, thienyl, pyridyl or indolyl groups are well-known for their biological activity as well as key substructure in bioactive compounds and pharmaceuticals.^[6] However, their syntheses were sporadically reported in a few papers via addition of organometallic reagents to heteroaryl-substituted carbonyl compounds or reduction of diaryl ketones bearing heteroaryl groups.^[7] The catalytic enantioselective addition of heteroaryl nucleophiles to organic carbonyl compounds provided a systematical approach to synthesize chiral heteroaryl alcohols.

  The optically active furyl alcohols have been realized through the asymmetric addition of furylaluminum reagent^[8] or furyltitanium reagent^[9] to ketones in the presence of 10 mol% (S)-1, 1'-binaphthol ((S)-BINOL). The optically active thienyl alcohols were also reported through the asymmetric additions of thienylboronic acid^[10] or thienylaluminum reagents^[11] to organic carbonyl compounds in good yields and high enantioselectivities. Recently, heteroaryl zincs^[12] and titanium reagents^[13] bearing thienyl, benzothienyl, furyl and indolyl groups were also applied to asymmetric addition of aldehydes affording aryl heteroaryl-or diheteroaryl-methanol derivatives in high enantio-selectivities. More recently, we have also reported the catalytic asymmetric addition of pyridylaluminums to aldehydes catalyzed by a titanium catalytic system of (R)-H₈-BINOLate.^[14] As a continuous research on asymmetric heteroaryl addition to organic carbonyl compounds, we herein report the catalytic asymmetric addition of 3-thienyl aluminum to ketones catalyzed by a titanium catalytic system of (S)-BINOL to afford the chiral diarylmethanols bearing 3-thienyl group.

  2.   Results and discussion

  Asymmetric addition reactions of (3-thienyl)AlEt₂-(OEt₂) to acetophenone (1a) were first optimized, and the results are summarized in Table 1. Tuning the amounts of Ti(OⁱPr)₄ and (3-thienyl)AlEt₂(OEt₂), the optimal reaction conditions of 3.5 equiv. of Ti(OⁱPr)₄ and 3.0 equiv. of (3-thienyl)AlEt₂(OEt₂) in the presence of 10 mol% (S)-BINOL in toluene at 0 ℃ were found to afford product 3a in a 88% yield with an excellent 90% ee (Entry 7). The investigations for the choice of the solvent showed that toluene was the best one (Entries 7, 9~12). For the optimal catalytic systems, different chiral ligands (Figure 1) were test for asymmetric addition reactions (Entries 7, 13~16). Results showed that the commercially available and relatively cheap chiral ligand, (S)-BINOL, was the most efficient one to afford the chiral alcohol 3a in a 88% yield with an excellent 90% ee (Entry 7).

  Table 1

  

  Table 1.  Optimization of enantioselective addition of 3-thienyl aluminum to acetophenone^a

  下载: 导出CSV

  Entry	Ligand	Ti(OiPr)4b/equiv.	(3-Thienyl)Al b/equiv.	Solvent	Yield/%	ee c/%
  1	(S)-BINOL	5.0	1.5	Toluene	21	82
  2	(S)-BINOL	5.0	2.0	Toluene	31	85
  3	(S)-BINOL	5.0	2.5	Toluene	53	84
  4	(S)-BINOL	5.0	3.0	Toluene	35	89
  5	(S)-BINOL	5.0	3.5	Toluene	40	82
  6	(S)-BINOL	2.5	3.0	Toluene	70	62
  7	(S)-BINOL	3.5	3.0	Toluene	88	90
  8	(S)-BINOL	4.0	3.0	Toluene	50	88
  9	(S)-BINOL	3.5	3.0	THF	62	84
  10	(S)-BINOL	3.5	3.0	n-Hexane	63	88
  11	(S)-BINOL	3.5	3.0	Et2O	93	81
  12	(S)-BINOL	3.5	3.0	CH2Cl2	85	31
  13	A	3.5	3.0	Toluene	50	25
  14	B	3.5	3.0	Toluene	40	-10
  15	C	3.5	3.0	Toluene	60	-51
  16	D	3.5	3.0	Toluene	45	15
  a Condition: acetophenone (1.00 mmol), solvent (5.0 mL), time: 12 h. b Equivalents of Ti(OiPr)4 and 2 are relative to acetophenone. c Enantioselectivities were determined by HPLC.

  Figure 1

  

  Figure 1.  Different chiral ligands

  下载: 全尺寸图片 幻灯片

  With the optimized conditions established, the asymmetric addition of 3-thienyl aluminum reagent to functionalized ketones were then studied, and the results were listed in Table 2. For aromatic ketones with either an electron-withdrawing substituent at the aryl ring, 3-thienyl additions afforded tertiary alcohols in high yields with excellent enantioselectivities of 90% ee or higher (Entries 1~7), except for substrates of 2'-nitroacetophenone (1b) and 4'-bromoacetophenone (1e), which afforded 3b and 3e in 88% and 86% ee (Entries 2 and 5). However, for aromatic ketones with an electrondonating substituent at the aryl ring, 3-thienyl additions afforded tertiary alcohols in high yields with slight lower enantioselectivities of 88%~70% ee (Entries 8~11). For heteroaromatic ketones, 3-thienyl addition to 1-(pyridin-3-yl)ethanone furnished the product 3l in a good yield with a excellent enantioselec-tivity of 90% ee (Entry 12).

  Table 2

  

  Table 2.  Enantioselective addition of 3-thienyl aluminum reagent to ketones^a

  下载: 导出CSV

  Entry	Ketone	Product	Yield/%	ee/%
  1		3a	88	90
  2		3b	91	91
  3		3c	90	88
  4		3d	90	90
  5		3e	82	86
  6		3f	87	90
  7		3g	80	90
  8		3h	80	85
  9		3i	78	85
  10		3j	83	90
  11		3k	85	70
  12		3l	79	91
  a Condition: (S)-BINOL (0.10 mmol), Ti(OiPr)4 (3.50 mmol), 2 (3.00 mmol), ketone (1.00 mmol), toluene (5.0 mL). b Enantioselectivities were determined by HPLC.

  Based on the previous study of titanium-catalyzed asymmetric arylation of organozinc, organoaluminum, or organotitanium, the catalytic reactions involve the similar acitve species which are proposed to be dititanium species Ⅰ containing one BINOLate ligand and the nucleophile.^{[4a, 15]} The roles of Ti(OⁱPr)₄ in the reaction not only gave the above active dititanium species, but also reacted with 3-thienyl aluminum reagent to afford an immediate of a bimetallic complex Ⅱ.^[4a]

  3.   Conclusions

  In summary, the catalytic enantioselective heteroarylation of 3-thienyl aluminum nucleophiles with various ketones has been successfully developed employing the simple titanium catalytical system of (S)-BINOL to afford a series of chiral arylethanols containing 3-thienyl groups in high yields with excellent enantioselectivities of up to 91% ee.

  4.   Experimental section

  4.1   General methods

  All syntheses and manipulations of air-and moisture-sensitive materials were performed under a dry argon atmosphere using standard Schlenk techniques or in a glovebox. Solvents were refluxed and distilled over sodium/benzophenone under argon prior to use. ¹H NMR and ¹³C NMR spectra in CDCl₃ were recorded on a Bruker AV-300 NMR spectrometer with chemical shifts from the internal TMS. HPLC analyses were recorded with an Agilent 1200 Series spectrometer using Chiralpak column.

  4.2   General procedure for the asymmetric addition of 3-thienyl aluminum to ketones

  Under a dry nitrogen atmosphere, (S)-BINOL (28.6 mg, 0.1 mmol) and Ti(OⁱPr)₄ (1.04 mL, 3.5 mmol) were mixed in dry toluene (5.0 mL) at room temperature. After stirring for 30 min, (3-thienyl)AlEt₂(OEt₂) (3.0 mmol) was added to the resulting solution at 0 ℃. The mixture was stirred for another 10 min, and a ketone (1.0 mmol) was added to the resulting solution at 0 ℃. The mixture was allowed to react for 12 h at this temperature, and then quenched with 1.0 mol•L^-1 NaOH. The aqueous phase was extracted with ethyl acetate (20.0 mL×3), dried over MgSO₄, filtered and con-centrated. The residue was purified by column chro-matography to give the tertiary alcohol. Enantiomeric excesses of products were determined by HPLC using suitable chiral columns from Daicel.

  1-Phenyl-1-(thien-3-yl)ethanol (3a):^[7e] Yellow oil (179 mg. 88% yield). ee＝90% [Chiralpak OD-H column, V(n-hexane):V(i-PrOH)＝90:10, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(minor)＝9.11 min, t_R(major)＝9.72 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.43~7.18 (m, 7H), 6.98 (s, 1H), 2.25 (s, H), 1.94 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 149.6, 147.4, 128.1, 127.0, 126.7, 126.0, 125.4, 120.7, 74.5, 31.1.

  1-(4-Nitrophenyl)-1-(thien-3-yl)ethanol (3b): Yellow oil (227 mg. 91% yield). ee＝91% [Chiralpak AD-H column, V(n-hexane):V(i-PrOH)＝93:7, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(major)＝35.537 min; t_R(minor)＝46.700 min. ¹H NMR (300 MHz, CDCl₃) δ: 8.19~8.16 (m, 2H), 7.69~7.66 (m, 2H), 7.29~7.26 (m, 1H), 6.97~5.95 (m, 2H), 2.52 (s, 1H), 2.04 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 154.3, 151.7, 147.0, 126.8, 126.3, 125.8, 124.5, 123.4, 74.4, 32.1. HRMS (ESI) calcd for C₁₂H₁₁O₃NSNa (M+ Na⁺) 272.0352, found 272.0349.

  1-(2-Nitrophenyl)-1-(thien-3-yl)ethanol (3c): Yellow oil (224 mg, 90% yield). ee＝88% [Chiralpak OD-H column, V(n-hexane):V(i-PrOH)＝97:3, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(minor)＝27.142 min, t_R(major)＝29.488 min. ¹H NMR (300 MHz, CDCl₃) δ: 8.36~8.35 (m, 1H), 8.14~8.10 (m, 1H), 7.77~7.74 (m, 1H), 7.51~7.46 (m, 1H), 7.32~7.26 (m, 2H), 6.98~6.96 (m, 1H), 2.30 (s, H), 1.99 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 149.7, 148.3, 148.2, 131.7, 129.1, 126.9, 126.2, 122.0, 121.3, 120.4, 74.0, 31.2. HRMS (ESI) calcd for C₁₂H₁₁O₃NSNa (M+Na⁺) 272.0352, found 272.0351.

  1-(Thien-3-yl)-1-(4-(trifluoromethyl)phenylethanol (3d): Yellow oil (245 mg, 90% yield). ee＝90%[Chiralpak AD-H column, V(n-hexane):V(i-PrOH)＝93:7, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(major)＝10.886 min, t_R(minor)＝14.053 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.62~7.57 (m, 4H), 7.27~7.26 (m, 1H), 6.97~6.93 (m, 2H), 2.49 (s, 1H), 2.02 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 152.3, 151.0, 126.7, 125.7, 125.4, 125.2, 125.1, 125.0, 124.4, 74.5, 32.1. HRMS (ESI) calcd for C₁₃H₁₀F₃S (M－OH)⁺ 255.0450, found 255.0449.

  1-(4-Bromophenyl)-1-(thien-3-yl)ethanol (3e): Yellow oil (232 mg, 82% yield). ee＝86% [Chiralpak OD-H column, V(n-hexane):V(i-PrOH)＝93:7, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(minor)＝9.101 min, t_R(major)＝10.056 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.45~7.42 (m, 2H), 7.38~7.28 (m, 3H), 7.18 (s, 1H), 6.97~6.95 (m, 1H), 2.29 (s, H), 1.90 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 149.0, 146.4, 131.1, 127.2, 126.5, 126.2, 120.9, 74.1, 31.0. HRMS (ESI) calcd for C₁₂H₁₁BrS (M－OH)⁺ 264.9681, found 264.9682.

  1-(4-Chlorophenyl)-1-(thien-3-yl)ethanol (3f): Yellow oil (208 mg, 87% yield). ee＝90% [Chiralpak OD-H column, V(n-hexane):V(i-PrOH)＝97:3, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(minor)＝15.427 min, t_R(major)＝18.464 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.44~7.40 (m, 2H), 7.31~7.23 (m, 3H), 6.94~6.89 (m, 2H), 2.42 (s, H), 1.99 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 152.8, 145.8, 133.0, 128.2, 126.8, 125.6, 125.2, 124.3, 74.4, 32.2. HRMS (ESI) calcd for C₁₂H₁₁OClSNa (M+Na⁺) 261.0111, found 261.0105.

  1-(2-Chlorophenyl)-1-(thien-3-yl)ethanol (3g): Yellow oil (191 mg, 80% yield). ee＝90% [Chiralpak AD-H column, V(n-hexane):V(i-PrOH)＝93:7, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(major)＝8.514 min, t_R(minor)＝9.488 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.81~7.78 (m, 1H), 7.33~7.23 (m, 4H), 6.91~6.90 (m, 1H), 6.76~6.74 (m, 1H), 2.33 (s, H), 2.09 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 152.4, 143.2, 131.3, 129.1, 127.6, 126.8, 126.6, 124.7, 124.1, 121.0, 74.5, 29.9. HRMS (ESI) calcd for C₁₂H₁₁OClSNa (M+Na⁺) 261.0111, found 261.0108.

  1-(Thien-3-yl)-1-(p-tolyl)ethanol (3h): Yellow oil (175 mg, 80% yield). ee＝85% [Chiralpak OD-H column, V(n-hexane):V(i-PrOH)＝93:7, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(major)＝14.415 min, t_R(minor)＝18.012 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.32~7.25 (m, 3H), 7.19~7.12 (m, 3H), 6.96~6.93 (m, 1H), 3.02 (s, 1H), 2.34 (s, 3H), 2.02 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 153.6, 144.3, 136.8, 128.7, 126.4, 125.2, 124.7, 124.0, 74.6, 32.1, 20.9. HRMS (ESI) calcd for C₁₃H₁₄OSNa (M+Na⁺) 241.0658, found 241.0658.

  1-(Thien-3-yl)-1-(o-tolyl)ethanol (3i): Yellow oil (170 mg, 78% yield). ee＝85% [Chiralpak OD-H column, V(n-hexane):V(i-PrOH)＝93:7, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(major)＝7.488 min, t_R(minor)＝8.388 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.73~7.69 (m, 1H), 7.25~7.21 (m, 3H), 7.15~7.12 (m, 1H), 6.91~6.88 (m, 1H), 6.76~6.74 (m, 1H), 2.30 (s, H), 2.14 (s, 3H), 2.03 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 153.2, 144.3, 136.4, 132.3, 127.8, 126.6, 125.5, 125.4, 124.6, 123.9, 74.8, 31.4, 21.3. HRMS (ESI) calcd for C₁₃H₁₄OSNa (M+Na⁺) 241.0658, found 241.0656.

  1-(4-Methoxyphenyl)-1-(thien-3-yl)ethanol (3j): Yellow oil (194 mg, 83% yield). ee＝90% [Chiralpak OD-H column, V(n-hexane):V(i-PrOH)＝93:7, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(minor)＝24.622 min, t_R(major)＝27.122 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.36~7.32 (m, 2H), 7.26~7.24 (m, 1H), 7.18~7.16 (m, 1H), 6.98~6.97 (m, 1H), 6.87~6.83 (m, 2H), 3.79 (s, 3H), 2.20 (s, H), 1.92 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 158.5, 150.0, 139.7, 126.6, 125.9, 120.5, 113.4, 74.3, 55.2, 31.1. HRMS (ESI) calcd for C₁₃H₁₄O₂SNa (M+Na⁺) 257.0607, found 257.0606.

  1-(3-Methoxyphenyl)-1-(thien-3-yl)ethanol (3k): Yellow oil (199 mg, 85% yield). ee＝70% [Chiralpak OD-H column, V(n-hexane):V(i-PrOH)＝93:7, flow rate＝1.0 mL/min, λ＝254 nm]. t_R(minor)＝15.076 min, t_R(major)＝18.947 min. ¹H NMR (300 MHz, CDCl₃) δ: 7.25~7.22 (m, 2H), 7.08~7.02 (m, 2H), 6.92~6.89 (m, 2H), 6.82~6.79 (m, 1H), 3.79 (s, 3H), 2.49 (s, H), 2.00 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 159.4, 153.2, 148.9, 129.1, 126.5, 124.9, 124.1, 117.8, 112.4, 111.4, 74.7, 55.2, 32.1. HRMS (ESI) calcd for C₁₃H₁₄O₂SNa (M+Na⁺) 257.0607, found 257.0611.

  1-(Pyridin-3-yl)-1-(thien-3-yl)ethanol (3l): Yellow oil (162 mg, 79% yield). ee＝91% [Chiralpak AS-H column, V(n-hexane):V(i-PrOH)＝90:10, flow rate＝0.8 mL/min, λ＝254 nm]. t_R(major)＝15.840 min, t_R(minor)＝18.044 min. ¹H NMR (300 MHz, CDCl₃) δ: 8.63~8.62 (m, 1H), 8.45~8.43 (m, 1H), 7.78~7.74 (m, 1H), 7.30~7.20 (m, 3H), 6.99~6.97 (m, 1H), 1.96 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 148.8, 148.1, 147.2, 142.9, 133.2, 126.5, 126.4, 122.9, 121.1, 73.2, 31.1. HRMS (ESI) calcd for C₁₁H₁₂ONS (M+H⁺) 206.0634, found 206.0629.

  Supporting Information Copies of HPLC analytic data, and ¹H NMR and ¹³C NMR spectra of the compounds 3a~3l. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

• 1. [1]

     For reviews, see:
     (a) Pu, L. ; Yu, H. -B. Chem. Rev. 2001, 101, 757.
     (b) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739.
     (c) Ramón, D. J. ; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284.
     (d) Schmidt, F. ; Stemmler, R. T. ; Rudolph, J. ; Bolm, C. Chem. Soc. Rev. 2006, 35, 454.
     (e) Hatano, M. ; Ishihara, K. Chem. Rec. 2008, 8, 143.
     (f) Hatano, M. ; Ishihara, K. Synthesis 2008, 1647.
     (g) Paixão, M. W. ; Braga, A. L. ; Lüdtke, D. S. J. Braz. Chem. Soc. 2008, 19, 813.

  2. [2]

     For asymmetric addition of arylboronic, see:
     (a) Bolm, C. ; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850.
     (b) Özçubukçu, S. ; Schmidt, F. ; Bolm, C. Org. Lett. 2005, 7, 1407.
     (c) Dahmen, S. ; Lormann, M. Org. Lett. 2005, 7, 4597.
     (d) Liu, X. ; Wu, X. ; Chai, Z. ; Wu, Y. ; Zhao, G. ; Zhu, S. J. Org. Chem. 2005, 70, 7432.
     (e) Wu, X. ; Liu, X. ; Zhao, G. Tetrahedron: Asymmetry 2005, 16, 2299.
     (f) Braga, A. L. ; Lüedtke, D. S. ; Vargas, F. ; Paixão, M. W. Chem. Commun. 2005, 2512.
     (g) Lu, G. ; Kwong, F. Y. ; Ruan, J. -W. ; Li, Y. -M. ; Chan, A. S. C. Chem. -Eur. J. 2006, 12, 4115.
     (h) Hatano, M. ; Gouzu, R. ; Mizuno, T. ; Abe, H. ; Yamada, T. ; Ishihara, K. Catal. Sci. Technol. 2011, 1, 1149.

  3. [3]

     For asymmetric addition of arylzinc, see:
     (a) Dosa, P. I. ; Ruble, J. C. ; Fu, G. C. J. Org. Chem. 1997, 62, 444.
     (b) Bolm, C. ; Muñiz, K. Chem. Commun. 1999, 1295-1296.
     (c) Huang, W. -S. ; Hu, Q. -S. ; Pu, L. J. Org. Chem. 1999, 64, 7940.
     (d) Huang, W. -S. ; Pu, L. J. Org. Chem. 1999, 64, 4222.
     (e) Bolm, C. ; Kesselgruber, M. ; Hermanns, N. ; Hildebrand, J. P. ; Raabe, G. Angew. Chem., Int. Ed. 2001, 40, 1488.
     (f) Qin, Y. -C. ; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 273.
     (g) Shannon, J. ; Bernier, D. ; Daniel, D. ; Woodward, S. Chem. Commun. 2007, 3945.
     (h) Glynn, D. ; Shannon, J. ; Woodward, S. Chem. -Eur. J. 2010, 16, 1053.

  4. [4]

     For asymmetric addition of arylaluminum, see:
     (a) Wu, K. -H. ; Gau, H. -M. J. Am. Chem. Soc. 2006, 128, 14808.
     (b) Wu, K. -H. ; Chen, C. -A. ; Gau, H. -M. Angew. Chem., Int. Ed. 2007, 46, 5373.
     (c) Zhou, S. ; Wu, K. -H. ; Chen, C. -A. ; Gau, H. -M. J. Org. Chem. 2009, 74, 3500.
     (d) Zhou, S. ; Chuang, D. -W. ; Chang, S. -J. ; Gau, H. -M. Tetrahedron: Asymmetry 2009, 20, 1407.

  5. [5]

     For asymmetric addition of aryltitanium, see:
     (a) Weber, B. ; Seebach, D. Tetrahedron 1994, 50, 7473.
     (b) Wu, K. -H. ; Zhou, S. ; Chen, C. -A. ; Yang, M. -C. ; Chiang, R. -T. ; Chen, C. -R. ; Gau, H. -M. Chem. Commun. 2011, 47, 11668.
     (c) Wu, K. -H. ; Kuo, Y. -Y. ; Chen, C. -A. ; Huang, Y. -L. ; Gau, H. -M. Adv. Synth. Catal. 2013, 355, 1001.
     (d) Chang, S. -J. ; Zhou, S. ; Gau, H. -M. ; RSC Adv. 2015, 5, 9368.
     (e) Shu, C. -C. ; Zhou, S. ; Gau, H. -M. RSC Adv. 2015, 5, 98391.

  6. [6]

     (a) Duchene-Marullaz, P. ; Jovanovic, D. ; Busch, N. ; Vacher, J. Arch. Int. Pharmacodyn. Ther. 1963, 141, 465.
     (b) Baumgold, J. ; Cohen, V. I. ; Paek, R. ; Reba, R. C. Life Sci. 1991, 48, 2325.

  7. [7]

     (a) Hatano, M. ; Suzuki, S. ; Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998.
     (b) Schneider, U. ; Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46, 5909.
     (c) Hatano, M. ; Miyamoto, T. ; Ishihara, K. Org. Lett. 2007, 9, 4535.
     (d) Salvi, L. ; Kim, J. G. ; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 12483.
     (e) Li, K. ; Hu, N. ; Luo, R. ; Yuan, W. ; Tang, W. J. Org. Chem. 2013, 78, 6350.

  8. [8]

     Wu, K.-H.; Chuang, D.-W.; Chen, C.-A.; Gau, H.-M. Chem. Commun. 2008, 2343.

  9. [9]

     Zhou, S. L.; Chen, C.-R.; Gau, H.-M. Org. Lett. 2010, 12, 48. doi: 10.1021/ol902454n

  10. [10]

      (a) Schmidt, F. ; Rudolph, J. ; Bolm, C. Adv. Synth. Catal. 2007, 349, 703.
      (b) Liu, X. ; Qiu, L. ; Hong, L. ; Yan, W. ; Wang, R. Tetrahedron: Asymmetry 2009, 20, 616.

  11. [11]

      Biradar, D. B.; Zhou, S.; Gau, H.-M. Org. Lett. 2009, 11, 3386. doi: 10.1021/ol901193q

  12. [12]

      Salvi, L.; Kim, J. G.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 12483. doi: 10.1021/ja9046747

  13. [13]

      Uenishi, A.; Nakagawa, Y.; Osumi, H.; Harada, T. Chem.-Eur. J. 2013, 19, 4896. doi: 10.1002/chem.201203946

  14. [14]

      Zhang, L.; Tu, B.; Ge, M.; Li, Y.; Chen, L. Wang, W. Zhou, S. J. Org. Chem. 2015, 80, 8307. doi: 10.1021/acs.joc.5b01410

  15. [15]

      (a) Balsells, J. ; Davis, T. ; Carroll, P. ; Walsh P. J. Am. Chem. Soc. 2002, 124, 10336.
      (b) Wu, K. -H. ; Gau, H. -M. Organometallics 2004, 23, 580.
      (c) Harada, T. ; Kanda, K. Org. Lett. 2006, 8, 3817.
      (d) Li, Q. ; Gau, H. -M. Chirality 2011, 23, 929.

• 

  Figure 1  Different chiral ligands

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of enantioselective addition of 3-thienyl aluminum to acetophenone^a

  Entry	Ligand	Ti(OiPr)4b/equiv.	(3-Thienyl)Al b/equiv.	Solvent	Yield/%	ee c/%
  1	(S)-BINOL	5.0	1.5	Toluene	21	82
  2	(S)-BINOL	5.0	2.0	Toluene	31	85
  3	(S)-BINOL	5.0	2.5	Toluene	53	84
  4	(S)-BINOL	5.0	3.0	Toluene	35	89
  5	(S)-BINOL	5.0	3.5	Toluene	40	82
  6	(S)-BINOL	2.5	3.0	Toluene	70	62
  7	(S)-BINOL	3.5	3.0	Toluene	88	90
  8	(S)-BINOL	4.0	3.0	Toluene	50	88
  9	(S)-BINOL	3.5	3.0	THF	62	84
  10	(S)-BINOL	3.5	3.0	n-Hexane	63	88
  11	(S)-BINOL	3.5	3.0	Et2O	93	81
  12	(S)-BINOL	3.5	3.0	CH2Cl2	85	31
  13	A	3.5	3.0	Toluene	50	25
  14	B	3.5	3.0	Toluene	40	-10
  15	C	3.5	3.0	Toluene	60	-51
  16	D	3.5	3.0	Toluene	45	15
  a Condition: acetophenone (1.00 mmol), solvent (5.0 mL), time: 12 h. b Equivalents of Ti(OiPr)4 and 2 are relative to acetophenone. c Enantioselectivities were determined by HPLC.

  下载: 导出CSV

  Table 2.  Enantioselective addition of 3-thienyl aluminum reagent to ketones^a

  Entry	Ketone	Product	Yield/%	ee/%
  1		3a	88	90
  2		3b	91	91
  3		3c	90	88
  4		3d	90	90
  5		3e	82	86
  6		3f	87	90
  7		3g	80	90
  8		3h	80	85
  9		3i	78	85
  10		3j	83	90
  11		3k	85	70
  12		3l	79	91
  a Condition: (S)-BINOL (0.10 mmol), Ti(OiPr)4 (3.50 mmol), 2 (3.00 mmol), ketone (1.00 mmol), toluene (5.0 mL). b Enantioselectivities were determined by HPLC.

  下载: 导出CSV
•