Imines derived from (1S,2R)-norephedrine as catalysts in the enantioselective addition of diethylzinc to aldehydes

Applied Catalysis A: General 357 (2009) 150–158

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Imines derived from (1S,2R)-norephedrine as catalysts in the enantioselective addition of diethylzinc to aldehydes Magdalena Jaworska, Krzysztof Z. Ła˛czkowski, Mirosław Wełniak *, Magdalena Welke, Andrzej Wojtczak Faculty of Chemistry, N. Copernicus University, Gagarina 7, 87-100 Torun´, Poland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 26 November 2008 Received in revised form 30 December 2008 Accepted 5 January 2009 Available online 9 January 2009

Purpose of the research was to determine the activity of chiral imine ligands prepared from (1S,2R)norephedrine for the enantioselective addition of diethylzinc to aldehydes. Imine ligands reveal medium enantioselectivity, with the ee exceeding 30%. The highest ee (97%) was obtained for imine with 9anthryl substituent, when p-methoxybenzaldehyde was used as substrate. The yields of the reaction obtained after 24–72 h reached 76–96%. The absolute configuration of the addition product depends on the geometry of presented transition states and p–p stacking interactions between the investigated ligands and the benzaldehyde substrate. Imine ligands derived 2-hydroxyacetophenone and with 9anthryl substituent reveal strong absorbance in UV–vis spectra. Intermediates for the imines – diethylzinc – based catalysis and probable mechanisms were proposed. ß 2009 Elsevier B.V. All rights reserved.

Keywords: Imine Diethylzinc addition Norephedrine derivatives Activity

1. Introduction The catalytic enantioselective addition of organozinc reagents to carbonyl compounds is a common route to the secondary optically active alcohols. The reaction can be catalyzed by means of different classes of ligands such as b-amino alcohols, diselenides or diols [1]. At present, many examples of the imines used in that reaction are known such as derivatives of phenylglycine 1 [2a], the Jacobsen’s chromium catalyst 2 [2b] and imines obtained from ketopinic acid 3 [2c] (Scheme 1). Some other similar ligands have been used for diethylzinc addition including 3-substituted or 3,30 substituted binaphthols [3–5], chiral [2,2]paracyclophane-based N,O-ligands [6,7] and other imines [8,9]. The ligands obtained from Ephedra alkaloids, especially aminoalcohols, were used with great success in asymmetric catalysis because of the possibility of their use in many types of reactions [10]. In particular, Soai et al. [11] also used N-alkylnorephedrine on alumina or silica gel as catalysts in addition of diethylzinc to benzaldehyde to obtain enantiomeric excess of 24–55%. Parrott and Hitchcock [12] described the family of b-amino alcohols being derivatives of the Ephedra alkaloids and having different substituents on a nitrogen atom. These ligands were obtained in the reaction of (1R,2S)-norephedrine or (1S,2S)-pseudonorephedrine with the respective aldehydes. The resulting imines have been reduced with NaBH4 without isolation because a condensation

* Corresponding author. Tel.: +48 56 6114521; fax: +48 56 6542477. E-mail address: [email protected] (M. Wełniak). 0926-860X/$ – see front matter ß 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.apcata.2009.01.007

with aldehydes and a further reduction were conducted as ‘‘onestep’’ process. The obtained N-alkyl b-amino alcohols used in an enantioselective addition of diethylzinc to benzaldehyde led to 10– 88% ee. We decided to conduct a similar synthesis to obtain new group of imines derived from (1S,2R)-norephedrine. In this paper we present five imines obtained by us and their enantioselective action in an addition of diethylzinc to benzaldehyde. Although the synthesis is mentioned in literature [11] no details are given. 2. Experimental 2.1. General Boiling points are uncorrected. Melting points were determined with a Bu¨chi apparatus in open capillaries and are also uncorrected. Optical rotation was measured with PolAAr 3000 automatic polarimeter in a 10 cm cell at 589 nm. Elemental analyses were performed at Elementary Analysensysteme GmbH VarioMACRO CHNanalyzer. 1H and 13C NMR spectra were recorded with Varian Gemini 200 multinuclear instrument and Bruker AMX 300 MHz instrument, respectively, in CDCl3 at ambient temperature. Chemical shifts are reported in parts per million (d scale), coupling constants (J values) are listed in Hertz and tetramethylsilane was used as the internal standard (d = 0 ppm). UV–vis spectra were recorded on Specord M-42 (Carl Zeiss Jena) in quartz cuvettes. Infrared spectra are reported in reciprocal centimeters (cm1) and are measured either as a neat liquid or KBr press disks. GC was performed on a PerkinElmer AutoSystem XL chromatograph using b-Dex 325 capillary column (30 m, 0.25 mm), or on Shimadzu

M. Jaworska et al. / Applied Catalysis A: General 357 (2009) 150–158

151

Scheme 1. Different kinds of imines used in addition of diethylzinc to aldehydes.

GC-14A using Zebron ZB-5 capillary column. HPLC analyses were performed on a Shimadzu LC-10AT chromatograph using Chiralcel OD-H column (250 mm  4.6 mm). TLC was performed on silica gel Polygram1 Sil G/UV254 (0.2 mm). Regular column chromatography was carried out using Silica Gel 60 (0.06–0.2 mm). Toluene was distilled from sodium while chloroform was distilled from P2O5 prior to use. The remaining reagents and solvents were purchased from Sigma–Aldrich or POCH Gliwice. Crystals of 5a and 5c have been obtained from the Et2O solutions and EtOH/water, respectively. The diffraction experiments were performed for yellow crystals: 0.54 mm  0.25 mm  0.14 mm at 291(2) K (5a) and 0.54 mm  0.46 mm  0.27 mm at 293(2) K (5c). The X-ray data were collected with an Oxford Sapphire CCD diffractometer using Mo Ka radiation l = 0.71073 A˚ by v–2u method. The numerical absorption correction was applied with CrysAlis171 package of programs, Oxford Diffraction, 2000 [13] with the maximum/minimum transmissions of 0.9886/0.9567 (5a) and 0.9806/0.9613 (5c). The structures were solved by direct methods and refined with the full-matrix leastsquares method on F2 with the use of SHELX-97 program package [14]. The hydrogen atoms have been located from the difference electron density maps and constrained during refinement. The data collection and refinement processes are summarized in Table 4. Selected bond lengths and angles of 5a and 5c are presented in Table 5. Geometry of the observed hydrogen bonds is presented in Table 6. The structural data have been deposited with Cambridge Crystallographic Data Centre, the CCDC numbers 711483 and 711484 for 5a and 5c, respectively. 2.2. Preparations of imines General procedure of synthesis of the investigated imines is shown in Scheme 2. Catalytic activity in asymmetric addition of diethylzinc to benzaldehyde is presented in Table 1 and to substituted aldehydes in Table 2. A 50-ml round-bottom flask equipped with a magnetic stirring bar and a Dean–Stark apparatus was charged with 13 mmol (2 g) of

(1S,2R)-norephedrine 4, 15 mmol (1.1 equiv.) of aldehyde or ketone, 20 mg of p-toluenesulphonic acid in 50 ml of toluene. The reaction mixture was refluxed for 18–24 h (until collection of water stopped), then it was cooled and filtered through a 1-cm Celite pad. The solvent was stripped and crude product was either crystallized or purified using a column chromatography. Yields and physical properties are presented below. 2.2.1. 2-((E)-1-((1S,2R)-1-hydroxy-1-phenylpropan-2ylimino)ethyl)phenol (5a) 2-Hydroxyacetophenone as a substrate. Yellow solid (60%). Purified by crystallization. Mp 134–136 8C (toluene), ½aD 20 ¼ 463 (c 0.45, MeOH). 1H NMR (200 MHz, CDCl3): d 1.34 (d, 3 JHH = 6.2 Hz (Me–H2), 3H, CH3), 2.14 (s, 1H, CH3), 2.20 (br s, 1H, OH), 4.07 (qt, 3JHH = 6.4 Hz (H2–Me), 1H, N–CH), 4.79 (d, 3 JHH = 6.2 Hz (H1–H2), 1H, CH), 6.73 (td, 4JHH = 1.2 Hz (H3–H5), 3 JHH = 7.8 Hz (H3–H4), 1H (H-3), ArH-in phenol ring), 6.90 (dd, 4 JHH = 1.2 Hz (H6–H4), 3JHH = 8.4 Hz (H6–H5), 1H, ArH-in phenol ring), 7.30 (m, 7H, ArH), 16.21 (br s, 1H, OH). 13C NMR (200 MHz, CDCl3): d 13.99, 17.24, 60.17, 77.41, 116.57, 118.83, 119.08, 126.61, 127.72, 128.16, 128.23, 132.59, 141.47, 164.80, and 170.65. IR (KBr): 3138.7, 1607.1, 1537.2, 1450.5, 1263.9, 1154.5, 1059.2, 1020.2, 962.4, 852.5, 742.1, and 708.38 cm1. Anal. calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20; O, 11.88. Found: C, 75.62; H, 6.80; N, 5.29. 2.2.2. (1S,2R,E)-1-phenyl-2-(1-(pyridin-2yl)ethylideneamino)propan-1-ol (5b) 2-Acetylpyridine as a substrate. Orange oil (76%). Purified by column chromatography (hexane:ethyl acetate = 3:1). ½aD 20 ¼ 50 (c 0.80, MeOH). 1H NMR (300 MHz, CDCl3): d 0.96 (d, 3 JHH = 6.6 Hz (Me–H2), 3H, CH3), 1.76 (s, 3H, CH3-pyridinyl), 2.85 (s br, 1H, OH), 4.00 (qt, 3JHH = 6.9 Hz (H2–Me–H1), 1H, CH), 5.20 (d, 3 JHH = 6.9 Hz (H1–H2), 1H, CH), 7.20–7.50 (m, 8H, ArH), 8.82 (d, 3 JHH = 7.8 Hz (H6–H5), 1H, CH-in pyridine ring). 13C NMR (200 MHz, CDCl3): d 16.35, 17.61, 56.87, 82.25, 120.30, 126.52,

Scheme 2. Synthesis of imines 5a–e derived (1S,2R)-norephedrine 4.

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Table 1 Addition of diethylzinc to benzaldehyde catalyzed by imines 5a–e. Entry 1 2 3 4 5

Ligand 5a 5b 5c 5d 5e

a b c d e

Time (h) 24 24 24 24 24

Solvent d

T–H T–H C–He T–H T–H

Yield (%)a

ee (%)b

Configurationc

59 30 88 69 76

16 26 33 14 37

R S S R R

Isolated products. Determined by GC using b-Dex capillary column. Determined by comparison with GC literature values [15]. Solvent: T–H = toluene:hexane = 3:1 (v/v). Solvent: C–H = chloroform:hexane = 3:1 (v/v).

128.12, 136.42, 141.24, 148.44, 161.68, and 163.21. IR (neat): 3435.4, 2957.9, 2926.1, 2855.0, 1702.0, 1600.0, 1508.9, 1458.6, 1304.0, 1261.6, 1092.1, and 1025.6 cm1. Anal. calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01; O, 6.29. Found: C, 75.38; H, 7.20; N, 10.90. 2.2.3. (1S,2R,E)-2-(anthracen-9-ylmethyleneamino)-1phenylpropan-1-ol (5c) 9-Anthraldehyde as a substrate. Yellow solid (79%). Purified by crystallization. ½aD 20 ¼ 37 (c 0.40, MeOH). Mp = 115–119 8C (toluene). 1H NMR (200 MHz, CDCl3): d 1.54 (d, 3JHH = 6.6 Hz (Me– H2), 3H, CH3), 2.74 (br s, 1H, OH), 3.99 (qt, 3JHH = 6.4 Hz (H2–Me– H1), 1H, CH), 5.01 (d, 3JHH = 6.2 Hz (H1–H2), 1H, CH), 7.20–7.60 (m, 9H, ArH), 7.95–8.10 (m, 4H, ArH), 8.46 (s, 1H, CH-imino). 13C NMR (200 MHz, CDCl3): d 18.21, 73.43, 77.64, 124.63, 125.18, 126.46, 127.07, 127.60, 128.31, 128.31, 12.46, 128.69, 128.98, 129.58, 131.15, and 141.94. IR (KBr): 3336.3, 1645.8, 1454.8, 1260.9, 1034.4, 886.1, 736.1, and 696.6 cm1. Anal. calcd for C24H21NO: C, 84.92; H, 6.24; N, 4.13; O, 4.71. Found: C, 84.45; H, 6.13; N, 4.17. 2.2.4. 2,4-Di-tert-butyl-6-((E)-((1S,2R)-1-hydroxy-1-phenylpropan2-ylimino)methyl)phenol (5d) 3,5-Di-tert-butyl-2-hydroxybenzaldehyde as a substrate. Yellow oil (98%). Purified by column chromatography (hexane:ethyl

acetate = 5:1). ½aD 20 ¼ 177 (c 0.064, MeOH). 1H NMR (200 MHz, CDCl3): d, 1.29 (s, 9H, 30 CH3), 1.28 (d, 3JHH = 7.6 Hz (Me–H2), 3H, CH3), 1.44 (s, 9H, 30 CH3), 2.13 (br s, 1H, OH), 3.65 (qt, 3JHH = 6.8 Hz (H2–Me–H1), 1H, CH), 4.82 (d, 3JHH = 4.9 Hz (H1–H2), 1H, CH), 7.05–7.40 (m, 7H, ArH), 8.30 (s, 1H, CH-imino), 13.50 (br s, 1H, OH). 13 C NMR (200 MHz, CDCl3): d, 17.50, 29.37, 31.46, 34.08, 34.99, 69.96, 77.58, 117.75, 126.03, 126.85, 126.96, 127.70, 127.83, 128.15, 131.87, 139.95, 140.97, 157.99, and 165.69. IR (neat): 3412.0, 2962.1, 1950.4, 1803.7, 1631.9, 1440.6, 1361.6, 1316.3, 1274.1, 1104.1, 1026.0, 878.8, 802.8, and 702.9 cm1. Anal. calcd for C24H33NO2: C, 78.43; H, 9.05; N, 3.81; O, 8.71. Found: C, 78.46; H, 9.09; N, 3.59. 2.2.5. 4-((E)-((1S,2R)-1-hydroxy-1-phenylpropan-2ylimino)(phenyl)methyl)benzene-1,3-diol (5e) 2,4-Dihydroxybenzophenone as a substrate. Light-yellow oil (12%). Purified by column chromatography (hexane:ethyl acetate = 1:1). ½aD 20 ¼ 244 (c 0.33, MeOH). 1H NMR (200 MHz, CD3OD): (, 1.25 (d, 3JHH = 6.6 Hz (Me–H2), 3H, CH3), 3.47 (qt, 3 JHH = 6.6 Hz (H2–Me–H1), 1H, CH), 4.63 (d, 3JHH = 6.4 Hz (H1–H2), 1H, CH), 5.88–6.39 (m, 4H, ArH), 7.13–7.27 (m, 10H, ArH), 7.50 (br s, 3H, 30 OH). 13C NMR (200 MHz, CDCl3): (, 17.77, 60.76, 77.57, 107.42, 111.94, 127.70, 128.63, 129.19, 129.67, 130.80, 133.17, 135.54, 143.19, 165.91, 174.36, and 176.33. IR (neat): 3582.2, 3050.0, 2362.7, 1720.3, 1656.2, 1585.8, 1510.3, 1261.9, 1100.1, and 856.8. Anal. calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03; O, 13.82. Found: C, 75.27; H, 6.77; N, 3.98. 2.3. Typical procedure for asymmetric addition of Et2Zn to aldehydes. Diethylzinc (2 mmol, 2 ml, 1 M solution in hexane) was added to a solution of chiral imine (10–20% mol) in dry solvent (5 ml) at 78 8C in an atmosphere of N2. After 1 h aldehyde (1 mmol) was added and the reaction mixture was turned to room temperature. The mixture was stirred for appropriated time (Tables 1 and 2) and was quenched with saturated solution of ammonium chloride (5 ml), extracted with ethyl acetate or MTBE (3 10 ml), dried over anhydrous MgSO4 and gravity filtrated. The solvent was stripped to

Table 2 Addition of diethylzinc to substituted aldehydes catalyzed by imines 5a–e. Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 a b c d e f g

Ligand 5a 5a 5a 5a 5a 5a 5b 5c 5c 5c 5c 5c 5c 5d 5d 5d 5d 5d 5e 5e 5e

Aldehyde p-Methoxybenzaldehyde p-Methoxybenzaldehyde p-Chlorobenzaldehyde o-Chlorobenzaldehyde o-Bromobenzaldehyde o-Methoxybenzaldehyde p-Methoxybenzaldehyde p-Methoxybenzaldehyde p-Methoxybenzaldehyde p-Chlorobenzaldehyde o-Chlorobenzaldehyde o-Bromobenzaldehyde o-Methoxybenzaldehyde p-Methoxybenzaldehyde p-Chlorobenzaldehyde o-Chlorobenzaldehyde o-Methoxybenzaldehyde o-Bromobenzaldehyde p-Methoxybenzaldehyde o-Chlorobenzaldehyde o-Methoxybenzaldehyde

Time (h) 72 72e 24 72 72 72 72 24 72 48 72 72 72 72 72 72 72 72 72 72 72

Solvent c

T–H T–H T–H T–H T–H T–H T–H C–Hg C–H C–H C–H C–H C–H T–H T–H T–H T–H T–H T–H T–H T–H

Yield (%)a 96 27 11 77 60 78 0 27 83 72 39 38 40 63 49 66 72 50 27 77 46

ee (%) d

80 36 76d 33f 18 8 – 97 97 47 38f 53 40 0 6 30 0 24 14 3 4

Determined by GC using Zebron ZB-5 capillary compared to the standards. Determined by comparison with HPLC and GC literature values [16]. Solvent: T–H = toluene:hexane = 3:1 (v/v). Determined by HPLC using Chiralcel OD-H column. Reaction was performed with 2 mmol of titanium tetraisopropoxide added after 1 h after dosing of diethylzinc to the ligand solution (in 78 8C). Determined by GC using b-Dex capillary column [17]. Solvent: C–H = chloroform:hexane = 3:1 (v/v).

Configurationb R R R R R R – S S S S S S – R R – R R R R

M. Jaworska et al. / Applied Catalysis A: General 357 (2009) 150–158 Table 3 Molar absorption coefficient e = f(l) for imines 5a and 5c. Ligand

Wavelength, l (nm)

Absorbance

e (dm3/(mol cm))

log e

5a

216 271 321 389

2.9817 1.4081 0.3084 0.6256

20,077.43534 9,481.3852 2,076.3445 4,212.3479

4.3027 3.9769 3.3173 3.6245

5c

216 253 349 365 384

0.6853 3.3807 0.1828 0.2809 0.2784

5,815.0600 28,687.9264 1,551.4579 2,383.8295 2,362.0210

3.7646 4.4577 3.1907 3.3773 3.3733

obtain enantiomerically enriched 1-phenyl-1-propanol. If necessary, the crude product was purified by column chromatography using appropriate eluents (hexane:ethyl acetate). The ee was determined with HPLC using ODH-Chiralcel column or GC analysis

Fig. 1. UV–vis spectra for imines 5a and 5c.

Scheme 3. (a) Mechanism of Et2Zn addition proposed for 5a, 5d and 5e ligands. (b) Mechanism of Et2Zn addition proposed for ligand 5c.

153

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using b-Dex capillary column. Yields were determined via GC analysis using ZB-5 capillary column or by isolation of the product (Tables 1 and 2). 2.4. Chiral HPLC analyses of the 1-arylpropan-1-ols A Chiralcel OD-H column was used in all cases. T = 25 8C, UV detection, l = 254 nm. 2.4.1. 1-(4-Methoxyphenyl)propan-1-ol Hexane:2-propanol 97:3; 0.8 mL/min. tR = 19.8 (R) and 22.6 (S) min. RS = 2.6.

reaction 0.0679 g to 20 mol). ½aD 20 ¼ 38:5 (c 0.38, MeOH). Mp = 116–118 8C. 1H NMR (200 MHz, CDCl3): d 1.50 (d, 3 JHH = 6.6 Hz (Me–H2), 3H, CH3), 2.90 (br s, 1H, OH), 4.07 (qt, 3 JHH = 6.5 Hz (H2–Me–H1), 1H, CH), 4.99 (d, 3JHH = 6.3 Hz (H1–H2), 1H, CH), 7.16–7.60 (m, 9H, ArH), 7.90–8.20 (m, 4H, ArH), 8.50 (s, 1H, CH-imino).13C NMR (200 MHz, CDCl3): d 18.21, 73.43, 77.64, 124.63, 125.18, 126.46, 127.07, 127.60, 128.31, 128.31, 12.46, 128.69, 128.98, 129.58, 131.15, and 141.94. IR (KBr): 3335.9, 1647.6, 1455.9, 1261.2, 1040.4, 890.3, 744.3, and 697.8 cm1. Anal. calcd for C24H21NO: C, 84.92; H, 6.24; N, 4.13; O, 4.71. Found: C, 84.45; H, 6.20; N, 4.21. 2.7. UV–vis spectra for 5a and 5c

2.4.2. 1-(4-Chlorophenyl)propan-1-ol Hexane:2-propanol 99:1; 0.7 mL/min. tR = 33.2 (S) and 36.3 (R) min. RS = 2.3. 2.4.3. 1-(2-Methoxyphenyl)propan-1-ol Hexane:2-propanol 99:1; 0.7 mL/min. tR = 35.40 (S) and 39.70 (R) min. RS = 2.76.

UV–vis spectra were recorded (Table 3). Spectra were recorded for the concentration of 0.00014 M in methanol, in quartz cuvettes 1 cm thickness. 3. Results and discussion

2.6. Typical procedure for ligands 5a and 5c recovery

(1S,2R)-Norephedrine (4) in reaction with o-hydroxyacetophenone, 2-acetylpyridine, 3,5-di-tert-butyl-2-hydroxybenzaldehyde, 2,4-dihydroxybenzophenone or 9-anthraldehyde formed the respective imines (5a–e) (Scheme 2) with good yields. Products were purified by crystallization or by means of column chromatography. Considering a very intensive yellow colour of imines 5a and 5c caused by the presence of an imine bond the UV–vis spectra have been done, the data on which have been listed in Table 3. For both compounds a very intensive absorbance has been noticed in the range of UV and less prominent in the vis spectra. The imine 5a showed a strong absorbance at l = 271 nm while the imine 5c showed an absorbance at l = 253 nm (Fig. 1). Compounds 5a and 5c were recrystallized from diethyl ether and aqueous ethanol, respectively. The X-ray crystal structures were determined to investigate their molecular conformation and the spatial arrangement of bulky moieties. The resulted ligands were employed in an enantioselective addition of diethylzinc to aromatic aldehydes. Ligands 5a–e were used in an amount of 20% mol with 2 equiv. of Et2Zn with respect to

The extract from diethylzinc addition to benzaldehyde was dried over anhydrous MgSO4 and gravity filtrated. The solvent was stripped to obtain a mixture of benzaldehyde, benzyl alcohol, 1phenyl-1-propanol and ligand 5a. The mixture was purified by the column chromatography using hexane:ethyl acetate = 5:1 (v/v) as an eluent. Fractions containing benzaldehyde, benzyl alcohol and ligand 5a (monitored by TLC, Rf = 0.49 for all compounds) were evaporated to dryness. Recrystallization of the mixture from toluene gave 0.042 g of 5a as a yellow solid (yield 78% relative to the amount used in reaction 0.0539 g to 20 mol%). Mp 135–136 8C, ½aD 20 ¼ 464 (c 0.32, MeOH). 1H NMR (200 MHz, CDCl3): d 1.35 (d, 3 JHH = 6.2 Hz (Me–H2), 3H, CH3), 2.16 (s, 1H, CH3), 2.30 (br s, 1H, OH), 4.10 (qt, 3JHH = 6.3 Hz (H2–Me–H1), 1H, CH), 4.79 (d, 3 JHH = 6.2 Hz (H1–H2), 1H, CH), 6.73 (td, 4JHH = 1.2 Hz (H3–H5), 3 JHH = 7.6 Hz (H3–H4), 1H (H-3), ArH-in phenol ring), 6.90 (dd, 4 JHH = 1.2 Hz (H6–H4), 3JHH = 8.6 Hz (H6–H5), 1H, ArH-in phenol ring), 7.20–7.40 (m, 7H, ArH), 15.06 (br s, 1H, OH). 13C NMR (200 MHz, CDCl3): d 13.99, 17.24, 60.17, 77.41, 116.57, 118.83, 119.08, 126.61, 127.72, 128.16, 128.23, 132.59, 141.47, 164.80, and 170.65. IR (KBr): 3140.2, 1608.8, 1540.3, 1452.3, 1263.1, 1153.6, 1058.1, 1021.8, 952.3, 848.9, 740.9, and 710.2 cm1. Anal. calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20; O, 11.88. Found: C, 75.80; H, 7.22; N, 5.15. Similar procedure was used for 5c. Recrystallization of the mixture containing 5c from toluene followed by filtration gave 0.050 g as a yellow solid (yield 74% relative to the amount used in

Fig. 2. Model of the structure of active complex for 5c (Scheme 3a) optimized by MM method with the UFF force field using ArgusLab 4.0.1. [20]. Zinc, oxygen, nitrogen and carbon atoms are displayed in magenta, red, blue and gray, respectively. Hydrogen atoms are omitted for clarity. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)

2.5. Chiral GC analyses of the 1-arylpropan-1-ols A chiral Supelco b-Dex 325 capillary column (30 m, 0.25 mm) was used. Isothermal conditions. FID detector. 2.5.1. 1-Phenylpropan-1-ol Isothermal T = 100 8C, gas flow = 35 cm/s. tR = 36.9 (R) and 37.8 (S) min. 2.5.2. 1-(2-Chlorophenyl)propan-1-ol Isothermal T = 130 8C, gas flow = 35 cm/s, tR = 22.5 (R) and 26.2 (S) min. 2.5.3. 1-(2-Bromophenyl)propan-1-ol Isothermal T = 140 8C, gas flow = 35 cm/s, tR = 26.5 (R) and 30.6 (S) min.

M. Jaworska et al. / Applied Catalysis A: General 357 (2009) 150–158

1 equiv. of benzaldehyde. Using of 3 equiv. of Et2Zn gave an excessive amount of benzyl alcohol (more than 70%) as a byproduct. The results of investigated reactions are summarized in Table 1. Ligands 5a–e showed only modest enantioselectivity. Opposite configurations of the produced 1-phenyl-1-propanol can be explained by the steric hindrance and an absence or a presence of an additional hydroxyl group derived from 2-hydroxyacetophenone. Two mechanisms of this reaction are proposed in Scheme 3a and b. Both of them are based on those presented in literature [12,18]. The expected mechanism for 5b is similar to that shown for 5c (Scheme 3b). Contrary, for the less crowded 5a, 5d and 5e ligands having an additional hydroxyl group, the formation of (R)-enantiomer was observed. Ligands 5a and 5c could be recovered in 70–80% by their separation from benzaldehyde and 1-phenyl-1-propanol by means of column chromatography and recrystallization from toluene. The unchanged structure of recovered ligands was confirmed by 1H NMR and repeatedly they were used in the further additions of diethylzinc to benzaldehyde which is its advantage. The enantioselective addition of diethylzinc to aldehydes catalyzed by 5a–e was also tested for other substrates (Table 2). It turned out that ligand 5b has not showed catalytic properties in the reactions of the substituted benzaldehydes, probably due to

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the ligand instability under the reaction conditions. We also found that the ligand could not be recovered from the reaction mixture. Our research also revealed that imine 5b was unstable and has undergone decomposition after about 2 weeks. That explanation is consistent with the small yield of the addition of diethylzinc to the unsubstituted benzaldehyde (Table 1: entry 2). On the other hand, interesting results were obtained for the ligands 5a and 5c–e. The use of the imine 5a, 5d, and 5e in most cases caused a formation of a product of (R) configuration. Addition of ZnEt2 to p-methoxybenzaldehyde substrate in a presence of 5a ligand gave the highest ee = 80% and 96% yield and the product of (R)-configuration (Table 2: entry 1). The ZnEt2 addition to the same aldehyde in a presence of titanium tetraisopropoxide was reported to increase both ee and yield [19]. Our results have shown that the use of titanium tetraisopropoxide has slowed down the reaction and lowered the enantiomeric excess to 36% (Table 2: entry 2). In this case when p-chlorobenzaldehyde was used, the ee = 76% with yield only 11% was obtained. The observed differences in the ee and yield for p-chloro- and p-methoxybenzaldehyde might be coupled to the substituent-induced charge density redistribution in the substrate molecules. Ligands 5d and 5e showed poor enantioselective activity in addition of diethylzinc to the substituted benzaldehydes (ee = 0–

Fig. 3. Crystal structure of 5c: (a) asymmetric unit of the structure, (b) details of molecular geometry (molecule A) with the atom numbering scheme. The thermal ellipsoids are plotted at 30% probability level. The atom numbering scheme is generated basing on molecule A by adding 20, 40 and 60 to the respective number of carbon atom for molecules B–D, respectively.

M. Jaworska et al. / Applied Catalysis A: General 357 (2009) 150–158

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Table 4 Collection data and refinement parameters for 5a and 5c. Compound

5a

5c

Formula Formula weight Colour T (K) Wavelength (A˚) Crystal system Space group

C17H19NO2 269.33 Yellow 291(2) 0.71073 Monoclinic P21

4C24H21NO  H2O  EtOH 1421.76 Yellow 293(2) 0.71073 Monoclinic P21

Unit cell dimensions a (A˚) b (A˚) c (A˚) a (8) b (8) g (8) V (A˚3) Z Dcalc (mg/m3) m (mm1) F (0 0 0) Crystal size u range Index ranges Reflections collected Independent reflections (Rint) Tmax/Tmin Data/restraints/parameters Absolute structure parameter Goodness-of-fit on F2 Final R indices [I > 2s(I)] R indices (all data) Largest difference in peak and hole (e. A˚3)

7.6145(8) 8.5973(9) 11.0051(9) 90.0 98.931(8) 90.0 711.7(1) 2 1.257 0.082 288 0.54  0.25  0.14 2.71–31.15 10  h  11, 11  k  12, 15  1  15 7084 3597 (0.0268) 0.9886/0.9567 3597/1/184 0.7(10) 0.976 R1 = 0.0424, wR2 = 0.0928 R1 = 0.0590, wR2 = 0.1004 0.124 and 0.141

11.585(1) 20.262(1) 17.024(1) 90.0 92.985(6) 90.0 3990.7(5) 2 1.183 0.073 1512 0.54  0.46  0.27 2.08–23.00 12  h  10, 22  k  22, 18  1  18 22,692 11,106 (0.0524) 0.9806/0.9613 11,106/4/989 1.1(13) 0.976 R1 = 0.0560, wR2 = 0.1016 R1 = 0.0890, wR2 = 0.1158 0.122 and 0.137

30%) (Table 2: entry 14–21). In fact Parrott et al. [18] also observed similar effect for the b-hydroxysalicylhydrazone ligand with 3,5di-(t-butyl)-2-hydroxyphenyl as a substituent. The use of 5d in a reaction of aldehydes with electron-donating substituents (o-OMe, p-OMe) resulted in a complete racemization of the product, unlike in case of using aldehydes with electron-withdrawing substituents (o-Cl) as substrates. Similar effect can be observed for with 2-OH substituted aryl group (ligands 5a and 5e). However, the opposite effects are found for 5c. Therefore, the variability of the reaction yields and ee seems to be a convolution of the induction and mesomeric effect of the substituents in the substrate ring, as well as the possibility of the polar interactions formed between these substituents and the 2-hydroxy group of the ligand. The use of the 5c ligand led exclusively to the products of the (S)-configuration. The best result in this case was obtained for p-

methoxybenzaldehyde: 97% ee and 83% yield (Table 2: entry 9), which was due to the large steric hindrance in a ligand caused by a presence of the anthryl fragment. Conformational flexibility of 5c molecules causes its unique spatial arrangement found in unit cell of the reported structure, but may also be coupled to its catalytic activity and the ability to form the catalytically active complexes with Et2Zn. On the other hand, the position of the large substituents such as anthracene moieties, might affect the enantioselectivity of these catalysts by determining the position of the carbonyl substrate in the coordination sphere of the formed intermediate zinc complex. The 3D model of the complex was built based on the determined crystal structure of 5c with both its heteroatoms involved in the bidentate coordination to Zn atom. Optimization of the model of active complex was performed by molecular

Table 5 Selected bond lengths [A˚] and angles [8] for 5a and 5c. Structure 5c

Molecule 1

Molecule 2

Molecule 3

Molecule 4

Structure 5a

C11 N1 N1–C12 C12–C14 C14–C15 C14–O1H C9–C11 N1 C11 N1–C12 C9–C11 N1–C12 N1–C12–C14 C12–C14–C15 N1–C12–C14–C15 nAnthryl; iminea

1.239(4) 1.479(4) 1.513(5) 1.499(5) 1.429(4) 124.2(3) 117.5(3) 180.0(3) 108.3(3) 114.0(3) 55.1(4) 68.6 (2) –

1.245(4) 1.456(4) 1.516(6) 1.498(7) 1.417(4) 121.8(4) 118.3(3) 176.7(4) 108.0(3) 112.1(4) 67.9(5) 52.9 (3) –

1.268(4) 1.468(4) 1.522(5) 1.505(5) 1.423(4) 124.6(3) 116.7(3) 178.8 (3) 107.3(3) 112.8(3) 66.0(4) 50.0 (2) –

1.244(4) 1.478(4) 1.530(5) 1.479(6) 1.432(4) 125.8(4) 118.7(3) 175.8(4) 109.4(3) 113.5(3) 53.7(4) 69.0 (3) –

C7 N1 N1–C9 C9–C11 C11–C12 C11–O2H C1–C7 N1 C7 N1–C9 C1–C7 N1–C9 N1–C9–C11 C9–C11–C12 N1–C9–C11–C12 nC1–C6; iminea nC1–C6, C12–C17a

1.304(2) 1.466(2) 1.539(2) 1.513(2) 1.414(2) 118.9(1) 125.9(1) 174.3(1) 109.6(1) 114.7(1) 73.7(2) 4.3(2) 38.7(1)

a The dihedral angles between the best planes are defined as follows: for 5c nanthryl; imine denotes the angle between the anthryl ring plane and the best plane of the C11–N1–C12 imine moiety or their equivalents in other molecules; for 5a nC1–C6; imine corresponds to the dihedral angle between the best planes of C1–C6 phenyl and C7–N1–C9 imine moiety, nC1–C6, C12–C17 is a dihedral angle between the best planes of two phenyl rings.

M. Jaworska et al. / Applied Catalysis A: General 357 (2009) 150–158

mechanics method with the UFF universal force field implemented in ArgusLab 4.0.1. [20], considering two potentially possible positions of the benzaldehyde substrate relative to the central Zn2O2 plane and the Re/Si orientation. The lowest energy was obtained for the ligand bound to the Zn atom in position allowing the Et addition to the Si side (Fig. 2). The attempts to minimize the structure with the Re positioning of benzaldehyde led to the reorientation of the substrate to Si. The model is consistent with the (S)-configuration of the stereogenic center of product, as obtained in the reaction. The performed optimization suggests the importance of the p–p stacking of aromatic rings of the substrate and the anthracene moiety for positioning of the ligand. 4. X-ray crystal structures The crystals suitable for the diffraction experiment have been obtained from EtOH/water solution. Asymmetric part of 5c unit cell (Fig. 3) contains four molecules of imine and two molecules of solvents (H2O and EtOH). Analysis reveals the statistically significant differences in the molecular geometry of four imine molecules (Table 4). Selected bond lengths and angles are presented in Table 5. Such content of asymmetric part of the unit cell is related to the conformational flexibility of molecules of the investigated compound (Fig. 4). Presence of the large anthracene substituent causes some steric hindrance that decreases the conformational space available for molecules. Geometry of molecules is typical for the moieties constituting molecules of the investigated compound. The imine bond lengths for all four molecules range from 1.239(4) to 1.268(4) A˚ and are similar to values 1.212 and 1.250 A˚ [21,22] reported for analogous compounds and extracted with the CCDC program suite [23]. The angles around C N bond are not identical, the C9–C11–N1 angles being 121.8(4)–125.8(4)8, and C11–N1–C12 varying from 116.7(3)8 to 118.7(3)8 (Table 5). The dihedral angles between the best planes of the anthracene and imine moieties are found between 50.0(2)8 and 69.0(3)8. That indicates the repulsive interactions of the anthracene moieties and the imine methylene C11 or its analogs in other molecules. Analysis of the intramolecular contacts revealed the short contacts between that methylene group and C8–H or equivalents in all imine molecules constituting the asymmetric unit of 5c. The C11–N1–C12 angle values smaller than 1208 (Table 5) for all four molecules can be observed. That seems to be caused by

Fig. 4. The conformational flexibility of 5c in the crystal lattice, visualized by the superposition of four molecules constituting the asymmetric part of the structure.

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Table 6 Hydrogen bonds for 5a and 5c. D–H  A

d(D–H)

d(H  A)


d(D  A)

5c O1–H1A  O1W O2–H2A  O4 [x  1, y, z] O3–H3A  O81 O4–H4A  N1 [x + 1, y, z] O81–H81  N4 [x, y, z  1] O1W–H1W  O2 O1W–H2W  N3 [x, y, z + 1]

0.820 0.820 0.820 0.820 0.820 0.872 0.901

1.913 1.951 1.970 2.100 1.995 2.012 2.016

167.52 159.93 175.16 160.24 176.16 152.17 171.22

2.719 2.736 2.788 2.885 2.814 2.812 2.909

5a N1–H1N_a  O1 O1–H1O_b  N1 O2–H2O  O1 [x + 1, y  1/2, z + 1]

0.879 0.866 0.820

1.746 1.719 1.926

147.62 155.58 158.46

2.533 2.533 2.705

participation of the imine nitrogen atoms in hydrogen bonds. The anthracene and norephedrine moieties 5c occupy the E positions around the imine bond revealed by C9–C11–N1–C12 torsion angle and its equivalents in other molecules being 175.8(4)–180.0(3)8 (Table 5). The structure of 5c reveals a network of H-bonds involving imine molecules and the solvent molecules. The hydroxyl groups of all four imine molecules are donors in the H-bond network found in the structure (Table 6). Water molecule is a donor in two hydrogen bonds to O2 and N3 [x, y, z + 1], and acts as an acceptor in the interaction with O1 hydroxyl within the asymmetric unit of the reported structure. The hydroxyl group of EtOH is a donor in the intermolecular interaction with N4 [x, y, z  1] atom and it is an acceptor in the H-bond formed with O3–H group (Table 6). Configuration at the chiral centers in each molecule of 5a and in 5c is (1S,2R). The flack parameters equal 1.1(1.3) and 0.7(1.3) for 5a and 5c, respectively, are inconclusive. Therefore, the absolute configuration was assigned based on the absolute configuration of the substrate centers not changed during formation of the imine bond. Structure of 5a contains one molecule in the asymmetric unit (Fig. 5). Selected bond lengths and angles are presented in Table 5. In 5a the distance of C7–N1 imine bond being 1.304(2) A˚ is significantly longer than the equivalent bonds in 5c, but fits the typical range of values as determined with CCDC [23]. The electron density maps revealed two discrete positions of the hydrogen atom, what reflects the proton transfer between O1–H hydroxyl and N1 imine atom (Fig. 5). The electron density indicated that the position of proton in the major population (75%) is at N1, while the minor population corresponds to the hydroxyl group (25%). The observed proton transfer explains the relative elongation of the imine bond (Table 5). The additional factor contributing to the observed elongation is the repulsion between the methyl group C8 and the norephedrine C9–H moiety.

Fig. 5. Molecule of 5a. The thermal ellipsoids are plotted at 30% probability level.

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Phenyl C1–C7 and norephedrine moieties occupy the E positions around the imine bond. In such molecular architecture, the presence of the C8 methyl substituent at C7 also affects the valence geometry of the imine moiety. The C7–N1–C9 angle in 5a of 118.9(1)8 is significantly smaller than those of 121.8(4)– 125.8(4)8 found for the corresponding angles in 5c, while C1–C7– N1 of 125.9(1)8 is larger than the corresponding angles of 116.6(3)– 118.7(3)8 in 5c. The dihedral angle between best planes of the imine bond (C7– N1–C9) and phenyl moiety (C1–C6) is 4.3(2)8, similar to the value of 9.158, reported for the close analog of 5a with the methoxy substituent in the phenyl ring [24]. The dihedral angle between the best planes of aromatic rings is 38.7(1)8. The intramolecular hydrogen bond is found between N1 and O1 groups, the N1  O1 distance being 2.533 A˚, but the position of hydrogen atom is reflected by the two populations described above. O2 hydroxyl acts as a donor in the intermolecular interaction with O1 [x + 1, y  1/2, z + 1], the O  O distance of 2.705 A˚. The details of hydrogen bonds for 5a are presented in Table 6. 5. Conclusions (1S,2R)-Norephedrine was employed as a template for preparation of a group of imine chiral ligands. It was determined that imine 5c afforded high ee = 97% when employed in the reaction of the diethylzinc addition with p-methoxybenzaldehyde. This catalyst favored the (S)-configuration of the product alcohol. When the nitrogen substituent was not large in size (2-hydroxyphenyl) the enantioselectivity was diminished and (R)-alcohol as major product was obtained. The X-ray crystal structure showed the conformational flexibility of ligand 5c and the observed proton transfer for the imine bond in ligand 5a, which can be important for the proposed complex of catalysts and diethylzinc. Also the substituent in phenyl group of benzaldehyde can have an influence on transition state. The proposed model of the transition state indicates the importance of the p–p stacking interactions between the most active of the investigated ligands and the benzaldehyde substrate as a factor determining the absolute configuration of the product. The reported results indicated that the electron – withdrawing substituents in the substrate ring improve both the ee and the yield obtained in the reaction of ZnEt2 addition, opposite to the electron – probably by affecting the charge density distribution and determination of the directionality of the polar

interactions within the transition state complex. The above observations showed only a small part of answers for the questions concerning the absolute reaction mechanism for this class of compounds.

Acknowledgment Research partly supported by the Nicolaus Copernicus University grant UMK CH-526.

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