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Synlett 2003(1): 0102-0106
DOI: 10.1055/s-2003-36215
LETTER
© Georg Thieme Verlag Stuttgart · New York

Ligand Electronic Effects in Enantioselective Diethylzinc Additions

Mike Casey*, Martin P. Smyth
Chemistry Department, the Centre for Synthesis and Chemical Biology, and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
Fax: +353(1)7162127; e-Mail: mike.casey@ucd.ie;
Further Information

Publication History

Received 15 November 2002
Publication Date:
18 December 2002 (online)

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Abstract

Enantiopure amino alcohols were converted into N-(2-hydroxyalkyl)formamides, which were converted into the chloroalkylformamides. Treatment with phosphorus pentachloride and anilines, followed by basic workup, gave 2-unsubstituted imidazolines bearing various 1-aryl substituents. Deprotonation using butyl­lithium and addition to pivaldehyde gave 2-(hydroxyalkyl)imidazolines. The hydroxy imidazolines proved to be efficient catalysts for the addition of diethylzinc to aldehydes, and the effect of tuning the steric and electronic properties of the ligands was studied. Pronounced ligand electronic effects were observed and high enantioselectivity was obtained in additions to both aliphatic and aromatic aldehydes.

Key words

diethylzinc addition reactions - asymmetric catalysis - ligands - imidazolines - electronic effects

16

General procedure for N -(2-hydroxyalkyl)formamide(1) preparation: Following a procedure by Meyers et al., [26] a solution of l-valinol (1.90 g, 18.4 mmol) in ethyl formate (10 mL, >3 equiv) was heated at reflux under nitrogen for 3 h. Excess ethyl formate was removed in vacuo, yielding (S)-N-[1-(hydroxymethyl)-2-methylpropyl]formamide, as a white solid, 2.11 g (87%), mp 82-83 °C, [α]D 22 +38.8 (c 0.27, CHCl3). (The product was a 65:35 mixture of two conformers, and NMR signals are indicated as Hmaj and Hmin for the major and minor conformers, respectively.) IR (KBr) 3362, 3171, 2832, 1666, 1538, 1385, 1241, 1054 cm-1. 1H NMR (300 MHz, CDCl3) δ 0.92 (d, 3 Hmin, J = 6.7 Hz, CH3), 0.93 (d, 3 Hmaj, J = 6.7 Hz, CH3), 0.96 (d, 3 Hmin, J = 6.0 Hz, CH3), 0.97 (d, 3 Hmaj, J = 6.9 Hz, CH3), 1.77-1.91 [m, 1 Hmaj & 1 Hmin, CH(CH3)2], 2.72 (br, s, 1 Hmin, OH), 3.07-3.19 (m, 1 Hmin, NCH), 3.54-3.79 (m, 4 Hmaj & 1 Hmin, CH2Omaj , OHmaj, NCHmaj, CHOHmin), 4.01-4.03 (m, 1 Hmin, CHO), 6.55 (d, 1 Hmaj, J = 7.9 Hz, NH), 6.81 (br t, 1 Hmin, J = 8 Hz, NH), 7.98 (d, 1 Hmin, J = 11.7 Hz, HCO), 8.21 (d, 1 Hmaj, J = 1.7 Hz, HCO). 13C NMR (75 MHz, CDCl3) δ 18.4 (CH3), 18.6 (CH3), 19.4 (CH3), 1.96 (CH3), 28.9 [C(CH3)2], 29.2 [C(CH3)2], 55.9 (NCH), 60.8 (NCH), 63.0 (CH2), 63.3 (CH2), 162.4 (C=O), 165.8 (C=O). Anal. Calcd for C6H13NO2: C, 54.94; H, 9.99; N, 10.68. Found: C, 54.71; H, 9.87; N, 10.60. MS (EI) m/z (rel. intensity) 132 (M+ + 1, 4), 101 (28), 100 (100), 88 (18), 72 (31), 71 (15), 60 (75), 55(85).

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General procedure for N -(2-chloroalkyl)formamide(2) preparation: A solution of (S)-N-[1-(hydroxymethyl)-2-methylpropyl]formamide 1 (1.90 g, 14.5 mmol) and thionyl chloride (1.28 mL, 2.05 g, 17.4 mmol, 1.2 equiv) in chloroform (30 mL) was stirred for 3 h at 50 °C. It was washed with aqueous 1 M NaOH (2 × 30mL) and the aqueous layer was extracted with chloroform. The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo affording (S)-N-[1-(chloromethyl)-2-methylpropyl]formamide, as a dark solid, 2.1 g (86%), which was used in the next step without purification, mp 44-45 °C, [α]D 21 -47.8 (c 0.21, CHCl3). (The product existed as a 85:15 mixture of two conformers, and NMR signals are indicated as Hmaj and Hmin for the major and minor conformers, respectively.) IR (KBr) 3225, 2898, 1678, 1547, 1381, 1260, 1025, 894 cm-1. 1H NMR (270 MHz, CDCl3) δ 0.89-1.01 (m, 6 Hmaj & 6 Hmin, CH3), 1.88-2.01 [m, 1 Hmaj & 1 Hmin, CH(CH3)2], 3.07-3.19 (m, 1 Hmin, NCH), 3.22-3.38 (m, 1 Hmin, CHOHmin), 3.63-3.74 (m, 2 Hmaj & 1 Hmin, CH2Omaj , CHOHmin), 4.01-4.09 (m, 1 Hmaj, NCH), 5.89-6.03 (br, 1 Hmaj, NH), 6.05-6.19 (br, 1 Hmin, NH), 8.05 (d, 1 Hmin, J = 11.5 Hz, HCO), 8.21 (br s, 1 Hmaj, HCO). 13C NMR (75 MHz, CDCl3) δ 18.1 (CH3), 18.9 (CH3), 19.4 (CH3), 19.7 (CH3), 29.4 [C(CH3)2], 30.5 [C(CH3)2], 46.6 (CH2), 47.1 (CH2), 53.8 (NCH), 59.7 (NCH), 161.1 (C=O), 164.6 (C=O). Anal. Calcd for C6H12NOCl: C, 48.17; H, 8.08; N, 9.36; Cl, 23.70. Found: C, 48.37; H, 7.85; N, 9.12; Cl, 24.01. MS (EI) m/z (rel. intensity) 150 (M+ + 1, 1), 108 (10), 106 (32), 100 (29), 78 (24), 72 (17), 70 (10), 61.0 (11), 55 (13), 46 (14), 45.0 (20), 43.0 (100%).

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General procedure for imidazoline(3) preparation: A solution of (S)-N-[1-(chloromethyl)-2-methylpropyl]form-amide (1.90 g, 12.7 mmol) and 4-trifluoromethylaniline (1.96 g, 12.2 mmol) in chloroform (30 mL) was cooled to 0 °C, and PCl5 (3.42 g, 16.5 mmol, 1.3 equiv) was added with care. The suspension was refluxed for 2 h, cooled and washed with aqueous 1 M NaOH (4 × 30 mL). The aqueous layer was extracted with chloroform. The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo providing the crude (S)-4-isopropyl-1-(4-trifluoromethylphenyl)-4,5-dihydroimidazole, which was recrystallised (CH2Cl2/toluene) yielding the pure compound, as a white solid, 2.71 g (87%), mp 94-95 °C, [α]20 D +195.2 (c 0.21, CHCl3). IR (KBr) 3063, 2975, 1606, 1529, 1386, 1314, 1196 cm-1. 1H NMR (300 MHz, CDCl3) δ 0.96 (d, 3H, J = 6.8 Hz, CH3), 1.01 (d, 3H, J = 6.8 Hz, CH3), 1.82-1.92 (m, 1H, CH(CH3)2), 3.40 (dd, 1 H, J = 8.3, 9.3 Hz, 5-H), 3.73 (dd, 1 H, J = 9.3, 10.3 Hz, 5-H), 4.05-4.14 (m, 1 H, 4-H), 6.96 (m, 2 H, HAr), 7.56 (m, 2 H, HAr), 7.62 (d, 1 H, J = 1.8 Hz, 2-H). 13C NMR (75 MHz, CDCl3) δ 18.2 (CH3), 18.7 (CH3), 33.0 (C(CH3)2), 48.7 (5-C), 72.5 (4-C), 113.5 (CAr), 126.8 (q, J = 3.8 Hz, CAr), 127.0 (quat., CAr), 147.5 (2-C) (CF3, CCF3 signals were not detected above noise). Anal. Calcd for C13H15N2F3: C, 60.93; H, 5.90; N; 10.93; F, 22.24. Found C, 60.55; H, 5.94; N, 10.80; F, 21.76. MS (EI) m/z (rel. intensity) 256 (M+, 11), 213 (100), 166 (10), 95 (4), 69 (4), 68 (6), 42 (12), 41 (21).

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General procedure for 2-hydroxyalkylimidazoline (4, 5) preparation: In a similar manner to the procedure of Jones et al, [19] a 2.5 M solution of BuLi in hexanes (4.11 mL, 10.25 mmol, 1.3 equiv) was added to a solution of (S)-4-isopropyl-1-(4-trifluoromethylphenyl)-4,5-dihydroimidazole (2.02 g, 7.8 mmol) in THF (20 mL) at -78 °C. The solution changed to a dark colour indicating formation of the anion and after 15 min trimethylacetaldehyde (0.74 g, 0.93 mL, 8.58 mmol, 1.1 equiv) was added and the solution was brought to r.t. and stirred for 15 h. The reaction mixture was added to a saturated solution of ammonium chloride and the aqueous layer was extracted with chloroform. The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo furnishing the crude product as a mixture of two diastereomers (55:45), which was chromatographed on silica (EtOAc/petroleum spirit, 80:20) to give 4b, as an oil, 1.02g (38%), and then 5b, as an oil, 820 mg (32%). An imidazolinium p-nitrobenzoate salt of adduct 4b was formed by combining equimolar amounts of the hydroxy-imidazoline and p-nitrobenzoic acid in chloroform. The product was filtered off and recrystallised (EtOAc), yielding the pure imidazolinium salt. (S)-1-[(S)-4-Isopropyl-1-(4-trifluoromethylphenyl)-4,5-dihydroimidazol-2-yl]-2,2-dimethyl-1-propanol 4b, mp (imidazolinium p-nitrobenzoate) 211-214 °C, [α]D 22 -135.2 (c 0.26, CHCl3). IR (thin film) 3368, 2958, 2872, 1608, 1521, 1324, 1118, 843, 810 cm-1. 1H NMR (300 MHz, CDCl3) δ 0.82 [s, 9 H, C(CH3)3], 0.86 (d, 3 H, J = 6.8 Hz, CH3), 0.93 (d, 3 H, J = 6.8 Hz, CH3), 1.75-1.83 [m, 1 H, CH(CH3)2], 3.37 (dd, 1 H, J = 9.3, 6.2 Hz, 5-H), 3.87-3.95 (m, 1 H, 4-H), 4.15 (dd, 1 H, J = 10.4, 9.3 Hz, 5-H), 4.22 [s, 1 H, CH(OH)], 7.12 (m, 2 H, HAr), 7.57-7.61 (m, 2 H, HAr). 13C NMR (75 MHz, CDCl3) δ 17.4 (CH3), 18.5 (CH3), 25.7 [CH3)3], 32.3 [CH(CH3)2], 36.9 [C(CH3)3], 58.9 (5-C), 68.9 [CH(OH)], 73.5 (4-C), 123.7 (CAr), 126.7 (q, J = 3.7 Hz, CAr), 145.9 (quat. C Ar), 164.5 (2-C) (CF3, CCF3 signals were not detected above noise). Anal. Calcd for C25H30N3O5F3 (imidazolinium p-nitrobenzoate) C, 58.93; H, 5.93; N, 8.25; F, 11.19. Found: C, 58,49; H, 5.80; N, 7.96; F, 10.90. MS (EI) m/z (rel. intensity) 342 (M+ + 1, 2), 286 (92), 285 (39), 213 (100), 187 (23), 174 (25), 145 (11). (R)-1-[(S)-4-Isopropyl-1-(4-trifluoromethylphenyl)-4,5-dihydro-imidazol-2-yl]-2,2-dimethyl-1-propanol 4b, [α]23 D +109.3 (c 0.22, CHCl3). IR (thin film) 3398, 2960, 2873, 1604, 1524, 1475, 1325, 845 cm-1. 1H NMR (300 MHz, CDCl3) δ 0.82 [s, 9 H, C(CH 3)3], 0.98 [d, 3 H, J = 6.7 Hz, CH3], 1.07 (d, 3 H, J = 6.7 Hz, CH3), 1.77-1.88 [m, 1 H, CH(CH3)2], 3.66 (dd, 1 H, J = 8.7, 9.4 Hz, 5-H), 3.83 (dd, 1 H, J = 10.1, 8.7 Hz, 5-H), 3.88-3.97 (m, 1 H, 4-H), 4.25 [s, 1 H, CH(OH)], 7.13 (m, 2 H, HAr), 7.58 (m, 2 H, HAr). 13C NMR (75 MHz, CDCl3) δ 18.9 (CH3), 19.7 (CH3), 25.9 [(CH3)3], 33.7 [CH(CH3)2], 37.0 [C(CH3)3], 57.1 (5-C), 70.2 [CH(OH)], 73.4 (4-C), 122.9 (CAr), 126.7 (q, J = 3.7 Hz, CAr), 145.1 (quat., CAr), 164.1 (2-C) (CF3, CCF3 signals were not detected above noise). MS (EI) m/z (rel. intensity) 342 (M+ + 1, 3), 286 (52), 285 (32), 213 (64), 145 (31), 142 (29), 57 (75), 41 (100%).

23

This assignment was supported by NOESY experiments and molecular mechanics calculations, as will be described in the full paper.

25

General procedure for diethylzinc additions: According to a procedure by Soai et al, [27] a 1 M solution of diethylzinc in hexane (2.2 mL, 2.2 mmol) was added to a solution of the chiral catalyst (6 mol%) and the aldehyde (1 mmol) in toluene (2 mL). The mixture was stirred until alkylation was complete (typically 15 h). The reaction was quenched by addition of dilute aqueous HCl. The mixture was extracted with dichloromethane and dried over MgSO4. The resulting oil was purified by flash chromatography on silica (EtOAc) yielding the product. Optical rotations were measured after further purification by kugelrohr distillation. 1-Phenyl-1-propanol: ee values were determined by HPLC analysis using a Chiralcel OD column, with 1% 2-propanol in hexane as eluent, at 1 mL/ min; retention times 21.5 min (R), 26.9 min (S). 1-(1-Naphthyl)-1-propanol: ee values were determined by HPLC analysis using a Chiralcel OD-H column, with 10% 2-propanol in hexane as eluent; retention times; 17.8 min (S), 32.3 min (R). 1-(Cyclohexyl)-1-propanol: ee values were determined by comparison of [α]D values with that reported. [28]