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Synlett 2003(13): 2047-2051  
DOI: 10.1055/s-2003-41485
LETTER
© Georg Thieme Verlag Stuttgart · New York

Further Application of an N-Ar Axially Chiral Mimetic-Type Ligand: Asymmetric Grignard Cross-Coupling Reaction

Hideo Horibea, Kumiko Kazutab, Minori Kotokua, Kazuhiro Kondo*b, Hiroaki Okunoa, Yasuoki Murakamia, Toyohiko Aoyama*b
a Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
b Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
e-Mail: aoyama@phar.nagoya-cu.ac.jp; e-Mail: kazuk@phar.nagoya-cu.ac.jp;
Further Information

Publication History

Received 6 August 2003
Publication Date:
08 October 2003 (online)

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Abstract

A novel chiral ligand mimicking N-Ar axial chirality, (S)-N-[2-(diphenylphosphanyl)naphthalen-1-yl]-2-(piperidinyl­meth­yl)piperidine, was found to exhibit good enantioselectivity (up to 80% ee) in the asymmetric cross-coupling reaction of 1-phenyl­ethylmagnesium chloride with β-bromostyrene derivatives. Additionall­y, this type ligand is appealing, because it allows the synthesis of a wide variety of analogues.

Key words

N-Ar axis - chiral mimetics - optically active ligand - Grignard cross-coupling - asymmetric Kumada-Corriu reaction

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12

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14

The use of ligand 1i at ca.-20 °C afforded the coupling product with 25% yield and 80% ee.

16

The use of vinyl bromide and 1-propenyl bromide as substrates resulted in no reaction.

17

The racemic and optically active carboxylic acid 7 were purchased from Aldrich Co., Ltd.

18

The ligands 1b, 1d, 1e, and 1g-i were reported by us. [1] The new ligands 1a, 1c, 1f, 1j-l and 1n were characterized by IR, 1H- and 13C NMR, FABMS, and elemental analysis. All ligands 1a-n were synthesized according to the typical procedure described below. ( S )- N -[2-(Diphenylphosphanyl)naphthalen-1-yl]-2-(piperidinylmethyl)piperidine ( 1j). To a stirred solution of (S)-2-(piperidinylmethyl)piperidine (700 mg, 3.84 mmol) in THF (4.0 mL) was gradually added BuLi (2.53 mL, 4.00 mmol, 1.58 M solution in hexane) at -30 °C, and the mixture was stirred for 2 h at the same temperature. To this solution was then added a solution of 1-methoxy-2-(diphenylphos-phinoyl)naphthalene (680 mg, 1.90 mmol) in THF (2.0 mL) at -30 °C. The whole mixture was stirred for 1 h at the same temperature, quenched with H2O and extracted with EtOAc. The organic extracts were successively washed with saturated aq NH4Cl and brine, dried (Na2SO4) and concentrated. Purification by silica gel column (Fuji Silysia Chromatorex NH, EtOAc/hexane=1:5) gave a mixture (724 mg) of 1-(S)-N-[2-(diphenylphosphonyl)naphthalen-1-yl]-2-(piperidinylmethyl)piperidine and small amounts of impurities. This mixture was used for the next step without further separation. IR (neat): ν = 1308, 1254, 1192, 1161 cm-1. 1H NMR (CDCl3): δ = 0.75-1.15 (m, 8 H), 1.24-1.45 (m, 2 H), 1.60-1.94 (m, 8 H), 2.46 (dd, J = 13.3, 5.9 Hz, 1 H), 2.92 (br d, J = 11.1 Hz, 1 H), 3.36 (dd, J = 11.1, 11.1 Hz, 1 H), 3.51-3.62 (br, 1 H), 6.97 (dd, J = 12.1, 8.6 Hz, 1 H), 7.35-7.57 (m, 10 H), 7.65-7.87 (m, 4 H), 8.23 (d, J = 8.4 Hz, 1 H). 13C NMR (CDCl3): 24.29, 24.90, 25.47, 25.63, 31.38, 54.80, 56.09, 60.55, 62.23, 125.15, 125.42, 125.62, 126.21, 127.02, 127.95, 128.13, 128.65, 129.02, 129.22, 129.77, 130.74, 131.09, 131.23, 131.37, 131.94, 132.07, 134.15, 134.65, 135.09, 135.22, 135.66, 136.22, 136.63, 155.14. FABMS: m/z = 509 (M+ + 1). The above mixture was dissolved in p-xylene (7.0 mL), and Et3N (2.10 mL, 15.1 mmol) and HSiCl3 (1.4 mL, 14 mmol) were added at 0 °C. The whole mixture was heated at 140 °C for 2 h. After being cooled to r.t., the reaction mixture was carefully poured into 10% NaOH, and the whole mixture was extracted with EtOAc. The organic extracts were successively washed with water and brine, dried (Na2SO4), and concentrated. Purification by silica gel column (Fuji Silysia Chromatorex NH, hexane/EtOAc = 20:1) gave (S)-N-[2-(diphenylphos-phanyl)naphthyl]-2-(piperidinylmethyl)piperidine (1j)
(505 mg, 54% in 2 steps) as a colorless amorphous.
[α]D 28 +115 (c 1.60, dioxane). IR(nujol): ν = 1300, 1275, 1206, 1159 cm-1. 1H NMR (CDCl3): δ = 0.83-2.22 (m, 18 H), 2.66 (br d, J = 11.5 Hz, 1 H × 4/5), 3.01 (br d, J = 11.2 Hz, 1 H × 1/5), 3.30 (br dd, J = 11.5, 10.6 Hz, 1 H × 4/5), 3.45-3.53 (br, 1 H × 1/5), 3.55-3.73 (br, 1 H × 4/5), 4.13-4.28 (br, 1 H × 1/5), 6.89 (dd, J = 8.6, 2.4 Hz, 1 H × 4/5), 7.09 (dd, J = 8.6, 3.8 Hz, 1 H × 1/5), 7.14-7.57 (m, 13 H), 7.72-7.77 (m, 1 H × 1/5), 7.81 (dd, J = 6.3, 3.5 Hz, 1 H × 4/5), 8.05 (dd, J = 6.3, 3.5 Hz, 1 H × 4/5), 8.63 (dd, J = 6.3, 3.5 Hz,
1 H × 1/5). 13C NMR (CDCl3): 24.05, 24.29, 24.41, 25.27, 25.71, 25.93, 26.02, 27.47, 29.75, 31.59, 32.34, 54.10, 54.32, 54.93, 55.10, 57.17, 57.38, 59.20, 61.70, 62.50, 62.59, 124.80, 124.94, 125.49, 125.57, 125.78, 125.95, 126.02, 126.71, 127.44, 127.90, 127.97, 128.00, 128.13, 128.17, 128.27, 128.37, 128.63, 129.50, 131.91, 132.72, 133.00, 133.29, 133.54, 133.80, 133.95, 134.10, 134.26, 134.54, 134.66, 135.01, 135.19, 136.92, 137.40, 137.60, 138.35, 138.54, 138.81, 139.00, 139.63, 139.87, 150.99, 151.30, 153.92, 154.28. FABMS: m/z = 493 (M+ + 1). Anal. Calcd for C33H37N2P: C, 80.46; H, 7.57; N, 5.69, Found: C, 80.27; H, 7.56; N, 5.85.
Typical Procedure for Grignard Cross-Coupling Reaction of ( E )-β-Bromostyrene(3a) with Ligand 1j (entry 3, Table 2). 1-Phenylethylmagnesium chloride (4) (2.10 mL, 1.50 mmol, 0.70 mol/L in Et2O) was added to the mixture of PdCl2(MeCN)2 (9.3 mg, 0.036 mmol) and the ligand 1j (18.2 mg, 0.0369 mmol) in α,α,α-trifluorotoluene (2.10 mL) at 0 °C, and the solution was stirred at the same temperature for 30 min (CAUTION: stirring at 0 °C for 30 min for the favorable complexation of Pd and ligand 1j is needed.). To the solution was added (E)-β-bromostyrene (3a) (133 mg, 0.727 mmol) at -10 °C. The resulting solution was stirred for 6 h at -10 °C. After usual work-up, purification by silica gel column(hexane) afforded the coupling product 5a (105 mg, 69%, 72% ee) as a colorless oil. The ee was determined by HPLC analysis (Daicel chiralcel OD, hexane/i-PrOH = 100:1, 0.3 mL/min, 254 nm): tR/min = 34.9 (S), 37.1 (R).