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

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.

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

References

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Grignard cross-coupling reaction is called the Kumada-Corriu reaction:

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12

The use of other solvents such as THF, CH₂Cl₂ and toluene, and the use of nickel salts in place of PdCl₂(MeCN)₂, gave less satisfactory results.

Use of the ligand 1o (Figure 4) possessing a pendant methoxy group resulted in no reaction. For the ligand 1o, see:

13a Miyano S, Hattori T, Komuro Y, and Kumobayashi H. inventors; Jpn. Kokai Tokkyo koho,  H09241277.  ; Chem. Abstr. 1997, 127, 302486h

13b Kondo K. Fujita H. Iida T. Suzuki T. Murakami Y. 30thCongress of Heterocyclic Chemistry, November 24-26^th   Hachioji; Japan: 1999. 

13c Mino T. Tanaka Y. Sakamoto M. Fujita T. Heterocycles  2000,  53:  1485 

14

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

The physical data of 3a, 3b, 3d and 3e were comparable to those reported:

15a Graven A. Jorgensen KA. Dahl S. Stanczak A. J. Org. Chem.  1994,  59:  3543 

15b Ranu BC. Samanta S. Guchhait SK. J. Org. Chem.  2001,  66:  4102 

15c

The new styrene derivative 3c was characterized by IR, ¹H- and ¹³C NMR, MS, and HRMS. The ¹H NMR data of 3c are shown below: ¹H NMR (CDCl₃): δ = 1.24 (d, J = 6.9 Hz, 3 H × 2), 2.88 (sept, J = 6.9 Hz, 1 H), 6.70 (d, J = 13.8 Hz, 1 H), 7.07 (d, J = 13.8 Hz, 1 H), 7.13-7.29 (m, 4 H).

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): t_R/min = 34.9 (S), 37.1 (R).

For other catalytic asymmetric Grignard cross-couplings, see:

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Another type of catalytic asymmetric cross-coupling, the Suzuki and Miyaura reaction, has been reported, see:

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22 During the completion of this manuscript, we became aware of a recent report by Mino, T. et al. of the Pd-catalyzed asymmetric allylic alkylation with the ligand 1m: Mino T. Tanaka Y. Sato Y. Saito A. Sakamoto M. Fujita T. Tetrahedron Lett.  2003,  44:  4677