1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane, and its synthesis and application

Abstract

The present invention relates to the design and synthesis of a class of novel chiral phosphine ligand, 1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane, and use in asymmetric catalytic reactions, such as asymmetric catalytic synthesis of pyrazoline-5-one with a chiral quaternary carbon center, i.e., highly enantioselective synthesis of 3-methyl-4-benzyl-4-(2-butyl-2,3-butadienyl)pyrazoline-5-one by using 3-methyl-4-benzylpyrazoline-5-one and benzyl (2-butyl-2,3-butadienyl) carbonate with tris(dibenzylideneacetone)dipalladium-chloroform adduct and this novel ligand as catalysts. The ligand designed by this present invention has the following advantages: the structure is novel, the synthesis and enlarge are simple, the enantioselective control effect in the practical reaction is excellent, which has a broad application prospect in chiral catalysis.

Claims

1. 1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane chiral phosphine ligands, wherein, the said 1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane has the following structure as formula(I): ##STR00021## wherein each instance of R.sup.1 is selected from the group consisting of a phenyl group, a phenyl group substituted by C.sub.1-C.sub.10 alkyl, a phenyl group substituted by halogen, or an -naphthyl group; or alternatively the group represents a (CH.sub.2).sub.3 or (CH.sub.2).sub.4 group; n=1-6.

2. A method for preparing 1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane, which comprises reacting, in an organic solvent, using-1,2-disubstituted-1,2-diaminoethane, diphenylphosphinoacetic acid, p-dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride as reaction raw materials to obtain 1,2-bis(diphenylphosphonylalkylamido)-1,2-disubstituted ethane through an amidation reaction, wherein said reaction has the following reaction equation: ##STR00022## wherein each instance of R.sup.1 is selected from the group consisting of a phenyl group, a phenyl group substituted by C.sub.1-C.sub.10 alkyl, a phenyl group substituted by halogen, or an -naphthyl group; or alternatively the group represents a (CH.sub.2).sub.3 or (CH.sub.2).sub.4 group.

3. The method of claim 2, wherein, the said organic solvent is dichloromethane; the molar ratio of diphenylphosphinoacetic acid, 1,2-disubstituted-1,2-diaminoethane, p-dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is (2.1-2.2):1.0:2.1:2.2; and the amidation reaction temperature is 20-30 C.

4. A method for preparing 1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane, which comprises reacting in an organic solvent, N-hydroxysuccinimide diphenylphosphonyl alkyl acid ester and 1,2-disubstituted-1,2-diaminoethane as reaction raw materials to obtain the said 1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane through an amidation reaction, wherein said reaction has the following reaction equation: ##STR00023## wherein each instance of R.sup.1 is selected from the group consisting of a phenyl group, a phenyl group substituted by C.sub.1-C.sub.10 alkyl, a phenyl group substituted by halogen, or an -naphthyl group; or alternatively the group represents a (CH.sub.2).sub.3 or (CH.sub.2).sub.4 group; n=1-6.

5. The method of claim 4, wherein, the said organic solvent is dichloromethane; the molar ratio of diphenylphosphinoalkyl acid N-hydroxysuccinimide ester and 1,2-disubstituted-1,2-diaminoethane is (2.1-2.2):1.0; and the amidation reaction temperature is 20-30 C.

6. A method of preparing a chiral 3-methyl-4-benzyl-4-(2-butyl-2,3-butadienyl)pyrazoline-5-one, which comprises using the 1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane according to claim 1 in an enantioselective reaction.

7. The method of claim 6, which comprises reacting in an organic solvent, tris(dibenzylideneacetone)dipalladium-chloroform adduct, 1,2-bis(diphenylphosphinoalkylamido)-1,2-disubstituted ethane, benzyl(2-alkyl- 2,3-butadienyl) carbonate and 3-methyl-4-benzyl-pyrazoline-5-one as reaction raw materials to obtain the said chiral 3-methyl-4-benzyl-4-(2-butyl-2,3-butadienyl)pyrazoline-5-one, wherein said reaction has the following reaction equation: ##STR00024## wherein, R.sup.2 is C1-C10 alkyl group; R.sup.3 is C1-C10 alkyl group; R.sup.4 is phenyl group substituted by halogen, phenyl group substituted by C1-C10 alkyl, benzyl group, -naphthyl group, C1-C10 alkyl group, alkenyl group.

8. The method of claim 7, wherein, the said organic solvent is of toluene; the said reaction temperature is 30-60 C.

9. The method of claim 7, wherein the molar ratio of benzyl (2-alkyl-2,3-butadienyl) carbonate and 3-methyl-4-benzyl-pyrazoline-5-one is 1.0:(1.2-1.4); the molar ratio of benzyl (2-alkyl-2,3-butadienyl) carbonate and organic solvent is 0.02-0.1 mmol/mL.

10. Chiral 3-methyl-4-benzyl-4-(2-alkyl-2,3-butadienyl)pyrazoline-5-one compounds, wherein, the said chiral 3-methyl-4-benzyl-4-(2-alkyl-2,3-butadienyl)pyrazoline-5-one compounds have the following structure as formula(6): Wherein, ##STR00025## R.sup.2 is C1-C10 alkyl group; R.sup.3 is C.sub.1-C.sub.10 alkyl group; R.sup.4 is phenyl group substituted by halogen, phenyl group substituted by C1-C10 alkyl group, benzyl group, -naphthyl group, C1-C10 alkyl group, alkenyl group.

Description

Example (1) (1R,2R)-1,2-bis(diphenylphosphinoacetamido) cyclohexane ((R,R)-L1) (zyc-4-7)

(1) ##STR00009## (R,R)-1,2-cyclohexanediamine (846.0 mg, 7.41 mmol, 99% ee) and dichloromethane (10 mL), diphenylphosphinoacetic acid (3800.0 mg, 15.56 mmol) and dichloromethane (20 mL), and p-dimethylaminopyridine (1899.4 mg, 15.56 mmol) were added to a dried three-necked flask. Then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (3125.5 mg, 16.30 mmol) dissolved in 20 mL dichloromethane was dropped into the three-necked flask, stirred for 10 hours at room temperature, transferred to a separatory funnel and washed with water (100 mL3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude residual was purified by chromatography on silica gel (dichloromethane/methanol=1000/1 (150 mL) to 100/1 (1000 mL)) to afford the product (R,R)-L1 (1718.7 mg, 41%) as a solid. (R,R)-L1: melting point: 217.4-218.0 C. (dichloromethane/n-hexane). [].sub.D.sup.20=+32.9 (c=0.995, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.61-7.11 (m, 20H, ArH), 5.99 (d, J=3.9 Hz, 2H, NH2), 3.62-3.36 (m, 2H, NCH2), 3.01-2.68 (m, 4H, CH.sub.22), 1.86-1.50 (m, 4H, CH.sub.22), 1.33-1.06 (m, 2H, CH.sub.2), 1.06-0.80 (m, 2H, CH.sub.2); .sup.13C NMR (75 MHz, CDCl.sub.3) 169.9 (d, J=8.3 Hz), 137.5 (d, J=13.8 Hz), 137.3 (d, J=13.8 Hz), 133.0, 132.7, 132.5, 132.3, 129.1, 128.8, 128.6, 128.54, 128.50, 128.46, 53.6, 37.4 (d, J=20.7 Hz), 32.0, 24.5; .sup.31P NMR (121.5 MHz, CDCl.sub.3) -16.8; IR (KBr) v (cm.sup.1) 3292, 3067, 3052, 2933, 2912, 2854, 1627, 1530, 1480, 1433, 1401, 1328, 1147; MS (EI): m/z (%) 566 ([M].sup.+, 29.26), 381 (100); Anal. Calcd. for C.sub.34H.sub.36N.sub.2O.sub.2P.sub.2 (%): C 72.07, H 6.40, N 4.94; Found: C 72.01, H 6.42, N 4.76.

Example (2) (1S,2S)-1,2-bis(diphenylphosphinoacetamido)cyclohexane (S,S)-(L1) (zyc-4-52)

(2) ##STR00010##

(3) Operations were conducted by referring to Example (1). (S,S)-1,2-cyclohexanediamine (764.1 mg, 6.70 mmol, 98% ee)/dichloromethane (10 mL), diphenylphosphinoacetic acid (3451.7 mg, 14.10 mmol)/dichloromethane (20 mL), p-dimethylaminopyridine (1723.0 mg, 14.10 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2826.6 mg, 14.74 mmol)/dichloromethane (20 mL) were added to a dried three-necked flask and stirred for 12 hours at room temperature to obtain (S,S)-L1 (1252.3 mg, 33%) (dichloromethane/methanol=1000/1 (300 mL) to 100/1 (800 mL)) as a solid. (S,S)-L1: melting point: 216.9-217.9 C. (dichloromethane/n-hexane). [].sub.D.sup.20=33.3 (c=0.990, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.53-7.20 (m, 20H, ArH), 5.99 (d, J=5.1 Hz, 2H, NH2), 3.59-3.40 (m, 2H, NCH2), 2.96-2.77 (m, 4H, PCH.sub.22), 1.86-1.70 (m, 2H, CH.sub.2), 1.70-1.54 (m, 2H, CH.sub.2), 1.28-1.08 (m, 2H, CH.sub.2), 1.06-0.84 (m, 2H, CH.sub.2); .sup.13C NMR (75 MHz, CDCl.sub.3) 170.0 (d, J=8.3 Hz), 137.5 (d, J=13.1 Hz), 137.3 (d, J=14.5 Hz), 133.0, 132.7, 132.5, 132.3, 129.1, 128.8, 128.6, 128.55, 128.51, 128.47, 53.6, 37.4 (d, J=20.7 Hz), 32.0, 24.5; .sup.31P NMR (121.5 MHz, CDCl.sub.3) -16.8; IR (KBr) v (cm.sup.1) 3292, 3067, 3051, 2931, 2854, 1628, 1529, 1481, 1433, 1399, 1327, 1190, 1143; MS (EI): m/z (%) 566 ([M].sup.+, 32.57), 381 (100); Anal. Calcd. for C.sub.34H.sub.36N.sub.2O.sub.2P.sub.2 (%): C 72.07, H 6.40, N 4.94; Found: C 72.03, H 6.44, N 4.81.

Example (3) (1R,2R)-1,2-bis(diphenylphosphinopropionamido)cyclohexane (R,R)-(L2) (zyc-3-118,186)

(4) ##STR00011##

(5) Compounds 3a (1564.1 mg, 4.4 mmol) and dichloromethane (4 mL), (R,R)-1,2-cyclohexanediamine (228.6 mg, 2.0 mmol, 99% ee) and dichloromethane (2 mL) were added to a dried reaction tube, then stirred for 16 hours at room temperature. Then 10 mL of water was added to quench the reaction, transferred to the separatory funnel, and extracted with dichloromethane (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude residual was purified by chromatography on silica gel (dichloromethane/methanol=100/0 (300 mL) to 100/1 (500 mL) to afford a solid. The resulting solid was recrystallized from ethyl acetate and collected by suction filtration washed with ethyl acetate to afford the product (R,R)-L2 (852.6 mg, 72%) as a solid.

(6) (R,R)-L2: melting point: 152.4-153.2 C. (ethyl acetate). [].sub.D.sup.20=+0.3 (c=1.045, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.46-7.32 (m, 8H, ArH), 7.32-7.22 (m, 12H, ArH), 6.11 (d, J=6.9 Hz, 2H, NH2), 3.68-3.51 (m, 2H, NCH2), 2.37-2.10 (m, 8H, CH.sub.24), 2.03-1.90 (m, 2H, CH.sub.2), 1.78-1.62 (m, 2H, CH.sub.2), 1.37-1.08 (m, 4H, CH.sub.22); .sup.13C NMR (75 MHz, CDCl.sub.3) 172.7 (d, J=13.1 Hz), 137.8 (d, J=3.5 Hz), 137.6 (d, J=3.5 Hz), 132.7, 132.6, 132.5, 132.4, 128.61, 128.58, 128.4, 128.3, 53.6, 32.7 (d, J=18.6 Hz), 32.0, 24.5, 23.3 (d, J=12.5 Hz); .sup.31P NMR (121.5 MHz, CDCl.sub.3) -15.9; IR (KBr) v (cm.sup.1) 3273, 3069, 2933, 2855, 1639, 1546, 1476, 1433, 1257; MS (EI): m/z (%) 594 ([M].sup.+, 11.45), 256 (100); HRMS calcd. for C.sub.36H.sub.40N.sub.2O.sub.2P.sub.2 [M.sup.+]: 594.2565; Found: 594.2563.

Example (4) (1R,2R)-1,2-bis(diphenylphosphinobutyramido)cyclohexane (R,R)-(L3) (zyc-3-198)

(7) ##STR00012##

(8) Compound 3b (890.5 mg, 2.2 mmol) and dichloromethane (2 mL), (R,R)-1,2-cyclohexanediamine (117.1 mg, 1.0 mmol, 99% ee) and dichloromethane (1 mL) were added to a dried reaction tube, then stirred at 30 C. for 18 hours. 5 mL water was added to quench the reaction, transferred to separatory funnel, and extracted with dichloromethane (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude residual was purified by chromatography on silica gel (dichloromethane/methanol=100/0 (300 mL) to 100/1 (600 mL), and then recrystallized with dichloromethane/n-hexane system to afford the product (R,R)-L3 (344.8 mg, 54%) as a solid.

(9) (R,R)-L3: melting point: 166.8-167.6 C.(dichloromethane/n-hexane). [].sub.D.sup.20=+22.4 (c=1.000, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.55-7.09 (m, 20H, ArH), 6.03 (d, J=4.5 Hz, 2H, NH2), 3.72-3.53 (m, 2H, NCH2), 2.28-2.06 (m, 4H, CH.sub.22), 2.06-1.88 (m, 6H, CH.sub.23), 1.84-1.59 (m, 6H, CH.sub.23), 1.38-1.08 (m, 4H, CH.sub.22); .sup.13C NMR (75 MHz, CDCl.sub.3) 172.9, 138.4 (d, J=2.8 Hz), 138.2 (d, J=3.5 Hz), 132.7, 132.5, 128.5, 128.4, 128.3, 53.6, 37.5 (d, J=13.1 Hz), 32.2, 27.4 (d, J=11.8 Hz), 24.6, 22.1 (d, J=17.9 Hz); .sup.31P NMR (121.5 MHz, CDCl.sub.3) -17.2; IR (KBr) v (cm.sup.1) 3344, 3068, 3045, 2943, 2854, 1636, 1521, 1478, 1432, 1409, 1375; MS (EI): m/z (%) 622 ([M].sup.+, 47.62), 270 (100); Anal. Calcd. for C.sub.38H.sub.44N.sub.2O.sub.2P.sub.2 (%): C 73.29, H 7.12, N 4.50; Found: C 73.11, H 7.13, N 4.30.

Example (5) (1R,2R)-1,2-diphenyl-1,2-bis(diphenylphosphinopropionamido)ethane (R,R)-(L4) (zyc-3-181)

(10) ##STR00013##

(11) (R,R)-1,2-diphenyl 1,2-ethylenediamine (212.6 mg, 1.0 mmol, 99% ee), compound 3a (781.9 mg, 2.2 mmol) and dichloromethane (8 mL) were added to a dried reaction tube, then stirred for 19.5 hours in room temperature. 10 mL of water was added to quench the reaction, transferred to a separatory funnel, extracted with dichloromethane (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude residual was purified by chromatography on silica gel (dichloromethane/methanol=100/0 (500 mL) to 100/1 (600 mL)) to afford a solid. The resulting solid was recrystallized from ethyl acetate and collected by suction filtration washed with ethyl acetate to afford the product (R,R)-L4 (561.3 mg, 79%, purity=98%) as a solid.

(12) (R,R)-L4: melting point: 140.8-141.9 C. (ethyl acetate). [].sub.D.sup.20=64.5 (c=1.050, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.44-7.22 (m, 20H, ArH), 7.20-7.11 (m, 6H, ArH), 7.11-7.01 (m, 4H, ArH), 6.76-6.62 (m, 2H, NH2), 5.28-5.16 (m, 2H, NCH2), 2.36-2.13 (m, 8H, CH.sub.24); .sup.13C NMR (75 MHz, CDCl.sub.3) 173.0 (d, J=13.1 Hz), 138.5, 137.8, 137.6 (d, J=1.4 Hz), 132.8, 132.7, 132.6, 132.5, 128.8, 128.7, 128.6, 128.5, 127.8, 127.5, 59.4, 32.7 (d, J=17.9 Hz), 23.2 (d, J=12.4 Hz); .sup.31P NMR (121.5 MHz, CDCl.sub.3) -16.1; IR (KBr) v (cm.sup.1) 3287, 3068, 3028, 2929, 1644, 1535, 1493, 1476, 1433, 1364, 1248; MS (EI): m/z (%) 692 ([M]f, 5.29), 346 (100); HRMS calcd. for C.sub.44H.sub.42N.sub.2O.sub.2P.sub.2 [M.sup.+]: 692.2722; Found: 692.2722.

Example (6) (1S,2S)-1,2-diphenyl-1,2-bis(diphenylphosphinopropionamido)ethane (S,S)-(L4) (zyc-4-15)

(13) ##STR00014##

(14) (S,S)-1,2-diphenyl 1,2-ethylenediamine (212.5 mg, 1.0 mmol, 99% ee), compound 3a (782.3 mg, 2.2 mmol) and dichloromethane (8 mL) were added to a dried reaction tube, then stirred for 16 hours at room temperature. 10 mL water was added to quench the reaction, transferred to separatory funnel, extracted with dichloromethane (10 mL3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude residual was purified by chromatography on silica gel (dichloromethane/methanol=100/1 (400 mL)) to afford a solid. The resulting solid was recrystallized from ethyl acetate and collected by suction filtration washed with ethyl acetate to afford the product (S,S)-L4 (538.6 mg, 78%) as a solid.

(15) (S,S)-L4: melting point: 143.6-144.4 C. (ethyl acetate). [].sub.D.sup.20=+66.9 (c=0.980, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.41-7.19 (m, 20H, ArH), 7.19-6.99 (m, 10H, ArH), 6.97-6.82 (m, 2H, NH2), 5.28-5.15 (m, 2H, NCH2), 2.33-2.09 (m, 8H, CH.sub.24); .sup.13C NMR (75 MHz, CDCl.sub.3) 173.0 (d, J=13.8 Hz), 138.6, 137.8 (d, J=2.8 Hz), 137.6 (d, J=3.5 Hz), 132.8, 132.7, 132.5, 132.4, 128.71, 128.66, 128.5, 128.43, 128.42, 127.7, 127.4, 59.3, 32.7 (d, J=17.9 Hz), 23.3 (d, J=12.4 Hz); .sup.31P NMR (121.5 MHz, CDCl.sub.3) -16.0; IR (KBr) v (cm.sup.1) 3285, 3067, 3050, 3024, 2912, 1642, 1535, 1491, 1478, 1431, 1364, 1250, 1049; MS (EI): m/z (%) 692 ([M].sup.+, 7.23), 346 (100); Anal. Calcd. for C.sub.44H.sub.42N.sub.2O.sub.2P.sub.2 (%): C 76.28, H 6.11, N 4.04; Found: C 76.09, H 6.14, N 3.93.

Example (7) 3-methyl-4-benzyl-4-(2-butyl-2,3-butadienyl)-1-phenylpyrazoline-5-one (6aa) (zyc-4-30)

(16) ##STR00015##

(17) Under a nitrogen environment, tris(dibenzylideneacetone)dipalladium-chloroform adduct (12.9 mg, 0.0125 mmol), (R,R)-L1 (14.3 mg, 0.025 mmol)/toluene (5 mL), 4a (131.5 mg, 0.5 mmol)/toluene (11.7 mL), and 5a (158.7 mg, 0.6 mmol)/toluene (8.3 mL) were added to a dried reaction flask, then stirred at 60 C. for 12 hours. The resulting mixture was filtrated through a short column of silica gel and eluted with ethyl acetate (15 mL3). After evaporation, the residue was purified by chromatography on silica gel (eluent: petroleum ether (60-90 C.)/ethyl acetate=60/1) to afford a pure part of 6aa and the impure part was further purified by chromatography on silica gel (eluent: petroleum ether (60-90 C.)/ethyl acetate=40/1). Two-round chromatography afforded 6aa (179.5 mg, 96%) as a liquid

(18) 6aa: 94.6% ee (HPLC condition: Chiralcel IA column, n-hexane/i-PrOH=90/10, 1.0 mL/min, =254 nm, t.sub.R (major)=5.7 min, t.sub.R (minor)=8.9 min); [].sub.D.sup.20=8.2 (c=1.250, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.55 (d, J=8.1 Hz, 2H, ArH), 7.30 (t, J=7.8 Hz, 2H, ArH), 7.22-7.02 (m, 6H, ArH), 4.56 (t, J=2.7 Hz, 2H, CH.sub.2=C), 3.18 (d, J=13.2 Hz, 1H, one proton of CH.sub.2), 2.89 (d, J=13.5 Hz, 1H, one proton of CH.sub.2), 2.69 (dt, J.sub.1=15.3 Hz, J.sub.2=3.3 Hz, 1H, one proton of CH.sub.2), 2.39 (d, J=15.0 Hz, 1H, one proton of CH.sub.2), 2.14 (s, 3H, CH.sub.3), 1.93-1.80 (m, 2H, CH.sub.2), 1.43-1.17 (m, 4H, CH.sub.23), 0.83 (t, J=7.1 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 205.3, 174.6, 161.4, 137.6, 134.1, 129.1, 128.5, 128.1, 127.2, 124.8, 119.3, 98.3, 77.7, 60.1, 42.8, 36.1, 32.3, 29.4, 22.1, 14.7, 13.8; IR (neat) v (cm.sup.1) 3063, 3031, 2956, 2927, 2859, 1954, 1712, 1597, 1500, 1455, 1440, 1402, 1366, 1123; MS (EI): m/z (%) 372 ([M].sup.+, 31.27), 186 (100); HRMS calcd. for C.sub.25H.sub.28N.sub.2O [M].sup.+: 372.2202; Found: 372.2202.

Example (8) 3-methyl-4-(4-methylbenzyl)-4-(2-butyl-2,3-butadienyl)-1-phenylpyrazoline-5-one (6ab) (zyc-4-75)

(19) ##STR00016##

(20) Operations were conducted by referring to Example (7). Under a nitrogen environment, tris(dibenzylideneacetone)dipalladium-chloroform adduct (12.8 mg, 0.0125 mmol), (R,R)-L1(14.3 mg, 0.025 mmol) and toluene (5 mL), 4a (131.1 mg, 0.5 mmol)/toluene (11.7 mL), 5b (167.0 mg, 0.6 mmol)/toluene (8.3 mL) were added to a dried reaction flask, and stirred at 60 C. for 12 hours to obtain the product 6ab (178.1 mg, 92%) (petroleum ether/diethyl ether=60/1 (600 mL) to 40/1 (1000 mL)) as a liquid.

(21) 6ab: 95.4% ee (HPLC condition: Chiralcel IA column, n-hexane/i-PrOH=90/10, 1.0 mL/min, =254 nm, t.sub.R (major)=5.7 min, t.sub.R (minor)=7.9 min); [].sub.D.sup.20=24.9 (c=1.125, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.60 (d, J=7.5 Hz, 2H, ArH), 7.30 (t, J=8.0 Hz, 2H, ArH), 7.10 (t, J=7.5 Hz, 1H, ArH), 7.00-6.90 (m, 4H, ArH), 4.55 (p, J=3.0 Hz, 2H, CH.sub.2=C), 3.14 (d, J=13.2 Hz, 1H, one proton of CH.sub.2), 2.84 (d, J=13.5 Hz, 1H, one proton of CH.sub.2), 2.68 (dt, J.sub.1=15.3 Hz, J.sub.2=3.3 Hz, 1H, one proton of CH.sub.2), 2.37 (dt, J.sub.1=15.3 Hz, J.sub.2=2.2 Hz, 1H, one proton of CH.sub.2), 2.19 (s, 3H, CH.sub.3), 2.12 (s, 3H, CH.sub.3), 1.92-1.80 (m, 2H, CH.sub.2), 1.40-1.17 (m, 4H, CH.sub.22), 0.82 (t, J=7.1 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 205.3, 174.7, 161.5, 137.7, 136.7, 131.0, 128.9, 128.8, 128.5, 124.7, 119.2, 98.3, 77.5, 60.1, 42.4, 36.1, 32.3, 29.4, 22.1, 20.9, 14.7, 13.7; IR (neat) v (cm.sup.1) 2956, 2925, 2869, 2856, 1955, 1708, 1597, 1515, 1500, 1457, 1441, 1402, 1365, 1326, 1121; MS (EI): m/z (%) 386 ([M].sup.+, 22.51), 105 (100); HRMS calcd. for C.sub.26H.sub.30N.sub.2O [M].sup.+: 386.2358; Found: 386.2361.

Example (9) 3-methyl-4-(4-chlorobenzyl)-4-(2-butyl-2,3-butadienyl)-1-phenylpyrazoline-5-one (6ac) (zyc-4-76)

(22) ##STR00017##

(23) Operations were conducted by referring to Example (7). Under a nitrogen environment, tris(dibenzylideneacetone)dipalladium-chloroform adduct (13.0 mg, 0.0125 mmol), (R,R)-L1(14.4 mg, 0.025 mmol) and toluene (5 mL), 4a (131.0 mg, 0.5 mmol)/toluene (11.7 mL), 5c (179.6 mg, 0.6 mmol)/toluene (8.3 mL) were added to a dried reaction flask, and stirred at 60 C. for 12 hours to obtain the product 6ac (197.0 mg, 97%) (petroleum ether/diethyl ether=40/1) as a liquid.

(24) 6ac: 95.1% ee (HPLC condition: Chiralcel IA column, n-hexane/i-PrOH=90/10, 1.0 mL/min, =254 nm, t.sub.R (major)=6.7 min, t.sub.R (minor)=8.7 min); [].sub.D.sup.20=27.9 (c=0.990, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.58 (d, J=7.8 Hz, 2H, ArH), 7.31 (t, J=8.0 Hz, 2H, ArH), 7.18-7.07 (m, 3H, ArH), 7.00 (d, J=8.4 Hz, 2H, ArH), 4.56 (p, J=2.9 Hz, 2H, CH.sub.2=C), 3.13 (d, J=13.5 Hz, 1H, one proton of CH.sub.2), 2.84 (d, J=13.2 Hz, 1H, one proton of CH.sub.2), 2.67 (dt, J.sub.1=15.0 Hz, J.sub.2=3.2 Hz, 1H, one proton of CH.sub.2), 2.36 (d, J=14.7 Hz, 1H, one proton of CH.sub.2), 2.13 (s, 3H, CH.sub.3), 1.92-1.79 (m, 2H, CH.sub.2), 1.42-1.17 (m, 4H, CH.sub.22), 0.82 (t, J=7.2 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 205.3, 174.3, 161.1, 137.5, 133.1, 132.6, 130.4, 128.6, 128.3, 124.9, 119.1, 98.1, 77.7, 60.0, 41.9, 36.1, 32.3, 29.3, 22.0, 14.6, 13.7; IR (neat) v (cm.sup.1) 3062, 3046, 2956, 2927, 2871, 2856, 1955, 1709, 1597, 1500, 1458, 1441, 1402, 1366, 1323, 1299, 1245, 1181, 1122, 1097, 1016; MS (EI): m/z (%) 408 ([M(Cl.sup.37)].sup.+, 15.32), 406 ([M(Cl.sup.35)].sup.+, 38.40), 125 (100); HRMS calcd. for C.sub.25H.sub.27.sup.35ClN.sub.2O [M].sup.+: 406.1812; Found: 406.1814.

Example (10) 3-methyl-4-(-naphthylmethyl)-4-(2-butyl-2,3-butadienyl)-1-phenylpyrazoline-5-one (6ad) (zyc-4-92)

(25) ##STR00018##

(26) Operations were conducted by referring to Example (7). Under a nitrogen environment, tris(dibenzylideneacetone)dipalladium-chloroform adduct (12.9 mg, 0.0125 mmol), (R,R)-L1(14.3 mg, 0.025 mmol) and toluene (5 mL), 4a (131.1 mg, 0.5 mmol)/toluene (11.7 mL), 5d (188.4 mg, 0.6 mmol)/toluene (8.3 mL) were added to a dried reaction flask, and stirred at 60 C. for 12 hours to obtain the product 6ad (200.9 mg, 95%) (petroleum ether/diethyl ether=50/1) as a liquid.

(27) 6ad: 96.7% ee (HPLC condition: Chiralcel IA column, n-hexane/i-PrOH=90/10, 1.0 mL/min, =254 nm, t.sub.R (major)=6.5 min, t.sub.R (minor)=11.1 min); [].sub.D.sup.20=47.4 (c=1.030, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 8.09 (d, J=8.7 Hz, 1H, ArH), 7.76 (d, J=8.1 Hz, 1H, ArH), 7.70-7.62 (m, 1H, ArH), 7.56 (d, J=8.7 Hz, 2H, ArH), 7.52-7.37 (m, 2H, ArH), 7.33-7.22 (m, 4H, ArH), 7.08 (t, J=7.4 Hz, 1H, ArH), 4.53 (p, J=3.0 Hz, 2H, CH.sub.2=C), 3.64 (d, J=14.1 Hz, 1H, one proton of CH.sub.2), 3.41 (d, J=14.4 Hz, 1H, one proton of CH.sub.2), 2.78 (dt, J.sub.1=15.3 Hz, J.sub.2=3.5 Hz, 1H, one proton of CH.sub.2), 2.48 (dt, J.sub.1=14.7 Hz, J.sub.2=2.3 Hz, 1H, one proton of CH.sub.2), 1.98-1.80 (m, 5H, CH.sub.3 and CH.sub.2), 1.42-1.15 (m, 4H, CH.sub.22), 0.82 (t, J=7.1 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 205.3, 175.1, 162.0, 137.8, 133.7, 132.0, 130.7, 128.7, 128.5, 128.1, 127.5, 125.8, 125.5, 124.9, 124.7, 123.6, 119.1, 98.3, 77.8, 59.5, 38.1, 36.1, 32.4, 29.4, 22.1, 15.1, 13.8; IR (neat) v (cm.sup.1) 3062, 3046, 2956, 2927, 2871, 2852, 1954, 1709, 1597, 1500, 1457, 1399, 1365, 1322, 1121; MS (EI): m/z (%) 422 ([M].sup.+, 21.84), 186 (100); HRMS calcd. for C.sub.29H.sub.30N.sub.2O [M].sup.+: 422.2358; Found: 422.2361.

Example (11) 3-methyl-4-ethyl-4-(2-butyl-2,3-butadienyl)-1-phenylpyrazoline-5-one (6ae) (zyc-4-64)

(28) ##STR00019##

(29) Operations were conducted by referring to Example (7). Under a nitrogen environment, tris(dibenzylideneacetone)dipalladium-chloroform adduct (12.9 mg, 0.0125 mmol), (R,R)-L1(14.3 mg, 0.025 mmol) and toluene (5 mL), 4a (131.0 mg, 0.5 mmol)/toluene (11.7 mL), 5e (141.6 mg, 0.7 mmol)/toluene (8.3 mL) were added to a dried reaction flask, and stirred at 60 C. for 13 hours to obtain the product 6ae (134.6 mg, 87%) (petroleum ether/diethyl ether=40/1, the impure part was subjected to the column chromatography again, petroleum ether/ethyl acetate=40/1, combined) as a liquid.

(30) 6ae: 93.8% ee (HPLC condition: Chiralcel IA column, n-hexane/i-PrOH=95/5, 1.0 mL/min, =254 nm, t.sub.R (minor)=5.3 min, t.sub.R (major)=5.8 min); [].sub.D.sup.20=+152.9 (c=0.990, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.89 (d, J=7.8 Hz, 2H, ArH), 7.38 (t, J=8.0 Hz, 2H, ArH), 7.15 (t, J=7.4 Hz, 1H, ArH), 4.55 (p, J=3.1 Hz, 2H, CH.sub.2=C=C), 2.55 (dt, J.sub.1=15.0 Hz, J.sub.2=3.3 Hz, 1H, one proton of CH.sub.2), 2.25 (d, J=15.0 Hz, 1H, one proton of CH.sub.2), 2.07 (s, 3H, CH.sub.3), 1.97-1.77 (m, 3H, one proton of CH.sub.2 and CH.sub.2), 1.74-1.58 (m, 1H, one proton of CH.sub.2), 1.40-1.13 (m, 4H, CH.sub.22), 0.81 (t, J=7.2 Hz, 3H, CH.sub.3), 0.72 (t, J=7.5 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 205.3, 175.1, 162.3, 138.0, 128.6, 124.6, 118.6, 98.3, 77.3, 59.2, 36.3, 32.2, 29.6, 29.3, 22.0, 13.9, 13.7, 7.9; IR (neat) v (cm.sup.1) 2960, 2931, 2873, 2856, 1955, 1713, 1619, 1597, 1500, 1458, 1403, 1386, 1365, 1311, 1261, 1136, 1094; MS (EI): m/z (%) 310 ([M].sup.+, 29.93), 187 (100); HRMS calcd. for C.sub.20H.sub.26N.sub.2O [M].sup.+: 310.2045; Found: 310.2042.

Example (12) 3-methyl-4-allyl-4-(2-butyl-2,3-butadienyl)-1-phenylpyrazoline-5-one (6af) (zyc-4-87)

(31) ##STR00020##

(32) Operations were conducted by referring to Example (7). Under a nitrogen environment, tris(dibenzylideneacetone)dipalladium-chloroform adduct (13.0 mg, 0.0125 mmol), (R,R)-L1(14.2 mg, 0.025 mmol) and toluene (5 mL), 4a (131.5 mg, 0.5 mmol)/toluene (11.7 mL), 5f (128.4 mg, 0.6 mmol)/toluene (8.3 mL) were added to a dried reaction flask, and stirred at 60 C. for 11 hours to obtain the product 6af (155.0 mg, 96%) (petroleum ether/diethyl ether=50/1) as a liquid. 6af: 92.8% ee (HPLC condition: Chiralcel OD column, n-hexane/i-PrOH=98/2, 1.0 mL/min, =254 nm, t.sub.R (major)=4.7 min, t.sub.R (minor)=5.2 min); [].sub.D.sup.20=+98.5 (c=0.975, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.87 (d, J=8.1 Hz, 2H, ArH), 7.37 (t, J=8.0 Hz, 2H, ArH), 7.14 (t, J=7.5 Hz, 1H, ArH), 5.57-5.39 (m, 1H, =CH), 5.18-4.96 (m, 2H, =CH.sub.2), 4.55 (p, J=2.9 Hz, 2H, CH.sub.2=C), 2.65-2.45 (m, 2H, CH.sub.2), 2.43-2.20 (m, 2H, CH.sub.2), 2.08 (s, 3H, CH.sub.3), 1.91-1.73 (m, 2H, CH.sub.2), 1.40-1.14 (m, 4H, CH.sub.22), 0.81 (t, J=6.9 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) 205.3, 174.6, 161.8, 137.9, 130.3, 128.6, 124.6, 119.5, 118.7, 98.2, 77.4, 58.4, 40.6, 35.7, 32.2, 29.3, 22.0, 14.2, 13.7; IR (neat) v (cm.sup.1) 3079, 3062, 3054, 2956, 2928, 2877, 2859, 1955, 1714, 1642, 1616, 1597, 1500, 1458, 1436, 1402, 1365, 1321, 1243, 1120, 1098, 1031; MS (EI): m/z (%) 322 ([M].sup.+, 41.06), 239 (100); HRMS calcd. for C.sub.21H.sub.26N.sub.2O [M].sup.+: 322.2045; Found: 322.2044.