A New Class of Chiral Pincer-Type PNN Ligands for Pd-Catalyzed Asymmetric Allylic Alkylation

Dunqi Wu Xuan Cheng Yankai Liu Guo Cheng Xiaoyu Guan Qinghai Deng

Citation:  Wu Dunqi, Cheng Xuan, Liu Yankai, Cheng Guo, Guan Xiaoyu, Deng Qinghai. A New Class of Chiral Pincer-Type PNN Ligands for Pd-Catalyzed Asymmetric Allylic Alkylation[J]. Chinese Journal of Organic Chemistry, 2020, 40(10): 3362-3370. doi: 10.6023/cjoc202005090 shu

新型手性钳形PNN类配体在钯催化不对称烯丙基烷基化反应中的应用

    通讯作者: 邓清海, qinghaideng@shnu.edu.cn
  • 基金项目:

    上海绿色能源化工工程技术研究中心 18DZ2254200

    国家自然科学基金 21772122

    国家自然科学基金(Nos.21402119,21772122)和上海绿色能源化工工程技术研究中心(No.18DZ2254200)资助项目

    国家自然科学基金 21402119

摘要: 从便宜、易得的手性氨基酸出发通过5至6步反应制备了一种新型手性钳形PNN类配体oxpma.该类手性配体含有2至3个手性中心.将其用于钯催化的烯丙基酯的不对称烯丙基烷基化反应,能够以高的对映选择性(最高可达96%)获得相应的手性目标产物.

English

  • Chiral tridentate ligands, also called as chiral pincer-type ligands, have achieved widespread applications in asymmetric catalysis since they allow exquisite control of electronic/steric features around the metal center as well as enhance the metal complex stability.[1] Among these, various chiral PNN-type pincer ligands with different chiral structural units have been designed (Figure 1). According to the source of chirality, these ligands can be majorly divided to chiral spiro PNN ligands (A), [2-3] the ligands bearing phosphine groups with chiral substituents (B), [4] chiral binaphthyl ligands (C), [5] chiral ferrocenyl ligands (D), [6-7] chiral amine-based ligands (E)[8] and chiral oxazoline-containing ligands (F).[9] Surprisingly, these ligands as well as the metal complexes have only been applied to asymmetric hydrogenation and asymmetric transfer hydrogenation. Therefore, the development of new kind of chiral PNN ligands to catalyze other kind of asymmetric transformations is an attractive target.

    Figure 1

    Figure 1.  Representative chiral pincer-type PNN ligands

    We have been interested in the synthesis and applications of chiral oxazoline-based ligands[10] due to their ready accessibility from cheap and diverse chiral amino alcohols as well as versatile utilities in a wide range of asymmetric transformations.[11] In contrast, only a few chiral pincer PNN ligands containing oxazoline ring have been reported. Recently, Shi and co-workers[9] developed oxazoline-based PNN ligands (F) for metal catalyzed polymerization of norbornene. In addition, Zhou and Zhang developed the chiral PNN ligands that associated chiral oxazoline ring with chiral spiro- (A2)[3] and ferrocenyl (D2)[7] backbones, respectively, which were both applied in iridium-catalyzed asymmetric hydrogenation. In this context, we report the synthesis of a new class of chiral PNN ligands, 1-(4, 5-dihydrooxazol-2-yl)-N-(2-(diphenylphosphanyl)benzyl)- methanamines (oxpma, 1) (Figure 1), which are derived from readily available amino alcohols and amino acids. In an evaluation of their potential in asymmetirc catalysis, it was found that they induced high enantioselectivity in the asymmetric allyl alkylation reaction catalyzed by palladium medium, [12] which is a powerful strategy for stereoselective construction of C—C bond.

    Chiral oxazoline ligand 1 was readily prepared starting from amino acid 2 in 5 or 6 steps (Scheme 1). First, amino acid 2 were transformed easily to Fmoc-protected amino acid 3, [13] which react with amino alcohol 4 to construct the oxazoline ring directly for providing Fmoc-oxazoline amines (for 6a~6d) in moderate yields (62%~72%).[14] When R1 is tert-butyl group, 6e could be obtained through the intermediate 5 in 2 steps.[15] After deprotection of 6, [14] oxazoline amines 7 were condensed with 2-(diphenyl- phosphanyl)benzaldehyde in the presence of 2 equiv. of tetraethoxytitanium to get imines 8, which are unstable upon purification with silica gel chromatography. Thus, the crude compounds 8 were converted directly to ligands 1 through reduction by NaBH4 or addition of Grignard reagents with sole diastereoselectivity.[16]

    Scheme 1

    Scheme 1.  Synthesis of chiral pincer-type PNN ligand oxpma (1)

    With the ligand library in hand, ligand 1b and [Pd(η3-C3H5)Cl]2 were chosen to study the asymmetric allylic alkylation of 9a with 10a (Table 1). Several commonly used bases were first examined (Table 1, Entries 1~3), and N, O-bis(trimethylsilyl)acetamide (BSA) proved to be the optimal one (98% yield, 95% ee). Solvent screening showed that both 1, 2-dichloroethane and acetonitrile are the suitable solvents, and dichloromethane was still chosen for further investigations due to the convenience of operation (Table 1, Entries 3~7). A series of ligands were subsequently screened (Table 1, Entries 3 and 8~14). It was found that the conversion and enantioselectivity were dependent upon the combination of substitutents at three stereocenters and ligand 1b gave the most promising result. Then, decreasing the amount of BSA to 2 equiv. (Table 1, Entry 15) and further reducing the catalyst loading (Table 1, Entry 17) achieved comparative results. Finally, changing the reaction temperature did not give better results (Table 1, Entries 19 and 20).

    Table 1

    Table 1.  Optimization of the reaction conditionsa
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    Entry Base (equiv.) L Solvent t/h Yieldb/% eec/%
    1 K2CO3 (3) 1b CH2Cl2 13 99 92
    2 Cs2CO3 (3) 1b CH2Cl2 13 99 87
    3 BSA (3) 1b CH2Cl2 13 98 95
    4 BSA (3) 1b ClCH2CH2Cl 13 99 95
    5 BSA (3) 1b MeCN 13 99 94
    6 BSA (3) 1b Toluene 13 11 89
    7 BSA (3) 1b THF 13 19 94
    8 BSA (3) 1a CH2Cl2 12 22 55
    9 BSA (3) 1c CH2Cl2 12 65 78
    10 BSA (3) 1d CH2Cl2 12 72 86
    11 BSA (3) 1e CH2Cl2 12 60 91
    12 BSA (3) 1f CH2Cl2 12 63 89
    13 BSA (3) 1g CH2Cl2 12 56 86
    14 BSA (3) 1h CH2Cl2 12 58 97
    15 BSA (2) 1b CH2Cl2 11 98 95
    16 BSA (1.5) 1b CH2Cl2 27 80 95
    17d BSA (2) 1b CH2Cl2 12 97 95
    18e BSA (2) 1b CH2Cl2 12 88 95
    19d, f BSA (2) 1b CH2Cl2 12 68 95
    20d, g BSA (2) 1b CH2Cl2 12 86 83
    a Reaction conditions: 9a (0.10 mmol), 10a (1.2 equiv.), base (x equiv.), [Pd(η3-C3H5)Cl]2 (2 mol%), ligand (5 mol%), solvent (1.0 mL), room temperature, nitrogen. b The yields of isolated products. c Determined by HPLC analysis. d 1 mol% [Pd(η3-C3H5)Cl]2 and 3 mol% 1b were used. e 0.5 mol% [Pd(η3-C3H5)Cl]2 and 1.5 mol% 1b were used. f The reaction was carried out under 0 ℃. gThe reaction was carried out under 40 ℃.

    The substrate scope of this reaction was subsequently investigated under the optimal reaction conditions (Table 1, Entry 17) which was shown in Table 2. A series of allylic acetates (9a~9e) are well tolerated to provide the corresponding products with high enantioselectivities (11aa~11ea, 91%~96% ee) regardless of the electronic nature of the substituents. The position of substituent affected the reaction outcome. The reaction of 1, 3-bis(3- methylphenyl)allyl acetate (9f) conducted well to afford the desired product 11fa in 79% yield with 90% ee, while the substrate with ortho-chlorine (9g) only gave product 11ga with 61% ee. In particular, the substrate with 2-naphthyl group (9h) is suitable for the reaction condition to get the product 11ga in 97% yield with 92% ee. Various nucleophiles 10 were then examined. The malonates with different substituents gave the corresponding products (11ab~11ae) with good enantioselecitivities (85%~94% ee) in moderate to high yields (48%~97%). The reaction of 9a with acetylacetone (10f) was also carried out to get the desired product 11af in 75% yield with 90% ee. However, malononitrile (10g) is not tolerated and gave the product 11ag in low yield with moderate enantioselectivity.

    Table 2

    Table 2.  Substrate scope of Pd-catalyzed asymmetric allylic alkylationa
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    Entry Ar (9) R1, R2 (10) Product Yieldb/% eec/%
    1 C6H5 (9a) H, CO2Me (10a) 11aa 97 95
    2 4-FC6H4 (9b) H, CO2Me (10a) 11ba 86 96
    3 4-ClC6H4 (9c) H, CO2Me (10a) 11ca 68 92
    4 4-BrC6H4 (9d) H, CO2Me (10a) 11da 89 92
    5 4-MeC6H4 (9e) H, CO2Me (10a) 11ea 75 91
    6 3-ClC6H4 (9f) H, CO2Me (10a) 11fa 79 90
    7 2-MeC6H4 (9g) H, CO2Me (10a) 11ga 84 61
    8 2-Np (9h) H, CO2Me (10a) 11ha 97 92
    9 C6H5 (9a) H, CO2iPr (10b) 11ab 51 88
    10 C6H5 (9a) H, CO2Bn (10c) 11ac 97 94
    11 C6H5 (9a) Ph, CO2Et (10d) 11ad 86 92
    12 C6H5 (9a) Me, CO2Et (10e) 11ae 48 85
    13 C6H5 (9a) H, COMe (10f) 11af 75 90
    14 C6H5 (9a) H, CN (10g) 11ag 21 74
    a Reaction conditions: 9 (0.10 mmol), 10 (1.2 equiv.), BSA (2 equiv.), [Pd(η3-C3H5)Cl]2 (1 mol%), ligand (3 mol%), CH2Cl2 (1.0 mL), room temperature, nitrogen. b The yields of isolated products. c Determined by HPLC analysis.

    A new class of chiral tridentate PNN ligands, oxpma, were developed. These ligands are derived from readily available amino acids. Their brief utility as stereodirecting ligands in Pd-catalyzed asymmetric allylic alkylation has been first evaluated, which achieved good enantioselectivites (up to 96% ee). Further applications on asymmetric transformations are currently being studied in our laboratory.

    1H NMR spectra were recorded on a 400 or 600 MHz NMR spectrometer and 13C NMR spectra were recorded on a 101 or 150 MHz NMR spectrometer. Infrared spectra were prepared as KBr pellets and recorded on a Varian Excalibur 3100 series FT-IR spectrometer. Mass spectra were recorded by the mass spectrometry service of Shanghai Institute of Organic Chemistry. HPLC analyses on a Waters 1596 or Shimadzu SPD-15C. All manipulations were maintained under an atmosphere of nitrogen unless otherwise stated. Commercially available reagents were used without further purification. Solvents were pre-dried over activated 4 Å molecular sieves and refluxed over sodium-benzophenone (toluene, tetrahydrofurane), phosphorus pentoxide (chloroform) or calcium hydride (dichloromethane, dichloroethane, acetonitrile) under an argon atmosphere and collected by distillation. Column chromatography was performed on silica gel (200~300 mesh).

    4.2.1   General procedure for the synthesis of 3

    To a solution of amino acid 2 (40.0 mmol) in dioxane (40 mL) was added Na2CO3 (aq., ω=10%, 100 mL) at room temperature, then the mixture was cooled to 0 ℃ with an ice bath. Fmoc-Cl (1.1 equiv.) in dioxane (100 mL) was added by dropping funnel slowly, and the mixture was stirred at 0 ℃ for 1 h, then the mixture was stirred at room temperature overnight. 100 mL of water was added to the solution, and the aqueous layer was washed with diethyl ether. The organic layer was extracted with saturated NaHCO3 and the combined aqueous layers were cooled to 0 ℃ and acidified to pH 1 with 1 mol/L HCl. The aqueous layer was then extracted with EtOAc (40 mL×3). The organic layers were combined and dried over MgSO4. After filtration and concentration, the resulting Fmoc-protected amino acid 3 was obtained.[13]

    (((9H-Fluoren-9-yl)methoxy)carbonyl)-L-valine (3a): White solid, 97% yield (13.17 g, 38.8 mmol). m.p. 74.3~75.7 ℃ (lit.[18] 144~145 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.77 (d, J=7.2 Hz, 2H), 7.60 (d, J=6.0 Hz, 2H), 7.40 (t, J=7.2 Hz, 2H), 7.31 (t, J=7.2 Hz, 2H), 5.28 (d, J=8.8 Hz, 1H), 4.42 (d, J=6.8 Hz, 2H), 4.36~4.33 (m, 1H), 4.24 (t, J=6.8 Hz, 1H), 2.27~2.21 (m, 1H), 1.01 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H).

    (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3, 3-dimethylbutanoic acid (3b):[18] White solid, 97% yield (13.71 g, 38.8 mmol). m.p. 72.3~73.4 ℃ (lit.[18] 71 ℃); 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J=7.6 Hz, 2H), 7.59 (d, J=7.2 Hz, 2H), 7.40 (t, J=7.2 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H), 5.34 (d, J=5.6 Hz, 1H), 4.48~4.38 (m, 2H), 4.24~4.22 (m, 2H), 1.04 (s, 9H).

    4.2.2   General procedure for the synthesis of 6a~6d

    To a flame-dried 500 mL three-neck bottle equipped with a constant dropping funnel, N-Fmoc-amino acid 3a (12 mmol), amino alcohol 4 (12 mmol), PPh3 (36 mmol) and CH2Cl2 (60 mL) were added. After further addition of diisopropylethylamine (DIPEA) (36 mmol), the mixture was cooled down to 0 ℃ with an ice bath. Then, CCl4 (60 mmol) in another 60 mL of CH2Cl2 was added through a funnel over 3 h. The mixture was stirred at room temperature overnight. After removal of solvent, the residue was dissolved in EtOAc (100 mL). After filtration and subsequent concentration in vacuo, the residue was purified by flash column chromatography (petroleum ether/EtOAc, V:V=5:1) to get products 6a~6d.[14]

    (9H-Fluoren-9-yl)methyl-((S)-2-methyl-1-((R)-4-phenyl-4, 5-dihydrooxazol-2-yl)propyl)carbamate(6a):[15] White solid, 68% yield (3.59 g, 8.2 mmol). m.p. 119.2~121.3 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J=7.6 Hz, 2H), 7.61 (t, J=6.8 Hz, 2H), 7.41~7.25 (m, 9H), 5.54 (d, J=8.8 Hz, 1H), 5.23 (t, J=9.6 Hz, 1H), 4.72 (t, J=9.4 Hz, 1H), 4.50~4.11 (m, 5H), 2.28~2.20 (m, 1H), 1.05 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H).

    (9H-Fluoren-9-yl)methyl-((S)-1-((R)-4-isopropyl-4, 5-dihydrooxazol-2-yl)-2-methylpropyl)carbamate (6b):[14] White solid, 72% yield (3.51 g, 8.6 mmol). m.p. 117.1~117.3 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.77 (d, J=7.6 Hz, 2H), 7.62 (t, J=7.6 Hz, 2H), 7.40 (t, J=7.6 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H), 5.41 (d, J=8.8 Hz, 1H), 4.42~4.23 (m, 5H), 4.01~3.91 (m, 2H), 2.17~2.09 (m, 1H), 1.80~1.73 (m, 1H), 0.98~0.89 (m, 12H).

    (9H-Fluoren-9-yl)methyl-((S)-1-((R)-4-benzyl-4, 5-dihydrooxazol-2-yl)-2-methylpropyl)carbamate (6c):[19] White solid, 64% yield (3.49 g, 7.7 mmol). m.p. 89.2~91.3 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.77 (d, J=7.6 Hz, 2H), 7.61 (dd, J=7.6, 7.2 Hz, 2H), 7.41 (t, J=7.6 Hz, 2H), 7.33~7.20 (m, 7H), 5.40 (d, J=9.2 Hz, 1H), 4.47~4.23 (m, 6H), 4.02 (t, J=8.0 Hz, 1H), 3.12 (dd, J=13.6, 4.8 Hz, 1H), 2.65 (dd, J=13.6, 8.8 Hz, 1H), 2.14~2.08 (m, 1H), 0.94 (dd, J=12.4, 6.8 Hz, 6H).

    (9H-Fluoren-9-yl)methyl-(S)-(1-(4, 4-dimethyl-4, 5-dihydrooxazol-2-yl)-2-methylpropyl)carbamate (6d): Whi- te solid, 62% yield (2.92 g, 7.4 mmol). m.p. 104~106 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J=7.6 Hz, 2H), 7.62 (t, J=7.8 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.2 Hz, 2H), 5.49 (d, J=8.8 Hz, 1H), 4.46~4.33 (m, 3H), 4.24 (t, J=7.0 Hz, 1H), 3.97 (s, 2H), 2.17~2.09 (m, 1H), 1.29 (s, 6H), 0.98~0.93 (m, 6H); 13C NMR (100 MHz, CDCl3) δ: 164.8, 156.2, 144.1, 143.9, 141.4, 127.7, 127.1, 125.2, 120.0, 79.5, 67.2, 66.9, 54.4, 47.3, 31.7, 28.5, 28.3, 18.8, 17.7; IR (KBr) vmax: 2965, 1716, 1663, 1624, 1394, 1366, 1237, 740 cm-1; HRMS (ESI) calcd for C24H29N2O3 (M+H+) 393, 2173, found 393.2168.

    4.2.3   Procedures for the synthesis of 6e

    Fmoc-protected amino acid 3b (20 mmol) was dissolved in dichloromethane (150 mL) at 0 ℃. Then, D-plenyl- glycinol (24 mmol, 1.2 equiv.), HOBt (30 mmol, 1.5 equiv.) and N, N'-carbonyldiimidazole (EDCI) (30 mmol, 1.5 equiv.) were added in sequence. After stirring at 0 ℃ for 15 min, N-methyl morpholine (34 mmol, 1.7 equiv.) was added. The reaction mixture was stirred at ambient temperature until the disappearance of 3b as monitored by thin layer chromatography (TLC). The resulting solution was washed successively with cold KHSO4 aqueous solution (ω=5%, 50 mL×3), saturated NaHCO3 solution (50 mL×3) and brine (75 mL). The combined organic layer was dried over MgSO4 and filtered. The solvent was removed under vacuum and the resulting residue was crystallized using CH2Cl2-hexanes (V:V=1:4) to afford (9H-fluoren-9-yl)methyl-((S)-1-(((R)-2-hydroxy-1-phenyl-ethyl)amino)-3, 3-dimethyl-1-oxobutan-2-yl)-carbamate (5), 72% yield (6.81 g, 14.4 mmol). m.p. 175~177 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J=7.6 Hz, 2H), 7.58 (d, J=7.6 Hz, 2H), 7.42~7.27 (m, 9H), 6.51 (d, J=7.6 Hz, 1H), 5.60 (d, J=9.2 Hz, 1H), 5.11~5.07 (m, 1H), 4.44~4.30 (m, 2H), 4.21 (t, J=6.8 Hz, 1H), 3.96 (d, J=9.2 Hz, 1H), 3.90~3.81 (m, 2H), 2.70 (br s, 1H), 0.98 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 171.4, 157.2, 144.0, 143.6, 141.4, 139.3, 128.6, 127.84, 127.82, 127.7, 127.22, 127.16, 127.0, 125.2, 125.1, 120.1, 120.0, 67.5, 65.7, 63.0, 55.6, 47.1, 34.8, 26.7; IR (KBr) vmax: 3421, 1627, 1398, 1323, 1230, 682, 669, 650 cm-1; HRMS (ESI) calcd for C29H33N2O4 (M+H+) 473.2435, found 473.2432.

    Compound 5 (5.0 mmol) was dissolved in dry CH2Cl2 (100 mL) and then the solution was cooled to 0 ℃ in an ice bath. 4-Dimethylaminopyridine (1.0 mmol, 0.2 equiv.) and freshly distilled triethylamine (17.5 mmol, 3.5 equiv.) were added in sequence. After stirring at 0 ℃ for 5 min, a solution of p-toluenesulfonyl chloride (15 mmol, 1.5 equiv.) in dry CH2Cl2 (50 mL) was added dropwise. Then, the reaction was stirred at ambient temperature until the disappearance of 5 as monitored by TLC. The reaction was quenched with saturated NH4Cl solution. The aqueous phase was extracted with CH2Cl2 (50 mL×3) and the combined organic layers were washed with brine, then dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by flash column chromatography (300 mL of hexane-EtOAc (V:V=6:4), then CH2Cl2-MeOH (V:V=98:2)) to afford (9H-fluoren-9- yl)methyl-((S)-2, 2-dimethyl-1-((R)-4-phenyl-4, 5-dihydroo-xazol-2-yl)propyl)carbamate (6e), [15] white solid, 86% yield (1.95 g, 4.3 mmol). m.p. 126~129 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.77 (d, J=7.6 Hz, 2H), 7.63 (d, J=7.6 Hz, 2H), 7.43~7.28 (m, 9H), 5.77 (br s, 1H), 5.24 (t, J=9.6 Hz, 1H), 4.68 (t, J=9.4 Hz, 1H), 4.48~4.40 (m, 3H), 4.24 (t, J=7.0 Hz, 1H), 4.08 (t, J=8.8 Hz, 1H), 1.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 167.8, 156.3, 144.1, 143.9, 141.8, 141.41, 141.39, 128.9, 127.81, 127.75, 127.1, 126.8, 125.2, 120.0, 74.9, 69.7, 67.0, 57.7, 47.4, 35.4, 26.7; IR (KBr) vmax: 3406, 1716, 1656, 1622, 1398, 1369, 1322, 1239 cm-1; HRMS (ESI) calcd for C29H31- N2O3 (M+H+) 455.2329, found 454.2322.

    4.2.4   General procedure for the synthesis of 7

    Fmoc-protected oxazoline 6 (6 mmol) was dissolved in MeOH (30 mL) at room temperature. Upon cooling to 0 ℃ and addition of Et2NH (30 mL), the reaction mixture was stirred for 1 h at 0~5 ℃. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc/petroleum ether, V:V=1:1 (100 mL) then EtOAc/EtOH, V:V=10:1) to furnish (S)-2-methyl- 1-((R)-4-phenyl-4, 5-dihydrooxazol-2-yl)-propan-1-amine (7a), [15] yellow oil, 96% yield (1.26 g, 5.8 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.37~7.24 (m, 5H), 5.21 (t, J=9.6 Hz, 1H), 4.66 (dd, J=10.0, 8.8 Hz, 1H), 4.12 (t, J=8.4 Hz, 1H), 3.45 (d, J=5.6 Hz, 1H), 2.12~2.04 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H).

    (S)-1-((R)-4-Isopropyl-4, 5-dihydrooxazol-2-yl)-2-meth-ylpropan-1-amine (7b):[14] Yellow oil, 64% yield (710 mg, 3.8 mmol). 1H NMR (400 MHz, CDCl3) δ: 4.24 (dd, J=9.2, 8.0 Hz, 1H), 3.98~3.87 (m, 2H), 3.31 (d, J=5.6 Hz, 1H), 1.99~1.91 (m, 1H), 1.79~1.71 (m, 1H), 0.97~0.92 (m, 9H), 0.88 (d, J=6.8 Hz, 3H).

    (S)-1-((R)-4-Benzyl-4, 5-dihydrooxazol-2-yl)-2-methyl-propan-1-amine (7c):[19] Yellow oil, 82% yield (1.14 g, 4.9 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.31~7.19 (m, 5H), 4.44~4.36 (m, 1H), 4.20 (t, J=9.0 Hz, 1H), 3.99 (dd, J=9.2, 8.4 Hz, 1H), 3.31 (d, J=5.6 Hz, 1H), 3.11 (dd, J=14.0, 5.2 Hz, 1H), 2.64 (dd, J=14.0, 8.8 Hz, 1H), 1.99~1.90 (m, 1H), 0.94 (dd, J=10.8, 6.8 Hz, 6H).

    (S)-1-(4, 4-Dimethyl-4, 5-dihydrooxazol-2-yl)-2-methyl-propan-1-amine (7d): Yellow oil, 76% yield (780 mg, 4.56 mmol). 1H NMR (400 MHz, CDCl3) δ: 3.87 (d, J=5.6 Hz, 2H), 3.23~3.21 (m, 1H), 1.92~1.85 (m, 1H), 1.53 (s, 2H), 1.21 (d, J=4.4 Hz, 6H), 0.91~0.85 (m, 6H); 13C NMR (100 MHz, CDCl3) δ: 168.1, 79.2, 66.7, 55.4, 32.2, 28.4, 28.3, 19.3, 17.5; IR (KBr) vmax: 3386, 2964, 1662, 1464, 1392, 1366, 992, 669 cm-1; HRMS (ESI) calcd for C9H19N2O (M+H+) 171.1492, found 171.1490.

    (S)-2, 2-Dimethyl-1-((R)-4-phenyl-4, 5-dihydrooxazol-2-yl)propan-1-amine (7e):[20] Yellow oil, 92% yield (1.28 g, 5.5 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.37~7.25 (m, 5H), 5.20 (t, J=9.6 Hz, 1H), 4.65 (dd, J=10.4, 8.8 Hz, 1H), 4.06 (t, J=8.8 Hz, 1H), 3.37 (s, 1H), 1.05 (s, 9H).

    4.2.5   General procedure for the synthesis of 8

    To a solution of 2-diphenylphosphine benzaldehyde (4 mmol) in anhydrous tetrahydrofuran (THF) (50 mL) was added tetraethyl titanate (8 mmol). The resulting solution was stirred at 0 ℃. Compound 7 (4 mmol) in anhydrous THF (15 mL) was added by syringe. After stirring at 0 ℃ for 2 h, the mixture was diluted with EtOAc, then washed with saturated sodium chloride solution and filtered with celite. The aqueous layer was extracted with EtOAc (40 mL×3). The organic layers were combined and dried over MgSO4. After filtration and concentration, the resulting crude compound 8 was obtained without further purification.

    4.2.6   Reduction by NaBH4 for the synthesis of 1a and 1g

    To a solution of crude compound 8 (4 mmol) in MeOH (30 mL) was added NaBH4 (14 mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ until the disappearance of 8 (monitored by TLC). Then, the reaction was quenched with a small amount of saturated ammonium chloride solution, and methanol was removed under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/Et2O, V:V=10:1) to afford product 1a or 1g.

    (S)-N-(2-(Diphenylphosphanyl)benzyl)-2-methyl-1-((R)-4-phenyl-4, 5-dihydrooxazol-2-yl)propan-1-amine (1a): Colorless oil, 77% yield (1.52 g, 3.1 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.65~7.62 (m, 1H), 7.40~7.26 (m, 17H), 7.18 (t, J=7.6 Hz, 1H), 6.92~6.89 (m, 1H), 5.19 (t, J=9.6 Hz, 1H), 4.62 (dd, J=8.8, 8.4 Hz, 1H), 4.18 (dd, J=1.6, 1.6 Hz, 1H), 4.05 (t, J=9.2 Hz, 1H), 4.02 (dd, J=1.6, 1.6 Hz, 1H), 3.25 (d, J=6.8 Hz, 1H), 1.96~1.88 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.4, 144.5 (Jc, p=23.6 Hz), 142.2, 137.0 (Jc, p=4.4 Hz), 136.9 (Jc, p=4.6 Hz), 135.7 (Jc, p=14.0 Hz), 134.0, 133.9 (Jc, p=12.9 Hz), 133.7, 133.6, 129.0, 128.9 (Jc, p=5.4 Hz), 128.8, 128.63 (Jc, p=5.7 Hz), 128.57 (Jc, p=1.7 Hz), 128.50 (Jc, p=1.0 Hz), 127.5, 127.2, 126.9, 74.6, 69.7, 62.0, 50.5 (Jc, p=22.3 Hz), 31.7, 19.4, 19.3; 31P NMR (162 MHz, CDCl3) δ: -15.67; IR (KBr) vmax: 3428, 2961, 1656, 1434, 983, 745, 698, 504 cm-1; HRMS (ESI) calcd for C32H34N2OP (M+H+) 493.2403, found 493.2424.

    (S)-N-(2-(Diphenylphosphanyl)benzyl)-2, 2-dimethyl-1-((R)-4-phenyl-4, 5-dihydrooxazol-2-yl)propan-1-amine (1g): Colorless oil, 79% yield (1.60 g, 3.2 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.67~7.64 (m, 1H), 7.40~7.27 (m, 17H), 7.20~7.16 (m, 1H), 6.92~6.89 (m, 1H), 5.18 (t, J=10.0 Hz, 1H), 4.62 (t, J=9.4 Hz, 1H), 4.17~3.97 (m, 3H), 3.21 (s, 1H), 1.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 169.4, 144.7 (Jc, p=23.7 Hz), 142.2, 137.2, 137.1, 135.9 (Jc, p=14.1 Hz), 134.1, 134.0 (Jc, p=12.3 Hz), 133.9, 133.8, 129.0, 128.9 (Jc, p=5.3 Hz), 128.8, 128.7, 128.6 (Jc, p=2.5 Hz), 128.5 (Jc, p=2.5 Hz), 127.5, 127.2, 127.0, 74.5, 69.8, 65.4, 51.0 (Jc, p=3.0 Hz), 34.3, 27.0; 31P NMR (162 MHz, CDCl3) δ: -15.60; IR (KBr) vmax: 3406, 2957, 1652, 1434, 1395, 1365, 744, 698 cm-1; HRMS (ESI) calcd for C33H36N2OP (M+H+) 507.2560, found 507.2565.

    4.2.7   Addition of Grignard reagents for the synthesis of 1b~1f and 1h

    Crude product 8 (ca. 4 mmol) and anhydrous dichloromethane (20 mL) were added to a 50 mL oven-dried reaction Schlenk tube. The mixture was cooled to -70 ℃, and Grignard reagent (16 mmol, 3 mol/L in THF) was added. After stirring at -70 ℃ for 1 h, the reaction mixture was allowed to warm up to ambient temperature. The reaction was quenched with a small amount of saturated ammonium chloride solution, and dichloromethane was removed under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/Et2O, V:V=10:1) to afford product 1b~1f or 1h.

    (S)-N-((R)-(2-(Diphenylphosphanyl)phenyl)(phenyl)-methyl)-2-methyl-1-((R)-4-phenyl-4, 5-dihydrooxazol-2-yl)propan-1-amine (1b): White solid, 70% yield (1.59 g, 2.8 mmol). m.p. 53~55 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.01~7.98 (m, 1H), 7.41~7.12 (m, 18H), 7.04~6.92 (m, 6H), 6.10 (d, J=8.8 Hz, 1H), 5.24 (t, J=9.6 Hz, 1H), 4.55 (t, J=9.2 Hz, 1H), 4.01 (t, J=8.8 Hz, 1H), 3.14 (d, J=6.0 Hz, 1H), 2.02~1.94 (m, 1H), 1.07 (d, J=6.4 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.1, 148.0 (Jc, p=23.1 Hz), 143.9, 142.5, 138.3 (Jc, p=11.8 Hz), 136.3 (Jc, p=2.3 Hz), 136.1 (Jc, p=13.2 Hz), 134.7 (Jc, p=1.4 Hz), 134.1 (Jc, p=20.1 Hz), 133.6 (Jc, p=18.9 Hz), 129.4, 128.8, 128.5 (Jc, p=6.1 Hz), 128.4, 128.3, 128.2 (Jc, p=1.3 Hz), 128.2 (Jc, p=1.1 Hz), 128.1, 127.9 (Jc, p=5.4 Hz), 127.5, 127.2, 127.0 (Jc, p=1.3 Hz), 126.7, 74.8, 70.1, 61.3 (Jc, p=27.1 Hz), 59.8, 32.3, 27.0, 19.8, 19.0; 31P NMR (162 MHz, CDCl3) δ: -18.50; IR (KBr) vmax: 3427, 2964, 1655, 1454, 1434, 1089, 744, 697 cm-1; HRMS (ESI) calcd for C38H38N2OP (M+H+) 569.2716, found 569.2693.

    (R)-1-(2-(Diphenylphosphanyl)phenyl)-2-methyl-N-((S)-2-methyl-1-((R)-4-phenyl-4, 5-dihydrooxazol-2-yl)propyl)-propan-1-amine (1c): Colorless oil, 66% yield (1.41 g, 2.6 mmol). 1H NMR (400 MHz, DMSO-d6) δ: 7.69 (s, 1H), 7.40~7.11 (m, 17H), 6.97~6.94 (m, 1H), 5.15 (t, J=9.6 Hz, 1H), 4.74 (s, 1H), 4.47 (t, J=9.2 Hz, 1H), 3.81 (t, J=8.5 Hz, 1H), 2.69 (d, J=4.8 Hz, 1H), 1.82~1.73 (m, 2H), 0.91 (d, J=6.4 Hz, 3H), 0.83 (d, J=6.4 Hz, 6H), 0.59 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.5, 149.4 (Jc, p=23.4 Hz), 142.8, 138.9 (Jc, p=12.5 Hz), 137.3 (Jc, p=11.7 Hz), 136.5 (Jc, p=13.1 Hz), 135.0, 134.3 (Jc, p=20.2 Hz), 133.3 (Jc, p=18.7 Hz), 129.0, 128.7, 128.6, 128.5, 128.45 (Jc, p=2.0 Hz), 128.38, 128.0, 127.4, 127.0 (Jc, p=1.3 Hz), 126.7, 74.5, 70.0, 59.3, 34.8, 32.5, 27.1, 20.4, 19.8, 19.0, 17.8; 31P NMR (162 MHz, CDCl3) δ: -19.96; IR (KBr) vmax: 2959, 1655, 1625, 1434, 1387, 743, 697, 669 cm-1; HRMS (ESI) calcd for C35H40N2OP (M+H+) 535.2873, found 535.2882.

    (S)-N-((R)-(2-(Diphenylphosphanyl)phenyl)(phenyl)-methyl)-1-((R)-4-isopropyl-4, 5-dihydrooxazol-2-yl)-2-methylpropan-1-amine (1d): Colorless oil, 75% yield (1.60 g, 3.0 mmol). 1H NMR (400 MHz, CDCl3) δ: 8.03~8.00 (m, 1H), 7.42~7.38 (m, 1H), 7.32~7.11 (m, 12H), 7.06~6.92 (m, 6H), 6.00 (d, J=8.8 Hz, 1H), 4.20 (dd, J=13.6, 12.0 Hz, 1H), 3.97~3.90 (m, 2H), 3.06 (d, J=6.4 Hz, 1H), 1.94~1.87 (m, 1H), 1.86~1.77 (m, 1H), 1.03 (t, J=6.0 Hz, 6H), 0.97 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.3, 148.1 (Jc, p=23.2 Hz), 144.1, 138.4 (Jc, p=12.2 Hz), 136.4 (Jc, p=10.8 Hz), 136.2 (Jc, p=14.7 Hz), 134.8 (Jc, p=1.5 Hz), 134.0 (Jc, p=20.0 Hz), 133.5 (Jc, p=19.0 Hz), 129.4, 128.5 (Jc, p=6.2 Hz), 128.33 (Jc, p=1.6 Hz), 128.31, 128.24, 128.18, 128.07, 127.9 (Jc, p=5.7 Hz), 127.2, 126.6, 72.6, 70.0, 61.3 (Jc, p=26.7 Hz), 59.9, 32.8, 32.2, 19.7, 19.6, 19.0, 18.6; 31P NMR (162 MHz, CDCl3) δ: -18.52; IR (KBr) vmax: 2989, 1662, 1625, 1434, 1386, 1365, 743, 696 cm-1; HRMS (ESI) calcd for C35H40N2OP (M+H+) 535.2873, found 535.2881.

    (S)-1-((R)-4-Benzyl-4, 5-dihydrooxazol-2-yl)-N-((R)-(2-(diphenylphosphanyl)phenyl)(phenyl)methyl)-2-methyl-propan-1-amine (1e): White solid, 69% yield (1.61 g, 2.8 mmol). m.p. 50~52 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.98~7.96 (m, 1H), 7.41~7.38 (m, 1H), 7.32~7.01 (m, 22H), 6.95~6.92 (m, 1H), 6.04 (d, J=8.8 Hz, 1H), 4.48~4.40 (m, 1H), 4.14 (t, J=9.0 Hz, 1H), 3.94 (t, J=8.0 Hz, 1H), 3.19 (dd, J=5.2, 4.8 Hz, 1H), 3.07 (d, J=6.8 Hz, 1H), 2.65 (dd, J=10.0, 9.6 Hz, 1H), 1.93~1.85 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.3, 148.0 (Jc, p=23.2 Hz), 144.0, 138.4, 138.2 (Jc, p=11.8 Hz), 136.3 (Jc, p=10.4 Hz), 136.1 (Jc, p=14.2 Hz), 134.8 (Jc, p=1.4 Hz), 134.0 (Jc, p=19.9 Hz), 133.5 (Jc, p=18.9 Hz), 129.5 (Jc, p=5.5 Hz), 129.3, 128.6, 128.5 (Jc, p=6.2 Hz), 128.4, 128.3, 128.23, 128.19 (Jc, p=1.4 Hz), 128.1, 127.8 (Jc, p=5.4 Hz), 127.2, 126.7, 126.5, 71.9, 67.4, 61.3 (Jc, p=27.2 Hz), 59.9, 42.1 (Jc, p=1.3 Hz), 32.1, 19.6, 19.1; 31P NMR (162 MHz, CDCl3) δ: -18.51; IR (KBr) vmax: 2960, 1656, 1454, 1434, 1396, 1231, 744, 696 cm-1; HRMS (ESI) calcd for C39H40N2OP (M+H+) 583.2873, found 593.2847.

    (S)-1-(4, 4-Dimethyl-4, 5-dihydrooxazol-2-yl)-N-((R)-(2-(diphenylphosphanyl)phenyl)(phenyl)methyl)-2-methyl-propan-1-amine (1f): Colorless oil, 80% yield (1.67 g, 3.2 mmol); 1H NMR (400 MHz, CDCl3) δ: 8.04~8.01 (m, 1H), 7.42~7.38 (m, 1H), 7.32~7.08 (m, 12H), 7.05~6.91 (m, 6H), 5.98 (d, J=9.2 Hz, 1H), 3.94 (d, J=8.0 Hz, 1H), 3.90 (d, J=7.6 Hz, 1H) 3.01 (d, J=6.8 Hz, 1H), 1.91~1.93 (m, 1H), 1.37 (s, 3H), 1.33 (s, 3H), 1.06 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.4, 147.9 (Jc, p=23.2 Hz), 143.9, 138.4 (Jc, p=12.1 Hz), 136.3 (Jc, p=10.6 Hz), 136.1 (Jc, p=14.5 Hz), 134.9 (Jc, p=1.6 Hz), 134.0 (Jc, p=19.9 Hz), 133.5 (Jc, p=18.8 Hz), 129.4, 128.5 (Jc, p=6.1 Hz), 128.35 (Jc, p=1.3 Hz), 128.30, 128.23, 128.16, 128.07, 127.7 (Jc, p=5.7 Hz), 127.2, 126.7, 79.1, 67.2, 61.5 (Jc, p=27.4 Hz), 59.9, 32.3, 28.81, 28.79, 19.6, 19.2; 31P NMR (162 MHz, CDCl3) δ: -18.87; IR (KBr) vmax: 3406, 1625, 1434, 1397, 1365, 1230, 743, 695 cm-1; HRMS (ESI) calcd for C34H38N2OP (M+H+) 521.2716, found 521.2718.

    (S)-N-((R)-(2-(Diphenylphosphanyl)phenyl)(phenyl)-methyl)-2, 2-dimethyl-1-((R)-4-phenyl-4, 5-dihydrooxazol-2-yl)propan-1-amine (1h): White solid, 73% yield (1.70 g, 2.9 mmol). m.p. 58~61 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.07~8.04 (m, 1H), 7.44~7.13 (m, 18H), 7.07~6.97 (m, 6H), 6.11 (d, J=9.6 Hz, 1H), 5.39 (t, J=9.8 Hz, 1H), 4.63 (dd, J=10.4, 8.4 Hz, 1H), 4.03 (t, J=9.0 Hz, 1H), 3.12 (s, 1H), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 169.9, 147.9 (Jc, p=23.2 Hz), 144.0, 142.5, 138.5 (Jc, p=12.0 Hz), 136.3 (Jc, p=14.2 Hz), 136.1 (Jc, p=9.8 Hz), 134.8, 134.1 (Jc, p=20.1 Hz), 133.5 (Jc, p=18.6 Hz), 129.4, 128.8, 128.5 (Jc, p=5.9 Hz), 128.4, 128.3, 128.23, 128.20, 128.1, 128.0, 127.5, 127.2, 127.1 (Jc, p=1.3 Hz), 126.6, 74.6, 70.4, 62.9, 61.3 (Jc, p=28.0 Hz), 34.7, 27.3; 31P NMR (162 MHz, CDCl3) δ: -18.92; IR (KBr) vmax: 3409, 3027, 2958, 1625, 1434, 1396, 1232, 696 cm-1; HRMS (ESI) calcd for C39H40N2OP (M+H+) 583.2873, found 583.2847.

    In a dried schlenk tube, ligand 1b (0.003 mmol, 3 mol%) and [Pd(η3-C3H5)Cl]2 (0.001 mmol, 1 mol%) were dissolved in anhydrous dichloromethane under N2 atmosphere, and the mixture was stirred for 30 min. Then, 9 (0.1 mmol, 1.0 equiv.), 10 (0.12 mmol, 1.2 equiv.) and N, O-bis(trimethylsilyl)acetamide (BSA) (0.2 mmol, 2.0 equiv.) were added sequentially. The reaction was stirred at room temperature. After completion (monitored by TLC plate), the residue was purified by column chromatography to get the desired product 11.

    Dimethyl (R, E)-2-(1, 3-diphenylallyl)malonate (11aa):[21] Yellow oil, 97% yield (31.5 mg, 0.097 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.32~7.26 (m, 8H), 7.23~7.18 (m, 2H), 6.48 (d, J=15.6 Hz, 1H), 6.34 (dd, J=16.2, 9.0 Hz, 1H), 4.27 (t, J=9.6, 1H), 3.95 (d, J=11.4 Hz, 1H), 3.70 (s, 3H), 3.52 (s, 3H). HPLC: AD-H, hexane/isopropanol (V:V=95:5), 1.0 mL/min, λ=254 nm, 18 ℃, tR1(major)=18.0 min, tR2(minor)=27.1 min, 95% ee.

    Dimethyl (R, E)-2-(1, 3-bis(4-fluorophenyl)allyl)malo- nate (11ba):[21] Yellow oil, 86% yield (31.0 mg, 0.086 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.29~7.25 (m, 4H), 7.03~6.95 (m, 4H), 6.43 (d, J=15.6 Hz, 1H), 6.25 (dd, J=16.0, 8.8 Hz, 1H), 4.27 (t, J=9.4 Hz, 1H), 3.90 (d, J=10.8 Hz, 1H), 3.71 (s, 3H), 3.54 (s, 3H). HPLC: AD-H, hexane/isopropanol (V:V=95:5), 1.0 mL/min, λ=254 nm, 22 ℃, tR1(major)=20.8 min, tR2(minor)=35.0 min, 96% ee.

    Dimethyl (R, E)-2-(1, 3-bis(4-chlorophenyl)allyl)malonate (11ca):[21] Yellow oil, 68% yield (26.7 mg, 0.068 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.33~7.27 (m, 5H), 7.25 (t, J=7.6 Hz, 3H), 6.44 (d, J=16.0 Hz, 1H), 6.31 (dd, J=16.0, 8.4 Hz, 1H), 4.28~4.23 (m, 1H), 3.92 (d, J=10.8 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 3H). HPLC: AD-H, hexane/isopropanol (V:V=80:20), 1.0 mL/min, λ=254 nm, 20 ℃, tR1(major)=13.7 min, tR2(minor)=21.1 min, 92% ee.

    Dimethyl (R, E)-2-(1, 3-bis(4-bromophenyl)allyl)malonate (11da):[21] Yellow oil, 89% yield (42.9 mg, 0.089 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.46 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.4 Hz, 4H), 6.40 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.4 Hz, 1H), 4.24~4.19 (m, 1H), 3.90 (d, J=10.8 Hz, 1H), 3.70 (s, 3H), 3.55 (s, 3H). HPLC: AD-H, hexane/isopropanol (V:V=80:20), 1.0 mL/min, λ=254 nm, 23 ℃, tR1(major)=16.8 min, tR2(minor)=25.2 min, 92% ee.

    Dimethyl (R, E)-2-(1, 3-di-p-tolylallyl)malonate (11ea):[21] Yellow oil, 75% yield (26.4 mg, 0.075 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.21~7.16 (m, 4H), 7.12~7.06 (m, 4H), 6.44 (d, J=15.6 Hz, 1H), 6.28~6.22 (m, 1H), 4.24~4.19 (m, 1H), 3.93 (d, J=10.8 Hz, 1H), 3.69 (s, 3H), 3.53 (s, 3H), 2.30 (s, 6H). HPLC: AD-H, hexane/isopropanol (V:V=80:20), 1.0 mL/min, λ=254 nm, 28 ℃, tR1(major)=7.7 min, tR2(minor)=9.9 min, 91% ee.

    Dimethyl (R, E)-2-(1, 3-bis(3-chlorophenyl)allyl)malo- nate (11fa):[22] Yellow oil, 79% yield (31.1 mg, 0.079 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.31~7.27 (m, 2H), 7.24~7.16 (m, 6H), 6.44 (d, J=15.6 Hz, 1H), 6.31 (dd, J=15.6, 8.4 Hz, 1H), 4.26~4.21 (m, 1H), 3.92 (d, J=10.8 Hz, 1H), 3.71 (s, 3H), 3.57 (s, 3H). HPLC: AD-H, hexane/isopropanol (V:V=80:20), 1.0 mL/min, λ=254 nm, 24 ℃, tR1(major)=6.8 min, tR2(minor)=8.9 min, 90% ee.

    Dimethyl (R, E)-2-(1, 3-di-o-tolylallyl)malonate (11ga):[23] Yellow oil, 84% yield (29.6 mg, 0.084 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.37~7.28 (m, 1H), 7.23~7.09 (m, 7H), 6.67 (d, J=15.6 Hz, 1H), 6.04 (dd, J=15.2, 8.4 Hz, 1H), 4.58~4.53 (m, 1H), 4.08 (d, J=11.2 Hz, 1H), 3.73 (s, 3H), 3.52 (s, 3H), 2.47 (s, 3H), 2.27 (s, 3H). HPLC: AD-H, hexane/isopropanol (V:V=98:2), 1.0 mL/min, λ=254 nm, 26 ℃, tR1(major)=19.2 min, tR2(minor)=20.8 min, 61% ee.

    Dimethyl (R, E)-2-(1, 3-di(naphthalen-2-yl)allyl)malonate (11ha):[22] White solid, 97% yield (41.2 mg, 0.097 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.84~7.68 (m, 8H), 7.55~7.40 (m, 6H), 6.70 (d, J=16.0 Hz, 1H), 6.57 (dd, J=15.6, 8.4 Hz, 1H), 4.54~4.49 (m, 1H), 4.15 (d, J=10.8 Hz, 1H), 3.73 (s, 3H), 3.50 (s, 3H). HPLC: AD-H, hexane/isopropanol (V:V=80:20), 1.0 mL/min, λ=254 nm, 28 ℃, tR1(major)=31.7 min, tR2(minor)=42.0 min, 92% ee.

    Diisopropyl (R, E)-2-(1, 3-diphenylallyl)malonate (11ab):[21] Yellow oil, 51% yield (19.4 mg, 0.051 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.30~7.17 (m, 10H), 6.48 (d, J=16.0 Hz, 1H), 6.36 (dd, J=15.6, 8.4 Hz, 1H), 5.08~5.00 (m, 1H), 4.85~4.79 (m, 1H), 4.26~4.22 (m, 1H), 3.87 (d, J=11.2 Hz, 1H), 1.22 (d, J=6.0 Hz, 3H), 1.17 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 0.97 (d, J=6.4 Hz, 3H). HPLC: AD-H, hexane/isopropanol (V: V=95:5), 1.0 mL/min, λ=254 nm, 25 ℃, tR1(major)=11.1 min, tR2(minor)=14.7 min, 88% ee.

    Dibenzyl (R, E)-2-(1, 3-diphenylallyl)malonate (11ac):[24] Yellow oil, 97% yield (46.2 mg, 0.097 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.34~7.33 (m, 2H), 7.29~7.18 (m, 16H), 7.05~7.03 (m, 2H), 6.43 (d, J=15.6 Hz, 1H), 6.33 (dd, J=15.6, 8.4 Hz, 1H), 5.14~5.07 (m, 2H), 4.96~4.89 (m, 2H), 4.32~4.27 (m, 1H), 4.05 (d, J=10.8 Hz, 1H). HPLC: AD-H, hexane/isopropanol (V:V=95:5), 1.0 mL/min, λ=254 nm, 28 ℃, tR1(major)=38.5 min, tR2(minor)=48.0 min, 94% ee.

    Diethyl (S, E)-2-(1, 3-diphenylallyl)-2-phenylmalonate (11ad):[21] Yellow oil, 86% yield (36.9 mg, 0.086 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.39~7.12 (m, 10H), 7.15~7.11 (m, 3H), 6.70~6.98 (m, 2H), 6.51~6.39 (m, 2H), 4.65 (t, J=7.6 Hz, 1H), 4.25~4.13 (m, 4H), 1.20 (m, 6H). HPLC: AD-H, hexane/isopropanol (V:V=99:1), 0.5 mL/min, λ=254 nm, 23 ℃, tR1(major)=29.5 min, tR2(minor)=32.0 min, 92% ee.

    Diethyl (S, E)-2-(1, 3-diphenylallyl)-2-methylmalonate (11ae):[21] Yellow oil, 48% yield (17.6 mg, 0.048 mmol). 1H NMR (600 MHz, CDCl3) δ: 7.34~7.32 (m, 4H), 7.30~7.27 (m, 3H), 7.24~7.18 (m, 2H), 6.72 (dd, J=16.2, 9.0 Hz, 1H), 6.45 (d, J=15.6 Hz, 1H), 4.30 (d, J=9.0 Hz, 1H), 4.22~4.19 (m, 2H), 4.10~4.05 (m, 2H), 3.44 (dd, J=14.4, 7.2 Hz, 1H), 1.47 (s, 3H), 1.24(t, J=7.2 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H). HPLC: AD-H, hexane/isopropanol (V:V=98:2), 1.0 mL/min, λ=254 nm, 25 ℃, tR1(minor)=17.8 min, tR2(major)=18.9 min, 85% ee.

    (R, E)-3-(1, 3-Diphenylallyl) pentane-2, 4-dione (11af):[21] Yellow oil, 75% yield (21.9 mg, 0.075 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.32~7.25 (m, 6H), 7.24~7.20 (m, 4H), 6.45 (d, J=16.0 Hz, 1H), 6.22~6.16 (m, 1H), 4.37~4.30 (m, 2H), 2.54 (s, 3H), 1.93 (s, 3H). HPLC: AD-H, hexane/isopropanol (V:V=95:5), 1.0 mL/min, λ=254 nm, 23 ℃, tR1(major)=11.0 min, tR2(minor)=11.9 min, 90% ee.

    (R, E)-2-(1, 3-Diphenylallyl) malononitrile (11ag):[25] Yellow oil, 21% yield (5.4 mg, 0.021 mmol). 1H NMR (400 MHz, CDCl3) δ: 7.51~7.32 (m, 10H), 6.69~6.59 (m, 1H), 6.50 (d, J=15.6 Hz, 1H), 4.05~3.91 (m, 1H), 3.79 (d, J=9.2 Hz, 1H). HPLC: OJ-H, hexane/isopropanol (V:V=80:20), 1.0 mL/min, λ=254 nm, 26 ℃, tR1(major)=27.2 min, tR2(minor)=31.7 min, 74% ee.

    Supporting Information  HPLC chromatographic data for chiral products and NMR spectra of new compounds. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.


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  • Figure 1  Representative chiral pincer-type PNN ligands

    Scheme 1  Synthesis of chiral pincer-type PNN ligand oxpma (1)

    Table 1.  Optimization of the reaction conditionsa

    Entry Base (equiv.) L Solvent t/h Yieldb/% eec/%
    1 K2CO3 (3) 1b CH2Cl2 13 99 92
    2 Cs2CO3 (3) 1b CH2Cl2 13 99 87
    3 BSA (3) 1b CH2Cl2 13 98 95
    4 BSA (3) 1b ClCH2CH2Cl 13 99 95
    5 BSA (3) 1b MeCN 13 99 94
    6 BSA (3) 1b Toluene 13 11 89
    7 BSA (3) 1b THF 13 19 94
    8 BSA (3) 1a CH2Cl2 12 22 55
    9 BSA (3) 1c CH2Cl2 12 65 78
    10 BSA (3) 1d CH2Cl2 12 72 86
    11 BSA (3) 1e CH2Cl2 12 60 91
    12 BSA (3) 1f CH2Cl2 12 63 89
    13 BSA (3) 1g CH2Cl2 12 56 86
    14 BSA (3) 1h CH2Cl2 12 58 97
    15 BSA (2) 1b CH2Cl2 11 98 95
    16 BSA (1.5) 1b CH2Cl2 27 80 95
    17d BSA (2) 1b CH2Cl2 12 97 95
    18e BSA (2) 1b CH2Cl2 12 88 95
    19d, f BSA (2) 1b CH2Cl2 12 68 95
    20d, g BSA (2) 1b CH2Cl2 12 86 83
    a Reaction conditions: 9a (0.10 mmol), 10a (1.2 equiv.), base (x equiv.), [Pd(η3-C3H5)Cl]2 (2 mol%), ligand (5 mol%), solvent (1.0 mL), room temperature, nitrogen. b The yields of isolated products. c Determined by HPLC analysis. d 1 mol% [Pd(η3-C3H5)Cl]2 and 3 mol% 1b were used. e 0.5 mol% [Pd(η3-C3H5)Cl]2 and 1.5 mol% 1b were used. f The reaction was carried out under 0 ℃. gThe reaction was carried out under 40 ℃.
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    Table 2.  Substrate scope of Pd-catalyzed asymmetric allylic alkylationa

    Entry Ar (9) R1, R2 (10) Product Yieldb/% eec/%
    1 C6H5 (9a) H, CO2Me (10a) 11aa 97 95
    2 4-FC6H4 (9b) H, CO2Me (10a) 11ba 86 96
    3 4-ClC6H4 (9c) H, CO2Me (10a) 11ca 68 92
    4 4-BrC6H4 (9d) H, CO2Me (10a) 11da 89 92
    5 4-MeC6H4 (9e) H, CO2Me (10a) 11ea 75 91
    6 3-ClC6H4 (9f) H, CO2Me (10a) 11fa 79 90
    7 2-MeC6H4 (9g) H, CO2Me (10a) 11ga 84 61
    8 2-Np (9h) H, CO2Me (10a) 11ha 97 92
    9 C6H5 (9a) H, CO2iPr (10b) 11ab 51 88
    10 C6H5 (9a) H, CO2Bn (10c) 11ac 97 94
    11 C6H5 (9a) Ph, CO2Et (10d) 11ad 86 92
    12 C6H5 (9a) Me, CO2Et (10e) 11ae 48 85
    13 C6H5 (9a) H, COMe (10f) 11af 75 90
    14 C6H5 (9a) H, CN (10g) 11ag 21 74
    a Reaction conditions: 9 (0.10 mmol), 10 (1.2 equiv.), BSA (2 equiv.), [Pd(η3-C3H5)Cl]2 (1 mol%), ligand (3 mol%), CH2Cl2 (1.0 mL), room temperature, nitrogen. b The yields of isolated products. c Determined by HPLC analysis.
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  • 发布日期:  2020-10-25
  • 收稿日期:  2020-05-30
  • 修回日期:  2020-06-16
  • 网络出版日期:  2020-07-08
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