Abstract
Here, we present an enantioselective and regioselective hydrophosphination of α,β-unsaturated substrates that feature both ketone and pyridine bifunctional groups. Interestingly, the activation of pyridine and ketone functionalities is selectively achieved through chiral phosphoric acid and oxazaborolidine, respectively. The regioselectivity of the phosphine nucleophiles toward the products can be well controlled by the choice of catalysts. In addition, the α-chiral phosphorus-containing pyridine products exhibit potential applications as chiral P,N-ligands.
1. Introduction
Chiral phosphine compounds play an important role in medicinal chemistry and asymmetric catalysis due to their properties as bioactive molecules and chiral ligands. Herein, a variety of methodologies have been established for the construction of chiral C–P bonds. Recently, the asymmetric hydrophosphination reactions have emerged as one of the most direct and effective approaches to achieve such transformations. Typically, the asymmetric phospha-Michael addition reactions are successfully catalyzed by transition metals, such as Pd, Ni, Cu, Mn, and Co, as well as organocatalysts, including chiral cinchona alkaloids, bifunctional thioureas/ureas, guanidines, carbenes, pyrrolidines, and phosphoric acids (Scheme A). Various α,β-unsaturated amides, esters, ketones, and nitroalkenes have been effectively utilized in these reactions to yield valuable chiral phosphine compounds.
1. (A) Reported Asymmetric Hydrophosphination Reactions, (B) Our Previous Work, and (C) This Work.
In our previous work, the commercial and cheap chiral oxazaborolidines (CBS) were first employed in the enantioselective hydrophosphination reactions of various α,β-unsaturated compounds, such as α,β-unsaturated ketones, esters, thioesters, and alkynes, furnishing the corresponding chiral phosphorus products in excellent yields and enantioselectivities (Scheme B). Furthermore, we reported the asymmetric hydrophosphination reactions of several α,β-unsaturated aza-heteroarenes, including pyridines, thiazoles, pyrazines, benzoxazole, benzothiazole, quinolines, and isoquinolines, catalyzed by chiral phosphopric acids (CPA), leading to the potential phosphorus ligands with high yields and ees (Scheme B). The successful methodologies catalyzed by CBS and CPA provide a green and efficient way to construct chiral C–P bonds.
In this work, novel α,β-unsaturated substrates featuring pyridine and ketone groups were introduced to investigate their regio- and enantioselective hydrophosphination reactions (Scheme C). Notably, regioselectivity can be precisely controlled by employing different catalysts. The CPA catalysts promote the α-1,4-addition products by activating the pyridine groups. In contrast, the CBS catalysts lead to the β-1,4-addition products by the activation of the ketone groups. Additionally, the CBS catalysts also yield products with up to 99% ee, which have potential applications as chiral P,N-ligands.
2. Results and Discussion
Our study commenced with the following model reaction: the reaction between the model substrate (1a) and diphenylphosphine oxide (2a), catalyzed by various CPA and CBS catalysts, aimed at controlling both regio- and enantioselectivity (Table ). Initially, the reaction was carried out at room temperature in the absence of any catalyst. As expected, the regioselectivity of products 3a and 4a could not be effectively controlled, leading to a ratio of 68:32 (entry 1). Interestingly, the regioselectivity was slightly improved to a ratio of 78:22 when achiral PA 1 was employed as the catalyst (entry 2). Subsequently, the use of chiral CPA 2 further enhanced the ratio to 84:16 (entry 3), whereas CPA 3 resulted in a lower regioselectivity (entry 4). To our delight, excellent regioselectivities were achieved when CPA 4 and CPA 5 were used (entries 5–6). Notably, CPA 5 enabled the formation of the pure product 3a. However, despite the regioselectivity being controlled by CPA catalysts, the enantioselectivity could not be effectively controlled. To further enhance the yield ratio of 4a, commercially available and cost-effective CBS was introduced into the model reaction. Unexpectedly, pure product 4a was obtained in full conversion with an enantiomeric excess of 90%. In addition, no trace of product 3a was detected in the 1H NMR spectrum (entry 7). Furthermore, with the CBS-controlled regioselectivity of 4a established, various solvents, including CH3CN, DCE, DME, THF, 2-MeTHF, and 1,4-dioxane, were evaluated to identify the optimal enantiomeric excess (ee) (entries 8–13). The results indicated that all tested solvents yielded pure product 4a when CBS was employed, with the highest ee of 94% achieved in 2-MeTHF. Subsequently, different reaction temperatures were investigated. Contrary to expectations, the ee of 4a decreased to 76% at 0 °C (entry 14). Moreover, higher temperatures of 40 and 80 °C also resulted in lower enantioselectivities (entries 15–16). In summary, the optimized reaction conditions for further substrate exploration were determined as follows: 10 mol % CPA 5 at room temperature in toluene for selective formation of 3a and 10 mol % CBS at room temperature in 2-MeTHF for selective formation of 4a.
1. Optimization of Reaction Conditions .
| entry | solvent | CPA | CBS | 3a:4a | ee (%) |
|---|---|---|---|---|---|
| 1 | Toluene | - | - | 68:32 | - |
| 2 | Toluene | PA 1 | - | 78:22 | 0 (3a) |
| 3 | Toluene | CPA 2 | - | 84:16 | 0 (3a) |
| 4 | Toluene | CPA 3 | - | 75:25 | 0 (3a) |
| 5 | Toluene | CPA 4 | - | 96:4 | 0 (3a) |
| 6 | Toluene | CPA 5 | - | 100:0 | 0 (3a) |
| 7 | Toluene | - | CBS | 0:100 | 90 (4a) |
| 8 | CH3CN | - | CBS | 0:100 | 74 (4a) |
| 9 | DCE | - | CBS | 0:100 | 62 (4a) |
| 10 | DME | - | CBS | 0:100 | 66 (4a) |
| 11 | THF | - | CBS | 0:100 | 81 (4a) |
| 12 | 2-MeTHF | - | CBS | 0:100 | 94 (4a) |
| 13 | 1,4-Diox | - | CBS | 0:100 | 80 (4a) |
| 14 | 2-MeTHF | - | CBS | 0:100 | 76 (4a) |
| 15 | 2-MeTHF | - | CBS | 0:100 | 92 (4a) |
| 16 | 2-MeTHF | - | CBS | 0:100 | 78 (4a) |
Reactions performed with 1a (0.24 mmol), 2a (0.2 mmol), CPA (10 mol %), or CBS (20 mol %) in solvent (2 mL) at room temperature for 12 h.
The ratios were determined by1H NMR.
Enantiomeric excesses were determined by HPLC analysis on the chiral stationary phase.
The reaction was performed at 0 °C.
The reaction was performed at 40 °C.
The reaction was performed at 80 °C.
With the optimal conditions established to prepare products 3 and 4, a variety of substrates (1) were evaluated to prove the applicability of this methodology, and the results were summarized in Scheme . As discussed in Table , 3a was obtained with a single product in 90% yield in the presence of CPA 5, and 4a was received in 96% yield and 94% ee catalyzed by CBS. Initially, we explored the influence of the electron-donating methyl at different positions of the pyridine ring. When the methyl was introduced at the 3-position of the pyridine ring, the product 3b was obtained with good regioselectivity (94:6), and the corresponding product 4b was attained with 98% yield and 92% ee. Moreover, the substrates (1c–1e) with a methyl group at the 4, 5 and 6-postion of the pyridine ring were examined. As expected, CPA 5 exhibited good catalytic ability to yield 3c-3e with up to 90% regioselectivities. To our delight, CBS still could lead to pure 4c–4e with excellent yields (up to 99%) and ee’s (up to 99%). Furthermore, the substrates with electron-withdrawing chlorine group at 3, 4, 5, and 6-postion of the pyridine ring were tested. Interestingly, the pure 3f and 3g were obtained, and the regioselectivity of 3h also can be up to 94%. However, when the 6-postion of the pyridine ring was replaced by chlorine and fluorine groups, only pure 4i and 4j were observed to be catalyzed by CPA 5 or CBS. The enantioselectivities and ees of 4i and 4j were well controlled by CBS. Interestingly, the substrate bearing a fluorine group at 5-postion of the pyridine ring showed a moderate regioselectivity of 66:34, and the substrate with a bromine at the 3-postion generated the pure product 3l. Therefore, the electron-withdrawing groups at the 6-position of pyridine rings probably have a significant effect on regioselectivity. However, the CBS-catalyzed β-addition was not influenced, furnishing 4k and 4l with high yields and ees. Subsequently, substrates (1m–1n) with aliphatic ketone groups were explored. The regioselectivities and enantioselectivities were successfully controlled and catalyzed by CPA 5 and CBS, producing the pure products with high yields and ees. In addition, when the pyridine group was replaced with quinoline, the corresponding products 3o and 4o were obtained with high regioselectivity (100%) and ee (90%).
2. Substrate Scope.
The synthetic transformations were described in Scheme A. Initially, the chiral product 4a (94% ee) was oxidized to N–O compound 5 with 72% yield and 86% ee (Scheme Aa). Subsequently, the interesting substrate 6 bearing two double bonds was introduced in this methodology, furnishing the product 7 with >99% ee and 87.5:12.5 er (Scheme Ab). Interestingly, product 7 was reported as a key intermediate to synthesize the chiral PNP pincer, which could combine with Pd to form the stable PNP-Pd catalyst. Furthermore, the PNP-Pd complex shows excellent catalytic ability on asymmetric hydrophosphination reactions.
3. Synthetic Transformations and the Proposed Mechanism.
To gain a deeper understanding of the reaction mechanism, the control experiments were carried out, as shown in Scheme B. First, substrate 8 without a pyridine ring was examined with CPA 5 and CBS catalysts. The results showed that 100% racemic product 10 was observed using CPA or no catalyst, which indicated that CPA 5 probably could not catalyze the reactions without the pyridine ring and catalyze the reactions in Scheme through activating the pyridine ring. In addition, CBS indeed can catalyze the asymmetric hydrophosphination of the α,β-unsaturated ketone, leading to 10 in 92% yield and 98% ee. In order to further explore the catalytic mechanism, the 3-pyridyl and 4-pyridyl substituted α,β-unsaturated pyridyl ketones were employed. Interestingly, CPA 5 could not catalyze the 3-pyridyl substrate but generated the racemic mixture of 4-pyridyl products (15 and 16). In addition, the CBS still exhibits a highly effective catalytic performance to activate the α,β-unsaturated ketones to produce 13 and 16 with high yields and ees.
Based on the control experiments and our previous studies, the proposed catalytic mechanism is outlined in Scheme C. The observed regioselectivity can be attributed to the selective activation of pyridine and ketone functionalities by chiral phosphoric acid (CPA) and oxazaborolidine. Initially, substrate 1a is activated by CPA to generate intermediate Int 1 . Subsequently, the phosphine nucleophile reacts with Int 1 to form intermediate Int 2 . Following the phosphorus-based Michael addition, desired product 3a is formed with the regeneration of CPA. Due to the failure of the enantioselectivity control (various CPAs have been examined), the CPA 5 probably just plays a role in activating the pyridine ring. The CBS catalytic process differs from that of CPA. In the CBS-catalyzed pathway, CBS acts as a Lewis pair to cleave 2a, yielding intermediate Int 4 , which further interacts with substrate 1a to generate Int 5 . A chiral intermediate, Int 6 , is then formed through a synergistic addition step. Finally, product 4a is released, and CBS is regenerated to participate in the next catalytic cycle.
3. Conclusion
In summary, we report a catalyst-controlled regioselective and enantioselective hydrophosphination methodology. Notably, various α,β-unsaturated substrates bearing ketone and pyridine bifunctional groups were selectively activated by chiral phosphoric acid and oxazaborolidine, affording the corresponding products in good yields and enantioselectivities. Importantly, the α-chiral phosphorus-containing pyridine products exhibit potential applications as chiral P,N-ligands.
4. Experimental Section
4.1. General Procedure for the Preparation 3
In a glovebox filled with argon, pyridine substrate (0.24 mmol, 1.2 equiv), diphenyl phosphorus oxide (0.2 mmol, 1.0 equiv), chiral phosphoric acid (0.02 mmol, 0.1 equiv), and methylbenzene (2 mL) were added to a reaction tube equipped with a magnetic stirring rod, The mixture was stirred at room temperature until the reaction was complete and then purified by rapid column chromatography.
4.2. General Procedure for the Preparation of Chiral Products 4
In a glovebox filled with argon, pyridine substrate (0.24 mmol, 1.2 equiv), diphenylphosphoric oxide (0.2 mmol, 1.0 equiv), (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (0.04 mmol, 0.2 equiv), and methyltetrahydrofuran (2 mL) were added to a reaction tube equipped with a magnetic stir bar; the mixture was stirred at room temperature until the reaction was complete and then purified by rapid column chromatography.
4.2.1. (E)-1-Phenyl-3-(pyridin-2-yl)prop-2-en-1-one (1a)
Yellow solid, 86% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.70–8.64 (m, 1H), 8.16–8.06 (m, 3H), 7.78 (d, J = 15.3 Hz, 1H), 7.74–7.67 (m, 1H), 7.61–7.54 (m, 1H), 7.52–7.41 (m, 3H), 7.29–7.23 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 190.4, 153.1, 150.1, 142.8, 137.8, 136.9, 133.1, 128.7, 128.6, 125.5, 125.4, 124.4; HRMS (ESI) m/z: [M + H]+ calcd for C14H12NO 210.0913; found, 210.0909.
4.2.2. (E)-3-(3-Methylpyridin-2-yl)-1-phenylprop-2-en-1-one (1b)
Yellow solid, 72% yield;1H NMR (400 MHz, Chloroform-d): δ 8.52 (dd, J = 4.6, 1.7 Hz, 1H), 8.24 (d, J = 14.9 Hz, 1H), 8.15–8.06 (m, 3H), 7.62–7.57 (m, 1H), 7.55–7.47 (m, 3H), 7.21 (dd, 1H), 2.50 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ 190.4, 151.2, 147.5, 139.2, 138.7, 137.9, 133.9, 133.1, 128.7, 128.6, 125.8, 124.4, 18.7; HRMS (ESI) m/z: [M + H]+ calcd for C15H14NO 224.1070; found, 224.1073.
4.2.3. (E)-3-(4-Methylpyridin-2-yl)-1-phenylprop-2-en-1-one (1c)
Yellow solid, 76% yield;1H NMR (400 MHz, Chloroform-d): δ 8.53 (d, J = 4.9 Hz, 1H), 8.15–8.07 (m, 3H), 7.75 (d, J = 15.2 Hz, 1H), 7.62–7.54 (m, 1H), 7.49 (dd, J = 8.4, 6.8 Hz, 2H), 7.29 (d, J = 2.7 Hz, 1H), 7.13–7.07 (m, 1H), 2.37 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ 190.4, 152.9, 149.9, 148.1, 143.0, 137.8, 133.0, 128.7, 128.6, 126.5, 125.4, 125.2, 20.9; HRMS (ESI) m/z: [M + H]+ calcd for C15H14NO 224.1070; found, 224.1072.
4.2.4. (E)-3-(5-Methylpyridin-2-yl)-1-phenylprop-2-en-1-one (1d)
Yellow solid, 69% yield;1H NMR (400 MHz, Chloroform-d): δ 8.51 (d, J = 2.3 Hz, 1H), 8.12–8.02 (m, 3H), 7.77 (d, J = 15.3 Hz, 1H), 7.62–7.54 (m, 1H), 7.54–7.46 (m, 3H), 7.38 (d, J = 7.9 Hz, 1H), 2.37 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ 190.5, 150.8, 150.5, 142.9, 137.9, 137.2, 134.6, 133.0, 128.7, 128.6, 125.0, 124.4, 18.6, 18.6; HRMS (ESI) m/z: [M + H]+ calcd for C15H14NO 224.1070; found, 224.1073.
4.2.5. (E)-3-(6-Methylpyridin-2-yl)-1-phenylprop-2-en-1-one (1e)
Yellow solid, 85% yield;1H NMR (400 MHz, Chloroform-d): δ 8.13–8.05 (m, 3H), 7.76 (d, J = 15.3 Hz, 1H), 7.65–7.55 (m, 2H), 7.54–7.47 (m, 2H), 7.33–7.26 (m, 1H), 7.16 (d, J = 7.7 Hz, 1H), 2.62 (s, 3H);13C NMR (101 MHz, Chloroform-d): δ 190.7, 159.0, 152.5, 143.3, 137.9, 136.9, 132.9, 128.7, 128.6, 125.3, 124.3, 122.5, 24.7; HRMS (ESI) m/z: [M + H]+ calcd for C15H14NO 224.1070; found, 224.1080.
4.2.6. (E)-3-(3-Chloropyridin-2-yl)-1-phenylprop-2-en-1-one (1f)
Yellow solid, 79% yield;1H NMR (400 MHz, Chloroform-d): δ 8.57 (dd, J = 4.5, 1.5 Hz, 1H), 8.25 (s, 2H), 8.16–8.06 (m, 2H), 7.75 (dd, J = 8.2, 1.5 Hz, 1H), 7.65–7.56 (m, 1H), 7.54–7.48 (m, 2H), 7.37–7.21 (m, 1H);13C NMR (101 MHz, Chloroform-d): δ 190.1, 150.2, 147.8, 137.8, 137.7, 137.4, 133.2, 133.1, 128.8, 128.7, 127.8, 125.2; HRMS (ESI) m/z: [M + H]+ calcd for C14H11NOCl 244.0524; found, 244.0530.
4.2.7. (E)-3-(4-Chloropyridin-2-yl)-1-phenylprop-2-en-1-one (1g)
Yellow solid, 88% yield;1H NMR (400 MHz, Chloroform-d): δ 8.56 (d, J = 5.2 Hz, 1H), 8.16–8.05 (m, 3H), 7.69 (d, J = 15.2 Hz, 1H), 7.64–7.55 (m, 1H), 7.54–7.42 (m, 3H), 7.29 (dd, J = 5.2, 2.0 Hz, 1H); 13C NMR (101 MHz, Chloroform-d): δ 189.9, 154.7, 150.8, 144.8, 141.3, 137.5, 133.2, 128.7, 126.7, 125.3, 124.3; HRMS (ESI) m/z: [M + Na]+ calcd for C14H10NOClNa 266.0343; found, 266.0341.
4.2.8. (E)-3-(5-Chloropyridin-2-yl)-1-phenylprop-2-en-1-one (1h)
Yellow solid, 74% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.63 (d, J = 2.4 Hz, 1H), 8.14–8.06 (m, 3H), 7.77–7.68 (m, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.43 (d, J = 8.3 Hz, 1H);13C NMR (101 MHz, Chloroform-d): δ 190.2, 151.3, 149.2, 141.3, 137.6, 136.5, 133.2, 132.7, 128.7, 128.7, 126.0, 125.8; HRMS (ESI) m/z: [M + H]+ calcd for C14H11NOCl 244.0524; found, 244.0534.
4.2.9. (E)-3-(6-Chloropyridin-2-yl)-1-phenylprop-2-en-1-one (1i)
Yellow solid, 85% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.15–8.09 (m, 2H), 8.08 (d, J = 1.5 Hz, 1H), 7.72–7.66 (m, 2H), 7.63–7.57 (m, 1H), 7.55–7.48 (m, 2H), 7.38 (dd, J = 7.6, 0.9 Hz, 1H), 7.32 (dd, J = 8.0, 0.8 Hz, 1H); 13C NMR (101 MHz, Chloroform-d): δ 190.1, 153.8, 151.8, 140.9, 139.5, 137.5, 133.3, 128.8, 128.7, 126.7, 125.1, 123.8; HRMS (ESI) m/z: [M + H]+ calcd for C14H11NOCl 244.0524; found, 244.0529.
4.2.10. (E)-3-(6-Fluoropyridin-2-yl)-1-phenylprop-2-en-1-one (1j)
Yellow solid, 75% yield;1H NMR (400 MHz, Chloroform-d): δ 8.16–8.05 (m, 3H), 7.84 (q, J = 8.0 Hz, 1H), 7.70 (dd, J = 15.1, 1.0 Hz, 1H), 7.64–7.57 (m, 1H), 7.51 (dd, J = 8.3, 6.8 Hz, 2H), 7.34 (dd, J = 7.3, 2.4 Hz, 1H), 6.95 (dd, J = 8.2, 2.9 Hz, 1H); 13C NMR (101 MHz, Chloroform-d): δ 190.0, (163.3, 161.9, d), (151.9, 151.8, d), (142.0, 141.9, d), 140.7, 137.5, 133.3, 128.7, 126.5, (123.0, 123.0, d), (110.1, 110.7, d);19F NMR (376 MHz, Chloroform-d): δ −65.06; HRMS (ESI) m/z: [M + H]+ calcd for C14H11NOF 228.0819; found, 228.0827.
4.2.11. (E)-3-(5-Fluoropyridin-2-yl)-1-phenylprop-2-en-1-one (1k)
Yellow solid,87% yield;1H NMR (400 MHz, Chloroform-d): δ 8.54 (d, J = 2.8 Hz, 1H), 8.12–8.08 (m, 2H), 8.04 (dd, J = 15.3, 0.7 Hz, 1H), 7.76 (d, J = 15.3 Hz, 1H), 7.64–7.56 (m, 1H), 7.54–7.48 (m, 3H), 7.47–7.41 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 190.2, (160.8,158.2, d), (149.5, 149.5, d), 141.2, (139.0, 138.8, d), 137.7, 133.1, (128.7, 128.7, d), (126.3, 126.3, d), 125.4, (123.4, 123.2, d); 19F NMR (376 MHz, Chloroform-d): δ −124.04; HRMS (ESI) m/z: [M + Na]+ calcd for C14H10NOFNa 250.0639; found, 250.0633.
4.2.12. (E)-3-(3-Bromopyridin-2-yl)-1-phenylprop-2-en-1-one (1l)
Yellow solid, 68% yield;1H NMR (400 MHz, Chloroform-d): δ 8.54 (dd, J = 4.5, 1.6 Hz, 1H), 8.19 (s, 2H), 8.11–8.05 (m, 2H), 7.83 (dd, J = 8.1, 1.6 Hz, 1H), 7.60–7.52 (m, 1H), 7.47 (dd, J = 8.5, 6.9 Hz, 2H), 7.10 (dd, J = 8.2, 4.5 Hz, 1H); 13C NMR (101 MHz, Chloroform-d): δ 189.9, 151.1, 148.3, 141.0, 139.5, 137.6, 133.2, 128.6, 128.0, 125.4, 123.4; HRMS (ESI) m/z: [M + H]+ calcd for C14H11NOBr 288.0019; found, 288.0024.
4.2.13. (E)-4-(Pyridin-2-yl)but-3-en-2-one (1m)
Yellow oil, 67% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.69–8.64 (m, 1H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.58–7.46 (m, 2H), 7.33–7.26 (m, 1H), 7.15 (d, J = 16.0 Hz, 1H), 2.42 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ 198.5, 153.0, 150.1, 141.9, 136.8, 130.1, 124.3, 124.2, 28.1; HRMS (ESI) m/z: [M + H]+ calcd for C9H10NO 148.0757; found, 148.0765.
4.2.14. (E)-1-Cyclopropyl-3-(pyridin-2-yl)prop-2-en-1-one (1n)
Yellow oil, 62% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.75 – 8.58 (m, 1H), 7.73 (td, J = 7.7, 1.8 Hz, 1H), 7.60 (d, J = 15.8 Hz, 1H), 7.47 (dt, J = 7.9, 1.1 Hz, 1H), 7.34 (d, J = 15.8 Hz, 1H), 7.32–7.24 (m, 1H), 2.34–2.24 (m, 1H), 1.24–1.14 (m, 2H), 1.01 (dt, J = 8.1, 3.5 Hz, 2H); 13C NMR (101 MHz, Chloroform-d): δ 200.3, 153.2, 150.1, 140.4, 136.8, 129.4, 124.6, 124.2, 20.2, 11.5; HRMS (ESI) m/z: [M + H]+ calcd for C11H12NO 174.0913; found, 174.0920.
4.2.15. (E)-1-Phenyl-3-(quinolin-2-yl)prop-2-en-1-one (1o)
Yellow solid, 52% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.24–8.08 (m, 5H), 7.95 (d, J = 15.5 Hz, 1H), 7.86–7.71 (m, 2H), 7.70–7.49 (m, 5H); 13C NMR (101 MHz, Chloroform-d): δ 190.7, 153.4, 148.3, 143.6, 137.8, 136.9, 133.1, 130.1, 128.8, 128.7, 128.2, 127.6, 127.1, 121.5; HRMS (ESI) m/z: [M + H]+ calcd for C18H14NO 260.1070; found, 260.1062.
4.2.16. 2-(Diphenylphosphoryl)-1-phenyl-3-(pyridin-2-yl)propan-1-one (3a)
Yellow solid, 88% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.34 (dd, J = 5.0, 1.7 Hz, 1H), 7.94–7.74 (m, 4H), 7.66 (d, J = 7.7 Hz, 2H), 7.51–7.33 (m, 6H), 7.30 (dd, J = 7.8, 3.9 Hz, 2H), 7.17 (t, J = 7.7 Hz, 2H), 7.06 (d, J = 7.8 Hz, 1H), 6.96 (dd, J = 7.5, 4.9 Hz, 1H), 5.57–5.45 (m, 1H), 3.89–3.76 (m, 1H), 3.43–3.32 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 197.5, (157.9, 157.8, d), 148.9, 138.7, 136.3, 132.3, (132.0, 132.0, d), (131.9, 131.9, d), (131.7, 131.9, d), (131.5, 131.4, d), 128.6, (128.5, 128.4, d), (128.4, 128.3, d), 128.0, 123.6, 121.5, (50.1, 49.5, d), 35.32; 31P NMR (162 MHz, Chloroform-d): δ 29.14; HRMS (ESI) m/z: [M + H]+ calcd for C26H23NO2P 412.1461; found, 412.1464.
4.2.17. 2-(Diphenylphosphoryl)-3-(3-methylpyridin-2-yl)-1-phenylpropan-1-one (3b)
Yellow solid, 85% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.14 (d, J = 4.8 Hz, 1H), 7.88–7.72 (m, 6H), 7.45–7.25 (m, 8H), 7.19 (td, J = 7.8, 1.5 Hz, 2H), 6.95–6.88 (m, 1H), 5.71–5.60 (m, 1H), 4.01–3.88 (m, 1H), 3.33–3.22 (m, 1H), 2.23 (d, J = 2.0 Hz, 3H); 13C NMR (101 MHz, Chloroform-d): δ 197.9, (155.9, 155.8, d), 145.8, 139.1, (132.0, 132.0, d), (131.8, 131.8, d), 131.6, 131.4, (128.6, 128.6, d), 128.5, (128.3, 128.2, d), 127.8, 121.5, 48.6, 32.2, 18.6; 31P NMR (162 MHz, Chloroform-d): δ 29.44; HRMS (ESI) m/z: [M + H]+ calcd for C27H25NO2P 426.1617; found, 426.1612.
4.2.18. 2-(Diphenylphosphoryl)-3-(4-methylpyridin-2-yl)-1-phenylpropan-1-one (3c)
Yellow solid, 65% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.22 (d, J = 5.1 Hz, 1H), 7.94–7.75 (m, 4H), 7.67 (d, J = 7.7 Hz, 2H), 7.52–7.25 (m, 7H), 7.19 (t, J = 7.8 Hz, 2H), 6.90 (s, 1H), 6.81 (d, J = 5.1 Hz, 1H), 5.58–5.47 (m, 1H), 3.82–3.70 (m, 1H), 3.40–3.29 (m, 1H), 2.18 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ 197.7, 157.7, 148.6, 147.4, 138.8, 132.3, 132.0, 131.9, (131.7, 131.6, d), (131.5, 131.4, d), 128.2, 128.4, (128.4, 128.2, d), 127.9, 124.6, 122.6, 49.6, 35.1, 20.8; 31P NMR (162 MHz, Chloroform-d): δ 29.26; HRMS (ESI) m/z: [M + NH4]+ calcd for C27H28N2O2P 443.1883; found, 443.1887.
4.2.19. 2-(Diphenylphosphoryl)-3-(5-methylpyridin-2-yl)-1-phenylpropan-1-one (3d)
Yellow solid, 40% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.18 (d, J = 2.2 Hz, 1H), 7.83–7.76 (m, 3H), 7.70–7.61 (m, 2H), 7.53–7.42 (m, 2H), 7.41–7.35 (m, 3H), 7.34–7.28 (m, 3H), 7.26–7.16 (m, 3H), 6.97 (d, J = 7.9 Hz, 1H), 5.55–5.44 (m, 1H), 3.86–3.71 (m, 1H), 3.39–3.30 (m, 1H), 2.17 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ (197.6, 197.6, d), (154.9, 154.7, d), 149.1, 138.8, 137.0, 132.3, (132.0, 131.9, d), (131.9, 131.9, d), (131.7, 131.6, d), (131.5, 131.4, d), 130.9, 128.6, (128.5, 128.5, d), (128.4, 128.3, d), 128.0, (50.2, 49.7, d), 34.8, 17.9; 31P NMR (162 MHz, Chloroform-d): δ 29.21; HRMS (ESI) m/z: [M + NH4]+ calcd for C27H28N2O2P 443.1883; found, 443.1887.
4.2.20. 2-(Diphenylphosphoryl)-3-(6-methylpyridin-2-yl)-1-phenylpropan-1-one (3e)
White solid, 87% yield; 1H NMR (400 MHz, Chloroform-d): δ 7.88–7.79 (m, 3H), 7.78–7.71 (m, 2H), 7.74–7.66 (m, 1H), 7.58–7.55 (m, 1H), 7.54–7.45 (m, 2H), 7.42 (dt, J = 7.1, 1.9 Hz, 1H), 7.37–7.30 (m, 4H), 7.21 (t, J = 7.8 Hz, 2H), 6.84 (dd, J = 24.1, 7.6 Hz, 2H), 5.59–5.45 (m, 1H), 3.93–3.75 (m, 1H), 3.46–3.33 (m, 1H), 2.25 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ 197.8, 157.4, 156.7, 139.0, 136.4, 132.2, (132.0, 131.9, d), (131.8, 131.7, d), (131.5, 131.4, d), (128.6, 128.5, d), (128.4, 128.3, d), 127.8, 120.8, 120.1, (49.8, 49.2, d), 35.3, 23.8; 31P NMR (162 MHz, Chloroform-d): δ 29.25; HRMS (ESI) m/z: [M + H]+ calcd for C27H25NO2P 426.1617; found, 426.1625.
4.2.21. 3-(3-Chloropyridin-2-yl)-2-(diphenylphosphoryl)-1-phenylpropan-1-one (3f)
Yellow solid, 90% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.14 (dd, J = 4.7, 1.5 Hz, 1H), 7.89–7.74 (m, 6H), 7.51 (dd, J = 8.0, 1.5 Hz, 1H), 7.45–7.38 (m, 2H), 7.38–7.31 (m, 5H), 7.21 (t, J = 7.8 Hz, 2H), 6.97 (dd, J = 8.0, 4.7 Hz, 1H), 5.65–5.41 (m, 1H), 4.17–4.04 (m, 1H), 3.52–3.41 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 197.5, 154.9, 146.3, 138.9, 136.5, 132.2, (132.0, 132.0, d), (131.7, 131.6, d), (131.4, 131.3, d), (128.6, 128.6, d), (128.4, 128.4, d), 128.3, 127.9, 122.5, (48.9, 48.3, d), 32.7; 31P NMR (162 MHz, Chloroform-d): δ 29.15; HRMS (ESI) m/z: [M + H]+ calcd for C26H21ClNO2P 446.1071; found, 446.1066.
4.2.22. 3-(4-Chloropyridin-2-yl)-2-(diphenylphosphoryl)-1-phenylpropan-1-one (3g)
Yellow solid, 90% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.24 (d, J = 5.4 Hz, 1H), 7.86–7.75 (m, 4H), 7.72–7.65 (m, 2H), 7.49–7.29 (m, 7H), 7.20 (t, J = 7.6 Hz, 2H), 7.11 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 5.5, 1.9 Hz, 1H), 5.55–5.44 (m, 1H), 3.87–3.75 (m, 1H), 3.43–3.31 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 197.2, (159.6, 159.5, d), 149.7, 144.2, 138.5, 132.5, (132.2, 132.1, d), (132.1, 132.0, d), (131.6,131.5, d), (131.4, 131.3, d), (128.7, 128.5, d), 128.4, 128.3, 128.0, 123.9, 122.0, (49.8, 49.3, d), 34.9; 31P NMR (162 MHz, Chloroform-d): δ 29.02; HRMS (ESI) m/z: [M + K]+ calcd for C26H21ClNO2PK 484.0630; found, 484.0636.
4.2.23. 3-(5-Chloropyridin-2-yl)-2-(diphenylphosphoryl)-1-phenylpropan-1-one (3h)
Yellow solid, 97% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.30 (d, J = 2.5 Hz, 1H), 7.87–7.75 (m, 4H), 7.74–7.63 (m, 2H), 7.52–7.48 (m, 1H), 7.48–7.43 (m, 1H), 7.43–7.34 (m, 4H), 7.34–7.28 (m, 2H), 7.24–7.16 (m, 2H), 7.04 (d, J = 8.3 Hz, 1H), 5.52–5.41 (m, 1H), 3.89–3.76 (m, 1H), 3.42–3.30 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 197.1, (156.0, 155.9, d), 147.3, 138.4, 136.5, 132.6, (132.1, 132.1, d), (131.6, 131.5, d), (131.4, 131.4, d), (128.7, 128.6, d), 128.4, 128.3, 128.1, 124.8, (50.0, 49.4, d), 34.3; 31P NMR (162 MHz, Chloroform-d): δ 28.99 (d, J = 3.6 Hz); HRMS (ESI) m/z: [M + H]+ calcd for C26H22ClNO2P 446.1071; found, 446.1070.
4.2.24. 2-(Diphenylphosphoryl)-3-(5-fluoropyridin-2-yl)-1-phenylpropan-1-one (3k)
Yellow solid, 82% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.20 (d, J = 2.9 Hz, 1H), 7.80 (dt, J = 11.6, 7.1 Hz, 4H), 7.65 (d, J = 7.7 Hz, 2H), 7.48–7.28 (m, 7H), 7.24–7.13 (m, 3H), 7.07 (dd, J = 8.6, 4.4 Hz, 1H), 5.50–5.39 (m, 1H), 3.87–3.75 (m, 1H), 3.42–3.30 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 197.4, 159.5, 157.0, (153.9, 153.8, d), 138.5, (137.1, 136.8, d), 132.5, (132.1, 132.0, d), (131.7, 131.6, d), (131.4, 131.4, d), (128.6, 128.5, d), (128.4, 128.4, d), 128.3, 128.0, (124.4, 124.3, d), (123.2, 123.0, d), (50.3, 49.7, d), 34.5; 31P NMR (162 MHz, Chloroform-d): δ 28.97; 19F NMR (376 MHz, Chloroform-d): δ −130.45; HRMS (ESI) m/z: [M + H]+ calcd for C26H22FNO2P 430.1367; found, 430.1375.
4.2.25. 3-(3-Bromopyridin-2-yl)-2-(diphenylphosphoryl)-1-phenylpropan-1-one (3l)
Yellow solid, 59% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.17 (d, J = 4.7 Hz, 1H), 7.89–7.74 (m, 6H), 7.70 (d, J = 7.9 Hz, 1H), 7.42 (tt, J = 6.3, 2.7 Hz, 2H), 7.35 (dq, J = 7.9, 3.4 Hz, 5H), 7.22 (t, J = 7.6 Hz, 2H), 6.90 (dd, J = 8.0, 4.7 Hz, 1H), 5.59–5.48 (m, 1H), 4.16–4.03 (m, 1H), 3.51–3.41 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 197.4, (156.0, 155.9, d), 146.8, 139.8, 138.9, 132.2, (132.1, 132.0, d), (132.0, 132.0, d), (131.7, 131.7, d), (131.4, 131.4, d), (128.6,128.6, d), (128.4, 128.3, d), 127.9, 122.8, 121.5, (48.2, 48.7, d), 34.9; 31P NMR (162 MHz, Chloroform-d): δ 29.12; HRMS (ESI) m/z: [M + Na]+ calcd for C26H21BrNO2PNa 512.0385; found, 512.0390.
4.2.26. 3-(Diphenylphosphoryl)-4-(pyridin-2-yl)butan-2-one (3m)
Yellow solid, 85% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.45 (dd, J = 4.9, 1.6 Hz, 1H), 7.97–7.67 (m, 4H), 7.60–7.45 (m, 7H), 7.06 (dd, J = 11.5, 7.3 Hz, 2H), 4.67–4.56 (m, 1H), 3.68–3.56 (m, 1H), 3.20–3.08 (m, 1H), 2.07 (d, J = 1.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d): δ 157.7, 148.9, 136.5, (132.3, 132.3, d), (132.3, 132.2, d), (131.5, 131.4, d), (131.4, 131.3, d), (128.9, 128.8, d), (128.7, 128.7, d), 123.5, 121.7, (54.8, 54.3, d), 34.3, 32.2; 31P NMR (162 MHz, Chloroform-d): δ 29.35; HRMS (ESI) m/z: [M + Na]+ calcd for C21H20NO2PNa 372.1124; found, 372.1116.
4.2.27. 1-Cyclopropyl-2-(diphenylphosphoryl)-3-(pyridin-2-yl)propan-1-one (3n)
Yellow solid, 89% yield; 1H NMR (400 MHz, Chloroform-d): δ 8.45 (d, J = 4.9 Hz, 1H), 7.90 (dt, J = 12.2, 6.0 Hz, 4H), 7.62–7.44 (m, 7H), 7.05 (t, J = 6.8 Hz, 2H), 4.71 (td, J = 11.5, 3.5 Hz, 1H), 3.75–3.62 (m, 1H), 3.30–3.18 (m, 1H), 1.96 (td, J = 8.7, 7.6, 4.3 Hz, 1H), 0.75–0.62 (m, 3H), 0.48 (td, J = 7.6, 7.2, 3.8 Hz, 1H); 13C NMR (101 MHz, Chloroform-d): δ (205.8, 205.7, d), (157.9, 157,8, d), 149.0, 136.2, 132.1, (131.5, 131.4, d), (131.3, 131.2, d), (128.6, 128.6, d), 123.6, 121.5, (56.1, 55.6, d), 34.2, 22.6, (12.2, 12.1, d); 31P NMR (162 MHz, Chloroform-d): δ 28.76; HRMS (ESI) m/z: [M + H]+ calcd for C23H23NO2P 376.1461; found, 376.1455.
4.2.28. 2-(Diphenylphosphoryl)-1-phenyl-3-(quinolin-2-yl)propan-1-one (3o)
Yellow solid, 89% yield; 1H NMR (400 MHz, Chloroform-d): δ 7.94–7.79 (m, 7H), 7.65 (dd, J = 8.2, 1.4 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.54–7.46 (m, 1H), 7.44–7.31 (m, 8H), 7.28–7.22 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 5.78–5.67 (m, 1H), 4.23–4.08 (m, 1H), 3.66–3.55 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 197.7, (158.0, 157.9, d), 147.3, 139.0, 136.1, 132.2, (132.1, 132.0, d), (131.8, 131.7, d), (131.5, 131.4, d), 129.2, 128.7, 128.6, (128.5, 128.4, d), 128.3, 127.9, 127.4, 126.8, 125.9, 121.4, (49.2, 48.7, d), 35.9; 31P NMR (162 MHz, Chloroform-d): δ 29.24; HRMS (ESI) m/z: [M + H]+ calcd for C30H25NO2P 462.1617; found, 462.1616.
4.2.29. (S)-3-(Diphenylphosphoryl)-1-phenyl-3-(pyridin-2-yl)propan-1-one (4a)
White solid, 96% yield, 95% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.40 (d, J = 4.8 Hz, 1H), 7.96–7.86 (m, 4H), 7.62 (dd, J = 11.4, 7.6 Hz, 2H), 7.57–7.44 (m, 4H), 7.39 (q, J = 7.6, 7.2 Hz, 4H), 7.32 (td, J = 7.6, 2.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 1H), 6.99 (t, J = 6.2 Hz, 1H), 4.75 (td, J = 10.4, 2.5 Hz, 1H), 4.45–4.32 (m, 1H), 3.53–3.41 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ (197.0, 196.9, d), 155.6, 149.1, 136.3, 135.9, 133.2, (132.0, 132.0, d), 131.6, (131.4, 131.4, d), (131.3, 131.3, d), (128.8, 128.7, d), 128.5, (128.2, 128.2, d), 128.1, 124.7, 121.8, 44.7, 44.0, 37.3; 31P NMR (162 MHz, Chloroform-d): δ 33.77; HRMS (ESI) m/z: [M + H]+ calcd for C26H23NO2P 412.1461; found, 412.1456; HPLC (OD-H, i-PrOH/n-heptane = 10/90, flow rate = 1.0 mL/min, l = 220 nm) tR = 17.0 min (major), 27.4 min (minor).
4.2.30. (S)-3-(Diphenylphosphoryl)-3-(3-methylpyridin-2-yl)-1-phenylpropan-1-one (4b)
White solid, 98% yield, 93% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.41 (d, J = 4.7 Hz, 1H), 7.90 (d, J = 7.8 Hz, 2H), 7.82 (dd, J = 10.8, 7.6 Hz, 2H), 7.59–7.45 (m, 6H), 7.39 (q, J = 8.2, 7.6 Hz, 3H), 7.30 (dd, J = 7.8, 2.9 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 6.99–6.92 (m, 1H), 4.78 (t, J = 11.2 Hz, 1H), 4.71–4.59 (m, 1H), 3.55–3.43 (m, 1H), 2.07 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ (197.7, 197.5, d), 154.6, 146.6, 137.6, 136.2, (133.5, 133.4, d), 133.2, (132.1, 132.0, d), (131.7, 131.7, d), (131.6, 131.6, d), (131.4, 131.3, d), (128.7, 128.6, d), 128.5, 128.2, (128.1, 128.0, d), (121.8, 121.8, d), 40.7, 40.0, 38.6, 18.9; 31P NMR (162 MHz, Chloroform-d): δ 33.55; HRMS (ESI) m/z: [M + H]+ calcd for C27H25NO2P 426.1617; found, 426.1612; HPLC (AD-H, i-PrOH/n-heptane = 40/60, flow rate = 1.0 mL/min, l = 254 nm) tR = 12.2 min (major), 18.9 min (minor).
4.2.31. (S)-3-(Diphenylphosphoryl)-3-(4-methylpyridin-2-yl)-1-phenylpropan-1-one (4c)
White solid, 94% yield, 92% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.25 (d, J = 5.0 Hz, 1H), 7.95–7.86 (m, 4H), 7.74–7.59 (m, 2H), 7.55–7.45 (m, 4H), 7.43–7.28 (m, 5H), 6.91 (s, 1H), 6.81 (d, J = 4.9 Hz, 1H), 4.69 (td, J = 10.5, 2.5 Hz, 1H), 4.46–4.33 (m, 1H), 3.52–3.39 (m, 1H), 2.11 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ (197.0,196.9, d), (155.3, 155.2, d), 148.7, 147.0, 136.4, 133.2, (132.0, 131.9, d), (131.6, 131.6, d), 131.5, 131.4, 131.3, 131.0, 130.6, (128.8, 128.6, d), 128.4, 128.2, 128.0, 125.7, 122.9, (44.6, 43.9, d), 37.1, 20.8; 31P NMR (162 MHz, Chloroform-d): δ 33.97; HRMS (ESI) m/z: [M + NH4]+ calcd for C27H28N2O2P 443,1883; found, 443,1873; HPLC (OD-H, i-PrOH/n-heptane = 10/90, flow rate = 1.0 mL/min, l = 220 nm) tR = 13.4 min (major), 23.3 min (minor).
4.2.32. (S)-3-(Diphenylphosphoryl)-3-(5-methylpyridin-2-yl)-1-phenylpropan-1-one (4d)
White solid, 96% yield, 99% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.23 (d, J = 2.2 Hz, 1H), 7.96–7.84 (m, 4H), 7.70–7.61 (m, 2H), 7.54–7.44 (m, 4H), 7.43–7.30 (m, 5H), 7.20 (dd, J = 8.0, 2.3 Hz, 1H), 7.06 (dd, J = 8.0, 1.9 Hz, 1H), 4.72 (td, J = 10.4, 2.5 Hz, 1H), 4.42–4.29 (m, 1H), 3.50–3.38 (m, 1H), 2.16 (d, J = 1.8 Hz, 3H); 13C NMR (101 MHz, Chloroform-d): δ (197.1, 196.9, d), (152.5,152.4, d), 149.5, 136.6, 136.4, 133.2, (132.0, 132.0, d), (131.6, 131.6, d), 131.5, (131.4, 131.3, d), 131.3, (128.8, 128.7, d), 128.5, 128.2, (128.2, 128.1, d), (124.2, 124.1, d), (44.1, 43.4, d), 37.3, 18.0; 31P NMR (162 MHz, Chloroform-d): δ 33.83; HRMS (ESI) m/z: [M + NH4]+ calcd for C27H28N2O2P 443,1883; found, 443,1887; HPLC (AD-H, i-PrOH/n-heptane = 25/75, flow rate = 1.0 mL/min, l = 254 nm) tR = 9.8 min (minor), 24.9 min (major).
4.2.33. (S)-3-(Diphenylphosphoryl)-3-(6-methylpyridin-2-yl)-1-phenylpropan-1-one (4e)
White solid, 99% yield, 96% ee; 1H NMR (400 MHz, Chloroform-d): δ 7.95–7.87 (m, 4H), 7.69–7.57 (m, 2H), 7.56–7.45 (m, 4H), 7.44–7.36 (m, 3H), 7.36–7.25 (m, 3H), 7.00–6.93 (m, 1H), 6.83 (dt, J = 7.5, 1.1 Hz, 1H), 4.71 (td, J = 10.7, 2.6 Hz, 1H), 4.41–4.28 (m, 1H), 3.49–3.37 (m, 1H), 2.32 (s, 3H); 13C NMR (101 MHz, Chloroform-d): δ (197.2, 197.1, d), 157.7, 154.5, 136.5, 136.2, 133.2, 132.0, (131.6, 131.5, d), (131.4, 131.3, d), (128.8, 128.7, d), (128.5, 128.2, d), (128.0, 127.9, d), 121.3, (44.8, 44.1, d), 37.0, 24.2; 31P NMR (162 MHz, Chloroform-d): δ 34.15; HRMS (ESI) m/z: [M + K]+ calcd for C27H24NO2PK 464.1176; found, 464.1177; HPLC (OD-H, i-PrOH/n-heptane = 8/92, flow rate = 0.6 mL/min, l = 220 nm) tR = 21.0 min (major), 34.3 min (minor).
4.2.34. (S)-3-(3-Chloropyridin-2-yl)-3-(diphenylphosphoryl)-1-phenylpropan-1-one (4f)
White solid, 99% yield, 98% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.45 (q, J = 4.1, 3.2 Hz, 1H), 8.00 (t, J = 8.6 Hz, 2H), 7.91 (t, J = 5.8 Hz, 2H), 7.60–7.44 (m, 6H), 7.41–7.32 (m, 4H), 7.24–7.19 (m, 2H), 6.96 (p, J = 4.6, 4.0 Hz, 1H), 5.21 (td, J = 10.1, 8.8, 2.6 Hz, 1H), 4.74–4.62 (m, 1H), 3.55–3.43 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ (197.2, 197.0, d), 153.8, 147.2, 136.6, 136.0, 133.3, (132.3,132.3, d), (131.7, 131.7, d), (131.6, 131.5, d), 131.2, (128.9, 128.8, d), 128.5, 128.2, (127.9, 127.8, d), 122.6, (40.4, 39.7, d), 38.1; 31P NMR (162 MHz, Chloroform-d): δ 33.30; HRMS (ESI) m/z: [M + H]+ calcd for C26H22ClNO2P 446.1071; found, 446.1066; HPLC (AD-H, EtOH/n-heptane = 30/70, flow rate = 1.0 mL/min, l = 220 nm) tR = 12.2 min (major), 13.4 min (minor).
4.2.35. (S)-3-(4-Chloropyridin-2-yl)-3-(diphenylphosphoryl)-1-phenylpropan-1-one (4g)
White solid, 95% yield, 99% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.30 (d, J = 5.4 Hz, 1H), 7.91 (dd, J = 14.0, 7.2 Hz, 4H), 7.62 (dd, J = 11.6, 7.5 Hz, 2H), 7.56–7.47 (m, 4H), 7.39 (tt, J = 14.9, 7.2 Hz, 5H), 7.11–6.97 (m, 2H), 4.68 (t, J = 10.4 Hz, 1H), 4.45–4.34 (m, 1H), 3.45 (dd, J = 18.2, 10.3 Hz, 1H); 13C NMR (101 MHz, Chloroform-d): δ (196.8, 196.6, d), (157.4, 157.4, d), 149.7, 143.9, 136.1, 133.4, (132.3, 132.2, d), (131.9, 131.9, d), (131.3, 131.2, d), (129.0, 128.8, d), 128.5, (128.4, 128.3, d), 128.1, (125.1, 125.1, d), 122.2, (44.6, 43.9, d), 37.0; 31P NMR (162 MHz, Chloroform-d): δ 33.56; HRMS (ESI) m/z: [M + Na]+ calcd for C26H21ClNO2PNa 468.0891; found, 468.0894; HPLC (AD-H, i-PrOH/n-heptane = 20/80, flow rate = 1.0 mL/min, l = 220 nm) tR = 18.1 min (minor), 26.4 min (major).
4.2.36. (S)-3-(5-Chloropyridin-2-yl)-3-(diphenylphosphoryl)-1-phenylpropan-1-one (4h)
White solid, 99% yield, 98% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.35 (d, J = 2.5 Hz, 1H), 7.93–7.85 (m, 4H), 7.75–7.58 (m, 2H), 7.59–7.44 (m, 5H), 7.46–7.37 (m, 1H), 7.39–7.32 (m, 4H), 7.09 (dd, J = 8.4, 1.8 Hz, 1H), 4.71 (td, J = 10.6, 2.4 Hz, 1H), 4.41–4.28 (m, 1H), 3.47–3.35 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ 196.7, (153.9, 153.8, d), 147.9, 136.2, 135.8, 133.4, (132.2, 132.2, d), (131.9, 131.9, d), (131.3, 131.3, d), (131.3, 131.2, d), (129.0, 128.8, d), 128.5, (128.4, 128.3, d), 128.1, 125.3, (44.0, 43.4, d), 37.2; 31P NMR (162 MHz, Chloroform-d): δ 33.55; HRMS (ESI) m/z: [M + K]+ calcd for C26H21ClNO2PK 484.0630; found, 484.0636; HPLC (AS-H, i-PrOH/n-heptane = 15/85, flow rate = 1.0 mL/min, l = 220 nm) tR = 12.6 min (major), 18.1 min (minor).
4.2.37. (S)-3-(6-Chloropyridin-2-yl)-3-(diphenylphosphoryl)-1-phenylpropan-1-one (4i)
White solid, 96% yield, 95% ee; 1H NMR (400 MHz, Chloroform-d): δ 7.88 (d, J = 8.3 Hz, 4H), 7.67 (dd, J = 11.4, 7.7 Hz, 2H), 7.49 (dt, J = 13.7, 8.5 Hz, 5H), 7.38 (q, J = 7.0 Hz, 5H), 7.07 (dd, J = 44.1, 7.9 Hz, 2H), 4.72 (t, J = 11.0 Hz, 1H), 4.32–4.19 (m, 1H), 3.47 (dd, J = 18.1, 10.2 Hz, 1H); 13C NMR (101 MHz, Chloroform-d): δ (196.7, 196.6, d), (156.6, 156.6, d), 150.4, (138.6, 138.6, d), 136.3, 133.4, (132.2, 132.2, d), (132.0, 131.9, d), (131.5, 131.5, d), (131.4, 131.3, d), (128.9, 128.7, d), 128.5, (128.3, 128.2, d), 128.2, 122.9, 122.4, (44.8, 44.1, d), 37.0; 31P NMR (162 MHz, Chloroform-d): δ 33.59; HRMS (ESI) m/z: [M + K]+ calcd for C26H21ClNO2PK 484.0630; found, 484.0636; HPLC (OD-H, i-PrOH/n-heptane = 10/90, flow rate = 0.9 mL/min, l = 220 nm) tR = 17.3 min (major), 24.4 min (minor).
4.2.38. (S)-3-(Diphenylphosphoryl)-3-(6-fluoropyridin-2-yl)-1-phenylpropan-1-one (4j)
White solid, 99% yield, 93% ee; 1H NMR (400 MHz, Chloroform-d): δ 7.94–7.85 (m, 4H), 7.71–7.62 (m, 2H), 7.58–7.32 (m, 10H), 7.07 (dd, J = 7.4, 2.2 Hz, 1H), 6.63 (dt, J = 8.3, 2.3 Hz, 1H), 4.70 (td, J = 10.8, 2.5 Hz, 1H), 4.35–4.22 (m, 1H), 3.52–3.39 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ (196.7, 196.6, d), (163.8, 161.4, d), (154.8, 154.7, d), (141.0, 140.9, d), 136.2, 133.4, (132.2, 132.2, d), (131.9, 131.9, d), (131.4, 131.3, d), 131.3, (128.9, 128.8, d), 128.5, (128.4, 128.2, d), 128.1, 121.9, (107.7, 107.3, d), (44.3, 43.6, d), 37.0; 31P NMR (162 MHz, Chloroform-d): δ 33.49; 19F NMR (376 MHz, Chloroform-d): δ −66.98 (d, J = 2.0 Hz); HRMS (ESI) m/z: [M + Na]+ calcd for C26H21FNO2PNa 452.1186; found, 452.1190; HPLC (OD-H, i-PrOH/n-heptane = 10/90, flow rate = 0.9 mL/min, l = 220 nm) tR = 21.4 min (major), 30.9 min (minor).
4.2.39. (S)-3-(Diphenylphosphoryl)-3-(5-fluoropyridin-2-yl)-1-phenylpropan-1-one (4k)
Yellow solid, 92% yield, 96% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.26 (d, J = 2.7 Hz, 1H), 7.96–7.85 (m, 4H), 7.67–7.58 (m, 2H), 7.57–7.47 (m, 4H), 7.45–7.31 (m, 5H), 7.20–7.09 (m, 2H), 4.81–4.70 (m, 1H), 4.42–4.29 (m, 1H), 3.49–3.37 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ (196.9, 196.7, d), (159.5, 159.5, d), (157.0, 157.0, d), (151.5, 151.5, d), (137.4, 137.4, d), (137.1, 137.1, d), 136.2, 133.4, (132.1, 132.1, d), (131.8, 131.8, d), (131.3, 131.2, d), (128.9, 128.8, d), (128.5,128.3, d), (128.2, 128.1, d), 125.4, (122.9, 122.9, d), (122.8, 122.7, d), (43.8, 43.2, d), 37.3; 31P NMR (162 MHz, Chloroform-d): δ 33.44 (d, J = 4.2 Hz); 19F NMR (376 MHz, Chloroform-d): δ −129.47 (d, J = 4.2 Hz); HRMS (ESI) m/z: [M + K]+ calcd for C26H21FNO2PK 468.0926; found, 468.0924; HPLC (OD-H, i-PrOH/n-heptane = 10/90, flow rate = 1.0 mL/min, l = 254 nm) tR = 14.0 min (major), 21.1 min (minor).
4.2.40. (S)-3-(3-Bromopyridin-2-yl)-3-(diphenylphosphoryl)-1-phenylpropan-1-one (4L)
White solid, 93% yield, 95% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.52 (d, J = 4.5 Hz, 1H), 8.08–7.99 (m, 2H), 7.94 (d, J = 7.7 Hz, 2H), 7.57 (dq, J = 9.2, 6.7, 6.3 Hz, 4H), 7.52–7.33 (m, 6H), 7.22 (td, J = 7.8, 2.9 Hz, 2H), 6.94–6.86 (m, 1H), 5.27–5.18 (m, 1H), 4.75–4.62 (m, 1H), 3.53–3.42 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ (197.2, 197.1, d), (155.1, 155.0, d), 147.8, 140.0, 136.1, 133.3, (132.3, 132.3, d), (131.8, 131.7, d), (131.7, 131.6, d), (131.3, 131.2, d), (128.9, 128.8, d), (128.5, 128.2, d), (127.9, 127.8, d), (123.9, 123.8, d), 122.9, (42.5, 41.9, d), 38.4; 31P NMR (162 MHz, Chloroform-d): δ 33.48; HRMS (ESI) m/z: [M + H]+ calcd for C26H22BrNO2P 490.0566; found, 490.0557; HPLC (AD-H, i-PrOH/n-heptane = 20/80, flow rate = 1.0 mL/min, l = 220 nm) tR = 31.2 min (major), 61.0 min (minor).
4.2.41. (S)-4-(Diphenylphosphoryl)-4-(pyridin-2-yl)butan-2-one (4m)
Yellow oil, 90% yield, 98% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.41 (d, J = 4.9 Hz, 1H), 7.90–7.67 (m, 2H), 7.64–7.46 (m, 5H), 7.44–7.37 (m, 2H), 7.36–7.26 (m, 2H), 7.09 (d, J = 7.9 Hz, 1H), 7.06–6.98 (m, 1H), 4.53 (td, J = 10.9, 2.9 Hz, 1H), 3.76–3.63 (m, 1H), 3.06–2.93 (m, 1H), 2.04 (d, J = 1.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d): δ (155.4, 155.3, d), 148.9, 136.1, (132.1, 132.1, d), (131.7, 131.7, d), (131.4, 131.3, d), (131.3, 131.3, d), (128.8, 128.7, d), (128.2, 128.1, d), (124.8, 124.7, d), 121.9, (44.5, 43.8, d), 41.6, 30.2; 31P NMR (162 MHz, Chloroform-d): δ 33.60; HRMS (ESI) m/z: [M + H]+ calcd for C21H21NO2P 350.1304; found, 350.1306; HPLC (AD-H, i-PrOH/n-heptane = 7/93, flow rate = 1.0 mL/min, l = 220 nm) tR = 40.4 min (minor), 102.2 min (major).
4.2.42. (S)-1-Cyclopropyl-3-(diphenylphosphoryl)-3-(pyridin-2-yl)propan-1-one (4n)
Yellow solid, 89% yield, >99.5% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.41 (d, J = 4.9 Hz, 1H), 7.86 (dd, J = 11.0, 7.5 Hz, 2H), 7.75–7.55 (m, 2H), 7.56–7.45 (m, 3H), 7.44–7.37 (m, 2H), 7.31 (dt, J = 9.5, 4.7 Hz, 2H), 7.12 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 6.2 Hz, 1H), 4.55 (td, J = 10.5, 3.0 Hz, 1H), 3.85–3.72 (m, 1H), 3.21–3.09 (m, 1H), 1.84 (tt, J = 8.2, 4.6 Hz, 1H), 0.92–0.59 (m, 4H); 13C NMR (101 MHz, Chloroform-d): δ (207.5, 207.4, d), (155.6, 155.6, d), 148.9, 136.0, (132.0, 131.9, d), (131.6, 131.6, d), (131.4, 131.4, d), (131.3, 131.3, d), (128.7, 128.6, d), (128.2, 128.1, d), (124.7, 124.7, d), 121.8, (44.5, 43.9, d), 41.2, 20.9, (10.8, 10.7, d); 31P NMR (162 MHz, Chloroform-d): δ 33.49; HRMS (ESI) m/z: [M + H]+ calcd for C23H23NO2P 376.1461; found, 376.1462; HPLC (AS-H, i-PrOH/n-heptane = 10/90, flow rate = 1.0 mL/min, l = 220 nm) tR = 10.1 min (minor), 24.3 min (major).
4.2.43. (S)-3-(Diphenylphosphoryl)-1-phenyl-3-(quinolin-2-yl)propan-1-one (4o)
White solid, 92% yield, 98% ee; 1H NMR (400 MHz, Chloroform-d): δ 7.94–7.87 (m, 5H), 7.84 (d, J = 8.5 Hz, 1H), 7.74–7.68 (m, 2H), 7.65 (dd, J = 8.1, 1.4 Hz, 1H), 7.61–7.55 (m, 1H), 7.54–7.44 (m, 4H), 7.43–7.34 (m, 4H), 7.32–7.26 (m, 2H), 7.20 (dd, J = 8.5, 1.3 Hz, 1H), 4.93 (td, J = 11.0, 2.5 Hz, 1H), 4.66–4.53 (m, 1H), 3.62–3.48 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ (197.2, 197.0, d), 155.9, 147.5, 136.4, 135.8, 133.2, (132.1, 132.1, d), (131.8, 131.8, d), (131.7, 131.6, d), (131.4, 131.3, d), (129.2, 129.1, d), (128.8, 128.7, d), 128.5, 128.2, 127.3, 126.2, 122.7, (45.8, 45.2, d), 37.2; 31P NMR (162 MHz, Chloroform-d): δ 33.50; HRMS (ESI) m/z: [M + H]+ calcd for C30H25NO2P 462.1617; found, 462.1612; HPLC (AD-H, i-PrOH/n-heptane = 20/80, flow rate = 1.0 mL/min, l = 220 nm) tR = 30.6 min (minor), 46.0 min (major).
4.2.44. (S)-2-(1-(Diphenylphosphoryl)-3-oxo-3-phenylpropyl)pyridine 1-Oxide (5)
White solid, 72% yield, 86% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.23–7.97 (m, 4H), 7.87–7.76 (m, 4H), 7.72 (dd, J = 6.3, 3.9 Hz, 1H), 7.60–7.45 (m, 4H), 7.40–7.32 (m, 3H), 7.29 (d, J = 4.9 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 6.02–5.92 (m, 1H), 4.10–3.96 (m, 1H), 3.66–3.54 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ (195.5, 195.4, d), 148.3, 139.3, 135.9, 133.5, (132.5, 132.5, d), (132.1, 132.1, d), (131.3, 131.2, d), (130.7, 130.6, d), (129.1, 129.0, d), 128.6, 128.2, 128.1, 126.2, 125.4, 123.9, 37.8, (33.8, 33.2, d); 31P NMR (162 MHz, Chloroform-d): δ 36.59 (d, J = 10.5 Hz); HRMS (ESI) m/z: [M + H]+ calcd for C26H23NO3P 428.1410; found, 428.1417; HPLC (AS-H, EtOH /n-heptane = 10/90, flow rate = 1.0 mL/min, l = 220 nm) tR = 10.3 min (minor), 14.5 min (major).
4.2.45. (S)-3-(Diphenylphosphoryl)-3-(6-((R)-1-(diphenylphosphoryl)-3-oxo-3-phenylpropyl)pyridin-2-yl)-1-phenylpropan-1-one (7)
White solid, 72% yield, >99% ee, 87.5:12.5 er; 1H NMR (400 MHz, Chloroform-d): δ 7.87–7.73 (m, 8H), 7.70–7.62 (m, 1H), 7.53–7.25 (m, 16H), 7.21 (td, J = 7.4, 1.5 Hz, 2H), 7.15–7.06 (m, 4H), 6.93 (d, J = 1.7 Hz, 1H), 6.91 (d, J = 1.7 Hz, 1H), 4.62 (td, J = 9.7, 2.3 Hz, 2H), 4.34–4.22 (m, 2H), 3.50–3.32 (m, 2H); 13C NMR (101 MHz, Chloroform-d): δ (196.7, 196.6, d), 155.8, 136.2, 133.2, (131.9, 131.9, d), (131.3, 131.2, d), (131.1, 131.0, d), (128.7, 128.6, d), (128.5, 128.3, d), 128.1, 123.3, (44.3, 43.7, d), 37.9; 31P NMR (162 MHz, Chloroform-d): δ 33.68; HRMS (ESI) m/z: [M + Na]+ calcd for C47H39NO4P2Na 766.2247; found, 766.2244; SFC (0.5%NH3(7 M in MeOH), flow rate = 3.0 mL/min, l = 214 nm) tR = 3.2 min (major), 6.5 min (minor).
4.2.46. (S)-3-(Diphenylphosphoryl)-1,3-diphenylpropan-1-one(10)
White solid, 92% yield, 98% ee; 1H NMR (400 MHz, Chloroform-d): δ 7.96–7.87 (m, 2H), 7.81–7.74 (m, 2H), 7.69–7.59 (m, 1H), 7.56–7.34 (m, 7H), 7.35–7.23 (m, 4H), 7.18–6.98 (m, 4H), 4.45–4.35 (m, 1H), 4.03–3.90 (m, 1H), 3.37–3.25 (m, 1H);13C NMR (101 MHz, Chloroform-d): δ 196.7, 136.3, 133.4, 132.0, (131.3, 131.2, d), (131.0, 130.9, d), (130.8, 130.6, d), (129.8, 129.8, d), 129.0, (128.9, 128.8, d), 128.5, 128.3, 128.1, 128.0, 38.9;31P NMR (162 MHz, Chloroform-d): δ 34.51.
4.2.47. (S)-3-(Diphenylphosphoryl)-1-phenyl-3-(pyridin-3-yl)propan-1-one(13)
Yellow solid, 90% yield, 98% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.48–8.21 (m, 2H), 8.02–7.67 (m, 5H), 7.51–7.35 (m, 6H), 7.33–7.16 (m, 5H), 7.04 (dd, J = 8.0, 4.7 Hz, 1H), 4.46–4.36 (m, 1H), 3.97–3.84 (m, 1H), 3.39–3.27 (m, 1H);13C NMR (101 MHz, Chloroform-d): δ (196.1, 196.0, d), 151.2, 148.3, (136.7, 136.6, d), 136.0, 133.6, (132.3, 132.3, d), (131.8, 131.8, d), (131.2, 131.1, d), (130.7, 130.7, d), (129.1, 129.0, d), 128.6, (128.5, 128.3, d), 128.0, 123.2, (38.9, 38.6, d), 38.2; 31P NMR (162 MHz, Chloroform-d): δ 33.89; HPLC (AD-H, i-PrOH/n-heptane = 10/90, flow rate = 1.0 mL/min, l = 220 nm) tR = 18.3 min (minor), 27.1 min (major).
4.2.48. (S)-3-(Diphenylphosphoryl)-1-phenyl-3-(pyridin-4-yl)propan-1-one(16)
Yellow solid, 91% yield, 98% ee; 1H NMR (400 MHz, Chloroform-d): δ 8.29 (d, J = 5.0 Hz, 2H), 7.99–7.73 (m, 4H), 7.52–7.26 (m, 9H), 7.26–7.16 (m, 4H), 4.41–4.32 (m, 1H), 4.01–3.88 (m, 1H), 3.38–3.26 (m, 1H); 13C NMR (101 MHz, Chloroform-d): δ (195.0, 194.8, d), 148.5, 144.4, 134.9, 132.6, (131.3, 131.3, d), (130.8, 130.8, d), (130.1, 130.0, d), (129.7, 129.7, d), (128.1, 128.0, d), 127.6, (127.4, 127.3, d), 127.0, 123.8, 52.4, (40.1, 39.5, d), 37.3; 31P NMR (162 MHz, Chloroform-d): δ 33.33; HPLC (AD-H, i-PrOH/n-heptane = 10/90, flow rate = 1 mL/min, l = 220 nm) tR = 18.8 min (minor), 21.3 min (major).
Supplementary Material
Acknowledgments
This work was supported by the National Natural Science Foundation of China (22361053), Yunnan Fundamental Research Projects (202301AU070125), and the Scientific Research of the Department of Education for Yunnan Province (2025Y0679).
The data underlying this study are available in the published article and its Supporting Information.
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c11261.
Experimental procedures, analytical data for all new compounds, NMR, HPLC spectra, and the data of HRMS (PDF)
The authors declare no competing financial interest.
References
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Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.