Catalytic Asymmetric Allylic Alkylation with Arylfluoroacetonitriles

Graphical Abstract

A palladium(phosphinoxazoline) catalyzed method for asymmetric allylic alkylation of α-aryl-α-fluoroacetonitriles is introduced. This reaction achieves C-C bond formation and incorporation of two adjacent chirality centers with moderate to good yields, high enantioselectivities and up to 15:1 dr.

Asymmetric synthesis of multifunctional fluorinated compounds plays a pivotal role in the chemical and health sciences by providing access to versatile building blocks that can be used for the development of pharmaceuticals, agrochemicals or materials. Despite significant progress, the catalytic construction of a quaternary carbon-fluoride unit has remained particularly challenging to date, in particular if the goal is to implement more than one stereocenter at once.¹ Several groups have demonstrated that this task can be achieved effectively when fluorinated nucleophiles with a neighboring carbonyl, imine or sulfonyl group are used.² By contrast, few reports on catalytic asymmetric aldol-type reactions with α-fluoro-α-arylacetonitriles devoid of an activating carbonyl group have appeared, Scheme 1.³ The scarcity of enantioselective carbon-carbon bond formation with arylfluoroacetonitriles can probably be attributed to the relatively low C-H acidity which hinders generation of a nucleophilic intermediate under mild reaction conditions, the general difficulty to control the stereofacial orientation of α-fluoronitrile carbanions, and complications that arise from side reactions including decomposition or HF elimination of fluoroacetonitriles in the presence of base.⁴

Scheme 1.

Asymmetric catalysis with α-fluoro-α-arylacetonitriles.

To expand the usefulness of α-aryl-α-fluoroacetonitriles beyond copper catalyzed asymmetric aldol-type reactions, we decided to investigate the possibility of asymmetric allylic alkylations in the presence of a palladium catalyst which to the best of our knowledge has not been reported. We found out that the formation of allylic arylfluoronitriles is a daunting task that requires careful optimization of reaction conditions to mitigate the high propensity for HF elimination toward a highly conjugated by-product. Through extensive screening efforts, however, we have been able to develop a palladium catalyzed method that addresses the aforementioned challenges with arylfluoroacetonitriles and uses readily available allylic carbonates to generate two adjacent chirality centers including a tetrasubstituted carbon-fluoride moiety with high enantioselectivity and good diastereoselectivity. We believe that this work will direct increasing attention to the currently underdeveloped utility of arylfluoroacetonitriles in asymmetric synthesis.

We initiated our search for a method that achieves catalytic asymmetric allylic alkylation (AAA) with α-aryl-α-fluoroacetonitriles using 1 and 1,3-diphenylallyl carbonate 2 in the presence of catalytic amounts of [η³-C₃H₅ClPd]₂, various ligands, and DBU at 25 °C in acetonitrile as our model reaction. At this early stage, a variety of chiral ligands were screened (Table 1, entries 1–15 and SI). We discovered that the phosphinoxazoline ligands L9 – L12 generally give higher conversion to the desired product with enantioselectivities ranging from 83–99% while competing elimination to 4 could be controlled. We were pleased to find that the reaction proceeded smoothly affording the desired product 3 with 96% conversion, 98% enantioselectivity, albeit in low diastereomeric ratio of 1.8:1 using 5 mol% of [η³-C₃H₅ClPd]_2, 12 mol% of L9 and 20 mol% of DBU as base (entry 9). Subsequently, we examined several palladium sources (entries 16, 17 and SI) and observed that the diastereomeric ratio did not increase whereas the conversion of 1 to the product varied considerably. We then tested the reaction in chloroform, THF, diethyl ether, 1,4-dioxane, toluene, ethyl acetate, acetonitrile, and DMF. The reaction was very sluggish (0 to 13% yield) in ethyl acetate, diethyl ether, 1,4-dioxane, THF and toluene (Table 1, entry 19 and SI). The best results were obtained in acetonitrile and DMF which allowed 96% and 84% formation of 3, respectively. Screening of organic and inorganic bases did not improve the diastereoselectivity (Table 1, entries 21–23 and SI). We therefore carried out the reaction at lower temperatures and found that 3 is produced in 77% yield, >99% ee and 4:1 dr at −20 °C (Table 1, entries 24–26). Unfortunately, this requires longer reaction times and yields are somewhat compromised by competing HF elimination.

Table 1.

Optimization of reaction conditions.

entry	conditions	conversion of 1 (%) a	3:4 a	dr b	% ee (major, minor)c
1	L1	25	63:37	1:1.1e	n.d.
2	L2	74	73:27	1:1	82, 88
3	L3	83	>99:1	1:1	83, 85
4	L4	78	88:12	1:1	80, 76 d
5	L5	81	82:18	1:1	91, 85
6	L6	85	>99:1	1.2:1	92, 91
7	L7	91	71:29	1.5:1	82, 83
8	L8	40	98:2	1.6:1	89, 74
9	L9	96	>99:1	1.8:1	98, 93
10	L10	68	>99:1	1.4:1	98, 83
11	L11	83	>99:1	1.7:1	>99, 95
12	L12	77	>99:1	1.6:1	95, 89
13	L13	82	96:4	1.8:1	65, 44
14	L14	76	96:4	1.4:1	2, 26
15	L15	94	>99:1	1.1:1	93, 92
16	L9, PdCl2(ACN)2	21	>99:1	1.8:1	90, 97
17	L9, Pd(dba)2	89	>99:1	1.8:1	>99, 99
18	L9, CH2Cl2	75	>99:1	1.5:1	87, 84
19	L9, THF	6	>99:1	1.4:1	n.d.
20	L9, DMF	84	>99:1	1.6:1	92, 88
21	L9, MTBD	87	98:2	1.4:1	>99, 95
22	L9, BTMG	72	94:6	1.5:1	>99, 95
23	L9, DBN	83	>99:1	1.6:1	>99, 94
24e	L9, 0 °C, 10 h	61	73:27	2.4:1	>99, 98
25e	L9, −20 oC, 10 h	38	89:11	3.3:1	>99, 98
26e	L9, −20 °C, 50 h	100	77:23	4:1	>99, 98

Conditions: 1(0.1 mmol), 2(0.135 mmol), allylpalladium chloride dimer (0.005 mmol), L9(0.012 mmol) and DBU (0.02 mmol) in 1.0 mL ACN at 25 ^oC for 18 hours.

^[a]1H NMR analysis of the crude reaction mixture.

^[b]19F NMR analysis of crude products.

^[c]Determined by chiral HPLC on a Chiralcel OJ column.

^[d]Reversed enantioselectivity.

^[e]Reversed dr. [e] 2.0 equivalents of DBU.

After establishing an optimized reaction protocol, we continued to determine the reaction scope of the catalytic asymmetric allylic alkylation. As shown in Scheme 2, the reaction is amenable to a series of substituted α-fluoroacetonitriles carrying ester, halogen, nitrile, and alkyl groups in ortho-, meta- and para-positions. The desired products were obtained in 62 to 78% yields, with at least 98% enantioselectivity and dr values up to 12.3:1. We found that all reactions proceed with excellent enantioselectivity while the diastereomeric ratios vary substantially without showing a clear trend. For example, (2R,3R,E)-2-(3-bromophenyl)-2-fluoro-3,5-diphenylpent-4-enenitrile, 3da, was isolated in 64% yield, >99% ee, and 12.3:1 dr whereas 3ga was obtained in 78% yield, >99% ee and 2.5:1 dr. Reaction monitoring revealed that the HF elimination is diastereoselective as the product dr generally increases over time. When we subjected 3fa (3.6:1 dr) to complete elimination the corresponding (E,E)- and (Z,E)-dienes were obtained in a 3.1:1 ratio which is in agreement with a dominant E2 mechanism while a stepwise E1CB sequence cannot be ruled out (see SI). It is noteworthy that the formation of 3ga was sluggish at −20 °C and had to be carried out at room temperature,⁵ while no reaction was observed with tert-butyl pent-3-en-2-yl carbonate even at room temperature, suggesting that 1,3-dialkylallyl carbonates devoid of an activating aryl group cannot be used. Single crystals of 3ba and 3fa were grown by slow evaporation of a dichloromethane solution and the absolute configuration was determined by X-ray analysis as R at both chirality centers.⁶

Scheme 2.

Substrate scope of the AAA reaction with fluoronitriles.

Reaction conditions: 1 (0.185 mmol), 2a (0.22 mmol), allylpalladium chloride dimer (0.009 mmol), L9 (0.022 mmol) and DBU (0.37 mmol) dissolved in 3.0 mL ACN at −20 °C. The absolute configuration of 3ba and 3fa was determined by X-ray analysis. The stereochemistry of the other products was assigned accordingly. [a] Reaction was performed with (E)-1,3-diphenylallyl acetate instead of (E)-1,3-diphenylallyl carbonate. [b] Reaction was performed at room temperature.

We then varied the substitution pattern of the 1,3-diphenylallyl carbonate moiety which revealed that 4a-c carrying either methoxy or halogen substituents in ortho or para positions reacted smoothly toward the corresponding AAA products. Compounds 5aa-5ac were formed in 60–67% yield, more than 99% ee and diastereomeric ratios ranging from 3.3:1 to >15:1 (Scheme 3). To underscore the synthetic utility of this protocol, three reactions were carried out with 0.5 to 1.0 gram of 1a, 1d and 1f, respectively. Gratifyingly, 3aa, 3da and 3fa were produced with very similar yields and stereoselectivities compared to the small scale reactions discussed above.

Scheme 3.

Variation of the allylic carbonates and reaction upscaling.

See SI for details.

We were particularly interested in testing whether the AAA products are sufficiently thermally stable to be used in Stille cross-coupling reactions which are widely used in drug development programs (Scheme 4). This was evaluated using allyl- or phenyltributylstannane and tetrakis(triphenylphosphine)palladium(0) as catalyst in THF at 65 °C following a modified literature protocol.^7,8 The coupling products 6da and 7da were obtained in 92% and 89% yield, respectively, without significant HF elimination.

Scheme 4.

Stille cross-coupling reactions with 3da.

See SI for details.

In summary, we have introduced a protocol for palladium catalyzed asymmetric allylic alkylation of α-aryl-α-fluoroacetonitriles. This reaction generates two contiguous chirality centers and affords multifunctional organofluorines in good yields, with excellent enantioselectivity and up to 15:1 diastereoselectivity. The procedure is scalable, and the AAA products can be further derivatized via Stille cross-coupling without significant HF elimination. This study underscores the potential of asymmetric catalysis with α-fluoronitriles which are likely to find important synthetic applications in the coming years.

Experimental Section

General Methods.

All commercially available reagents and solvents were used without further purification unless noted otherwise. Solvents were stored over 4Å molecular sieves prior to use. Reaction products were purified by column chromatography on silica gel (particle size 32–63 μm) as described below. NMR spectra were obtained at 400 MHz (¹H NMR), 100 MHz (¹³C NMR), and 376 MHz (¹⁹F NMR) in CDCl₃. Chemical shifts are reported in ppm relative to the chloroform signal. The α-fluoro-α-arylacetonitriles were prepared in two steps from the corresponding aldehyde. First, a cyanohydrin was formed via trimethylsilyl cyanide addition followed by deoxyfluorination using literature procedures.⁹ All AAA products were prepared in racemic form to develop a chiral HPLC method for ee analysis. The isolated asymmetric reaction products were then analyzed accordingly. The ¹H and ¹³C NMR chemical shifts are reported for the major diastereoisomer. HRMS data were obtained using electron spray ionization time-of-flight (ESI-TOF) spectrometry.

General Procedure for Allylic Alkylation of 2-Fluoro-2-Arylacetonitriles.

A mixture of (S)-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline (12 mol%) and [η³-C₃H₅ClPd]₂ (5 mol%) in dry ACN (2.0 mL) was stirred at room temperature under N₂ atmosphere for 30 minutes. The diphenylallyl carbonate (1.35 equiv.) was added followed by the 2-aryl-2-fluoroacetonitrile (0.185 mmol). The reaction mixture was cooled to −20 °C and a solution of ice cold DBU (2.0 equiv.) in 1.0 mL ACN was added. The resulting mixture was stirred at −20 °C and the reaction was monitored by NMR spectroscopy. Upon complete consumption of the fluoronitrile, the reaction was quenched with ammonium chloride solution followed by extraction with dichloromethane. The residue was purified by flash chromatography on silica gel as described below.

(2R,3R,E)-2-Fluoro-2,3,5-triphenylpent-4-enenitrile 3aa.

Compound 3aa was obtained as a white solid in 77% yield (46.6 mg, 0.14 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 2-fluoro-2-phenylacetonitrile (25 mg, 0.185 mmol) after 50 hours at −20 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : dichloromethane (96:4) as mobile phase. The dr was determined as 4:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 17.7 min, t_R (major) = 26.7 min.¹H NMR (Chloroform-d) δ 7.37 – 7.24 (m, 13H), 7.23 – 7.19 (m, 2H), 6.63 – 6.45 (m, 2H), 4.08 (m, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 136.3, 135.8, 135.7 (d, J = 1.1 Hz), 134.7 (d, J = 23.5 Hz), 129.7 (d, J = 1.5 Hz), 129.3 (d, J = 1.2 Hz), 128.6, 128.5, 128.4, 128.1, 128.0, 126.6, 125.3 (d, J = 6.3 Hz), 123.9 (d, J = 4.3 Hz), 116.6 (d, J = 32.6 Hz), 94.1 (d, J = 191.7 Hz), 59.7 (d, J = 24.8 Hz). ¹⁹F NMR (Chloroform-d) δ −148.70 (d, J = 16.6 Hz, minor), −152.76 (d, J = 18.8 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₃H₁₈FN, 350.1315; found, 350.1329.

Methyl 4-((1R,2R,E)-1-cyano-1-fluoro-2,4-diphenylbut-3-en-1-yl)benzoate 3ba.

Compound 3ba was obtained as an off-white solid in 71% yield (50.6 mg, 0.13 mmol) from (E)-1,3-diphenylallyl acetate (63.0 mg, 0.25 mmol) and methyl 4-(cyanofluoromethyl)benzoate (35.7 mg, 0.185 mmol) after 2.5 hours at 25 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : ethyl acetate (98:2) as mobile phase. The dr was determined as 3.2:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralpak IA, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 8.4 min, t_R (major) = 9.6 min. ¹H NMR (Chloroform-d) δ 7.99 (d, J = 8.2 Hz, 2H), 7.40 – 7.21 (m, 10H), 7.16 (m, 2H), 6.60–6.48 (m, 2H), 4.07 (m, 1H), 3.91 (d, J = 1.8 Hz, 3H). ¹³C {¹H} NMR (Chloroform-d) δ 163.5, 136.7 (d, J = 23.1 Hz), 133.6, 133.5, 132.6, 128.8 (d, J = 1.3 Hz), 127.0 (d, J = 2.0 Hz), 126.8 (d, J = 1.5 Hz), 126.7, 126.0, 125.6, 124.0, 122.8 (d, J = 6.5 Hz), 120.8 (d, J = 4.3 Hz), 113.8 (d, J = 32.9 Hz), 91.3 (d, J = 194.1 Hz), 57.1 (d, J = 24.1 Hz), 49.7. ¹⁹F NMR (Chloroform-d) δ −149.72 (d, J = 17.1 Hz, minor), −155.22 (d, J = 20.0 Hz, major). HRMS (ESI) m/z: [M+H]+ calcd for C₂₅H₂₀FNO₂, 386.1551; found, 386.1552.

3-((1R,2R,E)-1-Cyano-1-fluoro-2,4-diphenylbut-3-en-1-yl)benzonitrile 3ca.

Compound 3ca was obtained as a pale-yellow viscous oil in 67% yield (43.7 mg, 0.12 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 3-(cyanofluoromethyl)benzonitrile (29.7 mg, 0.185 mmol) after 18 hours at −20 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : dichloromethane (70:30) as mobile phase. The dr was determined as 10.7:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralpak IA, hexanes/EtOH, 90:10, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 11.4 min, t_R (major) = 9.5 min. ¹H NMR (Chloroform-d) δ 7.64 (m, 1H), 7.57 – 7.51 (m, 2H), 7.45 (m, 1H), 7.38 – 7.23 (m, 8H), 7.14 (m, 2H), 6.60 – 6.50 (m, 2H), 4.02 (ddd, J = 21.1, 5.2, 2.9 Hz, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 136.6 (d, J = 24.3 Hz), 136.5, 135.9, 134.7, 133.2, 129.6, 129.3 (d, J = 1.5 Hz), 129.3, 128.9, 128.6, 128.4, 126.6, 122.8 (d, J = 4.4 Hz), 117.6, 116.0 (d, J = 32.7 Hz), 112.9, 93.2 (d, J = 193.8 Hz), 59.7 (d, J = 23.8 Hz). ¹⁹F NMR (Chloroform-d) δ −147.9 (d, J = 16.3 Hz, minor), −152.9 (d, J = 19.4 Hz, major). HRMS (ESI) m/z: [M+H]+ calcd for C₂₄H₁₇FN₂, 353.1449; found, 353.1450.

(2R,3R,E)-2-(3-Bromophenyl)-2-fluoro-3,5-diphenylpent-4-enenitrile 3da.

Compound 3da was obtained as a white solid in 64% yield (48.1 mg, 0.12 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 2-(3-bromophenyl)-2-fluoroacetonitrile (39.6 mg, 0.185 mmol) after 30 hours at −20 °C by following the general procedure described above. The product was obtained by flash chromatography using hexanes : dichloromethane (93:7) as the mobile phase. The dr was determined as 12.3:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99% t_R (minor) = 5.6 min, t_R (major) = 14.1 min. ¹H NMR (Chloroform-d) δ 7.52 – 7.42 (m, 2H), 7.40 – 7.32 (m, 3H), 7.32 – 7.22 (m, 6H), 7.22 – 7.13 (m, 3H), 6.59 – 6.46 (m, 2H), 4.03 (m, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 136.9 (d, J = 23.4 Hz), 136.1, 135.2, 132.8 (d, J = 1.3 Hz), 129.8, 129.4 (d, J = 1.4 Hz), 128.6, 128.4 (d, J = 6.9 Hz), 128.3, 128.2, 126.6, 124.1 (d, J = 6.1 Hz), 123.4 (d, J = 4.3 Hz), 122.5, 116.3 (d, J = 32.7 Hz), 93.3 (d, J = 193.0 Hz), 59.7 (d, J = 24.2 Hz). ¹⁹F NMR (Chloroform-d) δ −149.3 (d, J = 16.3 Hz, minor), −153.9 (d, J = 19.4 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₃H₁₇BrFN, 430.0403; found, 430.0408.

(2R,3R,E)-2-(4-Bromophenyl)-2-fluoro-3,5-diphenylpent-4-enenitrile 3ea.

Compound 3ea was obtained as a white solid in 62% yield (46.6 mg, 0.11 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 2-(4-bromophenyl)-2-fluoroacetonitrile (39.6 mg, 0.185 mmol) after 30 hours at −20 °C by following the general procedure described above. The product was obtained by flash chromatography using hexanes : dichloromethane (93:7) as the mobile phase. The dr was determined as 9.1:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99% t_R (minor) = 15.0 min, t_R (major) = 31.4 min. ¹H NMR (Chloroform-d) δ 7.49 – 7.44 (m, 2H), 7.36–7.22 (m, 8H), 7.19 – 7.11 (m, 4H), 6.53–6.50 (m, 2H), 4.03 (ddd, J = 19.4, 8.3, 4.1 Hz, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 136.2, 135.2 (d, J = 1.2 Hz), 133.8 (d, J = 23.5 Hz), 131.5, 129.4 (d, J = 1.4 Hz), 129.3, 128.6, 128.5, 128.4, 128.3, 128.2, 127.0 (d, J = 6.3 Hz), 126.6, 126.5, 116.4 (d, J = 32.6 Hz), 93.6 (d, J = 192.3 Hz), 59.5 (d, J = 24.5 Hz). ¹⁹F NMR (Chloroform-d) δ −147.9 (d, J = 16.3 Hz, minor diastereomer), −152.9 (d, J = 19.4 Hz, major diastereomer). HRMS (ESI) m/z: [M+H]+ calcd for C₂₃H₁₇BrFN, 406.0601; found, 406.0593.

(2R,3R,E)-2-(4-Chlorophenyl)-2-fluoro-3,5-diphenylpent-4-enenitrile 3fa.

Compound 3fa was obtained as a pale yellow solid in 64% yield (42.8 mg, 0.12 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 2-(4-chlorophenyl)-2-fluoroacetonitrile (31.4 mg, 0.185 mmol) after 27.5 hours at −20 °C by following the general procedure described above. The product was obtained by flash chromatography using hexanes : dichloromethane (93:7) as the mobile phase. The dr was determined as 10.6:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99% t_R (minor) = 11.6 min, t_R (major) = 24.1 min. ¹H NMR (Chloroform-d) δ 7.37 – 7.21 (m, 12H), 7.20 – 7.17 (m, 2H), 6.58 – 6.46 (m, 2H), 4.03 (ddd, J = 19.4, 7.9, 4.1 Hz 1H). ¹³C {¹H} NMR (Chloroform-d) δ 136.2, 136.1, 135.9 (d, J = 1.7 Hz), 135.2, 133.3 (d, J = 23.5 Hz), 129.4 (d, J = 1.3 Hz), 128.6, 128.5, 128.2, 126.8 (d, J = 6.3 Hz), 126.6, 123.5 (d, J = 4.2 Hz), 116.5 (d, J = 32.6 Hz), 93.6 (d, J = 192.2 Hz), 59.6 (d, J = 24.5 Hz). ¹⁹F NMR (Chloroform-d) δ −147.9 (d, J = 16.3 Hz, minor), −152.9 (d, J = 19.4 Hz, major). HRMS (ESI) m/z: [M+H]+ calcd for C₂₃H₁₇ClFN, 362.1106; found, 362.1108.

(2R,3R,E)-2-(2-Fluorophenyl)-2-fluoro-3,5-diphenylpent-4-enenitrile 3ga.

Compound 3ga was obtained as a white solid in 78% yield (49.8 mg, 0.14 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 2-fluoro-2-(2-fluorophenyl)acetonitrile (28.3 mg, 0.185 mmol) after 2.5 hours at 25 °C by following the general procedure described above. The product was obtained by flash chromatography using hexanes : dichloromethane (93:7) as the mobile phase. The dr was determined as 2.6:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99% t_R (minor) = 23.9 min, t_R (major) = 39.5 min. ¹H NMR (Chloroform-d) δ 7.43 – 7.21 (m, 10H), 7.19 – 7.07 (m, 3H), 7.00 (m, 1H), 6.76 – 6.35 (m, 2H), 4.43 (m, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 158.2 (dd, J = 248.8, 5.0 Hz), 136.3, 135.8 (d, J = 20.2 Hz), 131.5 (d, J = 8.5 Hz), 129.1 (d, J = 1.7 Hz), 128.6, 128.4 , 128.3 , 128.1 , 127.9 , 126.9 (dd, J = 11.1, 2.2 Hz), 126.7, 124.2 (dd, J = 3.6, 1.6 Hz), 123.9 (d, J = 5.2 Hz), 122.6, 116.2 (dd, J = 21.2, 1.4 Hz), 115.6 (d, J = 33.2 Hz), 91.2 (dd, J = 191.7, 3.2 Hz), 57.0 (dd, J = 22.5, 3.2 Hz).¹⁹F NMR (Chloroform-d) δ −112.1 (m, minor), −112.2 (m, major), −156.2 (d, J = 15.4 Hz, minor), −161.8 (d, J = 26.4 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₃H₁₇F₂N, 368.1221; found, 368.1224.

(2R,3R,E)-2-(3-Chlorophenyl)-2-fluoro-3,5-diphenylpent-4-enenitrile 3ha.

Compound 3ha was obtained as a white solid in 71% yield (47.0 mg, 0.13 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 2-(3-chlorophenyl)-2-fluoroacetonitrile (31.4 mg, 0.185 mmol) after 33 hours at −15 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : dichloromethane (97:3) as mobile phase. The dr was determined as 2.7:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 34 min, t_R (major) = 40 min. ¹H NMR (Chloroform-d) δ 7.34 (m, 4H), 7.28 (m, 7H), 7.24 – 7.09 (m, 3H), 6.53 (m, 2H), 4.03 (m, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 136.7 (d, J = 23.4 Hz), 136.2, 136.1, 135.2, 134.6, 129.9 (d, J = 1.3 Hz), 129.6, 129.4 (d, J = 1.4 Hz), 126.6, 125.5 (d, J = 7.0 Hz), 123.6 (d, J = 6.1 Hz), 123.4, 123.3, 116.5 (d, J = 33.3 Hz), 94.2 (d, J = 192.7 Hz), 59.6 (d, J = 24.3 Hz). ¹⁹F NMR (Chloroform-d) δ −149.35 (d, J = 17.2 Hz, minor), −154.08 (d, J = 19.6 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₃H₁₇ClFN, 384.0930, found, 384.0926.

(2R,3R,E)-2-Fluoro-3,5-diphenyl-2-(4-tolyl)pent-4-enenitrile 3ia.

Compound 3ia was obtained as a white solid in 62% yield (39.2 mg, 0.11 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 2-fluoro-2-(4-tolyl)acetonitrile (27.6 mg, 0.185 mmol) after 50 hours at −20 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : dichloromethane (95:5) as mobile phase. The dr was determined as 3.4:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 90:10, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 17.8 min, t_R (major) = 42.5 min. ¹H NMR (Chloroform-d) δ 7.37 – 7.22 (m, 11H), 7.18–7.11 (m, 3H), 6.61 – 6.44 (m, 2H), 4.08 (m, 1H), 2.34 (s, 3H). ¹³C {¹H} NMR (Chloroform-d) δ = 139.8 (d, J=1.6 Hz), 136.4, 135.9 (d, J=1.2 Hz), 131.7 (d, J=23.3 Hz), 129.5 (d, J = 1.3 Hz), 129.0, 128.6, 128.4, 128.0 (d, J=3.4 Hz), 126.6, 125.4, 125.3, 124.0 (d, J = 4.3 Hz), 116.9 (d, J = 32.5 Hz), 95.4 (d, J = 190.9 Hz), 59.6 (d, J = 25.2 Hz), 21.2. ¹⁹F NMR (Chloroform-d) δ −147.30 (d, J = 16.2 Hz, minor), −150.59 (d, J = 17.9 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₄H₂₀FN, 364.1472; found, 342.1491.

(2R,3R,E)-2-(4-(tert-Butyl)phenyl)-2-fluoro-3,5-diphenylpent-4-enenitrile 3ja.

Compound 3ja was obtained as a white solid in 65% yield (46.1 mg, 0.12 mmol) from (E)-1,3-diphenylallyl ethyl carbonate (70.3 mg, 0.25 mmol) and 2-(4-(tert-butyl)phenyl)-2-fluoroacetonitrile (35.4 mg, 0.185 mmol) after 50 hours at −20 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : dichloromethane (99:1) as mobile phase. The dr was determined as 3.1:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 9.9 min, t_R (major) = 16.6 min. ¹H NMR (Chloroform-d) δ 7.39 – 7.15 (m, 14H), 6.56 – 6.42 (m, 2H), 4.08 (m, 1H), 1.29 (s, 9H). ¹³C {¹H} NMR (Chloroform-d) δ 153.0, 136.5, 135.7, 131.7 (d, J = 22.7 Hz), 129.5 (d, J = 1.3 Hz), 128.4, 128.0 (d, J = 1.6 Hz), 126.5, 125.3, 125.2, 125.1 (d, J = 6.1 Hz), 124.0 (d, J = 4.5 Hz), 116.8 (d, J = 32.6 Hz), 94.0 (d, J = 190.8 Hz), 59.5 (d, J = 25.2 Hz), 34.7, 31.2. ¹⁹F NMR (Chloroform-d) δ −147.98 (d, J = 16.6 Hz, minor), −149.98 (d, J = 17.1 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₇H₂₆FN, 406.1941; found, 406.1958.

(2R,3R,E)- 3,5-Bis(2-fluorophenyl)-2-fluoro-2-phenylpent-4-enenitrile 5aa.

Compound 5aa was obtained as a white solid in 67% yield (45.0 mg, 0.14 mmol) from ethyl (E)-2,4-bis(2-fluorophenyl)but-3-enoate (75.5 mg, 0.25 mmol) and 2-fluoro-2-phenylacetonitrile (25 mg, 0.185 mmol) after 50 hours at 25 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : dichloromethane (99:1) as mobile phase. The dr was determined as 3.3:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 99.5:0.5, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 11.6 min, t_R (major) = 24.0 min. ¹H NMR (Chloroform-d) δ 7.53 – 7.37 (m, 3H), 7.37 – 7.30 (m, 4H), 7.29 – 7.17 (m, 2H), 7.17 – 7.04 (m, 2H), 7.04 – 6.90 (m, 2H), 6.68 – 6.57 (m, 2H), 4.59 (m, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 161.6 (d, J = 23.3 Hz), 159.2 (d, J = 33.5 Hz), 134.5 (d, J = 23.3 Hz), 129.9 (m), 129.7 (d, J = 8.6 Hz), 129.5 (d, J = 8.5 Hz), 129.1 (d, J = 3.1 Hz), 128.4 , 127.8 (d, J = 3.5 Hz), 125.5 (m), 125.2 (d, J = 6.3 Hz), 124.3 (d, J = 3.6 Hz), 124.1 (dd, J = 3.6, 1.7 Hz), 123.9 (d, J = 12.3 Hz), 122.9 (d, J = 14.0 Hz), 116.5 (d, J = 32.8 Hz), 115.8 (d, J = 22.1 Hz), 115.5 (d, J = 22.8 Hz), 93.8 (d, J = 192.6 Hz), 51.3 (dd, J = 24.8, 2.9 Hz). ¹⁹F NMR (Chloroform-d) δ −116.61 (m, 1 F, minor), −116.93 (m, 1F, major), −117.37 (m, major), −117.52 (m, minor), −150.35 (d, J = 18.4 Hz, minor), −154.43 (d, J = 19.6 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₃H₁₆F₃N, 386.1127; found, 386.1126.

(2R,3R,E)- 3,5-Bis(4-bromophenyl)-2-fluoro-2-phenylpent-4-enenitrile 5ab.

Compound 5ab was obtained as a white solid in 60% yield (27.3 mg, 0.06 mmol) from ethyl (E)-2,4-bis(4-bromophenyl)but-3-enoate (53.5 mg, 0.125 mmol) and 2-fluoro-2-phenylacetonitrile (12.5 mg, 0.0925 mmol) after 44 hours at −20 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : dichloromethane (98:2) as mobile phase. The dr was determined as >15:1 by ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralcel OJ, hexanes/EtOH, 98.5:2, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 43 min, t_R (major) = 38.0 min. ¹H NMR (Chloroform-d) δ 7.45 – 7.37 (m, 4H), 7.37 – 7.31 (m, 3H), 7.31 – 7.26 (m, 2H), 7.21 – 7.16 (m, 2H), 7.07 – 7.00 (m, 2H), 6.52 – 6.37 (m, 2H), 4.01 (dd, J = 19.5, 8.2 Hz, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 135.0, 134.9, 134.4, 134.3 (d, J = 18.5 Hz), 131.8, 131.7, 131.0 (d, J = 1.5 Hz), 129.9 (d, J = 1.5 Hz), 128.5, 128.1, 125.2, 125.1, 124.0 (d, J = 4.2 Hz), 122.3 (d, J = 17.2 Hz), 116.5 (d, J = 32.6 Hz), 93.6 (d, J = 192.1 Hz), 59.1 (d, J = 24.5 Hz). ¹⁹F NMR (Chloroform-d) δ −154.17 (d, J = 19.2 Hz, major). Anal. Calcd for C₂₃H₁₆Br₂FN: C, 56.94; H, 3.32; N, 2.89. Found: C, 56.55; H, 3.53; N, 2.84.

(2R,3R,E)-3,5-Bis(3-methoxyphenyl)- 2-fluoro-2-phenylpent-4-enenitrile 5ac.

Compound 5ac was obtained as a white solid in 61% yield (27.3 mg, 0.06 mmol) from ethyl (E)-2,4-bis(3-methoxyphenyl)but-3-enoate (40.8 mg, 0.125 mmol) and 2-fluoro-2-phenylacetonitrile (12.5 mg, 0.0925 mmol) after 18 hours at −6 °C by following the general procedure described above. The reaction mixture was purified by flash chromatography using hexanes : dichloromethane (80:20) as mobile phase. The dr was determined as 5.3:1 using ¹⁹F NMR spectroscopy. The ee was determined by HPLC (Chiralpak IA, hexanes/EtOH, 95:5, flow rate 1 mL/min, λ = 254 nm) as >99%, t_R (minor) = 11.6 min, t_R (major) = 12.6 min. ¹H NMR (Chloroform-d) δ 7.38 – 7.27 (m, 5H), 7.25 – 7.15 (m, 2H), 6.94 (m, 1H), 6.88 – 6.65 (m, 5H), 6.55 – 6.41 (m, 2H), 4.04 (m, 1H), 3.80 (3H), 3.72 (3H). ¹³C {¹H} NMR (Chloroform-d) δ 159.8, 159.5, 137.7, 137.0, 135.7, 134.7 (d, J = 23.0 Hz), 129.6 (d, J = 1.5 Hz), 129.4, 128.4, 125.4, 125.3, 124.0 (d, J = 4.3 Hz), 121.8 (d, J = 1.3 Hz), 119.2, 115.2 (d, J = 1.4 Hz), 113.6 (d, J = 18.1 Hz), 112.1, 93.9 (d, J = 190.7 Hz), 59.7 (d, J = 24.4 Hz), 55.1, 55.2. ¹⁹F NMR (Chloroform-d) δ −148.73 (d, J = 15.7 Hz, major), −152.65 (d, J = 19.8 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₅H₂₂FNO₂, 410.1527; found, 410.1526.

(2R,3R,E)-2-(3-allylphenyl)-2-fluoro-3,5-diphenylpent-4-enenitrile 6da.

Tetrakis(triphenylphosphine)palladium(0) (30 mol%), 3da (0.09 mmol) and allyltributylstannane (2.0 equiv.) were dissolved in 2.5 mL THF under N₂ atmosphere. The reaction was stirred at 65 °C (oil bath) until complete consumption of 3da. The solvent was removed under reduced pressure and the residue was purified by column chromatography (97:3 hexanes/DCM) to give compound 6da (30.0 mg, 0.08 mmol) in 92% yield as an off-white solid. The dr was determined as >15:1 using ¹⁹F NMR. ¹H NMR (Chloroform-d) δ 7.44 – 7.30 (m, 3H), 7.30 – 7.25 (m, 5H), 7.24 – 7.07 (m, 6H), 6.67 – 6.43 (m, 2H), 5.81 (ddt, J = 16.8, 10.1, 6.6 Hz, 1H), 5.01 (dd, J = 10.2, 3.9 Hz, 1H), 4.95 (dd, J = 17.3, 4.0 Hz, 1H), 4.05 (m, 1H), 3.32 (d, J = 6.8 Hz, 2H). ¹³C {¹H} NMR (Chloroform-d) δ 140.4, 136.6, 136.3, 135.7, 134.8 (d, J = 22.9 Hz), 130.0 (d, J = 1.6 Hz), 129.5 (d, J = 1.4 Hz), 129.1, 128.5, 128.4 (d, J = 1.7 Hz), 128.0 (d, J = 3.5 Hz), 126.6, 126.5 (d, J = 4.8 Hz), 125.7 (d, J = 6.1 Hz), 123.9 (d, J = 4.3 Hz), 123.1 (d, J = 6.3 Hz), 116.8 (d, J = 32.7 Hz), 116.3, 94.0 (d, J = 191.6 Hz), 59.7 (d, J = 24.6 Hz), 39.9. ¹⁹F NMR (Chloroform-d) δ −152.69 (d, J = 18.9 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₆H₂₂FN, 390.1628; found, 390.1629.

(2R,3R,E)-2-([1,1’-Biphenyl]-3-yl)-2-fluoro-3,5-diphenylpent-4-enenitrile 7da.

Tetrakis(triphenylphosphine)palladium(0) (30 mol%), 3da (0.09 mmol) and phenyltributyltin (2.0 equiv.) were dissolved in 2.5 mL THF under N₂ atmosphere. The reaction was stirred at 65 °C (oil bath) until complete consumption of 3da. The solvent was removed under reduced pressure and the residue was purified by column chromatography (97:3 hexanes/DCM) to give compound 7da (32.3 mg, 0.08 mmol) in 89% yield as white solid. The dr was determined as >15:1 using ¹⁹F NMR. ¹H NMR (Chloroform-d) δ 7.56 (m, 1H), 7.44 (m, 1H), 7.43 – 7.38 (m, 5H), 7.38 – 7.25 (m, 10H), 7.23 – 7.20 (m, 2H), 6.64 – 6.49 (m, 2H), 4.11 (m, 1H). ¹³C {¹H} NMR (Chloroform-d) δ 141.5, 140.0, 136.3, 135.9, 135.60, 135.18 (d, J = 23.0 Hz), 129.53 (d, J = 1.4 Hz), 128.8, 128.6, 128.5 (d, J = 1.4 Hz), 128.1, 127.8, 127.1, 126.6, 124.3 (d, J = 6.3 Hz), 124.1 (d, J = 6.2 Hz), 123.8 (d, J = 4.1 Hz), 116.8 (d, J = 32.8 Hz), 94.0 (d, J = 192.0 Hz), 59.8 (d, J = 24.5 Hz). ¹⁹F NMR (Chloroform-d) δ −153.40 (d, J = 18.1 Hz, major). HRMS (ESI) m/z: [M+Na]+ calcd for C₂₉H₂₂FN, 426.1628; found, 426.1626.