Aminoalkyl-Phosphine (P,N) Ligands with Pentane-2,4-Diyl Backbone in Asymmetric Allylic

Supportinginformation

Aminoalkyl-phosphine (P,N) ligands with pentane-2,4-diyl backbone in asymmetric allylic substitution reactions

Zsófia Császár1 ●Patrik Imre1 ●Szabolcs Balogh2 ●Attila Bényei3 ● Gergely Farkas1 ● József Bakos1

General procedure for asymmetric allylic alkylation

A degassed solution of [Pd(η3-C3H5)Cl]2 (2.28 mg, 0.00625 mmol) and ligand (0.0125 mmol in the case of 1/1 Pd/ligand molar ratio) in the corresponding solvent (10 cm3) was stirred for 30 min, then the substrate (1.25 mmol) was added and the solution was stirred for a further 15 min. Subsequently, dimethyl malonate (495 mg, 3.75 mmol), potassium acetate (7.0 mg, 0.071 mmol) and N,O-bis(trimethylsilyl)-acetamide (0.91 mL, 3.75 mmol) were added and the reaction mixture was stirred for 1 h. After being stirred, it was diluted with ether (10 cm3) and a saturated aqueous solution of NH4Cl was added. The mixture was extracted with ether (3x10 cm3) and the extract dried over MgSO4. The solution was then passed through a short pad of silica and was eluted with ether. The solvent was then evaporated and the residue dissolved in a mixture of n-hexane/2-propanol. The enantioselectivity and the conversion were determined by chiral HPLC.The conversions were calculated by a response factor corrected HPLC analysis. The response factor was determined by making standard solutions of the pure starting materials with the pure products.No by-product formation was observed in the allylation reactions.The reported NMR data correspond to product samples purified by chromatography. The optical rotation was measured by using

(R,E)-dimethyl 2-(1,3-diphenylallyl)malonate (7)

Colorless oil. Yield: 95%.ee: 95%. [α]25D = 21.05 (c = 7.2, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.18 – 7.38 (aromatic 10 H), 6.51 (d, 3J(H,H) = 15.8 Hz, 1H, CH=), 6.35 (dd, 3J(H,H) = 15.8 Hz, 3J(H,H) = 8.4 Hz, 1H, CH=), 4.29 (dd, 3J(H,H) = 10.7 Hz, 3J(H,H) = 8.6 Hz, 1H, CH), 3.98 (d, 3J(H,H) = 10.9 Hz, 1H, CH), 3.73 (s, 3H, diast. CH3), 3.54 (s, 3H, diast.CH3) ppm.The enantiomericexcesswasdeterminedbychiral HPLC analysisusing a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 15/85; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retentiontimesforthetwoenantiomers: 10.6min for (R)-isomer(major) and 13.7 minfor (S)-isomer. The structurewasconfirmedbycomparisonwithliteraturedata [1].

(R,E)-diethyl 2-(1,3-diphenylallyl)malonate (8)

Colorless oil. Yield: 97%.ee: 88%. [α]25D = 6.56 (c = 3.2, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.30 – 7.14 (aromatic 10 H), 6.45 (broad d, 3J(H,H) = 15.8 Hz, 1H, CH=), 6.31 (dd, 3J(H,H) = 15.8 Hz, 3J(H,H) = 8.5 Hz, 1H, CH=), 4.24 (m, ddd, 3J(H,H) = 11.2 Hz, 3J(H,H) = 8.5 Hz, 4J(H,H) = 0.7 Hz, 1H, CH), 4.15 (m, 2H, diast. CH2), 3.95 (m, 2H, diast. CH2), 3.89 (d, 3J(H,H) = 11.2 Hz, 1H, CH), 1.18 (t, 3J(H,H) = 7.1 Hz, 3H, CH3), 0.98 (t, 3J(H,H) = 7.1 Hz, 3H, CH3) ppm. The enantiomericexcesswasdeterminedbychiral HPLC analysisusing a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 15/85; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retentiontimesforthetwoenantiomers: 8.4 min for (R)-isomer (major) and 10.4minfor (S)-isomer. The structurewasconfirmedbycomparisonwithliteraturedata [1].

(R,E)-dibenzyl 2-(1,3-diphenylallyl)malonate (9)

Colorless oil. Yield: 94%. ee: 86%. [α]25D = 4.40 (c = 3.3, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.35-7.03 (aromatic 20 H), 6.41 (d, 3J(H,H) = 15.8 Hz, 1H, CH=), 6.30 (dd, 3J(H,H) = 15.8 Hz, 3J(H,H) = 8.3 Hz, 1H, CH=), 5.10 (ABq, ΔδAB = 0.022, 2J(H,H) = 12.21 Hz, 2H, diast.CH2Ph), 4.93 (ABq, ΔδAB = 0.025, 2J(H,H) = 12.32 Hz, 2H, diast. CH2Ph), 4.30 (dd, 3J(H,H) = 10.9 Hz, 3J(H,H) = 8.3 Hz, 1H, CH), 4.04 (d, 3J(H,H) = 10.9 Hz, 1H, CH) ppm. The enantiomericexcesswasdeterminedbychiral HPLC analysisusing a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 15/85; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retentiontimesforthetwoenantiomers: 16.2 min for (R)-isomer (major) and 19.7 min for (S)-isomer. The structurewasconfirmedbycomparisonwithliteraturedata [1].

(R,E)-dimethyl 2-(1,3-bis(4-methoxyphenyl)allyl)malonate (10)

Colorless oil. Yield: 71%.ee: 89%. [α]25D= -0.19 (c = 3.5, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.23 – 7.17 (aromatic, 4 H), 6.83 – 6.77 (aromatic, 4H), 6.36 (d, 3J(H,H) = 15.7 Hz, 1H, CH=), 6.14 (dd, 3J(H,H) = 15.7 Hz, 3J(H,H) = 8.6 Hz, 1H, CH=), 4.17 (dd, 3J(H,H) = 10.9 Hz, 3J(H,H) = 8.6 Hz, 1H, CH), 3.87 (d, 3J(H,H) = 10.9 Hz, 1H, CH), 3.760 (s, 3H, CH3), 3.765 (s, 3H, CH3), 3.67 (s, 3H, diast. CH3), 3.51 (s, 3H, diast. CH3) ppm. The enantiomericexcesswasdeterminedbychiral HPLC analysisusing a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 15/85; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retentiontimesforthetwoenantiomers: 23.3for (R)-isomer (major) and 39.6 min for (S)-isomer. The structurewasconfirmedbycomparisonwithliteraturedata [1].

(R,E)-dimethyl 2-(1,3-bis(4-bromophenyl)allyl)malonate (11)

Colorless oil. Yield: 45%. ee: 92%. [α]25D = -1.87 (c = 25.1, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.44 – 7.36 (aromatic, 4 H), 7.16 – 7.12 (aromatic, 4 H), 6.36 (d, 3J(H,H) = 15.8 Hz, 1H, CH=), 6.25 (dd, 3J(H,H) = 15.8 Hz, 3J(H,H) = 8.4 Hz, 1H, CH=), 4.19 (dd, 3J(H,H) = 10.7 Hz, 3J(H,H) = 8.4 Hz, 1H, CH), 3.87 (d, 3J(H,H) = 10.7 Hz, 1H, CH), 3.68 (s, 3H, diast. CH3), 3.53 (s, 3H, diast. CH3) ppm. The enantiomericexcesswasdeterminedbychiral HPLC analysisusing a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 15/85; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retentiontimesforthetwoenantiomers: 18.8 min for (R)-isomer (major) and 28.4 min for (S)-isomer. The structurewasconfirmedbycomparisonwithliteraturedata [1].

General procedure for asymmetric allylic amination

A degassed solution of Pd2(dba)3.(CHCl3) (6.47 mg, 0.00625 mmol) and ligand (0.0125 mmol) in the given amount CH2Cl2 was stirred for 30 min, then the substrate (0.625 mmol) was added and the solution was stirred for a further 15 min. Subsequently, the corresponding amine (1.88 mmol) was added and the reaction mixture was stirred until TLC analysis indicated the disappearance of the starting material. After being stirred, an aliquot of the mixture was passed through a short pad of silica and was eluted with ether. The solvent was then evaporated and the residue dissolved in a mixture of n-hexane/2-propanol. (Reactions under solventfree conditions were carried out by solving the [Pd(η3-Ph2-C3H3)(3b)]BF4 (8,75 mg, 0.0125 mmol) complex in the amine (3.75 mmol) and then by addition of the substrate (315.39 mg, 1.25 mmol).) The enantioselectivity and the conversion were determined by chiral HPLC. The conversions were calculated by a response factor corrected HPLC analysis. The response factor was determined by making standard solutions of the pure starting material with the pure products.No by-product formation was observed in the allylation reactions.The reported NMR data correspond to product samples purified by chromatography.

(S,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (12)

Colorless oil. Yield: 94%. ee: 78%. [α]25D= 20.95 (c = 3.7, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.45 – 7.20 (m, 15H, aromatic), 6.63 (d, 3J(H,H) = 15.9 Hz, 1H, PhCH=), 6.34 (dd, 3J(H,H) = 15.9, 7.0 Hz, 1H, CHCH=), 5.01 (d, 3J(H,H) = 7.0 Hz, 1H, CHCH=), 3.79 (ABq, ΔδAB = 0.015, 2J(H,H) = 12.2 Hz, 2H, CH2Ph) ppm.The enantiomeric excess was determined by chiral HPLC analysis using a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 1/99; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retention times forthetwoenantiomers: 12.3 (minor) and 14.5 min (major).The structurewasconfirmedbycomparisonwithliteraturedata [1].

(S,E)-N-(1,3-diphenylallyl)cyclohexanamine (13)

Colorless oil. Yield: 93%. ee: 61%. [α]25D= -4.5 (c = 6.4, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.40 – 7.16 (m, 10H, aromatic), 6.51 (d, 3J(H,H) = 15.8 Hz, 1H, PhCH=), 6.30 (dd, 3J(H,H) = 15.8, 7.3 Hz, 1H, CHCH=), 4.56 (d, 3J(H,H) = 7.3 Hz, 1H, CHCH=), 2.45 (m, 1H, NCH), 1.96 (m, 1H, CH2), 1.88 (m, 1H, CH2), 1.67 (m, 2H, CH2), 1.56 (m, 2H, CH2), 1.20 – 1.08 (m, 4H, CH2) ppm. The enantiomeric excess was determined by chiral HPLC analysis using a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 3/97 and 0.03% triethylamine; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retention times forthetwoenantiomers: 7.6 (major) and 8.3 min (minor). The structurewasconfirmedbycomparisonwithliteraturedata [1].

(S,E)-N,N-diethyl-1,3-diphenylprop-2-en-1-amine (14)

Colorless oil. Yield: 97%. ee: 90%. [α]25D = 15.76 (c = 8.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.44 – 7.17 (m, 10H, aromatic), 6.53 (d, 3J(H,H) = 15.8 Hz, 1H, PhCH=), 6.35 (dd, 3J(H,H) = 15.8, 8.8 Hz, 1H, CHCH=), 4.29 (d, 3J(H,H) = 8.8 Hz, 1H, CHCH=), 2.61 (m, 4H, NCH2), 1.00 (t, 6H, 3J(H,H) = 7.1, CH3).The enantiomeric excess was determined by chiral HPLC analysis using a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 10/90; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retention times forthetwoenantiomers: 7.5 (minor) and 9.2 min (major). Thestructurewasconfirmedbycomparisonwithliteraturedata [1].

(S,E)-N-(1,3-diphenylallyl)aniline (15)

Colorless oil. Yield: 98%. ee: 70%. [α]25D= 39.05 (c = 9.3, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.45-7.18 (aromatic 15H), 6.58 (d, 3J(H,H) = 15.8 Hz, 1H, PhCH=), 6.34 (dd, 3J(H,H) = 15.8, 3J(H,H) = 7.5 Hz, 1H, CHCH=), 4.41 (d, 3J(H,H) = 7.5 Hz, 1H, CHCH=), 3.79 (m, 2H, CH2) ppm.The enantiomeric excess was determined by chiral HPLC analysis using a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 10/90; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retention times forthetwoenantiomers: 10.9 (minor) and 13.1 (major) min. The structurewasconfirmedbycomparisonwithliteraturedata [1].

(S,E)-4-(1,3-diphenylallyl)morpholine (16)

Colorless oil. Yield: 99%. ee: 82%. [α]25D= 4.41 (c = 4.4, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.44-7.21 (aromatic 10H), 6.57 (d, 3J(H,H) = 15.8 Hz, 1H, PhCH=), 6.41 (dd, 3J(H,H) = 15.8, 3J(H,H) = 8.6 Hz, 1H, CHCH=), 3.80 (d, 3J(H,H) = 8.6 Hz, 1H, CHCH=), 3.74- 3.68 (m, 4H, CH2), 2.54-2.33 (m, 4H, CH2) ppm. The enantiomeric excess was determined by chiral HPLC analysis using a Kromasil 3-CelluCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 10/90; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retention times forthetwoenantiomers: 6.6 (major) and 12.6 min (minor). Thestructurewasconfirmedbycomparisonwithliteraturedata [1].

(S,E)-1-(1,3-diphenylallyl)piperidine (17)

Colorless oil. Yield: 94%. ee: 86%. [α]25D = 7.90 (c = 1.7, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.42-7.18 (aromatic 10H), 6.53 (d, 3J(H,H) = 15.8 Hz, 1H, PhCH=), 6.36 (dd, 3J(H,H) = 15.8, 3J(H,H) = 8.8 Hz, 1H, CHCH=), 3.83 (d, 3J(H,H) = 8.8 Hz, 1H, CHCH=), 2.60- 2.28 (m, 4H, CH2), 1.73-1.37 (m, 6H, CH2) ppm.The enantiomeric excess was determined by chiral HPLC analysis using a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 10/90; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retention times forthetwoenantiomers: 5.9 (minor) and 6.7 min (major). Thestructurewasconfirmedbycomparisonwithliteraturedata [2].

(S,E)-1-(1,3-diphenylallyl)pyrrolidine (18)

Colorless oil. Yield: 97%. ee: 80%. [α]25D = 2.03 (c = 5.0, CHCl3).1H NMR (400 MHz, CDCl3): δ = 7.42-7.15 (aromatic 10H), 6.55 (d, 3J(H,H) = 15.8 Hz, 1H, PhCH=), 6.41 (dd, 3J(H,H) = 15.8, 3J(H,H) = 8.5 Hz, 1H, CHCH=), 3.76 (d, 3J(H,H) = 8.5 Hz, 1H, CHCH=), 2.61- 2.38 (m, 4H, CH2), 1.84-1.71 (m, 4H, CH2) ppm.The enantiomeric excess was determined by chiral HPLC analysis using a Kromasil 3-AmyCoat (4.6x150 mm) column (eluent: 2-propanol/n-hexane 5/95; flow rate: 0.5 cm3/min, detection: UV 254 nm). Retention times forthetwoenantiomers: 10.5 (minor) and 12.4min (major). The structurewasconfirmedbycomparisonwithliteraturedata [1].

References

[1] Liu QL, Chen W, Jiang QY, Bai XF, Li Z, Xu Z, Xu LW (2016) ChemCatChem 8:1495

[2] Wu H, Xie F, Wang Y, Zhao X, Liu D, Zhang W (2015) Org. Biomol. Chem. 13:4248