Enantioselective Morita Baylis Hillman Reaction of Acrylates with Nitrobenzaldehydes Promoted

Enantioselective Morita–Baylis–Hillman reaction of acrylates with nitrobenzaldehydes promoted by the bifunctional ferrocene-based phosphinothiourea organocatalysts

Chuang Li,1,a Peng-Fei Ma,2,a Yang Lei,1 Hui Chen,1 Shao-Yu Guan,1 Ru Jiang,*1 and Wei-Ping Chen*1

1Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, Xi’an, 710032, China

2Department of Pharmacy, the 60th Central Hospital of the PLA, Dali,671003, China

Email: ;

aThese authors contributed equally to this work

Full experimental details and analytical data

General methods.……………………………………………………………………S2

General procedure for synthesis of catalysts (RC,SFc)-5…………………….………S2

General procedure for the enantioselective MBH reaction..….……………………..S4

References………………………………………………………………………...... S5

NMR and HRMS spectra for catalysts (RC,SFc)-5 …………………………….....…S5

HPLC analysis of products…………………….………………………………...... S19

General methods

1H NMR, 13C NMR and 31P NMR spectra were recorded on Bruker 500 spectrophotometer. High-Resolution Mass Spectroscopy (HRMS) was carried out on a VARIA FT-ICR MS. High performance liquid chromatography (HPLC) was performed on an Agilent 1260 series using Daicel Chiralcel chiral column. All commercially available reagents and solvents were used without further purification. Solvents were purified by standard procedures. Compounds 8 were prepared according to published procedures.1

General procedure for synthesis of catalysts (RC,SFc)-5

Isothiocyanate (1.1 mmol) in dry THF (10 mL) was added dropwise into a solution of amino-phosphine compound 8 (1 mmol) in dry THF (10 mL) at room temperature under an N2 atmosphere, and the corresponding mixture was stirred at this temperature until the reaction completed (monitoring by TLC). The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate 5:1) to afford the chiral phosphinothiourea compounds 5.

(RC,SFc)-5a: Yellow amorphous solid, 90% yield; [α]D25 = +291.0 (c 0.25, CH2Cl2); 1H NMR(CDCl3, 500MHz): δ 8.07(s, 1H), 7.63-7.60 (m, 3H), 7.46 (m, 1H), 7.39-7.30(m, 5H), 7.27(d, J 4.0 Hz, 3H), 7.19(s, 2H), 7.14(s, 2H), 5.55-5.53(m, 1H), 4.48(s, 1H), 4.30(s, 1H), 3.88(s, 5H), 3.75(s, 1H), 1.33(d, J 6.5 Hz, 3H); 13C NMR(CDCl3, 125MHz): δ 177.8, 138., 136.2, 135.0, 134.9, 132.4, 132.3, 130.4, 129.3, 128.19, 128.17, 128.0, 127.5, 126.6, 96.2, 96.0, 72.4, 72.0, 69.7, 69.47, 30.9, 24.1; 31P MNR(CDCl3, 202MHz): δ -25.76; HRMS m/z calcd for C31H29FeN2PS [M+H]+ 549.1217, found 549.1208.

(RC,SFc)-5b: Yellow amorphous solid, 90% yield; [α]D25 = +278.7 (c 0.25, CH2Cl2); 1H NMR(CDCl3, 500MHz): δ 7.97(s, 1H), 7.61(s, 1H), 7.39-7.28 (m, 8H), 7.24-7.22(m, 2H), 7.14(d, J 9.0Hz, 4H), 5.51-5.48(m, 1H), 4.47(s, 1H), 4.30-4.29(m, 1H), 3.89(d, J 7.0Hz, 8H), 3.76(s, 1H), 1.30(d, J 6.5 Hz, 3H); 13C NMR(CDCl3, 125MHz): δ 178.8, 138.8, 138.8, 136.3, 135.0, 134.8, 132.3, 132.2, 129.4, 128.9, 128.7, 128.2, 128.1, 128.0, 128.0, 115.5, 96.3, 96.1, 72.5, 71.9, 71.5, 71.4, 69.7, 69.5, 65.9, 55.6, 30.9, 24.3; 31P MNR(CDCl3, 202MHz): δ -25.54; HRMS m/z calcd for C32H31FeN2OPS [M+H]+ 579.1322, found 579.1313.

(RC,SFc)-5c: Yellow amorphous solid, 91% yield; [α]D25 = +273.2 (c 0.25, CH2Cl2); 1H NMR(CDCl3, 500MHz): δ 7.88-7.78(m, 2H), 7.57 (d, J 8.5 Hz, 2H), 7.43-7.35 (m, 3H), 7.30-7.18(m, 7H), 7.15(s, 2H), 5.53-5.50(m, 1H), 4.49(s, 1H), 4.33(s, 1H), 3.88(s, 5H), 3.81(s, 1H), 1.36(d, J 6.5 Hz, 3H); 13C NMR(CDCl3, 125MHz): δ 171.2, 138.8, 136.1, 135.0, 134.8, 134.8, 133.1, 132.3, 132.2, 130.4, 129.8, 129.5, 128.2, 127.9, 126.9, 95.9, 95.7, 72.4, 72.0, 69.7, 69.6, 60.4, 30.9, 23.8; 31P MNR(CDCl3, 202MHz): δ -25.70; HRMS m/z calcd for C31H28ClFeN2PS [M+H]+ 583.0827, found 583.0810.

(RC,SFc)-5d: Yellow amorphous solid, 93% yield; [α]D25 = +251.7 (c 0.25, CH2Cl2); 1H NMR(CDCl3, 500MHz): δ 8.43(s, 1H), 7.90(s, 1H), 7.82 (d, J 8.0 Hz, 2H), 7.47(d, J 8.5 Hz, 2H), 7.39-7.32(m, 3H), 7.26-7.22(m, 5H), 7.15(m, 2H), 5.58-5.57(m, 1H), 4.51(s, 1H), 4.34(s, 1H), 3.88(s, 5H), 3.82(s, 1H), 1.42(d, J 6.5 Hz, 3H); 13C NMR(CDCl3, 125MHz): δ 171.2, 139.9, 138.8, 138.7, 136.0, 134.9, 134.7, 132.3, 132.2, 129.5, 127.3, 125.2, 125.0, 122.8, 95.6, 95.5, 72.2, 72.1, 70.5, 69.7, 69.6, 60.4, 30.9, 23.4. 14.2; 31P MNR(CDCl3, 202MHz): δ -25.85; HRMS m/z calcd for C32H28F3FeN2PS [M+H]+ 617.1091, found 617.1094.

(RC,SFc)-5e: Yellow amorphous solid, 92% yield; [α]D25 = +282.9 (c 0.25, CH2Cl2); 1H NMR(CDCl3, 500MHz): δ 7.73(s, 3H), 7.37-7.32 (m, 5H), 7.31-7.23 (m, 5H), 7.11(s, 2H), 5.59 (m, 1H), 4.51(s, 1H), 4.33(s, 1H), 3.97(s, 5H), 3.79(s, 1H), 1.47(s, 3H); 13C NMR(CDCl3, 125 MHz): δ 178.0, 138.9, 134.8, 134.7, 132.3, 132.2, 129.5, 128.3, 124.8, 124.0, 121.8, 119.4, 95.0, 94.8, 73.2, 72.1, 69.8, 69.7, 65.9, 60.4, 22.3, 15.3, 14.2; 31P MNR(CDCl3, 202 MHz): δ -24.80; HRMS m/z calcd for C33H27F6FeN2PS [M+H]+ 685.0964, found 685.0931.

(RC,SFc)-5f: Yellow amorphous solid, 92% yield. [α]D25 = +277.9 (c 0.25, CH2Cl2). 1H NMR(CDCl3, 500MHz): δ 7.54(s, 2H), 7.44(d, J 6.0 Hz, 4H), 7.31-7.30 (m, 4H), 7.23(s, 2H), 5.48(m, 1H), 4.53(s, 1H), 4.36(s, 1H), 4.08(s, 5H), 3.82(s, 1H), 2.14-2.08 (m, 2H), 2.07(s, 1H), 1.91(d, J 12.0 Hz, 1H), 1.84(d, J 13.0 Hz, 1H), 1.71(d, J 12.5 Hz, 2H), 1.54-1.49(m, 2H), 1.30-1.29(m, 5H); 13C NMR(CDCl3, 125MHz): δ 208.9, 136.1, 134.9, 134.7, 132.6, 132.4, 129.5, 128.5, 128.3, 128.3, 96.3, 96.1, 71.5, 70.4, 69.8, 69.5, 60.4, 52.4, 30.9, 25.4, 25.3, 24.9, 24.1; 31P MNR(CDCl3, 202MHz): δ -23.73; HRMS m/z calcd for C31H35FeN2PS [M+H]+ 555.1686, found 555.1678.

(RC,SFc)-5g: Yellow amorphous solid, 88% yield. [α]D25 = +312.9 (c 0.25, CH2Cl2). 1H NMR(CDCl3, 500MHz): δ 7.53(s, 3H), 7.43(d, J 5.0 Hz, 3H), 7.30-7.27 (m, 6H), 5.50(m, 1H), 4.53(s, 1H), 4.37(s, 1H), 4.08(s, 5H), 3.85(s, 1H), 1.69(s, 2H), 1.42(d, J 4.5Hz, 3H), 1.22-1.20(m, 3H); 13C NMR(CDCl3, 125MHz): δ 185.4, 138.9, 135.0, 132.7, 129.4, 128.4, 128.3, 72.2, 72.1, 72.1, 72.0, 71.4, 71.3, 70.5, 70.4, 69.9, 69.5, 38.4, 38.2, 30.9, 23.0, 14.2, 14.21, 14.17, 14.13; 31P MNR(CDCl3, 202MHz): δ -24.01; HRMS m/z calcd for C31H35FeN2PS [M+H]+ 501.1217, found 501.1211.

General procedure for the enantioselective MBH reaction

To a solution of the phosphine-thiourea 5 (0.02 mmol) in THF (1.0 mL) was added the acrylate (1.0 mmol) and NaOH solid (0.05 mmol) at 25 ℃ under N2. After stirring at this temperature for 10 minutes, the aromatic aldehyde (0.2 mmol) was added. The reaction mixture was stirred at 25 ℃ for 48 h. The solvent was removed under reduced pressure and the residue was purified by a flash column chromatography to afford the MBH adduct and the ee value was determined by HPLC analysis on a chiral stationary phase. Note that the ee value for the MBH adduct of HFIPA was determined after derivation.2

General procedure for the derivatizaition of MBH adduct

To a solution of the isolated product of HFIPA with aromatic aldehyde in EtOH (5.0 mL) was added the triethylamine (0.5 mL) at room temperature.After stirring for 30 min, the solvent was removed under reduced pressure and the residue was purified by a flash column chromatography to afford the ethyl derivatization of the product and the ee value was determined by HPLC analysis on a chiral stationary phase.

References

1.  Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. Tetrahedron: Asymmetry. 2006, 17, 1161-1164. doi:10.1016/j.tetasy.2006.04.033

2.  After the MBH reaction of HFIPA with aromatic aldehyde, the adduct was derivatized by stirred with ethanol(5ml) and triethylamine(0.5 ml) for 30min at rt, then the esterified product underwent chiral HPLC determination.

NMR and HRMS spectra for catalysts (RC,SFc)-5

1H NMR spectrum of phosphinothiourea catalyst 5a

13C NMR spectrum of phosphinothiourea catalyst 5a

31P NMR spectrum of phosphinothiourea catalyst 5a

HRMS spectrum of phosphinothiourea catalyst 5a

1H NMR spectrum of phosphinothiourea catalyst 5b

13C NMR spectrum of phosphinothiourea catalyst 5b

31P NMR spectrum of phosphinothiourea catalyst 5b

HRMS spectrum of phosphinothiourea catalyst 5b

1H NMR spectrum of phosphinothiourea catalyst 5c

13C NMR spectrum of phosphinothiourea catalyst 5c

31P NMR spectrum of phosphinothiourea catalyst 5c

HRMS spectrum of phosphinothiourea catalyst 5c

1H NMR spectrum of phosphinothiourea catalyst 5d

13C NMR spectrum of phosphinothiourea catalyst 5d

31P NMR spectrum of phosphinothiourea catalyst 5d

HRMS spectrum of phosphinothiourea catalyst 5d

1H NMR spectrum of phosphinothiourea catalyst 5e

13C NMR spectrum of phosphinothiourea catalyst 5e

31P NMR spectrum of phosphinothiourea catalyst 5e

HRMS spectrum of phosphinothiourea catalyst 5e

1H NMR spectrum of phosphinothiourea catalyst 5f

13C NMR spectrum of phosphinothiourea catalyst 5f

31P NMR spectrum of phosphinothiourea catalyst 5f

HRMS spectrum of phosphinothiourea catalyst 5f

1H NMR spectrum of phosphinothiourea catalyst 5g

13C NMR spectrum of phosphinothiourea catalyst 5g

31P NMR spectrum of phosphinothiourea catalyst 5g

HRMS spectrum of phosphinothiourea catalyst 5g

HPLC analysis of products

(R)-methyl-2-(hydroxy(4-nitrophenyl)methyl)acrylate(14a): 55% yield, 26% ee; HPLC analysis (Daicel CHIRALCEL IC-H column, λ=254 nm, eluent: n-hexane/i-propanol=98/2, flow rate: 0.8 mL/min): tR=42.2 min(minor), 46.1 min(major).

(R)-ethyl-2-(hydroxy(4-nitrophenyl)methyl)acrylate(14b): 53% yield, 62% ee; HPLC analysis (Daicel CHIRALCEL OD-H column, λ=254 nm, eluent: n-hexane/i-propanol=98/2, flow rate: 0.8 mL/min): tR=41.9 min(major), 45.9 min(minor).

(R)-benzyl-2-(hydroxy(4-nitrophenyl)methyl)acrylate(14c): 49% yield, 32% ee; HPLC analysis (Daicel CHIRALCEL IC-H column, λ=254 nm, eluent: n-hexane/i-propanol=90/10, flow rate: 1.0 mL/min): tR=22.4 min(major), 26.0 min(minor).

(R)-tert-butyl-2-(hydroxy(4-nitrophenyl)methyl)acrylate(14d): 41% yield, 35% ee; HPLC analysis (Daicel CHIRALCEL IC-H column,λ=254 nm, eluent: n-hexane/i-propanol =90/10, flow rate: 1.0 mL/min): tR=8.1 min (major), 9.9 min (minor).

(R)-1,1,1,3,3,3-hexafluoropropan-2-yl 2-(hydroxy(4-nitrophenyl)methyl)acrylate(14e): 85% yield, 98% ee; The ee value was determined by HPLC after derivation[2]. HPLC analysis (Daicel CHIRALCEL OD-H column, λ=254 nm, eluent: n-hexane/i-propanol=98/2, flow rate: 0.8 mL/min): tR=43.3 min(major), 47.7 min(minor).

(R)-1,1,1,3,3,3-hexafluoropropan-2-yl 2-(hydroxy(2-nitrophenyl)methyl)acrylate(14f): 45% yield, 90% ee; The ee value was determined by HPLC after derivation[2]. HPLC analysis (Daicel CHIRALCEL OD-H column, λ=254 nm, eluent: n-hexane/i-propanol=96/4, flow rate: 1.0 mL/min): tR=17.4 min(minor), 24.4 min(major).

(R)-1,1,1,3,3,3-hexafluoropropan-2-yl 2-(hydroxy(3-nitrophenyl)methyl)acrylate(14g): 84% yield, 94% ee; The ee value was determined by HPLC after derivation[2]. HPLC analysis (Daicel CHIRALCEL OD-H column, λ=254 nm, eluent: n-hexane/i-propanol=95/5, flow rate: 1.0 mL/min): tR=15.7 min (major), 17.7 min(minor).

(R)-1,1,1,3,3,3-hexafluoropropan-2-yl 2-(hydroxy(4-chloro-3-nitrophenyl)methyl)acrylate(14h):80% yield, 99.7% ee; The ee value was determined by HPLC after derivation.23 HPLC analysis (Daicel CHIRALCEL OD-H column, λ=254 nm, eluent: n-hexane/i-propanol=98/2, flow rate: 0.8 mL/min): tR=43.9 min (major), 48.5 min(minor).

S27