Catalytic Asymmetric Alkylation of α-Cyanocarboxylates Using a Phase-Transfer Catalyst

Abstract

The highly enantioselective catalytic alkylation of ­cyanoacetates was achieved using a chiral phase-transfer catalyst to give α,α-disubstituted α-cyanoacetates which have a chiral quaternary carbon. The product thus obtained was applied to the synthesis of an optically active oxindole.

Key words

phase-transfer catalysis - asymmetric synthesis - alkylation - halides - indoles

References and Notes

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9

Although other solvents such as toluene, CH₂Cl₂, CHCl₃, and EtOAc were investigated for the reaction, the results were inferior to the reaction using diethyl ether as solvent.

10

The yield and ee using other commercially available chiral PTC’s under the same reaction conditions, were as follows: N-benzylcinchoninium chloride (trace, 19% ee), N-benzyl-cinchonidinium chloride (yield: 13%, 17% ee), N-[4-(tri-fluoromethyl)benzyl]cinchonidinium bromide (yield: 10%, 28% ee), N-benzylquininium chloride (yield: 20%, 19% ee), N-benzylquinidinium chloride (yield: 19%, 3% ee), N-(9-anthracenylmethyl)cinchonidinium chloride (yield: 10%, 0% ee), TaDiAS-[(4R,5R)-2,2-dipropyl-N,N,N′,N′-tetrakis(4-methylbenzyl)]bis(tetrafluoroborate) (yield: 42%, 4% ee).

12

General procedure: A solution of tert-butyl 2-cyano-propanoate or tert-butyl 2-cyanopent-4-enoate (0.1 mmol) in Et₂O (2.4 mL) was cooled to -60 °C. The PTC (1a or 1b, 0.001mmol), alkyl halide (0.12 mmol) and then CsOH (75 mg, 0.5 mmol) were added to the solution. The reaction mixture was vigorously stirred for the time indicated in Table [2] and then diluted with Et₂O. The organic layer was washed with H₂O and brine, dried over MgSO₄ and the solvents evaporated. The residue was purified using flash column chromatography on silica gel (EtOAc-hexane) to give the corresponding 2-cyanocarboxylate in the yield indicated.
(R)-tert-Butyl 2-cyano-2-methyl-3-phenylpropanoate (3c)
Colorless oil; [α]_D ²⁵ -14.7 (c 2.00, CHCl₃) (97% ee). ¹H NMR (400 MHz, CDCl₃): δ = 1.42 (s, 9 H), 1.57 (s, 3 H), 2.98-3.01 (d, J = 13.7 Hz, 1 H), 3.17-3.21 (d, J = 13.4 Hz, 1 H), 7.30-7.33 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.1, 28.4, 44.3, 46.7, 83.1, 121.9, 128.5, 129.2, 130.9, 135.2, 169.2. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₅H₂₀O₂N: 246.1493; found: 246.1494. The ee was determined by HPLC analysis (Daicel CHIRALCEL OJ, 2-propanol-hexane, 1:400).
(R)-tert-Butyl 2-cyano-2-methylpent-4-enoate (4)
Colorless oil; [α]_D ²⁵ +2.2 (c 1.67, CHCl₃) (92% ee). ¹H NMR (400 MHz, CDCl₃): δ = 1.50 (s, 9 H), 1.54 (s, 3 H), 2.47 (dd, J = 13.8, 7.4 Hz, 1 H), 2.64 (dd, J = 13.8, 7.2 Hz, 1 H), 5.22-5.26 (m, 2 H), 5.82 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.7, 27.8, 42.1, 44.2, 83.9, 120.0, 120.7, 130.9, 167.8. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₁H₁₈O₂N: 196.1407; found: 196.1321. The ee was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol-hexane, 1:400).
tert-Butyl 2-cyano-2-methyl-3-pyridin-2-ylpropanoate (5)
Colorless oil; [α]_D ²⁵ +8.4 (c 3.45, CH₂Cl₂) (70% ee). ¹H NMR (400 MHz, CDCl₃): δ = 1.48 (s, 9 H), 1.65 (s, 3 H), 3.21 (d, J = 14.6 Hz, 1 H), 3.45 (d, J = 14.6 Hz, 1 H), 7.19 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H), 7.27 (m, 1 H), 7.64 (td, J = 7.6, 2.0 Hz, 1 H), 8.54 (ddd, J = 4.9, 2.1, 0.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 23.6, 27.7, 44.3, 44.9, 83.6, 120.3, 122.3, 123.8, 136.4, 149.1, 155.2, 168.0. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₄H₁₉O₂N₂: 247.1440; found: 247.1449. The ee was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol-hexane, 1:4).
1-tert-Butyl 4-ethyl 2-cyano-2-methylbutanedioate (6)
Colorless oil; [α]_D ²⁵ +15.6 (c 2.00, CHCl₃) (85% ee). ¹H NMR (400 MHz, CDCl₃): δ = 1.28 (t, J = 7.2 Hz, 3 H), 1.52 (s, 9 H), 1.63 (s, 3 H), 2.77 (d, J = 17.1 Hz, 1 H), 2.98 (d, J = 17.1 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 23.7, 27.7, 41.2, 41.6, 61.4, 84.1, 120.0, 167.4, 168.7. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₂H₂₀O₄N: 242.1332; found: 242.1411. The ee was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol-hexane, 1:200).
Di-tert-butyl 2-cyano-2-methylbutanedioate (7)
Colorless oil; [α]_D ²⁵ +19.3 (c 7.50, CHCl₃) (92% ee). ¹H NMR (400 MHz, CDCl₃): δ = 1.47 (s, 9 H), 1.51 (s, 9 H), 1.60 (s, 3 H), 2.69 (d, J = 16.8 Hz, 1 H), 2.89 (d, J = 16.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 23.7, 27.7, 28.0, 41.4, 42.6, 82.3, 83.9, 120.0, 167.5, 167.8. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₄H₂₄O₄N: 270.1694; found: 270.1709. The ee was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol-hexane, 1:800).
tert-Butyl 2-benzyl-2-cyanopent-4-enoate (8)
Colorless oil; [α]_D ²⁵ -18.1 (c 1.74, CHCl₃) (99% ee). ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (s, 9 H), 2.47 (dd, J = 13.6, 6.8 Hz, 1 H), 2.63 (dd, J = 13.7, 7.8 Hz, 1 H), 2.96 (d, J = 13.4 Hz, 1 H), 3.09 (d, J = 13.4 Hz, 1 H), 5.17-5.21 (m, 2 H), 5.78 (m, 1 H) 7.19-7.30 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 27.7, 41.7, 42.5, 84.2, 119.0, 120.8, 127.7, 128.4, 130.1, 130.7, 134.3, 166.9. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₇H₂₂O₂N: 272.1621; found: 272.1662. The ee was determined by HPLC analysis (Daicel CHIRALCEL OD, 2-propanol-hexane, 1:800).
1-tert-Butyl 4-ethyl 2-cyano-2-prop-2-en-1-ylbutane-dioate (9)
Colorless oil; [α]_D ²⁵ +13.9 (c 2.38, CHCl₃) (90% ee). ¹H NMR (400 MHz, CDCl₃): δ = 1.25 (t, J = 7.1 Hz, 3 H), 1.48 (s, 9 H), 2.50 (dd, J = 13.7, 7.3 Hz, 1 H), 2.62 (dd, J = 13.9, 7.3 Hz, 1 H), 2.72 (d, J = 17.1 Hz, 1 H), 2.96 (d, J = 16.8 Hz, 1 H), 4.16 (q, J = 7.3 Hz, 2 H), 5.20-5.26 (m, 2 H), 5.80 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 27.7, 40.0, 41.2, 45.9, 61.4, 84.3, 118.5, 121.3, 130.0, 166.6, 168.7. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₄H₂₂O₄N: 268.1560; found: 268.1545. The ee was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol-hexane, 1:100).

16

Compound 10 was prepared from 2′-bromophenylaceto-nitrile according to a literature procedure, see: Albarella J. P.; J. Org. Chem.; 1977, 42: 2009

17

(R)- tert -Butyl 2-(2-bromophenyl)-2-cyanopent-4-enoate (11)
A solution of 10 (29.6 mg, 0.1 mmol) in toluene (2.4 mL) was cooled to -10 °C, and PTC 1b (1.1 mg, 0.001 mmol), allyl iodide (18 µL, 0.2 mmol) and then CsOH (75 mg, 0.5 mmol) were added to the solution. The reaction mixture was stirred vigorously for 1 d and then diluted with H₂O. The mixture was extracted with CH₂Cl₂ and the combined organic layers were washed with brine and dried over MgSO₄. After the solvent was removed by evaporation, the residue was purified by flash column chromatography on silica gel (EtOAc-hexane, 1:16) to give 11 in quantitative yield; colorless oil; [α]_D ²⁵ -9.2 (c 2.00, CHCl₃) (93% ee). ¹H NMR (400 MHz, CDCl₃): δ = 1.48 (s, 9 H), 3.11 (dd, J = 7.6, 14.0 Hz, 1 H), 3.27 (dd, J = 6.8, 14.0 Hz, 1 H), 5.19-5.26 (m, 2 H), 5.78 (m, 1 H), 7.24 (dt, J = 1.6, 7.6 Hz, 1 H), 7.37 (dt, J = 1.2, 8.0 Hz, 1 H), 7.55 (dd, J = 1.4, 8.0 Hz, 1 H), 7.64 (dd, J = 1.6, 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 27.6, 39.7, 54.8, 84.7, 117.7, 120.7, 122.8, 127.7, 129.6, 130.1, 130.8, 133.9, 134.7, 165.2. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₆H₁₉O₂NBr: 336.0630; found: 336.0584. The ee was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol-hexane, 1:100).

18

This result suggested that the Si:Re selectivity of compounds 2 and 10 in the enolate-forming step was opposite to each other. Mechanistic consideration of the asymmetric induction is now under investigation.

19

( R )- N -Benzyl-2-(2-bromophenyl)-2-cyanopent-4-enamide (12)
Compound 11 (34 mg, 0.1 mmol) was dissolved in TFA (1.0 mL) and stirred at r.t. for 12 h under an argon atmosphere. The TFA was then removed by evaporation and CH₂Cl₂ (1.0 mL) was added. The solution was cooled to 0 °C and EDC·HCl (38 mg, 0.2 mmol), 1-hydroxy-7-azabenzotriazole (27 mg, 0.2 mmol), and BnNH₂ (16 µl, 0.15 mmol) were added. The reaction mixture was stirred overnight at r.t. under an argon atmosphere. After the addition of H₂O, the mixture was extracted with CH₂Cl₂. The organic layer was washed with brine, dried over MgSO₄ and the solvents removed by evaporation. The residue was purified by flash column chromatography on silica gel (EtOAc-hexane, 1:4) to give compound 12 in 88% yield; mp 124 °C (CH₂Cl₂); [α]_D ²⁵ -21.9 (c 3.07, CHCl₃) (93% ee). ¹H NMR (400 MHz, CDCl₃): δ = 3.19-3.30 (m, 2 H), 4.44 (dd, J = 5.1, 14.8 Hz, 1 H), 4.54 (dd, J = 6.0, 14.8 Hz, 1 H), 5.19-5.27 (m, 2 H), 5.75 (m, 1 H), 6.13 (br s, 1 H), 7.24-7.34 (m, 6 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 39.6, 44.8, 54.6, 118.4, 121.2, 123.0, 127.9, 128.1, 128.8, 130.3, 130.7, 130.7, 133.2, 135.3, 136.8, 165.3. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₉H₁₈ON₂Br: 369.0619; found: 369.0592. Anal. Calcd for C₁₉H₁₇ON₂Br: C, 61.80; H, 4.64; N, 7.59. Found: C, 61.78; H, 4.54; N, 7.48. The ee was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol-hexane, 1:20).

21

( R )-1-Benzyl-3-cyano-3-prop-2-en-1-yl)-1,3-dihydro-indol-2-one (13)
To a solution of compound 12 (44 mg, 0.11 mmol) in DMSO (1.1 mL) were added CuI (42 mg, 0.2 mmol) and CsOAc (106 mg, 0.5 mmol). The mixture was stirred for 10 h at 70 °C under an argon atmosphere. After the addition of Et₂O, the organic layer was washed with H₂O and brine, and dried over MgSO_4. The solvent was removed by evaporation and the residue was purified by flash column chromatography on silica gel (EtOAc-hexane, 1:7) to give compound 13 in quantitative yield; mp 122 °C (CH₂Cl₂); [α]_D ²⁵ +27.3 (c 5.81, CHCl₃) (93% ee). ¹H NMR (400 MHz, CDCl₃): δ = 2.83 (dd, J = 8.4, 13.6 Hz, 1 H), 3.05 (dd, J = 6.4, 13.2 Hz, 1 H,), 4.81 (d, J = 15.6 Hz, 1 H), 5.02 (d, J = 15.6 Hz, 1 H), 5.18-5.22 (m, 2 H), 5.65 (m, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 7.11 (t, J = 7.6 Hz, 1 H), 7.26-7.33 (m, 6 H), 7.41 (d, J = 7.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 41.1, 44.6, 46.4, 110.1, 116.7, 122.2, 123.6, 124.5, 124.7, 127.4, 128.1, 128.9, 129.0, 130.3, 134.7, 142.2, 170.1. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₉H₁₇ON₂: 289.1351; found: 289.1337. Anal. Calcd for C₁₉H₁₆ON₂: C, 79.14; H, 5.59; N, 9.72. Found: C, 79.02; H, 5.52; N, 9.75. The ee was determined by HPLC analysis (Daicel CHIRALCEL IA, 2-propanol-hexane, 1:10).