Chiral Lewis Acid Catalyzed Enantioselective Conjugate Radical Additions to α,β-Unsaturated 2-Pyridyl Ketones

Mukund P. Sibi; Yong-Hua Yang

doi:10.1055/s-2007-992386

LETTER

Chiral Lewis Acid Catalyzed Enantioselective Conjugate Radical Additions to α,β-Unsaturated 2-Pyridyl Ketones

Mukund P. Sibi*, Yong-Hua Yang
Department of Chemistry, North Dakota State University, Fargo, ND 58105, USA
e-Mail: Mukund.Sibi@ndsu.edu;

Abstract

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Abstract

We have investigated the utility of a pyridine-based achiral template in enantioselective conjugate radical additions.

Key words

conjugate radical reactions - chiral Lewis acids - pyridyl ketones - catalysis - achiral templates

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References

References and Notes

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All new compounds showed analytical and spectral characteristics consistent with their structure. An experi-mental procedure and spectral data for select products are provided.
General Procedure for Conjugate Radical Addition A solution of the appropriate Lewis acid (0.06 mmol) and bisoxazoline ligand (0.06 mmol) in CH₂Cl₂ (3 mL) was to stirred at r.t. for 30 min under N₂. Then, the substrate (0.20 mmol) in CH₂Cl₂ (1 mL) was added. After stirring for another 30 min, the solution was cooled to -78 °C in a dry ice-acetone bath. To the solution was added the radical precursor RX (2.0 mmol), Bu₃SnH (1.0 mmol), and Et₃B (1.0 M in hexane, 1.0 mL, 1.0 mmol) at -78 °C. A 10 mL aliquot of O₂ was then added via syringe. The reaction mixture was stirred at -78 °C for the time shown in Table [3] . After completion (TLC), ethylenediamine tetraacetic acid disodium salt solution (1.0 M in H₂O, 10 mL) was added to the reaction mixture. It was then extracted with CH₂Cl₂ (2 × 30 mL) and dried with Na₂SO₄. The crude product was purified by flash column chromatography to yield the alkylated products. Compound 3a Colorless liquid. The enantiomeric purity was determined by HPLC analysis (254 nm, 25 °C): t _R(minor) = 13.8 min; t _R(major) 15.0 min [Chiracel AD-H (0.46 cm × 25 cm; from Daicel Chemical Ind., Ltd.) hexane-i-PrOH (99:1), 0.5 mL/min] as 64% ee. [α]_D ²⁵ 14.2 (c 1.39, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 0.84 (d, J = 6.5 Hz, 3 H), 1.02 (d, J = 6.5 Hz, 3 H), 1.95-1.99 (m, 1 H), 3.21-3.25 (m, 1 H), 3.61 (dd, J = 17.5, 5.0 Hz, 1 H), 3.77 (dd, J = 17.5, 9.5 Hz, 1 H), 7.12-7.22 (m, 3 H), 7.22-7.40 (m, 2 H), 7.41-7.43 (m, 1 H), 7.73-7.76 (m, 1 H), 7.89-7.91 (m, 1 H), 8.68-8.69 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 20.5, 20.8, 33.5, 41.1, 47.6, 121.8, 125.9, 126.9, 127.9, 128.5, 136.7, 143.9, 148.8, 153.6, 201.0. IR (neat): 995, 1641, 1697, 2960, 3426 cm^-1. ESI-HRMS: m/z calcd for C₁₇H₁₉NONa⁺: 276.1364; found: 276.1349.
Compound 3b Colorless liquid. The enantiomeric purity was determined by HPLC analysis (254 nm, 25 °C): t _R(minor) = 14.9 min; t _R(major) = 17.9 min [Chiracel AD-H (0.46 cm × 25 cm; from Daicel Chemical Ind., Ltd.) hexane-i-PrOH (99:1) 0.5 mL/min] as 66% ee. [α]_D ²⁵ 13.8 (c 1.11, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 0.79 (d, J = 6.5 Hz, 3 H), 0.98 (d, J = 6.5 Hz, 3 H), 1.88-1.93 (m, 1 H), 3.14-3.18 (m, 1 H), 3.52 (dd, J = 17.5, 5.0 Hz, 1 H), 3.73 (dd, J = 17.5, 5.0 Hz, 1 H), 7.14 (d, 3 H), 7.19 (d, 3 H), 7.42-7.45 (m, 1 H), 7.75-7.88 (m, 1 H), 7.89-7.90 (m, 1 H), 8.66-8.67 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 20.3, 20.7, 33.4, 41.0, 47.1, 121.8, 127.0, 128.0, 129.8, 131.6, 136.8, 142.3, 148.8, 153.4, 200.8. IR (neat): 996, 1490, 1584, 1642, 1697, 2959, 3431 cm^-1. ESI-HRMS: m/z calcd for C₁₇H₁₈ClNONa⁺: 310.0975; found: 310.0962.
Compound 3g Colorless liquid. The enantiomeric purity was determined by HPLC analysis (254 nm, 25 °C): t _R(major) = 16.4 min; t _R(minor) = 18.9 min [Chiracel OJ-H (0.46 cm × 25 cm; from Daicel Chemical Ind., Ltd.) hexane-i-PrOH (99:1), 0.5 mL/min] as 43% ee. [α]_D ²⁵ 1.0 (c 0.87, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.85 (d, J = 6.0 Hz, 3 H), 0.87 (d, J = 6.0 Hz, 3 H), 1.24-1.30 (m, 1 H), 1.32-1.44 (m, 1 H), 1.60 (dt, J = 8.0, 7.6 Hz, 2 H), 1.74-1.78 (m, 1 H), 2.08-2.13 (m, 1 H), 2.56 (t, J = 7.6 Hz, 2 H), 3.08 (dd, J = 16.8, 6.1 Hz, 1 H), 3.15 (dd, J = 16.8, 6.1 Hz, 1 H), 7.11-7.14 (m, 3 H), 7.20-7.24 (m, 2 H), 7.42-7.45 (m, 1 H), 7.78-7.83 (m, 1 H), 8.00 (d, J = 7.6 Hz, 1 H), 8.65-8.67 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.7, 19.6, 29.3, 30.0, 31.2, 36.1, 38.9, 39.3, 121.8, 125.5, 126.9, 128.2, 128.3, 136.8, 142.7, 148.8, 153.8, 202.4. IR (neat): 995, 1583, 1642, 1692, 2957, 3431 cm^-1. ESI-HRMS: m/z calcd for C₂₀H₂₅NONa⁺: 318.1834; found: 318.1814.
Compound 3h Colorless liquid. The enantiomeric purity was determined by HPLC analysis (254 nm, 25 °C): t _R(minor) = 21.2 min; t _R(major) = 23.9 min [Chiracel AD-H (0.46 cm × 25 cm; from Daicel Chemical Ind., Ltd.) hexane-i-PrOH (99:1), 0.5 mL/min] as 69% ee. [α]_D ²⁵ 2.9 (c 1.00, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 0.81 (t, J = 7.5 Hz, 3 H), 1.62-1.65 (m, 1 H), 1.72-1.76 (m, 1 H), 3.19-3.22 (m, 1 H), 3.49 (dd, J = 17.5, 4.5 Hz, 1 H), 3.57 (dd, J = 17.5, 4.2 Hz, 1 H), 3.76 (s, 3 H), 6.80 (dd, J = 7.0, 2.5 Hz, 2 H), 7.16 (dd, J = 7.0, 2.5 Hz, 2 H), 7.41-7.44 (m, 1 H), 7.58-7.79 (m, 1 H), 7.93-7.95 (m, 1 H), 8.65-8.67 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 12.0, 29.7, 41.9, 44.4, 55.1, 113.6, 121.8, 126.9, 128.6, 136.8, 136.9, 148.8, 153.6, 157.8, 200.9. IR (neat): 995, 1035, 1247, 1512, 1584, 1612, 1640, 1691, 2961, 3436 cm^-1. ESI-HRMS: m/z calcd for C₁₇H₁₉NO₂Na⁺: 292.1313; found: 292.1325.
Compound 3i Colorless liquid. The enantiomeric purity was determined by HPLC analysis (254 nm, 25 °C): t _R(minor) = 22.9 min; t _R(major) = 24.9 min [Chiracel AD-H (0.46 cm × 25 cm; from Daicel Chemical Ind., Ltd.) hexane-i-PrOH (99:1), 0.5 mL/min] as 61% ee. [α]_D ²⁵ 2.8 (c 1.20, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 0.85 (t, J = 7.0 Hz, 3 H), 1.16-1.25 (m, 2 H), 1.56-1.74 (m, 2 H), 3.29-3.35 (m, 1 H), 3.48 (dd, J = 17.0, 6.0 Hz, 1 H), 3.55 (dd, J = 17.0, 7.5 Hz, 1 H), 3.75 (s, 3 H), 6.79 (dt, J = 6.5, 2.5 Hz, 2 H), 7.16 (dt, J = 6.5, 2.0 Hz, 2 H), 7.41-7.44 (m, 1 H), 7.76-7.79 (m, 1 H), 7.94 (dd, J = 8.0, 1.0 Hz, 1 H), 8.65-8.66 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.0, 20.6, 39.1, 39.9, 44.7, 55.1, 113.6, 121.8, 126.9, 128.5, 136.8, 137.2, 148.8, 153.6, 157.8, 200.8. IR (neat): 995, 1036, 1178, 1247, 1512, 1612, 1696, 2930, 2956, 3435 cm^-1. ESI-HRMS: m/z calcd for C₁₈H₂₁NO₂Na⁺: 306.1465; found: 306.1466.
Experimental Procedure for Cleavage of 2-Acylpyridine 3a To an oven-dried 6-dram vial containing a magnetic stirring bar, 4 Å MS (100 mg) and 3a (50.6 mg, 0.2 mmol), was added 2 mL of freshly distilled MeCN and MeOTf (0.6 mmol, 77 µL) successively under N₂ atmosphere. After stirring for 2 h at r.t., 6 M NaOH (50 µL) was added at 0 °C. The reaction temperature was increased to 90 °C and maintained at this temperature for 5 h. The reaction was cooled to r.t. and quenched with 2 M HCl (10 mL). The reaction was diluted with EtOAc and partitioned between EtOAc and H₂O. The combined organic phase was dried over anhyd Na₂SO₄, filtered, and evaporated. The residue was chromatographed on a silica gel column to give 6a in 95% yield (eluant: MeOH-CH₂Cl₂, 5:95).
Compound 6a [α]_D ²⁵ -21.4 (c 1.62, CHCl₃) {Lit.¹⁵ data for R-isomer (97% ee): [α]_D ²⁵ +33.54 (c 2.75, CHCl₃)}. ¹H NMR (400 MHz, CDCl₃): δ = 0.74 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 1.83-1.87 (m, 1 H), 2.60 (dd, J = 15.6, 9.6 Hz, 1 H), 2.78 (dd, J = 6.8, 15.6 Hz, 1 H), 2.83-2.87 (m, 1 H), 7.11-7.27 (m, 5 H), 10.39 (br, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.1, 20.5, 33.1, 38.1, 48.4, 126.4, 128.1, 128.2, 142.5, 179.0.

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