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Synlett 2008(1): 83-88  
DOI: 10.1055/s-2007-992386
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
Further Information

Publication History

Received 7 August 2007
Publication Date:
03 December 2007 (online)

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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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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.