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

Abstract

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

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

References and Notes

1a Noyori R. Asymmetric Catalysis in Organic Synthesis   Wiley-Interscience; New York: 1994. 

1b Gawley R. Aube J. Asymmetric Synthesis   Pergamon; New York: 1996. 

2a Evans DA. Chapman KT. Bisaha J. J. Am. Chem. Soc.  1988,  110:  1238 

2b Castellino S. Dwight WJ.
J. Am. Chem. Soc.  1993,  115:  2986 

2c Montaudo G. Librando V. Caccamese S. Maravigna P. J. Am. Chem. Soc.  1973,  95:  6365 

2d Corminboeuf O. Renaud P. Org. Lett.  2002,  4:  1731 

2e Gnas Y. Glorius F. Synthesis  2006,  1899 

Oxazolidinones:

3a Evans DA. Miller SJ. Lectka T. J. Am. Chem. Soc.  1993,  115:  6460 

3b Evans DA. Miller SJ. Lectka T. von Matt P. J. Am. Chem. Soc.  1999,  121:  7559 

Acyl pyrazoles:

3c Sibi MP. Shay JJ. Liu M. Jasperse CP. J. Am. Chem. Soc.  1998,  120:  6615 

3d Itoh K. Kanemasa S. J. Am. Chem. Soc.  2002,  124:  13394 

Imides:

3e Myers JK. Jacobsen EN. J. Am. Chem. Soc.  1999,  121:  8959 

3f Sammis GM. Jacobsen EN. J. Am. Chem. Soc.  2003,  125:  4442 

Pyrazolidinones:

3g Sibi MP. Stanley LM. Nie X. Venkatraman L. Liu M. Jasperse CP. J. Am. Chem. Soc.  2007,  129:  395 

4 For a study on achiral templates in Diels-Alder reactions, see: Sibi MP. Chen J. Stanley L. Synlett  2007,  298 

Acyl imidazoles:

5a Evans DA. Fandrick KR. Song H.-J. J. Am. Chem. Soc.  2005,  127:  8942 

5b Evans DA. Fandrick KR. Org. Lett.  2006,  8:  2249 

5c Evans DA. Song H.-J. Fandrick KR. Org. Lett.  2006,  8:  3351 

α-Hydroxy ketones:

6a Palomo C. Oiarbide M. Kardak BG. Garcia JM. Linden A. J. Am. Chem. Soc.  2005,  127:  4154 

6b Palomo C. Oiarbide M. Garcia JM. Gonzalez A. Arceo E. J. Am. Chem. Soc.  2003,  125:  13942 

Aza chalcones:

7a Matsumoto K. Jitsukawa K. Masuda H. Tetrahedron Lett.  2005,  46:  5687 

7b Otto S. Boccaletti G. Engberts JBFN. J. Am. Chem. Soc.  1998,  120:  4238 

7c Wittkopp A. Schreiner PR. Chem. Eur. J.  2003,  9:  407 

7d Rispens T. Engberts JBFN. J. Org. Chem.  2002,  67:  7369 

7e Otto S. Engberts JBFN. Kwak JCT. J. Am. Chem. Soc.  1998,  120:  9517 

For selected reviews on enantioselective radical reactions, see:

8a Sibi MP. Manyem S. Zimmerman J. Chem. Rev.  2003,  103:  3263 

8b Zimmerman J. Sibi MP. Top. Curr. Chem.  2006,  263:  107 

8c Sibi MP. Porter NA. Acc. Chem. Res.  1999,  32:  163 

Enantioselective conjugate radical additions using different achiral templates. For oxazolidinones, see:

9a Sibi MP. Ji J. Wu JH. Gurtler S. Porter NA. J. Am. Chem. Soc.  1996,  118:  9200 

Imides:

9b Sibi MP. Petrovic G. Zimmerman J. J. Am. Chem. Soc.  2005,  127:  2390 

Pyrazoles:

9c Sibi MP. Shay JJ. Ji J. Tetrahedron Lett.  1997,  38:  5955 

Pyrazolidinones:

9d Sibi MP. Prabagaran N. Synlett  2004,  2421 

Naphthosultams:

9e Sibi MP. Sausker JB. J. Am. Chem. Soc.  2002,  124:  984 

Pyrones:

9f Sibi MP. Zimmerman J. J. Am. Chem. Soc.  2006,  128:  13346 

10 Lee S. Lim CJ. Kim S. Subramaniam R. Zimmerman J. Sibi MP. Org. Lett.  2006,  8:  4311 

11a de Vries AHM. Meetsma A. Feringa BL. Angew. Chem., Int. Ed. Engl.  1996,  35:  2374 

11b G u C.-L. Liu L. Sui Y. Zhao J.-L. Wang D. Chen Y.-J. Tetrahedron: Asymmetry  2007,  18:  455 

11c Zhang Z. Dong Y.-w. Wang G.-w. Komatsu K. Synlett  2004,  61 

12

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.

13a Reetz MT. Jiao N. Angew. Chem. Int. Ed.  2006,  45:  2416 

13b Roelfes G. Boersma AJ. Feringa BL. Chem. Commun.  2006,  635 

14c For computational data on zinc triflate mediated Diels-Alder reaction using azachalcones with s-cis-rotamer geometry, see: Domingo LR. Andres J. Alves CN. Eur. J. Org. Chem.  2002,  2557 

14 Sibi MP. Ji J. J. Org. Chem.  1997,  62:  3800