Enantioselective Organocatalytic Conjugate Addition of Aromatic Ketones to Nitrodienes

Abstract

The organocatalytic asymmetric nitro-Michael addition of aromatic ketones to nitrodiene using various chiral primary amine thioureas was described. In the presence of 30 mol% of N-[(1R,2R)-2-amino-1,2-diphenylethyl]-N′-benzylthiourea, the Michael adducts were obtained in good yields and excellent enantio­selectivity (94-98% ee).

organic asymmetric catalysis - aromatic ketones - nitro-Michael additions - nitrodiene - chiral bifunctional thiourea

References and Notes

For recent reviews, see:

1a Krause N. Hoffmann-Roder A. Synthesis  2001,  171 

1b Berner OM. Tedeschi L. Enders D. Eur. J. Org. Chem.  2002,  1877 

1c Sibi MP. Manyem S. Tetrahedron  2000,  56:  8033 

1d Sulzer-Mossé J. Alexakis A. Chem. Commun.  2007,  3123 

1e Vicario JL. Badía D. Carillo L. Synthesis  2007,  2065 

2 Sakthivel K. Notz W. Bui T. Barbas CF. J. Am. Chem. Soc.  2001,  123:  5260 

3 List B. Pojarlier P. Martin HJ. Org. Lett.  2001,  3:  2423 

For recent reviews, see:

4a Tsogoeva SB. Eur. J. Org. Chem.  2007,  1701 

4b Almasi D. Alonso DA. Nájera C. Tetrahedron: Asymmetry  2007,  18:  299 

Very recent references for organocatalyzed asymmetric nitro-Michael reaction:

5a Zhu SL. Yu SY. Ma DW. Angew. Chem. Int. Ed.  2008,  47:  545 

5b Garcia P. Ladepeche A. Halder R. List B. Angew. Chem. Int. Ed.  2008,  47:  4719 

5c Hayashi Y. Itoh T. Ohkubo M. Ishikawa H. Angew. Chem. Int. Ed.  2008,  47:  4722 

5d Rabalakos C. Wulff WD. J. Am. Chem. Soc.  2008,  130:  13524 

5e Dong XQ. Teng HL. Wang CJ. Org. Lett.  2009,  11:  1265 

5f Peng FZ. Shao ZH. Fan BM. Song H. Li GP. Zhang HB. J. Org. Chem.  2008,  73:  5202 

5g Luo J. Xu LW. Hay RAS. Lu YX. Org. Lett.  2009,  11:  437 

5h Zhou W. Liu H. Du DM. Org. Lett.  2008,  10:  2817 

5i Ni BK. Zhang QY. Dhungana K. Headley AD. Org. Lett.  2009,  11:  1037 

5j Tan B. Zeng XF. Lu YP. Chua PJ. Zhong GF. Org. Lett.  2009,  11:  1927 

5k Chandrasekhar S. Tiwari B. Parida B. Reddy C. Tetrahedron: Asymmetry  2008,  19:  495 

5l Quintard A. Bournaud C. Alexakis A. Chem. Eur. J.  2008,  14:  7504 

5m Xu D. Yue H. Luo S. Xia A. Zhang S. Xu Z. Org. Biomol. Chem.  2008,  6:  2054 

6 Hayashi Y. Okano T. Aratake S. Hazelard D. Angew. Chem. Int. Ed.  2007,  46:  4922 

7 Tan B. Chua P. Li Y. Zhong G. Org. Lett.  2008,  10:  2437 

8 Evans DA. Mito S. Seidel D. J. Am. Chem. Soc.  2007,  129:  11583 

9 Belot S. Massaro A. Tenti A. Mordini A. Alexakis A. Org. Lett.  2008,  10:  4557 

10a Tsogoeva SB. Wei S.-W. Chem. Commun.  2006,  1451 

10b Huang H. Jacobsen EN. J. Am. Chem. Soc.  2006,  128:  7170 

11

All reactions were conducted in solvent (2 mL) using nitrodiene 2a (0.2 mmol) and acetophenone 3a (1 mmol, 5 equiv) in the presence of 10 mol% of catalyst 1d. Results of different solvent: toluene (30% yield, 97% ee), n-hexane (25% yield, 92% ee), i-PrOH (18% yield, 85% ee), EtOH (5% yield, 88% ee), CH₂Cl₂ (15% yield, 97% ee), CHCl₃ (16% yield, 97% ee), THF (5% yield, 95% ee), Et₂O (17% yield, 96% ee).

12a Yalalov DA. Tsogoeva SB. Schmatz S. Adv. Synth. Catal.  2006,  348:  826 

12b Wei S.-W. Yalalov DA. Tsogoeva SB. Schmatz S. Catal. Today  2007,  121:  151 

13

General Procedure for Enantioselective Conjugate Addition of Ketone with Nitrodiene
Organocatalyst 1d (43.32 mg, 0.12 mmol) was added to a vial containing acetophenone 3 (4 mmol) and toluene (2 mL) at r.t. The mixture was stirred vigorously for 10 min, and then the corresponding nitrodiene 2 (0.4mmol) was added. The reaction mixture was stirred at r.t. for 96 h. Then the solvent was evaporated, and the residue was purified by flash silica gel chromatography (PE-EtOAc, 10:1) to afford the corresponding product. The ee value was determined by chiral HPLC.
Characterization Data of Representative Compounds Compound 4a: 63% yield, 97% ee, [a]_D ^²0 +3.5 (c 1.0, CHCl₃). HPLC analysis [Chiralpak AD-H column, l = 254 nm, hexane-i-PrOH (90:10), flow rate 1.0 mL/min]: t _R = 16.0 min(major), 18.4 min(minor). ^¹H NMR (500 MHz, CDCl₃): d = 7.96 (d, J = 7.8 Hz, 2 H), 7.61-7.58 (m, 1 H), 7.50-7.47 (m, 2 H), 7.34-7.28 (m, 4 H), 7.25-7.23 (m, 1 H), 6.58 (d, J = 15.8 Hz, 1 H), 6.17 (dd, J = 15.8, 7.6 Hz, 1 H), 4.74-4.70 (m, 1 H), 4.64-4.60 (m, 1 H), 3.76 (m, 1 H), 3.30 (d, J = 6.3 Hz, 2 H). IR (film): n = 2958, 2918, 2850, 1679, 1542, 1450, 1410, 1379, 1365, 1271, 1218, 969, 758, 691 cm^-¹. HRMS: m/z calcd for C₁₈H₁₇NO₃ [M]: 295.1208; found: 295.1210.