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Synlett 2009(10): 1627-1630  
DOI: 10.1055/s-0029-1217331
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© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Nitrocyclopropanation of α,β-Unsaturated α-Cyanoimides Catalyzed by Bifunctional Thiourea

Tsubasa Inokuma, Shota Sakamoto, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax: +81(75)7534569; e-Mail: takemoto@pharm.kyoto-u.ac.jp;
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Publication History

Received 30 January 2009
Publication Date:
02 June 2009 (online)

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Abstract

The organocatalyzed asymmetric cyclopropanation of bromonitromethane with α-cyano-α,β-unsaturated imides is described. In addition, the same bifunctional thiourea was revealed to be a powerful catalyst for preparing these α-cyanoimides by Knoeve­nagel condensation.

Key words

asymmetric organocatalysis - cyclopropanation - Michael addition - α,β-unsaturated imides

    References

  • 1a Andres N. Wolf H. Zähner H. Rössner E. Zeek A. König WA. Sinnwell V. Helv. Chim. Acta  1989,  72:  426 
    Google Scholar
  • 1b Rössner E. Zeek A. König WA. Angew. Chem., Int. Ed. Engl.  1990,  29:  64 
    Google Scholar
  • 1c Gootz TD. Brighty KE. Med. Res. Rev.  1996,  16:  433 
    Google Scholar
  • 1d Brighty KE. Castaldi JM. Synlett  1996,  1097 
    Google Scholar
  • 1e Zlatopolskiy BD. Loscha K. Alvermann P. Kozhushkov SI. Nikolaev SV. Zeeck A. de Meijere A. Chem. Eur. J.  2004,  10:  4708 
    Google Scholar
  • 2a Ballini R. Bosica G. Fiorini D. Palmieri A. Petrini M. Chem. Rev.  2005,  105:  933 
    Google Scholar
  • 2b Gnad F. Reiser O. Chem. Rev.  2003,  103:  1603 
    Google Scholar
  • 2c Rosini G. Ballini R. Synthesis  1988,  833 
    Google Scholar
  • 3a Pellisier H. Tetrahedron  2008,  64:  7041 
    Google Scholar
  • 3b For an example, see: Donaldson WA. Tetrahedron  2001,  57:  8589 
    Google Scholar
  • 3c Moreau B. Charette AB. J. Am. Chem. Soc.  2005,  127:  18014 
    Google Scholar
  • 4a McCooey SH. McCabe T. Connon SJ. J. Org. Chem.  2006,  71:  7494 
    Google Scholar
  • 4b Fan R. Ye Y. Li W. Wang L. Adv. Synth. Catal.  2008,  350:  2488 
    Google Scholar
  • 4c Hansen HM. Longbottom DA. Ley SV. Chem. Commun.  2006,  4838 
    Google Scholar
  • 4d Vesely J. Zhao G. Bartoszewicz A. Cordova A. Tetrahedron Lett.  2008,  49:  4209 
    Google Scholar
  • 5a Xie J. Yoshida K. Takasu K. Takemoto Y. Tetrahedron Lett.  2008,  49:  6910 
    Google Scholar
  • 5b Inokuma T. Hoashi Y. Takemoto Y. J. Am. Chem. Soc.  2006,  128:  9413 
    Google Scholar
  • 5c Okino T. Hoashi Y. Takemoto Y. J. Am. Chem. Soc.  2003,  125:  12672 
    Google Scholar
  • 6 Jones G. Org. React.  1967,  15:  204 
    Google Scholar
  • 8 Moison H. Boullet F. Foucaud A. Tetrahedron  1987,  43:  537 
    CrossrefGoogle Scholar
  • 9 Hayashi T. J. Org. Chem.  1966,  31:  3253 
    CrossrefGoogle Scholar
7

Knoevenagel Reaction Catalyzed by Thiourea 1 A mixture of 3e (40.2 mg, 0.195 mmol), benzaldehyde 2a (22 µL, 0.215 mmol), and(rac)-thiourea 1 (8.1 mg, 0.0195 mmol) in toluene (2.0 mL) was stirred at 80 ˚C for 25 h. After the reaction mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography with hexane-EtOAc (3:1) to afford 4e (41.5 mg, 72%) as white needles.
( E )- N -(2-Cyano-3-phenylacryloyl)-2-fluorobenzamide (4e) White needles; R f  = 0.54 (hexane-EtOAc, 1:1); mp 186-188 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 9.96 (d, J = 16.3 Hz, 1 H) 8.47 (s, 1 H), 8.16 (td, J = 6.3, 1.7 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 2 H), 7.65-7.60 (m, 2 H), 7.55 (dd, J = 8.0, 7.2 Hz, 2 H), 7.36 (td, J = 7.7, 7.2 Hz, 1 H), 7.25 (dd, J = 12.0, 8.0 Hz). ¹³C NMR (126 MHz, CDCl3): δ = 161.5, 161.0 (2 C), 160.6 (d, J = 249 Hz), 158.3, 156.4, 135.6 (d, J = 9.9 Hz), 133.9, 132.7, 131.3, 129.2, 125.6 (d, J = 3.0 Hz), 116.0 (d, J = 10.2 Hz), 116.5 (d, J = 24.6 Hz), 116.0, 103.4. IR (KBr): 3364, 1737, 1513, 1289 cm-¹. MS-FAB+: m/z (%) = 295(10) [MH+], 154 [100]. Anal. Calcd for C17H11FN2O2C: 69.38, H: 3.77, N: 9.52. Found C: 69.57, H: 3.81, N: 9.55.

10

o-Fluorobenzimide is a better substrate for asymmetric Michael addition than nonsubstituted benzimide due to the intramolecular hydrogen bond between imide proton and fluoro atom, see: Inokuma T., Nagamoto Y., Sakamoto S., Miyabe H., Takasu K., Takemoto Y.; Heterocycles; 2009, in press

11

CCDC 717740 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

12

The methanolysis [cat. Er(OTf)3, MeOH, 60 ˚C] of 4d and 4e provided the same product 4a. Therefore, we concluded that the compounds 4a, 4d, and 4e have the same relative configuration. In addition, the minor product 6e was converted into 5e by the treatment with a catalytic amount of Et3N. The result suggests that 6e was a C2 epimer of 5e.

13

The relative configuration of 7e was assigned as follows: From the coupling constant of C2 and C3 protons (5e: 6.4 Hz, 7e: 6.6 Hz) in ¹H NMR, the relative configuration between the phenyl and nitro group of both 5e and 7e was determined to be trans. Then, 7e was deduced to be a C1 epimer of 5e.

14

We tried the one-pot process of Knoevenagel reaction and cyclopropanation. But, disappointingly, we obtained the same product 5e with lower ee (58% yield, 63:37 dr, 17% ee).

15

General Procedure for the Thiourea-Catalyzed Nitrocyclopropanation To a mixture of 4e (29.7 mg, 0.1 mmol) and thiourea 1 (4.7 mg, 10 mol%) in toluene (0.1 M) were added bromonitromethane (10 µL, 0.15 mmol) and Et3N (20 µL, 0.15 mmol) at -60 ˚C during the indicated period. The reaction mixture was directly purified by silica gel column chromatography with hexane-EtOAc (3:1) to afford 5e (19 mg, 53%, 97% ee) as white amorphous solids and 7e (11 mg, 31%, 90% ee) as a brown oil.
1-Cyano-2-nitro-3-phenylcyclopropanecarbonyl)-2-fluorobenzamide (5e; Major Diastereomer) White amorphous solids; R f  = 0.48 (hexane-EtOAc, 1:1); [α]D ²6 -19.01 (c 0.71, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 9.41 (d, J = 16.3 Hz, 1 H), 8.14 (dt, J = 6.0, 1.7 Hz, 1 H), 7.64-7.67 (m, 1 H), 7.48-7.40 (m, 5 H), 7.36 (dd, J = 7.7, 7.4 Hz, 1 H), 7.23 (dd, J = 12.3, 8.4 Hz, 1 H), 5.41 (d, J = 6.4 Hz, 1 H), 4.34 (d, J = 6.4 Hz, 1 H). ¹³C NMR (126 MHz, CDCl3): δ = 161.9, 161.8, 160.8 (d, J = 241 Hz), 159.7, 136.4 (d, J = 9.9 Hz), 132.9, 129.6, 129.2 (d, J = 24.6 Hz), 128.0, 125.6 (d, J = 3.6 Hz), 118.1 (d, J = 9.9 Hz), 116.7 (d, J = 24.6 Hz), 112.2, 68.4, 37.7, 35.9. IR (CHCl3): 3400 (NH), 2247 (CN), 1699 (C=O), 1617 (NO2), 1559 (C=O). MS-FAB-: m/z (%) = 352(100) [M - H]. HRMS-FAB-: m/z calcd for C18H11FN3O4 [M - H]: 352.0733; found: 352.0699. HPLC: Daicel Chiralcel AS-H; hexane-i-PrOH (90:10), 1 mL min-¹, 254 nm: t R(minor) = 67.8 min; t R(major) = 76.1 min.
1-Cyano-2-nitro-3-phenylcyclopropanecarbonyl)-2-fluorobenzamide (7e; Minor Diastereomer) Brown oil; R f  = 0.40 (hexane-EtOAc, 1:1); [α]D ²6 +91.9 (c 0.19, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 9.35 (d, J = 15.8 Hz, 1 H), 8.10 (dt, J = 6.6, 1.4 Hz, 1 H), 7.61-7.65 (m, 1 H), 7.27-7.36 (m, 5 H), 7.26 (dd, J = 10.1, 6.0 Hz, 1 H), 7.19 (dd, J = 8.3, 4.0 Hz, 1 H), 5.79 (d, J = 6.6 Hz, 1 H), 4.45 (d, J = 6.6 Hz, 1 H). ¹³C NMR (126 MHz, CDCl3): δ = 161.6, 161.8, 159.4 (d, J = 263 Hz), 158.7, 136.5 (d, J = 9.9 Hz), 132.9, 129.6, 129.2 (d, J = 24.6 Hz), 128.0, 125.6 (d, J = 3.6 Hz), 118.4 (d, J = 9.9 Hz), 116.6 (d, J = 24.6 Hz), 112.5, 65.1, 41.1, 34.1. IR (CHCl3): 3400 (NH), 2244 (CN), 1699 (C=O), 1615 (NO2), 1563 (C=O). MS-FAB-: m/z (%) = 352(20) [M - H]. HRMS-FAB-: m/z calcd for C18H11FN3O4 [M - H]: 352.0733; found: 352.0722. HPLC: Daicel Chiralcel AS-H; hexane-i-PrOH (90:10), 1 mL min-¹, 254 nm: t R(minor) = 91.0 min; t R(major) = 103.9 min.