Download PDF
Synlett 2008(6): 827-830  
DOI: 10.1055/s-2008-1042900
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Versatile Entry to 3-Unsubstituted 2-Isoxazolines

Antti Pohjakallio, Petri M. Pihko*
Laboratory of Organic Chemistry, Helsinki University of Technology, P.O. Box 6100, 02015 TKK, Espoo, Finland
Fax: +358(9)4512538; e-Mail: petri.pihko@tkk.fi;
Further Information

Publication History

Received 20 December 2007
Publication Date:
11 March 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

A new catalytic method for the preparation of 3-unsubstituted 2-isoxazolines is reported. The isoxazolines are easily prepared from the aliphatic α,β-unsaturated aldehydes and simple oximes in the presence of an anilinium salt catalyst.

Key words

aldehydes - oximes - catalysis - heterocycles - isoxazoline

    References and Notes

  • 1a Easton CJ. Hughes C. Merricc M. Savage GP. Simpson GW. Adv. Heterocycl. Chem.  1994,  60:  261 
    CrossrefGoogle Scholar
  • 1b For examples of the use of 2-isoxazolines in total synthesis setting, see: Kozikowski AP. Acc. Chem. Res.  1984,  17:  410 
    CrossrefGoogle Scholar
  • 2 Lang SA. Lin Y.-i. In Comprehensive Heterocyclic Chemistry   Vol. 6:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.88-98  
    Google Scholar
  • 3 Huisgen R. Christl M. Chem. Ber.  1973,  106:  3291 
    CrossrefGoogle Scholar
  • 4a Torssell K. Zeuthen O. Acta Chem. Scand. Ser. B  1978,  32:  118 
    CrossrefGoogle Scholar
  • 4b Sharma SC. Torssell K. Acta Chem. Scand. Ser. B  1979,  33:  379 
    CrossrefGoogle Scholar
  • 4c Das NB. Torssell KBG. Tetrahedron  1983,  39:  2247 
    CrossrefGoogle Scholar
  • 5 Jacquier R. Olive J.-L. Petrus C. Petrus F. Tetrahedron Lett.  1975,  16:  2337 
    CrossrefGoogle Scholar
  • 6 Pennicott L. Lindell S. Synlett  2006,  463 
    Article in Thieme ConnectGoogle Scholar
  • 7 Bertelsen S. Diner P. Johansen RL. Jørgensen KA.
    J. Am. Chem. Soc.  2007,  129:  1536 
    CrossrefGoogle Scholar
  • 8 Dirksen A. Hackeng TM. Dawson PE. Angew. Chem. Int. Ed.  2006,  45:  7581 
    CrossrefGoogle Scholar
  • 9 Acetone oxime has previously been used as a transoximation reagent. See: Juskowiak M. Krzyzanowski P. J. Prakt. Chem.  1989,  331:  870 
    Google Scholar
  • 11 Erkkilä A. Pihko PM. Clarke M.-R. Adv. Synth. Catal.  2007,  349:  802 
    CrossrefGoogle Scholar
  • 13 A related reaction for the preparation of 3-substituted 2-isoxazolines from β,γ-unsaturated ketones has been proposed to follow this mechanism. See: Norman AL. Shurrush KA. Calleroz AT. Mosher MD. Tetrahedron Lett.  2007,  48:  6849 
    CrossrefGoogle Scholar
  • 16 Gibert JP. Jacquier R. Pétrus C. Bull. Soc. Chim. Fr.  1979,  281 
    Google Scholar
10

For the preparation of volatile 10a, the use of acetaldehyde oxime under modified conditions is recommended. See ref. 21.

12

In control experiments, the reaction products did not equilibrate to starting materials when exposed to the reaction conditions [e.g., 3-pentanone (30 mol%), catalyst (50 mol%), r.t., 3 h].

14

We initially believed that this species is hydroxylamine. However, in control experiments, hydroxylammonium diphenylphosphate turned out to be relatively poor catalyst for the reaction, and exhibited a similar induction period than acid catalysts.

15

Moderate enantioselectivities (up to 63%) could be obtained using a chiral imidazolidinone base along with strong acids in colder temperatures. However, in these cases, the reaction rate and conversion were poor. Attempts to obtain enantioenriched products in the presence of chiral phosphoric acids failed. These studies will be reported separately.

17

General Procedure for the Preparation of 2-Isoxazolines Using Diethylketone Oxime To a solution of amine salt 11 (37.1 mg, 0.1 mmol, 20.7 mol%) in toluene (2.5 mL) at 0 °C was added aldehyde (0.6 mmol, 120 mol%). After 4 min, diethylketone oxime (55 µL, 0.5 mmol, 100 mol%) was added and the mixture was stirred at 0 °C for the indicated period of time. The reaction mixture was diluted with Et2O (15 mL), washed with sat. NaHCO3 (5 mL), and 5% oxalic acid (2 × 5 mL). The layers were separated. The acidic and basic aqueous layers were back-extracted separately with Et2O (2 × 6 mL and 5 mL, respectively). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to a volume of 1-2 mL. The residue was purified by column chromatography.

18

Analytical Data of Compound 10c Reaction time: 6.5 h; yield 0.076 g (86%); eluent: gradient: 10-30% MTBE in hexane; R f = 0.35 (40% EtOAc in hexane). IR (film): 3062, 3026, 2924, 2589, 1600, 1495, 1454, 1275, 843 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.31-7.27 (m, 2 H), 7.21-7.18 (m, 3 H), 7.12 (t, 1 H, J = 1.8 Hz), 4.52 (m, 1 H), 3.04 (ddd, 1 H, J 1 = 1.8 Hz, J 2 = 10.5 Hz, J 3 = 17.4 Hz), 2.80 (ddd, 1 H, J 1 = 5.6 Hz, J 2 = 9.5 Hz, J 3 = 13.9 Hz), 2.72 (ddd, 1 H, J 1 = 6.9 Hz, J 2 = 9.3 Hz, J 3 = 13.9 Hz), 2.62 (ddd, 1 H, J 1 = 1.8 Hz, J 2 = 7.8 Hz, J 3 = 17.4 Hz), 2.01 (dddd, 1 H, J 1 = 5.6 Hz, J 2 = 7.9 Hz, J 3 = 9.3 Hz, J 4 = 13.6 Hz), 1.83 (dddd, 1 H, J 1 = 5.2 Hz, J 2 = 6.9 Hz, J 3 = 9.5 Hz, J 4 = 13.6 Hz). 13C NMR (100 MHz, CDCl3): 145.9, 141.1, 128.5, 126.0, 77.8, 40.5, 36.9, 31.8. HRMS (ESI+): m/z calcd for [C11H13NO + H]: 176.1075; found: 176.1070.

19

Analytical Data of Compound 10d Reaction time: 15.5 h; yield 0.061 g (63%); eluent: 10-30% MTBE in hexane; R f = 0.25 (50% EtOAc in hexane). IR (film): 3419, 3064, 3031, 2918, 2852, 1726, 1602, 1496, 1453, 1367, 1114, 1027, 838 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.37-7.27 (m, 5 H), 7.12 (t, 1 H, J = 1.8 Hz), 4.71 (dtdd, 1 H, J 1 = 0.5 Hz, J 2 = 5.0 Hz, J 3 = 7.4 Hz, J 4 = 10.7 Hz), 4.58 (s, 2 H), 3.58 (dd, 1 H, J 1 = 5.0 Hz, J 2 = 10.4 Hz), 3.52 (dd, 1 H, J 1 = 5.0 Hz, J 2 = 10.4 Hz), 3.04 (ddd, 1 H, J 1 = 1.8 Hz, J 2 = 10.7 Hz, J 3 = 17.6 Hz), 2.90 (ddd, 1 H, J 1 = 1.8 Hz, J 2 = 7.4 Hz, J 3 = 17.6 Hz). 13C NMR (100 MHz, CDCl3): δ = 145.8, 137.8, 128.4, 127.71, 127.67, 77.1, 73.5, 70.7, 37.8. HRMS (ESI+): m/z calcd for [C11H13NO2 + H]: 192.1025; found: 192.1028.

20

Analytical Data of Compound 10h Reaction time: 15 h; yield 0.072 g (73%); eluent: gradient 50-65% MTBE in hexane; R f = 0.23 (30% MTBE in hexane). IR (film): 2949, 2862, 2738, 1723, 1690, 1657, 1436, 1273, 1161, 1128, 974 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.11 (t, 1 H, J = 1.7 Hz), 6.93 (td, 1 H, J 1 = 7.0 Hz, J 2 = 15.6 Hz), 5.82 (td, 1 H, J 1 = 1.6 Hz, J 2 = 15.6 Hz), 4.50 (m, 1 H), 3.70 (s, 3 H), 3.05 (ddd, 1 H, J 1 = 1.8 Hz, J 2 = 10.5 Hz, J 3 = 17.4 Hz), 2.60 (ddd, 1 H, J 1 = 1.8 Hz, J 2 = 7.9 Hz, J 3 = 17.4 Hz), 2.25 (m, 2 H), 1.72-1.47 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ = 166.9, 148.6, 145.8, 121.4, 78.2, 51.4, 40.5, 34.5, 31.8, 24.0. HRMS (ESI+): m/z calcd for [C10H15NO3 + Na]: 220.0950; found: 220.0946.

21

Synthesis of Compound 10b To a solution of salt 11 (0.743 g, 2.08 mmol, 10.4 mol%) in CHCl3 (50 mL) at 0 °C was added crotonaldehyde (1.99 mL, 24 mmol, 120 mol%). After 6 min, acetaldehyde oxime (1.23 mL, 20 mmol, 100 mol%) was added. The ice bath was removed and the reaction mixture was stirred at r.t. After 6 h, the reaction mixture was washed with 10% oxalic acid solution (10 mL) and then with 5% oxalic acid (30 mL, 20 mL). Hexanes (10 mL) was added22 and the layers were separated. The organic layer was washed with sat. NaHCO3 (20 mL) and both acidic and basic aqueous phases were back-extracted separately with Et2O (50 mL). The combined organic phases were dried (Na2SO4) and concentrated by distillation. The dark brown residue was distilled under reduced pressure (15 mmHg, water-aspirator vacuum) to give 0.871 g (51%) of 10b as colorless liquid (purity >95% by 1H NMR).
Analytical Data of Compound 10b Bp 52 °C/15 mmHg (lit. 65 °C/25 mmHg);16 R f = 0.57 (50% EtOAc in hexane, KMnO4 stain). IR (film): 2976, 2918, 1680, 1641, 1599, 1438, 1379, 1275, 843 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.11 (br s, 1 H), 4.71-4.60 (m, 1 H), 3.07 (ddd, 1 H, J 1 = 1.8 Hz, J 2 = 10.3 Hz, J 3 = 17.3 Hz), 2.57 (ddd, 1 H, J 1 = 1.8 Hz, J 2 = 7.7 Hz, J 3 = 17.3 Hz), 1.32 (d, 3 H, J = 6.2 Hz). 13C NMR (100 MHz, CDCl3): δ = 145.8, 74.8, 42.0, 20.7. HRMS (ESI+): m/z calcd for [C4H7NO - H]: 84.0449; found: 84.0453.

22

The catalyst is highly soluble in chlorinated solvents, but less soluble in hydrocarbons. Addition of hexanes assists in catalyst removal. The same yield has also been obtained in 50 mmol scale by direct distillation of the reaction mixture, without attempts to remove the catalyst components.