A Convenient and Chemoselective Method for the Reductive Ring Cleavage of Isoxazoles and Isoxazolines with EtMgBr/Ti(Oi-Pr)₄ Reagent

Abstract

The interaction of 3,5-disubstituted isoxazoles and isoxazolines with low-valent titanium isopropoxide reagent, prepared by treatment of Ti(Oi-Pr)₄ with one equivalent of EtMgBr in diethyl ether, leads to the reductive cleavage of the five-membered heterocycle to afford the corresponding β-enaminoketones and β-hy­droxy­ketones. The reaction proceeds smoothly with isoxazoline derivatives bearing alkynyl, hydroxymethyl, diethylacetal, acetyl, alkoxycarbonyl, alkylthiomethyl or alkylsulfonylmethyl substituents.

low valent titanium - Grignard reagents - isoxazoles - isoxazolines - reduction

References

<A NAME="RG16704ST-1A">1a</A> Curran DP. Adv. Cycloaddit.  1988,  1:  129 

<A NAME="RG16704ST-1B">1b</A> Lipshutz BH. Chem. Rev.  1986,  86:  795 

<A NAME="RG16704ST-1C">1c</A> Torssell KBG. Nitrile Oxides, Nitrones, and Nitronates in Organic Chemistry   VCH; Stuttgart: 1988. 

<A NAME="RG16704ST-2A">2a</A> Akhrem AA. Lakhvich FA. Khripach VA. Chem. Heterocycl. Compd. (Engl. Transl.)  1981,  853 

<A NAME="RG16704ST-2B">2b</A> Kozikowski AP. Acc. Chem. Res.  1984,  17:  410 

<A NAME="RG16704ST-2C">2c</A> Baraldi PG. Barco A. Benetti S. Pollini GP. Simoni D. Synthesis  1987,  857 

<A NAME="RG16704ST-2D">2d</A> Lakhvich FA. Koroleva EV. Akhrem AA. Chem. Heterocycl. Compd. (Engl. Transl.)  1989,  359 

<A NAME="RG16704ST-2E">2e</A> Litvinovskaya RP. Khripach VA. Russ. Chem. Rev (Engl. Transl.)  2001,  70:  405 

<A NAME="RG16704ST-2F">2f</A> Kotyatkina AI. Zhabinsky VN. Khripach VA. Russ. Chem. Rev. (Engl. Transl.)  2001,  70:  641 

<A NAME="RG16704ST-3A">3a</A> Stango d’Alcontres G. Gazz. Chim. Ital.  1950,  80:  41 

<A NAME="RG16704ST-3B">3b</A> Casnati G. Quilico A. Ricca A. Finzi PV. Tetrahedron Lett.  1966,  233 

<A NAME="RG16704ST-3C">3c</A> Akhrem AA. Lakhvich FA. Khripach VA. Klebanovich IB. Dokl. Akad. Nauk SSSR  1979,  244:  615 ; Chem. Abstr. 1979, 91, 19949

<A NAME="RG16704ST-3D">3d</A> Curran DP. J. Am. Chem. Soc.  1983,  105:  5826 

<A NAME="RG16704ST-3E">3e</A> Curran DP. Scanga SA. Fenk CJ. J. Org. Chem.  1984,  49:  3474 

<A NAME="RG16704ST-4">4</A> Buchi G. Vederas JC. J. Am. Chem. Soc.  1972,  94:  9128 

<A NAME="RG16704ST-5">5</A> Andersen SH. Sharma KK. Torsell KBG. Tetrahedron  1983,  39:  2241 

<A NAME="RG16704ST-6A">6a</A> Nitta M. Kobayashi T. J. Chem. Soc., Chem. Commun.  1982,  877 

<A NAME="RG16704ST-6B">6b</A> Baraldi PG. Barco A. Benetti S. Manfredini S. Simoni D. Synthesis  1987,  276 

<A NAME="RG16704ST-7A">7a</A> Natale NR. Tetrahedron Lett.  1982,  23:  5009 

<A NAME="RG16704ST-7B">7b</A> Bode JW. Carreira EM. Organic Lett.  2001,  3:  1587 

<A NAME="RG16704ST-8">8</A> Ignatovich ZhV. Chernikhova TV. Skupskaya RV. Bondar NF. Koroleva EV. Lakhvich FA. Chem. Heterocycl. Compd. (Engl. Transl.)  1999,  248 

<A NAME="RG16704ST-9">9</A> Matiushenkov EA. Sokolov NA. Kulinkovich OG. Synlett  2004,  77 

<A NAME="RG16704ST-10A">10a</A> Kulinkovich OG. Sviridov SV. Vasilevski DA. Savchenko AI. Pritytskaya TS. J. Org. Chem. USSR (Engl. Transl.)  1991,  27:  250 

<A NAME="RG16704ST-10B">10b</A> Kulinkovich OG. Sviridov SV. Vasilevski DA. Synthesis  1991,  234 

<A NAME="RG16704ST-11A">11a</A> Reetz MT. Organotitanium Reagents in Organic Synthesis   Springer-Verlag; Berlin-Heidelberg: 1986. 

<A NAME="RG16704ST-11B">11b</A> For recent reviews on low-valent titanium chemistry see: Gansäuer A. Bluhm H. Chem. Rev.  2000,  100:  2771 

<A NAME="RG16704ST-11C">11c</A> Fürstner A. Bogdanovic B. Angew. Chem., Int. Ed. Engl.  1996,  35:  2442 

<A NAME="RG16704ST-12">12</A>

Typical Procedure: The solution of butanal oxime (0.93 g, 7.64 mmol) in 5 mL of dry CHCl₃ was added dropwise to the suspension of N-chlorosuccinimide (0.92 g, 7.64 mmol) in 5 mL CHCl₃ containing pyridine (0.012 mL, 0.15 mmol). The reaction mixture was stirred additionally for 15 min, and the solution of 4,4-diethoxybutene-1 (1.10 g, 7.64 mmol) in 5 mL of CHCl₃ was introduced in one portion. The solution of Et₃N (1.06 mL) in 20 mL of CHCl₃ was added slowly to the reaction mixture and the latter was stirred overnight. The mixture was washed with H₂O, aq NaHCO₃, brine and dried over Na₂SO₄. After removing the solvent under reduced pressure, the isoxazoline 5e was isolated by column chromatography (petrol ether-EtOAc as eluent) as a viscous oil (1.50 g, 75%).

<A NAME="RG16704ST-13">13</A>

Entry 7: ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (t, J = 7.4 Hz, 3 H), 1.10-1.22 (m, 6 H), 1.54 (sext, J = 7.4 Hz, 2 H), 1.77 (ddd, J ₁ = 13.8 Hz, J ₂ = 7.6 Hz, J ₃ = 5.2 Hz, 1 H), 1.95 (ddd, J ₁ = 13.8 Hz, J ₂ = 8.0 Hz, J ₃ = 3.9 Hz, 1 H), 2.28 (t, J = 7.4 Hz, 2 H), 2.59 (dd, J ₁ = 16.7 Hz, J ₂ = 7.8 Hz, 1 H), 2.97 (dd, J ₁ = 16.7 Hz, J ₂ = 10.2 Hz, 1 H), 3.43-3.54 (m, 2 H), 3.57-3.72 (m, 2 H), 4.56-4.65 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.62, 15.19, 19.65, 29.58, 39.69, 42.38, 61.51, 62.65, 76.41, 100.58, 158.93.
Entry 9: ¹H NMR (400 MHz, CDCl₃): δ = 0.86 (t, J = 7.0 Hz, 3 H), 0.94 (t, J = 7.4 Hz, 3 H), 1.22-1.37 (m, 4 H), 1.50-1.63 (m, 4 H), 2.30 (t, J = 7.6 Hz, 2 H), 2.55 (t, J = 7.5 Hz, 2 H), 2. 58 (dd, J ₁ = 13.7 Hz, J ₂ = 7.7 Hz, 1 H), 2.75 (dd, J ₁ = 13.7 Hz, J ₂ = 4.6 Hz, 1 H), 2.80 (dd, J ₁ = 17.2 Hz, J ₂ = 6.7 Hz, 1 H), 3.00 (dd, J ₁ = 17.2 Hz, J ₂ = 10.2 Hz, 1 H), 4.64-4.72 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.65, 13.85, 19.67, 22.17, 29.31, 29.52, 30.86, 32.56, 35.90, 41.57, 79.11, 158.58.

<A NAME="RG16704ST-14">14</A>

Typical Procedure. To a solution of Ti(Oi-Pr)₄ (0.82 mL 2.76 mmol) in dry Et₂O (6.0 mL) under Ar atmosphere, a solution of EtMgBr prepared from Mg (73 mg, 3.00 mmol) and EtBr (0.23 mL, 3.10 mmol) in Et₂O (3.5 mL) was added within 2 min. The initially colorless solution turned black-brown and heterogeneous over the course of EtMgBr addition. The reaction mixture was stirred for 20 min at r.t. and 20 min at gentle boiling. After the addition of the solution of substrate 4 or 5 (1.20 mmol) in Et₂O (2.0 mL), the reaction mixture was heated to reflux and stirred until TLC indicated no starting compound, or until the dark-brown color of the reducing agent disappeared. Then the reaction mixture was treated with H₂O (1.0 mL) and stirred several hours at r.t. The organic solution was decanted and washed with brine and dried over Na₂SO₄. After removing of the solvent the residue was purified with column chromatography on silica gel (petrol ether-EtOAc as eluent).

<A NAME="RG16704ST-15">15</A>

Entry 1: ¹H NMR (400 MHz, CDCl₃): δ = 0.87 (t, J = 7.3 Hz, 3 H), 0.92 (t, J = 7.4 Hz, 3 H), 1.30 (sext, J = 7.4 Hz, 2 H), 1.47-1.62 (m, 4 ), 2.06 (t, J = 7.7 Hz, 2 H), 2.23 (t, J = 7.7 Hz, 2 H), 4.99 (s, 1 H), 5.04-5.24 (br s, 1 H), 9.62-9.88 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.51, 13.83, 21.18, 22.54, 28.04, 38.29, 42.14, 94.47, 164.76, 199.9. IR (CCl₄): 3484, 3360, 1623, 1591, 1521 cm^-1.
Entry 3: ¹H NMR (400 MHz, CDCl₃): δ = 0.85-0.91 (m, 6 H), 1.22-1.50 (m, 6 H), 1.58 (sext, J = 7.4 Hz, 2 H), 2.38 (t, J = 7.4 Hz, 2 H), 2.46 (dd, J ₁ = 17.4 Hz, J ₂ = 8.9 Hz, 1 H), 2.57 (dd, J ₁ = 17.4 Hz, J ₂ = 3 Hz, 1 H), 3.11-3.17 (br s, 1 H), 3.97-4.03 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.57, 13.90, 16.99, 22.53, 27.56, 36.12, 45.47, 48.94, 67.57, 212.42. IR (CCl₄): 3549, 1717 cm^-1.

<A NAME="RG16704ST-16">16</A>

Entry 7: ¹H NMR (400 MHz, CDCl₃): δ = 0.87 (t, J = 7.4 Hz, 3 H), 1.13-1.20 (m, 6 H), 1.56 (sext, J = 7.4 Hz, 2 H), 1.65-1.79 (m, 2 H), 2.38 (t, J = 7.4 Hz, 2 H), 2.50 (dd, J ₁ = 16.9 Hz, J ₂ = 3.9 Hz, 1 H), 2.57 (dd, J ₁ = 16.9 Hz, J ₂ = 8.1 Hz, 1 H), 3.41-3.54 (m, 3 H), 3.59-3.70 (m, 2 H), 4.16-4.24 (m, 1 H), 4.67 (t, J = 5.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.54, 15.19, 15.22, 16.91, 40.14, 45.47, 49.18, 61.91, 62.00, 64.64, 101.40, 211.13. IR (CCl₄): 3520, 1690 cm^-1.