Hydroxylamine Oxygen as Nucleophile in Palladium(0)- and Palladium(II)-Catalyzed Allylic Alkylation: A Novel Access to Isoxazolidines

Abstract

In search for novel heterocyclization processes, the intramolecular Pd-mediated allylic alkylation of homoallyl hydroxyl­amines is described. Depending on both the reaction conditions and the substrates, cis- or trans-3-substituted-5-vinyl isoxazolidines are preferentially obtained. The corresponding starting materials for the cyclization step are readily obtained through cross-metathesis of the easily accessible unsubstituted homoallyl hydroxylamines.

Key words

palladium - ring closure - hydroxylamines - allyl complexes - isoxazolidines

References and Notes

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9

To the best of our knowledge, the only precedent so far reported (see ref. 5) deals with intermolecular reactions, using carbonates as leaving groups, and necessitating an electron-withdrawing group on the hydroxylamine nitrogen atom.

15

Use of tert-butyldimethylsilyl chloride in the presence of several tertiary amines failed to give the corresponding protected hydroxylamine.

16

Data for 6a: (90%). R _f = 0.55 (hexane-EtOAc, 4:1); oil. ¹H NMR (400 MHz, CDCl₃, 25 °C, mixture of conformers): δ = 7.27-7.22 (m, 3 H), 7.21-7.13 (m, 4 H), 7.04-6.98 (m, 3 H), 5.61-5.55 (m, 1.6 H), 5.54-5.43 (m, 0.4 H), 4.58-4.50 (m, 0.4 H), 4.41-4.37 (m, 1.6 H), 4.20 (t, 1 H, J = 7.5 Hz), 2.79 (t, 2 H, J = 6.7 Hz), 2.06 (br, 0.6 H), 2.02 (br, 2.4 H), 0.3 (br, 9 H), -0.07 (br, 3 H), -0.31 (br, 0.6 H), -0.34 (br, 2.4 H). ¹³C NMR (100 MHz, CDCl₃, 25 °C, selected signals for the major conformer): δ = 170.7, 152,5, 137.8, 133.3, 131.9, 127.9, 127.5, 127.4, 125.8, 123.7, 121.2, 74.3, 65.0, 32.9, 26.1, 21.0, 18.0, -4.7, -5.5. Anal Calcd for C₂₅H₃₅NO₃Si: C, 70.55; H, 8.29; N, 3.29. Found: C, 70.59; H, 8.45; N, 3.22.

20

General Procedure for the Pd(0)-Mediated Intramolecular Allylic Alkylation The proper homoallylhydroxylamine (1 mmol) and (if needed) NaH (60% dispersion in a mineral oil, 1 mmol) were dissolved in DMF (20 mL) under an argon atmosphere and the resulting mixture was cooled to 0 °C. In a separate flask, Pd(OAc)₂ (5 mol%) and dppe (10 mol%) were mixed in DMF (5 mL) and stirred for ca 5 min. After having carefully verified that the initially brown solution turned into a paler brown suspension, the thus formed Pd(0) catalyst was added into the solution of hydroxylamine. The resulting mixture was stirred at r.t. for 30 min, then heated at 80 °C for 3 h. After cooling to r.t., the solution was poured into Et₂O (125 mL) and H₂O (50 mL) was added. The organic layer was separated and the aqueous layer was extracted with Et₂O. The combined organic extracts were washed with brine, dried over MgSO₄, filtered and evaporated under reduced pressure to give a residue which was purified by radial chromatography.

21

General Procedure for the Pd(II)-Mediated Intramolecular Allylic Alkylation The corresponding homoallylhydroxylamine (1 mmol), Pd(OAc)₂ (10 mol%) and lithium halide (5 mmol; if needed) were dissolved in DMF (20 mL) under an argon atmosphere. The resulting mixture was stirred at r.t. for 30 min, then heated at 80 °C for 3 h. After cooling to r.t., the solution was poured into Et₂O (125 mL) and H₂O (50 mL) was added. The organic layer was separated and the aqueous layer was extracted with Et₂O. The combined organic extracts were washed with brine, dried over MgSO₄, filtered and evaporated under reduced pressure to give a residue which was purified by radial chromatography.

22

The relative stereochemical assignment of compound 8a was based on ROESY experiments.

24

Submission of compounds 9 and 11 to the same reaction conditions as in entries 3 and 6 of Table [2] , but in the absence of Pd(OAc)₂, gave only starting material, thereby ruling out the possibility of a noncatalytic cyclization passing through the corresponding allylic bromide.

25

Data for 10: R _f = 0.36 (hexane-EtOAc, 4:1); [α]_D ²⁰ +92 (c 0.16, CHCl₃). ¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.45-7.40 (m, 2 H), 7.37-7.31 (m, 2 H), 7.30-7.24 (m, 1 H), 5.85 (ddd, 1 H, J = 17.2, 10.3, 7.1 Hz), 5.29 (d, 1 H, J = 17.2 Hz), 5.18 (d, 1 H, J = 10.3 Hz), 4.47 (dt, 1 H, J = 7.6, 7.1 Hz), 4.34 (d, 1 H, J = 14.0 Hz), 4.15 (dt, 1 H, J = 7.1, 6.5 Hz), 4.04 (dd, 1 H, J = 8.3, 6.5 Hz), 4.00 (d, 1 H, J = 14.0 Hz), 3.74 (dd, 1 H, J = 8.3, 7.1 Hz), 3.13 (dt, 1 H, J = 8.2, 7.1 Hz), 2.21-2.04 (m, 2 H), 1.44 (s, 3 H), 1.36 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 137.6, 137.2, 129.2, 128.2, 127.2, 117.5, 109.8, 78.4, 77.2, 67.2, 66.9, 62.2, 37.5, 26.7, 25.4. Anal. Calcd for C₁₇H₂₃NO₃: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.47; H, 8.13; N, 4.76.

26

Data for 12: R _f = 0.42 (hexane-EtOAc, 4:1); [α]_D ²⁰ +21 (c 1.38, CHCl₃). ¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.31-7.17 (m, 5 H), 5.89-5.79 (ddd, 1 H, J = 17.1, 10.2, 7.4 Hz), 5.20 (dt, 1 H, J = 17.1, 1.2 Hz), 5.10 (dt, 1 H, J = 10.2, 1.2 Hz), 4.50 (q, 1 H, J = 7.4 Hz), 4.04 (d, 1 H, J = 12.8 Hz), 3.98-3.92 (m, 2 H), 3.77 (d, 1 H, J = 12.8 Hz), 3.47-3.40 (m, 1 H), 3.16-3.10 (t, 1 H, J = 6.9 Hz), 2.48 (dddd, 1 H, J = 12.8, 9.2, 7.4, 1.6 Hz), 2.15 (ddd, 1 H, J = 12.8, 9.2, 7.4 Hz), 1.27 (s, 3 H), 1.24 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 138.2, 137.0, 129.3, 128.5, 127.6, 117.3, 109.3, 80.4, 75.7, 68.0, 67.4, 63.6, 36.1, 26.8, 25.3. Anal. Calcd for C₁₇H₂₃NO₃: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.70; H, 7.88; N, 5.01.