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Synlett 2007(6): 0944-0948  
DOI: 10.1055/s-2007-973868
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Pedro Merino*a, Tomas Tejeroa, Vanni Mannuccia,b, Guillaume Prestatb, David Madecb, Giovanni Poli*b
a Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, CSIC, 50009 Zaragoza, Aragon, Spain
Fax: +34(976)762075; e-Mail: pmerino@unizar.es;
b Université Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie Moléculaire (FR 2769), Case 183, 4 Place Jussieu, 75252 Paris Cedex 05, France
Fax: +33(1)44277567; e-Mail: giovanni.poli@upmc.fr;
Further Information

Publication History

Received 16 January 2007
Publication Date:
26 March 2007 (online)

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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

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.