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For a review on the synthesis and biological significance of C-substituted morpholines, see: Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
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For selected examples of biologically active cis-3,5-disubstituted morpholines, see: (a) O'Neil, S. V.; Wang, Y.; Laufersweiler, M. C.; Oppong, K. A.; Soper, D. L.; Wos, J. A.; Ellis, C. D.; Baize, M. W.; Bosch, G. K.; Fancher, A. N.; Lu, W.; Suchanek, M. K.; Wang, R. L.; De, B.; Demuth, T. P., Jr. Bioorg. Med. Chem. Lett. 2005, 15, 5434.
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For selected examples of biologically active cis-3,5-disubstituted morpholines, see: (a) O'Neil, S. V.; Wang, Y.; Laufersweiler, M. C.; Oppong, K. A.; Soper, D. L.; Wos, J. A.; Ellis, C. D.; Baize, M. W.; Bosch, G. K.; Fancher, A. N.; Lu, W.; Suchanek, M. K.; Wang, R. L.; De, B.; Demuth, T. P., Jr. Bioorg. Med. Chem. Lett. 2005, 15, 5434.
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(b) Allison, B. D.; Phuong, V. K.; McAtee, L. C.; Rosen, M.; Morton, M.; Prendergast, C.; Barrett, T.; Lagaud, G.; Freedman, J.; Li, L.; Wu, X.; Venkatesan, H.; Pippel, M.; Woods, C.; Rizzolio, M. C.; Hack, M.; Hoey, K.; Deng, X.; King, C.; Shankley, N. P.; Rabinowitz, M. H. J. Med. Chem. 2006, 49, 6371.
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For recent approaches to the synthesis of C-substituted morpholines, see: a
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For recent approaches to the synthesis of C-substituted morpholines, see: (a) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257.
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Temperini, A.7
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For stereoselective syntheses of trans-3,5-disubstituted morpholines, see: (a) Leijondahl, K.; Boren, L.; Braun, R.; Bäckvall, J.-E. Org. Lett. 2008, 10, 2027.
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For stereoselective syntheses of trans-3,5-disubstituted morpholines, see: (a) Leijondahl, K.; Boren, L.; Braun, R.; Bäckvall, J.-E. Org. Lett. 2008, 10, 2027.
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(d) Takahata, H.; Takahashi, S.; Kouno, S.-i.; Momose, T. J. Org. Chem. 1998, 63, 2224. For non-stereoselective syntheses of 3,5-disubstituted morpholines, see:
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in press, DOI:, 10.1016/j.tet.2009.04.017
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(b) Nakhla, J. S.; Schultz, D. M.; Wolfe, J. P. Tetrahedron 2009, in press, DOI:, 10.1016/j.tet.2009.04.017.
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For related syntheses of pyrrolidines, imidazolidin-2-ones, isoxazolidines, and pyrazolidines via Pd-catalyzed carboamination reactions, see: (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
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For related syntheses of pyrrolidines, imidazolidin-2-ones, isoxazolidines, and pyrazolidines via Pd-catalyzed carboamination reactions, see: (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
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For reviews on Pd-catalyzed carboamination reactions, see: a
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For reviews on Pd-catalyzed carboamination reactions, see: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571.
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Wolfe, J.P.1
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67650472024
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For a representative reaction sequence, chiral HPLC analysis indicated complete retention of enantiomeric purity (99% ee) during the preparation of substrate 2a from 1a. The Pd-catalyzed carboamination reaction of 2a to 3b also proceeded with no erosion of ee.
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For a representative reaction sequence, chiral HPLC analysis indicated complete retention of enantiomeric purity (99% ee) during the preparation of substrate 2a from 1a. The Pd-catalyzed carboamination reaction of 2a to 3b also proceeded with no erosion of ee.
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67650476939
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Use of other ligands provided greater amounts of 5a, led to formation of side products resulting from Heck arylation of the starting material, or both. See the Supporting Information for a table of results obtained with other phosphines.
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Use of other ligands provided greater amounts of 5a, led to formation of side products resulting from Heck arylation of the starting material, or both. See the Supporting Information for a table of results obtained with other phosphines.
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67650476938
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Side products of general structure 5 were also observed in crude reaction mixtures. NMR analysis indicated these side products were formed as ca. 10-35% of the mixture. See the Supporting Information for further details.
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Side products of general structure 5 were also observed in crude reaction mixtures. NMR analysis indicated these side products were formed as ca. 10-35% of the mixture. See the Supporting Information for further details.
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67650472027
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In some instances side products resulting from sequential N-arylation and Heck arylation of the substrate were also isolated.
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In some instances side products resulting from sequential N-arylation and Heck arylation of the substrate were also isolated.
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The known trans-2-(N-phenylamino)cycloalkanols were prepared in one step from aniline and cyclohexene oxide or cyclopentene oxide. See: (a) Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem. 2008, 73, 2270.
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The known trans-2-(N-phenylamino)cycloalkanols were prepared in one step from aniline and cyclohexene oxide or cyclopentene oxide. See: (a) Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem. 2008, 73, 2270.
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Arai, K.; Lucarini, S.; Salter, M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 8103. The cis-2-(N-phenylamino)cycloalkanols were prepared in three steps from the epoxides. See the Supporting Information for further details.
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(b) Arai, K.; Lucarini, S.; Salter, M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 8103. The cis-2-(N-phenylamino)cycloalkanols were prepared in three steps from the epoxides. See the Supporting Information for further details.
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Chair-like transition states for intramolecular syn-aminopalladation reactions that generate six-membered rings appear to be less favorable than boatlike transition states due to poor overlap between the alkene π-system and the Pd-N bond. For additional discussion of boat-like vs. chair-like transition states in Pd-catalyzed carboamination reactions that afford piperazine products, see ref 6b
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Chair-like transition states for intramolecular syn-aminopalladation reactions that generate six-membered rings appear to be less favorable than boatlike transition states due to poor overlap between the alkene π-system and the Pd-N bond. For additional discussion of boat-like vs. chair-like transition states in Pd-catalyzed carboamination reactions that afford piperazine products, see ref 6b.
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The modest diastereoselectivities observed in the reactions of 8 and 10 are presumably due to relatively small differences in the energies of transition states in which the substrate R-group is oriented in a psueduoaxial vs. pseudoequatorial position. For further discussion, see ref 6b
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The modest diastereoselectivities observed in the reactions of 8 and 10 are presumably due to relatively small differences in the energies of transition states in which the substrate R-group is oriented in a psueduoaxial vs. pseudoequatorial position. For further discussion, see ref 6b.
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0003779363
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2nd ed, Beller, M, Bolm, C, Eds; Wiley-VCH: Weinheim, Germany
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(b) Beller, M.; Zapf, A.; Reirmeier, T. H. In Transition Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds; Wiley-VCH: Weinheim, Germany, 2004; pp 271-305.
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Beller, M.1
Zapf, A.2
Reirmeier, T.H.3
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12344337689
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The rate of reductive elimination from Pd(II) decreases as ligand basicity increases and ligand size decreases. However, steric effects can outweigh electronic effects, as electron-rich ligands that are sterically bulky are known to promote reductive elimination. For reviews, see: (a) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
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The rate of reductive elimination from Pd(II) decreases as ligand basicity increases and ligand size decreases. However, steric effects can outweigh electronic effects, as electron-rich ligands that are sterically bulky are known to promote reductive elimination. For reviews, see: (a) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
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IPr = 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene. Although this electron-rich ligand is also sterically bulky, it appears that ligand electronic properties play a larger role than steric properties in this particular reaction. For further discussion on the steric and electronic properties of NHC ligands, see: Diez-Gonzalez, S.; Nolan, S. P. Coord. Chem. Rev. 2007, 251, 874.
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IPr = 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene. Although this electron-rich ligand is also sterically bulky, it appears that ligand electronic properties play a larger role than steric properties in this particular reaction. For further discussion on the steric and electronic properties of NHC ligands, see: Diez-Gonzalez, S.; Nolan, S. P. Coord. Chem. Rev. 2007, 251, 874.
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