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Volumn 9, Issue 17, 2007, Pages 3279-3282

A concise asymmetric synthesis of cis-2,6-disubstituted N-aryl piperazines via Pd-catalyzed carboamination reactions

Author keywords

[No Author keywords available]

Indexed keywords

PALLADIUM; PIPERAZINE DERIVATIVE;

EID: 34548185689     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol071241f     Document Type: Article
Times cited : (68)

References (44)
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    • For examples of biologically active 2,6-disubstituted piperazines, see: (a) Zheng, G, Dwoskin, L. P, Deaciuc, A. G, Zhu, J, Jones, M. D, Crooks, P. A. Bioorg. Med. Chem. 2005, 13, 3899
    • For examples of biologically active 2,6-disubstituted piperazines, see: (a) Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Zhu, J.; Jones, M. D.; Crooks, P. A. Bioorg. Med. Chem. 2005, 13, 3899.
  • 10
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    • For syntheses of racemic 2,6-dialkylpiperazines, see: (a) Berkheij, M.; van der Sluis, L.; Sewing, C.; den Boer, D. J.; Terpstra, J. W.; Hiemstra, H.; Bakker, W. I. I.: van den Hoogenband, A.; van Maarseveen, J. H. Tetrahedron Lett. 2005, 46, 2369.
    • For syntheses of racemic 2,6-dialkylpiperazines, see: (a) Berkheij, M.; van der Sluis, L.; Sewing, C.; den Boer, D. J.; Terpstra, J. W.; Hiemstra, H.; Bakker, W. I. I.: van den Hoogenband, A.; van Maarseveen, J. H. Tetrahedron Lett. 2005, 46, 2369.
  • 12
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    • For selected recent approaches to the synthesis of substituted piperazine derivatives, see: a
    • For selected recent approaches to the synthesis of substituted piperazine derivatives, see: (a) Mercer, G. J.; Sigman, M. S. Org. Lett. 2003, 5, 1591.
    • (2003) Org. Lett , vol.5 , pp. 1591
    • Mercer, G.J.1    Sigman, M.S.2
  • 26
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    • For examples of Cu-catalyzed intramolecular carboamination, see: (a) Sherman, E. S, Fuller, P. H, Kasi, D, Chemler, S. R. J. Org. Chem. 2007, 72, 3896
    • For examples of Cu-catalyzed intramolecular carboamination, see: (a) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem. 2007, 72, 3896.
  • 27
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    • 6, 1573. For Pd(II)-catalyzed alkoxycarbonylation of alkenes bearing tethered nitrogen nucleophiles
    • (b) Sherman E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org. Lett. 2004, 6, 1573. For Pd(II)-catalyzed alkoxycarbonylation of alkenes bearing tethered nitrogen nucleophiles,
    • (2004) Org. Lett
    • Sherman, E.S.1    Chemler, S.R.2    Tan, T.B.3    Gerlits, O.4
  • 29
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    • see: d, 3251. For carboamination of vinylcyclopropanes, see
    • see: (d) Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251. For carboamination of vinylcyclopropanes, see:
    • (2006) Org. Lett , vol.8
    • Scarborough, C.C.1    Stahl, S.S.2
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    • 529. For 1,1-carboamination of alkenes, see
    • (e) Larock, R. C.; Yum, E. K. Synlett 1990, 529. For 1,1-carboamination of alkenes, see:
    • (1990) Synlett
    • Larock, R.C.1    Yum, E.K.2
  • 34
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    • DEPBT = 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one. Use of other reagents (e.g., DCC/HOBT or CDI) resulted in partial epimerization to afford products with ∼85-90% ee. See: Li, H.; Jiang, X.; Ye, Y.-h.; Fan, C.; Romoff, T.; Goodman, M. Org. Lett. 1999, 1, 91.
    • DEPBT = 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one. Use of other reagents (e.g., DCC/HOBT or CDI) resulted in partial epimerization to afford products with ∼85-90% ee. See: Li, H.; Jiang, X.; Ye, Y.-h.; Fan, C.; Romoff, T.; Goodman, M. Org. Lett. 1999, 1, 91.
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    • Cu-catalyzed N-arylation reactions of alanine afforded products with ≤93% ee. See ref 9
    • Cu-catalyzed N-arylation reactions of alanine afforded products with ≤93% ee. See ref 9.
  • 37
    • 0042291889 scopus 로고    scopus 로고
    • Astruc, D, Ed, Wiley, VCH: Weinheim, Germany
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    • (2002) Modern Arene Chemistry , pp. 107
    • Hartwig, J.F.1
  • 39
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    • Initial studies on carboaminations of amides such as 4 or 6 suggest these transformations may be feasible, but further optimization is required; low yields ca. 10-20, of the desired products were obtained
    • Initial studies on carboaminations of amides such as 4 or 6 suggest these transformations may be feasible, but further optimization is required; low yields (ca. 10-20%) of the desired products were obtained.
  • 40
    • 34548161389 scopus 로고    scopus 로고
    • Diastereomeric ratios observed in crude reaction mixtures were identical with those obtained upon isolation. In some cases the minor diastereomer could be separated by careful chromatography. See the Supporting Information for complete details
    • Diastereomeric ratios observed in crude reaction mixtures were identical with those obtained upon isolation. In some cases the minor diastereomer could be separated by careful chromatography. See the Supporting Information for complete details.
  • 41
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    • Preliminary efforts to employ a N1 Boc-protected substrate resulted in the formation of a 1:1 mixture of diastereomers. Attempts to cyclize substrates bearing N1 Piv or Ac groups have thus far been unsuccessful.
    • Preliminary efforts to employ a N1 Boc-protected substrate resulted in the formation of a 1:1 mixture of diastereomers. Attempts to cyclize substrates bearing N1 Piv or Ac groups have thus far been unsuccessful.
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    • Alkene insertion into late M-H bonds is usually much faster than alkene insertion into late M-C bonds. See: (a) Brookhart, M, Hauptman, E, Lincoln, D. M. J. Am. Chem. Soc. 1992, 114, 10394
    • Alkene insertion into late M-H bonds is usually much faster than alkene insertion into late M-C bonds. See: (a) Brookhart, M.; Hauptman, E.; Lincoln, D. M. J. Am. Chem. Soc. 1992, 114, 10394.
  • 44
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    • The formation of unsaturated five-membered heterocycles analogous to 10 and 11 is generally not observed in N-aryl-2-benzylpyrrolidine-forming reactions. Instead, the generation of regioisomeric N-aryl-2-methyl-3- arylpyrrolidine side products, which result from reversible β-hydride elimination/reinsertion processes, is observed. These side products are usually formed in ca. 10% yield, whereas the combined yields of 10 and 11 is usually ca. 20-30%. For further discussion, see refs 7a and 7j.
    • The formation of unsaturated five-membered heterocycles analogous to 10 and 11 is generally not observed in N-aryl-2-benzylpyrrolidine-forming reactions. Instead, the generation of regioisomeric N-aryl-2-methyl-3- arylpyrrolidine side products, which result from reversible β-hydride elimination/reinsertion processes, is observed. These side products are usually formed in ca. 10% yield, whereas the combined yields of 10 and 11 is usually ca. 20-30%. For further discussion, see refs 7a and 7j.


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