A new access to 3,5-disubstituted piperazinones via Pd(0)-catalyzed amination

Tetrahedron Letters

Volumn 44, Issue 22, 2003, Pages 4213-4216

  Ferber, Benoit ^a   Lemaire, Sébastien ^a   Mader, Mary M ^b   Prestat, Guillaume ^a   Poli, Giovanni ^a  

^a CNRS   (France)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; NITROGEN; PALLADIUM; PIPERAZINE DERIVATIVE;

ADDITION REACTION; AMINATION; ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; CATALYSIS; CATALYST; CYCLIZATION; DIASTEREOISOMER; DRUG SYNTHESIS; MOLECULAR INTERACTION; PROTON NUCLEAR MAGNETIC RESONANCE; X RAY DIFFRACTION;

EID: 0038739205     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(03)00885-2     Document Type: Article

References (36)

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12. 3, 100 MHz): δ cis compound 21.0, 21.5, 46.9, 49.9, 52.8, 53.9, 117.8, 127.1, 127.7, 127.9, 128.4, 128.6, 128.7, 129.5, 129.9, 133.7, 135.7, 137.4, 143.6, 168.8; δ trans compound 21.3, 21.4, 47.3, 50.4, 53.2, 54.3, 118.3, 127.5, 128.2, 128.6, 129.0, 130.4, 136.1, 136.7, 144.3, 168.5.
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19. Sharp cis/trans isomer separation of the resulting piperazinones turned out to be rather hard, and traces of the undesired isomer often contaminated the selected one. As a consequence, measurement of the optical rotations values of these compounds was not attempted at this stage, except for the crystalline cis-21 .
20. Check for the full preservation of the enantiomeric integrity in the resulting piperazinones has not been specifically addressed. Nevertheless, related literature precedents clearly indicate that the reaction conditions are not expected to be racemizing. See for example: (a) Verhelst, S. H. L.; Wiednhof, W.; Ovaa, H.; van der Marel, G. A.; Overkleeft, H. S.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron Lett. 2002, 43, 6451-6455; (b) Kinderman, S. S.; Doodeman, R.; van Beijma, J. W.; Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.; Mohaselzadeh, H.; van Maarseveen, J. H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2002, 344, 736-748; (c) Zorn, C.; Gnad, F.; Salmen, S.; Herpin, T.; Reiser, O. Tetrahedron Lett. 2001, 42, 7049-7053.
21. Check for the full preservation of the enantiomeric integrity in the resulting piperazinones has not been specifically addressed. Nevertheless, related literature precedents clearly indicate that the reaction conditions are not expected to be racemizing. See for example: (a) Verhelst, S. H. L.; Wiednhof, W.; Ovaa, H.; van der Marel, G. A.; Overkleeft, H. S.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron Lett. 2002, 43, 6451-6455; (b) Kinderman, S. S.; Doodeman, R.; van Beijma, J. W.; Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.; Mohaselzadeh, H.; van Maarseveen, J. H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2002, 344, 736-748; (c) Zorn, C.; Gnad, F.; Salmen, S.; Herpin, T.; Reiser, O. Tetrahedron Lett. 2001, 42, 7049-7053.
22. Check for the full preservation of the enantiomeric integrity in the resulting piperazinones has not been specifically addressed. Nevertheless, related literature precedents clearly indicate that the reaction conditions are not expected to be racemizing. See for example: (a) Verhelst, S. H. L.; Wiednhof, W.; Ovaa, H.; van der Marel, G. A.; Overkleeft, H. S.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron Lett. 2002, 43, 6451-6455; (b) Kinderman, S. S.; Doodeman, R.; van Beijma, J. W.; Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.; Mohaselzadeh, H.; van Maarseveen, J. H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2002, 344, 736-748; (c) Zorn, C.; Gnad, F.; Salmen, S.; Herpin, T.; Reiser, O. Tetrahedron Lett. 2001, 42, 7049-7053.
23. Crystallographic data (excluding structure factors) for the structures in this paper, have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 202406. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
24. An equimolar mixture of the isolated piperazinone trans-21 and its precursor 15 was deliberately chosen for this test in order to reproduce the original reaction conditions. In fact, a potential interaction between the starting acetate and the catalytic system, which would affect the exact nature of the real catalyst, cannot be completely ruled out.
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28. For a related trans-to-cis equilibration of N-Boc-5-alkyl-pipecolaldehydes, see: (a) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155-158; (b) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109-1117; (c) Kotsuki, H.; Kusumi, T.; Inoue, M.; Ushio, Y.; Ochi, M. Tetrahedron Lett. 1991, 32, 4159-4162.
29. For a related trans-to-cis equilibration of N-Boc-5-alkyl-pipecolaldehydes, see: (a) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155-158; (b) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109-1117; (c) Kotsuki, H.; Kusumi, T.; Inoue, M.; Ushio, Y.; Ochi, M. Tetrahedron Lett. 1991, 32, 4159-4162.
30. For a related trans-to-cis equilibration of N-Boc-5-alkyl-pipecolaldehydes, see: (a) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155-158; (b) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109-1117; (c) Kotsuki, H.; Kusumi, T.; Inoue, M.; Ushio, Y.; Ochi, M. Tetrahedron Lett. 1991, 32, 4159-4162.
31. Conformational searches were performed by the Monte Carlo method, generating 1000-4000 structures within 10 kJ/mol energy window. The lowest energy structure in each search was found more than 20 times and converged to a low gradient, typically approx. 2 kJ/mol lower in energy than the next most frequently found structure, confirming it as a global energy minimum.
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34. The RMS between the calculated global minimum of cis-21 and the X-ray structure is 0.5752, the major difference being the orientation of the phenyl rings.
35. Found cis-trans relative steric energy differences (kJ/mol) 11: -14.5; 19: -12.3; 20: -22.0; 21: -14.9; 22: -9.9; 23: -14.5.
36. Precipitation of black palladium was constantly observed a few hours after completion of the reaction. As a consequence, further experiments at longer reaction times, in order to reach the final thermodynamic equilibrium, were not attempted.