M. Hepperle et al. / Tetrahedron Letters 43 (2002) 3359–3363
3363
Scheme 6. Novel synthesis of 1 via Pd0-catalyzed piperazine mono-N-arylation.
Acknowledgements
halides, please see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux,
J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805; (b)
Hartwig, J. F. Synlett 1997, 329; (c) Frost, C. G.; Men-
donc¸a, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615.
13. Typical experimental procedure (unless noted otherwise):
To a solution of piperazine (5.5 mmol) in toluene was
added Pd2(dba)3 (0.025 mmol) and (+), (−), or ( )-
BINAP (0.075 mmol). Arylhalide (5 mmol) was added
dropwise, followed by NaOtBu (7.5 mmol) as a suspen-
sion in THF. The resulting mixture was heated to 80–
90°C for prescribed amount of time. The reaction was
cooled to ambient temperature and diluted with EtOAc
and water. After separation of the layers, the organic
phase was washed once with water. The combined
aqueous layers were back extracted with EtOAc. The
resulting combined organic layers were extracted with 1N
HCl. The combined acidic layers were treated with
NaOH to pH 12. The mixture was then extracted with
CH2Cl2, dried over Na2SO4, filtered, and concentrated
under reduced pressure to afford the product. CsCO3,
NaHMDS, or KHMDS as bases offered no advantage
over NaOtBu.
We thank Dr. George Wu for many discussions on the
mechanism aspect of this project.
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14. Twice the amount of the catalyst/ligands added to
shorten the reaction time.
15. A gift of this compound from Dr. Anantha Sudhakar is
appreciated.
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17. Laboratory work had indicated that under the Pd0 catal-
ysis condition, electron withdrawing group containing 29
first monoarylates piperazine to form 30. When 30 was
allowed to react with fresh catalyst and more 29, the bis
arylation set in. The bis arylation was slow (required ꢀ3
days for ꢀ80% yield of the symmetrically N,N%-bis-sub-
stituted piperazine).
10. Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F. J.
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11. Typically, the aromatic halides (Ar-X) are converted to
Grignard reagents (Ar-Mg-X) which up on reaction with
trimethylborate (B(OMe)3) followed by hydrolysis lead to
arylborates (Ar-B(OH)2).
18. Presumably due to the steric bulk associated with the
reacting species.
12. For reviews on Pd0-catalyzed amination of aromatic