the high degree of tolerance for both electron-rich and
electron-deficient aryl halides make this transformation very
attractive.
Previous attempts to synthesize enantioenriched 2-aryl-
piperidines via Negishi coupling conditions have been less
successful. O’Brien recently reported an asymmetric
deprotonation of N-Boc-piperidine using s-BuLi and
O’Brien’s diamine12 (Figure 1), followed by trapping with
hoped that, during transmetalation from zinc to palladium,
the configurational integrity would be retained.
Considering that we are able to resolve N-Boc-2-lithiopi-
peridine catalytically, we investigated a CDR in the Negishi
arylations and vinylations. We herein expand the synthetic
potential of our methodology to the direct enantioselective
synthesis of 2-aryl and 2-vinyl-piperidines. Good yields and
er’s are obtained with a 5% catalyst loading. Our method
obviates the need for an enantioselective deprotonation or
the asymmetric synthesis of a precursor stannane.
The conditions for the CDR of rac-1 were optimized as
illustrated in Table 1, beginning with the previously opti-
Table 1. Optimization of the Enantioselective Arylation of
N-Boc-2-lithiopiperidine by CDR
Figure 1. Chiral ligands.
4-bromoveratrole, affording the arylated product in 33%
yield and 82:18 er (S:R).11 Although the Coldham group
successfully synthesized racemic members of this family
via Negishi coupling,13 attempts to effect enantioselec-
tivity by dynamic thermodynamic resolution (DTR) using
a stoichiometric amount of chiral ligand led to no arylation
products.14 They reported two examples of enantioenriched
2-aryl-piperidines (er 82:18 (R:S)) obtained by transmeta-
lation of an enantioenriched stannane to the organolithium
under conditions that ensured the configurational stability
of the latter.
We recently reported the highly enantioselective synthesis
of 2-substituted piperidines by catalytic dynamic resolution
(CDR) of N-Boc-2-lithiopiperidine 1 using diastereomeric
ligands (S,S)-2 and (S,R)-2 (Figure 1).15 In our report, we
utilized copper-mediated coupling to synthesize enantioen-
riched 2-allyl- and 2-benzyl-piperidines (Scheme 2) via an
(S,S)-2
(mol %)
time
(h)
yield (%)
of 3
er of 3
(R:S)
entry
solvent
1
2
3
4
5
6
10
10
5
5
5
3
3
3
5
5
3
Et2O
MTBE
Et2O
Et2O
MTBE
Et2O
74
65
70
68
60
71
90:10
86:14
93:7
96:4
89:11
53:47
100
mized conditions.15 In oven-dried septum-capped flasks,
rac-1 was generated by deprotonation of N-Boc-piperidine
in either Et2O or MTBE at -78 °C with s-BuLi/TMEDA,
followed by addition of (S,S)-2, warming to -45 °C for 3
to 5 h, and then cooling to -78 °C. A solution of ZnCl2 in
THF was added prior to warming to room temperature and
introduction of Pd(OAc)2, t-Bu3P·HBF4, and phenyl bromide
sequentially (details are in the Supporting Information). After
the mixture stirred for 3 h with 10 mol % of (S,S)-2 in the
presence of Et2O, we were pleased to obtain R-3 in 74%
yield and 90:10 er (entry 1). With MTBE, R-3 was obtained
in 65% yield and 86:14 er (entry 2). After lowering the
catalyst loading to 5 mol %, stirring at -45 °C for 3 h in
Et2O improved the er to 93:7 (entry 3). Performing the CDR
for an additional 2 h at -45 °C led to a further enhancement
in the er of R-3 to 96:4 (entry 4). However, with MTBE,
the same conditions afforded R-3 in 60% yield and 89:11 er
(entry 5).
Two important findings emerged from our optimization:
(i) the yields and er’s are lower in MTBE than in Et2O, (ii)
the er’s are higher with a lower loading of (S,S)-2. Intrigu-
ingly, when a DTR using a stoichiometric amount of (S,S)-2
was carried out, nearly racemic 3 was obtained (entry 6).
The reason for the loss of enantioselectivity is not fully
understood at this point.
Several other aryl and vinyl halides were evaluated under
the optimized CDR conditions, with the results summarized
in Table 2. In all cases, we obtained good yields and high
Scheme 2. CDR of N-Boc-2-lithiopiperidine Followed by
Copper-Mediated Allylation and Benzylation
organozinc reagent formed by transmetalation of the resolved
N-Boc-2-lithiopiperidine.
We know (Scheme 2) that during transmetalation of
lithium to zinc, then to copper, the configurational stability
is maintained. Based on Campos’ results (Scheme 1), we
(12) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am.
Chem. Soc. 2002, 124, 11870.
(13) Coldham, I.; Leonori, D. Org. Lett. 2008, 10, 3923.
(14) Coldham, I.; Raimbault, S.; Whittaker, D. T. E.; Chovatia, P. T.;
Leonori, D.; Patel, J. J.; Sheikh, N. S. Chem.sEur. J. 2010, 16, 4082.
(15) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132, 12216.
Org. Lett., Vol. 13, No. 3, 2011
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