Synthesis of 2-arylpiperidines by palladium couplings of aryl bromides with organozinc species derived from deprotonation of N-Boc-piperidine

Article abstract of DOI:10.1021/ol801579r

(Figure Presented) The organolithium species derived from proton abstraction of N-Boc-piperidine with s-BuLi and TMEDA can be transmetalated to the organozinc reagent, and this organometallic species can be coupled directly with aryl bromides in a Negishi-type reaction using palladium catalysis with the ligand tri-tert-butylphosphine (t-Bu₃P-HBF₄). The chemistry was applied to a very short synthesis of the alkaloid anabasine.

Full text of DOI:10.1021/ol801579r

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3923-3925
Synthesis of 2-Arylpiperidines by
Palladium Couplings of Aryl Bromides
with Organozinc Species Derived from
Deprotonation of N-Boc-Piperidine
Iain Coldham* and Daniele Leonori
Department of Chemistry, UniVersity of Sheffield, Sheffield S3 7HF, U.K.
i.coldham@sheffield.ac.uk
Received July 11, 2008
ABSTRACT
The organolithium species derived from proton abstraction of N-Boc-piperidine with s-BuLi and TMEDA can be transmetalated to the organozinc
reagent, and this organometallic species can be coupled directly with aryl bromides in a Negishi-type reaction using palladium catalysis with
the ligand tri-tert-butylphosphine (t-Bu3P-HBF4). The chemistry was applied to a very short synthesis of the alkaloid anabasine.
Aryl-substituted saturated heterocyclic compounds are a very
important class of compounds, present in many natural
products and biologically active molecules (for example, NK1
antagonists).1 Various methods have been developed for their
synthesis, although the most obvious is by coupling the aryl
unit with the intact heterocycle. Despite this, the direct
arylation by metalation and then coupling of saturated
heterocycles is rare.2 Dieter and co-workers reported the
lithiation of N-tert-butoxycarbonyl-pyrrolidine (N-Boc-pyr-
rolidine) followed by transmetalation with CuCN and pal-
ladium coupling.3 Other substrates were less successful under
these conditions, although a few examples using N-Boc-
piperidine were described.3 Recently, Campos and co-
workers at Merck found that 2-aryl-pyrrolidines could be
prepared by transmetalation of enantioenriched N-Boc-2-
lithiopyrrolidine to the organozinc species and coupling with
aryl bromides.4 This organozinc method using Pd(OAc)2 and
tri-tert-butylphosphine (as its HBF4 salt5) was superior to
the use of CuCN. We therefore investigated this Negishi-
type coupling6 methodology for the preparation of 2-aryl-
piperidines7 and report herein the results of this study.
Following the procedure reported by Beak and Lee,8
N-Boc-piperidine 1 was treated with s-BuLi and TMEDA
(1.05 equiv of each) in Et2O at -78 °C to effect lithiation at
the 2-position. Transmetalation with zinc chloride (1.3 equiv)
and warming to room temperature gave the required orga-
nozinc species, to which was added a solution containing
the palladium salt (4 mol %), the phosphine ligand (8 mol
(4) (a) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C. J. Am. Chem. Soc. 2006, 128, 3538. (b) Klapars, A.; Campos,
K. R.; Waldman, J. H.; Zewge, D.; Dormer, P. G.; Chen, C. J. Org. Chem.
2008, 73, 4986.
(5) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(6) Negishi, E.; Hu, Q.; Huang, Z.; Wang, G.; Yin, N. In The Chemistry
of Organozinc Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: Chich-
ester, 2006; Chapter 11.
(7) For alternative methods to prepare 2-arylpiperidines, see for example:
(a) Beak, P.; Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994, 59, 276.
(b) Madan, S.; Milano, P.; Eddings, D. B.; Gawley, R. E. J. Org. Chem.
2005, 70, 3066. (c) Xiao, D.; Lavey, B. J.; Palani, A.; Wang, C.; Aslanian,
R. G.; Kozlowski, J. A.; Shih, N.-Y.; McPhail, A. T.; Randolph, G. P.;
Lachowicz, J. E.; Duffy, R. A. Tetrahedron Lett. 2005, 46, 7653. (d) Hunt,
J. C. A.; Laurent, P.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 2002,
2378. (e) Abrunhosa-Thomas, I.; Roy, O.; Barra, M.; Besset, T.; Chalard,
P.; Troin, Y. Synlett 2007, 1613.
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893.
(2) O’Brien, P.; Bilke, J. L. Angew. Chem., Int. Ed. 2008, 47, 2734.
(3) (a) Dieter, R. K.; Li, S. J. Org. Chem. 1997, 62, 7726. (b) Dieter,
R. K. Tetrahedron Lett. 1995, 3613. (c) Dieter, R. K.; Oba, G.; Chandupatla,
K. R.; Topping, C. M.; Lu, K.; Watson, R. T. J. Org. Chem. 2004, 69,
3076.
(8) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
10.1021/ol801579r CCC: $40.75
Published on Web 08/07/2008
2008 American Chemical Society

Table 1. Optimization of the Coupling Reaction To Give 2a
Pd salt
phosphine
aryl halide
yield (%)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PhCN)2
Pd(OAc)2
Pd(OAc)2
PPh3
Cy3P-HBF4
PhBr
PhBr
PhBr
PhBr
PhBr
PhCl
PhI
0
52
75
t-Bu3P-HBF4
t-Bu3P-HBF4
t-Bu3P-HBF4
t-Bu3P-HBF4
t-Bu3P-HBF4
56a
trace
trace
61
a Inverse addition.
%), and the aryl halide (1.3 equiv). A selection of reagents
was screened as shown in Table 1 and Scheme 1. The best
Figure 1. Structures and yields of the products 2b-j.
.
Scheme 1. Negishi Coupling To Give 2a
the reaction to 40 °C. Quantitative removal of the N-Boc
group (using trifluoroacetic acid, TFA) gave the alkaloid
Scheme 3. Synthesis of (()-Anabasine 3
conditions were the use of palladium acetate and tri-tert-
butylphosphine·HBF4. Both bromobenzene and iodobenzene
were successful, although the bromide gave slightly superior
results. It is feasible that substoichiometric amounts of zinc
chloride could be used, depending on the active zinc species
in solution,4 although reaction with 0.3 equiv of ZnCl2 gave
only recovered starting material 1.
Using the optimized conditions for the coupling reaction,
a range of aryl bromides were tested (Scheme 2, Figure 1).
(()-anabasine 3.9 This represents an extremely short (two
steps) synthesis of this alkaloid.
We have explored two other substrates for this chemistry
(Scheme 4). Deprotonation of N-Boc-2-methylpiperidine 4
Scheme 2. Optimized Conditions for the Coupling To Give 2
Scheme 4. Application to Other Substrates
The reaction was found to be general for a variety of
substituted aromatic bromides, and successful couplings were
achieved with both electron-donating and electron-withdraw-
ing aryl substituents. Thus, methyl- and alkoxy-substituted
aryl bromides gave the products 2b-f. The coupling tolerated
unprotected 4-bromoaniline to give the product 2g. In
addition, 1-bromo-4-chlorobenzene, 3-bromoacetophenone,
and 1-bromonaphthalene were successful (to give 2h-j).
The chemistry was amenable to the use of heteroaromatic
bromides, as illustrated in Scheme 3. Coupling with 3-bro-
mopyridine gave the 2-arylpiperidine 2k. In this case the
yield was slightly improved (from 47% to 51%) by warming
is known to occur at the 6-position to give, after electrophilic
quench, trans-2,6-disubstituted piperidines.8 Deprotonation
3924
Org. Lett., Vol. 10, No. 17, 2008

of 4 and transmetalation to the organozinc compound
followed by cross-coupling with 4-bromoveratrole (using 8
mol % Pd(OAc)2 and 12 mol % t-Bu3P-HBF4) gave the
desired trans product 5. The lithiation of the seven-membered
ring compound 6 and electrophilic quench is known8 but is
less efficient than that of smaller ring analogs or of more
rigid carbamates.10 However, the Negishi-type coupling was
successful with this substrate to give the products 7a and
7b.
eridines and was applied to the shortest known synthesis of
(()-anabasine. Current work is investigating the asymmetric
synthesis of these products, which could derive from
asymmetric deprotonation of N-Boc-piperidine,11 or dynamic
resolution of the intermediate organolithium species.12
Acknowledgment. We thank the EPSRC (grant EP/
E012272/1) and the University of Sheffield for support of
this work.
In summary, we have extended the range of substitution
products that can be accessed from, in particular, N-Boc-2-
lithiopiperidine. A variety of 2-aryl-piperidines can be
prepared in good yield using transmetalation to the orga-
nozinc species and palladium-catalyzed cross-coupling. This
chemistry provides a direct access to aryl-substituted pip-
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for the products 2a-k, 3, 5,
and 7a,b. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL801579R
(11) (a) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg, K. B.
J. Am. Chem. Soc. 2002, 124, 1889. (b) McGrath, M. J.; Bilke, J. L.;
O’Brien, P. Chem. Commun. 2006, 2607. (c) Coldham, I.; O’Brien, P.; Patel,
J. J.; Raimbault, S.; Sanderson, A. J.; Stead, D.; Whittaker, D. T. E.
Tetrahedron: Asymmetry 2007, 18, 2113.
(9) (a) Larivee, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc.
2008, 130, 52. (b) Castro, A.; Ramirez, J.; Juarez, J.; Teran, J. L.; Orea, L.;
Galindo, A.; Gnecco, D. Heterocycles 2007, 71, 2699. (c) Amat, M.; Canto,
M.; Lior, M.; Bosch, J. Chem. Commun. 2002, 526. (d) Felpin, F.-X.; Girard,
S.; Vo-Thanh, G.; Robins, R. J.; Villie´ras, J.; Lebreton, J. J. Org. Chem.
2001, 66, 6305. (e) Wanner, M. J.; Koomen, G.-J. J. Org. Chem. 1996, 61,
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(12) (a) Coldham, I.; Patel, J. J.; Raimbault, S.; Whittaker, D. T. E.
Chem. Commun. 2007, 4534. (b) Coldham, I.;Raimbault, S.;Chovatia,
P. T.;Patel, J. J.;Leonori, D.;Sheikh, N. S.;Whittaker, D. T. E. Chem.
Commun. 2008, DOI: 10.1039/B810988E.
(10) Gross, K. M. B.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315.
Org. Lett., Vol. 10, No. 17, 2008
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