Palladium-catalyzed direct C-H arylation of N-iminopyridinium ylides: Application to the synthesis of (±)-anabasine

Article abstract of DOI:10.1021/ja710073n

Palladium-catalyzed direct C-H arylation of N-iminopyridinium ylides provides a powerful and versatile method for the synthesis of functionalized piperidines in good yields. Chemoselective functionalization of the pyridinium ring in the presence of a pyridine substituent is possible as exemplified by the expedient synthesis of anabasine in 61% overall yield over three steps. Copyright

Full text of DOI:10.1021/ja710073n

Published on Web 12/08/2007
Palladium-Catalyzed Direct C-H Arylation of N-Iminopyridinium Ylides:
Application to the Synthesis of (()-Anabasine
Alexandre Larive´e, James J. Mousseau, and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P. O. Box 6128, Station Downtown,
Montre´al, Quebec, Canada H3C 3J7
Received November 6, 2007; E-mail: andre.charette@umontreal.ca
Table 1. Palladium-Catalyzed Arylation of N-Iminopyridinium Ylide
with Aryl Halide Derivatives
Pyridine and piperidine motifs are important pharmacophores
that can be found in many natural products and bioactive mol-
ecules.1 Our group has been interested in using activated pyridinium
imidates and pyridinium ylides as starting materials to generate
substituted piperidines via stereoselective Grignard additions2,3 and
catalytic asymmetric hydrogenation reactions.4 This approach
enables the preparation of highly substituted enantioenriched
piperidines in a few steps from commercially available pyridine
derivatives.
entry
ligand
X
equiv of ylide
temp (
°
C)
yield (%)a
While pyridine is readily available, 2-aryl- and 2-heteroarylpy-
ridine substrates are less common and significantly more expensive.
These substrates are typically synthesized by cross-coupling reac-
tions between 2-halopyridines and aryl organometallic derivatives5
or by Grignard addition to the pyridine N-oxide.6 More recently,
considerable attention has been given to direct arylation reactions
as a more efficient approach for aryl-aryl bond formation.7 The
benefit of this approach is that it avoids the utilization of
stoichiometric amounts of organometallic reagents. While many
direct arylation reactions of heteroaryl compounds have been
reported, few exist for the direct arylation or heteroarylation of
pyridine derivatives.8 Furthermore, the chemoselective functional-
ization of one heterocycle in the presence of others is often difficult.
Herein, we disclose a novel reactivity of N-iminopyridinium ylides9
and a procedure that allows their direct arylation coupling with a
variety of functionalized aryl and heteroaryl bromides. We also
demonstrate that it is possible to further selectively functionalize
the pyridinium ylide ring in the presence of a pyridine ring.
We initially examined the direct arylation of N-benzoyliminopy-
ridinium ylides, which are easily prepared by the amination of
pyridine.10 A small portion of the optimization studies involving
ylide 1a is shown in Table 1. Treatment of 1a (1.5 equiv) with
bromobenzene in the presence of t-Bu3P/Pd(OAc)2 afforded the
2-arylated product in excellent yield (entry 1). Among the mono-
and bidentate phosphines that were tested, tri-t-butylphosphine was
found to be the most effective. Both the phosphine oxide (entry 2)
and the protonated t-Bu3P (entry 3) were less effective. The
preformed Pd(Pt-Bu3)2 complex was as effective as the in situ
prepared catalyst (entry 4). Lowering the temperature (entry 5),
the amount of ylide (entries 6 and 7) or the reaction concentration
(entries 8 and 9) resulted in lower yields. Although all reactions
were run in the presence of molecular sieves, only slightly lower
yields were observed without them (entry 10) or in the presence of
H2O (entry 11). While iodobenzene gave a slightly improved yield
(entry 12), chlorobenzene resulted in a significantly lower yield
(entry13).
1
2
3
4
5
tBu3P
tBu3P(O)
tBu3P‚HBF4
Pd(tBu3P)2
tBu3P
tBu3P
tBu3P
tBu3P
tBu3P
tBu3P
tBu3P
tBu3P
tBu3P
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
1.5
1.5
1.5
1.5
1.5
1.0
1.3
1.5
1.5
1.5
1.5
1.5
1.5
125
125
125
125
110
125
125
125
125
125
125
125
125
87
0
55
90
66
36
64
82
73
81
83
95
42
b
6
7
8c
9d
10e
11f
12
13
Cl
a Yields are measured by 1H NMR using 1,3,5-trimethoxybenzene as
the internal standard. b Reaction run using 5 mol % of Pd(Pt-Bu)3 instead
of Pd(OAc)2/ligand. c Run at 0.1 M. d Run at 0.05 M. e Run without 3 Å
molecular sieves. f Run without 3 Å molecular sieves and in the presence
of 5 equiv of H2O.
bromobenzene (1 equiv), the 2-phenyl-N-iminopyridinium ylide was
obtained in an 80% isolated yield. Both electron-rich (entries 2 and
3) and electron-poor (entries 4-8) aryl bromides are compatible
under the reaction conditions, although 2.5 equiv of the ylide are
necessary for the latter.
2-Bromotoluene (2i) gave a good yield of arylated product
showing that sterically hindered bromides are compatible. These
conditions were also successful for the coupling of heteroaryl
bromide derivatives resulting in the formation of highly valuable
bis(heteroaryl) substrates (entries 10-12).
Encouraged by these results, we explored the scope of the
N-iminopyridinium ylide coupling partner 1 (Table 3). Generally,
substituted N-iminopyridinium ylides resulted in lower yields and
required an excess of the aryl bromide. N-Iminoquinolinium (1b)
and N-iminoisoquinolinium ylides (1c) gave moderate and good
yields of arylated products, respectively. Various 2- and 3-alkyl
substituted N-iminopyridinium ylides also gave moderate yields of
products. Notably, 3-methyl-N-iminopyridinium ylide (1d) resulted
in a 10:1 regioselectivity, favoring the 2,5-disubstituted adduct 3o.
We also demonstrated the synthetic potential of this methodology
by chemoselectively functionalizing the pyridinium ylide ring in
the presence of a pyridine (Scheme 1). A substituent can be easily
The scope of the reaction was then investigated using various
aryl bromide derivatives (Table 2). Under the optimized reaction
conditions [1 (1.5 equiv), Pd(OAc)2 (5 mol %), P(tBu)3 (15 mol
%), K2CO3 (3 equiv), 3 Å mol. sieves, toluene 125 °C] using
9
52
J. AM. CHEM. SOC. 2008, 130, 52-54
10.1021/ja710073n CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Arylation of Other N-Imino Ilidesa
Table 2. Palladium-Catalyzed Arylation of N-Iminopyridinium Ylide
with Aryl and Heteroaryl Bromide Derivativesa
a Reaction conditions: 1 (1.0 equiv), 2a (2.5 equiv), Pd(OAc)2 (5 mol
%), P(tBu)3 (15 mol %), K2CO3 (3 equiv), M.S. 3 Å, toluene 125 °C (1.0
M), 16-20 h. b Yield of isolated product. c Yield in parentheses is that of
the pyridine or isoquinoline obtained after cleavage of the N-N bond using
MeI, acetone, 75 °C then Zn (dust), AcOH, room temp. d Run using 1.5
equiv of 1c, 1.0 equiv of 2a and 0.3 M concentration.
Scheme 1. Functionalization of 2-Heteroarylsubstituted Pyridinium
Ylides and the Synthesis of (()-Anabasine‚TFAa
a Reagents and conditions: (a) MeMgBr, CH2Cl2; (b) O2, TFA, CH2Cl2
(45%, two steps); (c) H2, 300 psi, PtO2 (9 mol %), MeOH (87%); (d) SmI2,
HMPA, THF, 0 °C; (Boc)2O, NaOH, room temp (84%); (e) TFA, CH2Cl2
(quantitative).
Scheme 2. Reductive Cleavage of the N-N Bonda
a Reagents and conditions: (a) Zn (dust), AcOH, room temp (80%); (b)
HCO2NH4, Pt/C, MeOH, 80 °C (83%); (c) TMS3SiH, AIBN, toluene,
80 °C (85%).
chemoselective hydrogenation of ylide 3l followed by a one-pot
SmI2 reduction of the N-N bond and in situ Boc protection afforded
N-protected anabasine in 61% yield over three steps. TFA treatment
resulted in (()-anabasine‚TFA (5) in quantitative yield.11
It is also possible to reductively cleave the N-N bond to afford
2-substituted N-heteroarene derivative (Scheme 2). The
a
methylation of ylide 3a afforded pyridinium salt 6 in quantitative
yield.12 Direct treatment of 6 either with zinc dust in acetic acid,12
with ammonium formate in the presence of platinum on carbon12
or with tris(trimethylsilyl)silane and AIBN13 led to 7 in excellent
yields. Some other representative cleavage yields are shown in Table
2 (entries 1 and 3) and Table 3 (entries 2 and 3).
a Reaction conditions: 1a (1.5 equiv), 2 (1.0 equiv), Pd(OAc)2 (5 mol
%), P(tBu)3 (15 mol %), K2CO3 (3 equiv), M.S. 3 Å, toluene 125 °C (0.3
M), 16-20 h. b Yield of isolated product. c Yield in parentheses is that of
the 2-substituted pyridine obtained after cleavage of the N-N bond using
MeI, acetone, 75 °C then Zn (dust), AcOH, room temp. d Run using 2.5
equiv of 1a instead of 1.5 equiv.
To gain further insight about the mechanism of this reaction we
directly compare the reactivity of the N-iminopyridinium ylide 1a
with that of the pyridinium N-oxide, a substrate that is also known
introduced at the 6-position by treatment of 3l with a Grignard
reagent followed by rearomatization (resulting in 4). Alternatively,
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J. AM. CHEM. SOC. VOL. 130, NO. 1, 2008 53

C O M M U N I C A T I O N S
Scheme 3. Competition Experiments and Attempted Arylation of
3a
the Canada Research Chairs Program, the Canadian Foundation for
Innovation, and the Universite´ de Montre´al. We thank Prof. Keith
Fagnou (Univ. of Ottawa) for useful discussions.
Supporting Information Available: Experimental procedures,
sample spectra and compound characterization data (PDF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For recent reviews on the stereoselective synthesis of piperidines, see:
(a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (b) Felpin, F.-X.;
Lebreton, J. M. Eur. J. Org. Chem. 2003, 3693. (c) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953.
(2) (a) Larive´e, A.; Charette, A. B. Org. Lett. 2006, 8, 3955. (b) Sales, M.;
Charette, A. B. Org. Lett. 2005, 7, 5773. (c) Charette, A. B.; Mathieu, S.;
Martel, J. Org. Lett. 2005, 7, 5401. (d) Lemire, A.; Charette, A. B. Org.
Lett. 2005, 7, 2747. (e) Lemire, A.; Beaudoin, D.; Grenon, M.; Charette,
A. B. J. Org. Chem. 2005, 70, 2368. (f) Lemire, A.; Grenon, M.;
Pourashraf, M.; Charette, A. B. Org. Lett. 2004, 6, 3517.
(3) (a) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 6360.
(b) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J.
Am. Chem. Soc. 2001, 123, 11829.
to give efficient C-H arylation under palladium catalysis.8b In the
latter case, however, 4 equiv of the N-oxide must be used to
minimize the formation of the 2,6-diarylated product. We conducted
a reaction with 2 equiv of pyridine N-oxide (8), 1.5 equiv of
N-iminopyridinium ylide 1a, and 1 equiv of bromobenzene (2a)
(eq 1). Surprisingly, no N-oxide arylated product 9 could be detected
and 2-phenyl-N-benzoyliminopyridinium ylide was obtained in 56%
yield. We believe that the amide functionality of the pyridinium
ylide acts as a strong Lewis base (stronger than the N-oxide) to
direct the C-H insertion reaction at the 2-position. The minimal
formation of the 2,6-diarylated product 10 when 1a was used as
starting material was also confirmed by the fact that the arylation
of 3a with bromobenzene proceeded very slowly under the standard
reaction conditions (Scheme 3).
This observation is consistent with a decrease in the accessibility
of the Lewis base for steric reasons in 3a relative to 1a. Upon the
2-substitution, the carbonyl group that is pointing above the
pyridinium ring becomes significantly less accessible for complex-
ation with palladium.
In conclusion, we have developed a new method for the
functionalization of N-iminopyridinium ylides with various aryl and
heteroaryl bromides. Furthermore, we have demonstrated that it is
possible to chemoselectively functionalize the ylide heterocycle in
the presence of pyridine. Further applications of this approach to
the preparation of 2-substituted piperidines will be reported in due
course.
(4) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966.
(5) (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302. (b) Littke,
A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(6) Andersson, H.; Almqvist, F.; Olsson, R. Org. Lett. 2007, 9, 1335.
(7) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174.
(b) LeClerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781. (c)
Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J.
Am. Chem. Soc. 2006, 128, 1066. (d) Miura, M.; Satoh, T. Top.
Organomet. Chem. 2005, 14, 55. (e) Wolfe, J. P.; Thomas, J. S. Curr.
Org. Chem. 2005, 9, 625. (f) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077. (g) Miura, M.; Nomura, M. Top. Curr. Chem. 2002,
219, 211. (h) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.
(8) (a) Ackermann, L.; Althammer, A.; Born, R.; Angew. Chem., Int. Ed.
2006, 45, 2619. (b) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am.
Chem. Soc. 2005, 127, 18020. (c) Jonkers, T. H. M.; Maes, B. U. W.;
Lemie`re, G. L. F.; Rombouts, G.; Pieters, L.; Haemers, A.; Dommisse,
R. A. Synlett 2003, 5, 615. (d) Oi, S.; Fukita, S.; Hirata, N.; Watanuki,
N.; Miyano, S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (e) Mukhopadhyay,
S.; Rothenberg, G.; Gitis, D.; Baidossi, M.; Ponde, D. E.; Sasson, Y. Perkin
Trans. 2 2000, 1809. (f) Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun.
1998, 2439. (g) Albrecht, K.; Reiser, O.; Weber, M.; Knieriem, B.; De
Meijere, A. Tetrahedron 1994, 50, 383. (h) Ames, D. E.; Opalko, A.
Tetrahedron 1984, 40, 1919. For the direct alkylation of pyridines see:
(i) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 5332.
(9) For examples of catalytic ortho-arylation of arylamides and anilides, see:
(a) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc.
2002, 124, 5286. (b) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed.
2005, 44, 4046. (c) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc.
2007, 129, 6066.
(10) Legault, C.; Charette, A. B. J. Org. Chem. 2003, 68, 7119.
(11) For recent syntheses of anabasine, see: (a) Amat, M.; Canto´, M.; Llor,
N.; Bosch, J. Chem. Commun. 2002, 526. (b) Barco, A.; Benetti, S.; De
Risi, C.; Marchetti, P.; Pollini, G. P.; Zanirato, V. Eur. J. Org. Chem.
2001, 975. (c) Felpin, F.-X.; Girard, S.; Vo-Thanh, G.; Robinis, R. J.;
Villie´ras, J.; Lebreton, J. J. Org. Chem. 2001, 66, 6305. (d) Andre´s, J.
M.; Herra´iz-Sierra, I.; Pedrosa, R.; Pe´rez-Encabo, A. Eur. J. Org. Chem.
2000, 1719.
(12) Mart´ınez-Barrasa, V.; Delgado, F.; Burgos, C.; Garc´ıa-Nav´ıo, J. L.;
Izquierdo, M. L.; Alvarez-Builla, J. Tetrahedron 2000, 56, 2481.
(13) Garc´ıa de Viedma, A.; Mart´ınez-Barrasa, V.; Burgos, C.; Izquierdo, M.
L.; Alvarez-Builla, J. J. Org. Chem. 1999, 64, 1007.
Acknowledgment. This work was supported by the Natural
Science and Engineering Research Council of Canada (NSERC),
Merck Frosst Canada Ltd., Boehringer Ingelheim (Canada), Ltd.,
JA710073N
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