Palladium-mediated functionalization of heteroaromatic cations: Comparative study on quinolizinium cations

Article abstract of DOI:10.1021/jo060634+

An efficient palladium-catalyzed cross-coupling reaction on heteroaromatic cations is described. A comparative study of the Stille and Suzuki reactions shows that only the Stille reaction is able to produce an efficient C-C bond formation between any of the four isomeric bromoquinolizinium bromides and a variety of stannanes. In the presence of the catalysts Pd(PPh3)4 or Pd2(dba)3P(o-Tol)3, vinyl, ethynyl, aryl, and heteroaryl groups are successfully incorporated into the quinolizinium system in satisfactory yields under mild reaction conditions. This procedure represents a marked improvement on the functionalization of this class of heteroaromatic cation.

Full text of DOI:10.1021/jo060634+

Palladium-Mediated Functionalization of Heteroaromatic Cations:
Comparative Study on Quinolizinium Cations
Domingo Garc´ıa-Cuadrado, Ana M. Cuadro,* Bernardo M. Barch´ın, Ana Nun˜ez,
Tatiana Can˜eque, Julio Alvarez-Builla, and Juan J. Vaquero*
Departamento de Qu´ımica Orga´nica, UniVersidad de Alcala´, 28871-Alcala´ de Henares, Madrid, Spain
juanjose.Vaquero@uah.es
ReceiVed March 23, 2006
An efficient palladium-catalyzed cross-coupling reaction on heteroaromatic cations is described. A
comparative study of the Stille and Suzuki reactions shows that only the Stille reaction is able to produce
an efficient C-C bond formation between any of the four isomeric bromoquinolizinium bromides and a
variety of stannanes. In the presence of the catalysts Pd(PPh3)4 or Pd2(dba)3P(o-Tol)3, vinyl, ethynyl,
aryl, and heteroaryl groups are successfully incorporated into the quinolizinium system in satisfactory
yields under mild reaction conditions. This procedure represents a marked improvement on the
functionalization of this class of heteroaromatic cation.
Introduction
Heteroaromatic cations are considered as a kind of hetero-
cyclic compounds that are structurally classified as azinium/
azolium- and quinolizium-type cations depending on the nature
of the quaternary nitrogen and aromatic heterocycle.1 Thus, in
azinium and azolium salts a nitrogen of an azine or azole is
quaternized, whereas in quinolizinium-type salts a bridgehead
quaternary nitrogen is the common feature of the charged system
(Figure 1).
These compounds have attracted attention in fields as diverse
as natural products,2 fluorescent dyes,3 antitumoral compounds,4
DNA intercalators,5 topoisomerase6 and telomerase7 inhibitors,
and, more recently, NLO materials8 and ionic liquids.9 Recently,
FIGURE 1. General structures for heteraromatic cations.
(1) (a) Scriven, E. F. V. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 1, pp
165-314. (b) Comins, D. L.; Joseph, S. P. In ComprehensiVe Heterocyclic
Chemistry II; Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 5, pp 245-300. (c) Bradsher, C. K. V. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 2, pp 525-579. (d) Avendan˜o, C.;
Mene´ndez, C. In ComprehensiVe Heterocyclic Chemistry II; Katrizky, A.
R., Rees, C. W., Scriven, Eds.; Pergamon: Oxford, 1996; Vol. 8, pp 507-
562.
we faced a problem associated with the functionalization and/
or introduction of substituents on some antiproliferative cations
(3) (a) Haugland, R. Handbook of Fluorescent Probes and Research
Chemicals, 8th ed.; Molecular Probes, Inc.: Eugene, OR, 2001. (b) In
Applied Fluorescence in Chemistry, Biology and Medicine; Rettig, W.,
Strehmel, B., Schrader, S., Seifert, H., Eds.; Springer: New York, 1999.
(4) (a) In Cancer Chemotherapeutic Agents; Foye, W. O., Ed.; American
Chemical Society: Washington, DC, 1995. (b) Neidle, S.; Thurston, D. E.
In New Targets for Cancer Chemotherapy; Kerr, D. J., Workman, P., Eds.;
CRC Press: Boca Raton, FL, 1994.
(2) (a) Lipinska, T. Tetrahedron Lett. 2002, 43, 9565. (b) Mat´ıa, M. P.;
Ezquerra, J.; Garc´ıa-Nav´ıo, J. L.; Vaquero, J. J.; Alvarez-Builla, J.
Tetrahedron Lett. 1991, 32, 7575.
10.1021/jo060634+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/14/2006
J. Org. Chem. 2006, 71, 7989-7995
7989

Garc´ıa-Cuadrado et al.
FIGURE 3. Isomeric bromoquinolizinium bromides.
proven to be extremely useful to build carbon-carbon12 or
carbon-heteroatom13 bonds. Although the methodology has
been applied to a variety of heterocycles,14 to the best of our
knowledge, only Zoltewicz15 has reported an example involving
a cationic heteroaromatic stannane. Our initial results demon-
strated that both haloquinolizinium16 and haloazinium cations17
are appropriate partners in the Stille reaction. We report here
our full investigations in a comparative study and discuss the
scope of the functionalization of quinolizinium salts using Stille
and Suzuki reactions.
FIGURE 2. DNA intercalators based on a quinolizinium and an aza-
quinolizinium core.
such as 1-3, which are based on a quinolizinium and an aza-
quinolizium core and behave as a new class of DNA interca-
lators and Topo I inhibitors5c,10 (Figure 2).
Results and Discussion
As an example, introduction of substituents in systems 1-3
in order to improve their DNA binding properties and/or
antiproliferative activity cannot easily be achieved using classical
methods in heterocyclic chemistry. In this respect, electrophilic
substitution is not a useful strategy for a positively charged
heterocycle; nucleophiles usually react to give addition reactions
that in many cases yield ring-opening products, and furthermore,
metalation is a process with poor selectivity and is restricted to
the use of non-nucleophilic bases. On the other hand, the
traditional strategy of using appropriately substituted starting
materials11 is limited by either the tolerance of such substituents
to the reaction conditions or their negative influence on the
reactivity of such substrates.
For our investigation we chose the quinolizinium cation as
the simplest model that offers four possible positions to explore
substitution on quinolizium-type cations by palladium-mediated
cross-coupling processes. The four isomeric bromoquinolizinium
cations 4-7 (Figure 3) appeared to be the most appropriate
models to study the scope of substitution on these charged
heterocycles since they exhibit markedly different behavior from
an electronic point of view at the C1/C3 and C2/C4 positions.
Moreover, one would also expect a different steric effect on
C1/C4 and C2/C3.
These four cations can be prepared according to previously
reported procedures,18 but their syntheses were not particularly
efficient, mainly for 1-bromoquinolizinium bromide (4), which
is obtained by bromination of quinolizinium bromide. This is a
difficult reaction that was carried out at 200 °C and afforded
only 10% yield of this bromo derivative (1.5% overall yield).18a
We were able to improve the syntheses of 4 and 618a using a
new approach to the quinolizinium system. This approach is
based on a ring-closing metathesis (RCM) reaction on 1-butenyl-
The lack of a general methodology to achieve substitutions
particularly on quinolizium-type cationssand our interest in this
field led us to study a promising approach involving a palladium-
catalyzed cross-coupling methodology. This approach has
(5) (a) Gago, F. Methods Enzymol. 1998, 14, 277. (b) Wilson, W. D.;
Jones, R. In Intercalation Chemistry; Whittingham, M. S., Jacobson, A. J.,
Eds.; Academic Press: New York, 1981. (c) Martinez, V.; Burgos, C.;
Alvarez-Builla, J.; Fernandez, G.; Domingo, A.; Garcia-Nieto, R.; Gago,
F.; Manzanares, I.; Cuevas, C.; Vaquero, J. J. J. Med. Chem. 2004, 47,
1136.
(6) (a) Froelich-Ammon, S. J.; Osheroff, N. J. Biol. Chem. 1995, 270,
21429. (b) Hsieh, T. In DNA Topology and Its Biologic Effects; Cozzarelli,
N. R., Wang, J. C., Eds.; Cold Spring Harbor: New York, 1990; Chapter
7.
(7) (a) Yokoyama, Y.; Takahashi, Y.; Shinohara, A.; Lian, Z.; Wan, X.;
Niwa, K.; Tamaya, T. Cancer Res. 1998, 58, 5406. (b) Pitts, A. E.; Corey,
D. R. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 11549.
(8) (a) Facchetti, A.; Abbotto, A.; Beverina, L.; van der Boom, M. E.;
Dutta, P.; Evmenenko, G.; Marks, T. J.; Pagani, G. A. Chem. Mater. 2002,
14, 4996. (b) Mata, J. A.; Uriel, S.; Llusar, R.; Peris, E. Organometallics
2000, 19, 3797.
(12) (a) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in
Organic Synthesis; John Wiley & Sons: Chichester, 1995; Chapter 4, p
125. (b) Farina, F. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995;
Vol. 12, Chapter 3.4, p 161. (c) In Metal-catalyzed Cross-coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(d) In PerspectiVes in Organopalladium Chemistry for the XXI Century;
Tsuji, J., Ed.; Elsevier Press: Lausanne, Switzerland, 1999.
(13) (a) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046. (b)
Harwig, J. F. Facc. Chem. Res. 1998, 31, 852. (c) Hartwig, J. F. J. Org.
Chem. 1999, 64, 5575. (d) Frost, C. G.; Mendoc¸a, P. J. Chem. Soc., Perkin
Trans. 1 1998, 2615. (e) Undheim, K.; Beneche, T. AdV. Heterocycl. Chem.
1995, 62, 330. (f) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Jingjun Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158.
(14) (a) Undheim, K.; Benneche, T. AdV. Heterocycl. Chem. 1995, 62,
330. (b) Kalinin, V. N. Synthesis 1992, 413. (c) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Pergamon: Oxford, 2000.
(15) (a) Zoltewicz, J. A.; Cruskie, M. P. J. Org. Chem. 1995, 60, 3487.
(b) Zoltewicz, J. A; Cruskie, M. P., Jr.; Dill, C. D. J. Org. Chem. 1995, 60,
0, 264.
(16) Barch´ın, B. M.; Valenciano, J.; Cuadro, A. M.; Alvarez-Builla, J.;
Vaquero, J. J. Org. Lett. 1999, 1, 545.
(17) Garc´ıa-Cuadrado, D.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero,
J. J. Synlett 2002, 11, 1904.
(18) For the synthesis of 1-bromo-(4), 3-bromo-(6), and 4-bromoquino-
lizinium (7), see: (a) Sanders, G. M.; van Dijk, M.; van der Plas, H. C.
Heterocycles 1981, 15, 213. For the synthesis of 2-bromoquinolizinium (5),
see: (b) Fozard, A.; Jones, G. J. Chem. Soc. 1963, 2203.
(9) (a) Seddon, K. R. Nat. Mater. 2003, 2, 363. (b) Welton, T. Chem.
ReV. 1999, 99, 2071.
(10) (a) Pastor, J.; Siro´, J.; Garc´ıa-Nav´ıo, J. L.; Vaquero, J. J.; Rodrigo,
M. M.; Ballesteros, M.; Alvarez-Builla, J. Bioorg. Med. Chem. Lett. 1995,
5, 3043. (b) Pastor, J.; Siro´, J.; Garc´ıa Nav´ıo, J. L.; Vaquero, J. J.; Alvarez-
Builla, J.; Gago, F.; Pascual-Teresa, B.; Pastor, M.; Rodrigo, M. J. Org.
Chem. 1997, 62, 5476. (c) Molina, A.; Vaquero, J. J.; Garc´ıa-Nav´ıo, J. L.;
Alvarez-Builla, J.; Rodrigo, M. M.; Castan˜o, O.; Andre´s, J. L. Bioorg. Med.
Chem. Lett. 1996, 6, 1453. (d) Molina, A.; Vaquero, J. J.; Garc´ıa-Nav´ıo, J.
L.; Alvarez-Builla, J.; Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M. J. Org.
Chem. 1999, 64, 3907. (e) Fontana, A.; Benito, E. J.; Mart´ın, J. M.; Sa´nchez,
N.; Alajarin, R.; Vaquero, J. J.; Alvarez-Builla, J.; Lambel-Giraudet, S. L.;
Pierre, A.; Caignard, D. Bioorg. Med. Chem. Lett. 2002, 12, 2611.
(11) Vaquero, J. J.; Alvarez-Builla, J. In AdVances in Nitrogen Hetero-
cycles; Moody, C. J., Ed.; JAI Press: Stamford, CT, 2000; Vol. 4, p 159.
7990 J. Org. Chem., Vol. 71, No. 21, 2006

Functionalization of Heteroaromatic Cations
SCHEME 1
SCHEME 2
2-vinylpyridinium salts followed by oxidation of the resulting
3,4-dihydroquinolizinium19 (Scheme 1).
However, this straightforward and efficient methodology
could not be applied to the other two isomeric bromoquinoli-
zinium cations.20 For 5 and 7 a new approach to the previously
reported precursor ketones 14a21 and 1722 was attempted, but
our method, which is based on the reaction of pyridinium
carboxylates with propenenitrile (Scheme 2), gave similar
yields to that previously reported for the pyridinium salt 14a
and failed to produce the bicyclic ketone 17. However, this
approach also led to an improvement in the preparation of 6
from 12b when compared with the classical method18a (28%
vs 17%).
Our initial strategy to achieve the functionalization of these
quinolizinium cations was to convert the bromoquinolizinium
derivatives into the heteroaryltin 18, heteroarylboronic acid 19,
and heteroaryl zinc 20 derivatives in order to test the well-known
Stille, Suzuki, and Negishi reactions with a variety of com-
mercially available alkyl, alkenyl, alkynyl, aryl, and heteroaryl
halides.
As stated earlier, the only precedent found for a metalated
heteroaromatic cation was reported by Zoltewicz et al.15 They
described the preparation of a pyridinium trialkylstannane by
quaternization of the corresponding pyridylstannane with methyl
iodide. This approach cannot be applied to the quinolizinium
system, but this precedent did demonstrate the feasibility of
preparing stable metalated heteroaromatic cations. For this
reason, preparation of stannane 18 initially seemed a viable goal
since other heteroarylstannanes have previously been prepared
by reaction of the corresponding lithiated heterocycle with
trialkyltin chlorides or by a palladium-mediated coupling
reaction between a haloheterocycle and a hexaalkyldistannane.23
We envisaged that the first approach to our target would be
associated with several disadvantages (low solubility of the salts
in the appropriate solvents for organolithium reagents, sensitivity
of the substrate to nucleophilic attack, and poor selectivity of
the lithiation reaction, inter alia) when compared with the cross-
coupling reaction. For this reason, this latter approach was
chosen as the most suitable to prepare 18. Using 2-bromoquino-
lizinium bromide (5) as a model, all our attempts to isolate 18
by reaction with hexamethyldistannane or hexabutyldistannane
in N,N-dimethylformamide (DMF) or N,N-dimethylacetamide
(DMAC) were unsuccessful. We tested three different catalytic
systems [Pd(PPh3)4/CuI, Pd2(dba)3/P(o-Tol)3, and Pd2(dba)3/
BINAP] at different temperatures with standard and inverse slow
addition of 5 and with addition of 1.2 equiv of KF when Pd2-
(dba)3/P(o-Tol)3 was used as the catalytic system. The results
obtained in all of these attempts to obtain 18 were variable,
and inseparable mixtures of the homocoupling compound 21,
debrominated quinolizinium 22, and starting material were
obtained. Decomposition products were also detected in most
of the attempted reactions.
The one-step procedure reported by Miyaura24 for the
preparation of arylboronic esters, based on a palladium-catalyzed
coupling reaction between the pinacol ester of diboron and 5,
also failed using the same palladium sources and phosphines
in DMF and DMSO at room temperature and at 70 °C in the
presence of K2CO3 and Et(i-Pr)2N as bases. As expected,
attempts to synthesize heteroarylboronic acid 19 using either
trimethoxyborane or the more selective triisopropoxyborane as
reagents (via the lithiated heterocycle) were also unsuccessful,
with extensive decomposition of the heterocycle being observed
(Scheme 3).
Finally, we studied formation of the organozinc 2025 using
1,2-dibromomethane26 and ultrasound27 as methods for activa-
tion of the Zn with DMAC being used as the solvent in both
cases. Under these conditions the presumably formed organozinc
20 was reacted with 4-iodotoluene in the presence of Pd(PPh3)4
at room temperature. Although we were able to detect by NMR
formation of the cross-coupling compound 24, formation of 21
and 22 was also observed. The best result afforded 24 in about
(19) Nun˜ez, A.; Cuadro, Ana M.; Alvarez-Builla, J.; Vaquero, J. J. Org.
Lett. 2004, 6, 4125.
(20) The RCM reaction for 5 required the use of 2,4-dibromopyridine
as the starting heterocycle. This compound could not be N-alkylated with
the 3-butenyl triflate. The RCM for 7 required the use of 2,6-dibromopy-
ridine, which could not be selectively transformed into the 2-bromo-6-
vinylpyridine, the appropriate precursor of the N-butenylpyridinium salt.
(21) Miyadera, T.; Iwai, I. Chem. Pharm. Bull. 1964, 12, 1338.
(22) Boekelheide, V.; Lodge, J. P., Jr. J. Am. Chem. Soc. 1951, 73, 3681.
(23) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(24) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508.
(25) Boudier, A.; Bromm, L.O.; Lotz, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2000, 39, 4414.
J. Org. Chem, Vol. 71, No. 21, 2006 7991

Garc´ıa-Cuadrado et al.
SCHEME 3
TABLE 1. Palladium-Catalyzed Cross-Coupling Reactions of
2-Bromoquinolizinum Bromide (5) under Suzuki and Stille
Conditions
TABLE 2. Reactions of 5 and 6 with Aryl and Heteroaryl Boronic
Acids and Stannanesa
entry stannane/boronic
conditions
yielda (%)
1
2
3
4
5
6
7
8
9
PhSnBu3
PhSnBu3
PhSnBu3
PhSnBu3
PhSnBu3
PhSnBu3
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
Pd(PPh3)4, CuI/r.t., 15 h
NR
NR
NR
dec.
60
Pd(PPh3)2Cl2, CuI/r.t., 12 h
Pd(PPh3)2Cl2, LiCl/r.t., 12 h
Pd(PPh3)2Cl2, LiCl/80 °C, 12 h
Pd(PPh3)4, 85 °C, 17 h
Pd2(dba)3P(o-Tol)3, 80 °C, 16 h
Pd(PPh3)4/K2CO3, r.t, 18 h
Pd(PPh3)4/K2CO3, 80 °C, 2 h
Pd(PPh3)4/(i-Pr)2EtN, r,t., 18 h
Pd(PPh3)4/(i-Pr)2EtN, 90 °C, 5 h
60
NR
traces
NR
NR
10
11
Pd2(dba)3/P(o-Tol)3, K2CO3, r.t., 16 h 47
a Isolated yield. NR: no reaction; dec.: decomposition.
35% yield, but this compound could not be isolated from the
reaction mixture.
a Reactions with stannanes and boronic acids were carried out under the
conditions shown in Table 1 (entries 5 and 11, respectively).
The failure of this approach led us to explore reaction of the
bromoquinolizinium derivatives as electrophilic partners with
aryl- and heteroarylboronic acids and stannanes. Initially,
optimization of the reaction conditions for Stille and Suzuki
reactions was carried out with 2-bromoquinolizium salt 5 in
order to compare the efficiency of these reactions on this high
electron-deficient position of the quinolizinium system. The
comparative study was carried out with tributylphenylstannane
and phenylboronic acid. A summary of the reaction conditions
and yields is given in Table 1.
The results showed that coupled compound 24a was formed
in both reactions, although yields were higher using Stille
conditions when compared with those obtained with the Suzuki
reaction. Under Stille conditions the best results were obtained
using either palladium tetrakistriphenylphosphine (entry 5,
method A) or tri-ortho-tolylphosphine/tris(dibenzylideneac-
etone)dipalladium (entry 6, method B) with heating at 80 °C
for 16-17 h in the absence of any additive. In both cases the
isolated yield of pure compound 24a (60%) was clearly lower
than that in the reaction itself (about 78% by NMR) due to losses
during the isolation and recrystallization of this compound.
The coupling reaction between 5 and phenylboronic acid
afforded the coupled compound in only 47% yield when Pd2-
(dba)3/P(o-Tol)3 or Pd2(dba)3/(2-biphenyl)di-tert-butylphosphine
was used in DMF in the presence of K2CO3 at room temperature
for 16 h (extensive decomposition was observed by heating at
80 °C). In this case the isolated yield was also lower than that
of the crude product (about 63%).
These results seem to indicate that the Stille reaction is the
most suitable process to study the scope of this palladium-
catalyzed cross-coupling reaction as a new methodology for the
functionalization of the quinolizinium system. However, de-
spite this we studied further examples to confirm our choice
prior to carrying out the reactions of 4-7 with a variety of
commercially available stannanes. Thus, two other electronic-
ally different heteroaromatic stannanes and their corre-
sponding boronic acids were tested under the optimized condi-
tions found for both reactions (Table 1, entries 5 and 11).
Moreover, the 3-bromoquinolizinium bromide (6) was also
subjected to Stille and Suzuki couplings in order to give a
broader overview of the reactivity of the C2 and C3 positions
of the quinolizinium system, which are electronically very
different and similar to C4 and C1, respectively. From Table 2
it is readily apparent that Stille coupling is more expedient
(26) Knochel, P.; Yeh, M. C. P.; Berck, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(27) Einhorn, C.; Einhorn, J.; Luche, J.-L. Synthesis 1990, 787.
7992 J. Org. Chem., Vol. 71, No. 21, 2006

Functionalization of Heteroaromatic Cations
TABLE 3. Stille Reaction on Bromoquinolizinium Bromides 4-7
For all compounds, yields are given for isolated products. a Method A: Pd(PPh3)4 (5 mmol %), CuI (10 mmol %), DMF, r.t. or heating at 80 °C.
b Method B: Pd2(dba)3/P(o-Tol)3 (5 mmol %), DMF, r.t. or heating at 80 °C. Most of the compounds were isolated as bromides (not shown). c Isolated as
the picrate. d Isolated as the hexafluorophosphate.
than the Suzuki coupling, particularly when performed with
electron-rich heteroaryl reagents. When an electron-poor sub-
strate (such as the commercially available 3-pyridineboronic
acid) was tested, the reaction failed to give the coupling com-
pound with either 2-bromo- or 3-bromoquinolizinium bromide
while the more electron-deficient 2-pyridinestannane afforded
the coupled compound in low yield with 5 and in moderate
yield with 6.
to positions C1 and C4 using a variety of stannanes to form
Csp2-Csp, Csp2-Csp2, and Csp2-Csp3 bonds. First, the other
possibility of forming a Csp2-Csp2 bond was studied by testing
the reaction between 5 and tributylvinylstannane under the
optimized conditions found for the coupling reaction with 5 and
tributylphenyltin. Both catalytic systems shown in Table 1
(entries 5 and 6) afforded the same yield, and so the cheaper
catalyst and less toxic phosphine (PPh3) were chosen to carry
out the coupling process. However, all experiments with the
1-bromoquinolizinium bromide (4) produced either decomposi-
On the basis of these results the Stille cross-coupling reaction
was chosen for functionalization of the quinolizinium system
J. Org. Chem, Vol. 71, No. 21, 2006 7993

Garc´ıa-Cuadrado et al.
tion of the substrate or recovery of large amounts of the starting
material. In addition, the same procedure was tested in the
presence of an additive such LiCl28 (3 equiv) in DMF, but the
reaction mixture contained only starting material. After further
experiments the desired coupling reaction was reproducibly
achieved in the presence of 10 mol % of copper(I) iodide.29
The reaction was complete in 17 h and produced 1-vinyl-
quinolizinium bromide (23b) (Table 3) in 55% yield.
(compounds 23d-f and 26d-f). In contrast, yields of the
coupling products are more comparable on 5 and 6, particularly
for tributyl-2-furanyl- (24a, 24d, 24f) and tributyl-2-thienyl-
stannanes (25a, 25d, 25f). Reactions of phenyltributylstannane
(or Ph4Sn) are very slow at room temperature, and heating at
80 °C and long reaction times (17-31 h) were necessary to
achieve moderate yields of the coupling products. Similar
reaction times were also required to obtain the coupled
compounds with the heteroarylstannanes if the reaction was
conducted at room temperature. Heating at 60-80 °C consider-
ably reduced the reaction times, and some processes were
completed within a few hours (3.30 h) for 1-bromoquinolizinium
4. However, such temperatures could not be generally used for
the other isomers due to formation of side products by transfer
of n-butyl groups. With the exception of the 2-thienyl derivative
26d, which was obtained using method A in 23% yield and
method B in 85% yield, method A was found to be superior in
all of the other examples tested.
Attempted coupling of 2-bromoquinolizinium (5), 3-bromo-
quinolizinium (6), and 4-bromoquinolizinium (7) with tribu-
tylvinylstannane under the optimized conditions found for 4
yielded the expected coupling product only with substrate 5
(Table 3, compound 24b), albeit in only 10% yield. Further
attempts on 5 and 6 with the experiment carried out at higher
temperatures produced extensive decomposition in the case of
5, but at 80 °C compound 6 gave the 3-vinylquinolizinium 25b
in 22% yield. In the case of substrate 7 the coupling proved
unsuccessful under these conditions. Alternatives to produce
coupling of tributylvinylstannane and 7 were tested in the
presence of tri-ortho-tolylphosphine (5 mmol %) and tris-
(dibenzylideneacetone)dipalladium [P(o-Tol)3/Pd2(dba)3] (5 mmol
%) at room temperature and heating in DMF. However, all of
these attempts were also unsuccessful. These latter conditions
were also tested for 4-6 in order to improve the yields of the
coupling products. However, lower yields were obtained than
under the original conditions. The failure of the coupling reaction
with 7 and the low yield obtained for 24b are probably related
to the high electron deficiency of these two positions of the
quinolizinium system, a situation that favors nucleophilic attack
instead of the usual substitution mechanism and can even lead
to polymerization of the coupled product.
In contrast to tributylvinylstannane, reaction of phenylethy-
nyltributylstannane was successful at room temperature with
all four bromoquinolizinium salts, although marked differences
in the reaction yields were observed. The 2-bromoquinolizinium
5 in this case produced an excellent yield (91%) of the coupling
product 24c, whereas the other three isomeric cations reacted
to give the coupling products (23c, 25c, and 26c) in moderate
yields (35-58%). These yields could not be improved in the
presence of [P(o-Tol)3/Pd2(dba)3].
Phenyl- and different heteroaryl groups on tin were also
successfully transferred to the four quinolizium cations with
significant differences in rates and yields, which in some cases
were large and dependent on the position of the bromo
substituent on the quinolizinium salt and the nature of the
stannane. For example, phenyl tributylstannane clearly afforded
lower yields in the coupling reaction with 4 and 7 (compounds
23a and 26a) when compared with stannanes on electron-rich
five-membered heterocycles such as pyrrole, furan, and thiophene
The coupling reaction with 4-tributylstannyl-1-trityl-1Hpyra-
zole (compounds 23g-26g) yielded analogous results to that
found for tributylphenylstannane with yields in the range 13-
96% depending on the bromoquinolizinium cation. Finally,
coupling of 4-7 with electron-deficient stannanes such as
pyridin-2-yl tributylstannane gave the coupling products 23h-
26h with an unexpectedly high yield (83%) for the coupling
product on 7 (26h).
The methodology described above, however, cannot be
applied to the transfer of alkyl groups, and all experiments with
tetramethylstannane were unsuccessful. It is generally accepted
that an sp3 carbon directly attached to the metal is less reactive
in Pd-catalyzed reactions than carbons with lower hybridiza-
tion,23 and this could explain the lack of reactivity observed.
In relation to the reactivity of the different bromoquinoliz-
iniums and yields of the coupling products, it is not easy to
establish a correlation between the halogenated position on the
quinolizinium and the efficiency of the Stille process. On the
basis of the isolated compounds the transfer of groups with
different electrodonicity does not have a large effect on the
yields of the coupled compounds in reactions involving the less
electrophilic C1 and C3 positions. However, the most activated
2-bromo- and 4-bromoquinolizinium cations seem to be much
more sensitive to the electronic effect on the ligands on tin,
and position C2 usually gave better yields than the C4 position.
One remarkable exception to this trend is 26h, which was
obtained in much better yield than 24h (83% vs 35%). These
results were confirmed in repetitive experiments, and this large
difference in yield cannot be attributed to experimental dif-
ficulties encountered in the isolation of 24h.
In summary, it has been shown that Stille coupling is the
most efficient procedure among other palladium-catalyzed cross-
coupling reactions such as the Suzuki and Negishi reactions to
produce acceptable yields of substituted quinolizinium cations.
Although we were not able to isolate the corresponding
trialkylquinolizinium stannanes, we developed a general method
for functionalization of the quinolizinium cation by reactions
between the four isomeric bromoquinolizinium bromides and
different vinyl-, ethynyl-, aryl-, and heteroarylstannanes using
Pd(PPh3)4 (5 mmol %), CuI (10 mmol %), and Pd2(dba)3/
P(o-Tol)3 (5 mmol %) as catalytic systems in DMF at room
temperature or heating at 80 °C. This procedure allows con-
venient quinolizinium substitution under mild conditions and
(28) Although there are few reports on LiCl/Pd(0)-promoted cross-
coupling reactions, the salt effects have been examined with different
electrophiles. (a) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108,
3033. (b) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109,
5478. (c) Tsuji, Y.; Kajita, S.; Isobe, S.; Funato, M. J. Org. Chem. 1993,
58, 3607. (d) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J.
Org. Chem. 1993, 58, 5434. (e) Cummins, C. H. Tetrahedron Lett. 1994,
35, 857. (f) Fujita, M.; Oka, H.; Ogura, K. Tetrahedron Lett. 1995, 36,
5247.
(29) For leading references, see: (a) Liebeskind, L. S.; Fengl, R. W. J.
Org. Chem. 1990, 55, 5359. (b) Gronowitz, S.; Bjo¨rk, P.; Malm, J.;
Ho¨rnfeldt, A.-B. J. Organomet. Chem. 1993, 460, 127. (c) Farina, V.;
Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994,
59, 5905. (d) Roht, G. P.; Farina, V.; Liebeskind, L. S.; Pen˜a-Cabrera, E.
Tetrahedron Lett. 1995, 36, 2191. (d) Allred, G. D.; Liebeskind, L. S. J.
Am. Chem. Soc. 1996, 118, 2748.
7994 J. Org. Chem., Vol. 71, No. 21, 2006

Functionalization of Heteroaromatic Cations
solid, which was recrystallized from EtOH affording 0.78 g (51%)
of a brown solid. The product was a 74:26 mixture of the oxo and
hydroxy tautomers. Mp 210-212 °C (lit.21 210-211 °C).
eliminates inherent limitations associated with the lack of
reactivity of this heteroaromatic cation.
7-Bromo-1-oxo-1,2,3,4-tetrahydroquinolizinium Bromide (14b).
A solution of 14b (1.95 g, 7.77 mmol) in aq. HBr (48%, 30 mL)
was heated at 120 °C for 24 h. The solvent was evaporated under
reduced pressure, and the residue was treated with EtOH to give a
solid, which was recrystallized from EtOH to afford a pale yellow
solid (2.12 g, 89%). The product was a 75:25 mixture of the oxo
and hydroxy tautomers. Mp 260-263 °C (lit.18a 261-264 °C).
General Procedures for Substituted Quinolizinium Salts 23-
26. (1) Method A. A flame-dried two-necked flask was charged
under argon with the corresponding bromoquinolizinium salts 4-7
(50 mg, 0.173 mmol) in dry DMF (2 mL). Then 10 mol % CuI (3
mg, 0.0173 mmol), 5 mol % Pd(PPh3)4 (10 mg, 0.0086 mmol),
and the corresponding stannane (0.225 mmol) were slowly added.
After stirring at room temperature for 15-20 h, the solution was
filtered through a small pad of Celite and washed with methanol.
The solution was concentrated, and the solid was isolated by
filtration. Some coupling products obtained from bromoquinoli-
ziniums 4 and 5 were isolated as picrates (TNP) by treatment of
the crude bromide with a slight excess of sodium picrate in refluxing
ethanol for 1 h. Other derivatives were isolated as hexafluorophos-
phates by treatment with ammonium hexafluorophosphate in water
followed by purification by column chromatography on silica gel
using CH2Cl2/MeOH (9.5:0.5) as the eluent. For the coupling
products obtained from 3- and 4-bromoquinolizinium salts 6 and
7, after washing with methanol, the solvent was removed and the
residue triturated with ether and EtOAc. Purification of the crude
product by column chromatography on silica gel (reverse phase)
using H2O/AcOH (100:0.5) as the eluent yielded the coupling
products 23 and 24, which were isolated as bromides.
Experimental Section
General. Literature procedures were used to prepare pyridinium
salts 12a,30 12b,31 and 15.32 4-Bromoquinolizinium bromide (7) was
prepared according to the method described in ref 18a. 1-Bromo-
and 3-bromoquinolizinium bromides 4 and 6 were prepared by the
method developed by us and reported in ref 19 (Scheme 1).
2-Bromoquinolizinium bromide 5 was obtained according to the
procedure reported in ref 18b. Compounds 5 and 6 were also
obtained by the method detailed in Scheme 2.
3,4-Dihydro-2-cyano-1-olate Quinolizinium (13a). To a solu-
tion of 12a (3.5 g, 0.012 mol) in CH2Cl2 (40 mL) was slowly added
N,N-ethyldiisopropylamine (4.16 mL, 0.024 mol), and the reaction
mixture was stirred at room temperature for 10 min. Propenenitrile
(7.86 mL, 1.2 mol) was added, and the mixture was heated under
reflux for 20 h. The resulting precipitate was filtered off, washed
with cold CH2Cl2, and recrystallized from CH3CN to afford 13a
(1.20 g, 58%) as an orange solid. Mp 259-260 °C. IR (KBr) υmax
2153, 1580, 1551, 1160 cm-1..1H NMR (CD3OD, 300 MHz) δ 8.75
(d, 1H, J ) 6.1 Hz), 8.56 (t, 1H, J ) 7.9 Hz), 8.43 (d, 1H, J ) 7.9
Hz), 7.92 (dd, 1H, J ) 7.6, 1.5 Hz), 4.71 (t, 2H, J ) 6.9 Hz), 2.84
(t, 2H, J ) 6.9 Hz). 13C NMR (CD3OD, 75 MHz): δ 163.7, 151.6,
146.8, 145.1, 127.2, 125.1, 122.3, 76.0, 56.5, 23.7. MS (ESI+) m/z
172 (M+). Anal. Calcd for C10H8N2O (172.19): C, 69.76; H, 4.68;
N, 16.27. Found: C, 69.85; H, 4.65; N, 16.37.
3,4-Dihydro-2-cyano-7-bromo-1-olate Quinolizinium (13b).
N,N-Ethyldiisopropylamine (3.0 mL, 16.63 mmol) was slowly added
to a solution of 12b (3.04 g 9.06 mmol) in CH3CN (10 mL), and
the reaction mixture was stirred at room temperature for 10 min.
Propenenitrile (6.3 mL, 95.64 mmol) was added, and the mixture
was heated under reflux for 48 h. The solvent was evaporated under
reduced pressure, and the residue was purified by chromatography
on silica gel (CH2Cl2:MeOH 8:2) to afford 13b (1.22 g, 51%) as a
red solid. Mp 196-197 °C. IR (KBr) υmax 2170,1578, 1541, 860
(2) Method B. A dried two-necked flask was charged under
argon with the corresponding quinolizinium salt (100 mg, 0.333
mmol) in dry DMF (5 mL). Pd2(dba)3 (5 mol %, 15.1 mg, 0.0165
mmol), P(o-Tol)3 (5 mol %, 5 mg, 0.0165 mmol), and the
corresponding stannane (1.3 equiv, 0.429 mmol) were slowly added.
The mixture was stirred at room temperature, filtered through a
small pad of Celite, and washed with methanol. The solvent was
removed, and the residue was triturated with EtOAc. Purification
of the crude product by column chromatography on silica gel
(reverse phase) using water as the eluent yielded the product, which
was isolated as the bromide.
1
cm-1. H NMR (DMSO, 300 MHz): δ 9.19 (d, 1H, J ) 1.7 Hz),
8.68 (dd, 1H, J ) 7.6, 0.9 Hz), 8.16 (d, 1H, J ) 8.8 Hz), 4.56 (t,
2H, J ) 7.0 Hz), 2.64 (t, 2H, J ) 6.7 Hz). 13C NMR (DMSO, 75
MHz): δ 161.3, 149.1, 146.6, 123.9, 123.4, 118.4, 113.7, 75.4,
54.7, 21.9. HRMS calcd for C10H7N2OBr m/z 250.9820, found
250.9817.
1-Oxo-1,2,3,4-tetrahydroquinolizinium Bromide (14a). A so-
lution of 13a (1.15 g, 6.7 mmol) in aq. HBr (48%, 24.5 mL) was
heated at 120 °C for 21 h. Then the solvent was evaporated under
reduced pressure, and the residue was treated with EtOH to give a
Acknowledgment. The authors acknowledge support for this
work from the Plan Nacional de Investigacio´n Cient´ıfica,
Desarrollo e Innovacio´n Tecnolo´gica, and Ministerio de Ciencia
y Tecnolog´ıa (projects BQU2002-03578 and CTQ2005-01060)
and grants from the Ministerio de Educacio´n y Ciencia (D.G.-
C.), Comunidad de Madrid (A.N.), and Universidad de Alcala´
(T.C.)
(30) (a) MacTavish, J.; Proctor, G. R.; Redpath, J. J. Chem. Soc., Perkin
Trans 1 1996, 20, 2545. (b) Greci, L.; Alberti, A.; Carelli, I.; Trazza, A.;
Casini, A. J. Chem. Soc., Perkin Trans 2 1984, 12, 2013. (c) Mackay, R.
A.; Landolph, J. R.; Poziomek, E. J. J. Am. Chem. Soc. 1971, 93, 5026. (d)
Kosower, E. M.; Skorcz, J. A.; Schwarz, W. M., Jr.; Patton, J. W. J. Am.
Chem. Soc. 1960, 82 2188.
(31) Lejeune, R.; Thunus, L.; Lapiere, C. L. J. Pharm. Belg. 1980, 35,
5.
(32) Yamaguchi, R.; Hata, E.; Matsuki, T.; Kawanisi, M. J. Org. Chem.
1987, 52, 2094.
Supporting Information Available: Complete experimental
procedures for the synthesis and analytical and characterization data
(1H NMR/13C NMR, IR, MS) of compounds 23-26. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO060634+
J. Org. Chem, Vol. 71, No. 21, 2006 7995