Use of the Stille coupling reaction on heteroaromatic cations: Synthesis of substituted quinolizinium salts

Article abstract of DOI:10.1021/ol990626y

(Matrix presented) We describe the first efficient application of the Stille coupling reaction on heteroaromatic cations. In the presence of Pd(0)/Cul, the reaction of bromoquinolizinium salts and various tributylstannyl compounds proceeds in satisfactory

Full text of DOI:10.1021/ol990626y

ORGANIC
LETTERS
1999
Vol. 1, No. 4
545-547
Use of the Stille Coupling Reaction on
Heteroaromatic Cations: Synthesis of
Substituted Quinolizinium Salts
Bernardo M. Barch´ın, Jesu´s Valenciano, Ana M. Cuadro, Julio Alvarez-Builla, and
Juan J. Vaquero*
Departamento de Qu´ımica Orga´nica, UniVersidad de Alcala´,
28871-Alcala´ de Henares, Madrid, Spain
qojjVl@quimor.alcala.es
Received April 30, 1999
ABSTRACT
We describe the first efficient application of the Stille coupling reaction on heteroaromatic cations. In the presence of Pd(0)/CuI, the reaction
of bromoquinolizinium salts and various tributylstannyl compounds proceeds in satisfactory yield under mild reaction conditions, affording
different substituted quinolizinium salts.
The palladium-catalyzed cross-coupling reaction of orga-
nostannanes with organic electrophiles (usually halides or
triflates), known as the Stille reaction,1 has emerged as an
extremely powerful tool for C-C bond formation.2 Although
this methodology has been applied to a variety of heterocyclic
substrates,3 a cross-coupling route involving heteroaromatic
cations such as azinium or quinolizinium salts has not been
previously described.
tion into bis-intercalators 2 with chromophores linked by
chains with different length, rigidity, and functionality (see
below), we examined the feasibility of using a palladium-
As part of a project focused on the development of a novel
class of DNA intercalators based on quinolizinium and aza-
quinolizinium-type systems 1,4 and subsequent transforma-
† FAX: 34-1-91-8854660.
(1) (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1. (b) Farina, V.; Roth, G. P. AdVances in Metal-Organic Chemistry;
Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1996; Vol. 5, p 1. (c) Mitchell,
T. N. Synthesis 1992, 803. (c) Ritter, K. Synthesis 1993, 735. (d) Stille, J.
K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(2) (a) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in
Organic Synthesis; John Wiley & Sons: Chichester, 1995; Chapter 4, p
125. (b) Farina, F. 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.
mediated catalyzed coupling reaction as a means of introduc-
ing different aryl/heteroaryl substituents and aliphatic side
chains in 1 in order to improve their intercalating properties
(3) (a) Undheim, K.; Benneche, T. AdV. Heterocycl. Chem. 1995, 62,
330. (b) Kalinin, V. N. Synthesis 1992, 413.
J.; Rodrigo, M. M.; Castan˜o, O.; Andre´s, J. L. Bioorg. Med. Chem. Lett.
1996, 1453. (d) Pastor, J.; Siro, J.; Garc´ıa-Navio, J. L.; Alvarez-Builla, J.;
Gago, F.; Pascual-Teresa, B.; Pastor, M.; Rodrigo, M. M. J. Org. Chem.
1997, 62, 5476. (e) Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-
Builla, J.; Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M. J. Org. Chem.
1999, 64, 3907.
(4) (a) Santiesteban, I.; Siro, J. G.; Vaquero, J. J.; Garcia-Navio, J. L.;
Alvarez-Builla, J.; Castan˜o, O. J. Org. Chem. 1995, 60, 5667. (b) Molina,
A.; Vaquero, J. J.; Garc´ıa-Navio, J. L.; Alvarez-Builla, J.; Pascual-Teresa,
B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. J. Org. Chem. 1996, 61,
5587. (c) Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla,
10.1021/ol990626y CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/22/1999

Table 1. Palladium-Catalyzed Cross-Coupling Reaction between Bromoquinolizinium Salts and Stannanes
as well as their antitumor activity. In this Letter, we report
our initial results on the transformation of some quinoliz-
inium salts 3, as simple models, into substituted quinoliz-
inium derivatives 4 (Scheme 1) via the Stille coupling
reaction.
inium salts. The bromo derivatives 3, being accessible
substrates to study the reactivity of the 1- and 2-bromo-
quinolizinium salts in various coupling processes, were
prepared in several steps by standard procedures.5
(5) (a) Sanders, G. M.; van Dijk, M.; van der Plas, H. C. Heterocycles
1981, 15, 213 and references therein. (b) Glover, E. E.; Jones, G. J. Chem.
Soc. 1958, 3021.
Our efforts to achieve a cross-coupling route to quinoliz-
inium derivatives focused on the 1- and 2-bromoquinoliz-
546
Org. Lett., Vol. 1, No. 4, 1999

comparison, the same coupling of 2-bromoquinolizinium 3b
with tributylvinylstannane under optimized conditions10
produced the desired substituted compound, although in poor
yield (entry 4). Similarly, coupling of 3b with phenylethy-
nyltributylstannane and 2-thiophenyl- and 2-furanyltributyl-
stannane produced yields ranging from good (entry 6) to
moderate (entries 7 and 8). On the other hand, heating (85
°C) was required in the coupling with tetraphenylstannane
to obtain the 2-phenylquinolizininium salt (entry 5) in a 60%
yield.
Scheme 1
The method was further extended to tributylstannylpyri-
dine, -thiazole, and -pyrazole, which were prepared according
to previously reported procedures.11 The results of the cross-
coupling with 2-bromoquinolizinium was successful for the
thiazole and pyrazole derivatives (entries 9 and 10) and, as
anticipated, resulted in a lower yield with the more electron-
deficient pyridine (entry 11).
The above methodology, however, is limited to the transfer
of alkyl groups. Our experiments with tetramethylstannane
were unsuccessful and it is generally accepted that an sp3
carbon directly attached to the metal is less reactive than
carbons with lower hybridization in Pd-catalyzed reactions,1d
which likely accounts for the lack of reactivity observed.
In summary, a new and simple route to substituted
heteroaromatic cations, with a bridgehead quaternary nitro-
gen, was developed involving palladium-catalyzed cross-
coupling between bromoquinolizinium and various aryl,
heteroaryl, vinyl, and ethynyl stannanes. This method
expands the scope of the Stille reaction and provides a good
alternative for substitution of quinolizinium derivatives,
which are usually very unstable when in contact with
nucleophilic species.
We initially examined the coupling process with 1-bromo-
quinolizinium salt 3a and tributylvinylstannane to establish
the best reaction conditions in the presence of 5 mol % of
PdCl2(PPh3)2 as the catalyst and in dimethylformamide
(DMF) or tetrahydrofuran (THF) as the solvents at different
temperatures. In all experiments, however, we found only
extensive decomposition of the substrate. In addition, under
the above conditions, the same procedure was tested in the
presence of 3 equiv of LiCl6 in DMF, a solvent that can
both solubilize lithium chloride and act as a ligand for
palladium. The reaction products, however, contained only
starting material. In the presence of 3 equiv of LiCl in DMF,
the use of tetraphenylstannane instead of tributylvinylstan-
nane produced homo-coupling of the heterocycle7,8 in a 44%
yield after 12 h of heating at 85 °C.
After further experiments, the desired coupling reaction
was reproducibly obtained from 3a and tributylvinylstannane
in the presence of 5 mol % of Pd(PPh3)4, in DMF at room
temperature, and with the addition of 10 mol % of copper-
(I) iodide as a cocatalyst. The reaction was completed in 17
h, producing 1-vinylquinolizinium (Table 1, entry 1) in a
55% yield, with CuI being essential for success of the
reaction. The beneficial effect of the Cu(I) salts in cross-
coupling reactions has been previously observed.9 Although
the exact role of copper is not clear, transmetalation of the
R groups has been suggested.9c
Acknowledgment. We wish to express our thanks for
financial support to the Comisio´n Interministerial de Ciencia
y Tecnolog´ıa (CICYT, Project SAF98-0093).
OL990626Y
Starting with 3a, alkenyl, alkynyl, and heteroaryl groups
on tin were all transferred in high yield (entries 1-3). By
(9) 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.
(10) Typical Procedure is a follows:. A flame-dried two-neck flask was
charged under argon with 50 mg (0.173 mmol) of bromoquinolizinium salt
in 2 mL of dry DMF, then 10 mol % of CuI (0.0173 mmol, 3 mg) and 5
mol % of Pd(PPh3)4 (0.0086 mmol, 10 mg) were slowly added, and then
0.225 mmol of the corresponding stannane was 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 isolated by filtration. All compounds were isolated as picrates (TNP)
by treatment of the crude bromide with a slight excess of sodium picrate in
refluxing ethanol for 1 h.
(6) Although there are a 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.
(7) Homocoupling products derived from the stannane have been
observed, with the homocoupling of the electrophile being less common.
(a) Dubois, E.; Beau, J.-M. Tetrahedron Lett. 1990, 31, 5165. (b) Friesen,
R. W.; Sturino, C. F. J. Org. Chem. 1990, 55, 2572. (c) Farina, V.; Roth,
G. P. Tetrahedron Lett. 1991, 32, 4243. (d) Reference 6d. (e) van Asselt,
R.; Elsevier: C. J. Organometallics 1994, 13, 1972, and references therein.
(f) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg, A. J.
Org. Chem. 1997, 62, 5583. (g) Jutand, A.; Mosleh, A. J. Org. Chem. 1997,
62, 261. (h) Danieli, B.; Lesma, G.; Martinelli, M.; Passarella, D.; Peretto,
I.; Silvani, A. Tetrahedron 1998, 54, 14081.
(11) (a) 2-Tributylstannylpyridine: Lee, A. S.-Y.; Dai, W.-C. Tetrahedron
1997, 53, 859. (b) 2-Tributylstannylthiazole: Dondoni, A.; Mastellari, A.
R.; Medici, A.; Negrini, E,; Pedrini, P. Synthesis 1986, 757. (c) 4-Tribu-
tylstannyl-1-trityl-1H-pyrazole: Elguero, J.; Jaramillo, C.; Pardo, C.
Synthesis 1997, 563.
(8) The homocoupling product [1,1′]biquinolizinium dipicrate has been
characterized (see Supporting Information).
Org. Lett., Vol. 1, No. 4, 1999
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