A unified approach to quinolizinium cations and related systems by ring-closing metathesis

Article abstract of DOI:10.1021/ol048177b

(Chemical Equation Presented) The first example of an olefin ring-closing metathesis reaction on cationic heteroaromatic systems is described. Dihydroquinolizinium cations and a variety of related cationic systems are synthesized in an efficient approach from N-alkenyl α-vinyl azinium salts using Grubbs' catalysts.

Full text of DOI:10.1021/ol048177b

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4125-4127
A Unified Approach to Quinolizinium
Cations and Related Systems by
Ring-Closing Metathesis†
Ana Nu´n˜ez, 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
juanjose.Vaquero@uah.es
Received September 9, 2004
ABSTRACT
The first example of an olefin ring-closing metathesis reaction on cationic heteroaromatic systems is described. Dihydroquinolizinium cations
and a variety of related cationic systems are synthesized in an efficient approach from N-alkenyl -vinyl azinium salts using Grubbs’ catalysts.
r
Quinolizinium-type cations,1 a class of heteroaromatic com-
pounds in which the cationic nature of the system is produced
by the presence of a bridgehead quaternary nitrogen, are one
of the three classes of charged heterocycles, the other two
being azinium and azolium salts. These compounds have
attracted attention in fields as diverse as natural products,2
fluorescent dyes,3 antitumoral compounds,4 DNA intercala-
tors,5 and topoisomerase6 and telomerase7 inhibitors and,
more recently, as NLO8 and ionic liquids.9
While azinium and azolium cations are easily obtained
by alkylation of the corresponding heterocycles, the synthesis
and functionalization of quinolizinium cations has remained
relatively unexplored.10 Recently, we reported a general
method for the introduction of C-substituents into the
quinolizium system based on palladium-catalyzed C-C bond
formation.11 In this communication, we report preliminary
results from an efficient olefin ring-closing metathesis
(RCM)12 approach to differently substituted 3,4-dihydro-
quinolizinium cations and related systems. This strategy
represents the first example of a RCM process involving
(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.; Vaquero, J. J. J. Med. Chem. 2004, 47, 1136.
(6) (a) Osheroff, N.; Froelich-Ammon, S. J. 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. A.; Shinohara, Z. L.; Lian, X. Y.;
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.
(9) (a) Seddon, K. R. Nat. Mater. 2003, 2, 363. (b) Welton, T. Chem.
ReV. 1999, 99, 2071.
(10) (a) Arai, S.; Ishikura, M.; Yamagishi, T. J. Chem. Soc., Perkin Trans.
1 1998, 1561. (b) Sanders, G. M.; van Dijk, M.; van der Plas, H. C.
Heterocycles 1981, 15, 213.
(11) Barchin, B. M.; Valenciano, J.; Cuadro, A. M.; Alvarez-Builla, J.;
Vaquero, J. J. Org. Lett. 1999, 4, 545.
(12) For recent reviews, see: (a) Deiters, A.; Martin, S. F. Chem. ReV.
2004, 2199. (b) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1. (c) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
† Dedicated to Prof. Jose´ Elguero on the occasion of his 70th birthday.
(1) (a) Vaquero, J. J.; Alvarez-Builla, J. AdV. Nitrogen Heterocycles;
Moody, C. J., Ed.; JAI Press: Stamford, Connecticut, Vol. 4, 2000; p 159.
(2) (a) Lipinska, T. Tetrahedron Lett. 2002, 43, 9565. (b) Mat´ıa, M. P.;
Ezquerra, J.; Garc´ıa, J. L.; Vaquero, J. J.; Alvarez-Builla, J. Tetrahedron
Lett. 1991, 31, 7575.
(3) (a) Haugland, R. Handbook of Fluorescent Probes and Research
Chemicals, 8th ed.; Molecular Probes, Inc.: Eugene, OR, 2001. (b) Applied
Fluorescence in Chemistry, Biology and Medicine; Rettig, W., Strehmel,
B., Schrader, S., Seifert, H., Eds.; Springer: New York, 1999.
(4) (a) 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.
10.1021/ol048177b CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/07/2004

heteroaromatic cations13 and cationic interconversion (azin-
ium to quinolizinium).
Table 1. Dihydroquinolizium Cations and Related Cationic
In our strategy for the synthesis of the quinolizinium
system 5, we envisaged that the dihydroquinolizium inter-
mediate 6 could be easily obtained by a ring-closing
metathesis (RCM) process from the key intermediate 7,
which would be accessible from the 2-haloazine 8 (Scheme
1).
Systems by Ring-Closing Metathesis
Scheme 1
Initial model studies with 2-(2′-propenyl)pyridine 9a
showed that N-alkylation with either allyl iodide or allyl
bromide produced not the expected pyridium salt 7a but the
more stable isomer 10a, as result of double-bond migration.
Double-bond isomerization also occurred when N-alkylation
was attempted with allyl- and homoallyltriflates. Aryl and
heteroaryl vinyl substrates have been used in RCM pro-
cesses.14 Thus, when the diolefinic compound 10a was
subjected to RCM conditions with Grubbs’ catalyst 115 (10
mol %), the dihydroquinolizium system 3a was successfully
formed in 55% yield (Scheme 2).
Scheme 2
a Reactions were carried out using 5 mol % catalyst 2 at room temperature
in CH2Cl2. b Isolated yield. c Performed with 2 mol % catalyst 1 at room
temperature. d High dilution (0.005 M).
pyridinium substrates, which would in turn react selectively
under RCM conditions to give the expected dihydroquino-
lizium cations 3. This idea was tested by preparing 1-(3′-
butenyl)-2-vinylpyridium salt 4a by N-alkylation of the
corresponding substituted 2-vinylpyridine with 3-butenyl-
triflate. It was found that 4a underwent the RCM process
Having obtained this initial result, 2-vinylpyridines16 11
clearly seemed to be the more promising starting azines for
transformation into the appropriate N-(3-butenyl) 2-vinyl-
4126
Org. Lett., Vol. 6, No. 22, 2004

on using either catalyst 1 (5 mol %) or 217 (5 mol %) for 1
h at room temperature in dichloromethane and that the
reactions gave good yields (Table 1, entry 1).
carried out at 0.1 M concentration. Under these conditions,
self-metathesis salts were formed in the reaction, and these
made the isolation of RCM products extremely difficult. A
simple modification of the reaction conditions working at
higher dilution (0.005 M) allowed compounds 3h and 3i to
be obtained in excellent yield (88 and 94%, entries 8 and 9)
and 3j in acceptable yield (54%, entry 10). As shown by
the results in Table 1, the one notable limitation of the RCM
was found in the formation of the indolizinium system 3k.
Attempts to produce the RCM on 4k using catalysts 1 and
2 and Hoveyda-Grubbs catalyst19 in dichloromethane at
room-temperature failed. Neither the salt 3k nor the most
stable neutral compound indolizine could be isolated from
the complex reaction mixtures obtained. Variations in the
reaction conditions, including a change of the solvent (DMF)
and/or temperature (50 °C), were also unsuccessful.
Differently substituted dihydroquinolizinium salts 3b-e
were obtained in a straightforward route starting from
substituted 2-bromopyridines (Table 1, entries 2-5), with
isolated yields of up to 80% in the RCM step. In a similar
way, substrates 4f and 4g were obtained from 3-bromo
isoquinoline (Table 1, entry 6) and 8-bromoquinoline (Table
1, entry 7). These intermediates then gave 3,4-dihydro-
pyridoisoquinolinium 3f and 3H-pyridoquinolinium 3g in 75
and 79% yields, respectively. These results show that the
RCM reaction works very efficiently on charged systems
and provides a general protocol for the preparation of the
dihydroquinolizinium system. Furthermore, the quinolizium
system can also be obtained since oxidation of 3 afforded 5
in good yields.18
In conclusion, the above results show that RCM is a viable
reaction on N-alkenyl-R-vinylazinium salts. The reactions
afford a variety of heteroaromatic cations, including dihy-
droquinolizium and pyridoisoquinolinium, -quinolinium,
-azepinylium, and -azocinylium, in good overall yield from
readily available starting materials. This approach should
allow access to biologically relevant cations based on the
quinolizium system.
The scope of this method was further expanded to seven-
(Table 1, entries 8 and 9) and eight-membered rings (entry
10). Unlike the formation of the six-membered system, RCM
is only successful with catalyst 2 (5 mol %), but yields of
between 6 and 46% were obtained when the reaction was
(13) Two examples of RCM on ammonium salts have been described
previously: (a) Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem.
1998, 63, 9904. (b) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
Soc. 1993, 115, 9856.
(14) For representative examples, see inter alia: (a) Theeraladanon, C.;
Arisawa, M.; Nishida, A.; Nakagawa, M. Tetrahedron 2004, 60, 3017. (b)
Lee, H. K.; Chun, J. S.; Pak, C. S. J. Org. Chem. 2003, 68, 2471. (c)
Gonzalez-Pe´rez, P.; Pe´rez-Serrano, L.; Casarrubios, L.; Dom´ınguez, G.;
Pe´rez-Castells, J. Tetrahedron Lett. 2002, 43, 4765. (d) Arisawa, M.;
Theeraladanon, C.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001, 42,
8029. (e) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446.
Acknowledgment. The authors acknowledge support of
this work from the Plan Nacional de Investigacio´n Cient´ıfica,
Desarrollo e Innovacio´n Tecnolo´gica, Ministerio de Ciencia
y Tecnolog´ıa, through Project BQU2002-03578 and a grant
from the Comunidad de Madrid (A.N.).
(15) Schwab, P.; France, Ziller, J. W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2039.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 3 and 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Compounds 11 were commercially available (2-vinyl pyridine) or
synthesized following previously described procedures: (a) Legros, J.;
Primault, G.; Toffano, M.; Riviere, M.; Fiaud, J. Org. Lett. 2000, 2, 433.
(b) Marsella, M. J.; Fu, D.-K.; Swager, T. M. AdV. Mater. 1995, 7, 154. (c)
Dupont, J.; Halfen, R.; Zinn, F. K.; Pfeffer, M. J. Organomet. Chem. 1994,
484, C8-C9. (d) Arata, I. J. Pharm. Soc. Jpn. 1960, 80, 709.
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
OL048177B
(18) Dihydroquinolizinium salts shown in Table 1 were oxidized to the
corresponding quinolizinium salts with Pd/C in acetic acid (80-90% yield)
following the procedure described by: Nakamichi, N.; Kawashita, Y.;
Hayashi, M. Org. Lett. 2002, 4, 3955.
(19) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) Hoveyda, A. H.; Gillingham,
D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.;
Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 1.
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