A new approach to polycyclic azonia cations by ring-closing metathesis

Article abstract of DOI:10.1021/ol070773t

The ring-closing metathesis (RCM) reaction of N-vinyl-α-(2-styryl) azinium salts, using the Hoveyda-Grubbs catalyst, leads to different tricyclic and tetracyclic azonia cations with moderate to good yields. This is the first time that a highly electron-de

Full text of DOI:10.1021/ol070773t

ORGANIC
LETTERS
2007
Vol. 9, No. 16
2977-2980
A New Approach to Polycyclic Azonia
Cations 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 March 30, 2007
ABSTRACT
The ring-closing metathesis (RCM) reaction of N-vinyl-
r
-(2-styryl)azinium salts, using the Hoveyda−Grubbs catalyst, leads to different tricyclic
and tetracyclic azonia cations with moderate to good yields. This is the first time that a highly electron-deficient alkene such as an
N-vinylpyridinium has been involved in an RCM process.
Recently, we reported the first examples of a diene1 and
enyne2 ring-closing metathesis on azinium cations 1, a pro-
cess that gave dihydroquinolizinium cations 2. This strategy
proved to be very efficient for the synthesis of quinolizinium
derivatives and related systems3,4 (Scheme 1). Indeed, it can
disconnection. For this class of cations, which includes the
dibenzo[a,g]quinolizinium cation 6 (the heterocyclic core of
cationic alkaloids such as coralyne,7 berberine, and proto-
berberines8), we envisaged an alternative diene ring-closing
metathesis (RCM) process through the disconnection of a â
bond (Scheme 2).
(1) For recent reviews on diene RCM, see: (a) Deiters, A.; Martin, S.
F. Chem. ReV. 2004, 104, 2199-2238. (b) Poulsen, C. S.; Madsen, R.
Synthesis 2003, 1-18. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18-29.
Scheme 1. 3,4-Dihydroquinolizinium from δ Bond
Disconnection
(2) For reviews on enyne metathesis, see: (a) Fu¨rstner, A.; Davies, P.
W. Chem. Commun. 2005, 2307-2320. (b) Hoveyda, A. H.; Hird, A. W.;
Kacprzynski, M. A. Chem. Commun. 2004, 1779-1785. (c) Diver, S. T.;
Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382. (d) Mori, M. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim;
Germany, Vol. 2003; Vol. 2, 176-204. (e) Mori, M. Top. Organomet. Chem.
1998, 1, 133-154.
(3) Nun˜ez, A.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Org.
Lett. 2004, 6, 4125-4127.
be envisaged as a unified approach to a range of azonia
cations,5 including the 3 benzoquinolizinium and many of
the 18 possible dibenzo- and naphthoquinolizinium cations.6
There are, however, a small number of dibenzo- and
naphthoquinoliziniums (4-6) for which this strategy, based
on the disconnection of the δ bond with respect to the
quaternary nitrogen, is not feasible because the presence of
two benzo fused rings precludes the appropriate bond
(4) Nun˜ez, A.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Chem.
Commun. 2006, 2690-2692.
(5) Ihmels, H.; Faulhaber, K.; Vedaldi, D.; Dall’Acqua, F.; Viola, G.
Photochem. Photobiol. 2005, 81, 1107-1115.
(6) Arai, S.; Hida, M. AdV. Heterocycl. Chem. 1992, 55, 261-358.
(7) (a) Kwang-Yuen, K.-Y.; Zee-Cheng, Y.; Paul, K. D.; Cheng, C. C.
J. Med. Chem. 1974, 17, 347-351. (b) Robert, K.; Zee-Cheng, Y.; Cheng,
C. C. J. Med. Chem. 1976, 19, 882-886. (c) Wilson, W. D.; Gough, A.
N.; Doyle, J. J.; Davidson, M. W. J. Med. Chem. 1976, 19, 1261-1263.
(d) Lee, J. S.; Latimer, L. J. P.; Hampel, K. J. Biochemistry 1993, 32, 5591-
5597. (e) Wang, L.-K.; Rogers, B. D.; Hecht, S. M. Chem. Res. Toxicol.
1996, 9, 75-83.
‡ Dedicated to Prof. Miguel Yus on the occasion of his 60th birthday.
10.1021/ol070773t CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/11/2007

Scheme 2. Azonia Cations from â Bond Disconnection
Scheme 3
In this communication we report this new approach to
polycyclic azonia cations by a diene ring-closing metathesis
process involving, for the first time, a highly deficient
N-vinylazinium system.9
Preliminay studies were carried out with the benzo[a]qui-
nolizinium cation (3a), which is the simplest azonia cation
that can be used as a model to study the feasibility of the
strategy represented in Scheme 2. Our initial goal was the
synthesis of the key intermediate 1-vinyl-2-(2-vinylphenyl)-
pyridinium salt 10a, which was envisaged to be achievable
from the corresponding pyridinium salt 9a by dehydrohalo-
genation. This salt seemed to be available from 2-(vinyl-
phenyl)pyridine 8a. The synthesis of 8a was attempted using
three different palladium-catalyzed reactions employing
2-bromo-pyridine and 2-vinylphenylboronic acid10 or 2-vinyl-
phenylzincate as reagents in Suzuki and Negishi couplings
and tributyl(2-pyridyl) tin and 1-bromo-2-vinylbenzene as
partners in the Stille reaction. Different conditions were
tried but only the Suzuki reaction was successful in pro-
ducing the coupled compound 8a, which was obtained in
83% yield after optimization. The conditions used for the
successful synthesis of the appropriate diene 10a are shown
in Scheme 3.
Although first (11) and second (12) generation Grubbs
catalysts did produce the metathesis reaction, the best yield
(83%) was obtained with Hoveyda-Grubbs catalyst (13) in
ClCH2CH2Cl (entry 8)sprobably because of its higher
stability at the reaction temperature14 (83 °C).
The scope of this metathesis reaction was studied with a
variety of substituents either on the pyridinium or benzene
rings of the divinylic compound as well as with the
appropriate dienic systems, which should produce the tetra-
cyclic azonia cations 4-7. Most of the substrates employed
in the RCM reaction were obtained by following the strategy
shown in Scheme 3, but in some cases it was necessary to
use alternative methods, for example, for 10e-g and 10j
(details are given in the Supporting Information).
Initially all the dienic substrates 10b-j were subjected to
the RCM under the optimized conditions found for 10a.
Although these conditions afforded good yields for the
2-methylbenzo[a]quinolizinium (3b) (Table 2, entry 2), [1,3]-
benzodioxolo[5,6-a]quinolizinium triflate (3f) (Table 2, entry
6) and the dibenzo[af]quinolizinium (4) (Table 2, entry 8),
in the remaining cases the RCM reaction gave only moderate
or low yields of the corresponding tricyclic or tetracyclic
azonia cations. Consequently, we studied a new set of
A study of the conditions for the metathesis reaction of
10a showed that this deficient diene was able to afford the
expected azonia cation 3a11 under different conditions using
either Grubbs catalysts 1112 and 1213 or the Hoveyda-Grubbs
catalyst 13.14 A summary of the different sets of conditions
tested is shown in Table 1 along with the results obtained in
this search for the optimum conditions.
Table 1. Results for the RCM of 10a
(8) Vennerstrom, J. L.; Klayman, D. L. J. Med. Chem. 1988, 31, 1084-
1087. (b) Henry, T. A. The Plant Alkaloids; Blakiston: Philadelphia, PA,
1949; p 334.
(9) For leading references on metathesis of divinylbiaryls, see: (a)
Iuliano, A.; Piccioli, P.; Fabbri, D. Org. Lett. 2004, 6, 3711-3714. (b)
Walker, E. R.; Leung, S. Y.; Barret, A. G. M. Tetrahedron Lett. 2005,
6537-6540. (c) Bonifacio, M. C.; Robertson, C. R.; Jung, J.-Y.; King, B.
T. J. Org. Chem. 2005, 70, 8522-8526. (d) Jones, S. B.; He, L.; Castle, S.
L. Org. Lett. 2006, 8, 3757-3760.
(10) Dale, W. J.; Rush, J. E. J. Org. Chem. 1962, 27, 2598-2603.
(11) For previous synthesis of benzo[a]quinolizinium cation, see: (a)
Glover, E. E.; Jones, G. J. Chem. Soc. 1958, 3021-3028. (b) Kimber, R.
W. L.; Parham, J. C. J. Org. Chem. 1963, 28, 3205-3206. (c) Bradsher, C.
K.; Lorh, D. F. J. Org. Chem. 1966, 31, 978-980. (d) Doolittle, R. E.;
Bradsher, C. K. J. Org. Chem. 1966, 31, 2616-2618.
entry
catalyst
conditions
(3a) yielda
1
1
2
3
4
6
7
8
11 (5%)
12 (5%)
12 (5%)
12 (5%)
12 (10%)
13 (5%)
12 (5%)
13 (5%)
CH2Cl2, rt, 24 h
CH2Cl2, rt, 4 h
CH2Cl2, rt, 24 h
CH2Cl2, 40 °C, 48 h
CH2Cl2, rt, 3 h
CH2Cl2, 40 °C, 24 h
ClCH2CH2Cl, 83 °C, 3 h
ClCH2CH2Cl, 83 °C, 2.5 h
39
40
39
25
33
39
58
83
a Isolated yield.
2978
Org. Lett., Vol. 9, No. 16, 2007

conditions to improve the yields of those reactions that gave
poor results. We found that the temperature of the reaction
and/or the amount of catalyst seemed to be significant factors
to increase the yields of cations 3e, 5, and 7. Thus, an
increase in the amount of catalyst from 5% to 10% improved
the yield of the naphtho[1,2-a]quinolizinium (7) from 45%
to 68% (Table 2, entry 10). A change in the solvent from
dichloroethane to tetrachloroethane allowed these reactions
to be carried out at 130 °C, with a considerable improvement
in the yield in the case of the dibenzo[af]quinolizinium (5)
(from 12% to 53%) (Table 2, entry 9). In the case of
8-chlorobenzo[a]quinolizinium (3e) the best yield (from 23%
to 81%) was obtained on heating the reaction mixture in a
sealed tube at 100 °C in the presence of 15% of the catalyst
(Table 2, entry 5). It is worth noting that none of these
conditions led to an improvement in the yields of 3c, 3d,
and 3g (Table 2, entries 3, 4, and 7).
Table 2. Azonia Cations 3-7 from RCM of Dienes 10
Some of these results can be rationalized by considering
the difficulty that dienic substrates 10 have in adopting the
appropriate planar conformation to produce the metathesis
reaction. When the molecule is planar, a maximum level of
steric repulsion is reached, whereas if the two rings adopt
an orthogonal arrangement both the steric repulsion and reso-
nance effect would be minimized. In the case of 3c it is likely
that the electronic effect would be determinant since the
bromo-substituent reduces further the already high electron
deficiency of the vinyl alkene attached to the pyridinium ring.
As stated earlier, the dibenzo[a,g]quinolizinium cation 6
was one of our target compounds since this cation is the
core heterocyclic system of some relevant natural alkaloids.
The precursor of this cation would be the dienic compound
10k, the synthesis of which was attempted according to the
method shown in Scheme 4. To date all our attempts to
Scheme 4
generate the diene from 9k in the presence of different bases
(CsCO3, KOH, LiOH, Li2CO3, t-BuOK, Et(i-Pr)2N) have
a Conditions: (5 mol %), ClCH2CH2Cl, 83 °C. b Conditions: (15 mol
%), ClCH2CH2Cl, 100 °C, sealed tube. c Conditions: (5 mmol %),
Cl2CHCHCl2, 130 °C. d Conditions: (10 mol %), ClCH2CH2Cl, 83 °C.
(12) For the first enyne metathesis with Grubbs catalyst, see: Kinoshita,
A.; Mori, M. Synlett 1994, 1020-1022. For a review, see: Schwab, M. B.
France, J.; Ziller, W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995,
34, 2039-2041.
Org. Lett., Vol. 9, No. 16, 2007
2979

proved unsuccessful, with decomposition or complete dealky-
lation of 9k observed.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 3, 10, and
precursors. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, the results described above show that RCM
is a viable and general reaction on N-vinyl-R-(2-styryl)-
azinium species to give polycyclic azonia cations using the
Hoveyda-Grubbs catalyst under mild conditions.15,16 The
utility of this strategy, based on a metathesis process in-
volving the formation of a â bond with respect to the bridge-
head quaternary nitrogen, was demonstrated by the synthesis
of benzo[a]-, dibenzo[af]-, dibenzo[af]-, and naphtho[1,2-
a]quinolizinium salts in moderate and good yields. Ongoing
work is focused on making available some cationic dienes,
which are advanced precursors in the total synthesis of some
biologically relevant cationic alkaloids such as coralyne,
berberines, sempervirine, and flavocorylene, inter alia.
OL070773T
(14) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791-799. (b) Garber, S. B.; Kingsbury,
J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168-
8179. (c) 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, 8-23.
(15) General procedure for benzo- and naphthoquinoliziniums 3-7. To
a solution of 10 (0.15 mmol) in ClCH2CH2Cl or Cl2CHCHCl2 under argon
atmosphere, 5-15% of the catalyst 13 was added, and the reaction mixture
was heated to 83-130 °C for 2.5-22 h. Then the solvent was removed
under reduced pressure, and the residue was purified by flash chromatog-
raphy on silica gel using CH2Cl2/MeOH as eluent.
(16) Compound 3a is described as picrate: (a) Ihmels, H. Science of
Synthesis 2005, 15, 907-945. Compound 3a is described as perchlorate:
(b) Kimber, W. L.; Parham, J. C. J. Org. Chem. 1963, 28, 3205-3206. (c)
Arai, S.; Takeuchi, T.; Ishikawa, M.; Takeuchi, T.; Yamazaki, M.; Hida,
M. J. Chem. Soc., Perkin Trans 1 1987, 481-487. Compound 3a is
described as hexafluorophosphate: (d) Arai, S.; Yamagishi, T. J. Heterocycl.
Chem. 1996, 33, 57-64. Compound 3b is described as perchlorate: (e)
Arai, S.; Yamazaki, M.; Hida, M. J. Heterocycl. Chem. 1990, 27, 1073-
1078. Compound 4 is described as perchlorate and chloride: (f) Fozard,
A.; Bradsher, C. K. J. Org. Chem. 1966, 31, 3683-3685. Compound 5
and 7 are described as perchlorate in ref 16c.
Acknowledgment. The authors acknowledge financial
support from the Spanish Ministerio de Educacio´n y Ciencia
(project CTQ2005/011060/BQU), Comunidad de Madrid
(CAM), and Universidad de Alcala´ (UAH) (Project CCG-
UAH/SAL-0660) and a grant from the Comunidad de Madrid
(A.N.).
(13) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
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