8528 Chem. Commun.

, 2013, 49, 8528--8530 This journal is c The Royal Society of Chemistry 2013
Cite this: Chem. Commun., 2013,
49, 8528
A convenient synthesis of quinolizinium salts through
Rh(III) or Ru(II)-catalyzed CH bond activation of
2-alkenylpyridines
Ching-Zong Luo, Parthasarathy Gandeepan and Chien-Hong Cheng*
An ecient synthesis of quinolizinium salts from 2-vinylpyridines
and alkynes via Rh(III) or Ru(II)-catalyzed CH activation and annu-
lation reaction is described. A possible mechanism involving pyr-
idine assisted vinylic ortho-CH activation, alkyne insertion and
reductive elimination is proposed.
Quinolizinium cations are important structural motifs found in
many naturally occurring compounds, for example, compounds 16
(Scheme 1) which exhibit many important biological activities.
1,2
In
addition, quinolizinium derivatives have been used as diverse
fluorescent dyes, non-linear optical (NLO) materials, and ionic
liquids.
3
They are also used as important intermediates in many
bio active
4
and heterocyclic compound syntheses.
5
Due to their wide
application, several traditional and metal-catalyzed methods have
been developed for the synthesis of quinolizinium salts. Initially,
Woodward demonstrated a [3+3] approach to synthesize quinolizi-
nium compounds using 1,3-dicarbonyl compounds and 2-methyl-
pyridine as substrates.
6
Later on, Westphal reported a representative
[4+2] cyclization reaction of pyridiniumsalt bearing active methylene
protons attached to the N1 and C2 positions with a 1,2-dicarbonyl
compound.
7
These methods suffer largely fromthe lack of availability
of the starting materials, lower yields, use of strong acidic or basic
conditions and high reaction temperature. To the best of our
knowledge, there are no reports on the synthesis of quinolizinium
salts via a CH bond activation reaction.
8
Recently, transition-metal-catalyzed CH bond activation has
been considered as an ideal method for the formation of carbon
carbon and carbonheteroatom bonds. In particular, Rh(III) and
Ru(II) complexes have shown great competence in the synthesis of
various heterocyclic and carbocyclic compounds through the CH
bond activation and annulation reactions.
9,10
Our recent success in
the development of a new CH bond activation methodology for
synthesis of isoquinolinium,
8c,d
cinnolinium
8e
salt compounds and
other transition-metal-catalyzed CH bond activation reactions
11
prompted us to explore the possibility of CH bond activation route
to the synthesis of quinoliziniumsalts. Herein, we report anefficient
method for the synthesis of quinoliziniumsalts fromthe reaction of
2-vinylpyridines with alkynes using a Rh(III) or a Ru(II) complex as
the catalyst system.
Treatment of 2-vinylpyridine 1a with diphenylacetylene 2a in
the presence of 1 mol% of [RhCp*Cl
2
]
2
and 0.5 equivalents of
Cu(BF
4
)
2
6H
2
O in MeOH at 60 1C under an O
2
atmosphere for 18 h
gave 3,4-diphenylquinolizin-5-ium salt 3aa in 91% isolated yield
(Scheme 2). In addition, we also investigated the reaction using
Ru(II) complexes as the catalysts. The reaction of 1a with 2a in the
presence of 2 mol% of [RuCl
2
(p-cymene)]
2
under the conditions
shown in Scheme 2 gave 3aa in 95% isolated yield. Quinolizinium
salt 3aa containing a BF
4

anion was confirmed by its

1
H,
13
C,
19
F
and
11
B NMR and HRMS data.
With reaction conditions A and B in hand, a variety of symme-
trical and unsymmetrical alkynes (2ak) were tested with 1a. Thus,
treating 4-Me, 4-OMe and 4-F substituted diphenylacetylenes 2bd
with 1a gave the corresponding salts in excellent yields under both
reaction conditions (Table 1, entries 24). Dialkyl alkynes 2ef also
Scheme 1 Natural products bearing quinolizinium cation cores.
Scheme 2 Rh(III) or Ru(II)-catalyzed quinolizinium salt synthesis.
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
E-mail: [email protected]; Fax: +886-3-5724698; Tel: +886-3-5721454
Electronic supplementary information (ESI) available: Experimental proce-
dures, compound characterization, and the copies of
1
H and
13
C NMR spectra.
CCDC 948578948580. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3cc45004j
Received 4th July 2013,
Accepted 23rd July 2013
DOI: 10.1039/c3cc45004j
www.rsc.org/chemcomm
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This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 8528--8530 8529
reacted with 1a under condition A to afford products 3ae and 3af in
76 and 88% yields, respectively. Unluckily, these reactions were
unsuccessful under condition B using [RuCl
2
(p-cymene)]
2
as the
catalyst. Heterocyclic alkyne, 1,2-di(thiophen-2-yl)ethyne (2g), also
reacted with 1a under both conditions to yield 3ag in 8283%. To
understand the regioselectivity of the present reaction, unsymme-
trical alkynes 2hk were investigated. Thus, 1-phenyl-1-propyne (2h)
reacted well with 1a to give two regioisomeric products in excellent
yield but moderate regioselectivity (entry 8). In a similar manner,
other unsymmetrical alkynes 2ik underwent cyclization with 1a
to afford two regioisomeric products in good yields (entries 911).
It is interesting to note that vinylpyridines 1bf with substitution
at the b-carbon reacted smoothly with 2a to give the expected
quinolizinium salts 3bafa, in good yields (entries 1216).
Table 1 Results of the reaction of 2-vinylpyridines with alkynes
Entry 1 2 Product 3
Yield
c
(%)
A
a
B
b
1 1a 2a 3aa R
4
, R
5
= Ph 91 95
2 1a 2b 3ab R
4
, R
5
= 4-MeC
6
H
4
84 92
3 1a 2c 3ac R
4
, R
5
= 4-OMeC
6
H
4
81 77
4 1a 2d 3ad R
4
, R
5
= 4-FC
6
H
4
82 70
5 1a 2e 3ae R
4
, R
5
= (CH
2
)
2
CH
3
76 0
6 1a 2f 3af R
4
, R
5
= CH
2
OCH
3
88 0
7 1a 2g 3ag R
4
, R
5
= 2-thiophene 82 83
8 1a 2h 3ah R
4
= Me, R
5
= Ph 87 (2.8 : 1)
d
75
(1.5 : 1)
d
9 1a 2i 3ai R
4
= Et, R
5
= Ph 90 (2.3 : 1)
d
69 (2 : 1)
d
10 1a 2j 3aj R
4
= Ph, R
5
= CO
2
Et 81 (1.2 : 1)
d,e
65
(1.3 : 1)
d
11 1a 2k 3ak R
4
= CH
2
OH, R
5
= 4-MeC
6
H
4
67 (1.4 : 1)
d
0
12 1b 2a 3ba R
3
= Ph 95 83
13 1c 2a 3ca R
3
= CO
2
Me 78
e
84
14 1d 2a 3da R
3
= Me 76
e
67
15 1e 2a 3ea R
3
= (CH
2
)
2
CH
3
77
e
90
16 1f 2a 3fa R
3
= cyclohexyl 70
e
79
17 1g 2a 3ga 86 81
18 1h 2a 3ha 88 91
19 1i 2a 3ia 84 91
20 1j 2a 3ja 87 87
Table 1 (continued)
Entry 1 2 Product 3
Yield
c
(%)
A
a
B
b
21 1k 2a 3ka 92 94
22 1l 2a 3la 95 89
23 1m 2a 3ma 67 63
a
Conditions A: unless otherwise mentioned, all reactions were carried
out using 2-vinylpyridine 1 (0.28 mmol), alkyne 2 (0.34 mmol),
[RhCp*Cl
2
]
2
(1 mol%, 0.0028 mmol), Cu(BF
4
)
2
6H
2
O (0.14 mmol) in
MeOH at 60 1C for 18 h under an O
2
atmosphere.
b
Conditions B: unless
otherwise mentioned, all reactions were carried out using 2-vinylpyri-
dine 1 (0.28 mmol), alkyne 2 (0.34 mmol), [RuCl
2
(p-cymene)]
2
(0.0056 mmol), AgBF
4
(0.028 mmol) and Cu(BF
4
)
2
6H
2
O (0.56 mmol)
in ethyl acetate at 100 1C for 24 h.
c
Isolated yield.
d
Ratios of regio-
isomers are given in parentheses and were determined by
1
H NMR
analysis; major isomers are shown.
e
t-Amyl alcohol, 100 1C.
Communication ChemComm
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8530 Chem. Commun., 2013, 49, 8528--8530 This journal is c The Royal Society of Chemistry 2013
Similarly, vinylpyridines 1i and 1j having methyl and phenyl sub-
stitution at the a-carbon also reacted smoothly with 2a, providing
3ia and 3ja in excellent yields, respectively (entries 19 and 20).
Interestingly, the reaction of 5-methyl-2-(thiophen-2-yl)pyridine 1k
and 2-(furan-2-yl)-5-methylpyridine 1l with diphenylacetylene 2a
proceeded effectively to give the corresponding quinolizinium salts
3ka and 3la in excellent yields. Likewise, 2-vinylquinoline (1m)
underwent reaction with 2a to afford salt 3ma in good yield (entry
23). Overall, Rh(III) and Ru(II) catalyzed reactions equally worked well
to produce quinolizinium salts. But, the Ru(II) system showed poor
reactivity to alkylaryl and dialkyl alkynes (entries 511). On the
other hand, Rh(III) showed slightly lower reactivity to sterically
crowded CH bonds (entries 1316).
The present quinolizinium salts can be readily converted to
the corresponding tetrahydroquinolizinium compounds by
hydrogenation. For example, compound 3aa was hydrogenated
to 3aa
0
by Pd/carbon under 1 atm hydrogen gas (Scheme 3) in
83% yield. It is interesting to note that the derivatives of
quinolizinium salts such as dihydroquinolizinium and tetra-
hydroquinolizinium salts also show pharmacological activities
and remarkable anity towards various receptors.
12
Based on our observations and the known metal-catalyzed
directing group-assisted CH bond activation and annulation reac-
tions,
810
a plausible mechanism for the present rhodium-catalyzed
annulation of 2-vinylpyridine (1a) with 2a is presented in Scheme 4.
The first step likely involves the coordination of the pyridine group
of 1a to the rhodium metal center, followed by vinylic CH bond
activation to form5-membered rhodacycle I. Coordination of alkyne
2a to I gives intermediate II and subsequent insertion into the RhC
bond affords 7-membered rhodacycle III. Finally, reductive elimina-
tion of III gives the quinolizinium salt product 3aa.
In summary, we have developed an ecient approach to synthe-
size quinolizinium salts by Rh(III) or Ru(II)-catalyzed vinylic CH
bond activation and annulation reaction. Although in many cases
the Rh catalyst is more active than the corresponding Ru one, the
two metal catalysts display complementary reactivity in the for-
mation of some quinolizinium salts. The intramolecular version of
this reaction and the application of these novel salts are currently in
progress in our laboratory.
We thank the National Science Council of Republic of China
(NSC-101-2628-M-007-004) for support of this research.
Notes and references
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Scheme 3 Synthesis of tetrahydroquinolizinium salt 3aa
0
.
Scheme 4 Proposed mechanism for the formation of quinolizinium salts.
ChemComm Communication
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