Ru(II)-catalyzed C-H bond activation for the synthesis of substituted isoquinolinium salts from benzaldehydes, amines, and alkynes

Article abstract of DOI:10.1021/ol301445r

An efficient method for the synthesis of substituted isoquinolinium salts from benzaldehydes, amines, and alkynes via ruthenium-catalyzed C-H bond activation and annulation in one pot is described.

Full text of DOI:10.1021/ol301445r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ru(II)-Catalyzed CꢀH Bond Activation for
the Synthesis of Substituted
Isoquinolinium Salts from Benzaldehydes,
Amines, and Alkynes
Kanniyappan Parthasarathy, Natarajan Senthilkumar, Jayachandran Jayakumar, and
Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received May 25, 2012
ABSTRACT
An efficient method for the synthesis of substituted isoquinolinium salts from benzaldehydes, amines, and alkynes via ruthenium-catalyzed CꢀH
bond activation and annulation in one pot is described.
Highly substituted isoquinolinium salts are versatile
building blocks for a number of naturally occurring
products1aꢀd and have attracted much attention due to
their unique biological activities.1eꢀh Previously, metal-
mediated isoquinolinium salt synthesis has been demon-
strated.2 Later, several metal-catalyzed syntheses of
isoquinolines from N-tert-butyl-o-halobenzaldimines,3aꢀc
N-tert-butyl benzaldimines,3d aryl ketoximes,3eꢀh and alkynes
were reported. In all of these reactions, isoquinolinium
salts were proposed as the intermediates but were never
isolated. Recently, we reported an efficient regioselective
nickel-catalyzed annulation of 2-halobenzaldimines,4a,b
ortho-iodoketimines with alkynes to give isoquinolinium
salts.4c However, this nickel-catalyzed reaction requires a
halide source, 2-halobenzaldimine or ketimine, as the
substrate. Recently, the preparation of isoquinolinium
salts involving CꢀH bond activation as a key step was
reported. A [RhCp*Cl2]2-mediated CꢀH bond activation/
annulation reaction of 2-phenylpyridine and benzo-
[h]quinoline with DMAD (dimethyl acetylenedicarbox-
ylate) to form isoquinolinium salts was shown by Jones
et al. in 2008.5 Very recently, we observed a [RhCp*]-
catalyzed one-pot three-component reaction of aryl alde-
hydes, amines, and alkynes to afford isoquinolinium salts
through CꢀH activation and annulation.6 However, the
methods described above require an expensive rhodium
metal complex as the catalyst. The use of cheaper, envi-
ronmentally benign alternative catalysts is still desirable in
metal-catalyzed organic synthesis.
(1) (a) Krane, B. D.; Fagbule, M. O.; Shamma, M. J. Nat. Prod. 1984,
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r
10.1021/ol301445r
XXXX American Chemical Society

CꢀH bond activation has been reported by Murai
and other research groups.8 Recently, many [RuCl2-
(p-cymene)]2-catalyzed CꢀH activation reactions have
been reported.9
Table 1. Optimization Studies for the Ru(II)-Catalyzed Isoqui-
nolinium Salts from Aryl Aldehyde, Propyl Amine with Al-
kynesa
Treatment of benzaldehyde 1a (0.36 mmol) with diphe-
nyl acetylene 2a (0.30 mmol) and propyl amine 3a (0.60
mmol) in the presence of [RuCl2(p-cymene)]2 (2.0 mol %),
AgBF4 (10 mol %), and Cu(BF4)2 6H2O (2.0 equiv) in
3
EtOH at 110 °C for 12 h gave isoquinolinium salt 4a in
90% isolated yield (Table 2, entry 1). The structure of 4a
containing an isoquinolinium cation and a tetrafluorobo-
rateanion was confirmed byits 1H, 13C, 19F, and 11B NMR
and mass data. The 19F and 11B NMR spectral data of
tetrafluoroborate anion are in agreement with those re-
ported previously.10
This ruthenium-catalyzed CꢀH activation and annula-
tion reaction depends greatly on the reaction conditions.
To understand the nature of this reaction and to find the
optimized reaction conditions, the effects of ruthenium
complex and solvent on the yield of 4a were examined.
Ruthenium complex [RuCl2(p-cymene)]2 is most effective
forming isoquinolinium salt product 4a in 92% yield
determined by an NMR integration method (Table 1,
entry 1) or 90% isolated yield (Table 2, entry 1). Other
ruthenium complexes including [RuCl2(benzene)]2,
[RuCl2(COD)]n, and RuCl2(PPh3)3 were also active, giving
entry
catalyst
solvent
EtOH
yield (%)b
1
2
[RuCl2(p-cymene)]2
[RuCl2(benzene)]2
[RuCl2(COD)]n
92(90)
69
56
8
EtOH
3
EtOH
4
RuCl2(PPh3)3
EtOH
5
RuCl3 xH2O
EtOH
0
3
6
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
t-amylOH
t-BuOH
2-ethoxyethanol
DCE
87
67
54
28
16
0
7
8
9
10
11
toluene
EtOH
a Unless otherwise mentioned, all reactions were carried out using
aryl aldehyde 1 (0.36 mmol), alkyne 2 (0.30 mmol), amine 3 (0.6 mmol),
[RuCl2(p-cymene)]2 (2.0 mol %), AgBF4 (10.0 mol %), Cu(BF4)2 6H2O
3
(0.6 mmol), and EtOH (2.5 mL) at 110 °C for 12 h. b Yields were
determined by the 1H NMR integration method.
4a in 69ꢀ8% yields (entries 2ꢀ4), but RuCl3 xH2O was
3
Our continuing interest in metal-catalyzed CꢀH activa-
tion6,7 and the reactions of isoquinolinium salts4,6 pro-
mpted us to explore the formation of isoquinolinium
salts via CꢀH activation using different metal complexes
as the catalysts. Herein, we report an effective Ru(II)-
catalyzed three-component reaction of aryl aldehydes,
amines, and alkynes to form isoquinolinium salts
through CꢀH activation and annulation. Previously, the
most efficient ruthenium(0)-catalyzed chelation-assisted
totally inactive (entry 5). The choice of solvents is also vital
to the catalytic reaction. The best solvent is EtOH in which
4a was obtained in 90% yield. t-Amyl alcohol is also
effective giving 4a in 87% yield (entry 6). Other solvents
such as t-BuOH, 2-ethoxyethanol, DCE, and toluene were
less effective for the catalytic reaction giving 4ain 67, 54, 28
and 16% yield, respectively (entries 7ꢀ10). Control experi-
ments revealed that in the absence of a ruthenium catalyst
or copper salt, no 4a was obtained (entry 11). In the
absence of silver salt, 4a was observed in 86% yield.
However, longer reaction time (24 h) is necessary (see
Supporting Information for detailed studies).
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Under similar reaction conditions, various substituted
benzaldehydes (1bꢀg) reacted with diphenyl acetylene 2a
and propylamine 3a to give the corresponding isoquinoli-
nium salts in Table 2. Thus, 4-methylbenzaldehyde 1b
afforded 4b in 89% yield (entry 2). Similarly, 4-methoxy
benzaldehyde 1c gave 4c in 91% yield (entry 3). It is
noteworthy that the structure of compound 4c was further
confirmed by a single-crystal X-ray diffraction. The cata-
lytic reaction is also compatible with halo substituents on
the aromatic ring of benzaldehyde 1. Thus, the reaction of
4-bromo- and 4-chlorobenzaldehydes 1dꢀe with 2a and 3a
gave isoquinolinium salts 4d and 4e in 72 and 80% yield,
respectively (entries 4 and 5). To understand the regio-
selectivity of meta-substituted benzaldehyde with 2a and 3a,
we chose 3-chlorobenzaldehyde (1f) and 3,4-(methylene-
dioxy)benzaldehyde (1g) as the substrates. Thus, 1f gave
regioisomers 4f and 4f0 in a 70:30 ratio in 78% combined
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Results of Ruthenium-Catalyzed CꢀH Activation and Annulation of Benzaldehydes, Amines, and Alkynesa
a Unless otherwise mentioned, all reactions were carried out using aryl aldehyde 1 (0.36 mmol), alkyne 2 (0.30 mmol), amine 3 (0.60 mmol), [RuCl2(p-
cymene)]2 (2.0 mol %), AgBF4 (10.0 mol %), Cu(BF4)2 6H2O (0.6 mmol), and EtOH (2.5 mL) at 110 °C for 12 h. b Isolated yields. c Regioisomeric ratio;
3
the structure of the major isomer is shown in the table. d Methylamine (35% aqueous solution).
yield (entry 6). For 1g, the reaction with 2a and 3a
proceeded in a regioselective manner to give 4g in 65%
yield (entry 7). In this reaction, there are two possible
CꢀH bond activation sites at C2 and C6 of 1g, but the
activation occurs at steric-hindered C6. In addition, the
reaction of 1-napthaldehyde 1f with 2a and 3a gave
isoquinolinium salts 4h in 90% yield (entry 8).
To understand the regioselectivity of the present reaction,
unsymmetrical alkynes were employed as the substrates for
the reaction with 1a and 3a. Thus, 1-phenyl-1-propyne (2b)
gave 4i in 77% yield (entry 9). No other regioisomeric
product was detected in the reaction. The regiochemistry
of product 4i was confirmed by NOE experiments. In a
similar fashion, phenyl-1-butyne (2c) and propargylic
ether 2d also reacted with 1a and 3a in a highly regiose-
lective manner, providing isoquinolinium salt derivatives
4j and 4k in 74 and 69% yield, respectively (entries 10 and 11).
In a similar manner, the reaction of phenyl-1-propyne (2b)
and phenyl-1-butyne (2c) with 1c and 3a gave isoquino-
linium salts 4l and 4m in 79 and 76% yield, respectively
Org. Lett., Vol. XX, No. XX, XXXX
C

(entries 12 and 13). The regioselectivity of unsymmetrical
for 6 h led tothe isolationof five-membered ruthenacycleA
in 75% yield. The five-membered ruthenacycle is a salt
with BF4ꢀ as the counteranion and is characterized by its
1H, 13C NMR, and IR data. However, attempt to crystal-
lize intermediate A by various solvents under different
conditions failed. Fortunately, when intermediate A was
treated with NaI in MeOH at room temperature for 0.15 h,
A0 with iodide as the counteranion was isolated in 70%
yield (Scheme2). SinglecrystalsofA0 werereadily obtained
from a methanol solution, and the structure was deter-
mined by X-ray diffraction. As shown in Scheme 2, the
ruthenium complex is a 16-electron system containing a
cyclometalated benzaldehyde imine and p-cymene ligand
only. The iodide is not coordinated to the ruthenium(II)
center. As expected, the reaction of A0 with 1-phenyl-1-
propyne (2b) in EtOH at 80 °C for 2 h gave regioselective
isoquinolinium salt 5a in 82% yield (Scheme 2).
c
alkynes is similar to those observed previously.2 ,4 On the
other hand, 3,4-(methylenedioxy)benzaldehyde (1g) re-
acted with 2c and 2a, affording 4n in 56% yield along with
trace of C6 CꢀH bond activation product (entry 14). The
result indicates that the CꢀH activation occurs mainly at
the sterically more hindered C2 instead of C6 position.
The scope of the amine used in the present catalytic
reaction was also tested. In addition to propylamine,
methyl- and 2-(3-methoxyphenyl)ethylamine (3b,c) re-
acted smoothly with 1a and 1c to afford 4o and 4p in 94
and 67% yield, respectively (entries 15 and 16). Similarly,
aromatic amines also worked for this reaction. Thus,
aniline 3d reacted nicely with 1a and 1c with 2a to give 4q
and 4r, respectively, in good yield (entries 17 and 18). In a
similar fashion, p-toluidine (3e) reacted nicely with 1c and
2a to give 4s in 75% yield (entry 19).
On the basis of the chemistry of known metal-catalyzed
CꢀH bond activation/annulation reactions,6ꢀ9,11 a possi-
ble mechanism to account for the present catalytic reaction
is proposed (Scheme 1). The catalytic cycle is likely in-
itiated by the removal of chloride by Agþ in [RuCl2(p-
cymene)]2 followed by coordination of imine nitrogen (in
situ generation of imine from 1a and 3a) to the ruthenium
species and subsequent ortho-CꢀH bond activation to
form a five-membered ruthenacycle A. Regioselective in-
sertion of alkyne 2b into the rutheniumꢀcarbon bond of
intermediate B gives the seven-membered ruthenacycle C.
Reductive elimination of C affords the final isoquinoli-
nium salt 4i and Ru(I). The ruthenium species is reoxidized
by Cu(BF4)2 to regenerate the active Ru(II) species for the
next cycle.
Scheme 2. Structure and Reactivity of Intermediate A
Scheme 1. Proposed Mechanism for the Formation of Isoqui-
nolinium Salt
In conclusion, we have successfully developed a new
highly regioselective ruthenium-catalyzed synthesis of sub-
stituted isoquinolinium salts from the reaction of benzal-
dehydes, amines, and alkynes via CꢀH bond activation and
annulation. The proposed mechanism is strongly supported
by the isolation of a five-membered ruthenacycle and an
intermediate organic compound. Further application of this
methodology in natural product synthesis and investigation
of the detailed mechanism are in progress.
To support the proposed mechanism, we tried to isolate
the keyintermediate A (Scheme 1). Thus, heating 1a and 3a
in the presence of 0.10 equiv of [RuCl2(p-cymene)]2 and
0.40 equiv of AgBF4 in EtOH (or) t-amyl alcohol at 110 °C
Acknowledgment. We thank the National Science
Council of the Republic of China (NSC-100-2119-M-
007-002) for support of this research.
Supporting Information Available. General experimen-
tal procedure and characterization details. This material
is available free of charge via the Internet at http://pubs.
acs.org.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX