Isoquinolinium salts from o-halobenzaldehydes, amines, and alkynes catalyzed by nickel complexes: Synthesis and applications

Article abstract of DOI:10.1002/chem.200901366

Aza-nickelacycles: An atom-economic nickel-catalyzed synthesis of isoquinolinium salts is reported. The salts are readily reduced to the corresponding reductive homo-coupling products and oxidized to isoquinolinones (see scheme). Isoquinolinones are impor

Full text of DOI:10.1002/chem.200901366

COMMUNICATION
DOI: 10.1002/chem.200901366
Isoquinolinium Salts from o-Halobenzaldehydes, Amines, and Alkynes
Catalyzed by Nickel Complexes: Synthesis and Applications
Rajendra Prasad Korivi, Yu-Chen Wu, and Chien-Hong Cheng*[a]
Despite the wide presence[1a] and application[1,2] of isoqui-
nolinium salts in natural product and drug formulations,
there is no general synthetic method available for these de-
rivatives. Traditional synthesis of isoquinolinium salts from
isoquinolines and alkyl halide derivatives is limited by the
number of substituted isoquinolines that are readily avail-
able. Moreover, it is not feasible for N-aryl substituted salts.
Previously, Heck and co-workers observed the formation of
isoquinolinium salts from the reaction of cyclopalladated
benzaldimines and alkynes,[3a,b] but they did not succeed in
making the reaction catalytic. It is necessary to convert the
N-phenylbenzaldimine cyclopalladated chloro dimer to the
Scheme 1. Stoichiometric synthesis of isoquinolinium derivatives from cy-
clopalladated benzaldimine and alkynes.
corresponding cyclopalladated tetrafluoroborate for efficient
formation of the isoquinolinium derivative (Scheme 1).[3]
The use of stoichiometric amounts of the palladium complex
for the reaction greatly limits its application. Later, Larock
and co-workers reported the synthesis of isoquinoline deriv-
atives from N-tert-butyl o-halobenzaldimines and alkynes
catalyzed by palladium systems.[4] We also observed a similar
but much more rapid reaction catalyzed by nickel complex-
es.[3c] In these reactions, isoquinolinium salts were proposed
as the intermediates although they were not observed.
Recently, the formation of dihydroisoquinolines through
the catalytic electrophilic activation of the alkyne group in
o-alknylbenzaldimines were described.[5] In all of these reac-
tions, isoquinolinium salts were proposed as the intermedi-
ates but were not isolated, probably owing to the high reac-
tivity of these salts. Herein, we report an efficient regiose-
lective nickel-catalyzed annulation of o-halobenzaldimines
with various alkynes to give isoquinolinium salts. For the
first time a general method for the synthesis of N-aryl iso-
quinolinium salts, a difficult task by using classical methods,
was achieved. The easy isolation of these salts is important
because they can be transformed into various useful organic
species.[2,6] We demonstrate an interesting application of the
salts in the synthesis of isoquinolinones,[2] which are key in-
termediates in the total synthesis of diverse isoquinoline al-
kaloids.[6] The construction of isoquinolinone structures
through previous methods requires multistep synthesis.
Recent disclosure of the therapeutic utility of N-aryl isoqui-
nolinium salts and N-aryl isoquinolinones in the treatment
of infections,[1b] diseases by cytokines,[2b,c] and ADP–platelet
aggregation[2a] by pharmaceutical companies further shows
the importance of the present research.
When we employed [NiBr2ACTHNUTRGNE(UNG dppe)]/zinc powder for the
treatment of N-tolyl o-iodobenzaldimine (1a) with diphenyl
acetylene (2a), our original reaction conditions for the syn-
thesis of isoquinolines,[3c] no expected isoquinolinium salt 3a
was observed (see below). Fortunately, by using [Ni
alone without Zn, the expected salt 3a was obtained in 93%
yield. When [Ni(cod)2] was used with 2 equiv of PPh3 or P-
(o-Tol)3, the corresponding isoquinolinium derivative 3a
ACHTUNGTRENNUNG(cod)2]
AHCTUNGTRENNUNG
[a] Dr. R. P. Korivi, Y.-C. Wu, Prof. Dr. C.-H. Cheng
Department of Chemistry
AHCTUNGTRENNUNG
National Tsing Hua University
Hsinchu, 30013 (Taiwan)
Fax : (+886)35724698
was obtained in 87 and 99% yield, respectively (the yields
were determined by the NMR spectroscopic integration
method, see the Supporting Information). Also, the present
reaction can be carried out by using Ni0 species generated in
situ from air-stable NiII complexes and Et3B or nBuLi.
E-mail: chcheng@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901366.
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Table 1. Multicomponent synthesis of polysubstituted isoquinolinium and pyridinium salts.[a]
These experiments show that
most Ni0 complexes, under
suitable conditions, are effec-
tive catalysts. Attempts to use
palladium complexes including
[Pd
[Pd
N
ACHTUNGTRENNUNG(dba)2], and
various reaction conditions
failed to produce the isoquino-
linium salt 3a. The results are
in accordance with those previ-
ously reported.[3b] The reaction
could also be carried out by
using o-iodobenzaldehyde and
p-toluidine in a 1:1 molar ratio
to generate imine 1a in situ.
As shown in Table 1, entry 1,
both reaction conditions gave
nearly the same yield of 3a.
Note that the reaction also
proceeded smoothly, even at
room temperature, to give 3a
in approximately the same
yield in 12 h. Similarly, the re-
action of o-iodobenzaldehyde
and p-toluidine with 3-hexyne
(2b) gave 3b in 91% yield
(Table 1, entry 2).
Entry
Imine[b]
2
Product
Yield [%][c,d]
1[b]
2[b]
3[b]
4[b]
A
2a
2b
2c
2d
3a (R4 =R5 =Ph)
94 (92)[c]
(91)[c]
3b (R4 =R5 =Et)
N
3c (R4 =Ph, R5 =Me)
3d (R4 =Ph, R5 =CO2Et)
(84)[c]
R
(87)[c]
5
2c
86:2
1b
3e+3e’
To investigate the regioselec-
tivity of the catalytic reaction,
unsymmetrical alkynes were
tested. Both 1-phenylpropyne
(2c) and ethyl 3-phenylpropio-
late (2d) reacted highly regio-
selectively with o-iodobenzal-
dehyde and p-toluidine to give
isoquinolinium salts 3c and 3d
in yields of 84 and 87%, re-
spectively. In both products,
the phenyl substituent is adja-
cent to the nitrogen atom, de-
spite the great difference in
the electronic properties of al-
kynes 2c and 2d, which have
an electron-donating Me and
6[b]
2c
(86:4)[c]
ACHTUNGTRENNUNG
(1c)
3 f+3 f’
7[b]
2c
2a
(89:2)[c]
ACHTUNGTRENNUNG
A
3g+3g’
8
81
94
1e
3h
an
electron-withdrawing
9
2e
2b
CO2Et group, respectively. In
addition, only one regioisomer-
ic product was observed in
each case. Apart from the
NMR spectroscopic analysis,
the structure of 3d was further
confirmed by single-crystal X-
ray diffraction. When imines
1b, which have two electron-
rich methoxy groups on the ar-
omatic ring, and 1c and 1d,
1 f
1g
3i
3j
10
96
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Synthesis and Applications of Isoquinolinium Salts
Table 1. (Continued)
COMMUNICATION
All of these salts are stable at
Imine[b]
2
Product
Yield [%][c,d]
(95)[c]
room temperature for several
months without decomposi-
tion.
The present reaction can
also be applied to the synthesis
of pyridinium salts. Thus, by
treating (Z)-3-iodo-3-phenyl-
Entry
11[b]
(1d)
2 f
3k
AHCTUNGTERGaNNUN crylaldehyde and p-toluidine
12[b]
G
2g
(98)[c]
in 1:1 molar ratio with 1-phe-
nylpropyne and 1-cyclohexeny-
lethyne, the pyridinium salts
3q and 3r were obtained in
yields of 91 and 90%, respec-
tively (Scheme 2).
The reaction likely proceeds
via an aza-nickelacycle 4[7] in-
termediate obtained by a che-
lation-assisted oxidative inser-
tion of Ni0 to the aryl–iodine
bond of 2-iodobezaldimine 1.
3l
13
14
2h
96
3m
2i
92:5
Then, regioselective alkyne in-
[8]
À
sertion to either the C Ni or
3n+3n’
3o+3o’
3p
À
the N Ni bond and reductive
elimination of NiII leads to the
formation of isoquinolinium
salt 3 and Ni0.[3c] There are two
possible modes for the inser-
tion reaction of alkynes with 4.
For the insertion of electron-
deficient alkynes such as 2d,
the insertion is likely to be
15
16
1b
1g
2j
71:11
78
2k
À
into the N Ni bond through a
[a] Reaction conditions: o-iodobenzaldimine 1 (0.20 mmol), alkyne 2 (0.25 mmol), acetonitrile (3.0 mL), [Ni-
(cod)2] (0.011 mmol), and P(o-Tol)3 (0.023 mmol) at 808C for 1.5 h. [b] The o-iodobenzaldimines in parenthe-
ses were generated in situ from the corresponding aldehydes (0.20 mmol) and amines (0.20 mmol). [c] Isolated
yields. Yields in parentheses are for three-component reactions with aldehydes, amines, and alkynes. [d] No
chromatography was necessary for product isolation.
Michael-type addition (inter-
mediate A, SEWG=strong
electron-withdrawing group),
whereas for alkynes without a
A
ACHTUNGTRENNUNG
which have electron-withdrawing functionalities over the N-
substituent, were employed for the reaction with alkyne 2c,
the salts 3e–g were obtained in excellent yields, along with
minor regioisomers 3e’–g’ in approximately 2–4% yield
(Table 1, entries 5–7). Imines 1e–g with different functional-
ities over the N-substituent also efficiently reacted with sym-
metric alkynes 2a, 2e, and 2b, respectively, to give the ex-
pected salts 3h–j in excellent yield (Table 1, entries 8–10).
The present catalytic reaction can be extended to terminal
alkynes. Phenyl acetylene, 4-fluorophenyl acetylene, and 3-
thiofuranyl acetylene reacted with 1d, 1 f, and 1g, respec-
tively, to give the single regioisomeric products 3k–m in ex-
cellent yield (the yields in parenthesis are for three-compo-
nent reactions, see Table 1). On the other hand, cyclohex-
Scheme 2. Synthesis of pyridinium salts from (Z)-3-iodo-3-phenylacrylal-
dehyde, p-toluidine, and alkyne derivatives.
strong electron-withdrawing substituent, the insertion is into
[8]
À
the C Ni bond (B). In both situations, the aryl substituent
on the alkyne is generally next to the nitrogen atom of 3.
For aryl alkynes without strong withdrawing groups, the re-
giochemistry of the alkyne in the seven-membered azacycle
B is similar to the five-membered azacycles proposed in the
reductive-coupling reaction between imines and alkynes.[8d,e]
ACHTUNGTRENNUNGenylethyne and 1-octyne reacted with 1g and 1b to afford
regioisomers 3n and 3n’ in 92 and 5% yield and 3o and 3o’
in 71 and 11% yield, respectively. Acetylene gas (2k) also
reacted with 1g to give isoquinolinium salt 3p in 78% yield.
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C.-H. Cheng et al.
96% yield. Compound 6a can also be prepared by treating
1a with 2a in the presence of [NiBr2ACHTNUTRGNEUNG(dppe)] and Zn at
808C. No isoquinolinium salt was observed under the reac-
tion conditions, but 6a was isolated in 93% yield (Table 2,
Table 2. Catalytic synthesis of isoquinoline dimers 6 by using aldimine
1a and alkynes.[a]
Similarly, greater regio-selectivity was observed with termi-
nal aryl alkynes than with internal aryl alkynes.
The nature of the nickel and palladium benzaldimine cy-
clometalated complexes reflects the difference in catalytic
activity between the two metal complexes for the present
isoquinolinium salt formation. It is known that nickel com-
plexes are much more susceptible than palladium complexes
to ligand-substitution reactions, and thus are also more sus-
ceptible to alkyne-coordination and insertion reactions.[9]
On the other hand, the high stability and the inertness of
the benzaldimine cyclopalladated halo dimer (see Scheme 1)
probably explain the fact that palladium complexes do not
catalyze the reaction.
An interesting application of the isoquinolinium salts pre-
pared by the above method is the transformation of these
salts into isoquinolinones.[1,2,6] Thus, isoquinolinium iodides
3a and 3g were converted to 5a and 5g in the presence of
CsOH and K3[Fe(CN)6] in a mixture of CH3CN, H2O, and
MeOH in yields of 80 and 89%, respectively (Scheme 3),
Entry Imine
2
Product
Yield
[%][b]
1
2
3
1a
1a
1a
6a (R4 =R5 =Ph)
6b (R4 =R5 =Et)
6c (R4 =Ph, R5 =Et)
6d (R4 =Ph,
93
87
85
4
1a
82
R5 =CO2Me)
6e (R4 =Me,
5
6
1a
1b
74[c]
91
R5 =CO2Me)
6 f (R4 =Ph, R5 =H)
[a] Reaction conditions: o-iodobenzaldimine (0.20 mmol), alkyne
(0.25 mmol), acetonitrile (3.0 mL), [NiBr2A(dppe)] (0.011 mmol), and Zn
(0.60 mmol) at 808C for 1.5 h. [b] Isolated yields. [c] A mixture of re-
CTHUNGTRENNUNG
gioisomers was isolated.
entry 1). We think that isoquinolinium salt 3a was formed
during the catalytic reaction, but was then quickly reduced
to dimer 6a. In a similar manner, symmetrical (2b), unsym-
metrical (2 l, 2m, and 2n), and terminal alkynes (2 f) reacted
with 1a and 1b to afford the corresponding dimers 6b–f in
good to excellent yields (Table 2, entries 2–6). Based on the
1H NMR spectroscopy data, products 6a–f consist of a mix-
ture of meso and d,l isomers with a ratio of these diastereo-
mers of approximately 2:1. The structure of the meso diaste-
reoisomers of 6d and 6e were further verified by single-
crystal X-ray diffraction. In all of the mass spectra of 6, the
corresponding molecular ions did not appear, but only the
ions with mass values equivalent to the monomeric form 7
were observed.
Scheme 3. Synthesis of isoquinolinone derivatives from the corresponding
isoquinolinium salts by using CsOH and K3[Fe(CN)6].
through a modified reported procedure.[10] The transforma-
tion reaction probably involves the addition of a hydroxide
ion at the C1 carbon of the isoquinolinium salt followed by
the oxidation of the resulting 1-hydroxy-dihydroisoquinoline
species with a ferric cyanide ion.
Another interesting property of isoquinolinium salts 3 is
their easy reductive dimerization to give 6 in the presence
of zinc powder as the reducing agent (Scheme 4).[11] For ex-
ample, when 3a was treated with zinc in acetonitrile at 808C
for 40 min, the corresponding dimer 6a was obtained in
In conclusion, we have demonstrated for the first time a
general method for the synthesis of N-aryl and N-alkyl iso-
quinolinium salts by using readily available starting materi-
als. A vast number of functionalities can be introduced to
the salts. The application of this methodology is illustrated
by the facile transformation of
the salts to other structures
such as isoquinolinones 5 and
reductive dimerization prod-
ucts 6. Isoquinolinone is an im-
portant core structure for a
vast number of natural prod-
ucts. Application of this meth-
odology in the total synthesis
Scheme 4. Mechanism for the formation of isoquinoline dimer 6.
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Synthesis and Applications of Isoquinolinium Salts
COMMUNICATION
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Experimental Section
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Procedure for the preparation of isoquinolinium salt 3a: A screw-cap
sealed tube fitted with
(0.20 mmol) and p-toluidine (0.20 mmol) was evacuated and purged with
nitrogen gas three times. The tube was charged with [Ni(cod)2]
(0.011 mmol, 3.0 mg) and P(o-Tol)3 (0.023 mmol, 7.0 mg) inside a glove
a septum containing 2-iodobenzaldehyde
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
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box. The tube was then kept under an atmosphere of nitrogen on a dual-
manifold Schlenk line. Alkyne 2a (0.25 mmol) was dissolved in acetoni-
trile (3.0 mL) and was added to the stirred mixture through a syringe.
The septum was quickly exchanged for a screw cap and the reaction mix-
ture was stirred at 808C for 1.5 h. At the end of the reaction, the reaction
mixture was diluted with CH2Cl2 and then filtered through a silica-gel
pad
by
using
methanol
as
the
eluent
(~20 mL). The combined filtrate was concentrated in vacuo and the resi-
due was carefully washed with ethyl acetate and hexane to afford the de-
sired pure product 3a in 92% yield. 1H NMR (500 MHz, CDCl3, 25 8C,
TMS): d=2.19 (s, 3H), 6.94 (d, J=7.5 Hz, 2H), 6.97 (d, J=6.5 Hz, 1H),
7.03 (d, J=7.5 Hz, 2H), 7.11 (d, 7.0 Hz, 2H), 7.22–7.24 (m, 5H), 7.52 (d,
J=7.5 Hz, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.87 (t, J=7.0 Hz, 1H), 7.97 (t,
J=7.5 Hz, 1H), 8.77 (d, J=7.5 Hz, 1H), 10.16 ppm (s, 1H); 13C NMR
(125 MHz, CDCl3, 25 8C, TMS): d=21.0, 126.3, 126.4, 126.8, 127.6, 128.1,
128.4, 128.9, 129.7, 130.1, 130.8, 130.9, 131.1, 131.7, 133.0, 137.4, 138.6,
139.1, 139.4, 140.4, 144.1, 149.8 ppm; IR (KBr): u¯ =1250, 1440, 1718,
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2933, 2959 cmÀ1
.
Acknowledgements
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We thank the National Science Council of Republic of China (NSC 96-
2113-M-007-020-MY3) for support of this research.
Keywords: aza-nickelacycles
reductive coupling · zinc
· isoquinolines · nickel ·
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Received: May 22, 2009
Published online: September 11, 2009
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10731