Nickel-catalyzed cyclization of ortho-iodoketoximes and ortho-iodoketimines with alkynes: Synthesis of highly substituted isoquinolines and isoquinolinium salts

Article abstract of DOI:10.1002/asia.201100834

A convenient method for the synthesis of highly substituted isoquinolines and isoquinolinium salts by the nickel-catalyzed cyclization of ortho-haloketoximes and -ketimines, respectively, with alkynes is described. The reaction of ortho-haloketoximes and various alkynes in the presence of [Ni(PPh₃)₂Br₂] and zinc powder in a mixture of acetonitrile and tetrahydrofuran at 80 °C for 15 hours gave 1,3,4-trisubstituted isoquinoline products in moderate to excellent yields and high regioselectivity. The corresponding isoquinoline N-oxide was found to be the intermediate in the cyclization reaction pathway. In contrast, the reaction of ortho-haloketimines and alkynes under similar catalytic conditions in tetrahydrofuran at 70 °C for two hours gave 1,2,3,4-tetrasubstituted isoquinolinium salts in good to excellent yields. In the nickel of time: ortho-Haloketoximes and -ketimines undergo [4+2] cyclization reactions with alkynes, catalyzed by nickel complexes to give highly substituted isoquinolines and isoquinolinium salts, respectively, in good to excellent yields (see scheme).

Full text of DOI:10.1002/asia.201100834

FULL PAPERS
DOI: 10.1002/asia.201100834
Nickel-Catalyzed Cyclization of ortho-Iodoketoximes and ortho-
Iodoketimines with Alkynes: Synthesis of Highly Substituted Isoquinolines
and Isoquinolinium Salts
Wei-Chun Shih, Chu-Chun Teng, Kanniyappan Parthasarathy, and Chien-Hong Cheng*[a]
306
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 306 – 313

Abstract: A convenient method for the
synthesis of highly substituted isoqui-
nolines and isoquinolinium salts by the
nickel-catalyzed cyclization of ortho-
haloketoximes and -ketimines, respec-
tively, with alkynes is described. The
reaction of ortho-haloketoximes and
various alkynes in the presence of [Ni-
ture of acetonitrile and tetrahydrofuran
at 808C for 15 hours gave 1,3,4-trisub-
stituted isoquinoline products in mod-
erate to excellent yields and high regio-
selectivity. The corresponding isoquino-
line N-oxide was found to be the inter-
mediate in the cyclization reaction
pathway. In contrast, the reaction of
ortho-haloketimines and alkynes under
similar catalytic conditions in tetrahy-
drofuran at 708C for two hours gave
1,2,3,4-tetrasubstituted isoquinolinium
salts in good to excellent yields.
Keywords: alkynes · cyclization ·
isoquinolines · ketimines · nickel
ACHTUNGTRENNUNG(PPh3)2Br2] and zinc powder in a mix-
Introduction
under various reaction conditions, probably owing to the
steric hindrance of the N-tert-butyl group with substituents
at the C1 and C3 positions. Therefore, the synthesis of 1,3,4-
trisubstituted isoquinolines required a new method.
Our continued efforts in nickel-catalyzed cyclization reac-
tions and isoquinoline synthesis[11,12] prompted us to explore
the reaction of ortho-halogenated ketoximes or ketimines
with alkynes. Herein, we report the synthesis of 1,3,4-trisub-
stituted isoquinolines and 1,2,3,4-tetrasubstituted isoquinoli-
nium salts by the nickel-catalyzed cyclization of ortho-iodo-
ketoximes and -ketimines, respectively, with alkynes
(Scheme 2).
Highly substituted isoquinolines and isoquinolinium salts
are important classes of heterocycles. These types of skele-
tons are found in a wide range of naturally occurring com-
pounds that show various biological activities, such as anti-
HIV,[1,2] antimalarial,[3] ion-channel blocker,[4] and dopamine
agonist.[5] Furthermore, these compounds are useful ligands
in the synthesis of chiral compounds[6] and phosphorescent
emitters for organic light-emitting diodes (OLEDs).[7] They
are usually synthesized using the traditional Bischler–Na-
pieralski, Pomeranz–Fritsch, and Pictet–Spengler reactions,
which involve intramolecular cyclizations and require harsh
conditions.[8] More recently, the synthesis of isoquinolines
has gained much attention in metal-catalyzed organic syn-
thesis.[9] Larock and co-workers developed a synthesis of iso-
quinolines that proceeds via the palladium-catalyzed annula-
tion of ortho-haloaldemines with internal alkynes.[10] In
2006, we reported an efficient nickel-catalyzed synthesis of
isoquinolines from alkynes and 2-iodobenzaldimines.[11]
However, the above methods are only applicable for synthe-
sizing 3,4-disubstituted isoquinoline derivatives (Scheme 1).
To synthesize 1,3,4-trisubstituted isoquinolines by a similar
method, we would need to prepare N-tert-butyl ortho-halo-
ketimines. Unfortunately, we were unable to prepare any N-
tert-butyl-ortho-haloketimines from ortho-bromoacetophe-
nones or ortho-iodoacetophenones with N-tert-butylamine
Scheme 2. Nickel-catalyzed synthesis of isoquinolines and isoquinolinium
salts from ketoximes and ketimines with alkynes.
Results and Discussion
The reaction of 1a with diphenylacetylene (2a) in the pres-
ence of [NiACHTUNGRTNEUNG(PPh3)2Br2] and zinc powder in acetonitrile/tetra-
hydrofuran=1:1 at 808C for 15 hours gave 1,3,4-trisubstitut-
ed isoquinoline 3a in 87% yield (Table 1, entry 1). The
structure of compound 3a was confirmed by 1H and
13C NMR spectroscopy and mass spectrometry. Substrate
(E)-2-iodoacetophenone oxime was prepared from 2-iodo-
AHCTUNGTREGaNNUN cetophenone and hydroxylamine hydrogen chloride in
methanol, followed by recrystallization in dichloromethane
and n-hexane.
Scheme 1. Palladium- or nickel-catalyzed synthesis of 3,4-disubstituted
isoquinolines.
To see the effect of solvent and catalyst on the formation
of isoquinolines, various nickel complexes were investigated
for the reaction of 1a (0.20 mmol) with 2a (0.40 mmol) in
the presence of a nickel complex (3.0 mol%), and zinc
powder (0.3 mmol) in acetonitrile/tetrahydrofuran (1:1,
2.0 mL) at 1008C for 15 hours. First, we examined the cata-
lytic activity of bidentate phosphine nickel(II) complexes
[a] W.-C. Shih, C.-C. Teng, Dr. K. Parthasarathy, Prof. Dr. C.-H. Cheng
Department of Chemistry
National Tsing Hua University
Hsinchu 30013 (Taiwan)
Fax : (+886)3-572-4698
E-mail: chcheng@mx.nthu.edu.tw
Homepage: http://mx.nthu.edu.tw/%7Echcheng
Supporting information for this article, including characterization
[Ni
(dppb)Br2], which provided the product 3a in 30%, 32%,
40%, and 42% yield, respectively (dppm=1,1-bis(diphenyl-
ACHTNUGTERN(UNNG dppm)Br2], [NiAHCTUNRTEGGN(NNU dppe)Br2], [NiACHTNGURTEN(NUGN dppp)Br2], and [Ni-
1
data of the remaining compounds and copies of H and 13C NMR
AHCTUNGTRENNUNG
spectra of all compounds, is available on the WWW under http://
dx.doi.org/10.1002/asia.201100834.
Chem. Asian J. 2012, 7, 306 – 313
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307

C.-H. Cheng et al.
FULL PAPERS
Table 1. The nickel-catalyzed synthesis of isoquinolines from ketoximes 1
and alkynes 2.[a]
Table 1. (Continued)
Entry
1
2
Product 3
Yield
[%][b]
11
83
72
Entry
1
1
2
Product 3
Yield
[%][b]
12
13
87
45[d]
82
2
3
4
75
E-1d
2a
14
15
16
17
35[d]
58
95[c]
48[d]
64[d]
41[d]
5
6
7
83
99
84
[a] General conditions: ketoxime 1 (0.20 mmol), alkyne 2 (0.40 mmol),
[Ni(PPh3)2Br2] (3.0 mol%), Zn powder (0.7 mmol), CH3CN/THF=1:1
(1.0 mL), 808C, 15 h. [b] Yield of isolated product. [c] PPh3 (12 mol%)
was added. [d] A mixture of E/Z isomers of substrates 1d–1g were used
and the reactions were performed for 24 h.
AHCTUNGTRENNUNG
8
67
88
80
phosphino)methane,
dppe=1,2-bis(diphenylphosphino)-
ethane, dppp=1,3-bis(diphenylphosphino)propane, dppb=
1,4-bis(diphenylphosphino)butane). The nitrogen-containing
9
nickel(II) complexes [Ni
ACHUTGTNRENN(GU tmeda)Br2], [NiACHTUNGTRENN(GUN phen)Br2], [Ni-
A
ACHTUNGTRENNUNG
(tmeda=tetramethylethylenediamine, phen=phenanthro-
line, bpy=2,2’-bipyridine). Monodentate-phosphine/nickel-
10
A
ACHTUGNTNERN(UNG PPh3)2Cl2] gave
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
92% yield, as determined by integration of the crude NMR
spectrum, and isolated in 87% yield (Table 1, entry 1). The
solvent systems also played an important role in this reac-
Abstract in Chinese:
tion. The best solvent system using [NiACTHUNTGRNEG(UN PPh3)2Br2] as the cat-
alyst was acetonitrile/tetrahydrofuran (1:1) in which com-
pound 3a was obtained in 87% yield. Toluene was also an
308
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Chem. Asian J. 2012, 7, 306 – 313

Nickel-Catalyzed Cyclization of ortho-Iodoketoximes and ortho-Iodoketimines with Alkynes
effective solvent, giving compound 3a in 53% yield. Other
solvent mixtures, such as acetonitrile with 1,2-dichloro-
ethane, dimethyl sulfoxide, N,N-dimethyl formamide, and
ethanol were less effective in the catalytic reaction (see the
the alkyne to give the corresponding isoquinoline, owing to
the fact that the electron lone pair on the nitrogen atom
should be in the endo position to form catalytic intermediate
A and for the cyclization to proceed (see below). The
Z isomer cannot react with an alkyne to give the cyclized
product unless it undergoes isomerization into the E isomer.
To clarify this concept, the E- and Z isomers of oxime 1g
were carefully separated and isolated. The E/Z ratio of com-
pound 1g based on the amount isolated was about 3:2. As
expected, the E isomer of compound 1g reacted well with
Supporting Information). Finally, [NiACTHUNTGRNEG(UN PPh3)2Br2] with zinc
powder (0.7 mmol) in acetonitrile/tetrahydrofuran (1:1,
1.0 mL) at 808C for 15 hours were found to be the most-
suitable reaction conditions for the reaction of compounds
1a and 2a, thus forming product 3a in 87% yield.
Under the optimized reaction conditions, various alkynes
reacted smoothly with compound 1a to give the correspond-
ing substituted isoquinolines. Thus, symmetrical dialkyl
alkyne 2b and ethyne 2c underwent cyclization with com-
pound 1a to give products 3b and 3c in 75% and 58%
yield, respectively (Table 1, entries 2 and 3). The cyclization
reaction also worked well with unsymmetrical alkynes. Ac-
cordingly, the reaction of ethyl phenyl acetylene 2d with
compound 1a afforded the product 3d in 95% yield with
excellent regioselectivity (Table 1, entry 4). The regiochem-
istry of product 3d was confirmed by NOESY experiments.
Similarly, unsymmetrical alkynes such as 3-phenylpropargyl
alcohol (2e), 3-phenylpropiolate (2 f), 4-phenylbut-3-yn-2-
one (2g), hex-3-yn-2-one (2h), phenylacetylene (2i), and 4-
tolylacetylene (2j) reacted well with compound 1a to afford
substituted isoquinolines in good to excellent yields
(Table 1, entries 5–10) and excellent regioselectivity. We
have previously observed similar regioselectivities of the
alkyne moieties in the products.[11] This nickel-catalyzed cyc-
lization reaction was successfully extended to various substi-
tuted ketoximes 1b–1g. It should be noted that ketoximes
are easily prepared by the condensation of ketones with hy-
droxylamine hydrochloride. Thus, electron-donating 5-
methyl-2-iodoacetophenone oxime (1b) and electron-with-
drawing 5-fluoro-2-iodoacetophenone oxime (1c) reacted
well with compound 2 f to afford the corresponding cyclized
products 3k and 3l in 83% and 72% yield, respectively
(Table 1, entries 11 and 12). Changing the methyl group in
acetophenone oxime (1a) into other bulkier substituents
had a dramatic effect on the yield of the reaction. Thus, 2-
iodobenzophenone oxime (1d) and oxime 1e reacted with
compound 2a to provide compounds 3m and 3n in only
45% and 35% yield, respectively (Table 1, entries 13 and
14). In a similar manner, (2-iodophenyl)pentanone oxime
(1 f) and 2-iodophenyl benzyl ketone oxime (1g) reacted
with compounds 2a and 2 f to give the corresponding isoqui-
nolines 3o, 3p, and 3q in 48%, 64%, and 41% yields, re-
spectively (Table 1, entries 15–17).
compound 2a in the presence of [NiACTHUNRGTNEG(UN PPh3)2Br2] and zinc
powder in acetonitrile/tetrahydrofuran (1:1) at 808C for
24 hours to give the isolated isoquinoline 3q in 79% yield
(Scheme 3). Under similar reaction conditions, the Z isomer
of compound 1g gave compound 3q in only 9% yield
Scheme 3. The reactivity of the E- and Z forms of ketoxime 1g with
alkyne 2a.
(Scheme 3). It is noteworthy that the use of oximes in relat-
À
ed isoquinoline syntheses involving rhodium-catalyzed C H
activation and alkyne insertion[13] is also known.
This nickel-catalyzed cyclization reaction has been suc-
cessfully extended to various ketimines, but the cyclization
products observed are isoquinolinium salts and N-substitut-
ed-1,2-dihydroisoquinolines. For example, the reaction of
ketimine (4a) with diphenylacetylene (2a) under similar re-
action conditions gave isoquinolinium salt 5a in 37% yield
along with 1,2-dihydroisoquinoline 6a in 43% yield
(Table 2, entry 1). The latter is likely to have formed from
the reduction of compound 5a by zinc metal. A few reports
have described the synthesis of isoquinolinium salts using
the traditional coupling reaction of isoquinolines and alkyl
halides and the stoichiometric metal-mediated addition reac-
tion.[14] Until now, methods for the catalytic formation of
isoquinolinium salts have been extremely limited. Very re-
cently, we reported the synthesis of isoquinolinium salts
using a nickel-catalyzed annulation of ortho-halobenzaldi-
mines with alkynes.[15] In that report, we were unable to pre-
pare isoquinolinium salts from the reaction of ketimines
with alkynes. Our continued interest in the synthesis of vari-
ous substituted isoquinolinium salts prompted us to search
for optimal reaction conditions for the synthesis of isoquino-
line salts from ketimines and alkynes. The amount of zinc
used was found to be crucial for the formation of the ex-
The above results indicate that oxime substrates 1d–1g
gave much-lower yields of the expected products (3) com-
pared to those from 2-iodoacetophenone oxime derivatives
1a–1c. We believe that the low product yields obtained
from the reactions of oxime substrates 1d–1g is due to the
existence of E- and Z isomers, which are difficult to sepa-
rate and which undergo very slow interconversion because
of the presence of a relatively large substituent (R1) at the
C1 position of the substrates at the reaction temperature
808C. It is expected that only the E isomer will react with
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C.-H. Cheng et al.
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Table 2. Effect of zinc on the formation of isoquinolinium salt 5a.[a]
Table 3. Results of nickel-catalyzed synthesis of isoquinolinium salts
from ketimines 4 with alkynes 2.[a]
Entry
Zn [equiv]
Yield of 5a [%][b]
Yield of 6a [%][b]
1
2
3
4
5
2
1
0.5
0.2
0.1
37
80
97
77
41
43
12
0
0
0
[a] General conditions: ketimine 4a (0.20 mmol), diphenylacetylene 2a
(0.20 mmol), Zn powder (x equiv), [Ni(PPh3)2Br2] (5.0 mol%), THF
(3.0 mL), 708C, 2 h. [b] Yields were measured from integration of the
1H NMR spectrum of the crude products using mesitylene as an internal
standard.
AHCTUNGTRENNUNG
Entry
1
4
2
Product 5
Yield [%][b]
4a
2a
92[c]
pected isoquinoline salt. After examining different ratios of
zinc dust in the reaction of substrate 4a (see Table 2), we
found that 0.5 equivalents of zinc powder in tetrahydrofuran
at 708C for 2hours gave compound 5a in 97% yield, as de-
termined by integration of the NMR spectrum (Table 2,
entry 3) and isolated in 92% yield (Table 3, entry 1).
2
3
4
4a
4a
4a
2b
2c
2d
70
80
Under the above reaction conditions, various aliphatic al-
kynes reacted smoothly with compound 4a to give the cor-
responding substituted isoquinolinium salts. Thus, oct-4-yne
(2b) underwent cyclization with compound 4a to give com-
pound 5b in 70% yield (Table 3, entry 2). Similarly, acety-
lene (2c) reacted well with compound 4a to afford the cor-
responding salt product 5c in 80% yield (Table 3, entry 3).
To understand the regioselectivity of this reaction, unsym-
metrical alkynes 2d, 2k, and 2h were investigated. 1-
Phenyl-1-butyne (2d) and 3-hexyne-2-one (2h) reacted effi-
ciently with compound 4a to give two regioisomeric prod-
ucts in excellent yield and high regioselectivity (Table 3, en-
tries 4 and 5). Interestingly, methyl propiolate 2k gave a
single regioisomer (5 f) in 85% yield (Table 3, entry 6). En-
couraged by the above results, various terminal alkynes
were tested for this cyclization reaction. Under the standard
catalytic conditions, phenylacetylene (2i) reacted successful-
ly with compound 4a to give the corresponding salt product
(5g) in excellent yield and regioselectivity. Similarly, termi-
nal alkynes 2l and 2m reacted smoothly with compound 4a
to afford mixtures of two regioisomers in good yields
(Table 3, entries 8 and 9). It should be noted that this reac-
tion appears to be the only method for the preparation of
N-aryl-substituted isoquinolinium salts reported so far. This
annulation reaction also worked well for the reaction of var-
ious ketimines with diphenylacetylene (2a) to give isoquino-
linium salts in good to excellent yields (Table 3, entries 10–
14).
99 (8:1)
5
4a
2h
99 (4:1)
6
7
8
4a
4a
4a
2k
2i
2l
85
94
88 (1.5:1)
9
4a
2m
80 (7.4:1)
10
11
4b
4c
2a
2a
95
87
Under similar reaction conditions, different regioselectivi-
ties were observed in the reaction of iodo-ketimines and
bromo-ketimines with alkyne 2 f. Thus, ketimine 4a reacted
well with compound 2 f to give regioisomers 5o and 5o’
(6:1) in 99% combined yield (Scheme 4). Interestingly, the
310
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Chem. Asian J. 2012, 7, 306 – 313

Nickel-Catalyzed Cyclization of ortho-Iodoketoximes and ortho-Iodoketimines with Alkynes
Table 3. (Continued)
Entry
4
2
Product 5
Yield [%][b]
12
4d
2a
80
13
14
4e
4 f
2a
2a
93
88
[a] General conditions: ketimine 4 (0.2 mmol), alkyne 2 (0.2 mmol), [Ni-
(PPh3)2Br2] (5.0 mol%), Zn powder (0.10 mmol), THF (3.0 mL), 708C,
ACHTUNGTRENNUNG
2 h. [b] Yield of isolated product. [c] Reaction was carried out in CH3CN/
THF=1:1 (3.0 mL).
Scheme 5. Possible mechanism for the nickel-catalyzed cyclization reac-
tion.
isoquinoline-N-oxide or isoquinolinium salt and the regener-
ation of the nickel(0) catalyst for the next catalytic cycle.
During the reaction, isoquinoline-N-oxide was reduced by
the zinc powder to give the final product (3).
To support the proposed mechanism in Scheme 5, we
tried to isolate the isoquinoline-N-oxide from (E)-2-iodoace-
tophenone oxime (1a) with diphenylacetylene (2a). Thus,
the reaction of oxime (1a) with compound 2a in the pres-
Scheme 4. The effect of iodo- and bromo-ketimines on the regioselectivi-
ty of product.
ence of [NiACHTUNGRTNEUNG(PPh3)2Br2] and zinc powder in acetonitrile/tetra-
reaction of bromo-ketimine 4a’ with compound 2 f in the
presence of [NiACHTUNGTRENNUNG(dppe)Br2] and zinc powder in tetrahydrofur-
hydrofuran at 808C for 2 hours gave isoquinoline-N-oxide
3D in 53% yield along with isoquinoline 3a in 38% yield
(Scheme 6). It is surprising to note that we can isolate this
an at 808C for 6hours provided isoquinolinium salt 5o in
82% yield with only a trace amount of 5o’ observed by
1H NMR spectroscopy (Scheme 4). The observed different
regiochemistry in the reactions of iodo-ketimines and
bromo-ketimines with unsymmetrical alkyne 2 f to give dif-
ferent ratios of the products 5o and 5o’ is interesting, but
difficult to explain. The difference is likely related to the
À
À
relative rate of insertion of the alkyne into the Ni N or Ni
C bonds (intermediates A, B, and C, Scheme 5).
Proposed Mechanism
On the basis of known metal-catalyzed cyclization reac-
tions,[9–11] a possible reaction mechanism is proposed to ac-
count for our nickel-catalyzed reaction (Scheme 5). The re-
action likely starts with reduction of nickel(II) to nickel(0)
with the aid of zinc powder. Oxidative addition of 2-iodoa-
cetophenone oxime or 2-iodoketimine to nickel(0) leads to
the formation of a five-membered nickelacycle A. Different
coordinative insertions of the alkyne into the nickelacycle
give intermediates B and C. This different coordinative in-
sertion greatly depends on the nature of the alkyne.[10,14] Re-
ductive elimination of intermediates B and C afforded the
Scheme 6. Isolation of isoquinoline-N-oxide 3D and its conversion into
isoquinoline 3a.
product that contains a relatively high energy and highly ox-
idizing N-oxide group in the presence of zinc metal. Further-
more, when compound 3D was treated with zinc in acetoni-
trile at 808C for 12 hours, the corresponding isoquinoline
derivative 3a was isolated in 93% yield (Scheme 6). The iso-
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C.-H. Cheng et al.
FULL PAPERS
lation of compound 3D and its conversion into product 3a
strongly supports the proposed mechanism in Scheme 5.
Acknowledgements
We thank the National Science Council (NSC-99-2119-M-007-010) of the
Republic of China for their support of this research.
Conclusions
We have successfully developed a convenient and efficient
method for the synthesis of highly substituted isoquinolines
and isoquinolinium salts by the nickel-catalyzed annulation
reaction of ketoximes and ketimines with various alkynes.
Highly regioselective substituted isoquinolines were pre-
pared in good to moderate yields. Further studies toward
the synthesis of isoquinoline-N-oxide derivatives and appli-
cations of this methodology in natural product synthesis are
in progress.
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Experimental Section
General procedure for the synthesis of isoquinolines 3
[6] a) C. W. Lim, O. Tissot, A. Mattison, M. W. Hooper, J. M. Brown,
A. R. Cowley, D. I. Hulmes, A. J. Blacker, Org. Process Res. Dev.
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A sealed tube (15 mL volume) initially fitted with a septum containing
[NiACHTUNGTRENNUNG(PPh3)2Br2] (3.0 mol%), Zn (0.70 mmol), ketoxime 1 (0.20 mmol),
and alkyne 2 (0.40 mmol) was evacuated and purged with N2 three times.
Freshly distilled CH3CN (0.50 mL) and THF (0.50 mL) were added and
the solution was stirred at 808C for 15 h. The mixture was filtered
through a Celite and silica-gel pad and the system was then washed with
MeOH (50 mL). The combined filtrate was concentrated, and the residue
was purified by column chromatography on silica gel (hexanes/EtOAc
9:1) to give the corresponding pure isoquinoline product.
[7] a) A. Tsuboyama, H. Iwawaki, M. Furugori, T. Mukaide, J. Kamata-
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1-Methyl-3,4-diphenylisoquinoline (3a)
White solid; m.p. 157–1588C; 1H NMR (400 MHz, CDCl3): d=8.20–8.18
(m, 1H), 7.66–7.63 (m, 1H), 7.36–7.29 (m, 5H), 7.22–7.13 (m, 5H),
3.07 ppm (s, 3H). 13C NMR (100 MHz, CDCl3): d=157.7, 149.4, 140.9,
137.5, 135.9, 131.3, 130.2, 139.9, 129.1, 128.1, 127.5, 127.1, 126.9, 126.5,
126.2, 126.1, 125.5, 22.7 ppm; HRMS (EI+): calcd for C22H17N: 295.1361;
found: 295.1356. IR: n˜ =3062, 1612, 1550, 1504, 1389 cmÀ1
.
General procedure for the synthesis of isoquinolinium salts 5
A sealed tube (15 mL volume) initially fitted with a septum containing
[NiACHTUNGTRENNUNG(PPh3)2Br2] (5.0 mol%), Zn (0.1 mmol), ketimine 4 (0.20 mmol), and
alkyne 2 (0.20 mmol) was evacuated and purged with nitrogen gas three
times. Freshly distilled THF (3.0 mL) was added and the solution was
stirred at 708C for 2 h. The mixture was diluted with dichloromethane
(ca. 15 mL), filtered through a Celite and silica-gel pad, and washed with
MeOH (50 mL). The filtrate was concentrated, and the residue was puri-
fied by column chromatography on silica gel (EtOAc/acetone 1:2) as
eluent to give the corresponding pure isoquinoline salt.
2-(4-Methoxyphenyl)-1-methyl-3,4-diphenylisoquinolinium iodide (5a)
Yellow solid; m.p. 238.58C; 1H NMR (400 MHz, CD2Cl2): d=3.18 (s,
3H), 3.75 (s, 3H), 6.89 (d, J=8.8 Hz, 2H), 7.02–7.03 (m, 3H), 7.18–7.20
(m, 2H), 7.28–7.32 (m, 5H), 7.48 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.0 Hz,
1H), 8.05–8.08 (m, 2H), 8.73 ppm (d, J=8.0 Hz, 1H); 13C NMR
(100 MHz, CD2Cl2): d=1.55, 35.98, 95.72, 107.41, 107.57, 107.85, 108.51,
108.72, 109.04, 109.99, 110.85, 111.66, 111.77, 112.66, 113.15, 114.15,
117.15, 117.38, 118.16, 125.45, 140.53, 141.47 ppm; HRMS (FAB): calcd
for C29H24NO: 402.1852; found: 402.1859; IR: n˜ =1257, 1445, 1504, 1612,
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Received: October 7, 2011
Published online: December 16, 2011
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