Nickel-catalyzed cycloaddition of aromatic (O-benzyl)ketoximes with alkynes to produce isoquinoline and isoquinoline N-oxide derivatives

Article abstract of DOI:10.1246/cl.2011.1140

A nickel-catalyzed cycloaddition of aromatic (O-benzyl)-ketoximes with alkynes to afford 3,4-disubstituted isoquinoline derivatives has been developed. The reaction involves oxidative addition of N-O bond of O-benzylketoxime to Ni(0) and subsequent intermolecular C-H bond activation via elimination of benzyl alcohol. It was also found that ketoximes participate in the nickel-catalyzed reaction with alkynes to furnish isoquinoline N-oxide derivatives.

Full text of DOI:10.1246/cl.2011.1140

doi:10.1246/cl.2011.1140
1140
Published on the web September 23, 2011
Nickel-catalyzed Cycloaddition of Aromatic (O-Benzyl)ketoximes with Alkynes
to Produce Isoquinoline and Isoquinoline N-Oxide Derivatives
Yuji Yoshida, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510
(Received July 4, 2011; CL-110559; E-mail: tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp)
Table 1. Nickel-catalyzed cycloaddition of 1 with 2a
A nickel-catalyzed cycloaddition of aromatic (O-benzyl)-
ketoximes with alkynes to afford 3,4-disubstituted isoquinoline
derivatives has been developed. The reaction involves oxidative
addition of N-O bond of O-benzylketoxime to Ni(0) and
subsequent intermolecular C-H bond activation via elimination
of benzyl alcohol. It was also found that ketoximes participate in
the nickel-catalyzed reaction with alkynes to furnish isoquino-
line N-oxide derivatives.
R2
OR1
R3
[Ni(cod)2] (10 mol %)
N
N
dppf (10 mol %)
R2
R3
+
toluene, 110 °C, 6 h
2
3
1
Entry
1
R1
2
3, Yieldb
/%
Pr
Pr
N
Pr
Pr
In recent years, transition-metal-catalyzed reactions, which
involve C-H bond cleavage as a key reaction step,1 have been
recognized as powerful methodologies for the synthesis of
structurally diverse isoquinolines,2,3 because they allow syn-
thesis of isoquinolines which are difficult to prepare with
conventional methods.4-10 However, the reactions generally
need to be performed in the presence of an external oxidant to
enable a catalytic process. Herein, we wish to report a catalytic
N-O/C-H bond cleavage tandem process for the construction of
isoquinolines with cycloaddition of aromatic (O-benzyl)keto-
ximes and alkynes via elimination of benzyl alcohol. The
process does not require an additional oxidant.
Initially, when O-benzylketoxime 1a and 4-octyne (2a)
were treated in the presence of a nickel catalyst, which was
prepared in situ from [Ni(cod)2] (10 mol %) and dppe (10 mol %)
in toluene at 110 °C for 6 h, isoquinoline 3aa was obtained in
48% yield along with benzyl alcohol in 31% yield (Table 1,
Entry 1). Upon optimization of the nickel catalyst, 3aa was
obtained in excellent yield; a combination of [Ni(cod)2] and
dppf was found to be effective in affording 3aa in 80% yield
(Entry 4). We then evaluated the effects of the O-substituent on
an oxime. Oximes consisting of the O-methyl and O-(mesityl-
methyl) group afforded 3aa in lower yields (Entries 5 and 6),
whereas 1d and 1e failed to participate in the reaction to afford
3aa (Entries 7 and 8). The reaction of 1a with 2-octyne (2b)
afforded the isoquinoline 3ab in 76% yield with regioisomer
ratio of 1/1 (Entry 9). The reaction of 1a with unsymmetrical
alkynes, such as 2c and 2d, also gave the isoquinolines
consisting of regioisomers in 1/1 ratio (Entries 10 and 11).
The cycloaddition is also compatible with aryl-substituted
unsymmetrical alkynes and afforded the corresponding isoqui-
noline with higher regioselectivity (Entries 13 and 14, Figure 1).
We next examined effects of substituents on O-benzyl-
ketoxime 1 to gain insight into the cycloaddition. The results of
this investigation are summarized in Table 2. Aromatic (O-
benzyl)ketoxime 1f consisting of the aryl moiety with electron-
withdrawing fluoride substituent, afforded 3fa in good yield
(Entry 2). Whereas O-benzylketoximes 1g and 1h possessing
the aryl moiety with electron-donating substituents reacted with
2a to afford cycloadducts 3ga and 3ha in lower yields of 47%
and 26%, respectively (Entries 3 and 4). It was found that
1
CH2Ph
3aa, 48c
1a
2a
Ph
2
3
4
5
6
7
8
3aa, 62d
3aa, 56e
3aa, 80
3aa, 10
3aa, 5
1a
1a
1a
1b
1c
1d
1e
2a
2a
2a
2a
2a
2a
2a
Me
CH2Mes
OC(O)Ph
3aa <1
3aa <1
OC(O)C6F5
C5H11
Me
N
N
N
C5H11
Me
3ab, 76
9
CH2Ph
1a
1a
(1/1)f
2b
2c
Ph
Ph
Ph
i-Pr
Me
3ac, 60
i-Pr
Me
10
CH2Ph
CH2Ph
(1/1)f
i-Pr OMe
i-Pr
3ad, 43
OMe
11
1a
(1/1)f
2d
Ph
Ph
N
N
N
Ph
Ph
Ph
Ph
Me
Pr
12
13
14
CH2Ph
CH2Ph
CH2Ph
3ae, 37
1a
1a
1a
2e
2f
Ph
Ph
Ph
Ph
Me
3af, 59
(4/1)f
Ph
Pr
3ag, 66
(5/1)f
2g
aReactions were carried out using [Ni(cod)2] (10 mol %), dppf
(10 mol %), 1 (0.6 mmol), and 2 (0.3 mmol) in 1 mL of toluene
at 110 °C for 6 h in a sealed tube. Isolated yields are given.
cdppe (10 mol %). dppp (10 mol %). dppb (10 mol %). Ratio
b
d
e
f
of regioisomers.
Chem. Lett. 2011, 40, 1140-1142
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1141
Table 2. Nickel-catalyzed cycloaddition of 1 with 2aa
Pr
OBn
Pr
[Ni(cod)2] (10 mol %)
dppf (10 mol %)
N
N
+
Pr
Pr
R4
R4
toluene, 110 °C, 24 h
R5
R5
3
1
2a
Entry
1
1
3, Yieldb/%
Figure 1. ORTEP drawings of 3ag and 5ag.
Pr
OBn
N
Pr
N
Pr
Pr
O
N
N
3aa, 80
3fa, 67
3ga, 47
3ha, 26c
1a
3aa
1a
Ni(0)Ln
Pr
OBn
OBn
OBn
N
Pr
N
2
3
4
5
6
7
8
9
Pr
O
F
F
Ni
F
F
Ni
Pr
1f
N
H
N
Pr
N
Pr
N
Pr
Me
Me
Me
Me
1g
HO
Pr
Ni
N
Pr
N
Pr
Pr
Pr
N
2a
MeO
OMe
Scheme 1. Plausible reaction mechanism.
MeO
MeO
OMe
1h
Pr
unsymmetrical O-benzylketoxime 1i reacts with alkyne 2a to
give a mixture of regioisomer 3ia and 3ia¤ in a ratio of 1/1
(Entry 5). The reaction of imidamide 1j with 2a did not give 3ja
(Entry 6). Neither five-membered-ring nor seven-membered-
ring fused O-benzylketoximes reacted with 2a to afford cyclo-
adducts (Entries 7 and 9). However, six-membered-ring fused
O-benzylketoxime 1l reacted with 2a to furnish 3la in 65% yield
(Entry 8).
While the mechanism of this reaction has not been
elucidated completely, we propose the following reaction
pathway based on the results that we observed (Scheme 1). It
is reasonable to consider that the catalytic cycle of the present
reaction should consist of the oxidative addition of an oxime
N-O bond to a Ni(0) complex.11 Subsequent elimination of
benzyl alcohol via C-H bond cleavage affords five-membered
nickelacycle intermediate. Even though we were not successful
in an isolation of the nickelacycle intermediate, we found that
treatment of 1a with stoichiometric amount of Ni(0)/dppf in the
absence of alkyne furnished benzyl alcohol.12 The alkyne would
then insert into the C-Ni bond to give seven-membered
nickelacycle. With its seven-membered ring strain, Ni can
undergo a facile reductive elimination to give 3aa, and
regenerates the starting Ni(0) complex.
Pr
OBn
N
N
MeO
F
F
3ia, 60
(1/1)d
1i
Pr
OBn
N
Pr
N
N
N
3ja, <1
3ka, <1
3la, 65
3ma, <1
1j
Pr
OBn
OBn
N
Pr
N
1k
Pr
N
Pr
N
O
O
1l
Pr
OBn
N
Pr
N
Lastly, it should be noted that the use of ketoximes 4
in place of O-benzylketoximes with the reaction of alkynes
resulted in formation of 3,4-disubstituted isoquinoline N-oxides
5 (Table 3). Upon optimization of the nickel catalyst, 5aa was
obtained in good to moderate yield along with 3aa when
[Ni(cod)2] was used as a catalyst in the absence of ligand
(Entry 1). The reaction is also compatible with aryl-substituted
alkynes and afforded the corresponding isoquinolines N-oxide 5
1m
aReactions were carried out using [Ni(cod)2] (10 mol %), dppf
(10 mol %), 1 (0.6 mmol), and 2 (0.3 mmol) in 1 mL of toluene
at 110 °C for 6 h in a sealed tube. Isolated yields are given.
b
cReaction time: 24 h. Ratio of regioisomers.
d
Chem. Lett. 2011, 40, 1140-1142
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1142
Table 3. Nickel-catalyzed cycloaddition of 4 with 2a
This work was supported by Grants-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan. T.K. also acknowledges the Asahi Glass Foundation,
Kansai Research Foundation, and Toyota Physical and Chemical
Research Institute.
R2
OH
O
R3
N
N
[Ni(cod)2] (10 mol %)
toluene, 110 °C, 6 h
R2
R3
+
+
3
R4
R4
R5
R5
4
5
2
References and Notes
Entry
1
4
2
Yieldb/%, Products
1
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Pr
OH
O
Pr
N
N
2a
57, 5aa/3aa = 3/1
4a
Ph
OH
O
Ph
N
N
2
3
4
5
6
2e
2g
2a
2a
2a
2
3
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60, 5ae/3ae = 1.2/1
4a
Ph
OH
OH
O
Pr
N
N
56, 5ag/3ag = 1/1c
4a
Pr
N
O
Pr
N
4l
<1
Pr
OH
N
O
Pr
N
4
5
O
O
4m
34, 5ma/3ma = 2/1
OH
Pr
N
Pr
O
N
6
7
4n
<1
8
9
aReactions were carried out using [Ni(cod)2] (10 mol %), 4
(0.3 mmol), and 2 (0.9 mmol) in 1 mL of toluene at 110 °C for
6 h in a sealed tube. Isolated yields are given. 5ag/5ag¤ =
99/1, 3ag/3ag¤ = 13/1.
b
c
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along with isoquinolines 3 (Entries 2 and 3, Figure 1). Although
4l and 4n did not react with 2a to afford any cycloadducts 5
(Entries 4 and 6), 4m reacted with 2a to furnish 5ma along with
3ma (34%, Entry 5).
In conclusion, we have demonstrated that O-benzylketo-
ximes reacted with alkynes in the presence of nickel catalyst
via elimination of benzyl alcohol to furnish 3,4-disubstituted
isoquinolines. It was also found that the use of ketoxime in place
of O-benzylketoximes resulted in formation of 3,4-disubstituted
isoquinoline N-oxides as a major product.13
13 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2011, 40, 1140-1142
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/