Communication
were also suitable for this coupling process. However,
3-hydroxyl-benzaldimine 1l gave a complicated reac-
tion mixture with unidentifiable products. In contrast,
1m was utilized but with lower efficiency, which
gave 3ma in only 31% yield. Surprisingly, when
oxime 1n was subjected to the standard reaction
conditions, polycyclic mesoionic isoquinoline salt 4
was isolated in 41% yield [Eq. (1)].
Table 1. Optimization studies.[a]
Entry
Additive
Acid
Solvent
Yield [%][b]
4aa
3aa
5aa
We next studied the scope and generality of this
coupling reaction (Table 3). The examination of the
scope of diaryl alkynes revealed that both electron-
donating and -withdrawing substituents on different
positions of the phenyl ring proceeded smoothly
with 1a to furnish mesoionic isoquinoline salts 3ab–
3af in good yield. The reaction with dialkyl-substitut-
ed alkyne 2g also reacted smoothly, affording the
corresponding product in 82% yield. Unsymmetrical
alkyne 1h was also tested but gave a mixture of re-
gioisomers.
1[c]
2[d]
3
4
5
6
7
8
9
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OTf)2
AgSbF6
AgBF4
Cu(OAc)2··H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuOAc
–
–
–
–
–
–
–
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
IPA
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
22
20
48
-
20
trace
19
trace
–
–
trace
58
–
21
–
trace
trace
trace
–
trace
trace
–
–
10
–
–
–
–
–
–
12
–
–
–
–
–
–
–
N.R.
trace
13
30
N.R.
61
80
93
90
82
80
50
60
–
10
11
CF3COOH
CH3SO3H
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
12[e]
13[e,f]
14[e,f]
15[e,g]
16[e,h]
17[e,i]
A plausible mechanism for the oxidative annula-
tion was proposed (Scheme 2). The ortho CÀH bond
of the benzaldimine is initially cleaved by the RhIII
catalyst to afford the five-membered rhodacycle in-
termediate I, which coordinates to the alkyne to pro-
vide intermediate II. Subsequent insertion of the
alkyne into the RhÀC bond yields the seven-mem-
bered ring III. Then, the reductive elimination occurs
to give intermediate IV and a RhI species, which can
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
[a] Reaction conditions unless otherwise specified: 1a (0.05 mmol), 2a (0.1 mmol),
[{Cp*RhCl2}2] (5 mol%), additive (1 equiv), acid (1 equiv), and solvent (0.5 mL) at 110 8C
for 20 h under Ar atmosphere. [b] Isolated yield. [c] [RhCp*(MeCN)3][(SbF6)2] (5 mol%).
[d] [RuCl2(p-cymene)2] (5 mol%). [e] Reaction time was 5 h. [f] additive (2 equiv).
[g] [{Cp*RhCl2}2] (2 mol%). [h] TsOH (0.5 equiv). [i] TsOH (2 equiv).
system in the presence of Cu(OAc)2·H2O as an additive, giving
the expected mesoionic isoquinoline salt 3aa in good yield,
albeit with side products benzisoxazoline (4aa)[16] and chro-
mone derivative 5aa[17] (entries 1–3). Other additives exhibited
lower reactivity towards the reaction (entries 4–6). Next, a varie-
ty of solvents, such as IPA and DMF, were examined that pro-
vided inferior results (entries 7–9). To our delight, the reaction
was carried out with excellent efficiency when TsOH was uti-
lized (entries 10–12). However, Cu(OAc)2·H2O (2 equiv) slightly
decreased the yield of 3aa, while CuOAc exhibited good reac-
tivity in the oxidative annulation (entries 13 and 14). Decreas-
ing the catalyst loading resulted in a lower yield (entry 15). The
reactivity was reduced when the amount of TsOH was changed
(entries 16 and 17).
be oxidized by the CuII to complete the catalytic cycle. Mean-
while CuII is reduced to CuI or Cu(0).[18] Finally, anion of the
acid removes the proton of the phenol, probably due to its
good acidity, to produce the mesoionic isoquinoline product
3aa.
In conclusion, a simple strategy, the use of benzaldimines
bearing an OH group as substrates coupled with alkynes, has
been successfully developed in the field of CÀH activation and
oxidative annulation. In this RhIII-catalyzed coupling system,
unique mesoionic isoquinoline salts have been prepared for
the first time. In comparison with the previous methodologies
of isoquinoline salts, the current approach is more general and
efficient. Further investigations of the catalytic mechanism,
studies on both applications of this coupling reaction in the
synthesis of complex molecules, and the synthetic utility of the
mesoionic isoquinoline derivatives are underway in our labora-
tory.
With the developed optimized conditions for the catalytic
coupling reaction in hand, we investigated reactions with
a wide variety of hydroxyl-substituted benzaldimines as sub-
strates (Table 2). The effect of steric and electronic influences
was first investigated; thus, 2-hydroxyl-benzaldimine with the
methoxy substitution at the ortho-, meta-, and para-positions
of the phenyl ring reacted smoothly to provide mesoionic iso-
quinoline salts 3ba–3da in good yield. The para-chlorine-sub-
stituted 2-hydroxyl-benzaldimine 1e had a less pronounced
effect. Imines bearing various N-aryl groups were also tolerat-
ed, giving desired products in good to excellent yields (3 fa–
3ha). Furthermore, the N-substituent is not limited to aryl
groups, the N-benzyl- and N-alkyl-substituted imines (1i–1k)
Chem. Eur. J. 2016, 22, 907 – 910
908
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