Construction of isoquinolin-1(2H)-ones by copper-catalyzed tandem reactions of 2-(1-Alkynyl)benzaldimines with water

Article abstract of DOI:10.1002/ejoc.201500908

The Cu(OAc)₂-catalyzed tandem reaction of 2-(1-alkynyl)benzaldimines with water for the synthesis of isoquinolin-1(2H)-ones was developed. Moreover, 4-halogen-substituted isoquinolin-1(2H)-ones were obtained in good yields simply by including N-halosuccinimides (NXS: X = Cl, Br, I) in the reaction system. Mechanistic studies indicated that the reactions are probably initiated by highly regioselective intramolecular cyclization of 2-(1-alkynyl)benzaldimines to give the corresponding isoquinolinium intermediates. The Cu(OAc)₂-catalyzed tandem reaction of 2-(1-alkynyl)benzaldimines with water for the synthesis of isoquinolin-1(2H)-ones is developed. 4-Halogen-substituted isoquinolin-1(2H)-ones can be obtained in good yields simply by including N-halosuccinimides (NXS) in the reaction system. Mechanistic studies are also undertaken.

Full text of DOI:10.1002/ejoc.201500908

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500908
Construction of Isoquinolin-1(2H)-ones by Copper-Catalyzed Tandem
Reactions of 2-(1-Alkynyl)benzaldimines with Water
Mingliang Zhang,[a] Hui-Jun Zhang,*[a] Wenqing Ruan,[a] and Ting-Bin Wen*[a]
Keywords: Homogeneous catalysis / Copper / Cyclization / Oxidation / Tandem reaction / Nitrogen heterocycles
The Cu(OAc)2-catalyzed tandem reaction of 2-(1-alkynyl)-
benzaldimines with water for the synthesis of isoquinolin-
1(2H)-ones was developed. Moreover, 4-halogen-substituted
isoquinolin-1(2H)-ones were obtained in good yields simply
by including N-halosuccinimides (NXS: X = Cl, Br, I) in the
reaction system. Mechanistic studies indicated that the reac-
tions are probably initiated by highly regioselective intra-
molecular cyclization of 2-(1-alkynyl)benzaldimines to give
the corresponding isoquinolinium intermediates.
Introduction
The isoquinolin-1(2H)-one skeleton represents an impor-
tant heterocyclic structure that is found in numerous biolo-
gically active compounds and pharmaceuticals.[1] Signifi-
cant effort has been devoted to develop efficient methods
for its construction.[2,3] Among these methods, intramolec-
ular cyclization of 2-alkynylbenzamides, as one of the most
straightforward strategies, has attracted considerable atten-
tion.[4] It has been found that both transition-metal cata-
lysts and electrophilic reagents can promote this cycliza-
tion.[5] However, this route suffers from several limitations,
especially the lack of regioselectivity and chemoselectivity,
see Scheme 1, Equation (1).[5,6] Notably, Too and Chiba re-
cently developed an efficient CuBr-mediated aerobic reac-
tion of 2-alkynylbenzaldehydes with primary amines for the
direct synthesis of 4-bromoisoquinolones[7] that proceeds
selectively through 6-endo cyclization of hemiaminal inter-
mediates generated in situ, see Scheme 1, Equation (2).
However, a large excess amount of CuBr·SMe2 is required,
and the reaction fails with aromatic amines. Herein, we re-
port a highly selective and efficient copper-catalyzed tan-
dem cyclization process for the synthesis of isoquinolin-
1(2H)-ones starting from 2-(1-alkynyl)arylaldimines, see
Scheme 1, Equation (3).
Scheme 1. Construction of isoquinolin-1(2H)-ones through intra-
molecular cyclization strategies.
2-(1-Alkynyl)arylaldimines are a class of useful organic
molecules and are widely used to construct isoquinolines
and 1,2-dihydroisoquinolines.[8–10] Starting from 2001,
Larock and co-workers reported the formation of 3,4-di-
substituted isoquinolines through the palladium-catalyzed
carboamination of the tert-butylimines of 2-(1-alkynyl)aryl
aldehydes.[8a–8g] Later, they found that electrophilic reagents
could also promote the cyclization to give substituted iso-
quinolines.[8h,8i] During the same time, Asao and co-
workers reported the synthesis of 1,3-disubstituted 1,2-di-
hydroisoquinolines by AgI-promoted cyclization of 2-alk-
ynylarylimines followed by intermolecular nucleophilic ad-
dition.[9a] In addition, Takemoto et al. developed a carbo-
philic Lewis acid catalyzed method for the synthesis of 1,2-
dihydroisoquinolines through tandem nucleophilic ad-
dition/cyclization of 2-(1-alkynyl)arylaldimines.[10a,10b] In-
[a] Department of Chemistry, College of Chemistry and Chemical
Engineering, Xiamen University,
Xiamen 361005, Fujian, P. R. China
E-mail: meghjzhang@xmu.edu.cn
chwtb@xmu.edu.cn
http://chemistry.xmu.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500908.
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Construction of Isoquinolin-1(2H)-ones
spired by these results, we envisioned that the tandem cycli- estingly, the reaction also performed smoothly in the pres-
zation of 2-(1-alkynyl)arylaldimines and nucleophilic ad- ence of Fe(OAc)2 (30 mol-%) to afford the desired product
dition of water followed by oxidation might lead to the se- in 73% yield. Subsequently, various solvents were also
lective formation of isoquinolin-1(2H)-ones, see Scheme 1, screened, and toluene proved to be the best choice (Table 1,
Equation (3).
entries 13–16).
After the establishment of the optimal reaction condi-
tions, the scope of the substrates was surveyed (Table 2).
Both electron-withdrawing and -donating substituents (e.g.,
MeO–, Cl–, F–) on the phenyl ring were well tolerated (see
products 2b–d). Moreover, iminoalkynes derived from a
variety of aromatic amines were also suitable substrates,
and the corresponding isoquinolin-1(2H)-ones were ob-
tained in high yields (see products 2e–i). In contrast, the
reactions of iminoalkynes derived from aliphatic amines
were less successful. Whereas the phenethylamine-derived
Results and Discussion
Our investigation began with the reaction of iminoalkyne
1a with Cu(OAc)2·H2O (20 mol-%) in toluene at 130 °C in
air. To our delight, desired cyclization product 2a was ob-
tained in 64% yield and no isoquinolines-type product was
observed (Table 1, entry 1). Upon performing the reaction
under an O2 atmosphere instead of in air, product 2a was
isolated in 41% yield along with N-phenylphthalimide (2Ј)
in 36% yield (Table 1, entry 2).[11] As the reaction time was
extended from 6 to 12 h, the yield of 2a increased to 73%
(Table 1, entry 3). Increasing the loading of Cu(OAc)2·H2O
to 30 mol-% further boosted the yield of 2a to 79%
(Table 1, entry 4). No reaction took place in the absence
of the copper catalyst (Table 1, entry 5). Gratifyingly, the
addition of H2O (5 equiv.) to the reaction system led to an
optimal yield (89%; Table 1, entry 6). However, increasing
the amount of water to 10 equiv. resulted in inferior results
(Table 1, entry 7). Further screening of the amount of
Cu(OAc)2·H2O and water revealed that 2a could be ob-
tained in 86% yield if 10 mol-% of Cu(OAc)2·H2O and
3 equiv. of H2O were used (Table 1, entry 8).[12] In addition,
a series of other metal catalysts, such as CuCl2, Cu(OTf)2
(Tf = CF3SO2), CuI, and Fe(OAc)2, were evaluated and
were found to be less efficient (Table 1, entries 9–12). Inter-
Table 2. Substrate scope.[a,b]
Table 1. Selected results from screening of the optimal conditions.[a]
Entry [M] (mol-%)
Solvent
Additive
(equiv.)
Yield [%][b]
1[c]
2[d]
3
4
5
Cu(OAc)2·H2O (20) PhMe
Cu(OAc)2·H2O (20) PhMe
Cu(OAc)2·H2O (20) PhMe
Cu(OAc)2·H2O (30) PhMe
–
–
–
–
64
41
73
79
0
–
PhMe
–
6
7
8
9
10
11
12[e]
13
14
15
16
Cu(OAc)2·H2O (30) PhMe
Cu(OAc)2·H2O (30) PhMe
Cu(OAc)2·H2O (10) PhMe
H2O (5)
H2O (10)
H2O (3)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
89
54
86
50
trace
59
73
66
62
27
23
CuCl2 (30)
Cu(OTf)2 (30)
CuI (30)
PhMe
PhMe
PhMe
PhMe
Fe(OAc)2 (30)
Cu(OAc)2·H2O (30) 2-methylbutan-2-ol H2O (5)
Cu(OAc)2·H2O (30) DMF
Cu(OAc)2·H2O (30) 1,4-dioxane
Cu(OAc)2·H2O (30) DCE
H2O (5)
H2O (5)
H2O (5)
[a] Reaction conditions: 1 (0.2 mmol), Cu(OAc)2·H2O (0.06 mmol),
PhMe (1.5 mL), air, sealed tube, 130 °C, 12 h. [b] Yields of isolated
products are given; yields of the products obtained for reactions
performed in the presence of Cu(OAc)2 (10 mol-%) and H2O
(3 equiv.) are shown in parentheses. [c] Yield of the product ob-
tained for the reaction performed in the presence of Fe(OAc)2
(30 mol-%). [d] Al2O3 (20 mg).
[a] Reaction conditions: 1a (0.2 mmol), [M] (5–30 mol-%), and sol-
vent (1.5 mL) in air for 12 h, sealed tube, 130 °C. DCE = 1,2-
dichloroethane. [b] Yield of isolated product. [c] 6 h. [d] Under O2
atmosphere. [e] Fe(OAc)2 (95% purity).
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M. Zhang, H.-J. Zhang, W. Ruan, T.-B. Wen
SHORT COMMUNICATION
substrate reacted with water to afford product 2j in 36% ation at the 4-position, which supports the formation of an
yield, iminoalkynes derived from tert-butylamine and benz- intermediate with a C–Cu bond.[15] In addition, through the
ylamine did not afford any isoquinolin-1(2H)-one products. addition of H2O18, an O18-substituted product was ob-
In the latter two cases, corresponding isoquinoline served (see the Supporting Information), which suggests
2ЈЈ[8f,8g,13] was formed instead, which suggests that the reac- that the oxygen in the product comes from water, see
tions may be proceeded through isoquinolinium intermedi- Scheme 2, Equation (6). On the basis of these results, a pos-
ates. Furthermore, both aromatic and aliphatic functional sible mechanism is proposed in Scheme 3.[16] First, com-
groups on the alkynyl part were well tolerated (see products plexation of CuII with the alkynyl moiety of substrate 1
2m–t), although aliphatic substituents gave relatively lower activates the triple bond for nucleophilic attack by the imine
yields (see products 2s and 2t). Notably, 2d, 2f, 2m, and 2r nitrogen atom to form isoquinolinium intermediate B. Sub-
were also obtained in good yields in the presence of sequently, nucleophilic addition of water onto intermediate
Fe(OAc)2 (30 mol-%) as the catalyst.
B followed by oxidation of hemiaminal C with CuII and O2
To introduce halogen atoms at the C4 position of the leads to final product 2. On the other hand, electrophiles
isoquinolin-1(2H)-ones, N-halosuccinimides (NXS: X = Cl, could also promote the cyclization of substrate 1, which
Br, I) were added to the reaction system as a halogen atom would lead to isoquinolinium intermediate BЈ, and this
source (Table 3). After optimization of the reaction condi- intermediate could undergo nucleophilic addition with
tions (see the Supporting Information), we found that in water to give CЈ.[17] Oxidation of CЈ affords corresponding
the presence of Cu(OAc)2·H2O (30 mol-%), NBS (1 equiv.), halogenated product 3.
and H2O (3 equiv.) the tandem reaction of iminoalkyne 1a
worked well at 100 °C in chlorobenzene. Therefore, the
cyclization of several 2-(1-alkynyl)arylaldimines under these
conditions was performed (Table 3). The corresponding 4-
bromo-, 4-iodo-, and 4-chloroisoquinolin-1(2H)-ones (see
products 3a–c, 3r, 3aЈ, and 3aЈЈ) were isolated in moderate
to high yields (53–75%).[14] Notably, in the absence of
Cu(OAc)2·H2O, 4-bromo-substituted isoquinolin-1(2H)-
one 3a was obtained in only 14% yield starting from 1a (see
the Supporting Information).
Table 3. Substrate scope.[a,b]
Scheme 2. Preliminary mechanism study.
[a] Reaction conditions: 1 (0.2 mmol), Cu(OAc)2·H2O (0.06 mmol),
NXS (0.2 mmol), H2O (0.6 mmol), PhCl (1.5 mL), sealed tube,
100 °C. [b] Yields of the isolated products are given. [c] 1,2-Di-
chloroethane (1.5 mL).
Several experiments were conducted to shine light on the
reaction mechanism (Scheme 2). The reaction of 1a in the
presence of Cu(OAc)2 (30 mol-%) performed under an Ar
atmosphere furnished desired product 2a in only 10% yield,
which suggests that O2 is necessary for the transformation,
see Scheme 2, Equation (4). The fate of D2O in the reaction
shown in Equation (5) (Scheme 2) clearly indicates proton- Scheme 3. The proposed mechanism.
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Construction of Isoquinolin-1(2H)-ones
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Conclusions
We developed a copper-catalyzed tandem reaction of 2-
(1-alkynyl)benzaldimines with water. This method provides
straightforward and facile entry to various isoquinolin-
1(2H)-one derivatives. Further study of the reaction scope
and applications is still underway in our laboratory.
Experimental Section
General Procedures for the Synthesis of Isoquinolin-1(2H)-ones 2: A
25 mL tube was charged with 2-alkynylbenzaldehydeimine deriva-
tive 1 (0.2 mmol), Cu(OAc)2·H2O (0.06 mmol), H2O (1.0 mmol),
and toluene (1.5 mL). The tube was sealed with a Teflon®-lined
cap, and the mixture was stirred at 130 °C for 12 h. Subsequently,
the mixture was purified by column chromatography (silica gel; pe-
troleum ether/ethyl acetate, 5:1) to give the desired product.
General Procedures for the Synthesis of 4-Halogenoisoquinolin-
1(2H)-ones 3: A 25 mL tube was charged with 2-alkynylbenzalde-
hyde derivative 1 (0.2 mmol), Cu(OAc)2·H2O (0.06 mmol), NXS
(0.2 mmol), H2O (0.6 mmol), and chlorobenzene (1.5 mL). The
tube was sealed with a Teflon-lined cap, and the mixture was stirred
at 100 °C for 12 h. Subsequently, the mixture was purified by col-
umn chromatography (silica gel; petroleum ether/ethyl acetate, 5:1)
to give the desired product.
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Acknowledgments
This work was financially supported by the National Natural Sci-
ence Foundation of China (NSFC) (No. 21302157), National Basic
Research Program of China (973 Program, No. 2012CB821600),
Program for Changjiang Scholars and Innovative Research Team
in University (PCSIRT), and Fundamental Research Funds for the
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M. Zhang, H.-J. Zhang, W. Ruan, T.-B. Wen
SHORT COMMUNICATION
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10666–10668.
[11] For the crystal structures of 2a and 2Ј, see the Supporting In-
formation. CCDC-1056202 (for 2a) and -1057701 (for 2Ј) con-
tain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[17] For analogous electrophilic tandem cyclizations, see: a) H. C.
Ouyang, R. Y. Tang, P. Zhong, X. G. Zhang, J. H. Li, J. Org.
Chem. 2011, 76, 223–228; b) S. U. Dighe, S. Batra, Tetrahedron
2013, 69, 9875–9885.
Received: July 8, 2015
Published Online: August 20, 2015
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Eur. J. Org. Chem. 2015, 5914–5918