AgOTf-catalyzed one-pot reactions of 2-alkynylbenzaldoximes with α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.3762/bjoc.9.231

AgOTf-catalyzed one-pot reactions of 2-alkynylbenzaldoximes with various α,β-unsaturated carbonyl compounds under mild conditions are described, which provides a facile and efficient pathway for the synthesis of 1-alkylated isoquinoline derivatives. The m

Full text of DOI:10.3762/bjoc.9.231

AgOTf-catalyzed one-pot reactions of
2-alkynylbenzaldoximes with α,β-unsaturated
carbonyl compounds
Qiuping Ding1, Dan Wang1, Puying Luo*2, Meiling Liu1, Shouzhi Pu*3
and Liyun Zhou1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1949–1956.
1Key Laboratory of Functional Small Organic Molecules, Ministry of
Education and College of Chemistry & Chemical Engineering, Jiangxi
Normal University, Nanchang, Jiangxi 330022, P. R. China,
2Department of Obstetrics and Gynecology, Jiangxi Provincial
people's Hospital, Nanchang, Jiangxi 330006, P. R. China and
3Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science &
Technology Normal University, Nanchang, Jiangxi 330013, P. R.
China
doi:10.3762/bjoc.9.231
Received: 28 June 2013
Accepted: 05 September 2013
Published: 27 September 2013
Associate Editor: J. P. Wolfe
© 2013 Ding et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Puying Luo* - luopuying1979@gmail.com; Shouzhi Pu* -
pushouzhi@tsinghua.org.cn
* Corresponding author
Keywords:
2-alkynylbenzaldoxime; cyclization; 2-(isoquinolin-1-yl)ethanol;
rearrangement; α,β-unsaturated carbonyl compound
Abstract
AgOTf-catalyzed one-pot reactions of 2-alkynylbenzaldoximes with various α,β-unsaturated carbonyl compounds under mild
conditions are described, which provides a facile and efficient pathway for the synthesis of 1-alkylated isoquinoline derivatives.
The method tolerates a wide range of substrates and allows for the preparation of the products of interest in moderate to excellent
yields.
Introduction
One-pot combinations of multi-catalysis and multi-component thetic processes. Isoquinoline derivatives, an important class of
cascade reactions [1-6], in which several bond-forming steps nitrogen-containing polycyclic heteroarenes, have attracted
take place in a single operation, play an important role in atom- considerable attention because of their pharmacological activi-
economical organic chemistry. A cascade reaction is the most ties, including antitumor, antifungal, antimalarial, antihyperten-
efficient way for targeting fine chemicals, agrochemicals, phar- sive and antihistaminic activity, and their photo- and electro-
maceutical drugs, drug intermediates and ingredients by a one- chemical properties [7-15]. Over the past decade, there has been
pot reaction in environmentally and economically friendly syn- growing interest in the development of new methods for the
1949

Beilstein J. Org. Chem. 2013, 9, 1949–1956.
construction of isoquinoline. For instance, Yamamoto [16-19], leading to 2,10b-dihydro-1H-isoxazolo[3,2-a]isoquinoline
Larock [20-27], and Wu [28-35] have reported mild and effi- intermediate B [44,45], which may then suffer a rearrangement
cient methodologies to synthesize substituted isoquinolines.
or fragmentation resulting in compound 3 (Scheme 1)
[35,36,38,42]. To demonstrate the feasibility of this assumed
Despite the aforementioned versatile and efficient methods for route, we started to investigate the possibility of this one-pot
the direct construction of isoquinolines, the selective functional- process.
ization of isoquinoline species is still a challenging task.
Recently, there has been some progress in this aspect. Wu and
co-workers described an efficient three-component reaction of a
2-alkynylbenzaldoxime and an α,β-unsaturated carbonyl com-
pound with bromine or iodine monochloride under mild condi-
tions, which generates the 1-alkylated isoquinolines in good to
excellent yields [36]. Wu and co-workers also reported
many other highly functionalized isoquinoline derivatives by
cascade reactions in good yields under mild conditions, such as
1-aminoisoquinolines [37] and 1-(isoquinolin-1-yl)ureas
[38,39]. Recently, Deng and co-workers also described a new
Pd-catalyzed C–H oxidation system for the regioselective alkyl-
ation of isoquinoline N-oxide and its derivatives with sulfox-
ides for the synthesis of 1-alkylated isoquinolines [40].
Scheme 1: Proposed route for the AgOTf-catalyzed one-pot reaction
of 2-alkynylbenzaldoxime with an α,β-unsaturated carbonyl compound.
We also reported the synthesis of 1-arylated 1,3-disubstituted
isoquinoline N-oxides in a one-pot reaction characterized by a
Ag-catalyzed intramolecular addition cyclization/Pd-catalyzed
direct arylation of 2-alkynylbenzaldoximes [41]. Inspired by the Results and Discussion
key contributions from the groups of Wu [36-39] and Deng Initially, a set of experiments was carried out with 2-alkynyl-
[40], we envisioned that 1-alkylated isoquinolines could be benzaldoxime 1a and methyl methacrylate (2a) as model
generated in a one-pot AgOTf-catalyzed cyclization/1,3-dipolar substrates in the presence of AgOTf (5 mol %). As expected,
cycloaddition/rearrangement or fragmentation from 2-alkynyl- the reaction proceeded smoothly in CH2Cl2 at room tempera-
benzaldoximes and α,β-unsaturated carbonyl compounds.
ture to afford the desired product 3a in 55% yield. We also
tested other solvents, such as 1,4-dioxane, NMP, DMSO, DMA,
Based on previous results [36-39,41-43], we expect 2-alkynyl- toluene and DMF (Scheme 2). The solvent screening demon-
benzaldoxime 1 to easily convert at room temperature to strated that DMF was the best choice for the reaction at 60 °C.
isoquinoline N-oxide A by a AgOTf-catalyzed cyclization. From these results, it was found that this one-pot process was
Compound A produced in situ might undergo a 1,3-dipolar highly efficient to construct 1-alkylated isoquinolines under
cycloaddition with α,β-unsaturated carbonyl compound 2 very mild conditions.
Scheme 2: Synthesis of 1-alkylated isoquinoline 3a by a AgOTf-catalyzed one-pot reaction in different solvents.
1950

Beilstein J. Org. Chem. 2013, 9, 1949–1956.
With the optimized conditions in hand, the scope of the unsaturated carbonyl compounds 2a–g (Table 1). In most cases,
procedure was investigated for the reaction of 2-(p- substrate 1b reacted with α,β-unsaturated carbonyl compounds
tolylethynyl)benzaldehyde oxime (1b) with a series of α,β- 2 leading to the corresponding 1-alkylated isoquinolines in
Table 1: AgOTf-catalyzed one-pot reactions of 2-(p-tolylethynyl)benzaldehyde oxime (1b) with α,β-unsaturated carbonyl compounds 2.
Entry
2
Product 3
Yielda (%)
1
70
2a
2b
2c
3b
3c
3d
3e
3f
2
3
4
5
6
81
50
61
98
2d
2e
2f
80
(1/6)b
3g
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Beilstein J. Org. Chem. 2013, 9, 1949–1956.
Table 1: AgOTf-catalyzed one-pot reactions of 2-(p-tolylethynyl)benzaldehyde oxime (1b) with α,β-unsaturated carbonyl compounds 2. (continued)
7
8
40
2g
2h
3h
–
3i
aIsolated yield based on 1b. bRatio of syn/anti, determined by 1H NMR.
moderate to excellent yields. For instance, the reaction with 2b tion (83% yield, Table 2, entry 3). The usage of 2-(cyclopropyl-
under standard conditions gave rise to the desired product 3c in ethynyl)benzaldehyde oxime (1f) in the reaction led to a similar
81% yield (Table 1, entry 2). An excellent yield was observed yield (80% yield, Table 2, entry 5). However, low yields were
when butyl acrylate (2e) was utilized in the reaction (98% yield, obtained when 2-(hex-1-yn-1-yl)benzaldehyde oxime (1g)
Table 1, entry 5). When tert-butyl acrylate (2f) was employed, reacted with methyl methacrylate (2a). In the case of substrate
the reaction led to the formation of the desired 1-alkylated 1h (R2 = SiMe3) only desilyl product 3p was observed in poor
product 3g (80% yield, Table 1, entry 6) with a molar ratio yield due to the instability of the product. When R2 was
of syn- and anti-isomers of ~1/6. It is noteworthy, that changed to H (2-ethynylbenzaldehyde oxime (1i), Table 2, entry
in other cases only a single product was observed. But-3-en-2- 8), there was no reaction at all. Good yields were obtained when
one (2g) was less reactive than the investigated acrylic acid 2-alkynylbenzaldoximes substituted with other electron-with-
esters and delivered the desired product only in moderate yield drawing groups (such as 1j and 1k) reacted with acrylate 2a
(40%, Table 1, entry 7). On the other hand, when substrate 1b (Table 2, entries 9–12). However, substrates with electron-
was treated with acrylonitrile 2h under such conditions, the donating groups attached on the aromatic ring of 2-alkynylbenz-
starting materials were recovered almost completely (Table 1, aldoxime (such as substrate 1l, Table 2, entry 13) did not afford
entry 8).
a desired product.
Next, we examined the effect of substituents at the 2-alkynyl- Recently, 1-alkenylated isoquinoline 4 was synthesized via a
benzaldoxime 1. In most cases, 2-alkynylbenzaldoxime 1 Pd-mediated C–H bond activation approach in a one-pot reac-
reacted with acrylates 2 leading to the desired products 3 in tion. The intermediate isoquinoline N-oxide A was produced in
moderate to good yields. For instance, reaction of 2-((4- situ from 2-alkynylbenzaldoximes and reacted with the α,β-
methoxyphenyl)ethynyl)benzaldehyde oxime (1c) with methyl unsaturated carbonyl compound 2e to yield 1-alkenylated
methacrylate (2a) under the conditions described above gave isoquinoline 4 (Scheme 3). This observation indicated that the
the desired product 3j in 75% yield (Table 2, entry 1). A better Palladium-catalyzed alkenylation reaction mechanism might be
yield was obtained when substrate 1e was employed in the reac- similar to that described by Cui and Wu [46].
Scheme 3: Pd-catalyzed one-pot alkenylation reaction of 2-alkynylbenzaldoxime 1a and butyl acrylate (2e).
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Beilstein J. Org. Chem. 2013, 9, 1949–1956.
Table 2: One-pot reactions of 2-alkynylbenzaldoximes 1 with acrylates 2.
Entry
2-Alkynylbenzaldoxime 1
2
Product 3
Yielda (%)
1
2a
75
3j
1c
2
2a
48
1d
3k
3
2a
83
1e
3l
70
(1/4)b
4
2f
1e
3m
5
6
2a
2a
80
35
1f
3n
3o
1g
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Beilstein J. Org. Chem. 2013, 9, 1949–1956.
Table 2: One-pot reactions of 2-alkynylbenzaldoximes 1 with acrylates 2. (continued)
7
8
2a
2a
12
1h
3p
–
1i
3p
3q
3r
9
2a
2e
2f
80
1j
1j
10
11
12
13
72
71
85
–
1j
3s
2a
2a
1k
3t
1l
3u
aIsolated yield based on 1b. bRatio of syn/anti, determined by 1H NMR.
Conclusion
pathway for the synthesis of 1-alkylated isoquinoline deriva-
In summary, we have demonstrated that one-pot reactions of tives in moderate to excellent yields with a wide range of
2-alkynylbenzaldoximes with α,β-unsaturated carbonyl com- substrates. The present one-pot catalyst system was also found
pounds catalyzed by AgOTf occur smoothly under mild condi- to be applicable to the synthesis of 1-alkenylated isoquinoline
tions. The present method provides a facile and efficient derivatives.
1954

Beilstein J. Org. Chem. 2013, 9, 1949–1956.
Experimental
General
Supporting Information
All reactions were performed in test tubes under a nitrogen
atmosphere. Flash column chromatography was performed with
silica gel (200–300 mesh). Analytical thin-layer chromatog-
raphy was performed on glass plates pre-coated with 0.25 mm
230–400 mesh silica gel and impregnated with a fluorescent
indicator (254 nm). Spots on thin-layer chromatography plates
were visualized by exposure to ultraviolet light. Organic solu-
tions were concentrated on rotary evaporators at 25–35 °C.
Commercial reagents and solvents were used as received. 1H
and 13C NMR spectra were recorded on a Bruker AV 400 spec-
trometer at 400 MHz (1H) and 100 MHz (13C) at ambient
temperature. Chemical shifts are reported in parts per million
(ppm) on the delta scale (δ) and referenced to tetramethylsilane
(0 ppm). HRMS analyses were performed in ESI mode on a
Bruker mass spectrometer.
Supporting Information File 1
Experimental part.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-231-S1.pdf]
Acknowledgements
Financial supported from the National Natural Science Founda-
tion of China (21002042), the Jiangxi Educational Committee
(GJJ12169), the Project of Jiangxi Youth Scientist
(20122BCB23012), and the Open Project Program of Key
Laboratory of Functional Small Organic Molecule, the Ministry
of Education, and the Jiangxi Normal University (No. KLFS-
KF-201204 and KLFS-KF-201217) is gratefully acknowledged.
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