Efficient synthesis of isoquinoline derivatives via AgOTf/Cu(OTf) 2-cocatalyzed cyclization of 2-alkynyl benzaldoxime

Article abstract of DOI:10.1080/00397911.2012.666314

An efficient, AgOTf and Cu(OTf)₂ multicatalytic intramolecular cycloisomerization of 2-alkynylbenzaldoxime is reported. Isoquinoline N-oxides have been found to be deoxygenated to the corresponding quinolines in good yields in dimethylformamide/ dichloroethane (v/v 5:1) as solvent at 120 °C. Copyright Taylor & Francis Group, LLC.

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Efficient Synthesis of Isoquinoline
Derivatives via AgOTf/Cu(OTf)2-
Cocatalyzed Cyclization of 2-Alkynyl
Benzaldoxime
Xiaona Zhao a , Weidong Fan a , Zhiwei Miao a b & Ruyu Chen a
a State Key Laboratory of Elemento-organic Chemistry, Research
Institute of Elemento-organic Chemistry, Nankai University, Tianjin,
China
b Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Tsinghua University, Beijing, China
Accepted author version posted online: 08 Aug 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Xiaona Zhao , Weidong Fan , Zhiwei Miao & Ruyu Chen (2013): Efficient Synthesis
of Isoquinoline Derivatives via AgOTf/Cu(OTf)2-Cocatalyzed Cyclization of 2-Alkynyl Benzaldoxime,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:12, 1714-1720
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Synthetic Communications1, 43: 1714–1720, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.666314
EFFICIENT SYNTHESIS OF ISOQUINOLINE
DERIVATIVES VIA AgOTf/Cu(OTf)2-COCATALYZED
CYCLIZATION OF 2-ALKYNYL BENZALDOXIME
Xiaona Zhao,1 Weidong Fan,1 Zhiwei Miao,1,2 and Ruyu Chen1
1State Key Laboratory of Elemento-organic Chemistry, Research Institute of
Elemento-organic Chemistry, Nankai University, Tianjin, China
2Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education), Tsinghua University, Beijing, China
GRAPHICAL ABSTRACT
Abstract An efficient, AgOTf and Cu(OTf)2 multicatalytic intramolecular cycloisomeri-
zation of 2-alkynylbenzaldoxime is reported. Isoquinoline N-oxides have been found to be
deoxygenated to the corresponding quinolines in good yields in dimethylformamide/
dichloroethane (v/v 5:1) as solvent at 120 ꢀC.
Keywords Intramolecular cycloisomerization; isoquinoline; isoquinoline N-oxide;
multicatalytic deoxygenation
INTRODUCTION
Isoquinoline derivatives are an important class of heterocycles and are found in
many naturally occurring compounds that exhibit a variety of biological activities
such as antitumor, analgesic, antihistaminic, and antifertility activities.[1] Isoquinoline
species are not only key structural units in many natural products but are also known
as chiral ligands for transition-metal catalysts.[2] For these reasons, the efficient
synthesis of the isoquinoline ring system continues to attract the interest of synthetic
chemists.[3] A number of classical methods are available for the synthesis of isoquino-
line derivatives, including the Bischler–Napieralski,[4] the Pictet–Spengler,[5] and the
Pomeranz–Fritsch[6] reactions. However, these methods often suffer from tedious
reaction procedures and harsh reaction conditions.
Received September 27, 2011.
Address correspondence to Zhiwei Miao, State Key Laboratory of Elemento-organic Chemistry,
Research Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China. E-mail:
miaozhiwei@nankai.edu.cn
1714

INTRAMOLECULAR CYCLE ISOMERIZATION
1715
Over the past two decades, the transition-metal chemistry focusing on isoquino-
line synthesis has been developed. Zhu and coworkers developed a novel palladium-
catalyzed domino annulation process for the formation of biologically relevant
phenanthridines and isoquinolines.[7] Miura reported the rhodium-catalyzed oxidat-
ive coupling of aromatic imines with internal alkynes to produce indenone imine
and isoquinoline derivatives.[8] In particular, a very recent report by Wu and
coworkers has shown that silver triflate could catalyze a novel reaction of 2-alkynyl-
benzaldoxime with O-(trimethylsilyl)aryl triflate to produce the isoquinoline deriva-
tives of 2-oxa-6-aza-bicyclo[3.2.2]nona-6,8-diene.[9] Recent studies have shown that
silver species exhibited interesting catalytic activities functioning as a transition-metal
catalyst.[10] In 2009, Liang and coworkers have demonstrated that Agþ-catalyzed
cyclization of 2-alkynyl benzyl azides can produce 3-substituted or 1,3-disubstituted
isoquinolines.[11]
Oximes often function as stable precursors of amino compounds through the
reductive cleavage of the N-O bond.[12] A variety of redox processes of the cleavage
N-O bond induce the conversions of oximes into amides,[13] nitriles,[14] and enam-
ides.[15] Recently, 2-alkynylbenzaldoximes have been reported as a versatile building
block for the synthesis of nitrogen-containing heterocycles.[16] Wu and others discov-
ered that in the presence of Lewis acids, 2-alkynylbenzaldoxime could be transferred
to isoquinoline-N-oxide.[17] As part of a continuing effort in our laboratory to
synthesize biologically relevant heterocyclic compounds,[18] we report that ortho-
alkynylaryl aldehyde oxime derivatives catalyzed by transition-metal complexes
would afford an intermediate isoquinolinium salt and subsequently transfer into
isoquinoline derivatives.
RESULTS AND DISCUSSION
The required 2-alkynylbenzaldoximes 1 were prepared by the condensation of
hydroxylamine with the corresponding aldehydes.[19] When 1a was heated with
AgOTf (10 mol%) in CH2Cl2 at room temperature, the corresponding cyclized pro-
duct 2a was obtained in 94% isolated yield after 3 h. The reaction proceeds through
6-endo-dig addition of the oxime N-atom on Agþ-activated alkyne to afford isoqui-
nolinium salt 2a. The deoxygenation of amine-N-oxide to amines has been developed
in the synthesis of heterocycles in many procedures.[20] We studied various catalysts
for the deoxygenation of amine-N-oxide reaction using 2a as substrate. The results
revealed that there was no product formed without the aid of a Lewis acid (entry
1, Table 1). When 2a was reacted with AgOTf (10 mol%) in dimethylformamide
(DMF) at 120 ꢀC, isoquinoline 3a was obtained in 38% isolated yield after 48 h (entry
2, Table 1). Other silver salts screened (e.g., AgSbF6, Ag2O, and AgClO4) were also
able to promote the deoxygenation reaction in dimethylformamide (DMF) (entries
3–5, Table 1). The use of Cu(OTf)2 cocatalyst (10 mol%) along with AgOTf
(10 mol%) further boosted the reactivity, giving 3a in 82% yield in 24 h. Use of
Cu(OTf)2 in less than 5 mol% led to a poor yield, due to the decomposition. Change
of cocatalyst to Zn(OTf)2 also led to a lower yield of 3a (entries 6–8, Table 1).
With the best multicatalytic system [AgOTf=Cu(OTf)2] being identified, we
next carried out the reaction in different solvents. Among the solvents screened, tolu-
ene and MeCN were providing 3a in lower yields, while more polar solvent mixtures

1716
X. ZHAO ET AL.
Table 1. Screening of the reactions of (E)-2-(2-phenylethynyl)benzaldehyde oxime 1a under different con-
ditionsa
Entrya
Catalyst (equiv.)
—
Solvent
DMF
DMF
Time (h)
Yield (3a)e
1
2
24
48
48
36
36
24
24
24
24
36
24
24
24
—
38
42
41
48
82
69
62
44
32
82
85
90
AgOTf (0.1)
AgSbF6 (0.1)
3
DMF
DMF
4
Ag2O (0.1)
AgClO4 (0.1)
5
DMF
DMF
6
AgOTf (0.1) = Cu(OTf)2 (0.1)
AgOTf (0.1) = Cu(OTf)2 (0.05)
AgOTf (0.1) = Zn(OTf)2 (0.1)
AgOTf (0.1) = Cu(OTf)2 (0.1)
AgOTf (0.1) = Cu(OTf)2 (0.1)
AgOTf (0.1) = Cu(OTf)2 (0.1)
AgOTf (0.1) = Cu(OTf)2 (0.1)
AgOTf (0.1) = Cu(OTf)2 (0.1)
7
DMF
DMF
8
9
Toluene
MeCN
10
11b
12c
13d
DMF=DCE
DMF=DCE
DMF=DCE
aUnless otherwise noted all the reactions were performed with 0.5 mmol of 2a and 10 mol% catalyst in
5 ml solvent at 120 ꢀC.
bDMF=DCE (v=v ¼ 1:1).
cDMF=DCE (v=v ¼ 1:3).
dDMF=DCE (v=v ¼ 1:5).
eIsolated yields.
[DMF=dichloroethane (DCE)] with diffenent ratios displayed steady and the
greatest conversion (entries 9–13, Table 1). Therefore, the tentatively optimized reac-
tion conditions were determined as DMF=DCE (v=v ¼ 5:1) as the solvent in further
investigations.
Under these optimum conditions, we next examine the generality of the reaction
in the synthesis of various isoquinoline skeletons (Table 2). It was found that all the
reactions of substrates bearing no further substituent at the benzylic position
(R1 ¼ H) went to completion in the presence of catalytic amounts of AgOTf=
Cu(OTf)2 in DMF=DCE (v=v ¼ 5:1) at 120 ꢀC within 24 h and the desired products
3 were obtained in good to excellent yields. When R2 was replaced by 4-methylphenyl
or 4-fluorophenyl, the reaction was still going very well and the desired products were
isolated (3a–g, Table 2). The results indicated that the electron-donating or
electron-withdrawing group attached on the aromatic ring of isoquinolinium salt 2
was not influencing this deoxygenation reaction. When R2 was replaced by an alkyl
group, the reaction was performed smoothly but with lower yields (3d–g, Table 2).
We also explored ketoxime derivatives and the reactions of ketoximes occurred with
lower yields than those of aldoximes (3h–k, Table 2).
A plausible mechanism for the reductive N-O bond cleavage of amine-N-oxide
is outlined in Scheme 1. In the first step, the reaction was assumed to proceed by the

INTRAMOLECULAR CYCLE ISOMERIZATION
1717
Table 2. AgOTf=Cu(OTf)2-catalyzed reactions of isoquinoline-N-oxides 2
Producta
R1
R2
C6H5
Yield (%)b
3a
3b
3c
3d
3e
3f
H
90
83
70
76
75
68
80
78
73
68
64
H
4-MeC6H4
4-FC6H4
n-Pr
H
H
H
n-Bu
t-Bu
H
3g
3h
3i
H
Cyclopropyl
C6H5
CH3
CH3
CH3
CH3
4-MeC6H4
4-FC6H4
n-Bu
3j
3k
aUnless otherwise noted all the reactions were performed with 0.5 mmol of 2 and 10 mol%
AgOTf along with 10 mol% Cu(OTf)2 in 2 ml DMF and DCE (v=v ¼ 5:1) at 120 ꢀC for 24 h.
bIsolated yields.
Scheme 1. Plausible reaction mechanism.

1718
X. ZHAO ET AL.
DMF coordinate to M(OTf)x (M ¼ Ag or Cu, x ¼ 1 or 2) to give complex 4. Then,
isoquinoline-N-oxide 2 attacked the carbonyl group of complex 4 and removed the
M(OTf)x to get a intermediate 5. In a subsequent step, removal of CO2 and HNMe2
and cleavage of the N-O bond led to the formation of the corresponding amine 3a.
The notable advantages of the present procedure are the ease of manipulation, the
good yields, the mild reaction conditions, and the tolerance of the reaction substrates.
EXPERIMENTAL
All reactions were carried out under an inert atmosphere and in heat-dried glass-
ware. Column chromatography was performed on silica gel (particle size 10–40 mm,
1
Ocean Chemical Factory of Qingdao, Qingdao, China). H and 13C NMR spectra
1
were recorded on Brucker 400 (400 MHz for H, 162 MHz for 13C) and Brucker
300 (300 MHz for 1H, 75 MHz for 13C) spectrometers. Chemical shifts were reported
in parts per million (ppm) downfield from internal tetramethylsilane (TMS). Mass
spectra were recorded on a LCQ advantage spectrometer with electrospray ionization
(ESI) resource. HR-MS were recorded on APEXII and ZAB-HS spectrometers.
General Procedure for Preparation of 2-Alkynylbenzaldoxime 1
A solution of 2-alkynylbenzaldehyde (3.0 mmol), hydroxylamine hydrochloride
(6 mmol, 2.0 equiv), and pyridine (6.0 mmol, 2.0 equiv) in C2H5OH (15 mL) was stirred
under reflux for 2 h. After completion of the reaction as indicated by thin-layer chro-
matography (TLC), the solvent was evaporated, and the reaction was quenched with
water (10 mL), extracted with AcOEt (2 ꢁ 30 mL), and dried by anhydrate Na2SO4.
Evaporation of the solvent followed by purification on silica gel [AcOEt=petroleum
ether (bp 60–90 ꢀC) 1:3] provided the corresponding 2-alkynylbenzaldoxime 1.
General Procedure for the Synthesis of Isoquinoline-N-oxide 2
AgOTf (7 mg, 10 mmol%) was added to a solution of oxime 1 (0.27 mmol) in
CH2Cl2 (2 mL), and the mixture was stirred at rt for 30 min. The solvent was
removed, and the residue was purified by silica-gel chromatography (CH2Cl2=
MeOH, 10:1) to give product 2 as a white solid.
General Procedure for the Synthesis of Isoquinoline 3
Isoquinoline-N-oxide 2 (0.5 mmol) in DMF=DCE (v=v ¼ 5:1) was stirred at
room temperature for 10 min. AgOTf (13 mg, 10 mol%) and Cu(OTf)2 (18 mg,
10 mol%) were added to the mixture subsequently, and the mixture was kept stirring
for 24 h [TLC (silica gel) monitoring] at 120 ꢀC. The resulting mixture was filtered
through a silica-gel column and concentrated. The residue was purified by flash
column chormatography [silica gel, AcOEt=petroleum ether (bp 60–90 ꢀC) 1:20] to
afford the product 3.
CONCLUSION
In conclusion, we have described an efficient method for the synthesis of
isoquinoline derivatives via multicatalytic deoxygenation of amine-N-oxides to the

INTRAMOLECULAR CYCLE ISOMERIZATION
1719
corresponding amines. The feature of this procedure is its simplicity, mild reaction
conditions, and its generality with regard to aromatic substrates. Further studies
to elucidate the mechanism of this novel reaction and to extend the scope of its
synthetic utility are in progress in our laboratory.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (21072102), the
Committee of Science and Technology of Tianjin (11JCYBJC04200), and State
Key Laboratory of Elemento-organic Chemistry in Nankai University for financial
support.
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