Silver triflate-copper(ii) acetate cooperative catalysis in a cascade reaction for concise synthesis of 2-carbonyl H-pyrazolo[5,1-a]isoquinolines

Article abstract of DOI:10.1039/c2cc30413a

A cascade reaction of N′-(2-alkynylbenzylidene)hydrazide with allenoate in the presence of dioxygen co-catalyzed by silver triflate and copper(ii) acetate under mild conditions is described, which provides an efficient approach to 2-carbonyl H-pyrazolo[5,

Full text of DOI:10.1039/c2cc30413a

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COMMUNICATION
Silver triflate–copper(II) acetate cooperative catalysis in a
cascade reaction for concise synthesis of 2-carbonyl
H-pyrazolo[5,1-a]isoquinolinesw
Zhiyuan Chen,*a Liang Gao,a Shengqing Ye,b Qiuping Dinga and Jie Wu*b
Received 18th January 2012, Accepted 14th February 2012
DOI: 10.1039/c2cc30413a
A
cascade reaction of N0-(2-alkynylbenzylidene)hydrazide
that a peroxy–copper(III) intermediate could be introduced
into the cycloaddition adduct B (Scheme 1) as well. Compound B
would coordinate with a copper(II) catalyst, which then under-
goes a single-electron transfer from copper(II) to dioxygen to
produce the peroxy–copper(III) intermediate C. Formation of a
carbon–oxygen bond occurs via an isomerization of the resulting
peroxy–copper(III) intermediate C. Elimination of CuII–OH
generates a carbonyl compound E, which undergoes sponta-
neous aromatization to yield H-pyrazolo[5,1-a]isoquinoline 3. In
the reaction process, Ag(I)/Cu(II) cooperative catalysis9 would be
essential for the successful transformation. Herein, we describe
the results of the above investigation for the preparation of
2-carbonyl H-pyrazolo[5,1-a]isoquinolines, co-catalyzed by silver
triflate and copper(II) acetate in the presence of dioxygen.
with allenoate in the presence of dioxygen co-catalyzed by
silver triflate and copper(II) acetate under mild conditions is
described, which provides an efficient approach to 2-carbonyl
H-pyrazolo[5,1-a]isoquinolines.
The presence of the isoquinoline and pyrazolo[1,5-a]pyridine
scaffolds in many biologically active compounds has stimulated
the development of methods for their preparation.1,2 Recently,
H-pyrazolo[5,1-a]isoquinoline which incorporates both isoquino-
line and pyrazolo[1,5-a]pyridine skeletons was discovered to
display promising activities for inhibition of CDC25B, TC-PTP,
and PTP1B.3 With an expectation for the discovery of lead
compounds, methods development for the efficient synthesis of
diverse H-pyrazolo[5,1-a]isoquinolines is in great demand.
Conditions for the Ag(I)/Cu(II) co-catalyzed cascade reaction of
N0-(2-alkynylbenzylidene)hydrazide with allenoate in the presence
of dioxygen were explored using N0-(2-alkynylbenzylidene)hydra-
zide 1a and n-butyl buta-2,3-dienoate 2a as the model substrates
(Table 1). Since silver triflate was demonstrated as the choice for
the 6-endo-cyclization of N0-(2-alkynylbenzylidene)hydrazide in
dichloroethane (DCE), initially the reaction occurred in DCE/
DMF at room temperature in the presence of 10 mol% of silver
As a versatile building block, allene has been applied widely in
organic synthesis, and the chemistry of allene has been extensively
explored.4 Recently, we have been involved in the transformations
of N0-(2-alkynylbenzylidene)hydrazides.3,5 By considering the
features of our recent synthesis of H-pyrazolo[5,1-a]isoquinolines
and the advancement of allene chemistry, we envisaged that an
allenoate could take part in the reaction of N0-(2-alkynylbenzyli-
dene)hydrazide. After an electrophilic 6-endo-cyclization and the
subsequent [3+2] cycloaddition, an intermediate B would be
formed (Scheme 1). It is well known that the utilization of
molecular oxygen as an oxidant has attracted considerable
attention because of its ready availability and its inexpensive
and environmental benign character.6,7 Recently, Zhu and
co-workers reported an intramolecular dehydrogenative amino-
oxygenation reaction, resulting in the formation of aromatic
N-heterocycles substituted with a formyl group.8 It was found
that the carbonyl oxygen in the aldehyde products was from
dioxygen and the reaction proceeded through a peroxy–
copper(III) intermediate. Inspired by this result, we hypothesized
a Key Laboratory of Functional Small Organic Molecules, Ministry of
Education and College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang, Jiangxi 330022, China
b Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
w Electronic supplementary information (ESI) available. CCDC
868983. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc30413a
Scheme 1 Proposed synthetic route for the generation of 2-carbonyl
H-pyrazolo[5,1-a]isoquinolines in the presence of cooperative catalysis
under oxygen.
c
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Table 1 Initial studies for the reaction of N0-(2-alkynylbenzylidene)-
hydrazide 1a with n-butyl buta-2,3-dienoate 2a under dioxygen in the
presence of cooperative catalysis
Table 2 Reactions of N0-(2-alkynylbenzylidene)hydrazides 1 with
allenoate 2 in the presence of dioxygen co-catalyzed by silver triflate
and copper(II) acetate
Entry
1
Substrate 1
Allene 2
Yielda (%)
Entry [Cu] catalyst
Base
Solvent
Yielda (%)
1
2
3
—
Cu(OTf)2
CuCl2
—
—
—
—
—
—
Cs2CO3
K2CO3
Et3N
K3PO4
t-BuOK
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
DCE/DMF
nd
33
29
42
39
43
39
38
55
66
52
48
53
23
45
31
66 (3a)
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CuCO3ꢀCu(OH)2
Cu(NO3)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
2
3
1a
1a
45 (3b)
60 (3c)
t-BuONa DCE/DMF
NaOAc
K3PO4
K3PO4
K3PO4
K3PO4
DCE/DMF
DCE/THF
DCE/DMA
DCE/MeCN
4
5
2a
2c
53 (3d)
68 (3e)
1b
DCE/toluene 12
a
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1a.
6
7
2a
2c
55 (3f)
45 (3g)
triflate without the addition of copper(II) salt under dioxygen.
In addition, no base was presented at the outset since DMF
could act as a Lewis base in the reaction mixture. As predicted,
no desired product 3a was detected (Table 1, entry 1). Only a
trace amount of product was observed when the reaction was
performed under nitrogen (data not shown in Table 1). 2-Carbonyl
H-pyrazolo[5,1-a]isoquinoline 3a could be isolated in 33% yield
when 20 mol% of copper(II) triflate was added in the reaction
(Table 1, entry 2). The structural elucidation of compound 3a by
X-ray diffraction analysis is presented in Fig. 1 (see the ESIw).
Different copper(II) salts including CuCl2, CuCO3ꢀCu(OH)2,
Cu(NO3)2, and Cu(OAc)2 were screened (Table 1, entries 3–6). It
was found that the reaction worked efficiently when Cu(OAc)2 was
used as the co-catalyst, which afforded the corresponding product
in 43% yield (Table 1, entry 6). Next, various bases were added in
the reaction (Table 1, entries 7–13). From the results, K3PO4 was
the best choice, which led to the desired product in 66% yield
(Table 1, entry 10). In the meantime, the solvent effect was
investigated (Table 1, entries 14–17). However, no better results
were obtained. The reaction was retarded when the amount of
1c
1d
8
9
2a
2c
70 (3h)
63 (3i)
10
2c
71 (3j)
11
12
2a
2a
42 (3k)
58 (3l)
13
14
2a
2b
62 (3m)
42 (3n)
1h
15
2c
2a
63 (3o)
50 (3p)
16
Fig. 1 X-Ray ORTEP illustration of H-pyrazolo[5,1-a]isoquinoline
3a (30% probability ellipsoids).
a
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazides 1.
c
3976 Chem. Commun., 2012, 48, 3975–3977
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silver triflate or copper acetate was reduced. The result could
not be improved when the temperature was elevated.
We next explored the reaction scope under the optimized
conditions (10 mol% of silver triflate, 20 mol% of copper
acetate, DCE/DMF, rt). Table 2 shows the summary of results for
the evaluation of various substituted N0-(2-alkynylbenzylidene)-
hydrazides with allenoate under dioxygen. The presence of carbonyl
group adds flexibility to further elaborate the final products. Not
only aldehyde but also ketone could be formed, depending on the
allenoates utilized. For example, when methyl or phenyl-substituted
allenoate was employed in the reaction of N0-(2-alkynyl-
benzylidene)hydrazide 1a under the standard conditions, the
corresponding ketone was obtained as expected (Table 2,
entries 2 and 3). Moreover, incorporation of the alkyl
substituents into the triple bond does not hamper the efficiency
of the process. For instance, the reactions proceeded smoothly
when N0-(2-alkynylbenzylidene)hydrazide 1b or 1c was used in
the reactions of allenoate under dioxygen (Table 2, entries
4–7). The nature of the substituents on the aromatic ring of the
N0-(2-alkynylbenzylidene)hydrazides can include methyl, methoxy,
chloro, and fluoro groups. Furthermore, heteroaromatic-
substituted N0-(2-alkynylbenzylidene)hydrazide 1k also underwent
this transformation, leading to the desired product 3p in 50% yield
(Table 2, entry 16).
In summary, a cascade reaction of N0-(2-alkynylbenzylidene)-
hydrazide with allenoate in the presence of dioxygen co-catalyzed
by silver triflate and copper(II) acetate under mild conditions is
described, which provides an efficient approach to 2-carbonyl
H-pyrazolo[5,1-a]isoquinolines. The silver triflate–copper(II)
acetate cooperative catalysis is essential for the successful
transformation. A possible mechanism is illustrated, which
indicates that the reaction proceeds through a peroxy–
copper(III) intermediate. Activation of dioxygen by using the
strategy of cooperative catalysis in other transformations is in
progress in our laboratory, and the results will be reported in
due course.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3975–3977 3977