Synthesis of H-pyrazolo[5,1-a]isoquinolines via copper(II)-catalyzed oxidation of an aliphatic C-H bond of tertiary amine in air

Article abstract of DOI:10.1021/ol102939r

A multicomponent reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and tertiary amine is discovered, which generates the unexpected H-pyrazolo[5,1-a]isoquinolines in good yields under mild conditions. In the reaction process, silver(I)-catalyzed intramolecular cyclization and copper(II)-catalyzed oxidation of an aliphatic C-H bond of tertiary amine in air are involved.

Full text of DOI:10.1021/ol102939r

ORGANIC
LETTERS
2011
Vol. 13, No. 4
712–715
Synthesis of H-Pyrazolo[5,1-a]isoquinolines
via Copper(II)-Catalyzed Oxidation
of an Aliphatic C-H Bond of
Tertiary Amine in Air
Shaoyu Li† and Jie Wu*,†,‡
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China
jie_wu@fudan.edu.cn
Received December 5, 2010
ABSTRACT
A multicomponent reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and tertiary amine is discovered, which generates the unexpected H-
pyrazolo[5,1-a]isoquinolines in good yields under mild conditions. In the reaction process, silver(I)-catalyzed intramolecular cyclization and
copper(II)-catalyzed oxidation of an aliphatic C-H bond of tertiary amine in air are involved.
Recently, studies of copper-dioxygen interactions mi-
micked for the biological pathway involving the activation
of dioxygen by copper enzymes have been explored.1 Many
applications of dioxygen-copper systems in organic synthe-
sis have been discovered, and most of them focus on the
oxidation reactions of aliphatic C-H bonds.2-4 For in-
stance, Loh and co-workers reported the synthesis of
R-amino acetals via a rearrangement of tertiary amine
through the oxidation of an aliphatic C-H bond with a
dioxygen-copper catalytic system.4n Shi described the
† Fudan University.
‡ Chinese Academy of Sciences.
(1) (a) Aboelella, N. W.; Gherman, B. F.; Hill, L. M. R.; York, J. T.;
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Soc. 2006, 128, 3445. (b) Mahadevan, V.; Hou, Z. G.; Cole, A. P.; Root, D. E.;
Lal, T. K.; Solomon, E. I.; Stack, T. D. P. J. Am. Chem. Soc. 1997, 119,
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r
10.1021/ol102939r
Published on Web 01/06/2011
2011 American Chemical Society

pyrroles formation via dehygronative deamination process.2e
Compared with the commonly used methods which em-
ployed expensive metal catalysts and stoichiometric metal
oxidants,3 dioxygen-copper systems are more attractive
for C-H bond activation.4 Herein, we report an interesting
and unprecedented result for a three-component reaction of
2-alkynylbenzaldehyde, sulfonohydrazide, and tertiary
amine, which generates H-pyrazolo[5,1-a]isoquinolines in
good yields. In the reaction process, the tertiary amine is
activated via oxidation of an aliphatic C-H bond catalyzed
by a dioxygen-copper system.
The development of new strategies with a high efficiency
has been an important goal as well as a great challenge in
synthetic chemistry.5 The multicomponent reaction is an
attractive device since it can serve as a powerful tool for the
assembly of complex structures.6 Currently, much atten-
tion has been paid to this exciting research area, especially
for construction of natural product-like compounds. It is
well recognized that the isoquinoline nucleus is one of the
most abundant structural motifs found in natural products
and biologically active molecules.7 Additionally, many com-
pounds possessing this subunit exhibit a broad range of
pharmacological activity, including antifungal, antimalarial,
antihypertensive, antitumor, and antihistaminic activity.8-11
For instance, the opium alkaloid papaverine is discovered to
be useful as a vasodilator.10 Decumbenine B is efficient for
inhibition of spontaneous contraction of the intestine.11
Therefore, extensive studies have been performed toward
the design and synthesis of this ring system.12,13 For example,
Larock, Takemoto, and Yamamoto reported isoquinoline
generation via transition-metal catalyzed cyclization of
ortho-alkynylaryl aldimines, respectively.13 We also devel-
oped methods for formation of diverse isoquinolines starting
from 2-alkynylbenzaldehyde and related compounds.14
Among the compounds synthesized, it was found that H-
pyrazolo[5,1-a]isoquinoline was effective for inhibition
of PTP1B (protein tyrosine phosphatase 1 B, IC50 1.75
μg/mL).14a With an expectation to find better hits, it is highly
desirable to generate functionalized fused isoquniolines using
diversity-oriented synthesis.
In our previous reports,14,15 we demonstrated that N0-(2-
alkynylbenzylidene)hydrazide was the key species in tan-
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713

Table 1. Initial Studies for the Reaction of N0-(2-Alkynylbenzy-
lidene)hydrazide A1 with N,N-Diisopropylethylamine 2a
Scheme 1. Initial Studies for the Reaction of N0-(2-
Alkynylbenzylidene)hydrazide A1 with 4-Nitrophenylaldimine
in the Presence of N,N-Diisopropylethylamine (DIPEA)
metal
time
(h)
yield
(%)a
entry
catalyst
solvent
DCE
successfully employed as partners in the reaction of N0-(2-
alkynylbenzylidene)hydrazide, since 1,3-dipolar cycloaddi-
tion of ylidic species is a powerful method for the construc-
tion of complex N-heterocycles.16 As mentioned above, we
would like to develop efficient methods to produce novel
structures of isoquniolines. Initially, we conceived that
imine might be a good substrate as well in the reaction of
N0-(2-alkynylbenzylidene)hydrazide. Thus, 4-nitropheny-
laldimine was treated with N0-(2-alkynylbenzylidene)hy-
drazide A1 in the presence of silver(I) triflate (10 mol %)
and N,N-diisopropylethylamine (DIPEA) in dichloro-
ethane (DCE) at room temperature (Scheme 1). To our
surprise, we found that 4-nitrophenylaldimine was not
involved in the reaction. An unexpected product was
isolated in low yield (8%), which was identified as com-
1
-
-
15
24
10
40
45
24
24
10
10
30
30
30
4
8
NR
75
65
50
63
62
69
54
12
13
12
65
78
60
73
77
50
76
2b
3
DCE
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
FeCl3
DCE
4
EtOH
toluene
DCM
1,4-dioxane
MeCN
DMF
DCE
5
6
7
8
9
10
11
12
13
14
15
16c
17d
18e
19
BiCl3
DCE
ZnCl2
Cu(OTf)2
CuCl2
Cu(OAc)2
CuBr
DCE
DCE
DCE
2
DCE
14
4
DCE
CuCl2
CuCl2
CuCl2
DCE
2
1
pound 3a. The structure was confirmed by H and 13C
DCE
48
48
DCE
NMR, mass spectrum, and X-ray diffraction analysis (see
the Supporting Information).
a Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide A1. b The
reaction occurred under argon or nitrogen atmosphere. c In the presence of
AgOTf (5 mol %) and CuCl2 (5 mol %). d In the presence of AgOTf
(10 mol %) and CuCl2 (2 mol %). e In the presence of AgOTf (10 mol %)
and CuCl2 (20 mol %).
With this unexpected result in hand, we recognized that
N,N-diisopropylethylamine might be the reactant in this
transformation. Therefore, we commenced to optimize the
reaction conditions (Table 1). We found that the reaction
occurred under an air atmosphere and no reaction took
place under an argon or a nitrogen atmosphere (Table 1,
entry 2). From this result, it seemed that oxygen was
indispensable which played the key role in the process.
Thus, we considered that the reaction route might proceed
through the oxidation of an aliphatic C-H bond of N,N-
diisopropylethylamine. As mentioned above, dioxygen-
copper systems have been demonstrated efficiently for
C-H bond activation.4 Thus, copper(II) bromide was
added to the reaction system. To our delight, the desired
product 3a was isolated with 75% yield when 10 mol % of
CuBr2 was utilized (Table 1, entry 3). Further screening of
solvents demonstrated that DCE was the best choice for
this transformation and reactions performed in other
solvents led to inferior yields (Table 1, entries 4-9).
Different metal salts were examined as a catalyst subse-
quently. It was found that copper salts were superior to
other metal reagents. The reaction time was shortened to
2 h with a 78% yield when copper chloride was utilized as a
catalyst in the reaction (Table 1, entry 14). The amount of
catalyst was examined as well. A similar result was observed
when the amounts of CuCl2 and AgOTf were all lowered to
5 mol % (77% yield, Table 1, entry 17). However, no better
yield was obtained when the catalytic amount of CuCl2
was changed to 2 mol % or 20 mol % (Table 1, entries 18
and 19). Since selectivity has been attributed to both steric
and kinetic acidity effects on the deprotonation step as
mentioned by Lewis,17 it is reasonable that the ethyl group
in the diisopropylethylamine selectively incorporated into
the final product rather than the isopropyl group in this
transformation.
Since (2-alkynylbenzylidene)hydrazide A could be traced
back to 2-alkynylbenzaldehyde 1 with sulfonohydrazide,
thus under the optimized reaction conditions (AgOTf
5 mol %, CuCl2 5 mol %, DCE, air), we next explored
the three-component reaction of 2-alkynylbenzaldehyde 1,
sulfonohydrazide, and tertiary amine 2. The results are
summarized in Table 2. It was found that most of the
reactions provided good yields under the standard condi-
tions. For example, the reaction of 2-alkynylbenzaldehyde
1a, 4-methylbenzenesulfono-hydrazide, and triethylamine
2b gave rise to the corresponding product 3a in 71% yield
(Table 2, entry 2). A similar result was obtained when tri(n-
propyl)amine 2c or tri(n-butyl)amine 2d was employed in
the above reaction (Table 2, entries 3 and 4). The reaction
(16) For recent reviews on the [3þ2] cycloaddition reaction, see: (a)
Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. (b) Najera, C.;
Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44, 6272. (c) Najera, C.;
Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105.
(17) Lewis, F. D.; Ho, T.-I. J. Am. Chem. Soc. 1980, 102, 1751.
Org. Lett., Vol. 13, No. 4, 2011
714

Table 2. Three-Component Reaction of 2-Alkynylbenzalde-
hyde 1, Sulfonohydrazide, and Tertiary Amine 2
Scheme 2. Proposed Synthetic Route for the Reaction of 2-
Alkynylbenzaldehyde 1, Sulfonohydrazide, and Tertiary Amine 2
T
time
(h)
yield
(%)a
entry
R1, R2
R3, R4
(°C)
1
2
3
4
5
H, C6H5 (1a)
H, C6H5 (1a)
H, C6H5 (1a)
H, C6H5 (1a)
H, cyclopropyl
(1b)
H, iPr (2a)
H, Et (2b)
Me, nPr (2c)
Et, nBu (2d)
Et, nBu (2d)
30
30
30
30
30
2
2
2
2
4
77 (3a)
71 (3a)
75 (3b)
78 (3c)
98 (3d)
6
7
8
9
H, nBu (1c)
5-Cl, C6H5 (1d)
5-Cl, C6H5 (1d)
5-Cl, cyclopropyl
(1e)
Et, nBu (2d)
H, iPr (2a)
Et, nBu (2d)
H, iPr (2a)
30
30
30
30
5
3
4
5
84 (3e)
77 (3f)
92 (3g)
99 (3h)
10
5-Cl, cyclopropyl
(1e)
Et, nBu (2d)
30
4
98 (3i)
tri(n-butyl)amine 2d was utilized as a replacement in the reac-
tion (Table 2, entry 22). The reaction of 4-methylbenzene-
sulfonohydrazide, tri(n-butyl)amine 2d, and 2-alkynylbenzal-
dehyde 1n or 1o was examined meanwhile. As expected, the
reactions worked well to afford the desired product in good
yields (Table 2, entries 23 and 24). Prompted by the advance-
ment of an oxygen-copper catalytic system applied in the
oxidation of aliphatic C-H bonds,4 we reasoned that, in the
presence of a copper catalyst in air, the tertiary amine 2would
be transferred to an enamine C through oxidation of an
aliphatic C-H bond. Meanwhile, isoquinolinium-2-ylamide
D would be formed via silver-catalyzed cyclization of N0-(2-
alkynylbenzylidene)hydrazide A. Therefore, the intermolecu-
lar nucleophilic attack would occur to generate the inter-
mediate E, which then underwent tosyl group release and
subsequent aromatization to afford the H-pyrazolo[5,1-a]-
isoquinoline 3 (Scheme 2).
11
12
13
14
15
5-Cl, nBu (1f)
5-Cl, nBu (1f)
4-F, C6H5 (1g)
4-F, C6H5 (1g)
4-F, cyclopropyl
(1h)
4-F, nBu (1i)
5-Me, C6H5 (1j)
5-Me, C6H5 (1j)
5-Me, cyclopropyl Et, nBu (2d)
(1k)
5-Me, nBu (1l)
4,5-(OMe)2,
C6H5 (1m)
H, iPr (2a)
Et, nBu (2d)
H, iPr (2a)
Et, nBu (2d)
Et, nBu (2d)
30
30
30
30
30
6
6
5
5
5
95 (3j)
96 (3k)
60 (3l)
72 (3m)
86 (3n)
16
17
18
19
Et, nBu (2d)
H, iPr (2a)
Et, nBu (2d)
30
30
30
50
5
8
87 (3o)
56 (3p)
64 (3q)
78 (3r)
8
12
20
21
Et, nBu (2d)
H, iPr (2a)
50
60
18
12
75 (3s)
38 (3t)
22
4,5-(OMe)2,
C6H5 (1m)
Et, nBu (2d)
60
40
trace
23
24
H, p-ClC6H4 (1n)
H, p-MeC6H4 (1o) Et, nBu (2d)
Et, nBu (2d)
30
30
5
5
63 (3u)
67 (3v)
In conclusion, we have described an unprecedented silver
and copper cocatalyzed three-component reaction of 2-
alkynylbenzaldehyde, sulfonohydrazide, and tertiary amine,
which provides a novel and efficient route for the genera-
tion of H-pyrazolo[5,1-a]isoquinolines. In this reaction
process, the tertiary amine is activated via oxidation of
an aliphatic C-H bond catalyzed by a dioxygen-copper
system. Application of rearrangement of tertiary amine in
other transformations is under investigation, and the results
will be reported in due course.
a Isolated yield based on 2-alkynylbenzaldehyde 1.
proceeded smoothly when 2- alkynylbenzaldehyde 1b or 1c
was used in the reaction of 4-methylbenzene-sulfonohydra-
zide with tri(n-butyl)amine 2d (Table 2, entries 5 and 6). 5-
Chloro- or 4-fluoro substituted 2-alkynylbenzaldehydes 1d-
1i were suitable substrates as well in this three-component
reaction. For instance, an almost quantitative yield was
generated for the reaction of 2-alkynylbenzaldehyde 1e,
4-methylbenzenesulfonohydrazide, and N,N-diisopropyl-
ethylamine 2a (Table 2, entry 9). The structure of compound
3g was confirmed by X-ray diffraction analysis meanwhile
(see the Supporting Information). However, inferior results
were observed for the 2-alkynylbenzaldehydes with electron-
donating group R1 attached on the aromatic ring. The reac-
tion of 4,5-dimethoxy 2-alkynylbenzaldehyde 1m, 4-methyl-
benzenesulfonohydrazide, and N,N-diisopropylethylamine
2a led to the desired product 3t in 38% yield (Table 2, entry
21). Only a trace amount of product was detected when
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20972030) is grate-
fully acknowledged.
Supporting Information Available. Experimental pro-
cedures, characterization data, 1H and 13C NMR spectra
of compounds 3, X-ray crystal data of compounds 3a and
3g. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
715