Three-component reaction of N ′-(2-alkynylbenzylidene)hydrazide, alkyne, with sulfonyl azide via a multicatalytic process: A novel and concise approach to 2-amino-H-pyrazolo[5,1-a]isoquinolines

Article abstract of DOI:10.1021/ol201653j

A novel and efficient route for the synthesis of 2-amino-H-pyrazolo[5,1-a] isoquinolines via a three-component reaction of N′-(2-alkynylbenzylidene) hydrazide, alkyne, and sulfonyl azide is described. This transformation, co-catalyzed by silver triflate a

Full text of DOI:10.1021/ol201653j

ORGANIC
LETTERS
Three-Component Reaction of N0-(2-
Alkynylbenzylidene)hydrazide, Alkyne,
with Sulfonyl Azide via a Multicatalytic
Process: A Novel and Concise Approach
to 2-Amino-H-pyrazolo[5,1-a]-
2011
Vol. 13, No. 16
4312–4315
isoquinolines
Shaoyu Li,† Yong Luo,† 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 June 20, 2011
ABSTRACT
A novel and efficient route for the synthesis of 2-amino-H-pyrazolo[5,1-a]isoquinolines via a three-component reaction of N0-(2-
alkynylbenzylidene)hydrazide, alkyne, and sulfonyl azide is described. This transformation, co-catalyzed by silver triflate and copper(I)
bromide under mild conditions, proceeds efficiently to generate the 2-amino-H-pyrazolo[5,1-a]isoquinolines in good to excellent yields.
Libraries of small molecules are used in drug discovery
programs to search for lead structures active in biological
assays. Thus, the pursuit of practical and efficient ap-
proaches for rapid generation of natural product-like
compounds is of utmost urgency and importance.1 Re-
cently, we have successfully prepared a small library of H-
pyrazolo[5,1-a]isoquinolines2 via tandem reactions.3 Some
ofthese compounds showedpromisinginhibitoryactivities
versus targets such as CDC25B, TC-PTP, or PTP1B in
preliminary biological assays.2d Consequently, synthetic
methodology development for functionalized H-pyrazolo-
[5,1-a]isoquinolines is highly desirable to obtain additional
compounds for biological evaluation.
Ketenimine chemistry which involves a copper(I)-cata-
lyzed azideꢀalkyne cycloaddition4ꢀ6 has been used as an
efficient approach for the generation of various hetero-
cycles. Recently, N0-(2-alkynylbenzylidene)hydrazide has
been employed as a versatile substrate for reaction
development.2 Prompted by the achievement of keteni-
mine chemistry, we envisioned that N0-(2-alkynyl-
benzylidene)hydrazide might be utilized in the azideꢀ
alkyne cycloaddition process. We envisioned a three-com-
ponent reaction of N0-(2-alkynylbenzylidene)hydrazide,
alkyne, and sulfonyl azide, as proposed in Scheme 1.
Since a copper(I) catalyst is essential for the generation
of a ketenimine intermediate and silver triflate has been
† Fudan University.
‡ Shanghai Institute of Organic Chemistry.
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Arya, P.; Chou, D. T. H.; Baek, M.-G. Angew. Chem., Int. Ed. 2001, 40,
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J. Tetrahedron 2011, 67, 1145. (c) Chen, Z.; Pan, X.; Wu, J. Synlett 2011,
964. (d) Chen, Z.; Wu, J. Org. Lett. 2010, 12, 4856. (e) Ye, S.; Yang, X.;
Wu, J. Chem. Commun. 2010, 46, 5238. (f) Yu, X.; Ye, S.; Wu, J. Adv.
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Comb. Chem. 2010, 12, 374. (h) Ren, H.; Ye, S.; Liu, F.; Wu, J.
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r
10.1021/ol201653j
Published on Web 07/26/2011
2011 American Chemical Society

demonstrated to be the most effective catalyst for the
cyclization of N0-(2-alkynylbenzylidene)hydrazide,2 a mul-
ticatalytic process is proposed. It is well-documented that
multicatalytic processes7,8 can be highly efficient in tandem
reactions. For example, a one-pot Beckmann rearrange-
ment/intramolecular cyclization/halogenation reaction of
1-(2-alkynylphenyl)ketoxime cocatalyzed by indium(III)
and palladium(II) salts was developed to give the indole
derivatives in good yields.8d As shown in Scheme 1, the
presence of silver would promote the 6-endo-cyclization of
N0-(2-alkynylbenzylidene)hydrazide 1 to form isoquinoli-
nium-2-yl amide c. Ketenimine b would be formed via a
Scheme 1. Proposed Route for a Three-Component Reaction of
N0-(2-Alkynylbenzylidene)hydrazide 1, Alkyne 2, and Sulfonyl
Azide 3
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copper(I)-catalyzed azideꢀalkyne cycloaddition. Subse-
quently, intermolecular [3 þ 2] cycloaddition would afford
compound d, which would then undergo aromatization
to furnish 2-amino-H-pyrazolo[5,1-a]isoquinoline 4. This
strategy rapidly introduces molecular complexity and
diversity.
€
Table 1. Initial Studies for Silver(I) and Copper(I) Co-Catalyzed
Three-Component Reaction of N0-(2-Alkynylbenzylidene)-
hydrazide 1a, Phenylacetylene 2a, with 4-Methylbenzenesulfo-
nyl azide 3a
(6) (a) Shen, Y.; Cui, S.; Wang, J.; Chen, X.; Lu, P.; Wang, Y.-G. Adv.
Synth. Catal. 2010, 352, 1139. (b) Yao, W.; Pan, L.; Zhang, Y.; Wang,
G.; Wang, X.; Ma., C. Angew. Chem., Int. Ed. 2010, 49, 9210. (c) Shang,
Y.; Ju, K.; He, X.; Hu, J.; Yu, S.; Zhang, M.; Liao, K.; Wang, L.; Zhang,
P. J. Org. Chem. 2010, 75, 5743. (d) Cano, I.; Alvarez, E.; Nicasio, M. C.;
ꢀ
Perez, P. J. J. Am. Chem. Soc. 2011, 133, 191. (e) Husmann, R.; Na, Y. S.;
Bolm, C.; Chang, S. Chem. Commun. 2010, 46, 5494. (f) Jin, H.; Xu, X.;
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entry
[Cu]
solvent
base
Et3N
yielda (%)
1
2
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuBr (10 mol %)
CuCl (10 mol %)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
complex
complex
complex
trace
34
pyridine
Cs2CO3
K2CO3
K3PO4
3
4
5
6
ClCH2CH2Cl K3PO4
33
7
THF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
28
8
n-hexane
cyclohexane
MeCN
nr
9
20
10
11
12
13
14
15
16b
17
18c
25
toluene
DMF
51
complex
67
toluene
toluene
52
CuOTf (10 mol %) toluene
toluene
65
CuBr (5 mol %)
CuBr (5 mol %)
toluene
toluene
59
57
(8) For recent selected examples, see: (a) Cernak, T. A.; Lambert,
T. H. J. Am. Chem. Soc. 2009, 131, 3124 and references cited therein.
(b) Kelly, B. D.; Allen, J. M.; Tundel, R. E.; Lambert, T. H. Org. Lett.
2009, 11, 1381. (c) Lu, L.-Q.; Cao, Y.-J.; Liu, X.-P.; An, J.; Yao, C.-J.;
Ming, Z.-H.; Xiao, W.-J. J. Am. Chem. Soc. 2008, 130, 6946. (d) Qiu, G.;
Ding, Q.; Ren, H.; Peng, Y.; Wu, J. Org. Lett. 2010, 12, 3975. (e) Chen,
Z.; Yu, X.; Su, M.; Yang, X.; Wu, J. Adv. Synth. Catal. 2009, 351, 2702.
a Isolated yield based on N’-(2-alkynylbenzylidene)hydrazide 1a.
b Only isoquinolinium-2-yl amide was obtained. c The reaction was
performed at 50 °C.
Org. Lett., Vol. 13, No. 16, 2011
4313

The initial studies were performed for the reaction of
N0-(2-alkynylbenzylidene)hydrazide 1a, phenyl acetylene
2a, and sulfonyl azide 3a in the presence of 10 mol % of
silver triflate and a copper(I) catalyst at room temperature.
Different copper(I) salts, solvents, and bases were then
screened. The result was a complex mixture when the
reaction occurred in 1,4-dioxane with the addition of 10
mol % of copper(I) iodide and 3.0 equiv of triethylamine
(Table 1, entry 1). Similar results were observed when the
base was changed to pyridine or Cs2CO3 (Table 1, entries 2
and 3). A trace amount of product was detected when
K2CO3 was employed as the base in the above reaction
(Table 1, entry 4). Gratifyingly, the desired product 4a was
isolated in 34% yield when K3PO4 was added as the base
(Table 1, entry 5). The structure of 2-amino-H-pyrazolo-
[5,1-a]isoquinoline 4a was unambiguously determined by
X-ray crystallography analysis (see the Supporting
Information). With this promising result in hand, the
reaction was then explored in various solvents. The yield
could not be improved in ClCH2CH2Cl, THF, n-hexane,
cyclohexane, or MeCN (Table 1, entries 6ꢀ10). Further
screening revealed that toluene was the best choice (51%
yield, Table 1, entry 11). The reaction led to a complex
mixture when DMF was used as the solvent (Table 1, entry
12). A comparable yield (52%) was afforded when copper-
(I) chloride was employed as the catalyst (Table 1, entry
14). The yield was increased when copper(I) bromide or
copper(I) triflate was utilized (Table 1, entries 13 and 15).
No expected product was obtained in a blank experiment
without the addition of a copper(I) salt, which indicated
Table 3. Silver(I) and Copper(I) Co-Catalyzed Three-Compo-
nent Reaction of N0-(2-Alkynylbenzylidene)hydrazide 1 and
Alkyne 2 with Sulfonyl Azide 3a
Table 2. Silver(I) and Copper(I) Co-Catalyzed Three-Compo-
nent Reaction of N0-(2-Alkynylbenzylidene)hydrazide 1a and
Alkyne 2 with Sulfonyl Azide 3
a Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1a.
b The desilyl product was afforded.
a Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1.
Org. Lett., Vol. 13, No. 16, 2011
4314

the essential role of copper(I) in the conversion (Table 1,
entry 16). No better results were obtained when the
amount of copper(I) bromide was reduced to 5 mol % or
the reaction temperature was elevated to 50 °C (Table 1,
entries 17 and 18). When the amount of base (K3PO4) was
decreased to 2.5 or 2.0 equiv, a slightly lower yield was
obtained. No improvement was observed when the
amount of K3PO4 was increased to 4.0 equiv (data not
shown in Table 1).
smoothly to afford the expected products 4 under the
standard experimental conditions. For example, fluoro-
substituted N0-(2-alkynylbenzylidene)hydrazide1b reacted
with phenylacetylene 2b and 4-methylbenzenesulfonyl
azide 3a leading to the desired 2-amino-H-pyrazolo[5,1-a]-
isoquinoline 4l in 75% yield (Table 3, entry 1). The
product was isolated in a slightly lower yield when ethy-
nylcyclopropane 2h was used as a replacement (66% yield,
Table 3, entry 2). The products were isolated in similar
yields when chloro-, methoxy-, and methyl-substituted
N0-(2-alkynylbenzylidene)hydrazides were employed in
the transformation (Table 3, entries 3, 4, 6ꢀ8). However,
the reactionwas complicated whennitro-substitutedN0-(2-
alkynylbenzylidene)hydrazide 1d was employed in the
reaction of phenylacetylene 2b with 4-methylbenzenesul-
fonyl azide 3a (Table 3, entry 5). Further investigation
revealed that not only aryl groups but also alkyl groups at
the R2 position were tolerated (Table 3, entries 10ꢀ14). Itis
noteworthy that thiophene-yl-incorporated hydrazide 1k
was a good partner as well in this three-component reac-
tion, although the final outcome was not as good as
expected (Table 3, entries 15 and 16). Overall, most of
the successful transformation of a variety of substrates
indicated good functional group tolerability and generality
for this multicomponent reaction.
In conclusion, we have described a novel and efficient
route for the generation of 2-amino-H-pyrazolo[5,1-a]-
isoquinolines via a silver(I) and copper(I) co-catalyzed
three-component reaction of N0-(2-alkynylbenzylidene)-
hydrazide, alkyne, and sulfonyl azide. The key intermedi-
ates are believed to be isoquinolinium-2-yl amide and
ketenimine, which are generated in situ. This transforma-
tion proceeds with high efficiency through 6-endo cycliza-
tion, [3 þ 2] cycloaddition, and subsequent aromatization.
Currently, the related library construction is ongoing, and
the evaluation of different biological activities will be
reported in due course.
We then investigated the reaction scope of this multi-
catalytic system and its tolerance of functional groups in
the case of N0-(2-alkynylbenzylidene)hydrazide 1, alkyne
2, and sulfonyl azide 3 under the optimized conditions
[AgOTf (10 mol %), CuBr (10 mol %), K3PO4 (3.0 equiv),
toluene, 25 °C] (Tables 2 and 3). With respect to alkynes
2aꢀh, the expected 2-amino-H-pyrazolo[5,1-a]isoquino-
lines resulting from reactions of N0-(2-alkynylbenzylidene-
)hydrazide 1a with 4-methylbenzenesulfonyl azide 3a were
isolated in moderate to good yields (Table 2, entries 1ꢀ8).
For instance, phenyl acetylenes 2bꢀd with chloro-, methyl-,
and methoxy groups attached on the aromatic ring were all
good reactants in the transformation (Table 2, entries
2ꢀ4). Interestingly, trimethylsilyl acetylene 2f was com-
patible with this reaction, and the desilyl product 4f
was generated (Table 2, entry 6). Reactions of N0-(2-
alkynylbenzylidene)hydrazide1aand 4-methylbenzenesul-
fonyl azide 3a with other alkynes such as 1-hexyne 2g and
ethynylcyclopropane 2h were examined, which gave rise to
the desired products 4g and 4h in 44% and 74% yield,
respectively (Table 2, entries 7 and 8). However, only a
trace amount of product was generated when 1-ethynyl-4-
nitrobenzene 2i or 2-ethynylpyridine 2j was used in this
three-component reaction (Table 2, entries 9 and 10).
Other sulfonyl azides were then explored in the reaction
of N0-(2-alkynylbenzylidene)hydrazide 1a with ethynylcy-
clopropane 2h. Benzenesulfonyl azide 3b worked well in
the reaction, leading to the corresponding product 4i in
67% yield (Table 2, entry 11). The product was isolated in
moderate yield when 4-bromobenzenesulfonyl azide 3c
was employed in the transformation (Table 2, entry 12).
However, reaction of 4-nitrobenzenesulfonyl azide 3d
afforded the desired 2-amino-H-pyrazolo[5,1-a]isoquino-
line 4k in a lower yield (37%, Table 2, entry 13).
Acknowledgment. Financial support from National
Natural Science Foundation of China (No. 21032007)
is gratefully acknowledged. We thank Dr. Jason Wong
(Roche Pharma Research and Early Development,
China) for English review.
In a second set of experiments, the scope of the process
with respect to N0-(2-alkynylbenzylidene)hydrazide sub-
stituted with electron-rich and -poor substituents was
investigated (Table 3). We rapidly noticed that most of
the reactions of 4-methylbenzenesulfonyl azide 3a with
phenyl acetylene 2b or ethynylcyclopropane 2h proceeded
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra of
compounds 4, and X-ray data for compound 4a (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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