Silver triflate-catalyzed three-component reaction of 2- alkynylbenzaldehyde, sulfonohydrazide, and α,β-unsaturated carbonyl compound

Article abstract of DOI:10.1039/c0cc00905a

A highly efficient silver triflate-catalyzed three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and α,β-unsaturated carbonyl compound is reported, which affords H-pyrazolo[5,1-a]isoquinoline-1- carboxylates in good yield.

Full text of DOI:10.1039/c0cc00905a

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Silver triflate-catalyzed three-component reaction of
2-alkynylbenzaldehyde, sulfonohydrazide, and a,b-unsaturated carbonyl
compoundw
Shengqing Ye,a Xiaodi Yangc and Jie Wu*ab
Received 13th April 2010, Accepted 16th June 2010
First published as an Advance Article on the web 28th June 2010
DOI: 10.1039/c0cc00905a
A highly efficient silver triflate-catalyzed three-component
reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and
a,b-unsaturated carbonyl compound is reported, which affords
H-pyrazolo[5,1-a]isoquinoline-1-carboxylates in good yield.
results and the advancement of multicomponent reactions,
we envisioned that three-component reaction of 2-alkynyl-
benzaldehyde, sulfonohydrazide, and a,b-unsaturated esters
or ketones might be a good vehicle for the fused isoquinoline
generation.
As mentioned previously, isoquinolinium-2-yl amide B
could be easily generated via 6-endo-cyclization of N0-(2-
alkynylbenzylidene)hydrazide in the presence of silver triflate.9
In order to simplify the optimization process, our initial
studies were performed for the reaction of isoquinolinium-2-yl
amide B (R1 = H, R2 = Ph) with ethyl acrylate 2a in the
presence of different bases and solvents (Scheme 1, for details,
please see ESIw). Gratifyingly, we observed the formation of a
product (21% yield) when the reaction was carried out with
DABCO in THF. However, structural identification revealed
the product was H-pyrazolo[5,1-a]isoquinoline-1-carboxylate
3a, instead of the expected product C (R1 = H, R2 = Ph). The
structure was also confirmed by X-ray diffraction analysis
The development of efficient strategies for nitrogen-containing
heterocycles formation continues to be of major importance in
synthetic organic chemistry. Among the approaches utilized,
multi-component reactions are very attractive since this method
can create novel products while increasing the efficiency and
modularity of the reactions by reducing the number of chemical
transformations and chemical waste.1 Especially, the MCRs
are ideally suited for the construction of natural product-like
compounds in the field of combinatorial chemistry prone to
display biological activity.2
Since the isoquinoline ring system is present in numerous
naturally occurring alkaloids, the synthesis of isoquinolines
and related compounds has received considerable attention.3–5
Among the isoquinoline family, the fused isoquinoline such as
lamellarin alkaloid is an attractive scaffold due to its promising
biological activities.6 In order to build up a focused library of
fused isoquinolines for our biological assays, development of
efficient synthetic methodologies is extremely important to
ensure diversity-oriented synthesis.
1
(Fig. 1). The H NMR data indicated that presumably there
is a space effect of the carbonyl group to one of the aromatic
protons. Subsequently, a variety of bases and solvents were
examined. Compound 3a could be isolated in 73% yield when
DMF was utilized as the solvent as well as a base.11 With
this promising result in hand, we started to explore the
Recently, 2-alkynylbenzaldehyde has been discovered as a
useful building block for construction of heterocycles.7 We
also developed tandem reactions8 of N0-(2-alkynylbenzylidene)-
hydrazide, which was derived from 2-alkynylbenzaldehyde.9
During the studies, we recognized that N0-(2-alkynylbenzylidene)-
hydrazide could be easily cyclized to isoquinolinium-2-yl
amide via 6-endo-cyclization in the presence of silver salts or
electrophiles. Thus, further cycloadditions might occur under
suitable conditions. Indeed, dimethyl acetylenedicarboxylate
has been successfully employed as a partner in the reaction of
N0-(2-alkynylbenzylidene)hydrazide,9b since 1,3-dipolar cyclo-
addition of ylidic species is a powerful method for the
construction of complex N-heterocycles.10 Prompted by these
a 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
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Shanghai 200032, China
c Laboratory of Advanced Materials, Fudan University,
220 Handan Road, Shanghai 200433, China
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, 1H and 13C NMR spectra of
compounds 3. CCDC 773018. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0cc00905a
Scheme 1 Initial studies for the three-component reaction of 2-alkynyl-
benzaldehyde, sulfonohydrazide, and acrylate.
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Table 1 Silver triflate-catalyzed three-component reaction of 2-alkynyl-
benzaldehyde, sulfonohydrazide, and a,b-unsaturated carbonyl
compound
Yield
Product (%)a
Entry R1, R2
R3, R4
1
2
3
4
5
6
7
8
H, C6H5 (1a)
H, C6H5 (1a)
H, C6H5 (1a)
H, C6H5 (1a)
H, C6H5 (1a)
H, cyclopropyl (1b)
H, cyclopropyl (1b)
H, cyclopropyl (1b)
H, n-Bu (1c)
H, n-Bu (1c)
H, n-Bu (1c)
4-F, C6H5 (1d)
4-F, C6H5 (1d)
4-F, C6H5 (1d)
4-F, cyclopropyl (1e)
4-F, n-Bu (1f)
OEt, H (2a)
OMe, H (2b) 3b
OnBu, H (2c) 3c
Me, H (2d)
–(CH2)3– (2e) 3e
OnBu, H (2c) 3f
Me, H (2d)
–(CH2)3– (2e) 3h
OnBu, H (2c) 3i
Me, H (2d)
–(CH2)3– (2e) 3k
OnBu, H (2c) 3l
3a
88
85
82
54
56
85
55
54
84
62
50
81
72
51
74
80
90
82
83
81
52
60
88
62
80
77
Fig.
1
ORTEP illustration of compound 3a (30% probability
ellipsoids).
3d
three-component reaction of 2-alkynylbenzaldehyde 1a,
sulfonohydrazide, and ethyl acrylate 2a (Scheme 1). Finally,
we realized that the reaction worked most efficiently (88%
yield) in the presence of AgOTf (5 mol%) as catalyst in
DCE/DMAc at 60 1C.
For the possible mechanism, we reasoned that after
condensation of 2-alkynylbenzaldehyde 1 with sulfonohydrazide,
N0-(2-alkynylbenzylidene)hydrazide A would be obtained. In
the presence of AgOTf, the triple bond would be activated
and then the 6-endo-cyclization occurred to afford the iso-
quinolinium-2-yl amide B. Subsequently, acrylate would be
involved in the [3+2] cycloaddition process to generate the
intermediate C. After release of tosyl group and aromatization,
H-pyrazolo[5,1-a]isoquinoline-1-carboxylate 3 was then afforded
(Scheme 1).
3g
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3j
Me, H (2d)
3m
–(CH2)3– (2e) 3n
OnBu, H (2c) 3o
OnBu, H (2c) 3p
OnBu, H (2c) 3q
5-Cl, C6H5 (1g)
5-Cl, C6H5 (1g)
5-Cl, cyclopropyl (1h)
5-Cl, n-Bu (1i)
Me, H (2d)
3r
OnBu, H (2c) 3s
OnBu, H (2c) 3t
4,5-(OMe)2, cyclopropyl (1j) OnBu, H (2c) 3u
4,5-(OMe)2, n-Bu (1k)
4-Me, C6H5 (1l)
4-Me, C6H5 (1l)
4-Me, cyclopropyl (1m)
4-Me, n-Bu (1n)
OnBu, H (2c) 3v
OnBu, H (2c) 3w
Me, H (2d)
3x
OnBu, H (2c) 3y
OnBu, H (2c) 3z
To establish the scope of this reaction, the effects of changing
the a,b-unsaturated carbonyl compounds and the substituents
at the 2-alkynylbenzaldehydes were tested under the optimized
conditions (AgOTf (5 mol%), DCE/DMAc, 60 1C) (Table 1).
This silver triflate-catalyzed three-component reaction of
2-alkynylbenzaldehyde 1, sulfonohydrazide, and a,b-unsaturated
a
Isolated yield based on 2-alkynylbenzaldehyde 1.
are readily available and this reaction proceeds with wide
scope under mild conditions with high efficiency and excellent
selectivity. Well tolerated functional groups at different
positions of the substrates are demonstrated. The focused
library construction is currently in progress, which will be
directly used for different biological assays.
carbonyl compound
2 occurred smoothly to generate
the desired H-pyrazolo[5,1-a]isoquinoline-1-carboxylates 3 in
good yields (Table 1). For instance, 2-alkynylbenzaldehyde 1a
reacted with sulfonohydrazide and methyl acrylate 2b, leading
to the corresponding product 3b in 85% yield (entry 2).
Similar yield (82%) was obtained when n-butyl acrylate 2c
was employed in the above reaction (entry 3). With respect to
the but-3-en-2-one 2d and cyclohex-2-enone 2e, the expected
H-pyrazolo[5,1-a]isoquinoline-1-carboxylates resulting from
reactions of 2-alkynylbenzaldehyde 1a with sulfonohydrazide
were obtained and isolated in moderate yields (entries 4 and 5).
This methodology could also be extended to the reactions of
2-alkynylbenzaldehyde with cyclopropyl or n-butyl group
attached to the CRC triple bond, and all reactions proceeded
smoothly to afford the corresponding products in good yields
(entries 6–11). Other substrates were examined as well and this
three-component reaction was found to be workable with
2-alkynylbenzaldehydes 1d–1n with electron-withdrawing
and -donating substituents on the aromatic backbone.
Financial support from the National Natural Science
Foundation of China (20972030) and the Science & Technology
Commission of Shanghai Municipality (09JC1404902) is
gratefully acknowledged.
Notes and references
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novel approach to various functionalized H-pyrazolo[5,1-a]-
isoquinoline-1-carboxylates via silver triflate-catalyzed three-
component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide,
and a,b-unsaturated carbonyl compound. The starting materials
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5240 | Chem. Commun., 2010, 46, 5238–5240