Rapid access to H-pyrazolo[5,1-a]isoquinolines via sequential reaction of N-(2-alkynylbenzylidene)hydrazides

Article abstract of DOI:10.1055/s-0030-1259704

Diverse H-pyrazolo[5,1-a]isoquinolines are efficiently synthesized via sequential reaction of N-(2-alkynylbenzylidene)hydrazides. Bromo-containing isoquinolinium, generated from N-(2-alkynylbenzylidene)hydrazide with bromine, reacts with ,-unsaturated ald

Full text of DOI:10.1055/s-0030-1259704

964
LETTER
Rapid Access to H-Pyrazolo[5,1-a]isoquinolines via Sequential Reaction of
N′-(2-Alkynylbenzylidene)hydrazides
Rapid
A
ccess to
h
H
-Pyrazolo
i
[5,1-
a
]
y
isoquinoline
u
s
an Chen,a Xiaolin Pan,a Jie Wu*a,b
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
Fax +86(21)65641740; E-mail: jie_wu@fudan.edu.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. of China
Received 1 October 2010
Dedicated to Professors Xiyan Lu and Lixin Dai
ing H-pyrazolo[5,1-a]isoquinolines could be formed in a
one-pot reaction of N¢-(2-alkynylbenzylidene)hydrazide,
bromine, methanol, and a,b-unsaturated aldehyde under
suitable conditions. These compounds could be further
Abstract: Diverse H-pyrazolo[5,1-a]isoquinolines are efficiently
synthesized via sequential reaction of N′-(2-alkynylben-
zylidene)hydrazides. Bromo-containing isoquinolinium, generated
from N′-(2-alkynylbenzylidene)hydrazide with bromine, reacts
with a,b-unsaturated aldehyde and methanol under mild conditions, decorated via palladium-catalyzed cross-coupling reac-
leading to 6-bromo-1-(methoxymethyl)-H-pyrazolo[5,1-a]isoquin-
tions to generate diverse H-pyrazolo[5,1-a]isoquinolines.
olines in moderate to good yields. Further elaboration via palladium
With these considerations in mind, we started to investi-
catalyzed Suzuki–Miyaura coupling or Heck reaction produces di-
gate this transformation.
verse H-pyrazolo[5,1-a]isoquinoline compounds.
Key words: alkynes, hydrazide, bromine, methanol, isoquinoline,
OMe
R4
N
a,b-unsaturated aldehyde
R3
TsNHNH2
MeOH
CHO
AgOTf (5 mol%)
KOH (3.0 equiv)
R1
+
O
N
DCE
R1
A multi-component reaction is a highly attractive device
that can be used to generate complex and diverse small
molecules in a one-pot procedure.1 This strategy has been
widely applied in drug discovery programs as a practical
and efficient tool for providing large collections of natu-
ral-product-like compounds.2 Over the last few years, we
have been involved in the development of methodologies
for accessing privileged scaffolds that can be used in a
range of biological assays.3,4 Very recently, we reported a
multi-component reaction of 2-alkynylbenzaldehydes,
sulfonohydrazides, alcohols, and a,b-unsaturated alde-
hydes or ketones.4a This reaction was highly efficient,
leading to H-pyrazolo[5,1-a]isoquinolines in good yields.
Moreover, promising biological results were obtained
with these compounds, which acted as a CDC25B inhibi-
tor, a TC-PTP inhibitor, and a PTP1B inhibitor
(Scheme 1). The moderate activity prompted us to devel-
op an efficient synthetic protocol and to evaluate the re-
sulting analogues, with the expectation of finding
improved inhibitors. Additionally, other biological assays
would be performed,5–7 because this skeleton could be re-
garded as a privileged scaffold. Thus, we initiated a pro-
gram to explore a facile route for rapid access to diverse
H-pyrazolo[5,1-a]isoquinoline molecules. The proposed
synthetic route is presented in Scheme 1. Because N¢-(2-
alkynylbenzylidene)hydrazide could be easily cyclized
with bromine under mild conditions, affording isoquino-
linium-2-yl amide,8 we expected that the bromo-contain-
ref. 4a
R2
R3
OMe
R2
R4
OMe
4-MeC6H4
Cl
R3
N
N
N
N
R1
A
Ph
R2
R4
CDC25B, IC50 2.19 μg/mL
TC-PTP, IC50 4.50 μg/mL
PTP1B, IC50 1.75 μg/mL
[Pd], R4M
OMe
R3
MeOH
NHTs
MCR
N
N
R1
N
O
Br2
R3
R1
R2
R2
R4
Br
Scheme 1 Proposed synthetic route for the generation of diverse H-
pyrazolo[5,1-a]isoquinolines
To establish the optimized conditions, we tested the reac-
tion of N¢-(2-alkynylbenzylidene)hydrazide (1a), bro-
mine, methanol, and cinnamaldehyde (2a) in the presence
of different bases and solvents (Table 1). To our delight,
we obtained the desired product 3a in 35% yield when the
reaction was carried out in tetrahydrofuran (THF) with
KOH as the base at 40 °C (Table 1, entry 1). A similar re-
sult was afforded when t-BuOK was used as base in the
above reaction (Table 1, entry 2). Other inorganic bases,
such as K3PO4, NaOH, and Cs2CO3 were then tested
SYNLETT 2011, No. 7, pp 0964–0968
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259704; Art ID: W31810ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rapid Access to H-Pyrazolo[5,1-a]isoquinolines
965
Table 1 Initial Studies for the One-Pot Reaction of N¢-(2-Alkynylbenzylidene)hydrazide (1a), Bromine, Methanol, and Cinnamaldehyde (2a)
OMe
MeOH
–NTs
Ph
Ph
NHTs
Ph
+
N
Ph
N
Br2
2a
CHO
N
N
base (2.0 equiv)
solvent, temp
Br
Ph
1a
A
3a
Br
Entry
1
Base
Solventa
THF
Temp. (°C)
Time (h)
48
Yield (%)b
KOH
40
40
40
40
40
40
40
40
40
40
40
40
40
40
50
60
35
32
22
15
9
2
t-BuOK
K3PO4
NaOH
Cs2CO3
DBU
DBU
DBU
DBU
DBU
THF
48
3
THF
48
4
THF
48
5
THF
48
6
THF
48
44
41
64
39
73
trace
55
65
27
80
79
7
DCE
48
8
CH2Cl2
CHCl3
CCl4
48
9
48
10
11
12
13
14
15
16
48
DBU
DBU
DMF
48
MeCN
toluene
1,4-dioxane
CCl4
48
DBU
48
DBU
DBU
48
24
DBU
CCl4
24
a DCE = 1,2-dichloroethane, DMF = N,N-dimethylformamide.
b Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide (1a).
(Table 1, entries 3–5), however, all gave inferior results (E)-3-(4-methoxyphenyl)acrylaldehyde (2c) was em-
compared with KOH. The yield was increased to 44% ployed in the reaction of N′-(2-alkynylbenzylidene)hy-
when 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was drazide (1a), bromine, and methanol, the desired product
used as a base in the reaction (Table 1, entry 6). The sol- was formed in moderate yield (Table 2, entries 2 and 3).
vent screening showed that CCl4 was superior to other sol- However, compound 3d could be obtained in 87% yield
vents, which furnished the corresponding product 3a in when (E)-3-(4-bromophenyl)acrylaldehyde (2d) was used
73% yield (Table 1, entry 10). The result could be im- in the reaction (Table 2, entry 4). In addition, a good result
proved further when the reaction was performed at 50 °C was generated when (E)-3-(pyridin-3-yl)acrylaldehyde
(80% yield, Table 1, entry 15). However, no difference (2e) was employed as a substrate in the above reaction
was observed when the reaction was carried out at higher (Table 2, entry 5). To our surprise, in contrast to 3-aryl-
temperatures (Table 1, entry 16).
acrylaldehyde, 3-alkylacrylaldehyde was not suitable for
this transformation (Table 2, entry 6). Subsequently, we
examined other N′-(2-alkynylbenzylidene)hydrazides
with various substituents on the aromatic ring or attached
to the triple bond. As can be seen, the substituents were
tolerated, leading to the desired products in good yields
(Table 2, entries 7–16).
With the optimized conditions in hand, we investigated
the scope of the one-pot reaction of N′-(2-alkynylben-
zylidene)hydrazide 1, bromine, methanol, and a,b-unsat-
urated aldehyde 2 (Table 2). Electronic variation of the
aryl group of the cinnamaldehyde did influence the yield.
For instance, when (E)-3-p-tolylacrylaldehyde (2b) or
Synlett 2011, No. 7, 964–968 © Thieme Stuttgart · New York

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Z. Chen et al.
LETTER
Table 2 One-Pot Reaction of N¢-(2-Alkynylbenzylidene)hydrazide 1, Bromine, Methanol, and a,b-Unsaturated Aldehyde 2
OMe
R3
MeOH
NHTs
R2
R3
N
2
Br2
R1
CHO
N
N
DBU, CCl4
50 °C
R1
R2
1
Br
3
Entry
1
R1, R2
R3
Product
3a
Yield (%)a
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
Ph (2a)
80
51
54
87
78
0
2
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-BrC6H4 (2d)
pyridin-3-yl (2e)
Et (2f)
3b
3c
3
4
3d
3e
5
6
3f
7
H, n-Bu (1c)
Ph (2a)
3g
70
56
80
44
40
73
63
54
50
60
8
H, n-Bu (1c)
pyridin-3-yl (2e)
Ph (2a)
3h
3i
9
5-Me, Ph (1d)
10
11
12
13
14
15
16
5-Me, Ph (1d)
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-BrC6H4 (2d)
pyridin-3-yl (2e)
pyridin-3-yl (2e)
Ph (2a)
3j
5-Me, Ph (1d)
3k
3l
5-Me, Ph (1d)
5-Me, Ph (1d)
3m
3n
3o
4-F, cyclopropyl (1e)
5-F, cyclopropyl (1e)
5-F, cyclopropyl (1e)
4-BrC6H4 (2d)
3p
a Isolated yield based on N¢-(2-alkynylbenzylidene)hydrazide 1.
Table 3 Palladium-Catalyzed Suzuki–Miyaura Coupling Reaction of H-Pyrazolo[5,1-a]isoquinoline 3 with Arylboronic Acid
OMe
OMe
R3
R3
N
N
N
N
Pd(PPh3)2Cl2 (10 mol%)
R1
R1
R4 B(OH)2
+
R2
R2
K2CO3, H2O–DMF
50 °C, 8~10 h
R4
Br
3
4
Entry
Compound 3
R4
Product 4
Yield (%)a
1
2
3
4
5
6
3a
3a
3a
3a
3e
3i
Ph
4a
4b
4c
4d
4e
4f
99
98
90
94
98
96
4-MeC6H4
4-MeOC6H4
4-F3CC6H4
Ph
Ph
Synlett 2011, No. 7, 964–968 © Thieme Stuttgart · New York

LETTER
Rapid Access to H-Pyrazolo[5,1-a]isoquinolines
967
Table 3 Palladium-Catalyzed Suzuki–Miyaura Coupling Reaction of H-Pyrazolo[5,1-a]isoquinoline 3 with Arylboronic Acid (continued)
OMe
OMe
R3
R3
N
N
N
N
Pd(PPh3)2Cl2 (10 mol%)
R1
R1
R4 B(OH)2
+
R2
R2
K2CO3, H2O–DMF
50 °C, 8~10 h
R4
Br
3
4
Entry
Compound 3
R4
Ph
Ph
Product 4
Yield (%)a
7
8
3m
3o
4g
4h
93
83
a Isolated yield based on H-pyrazolo[5,1-a]isoquinoline 3.
We subsequently explored the application of bromo-con- ated aldehyde, and methanol that generates 6-bromo-1-
taining H-pyrazolo[5,1-a]isoquinoline 3 in palladium-cat- (methoxymethyl)H-pyrazolo[5,1-a]isoquinolines in mod-
alyzed Suzuki–Miyaura coupling reactions (Table 3).9 erate to good yields. Further elaboration via palladium-
The reactions worked efficiently with arylboronic acids in catalyzed Suzuki–Miyaura coupling or Heck reaction pro-
the presence of [PdCl2(PPh3)2] (10 mol%) and K2CO3 in duces diverse H-pyrazolo[5,1-a]isoquinoline compounds.
DMF–H2O at 50 °C. As expected, all products were af- Efforts to screen the biological activity of these small
forded in good to excellent yields. For example, almost molecules are underway in our laboratory, and the results
quantitative yield of product 4a was obtained when H- will be reported in due course.
pyrazolo[5,1-a]isoquinoline (3a) reacted with phenylbo-
ronic acid under the conditions described above (Table 3,
entry 1). Interestingly, when compound 3l was utilized as
a substrate, product 4i could be generated in the presence
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
of 2.2 equivalents of phenylboronic acid (Scheme 2, eq.
1). n-Butyl acrylate was also used as a coupling partner in
the reaction of H-pyrazolo[5,1-a]isoquinoline (3a), which
furnished compound 4j in 80% yield (Scheme 2, eq. 2).
Acknowledgment
Financial support from the National Natural Science Foundation of
China (No. 20972030) is gratefully acknowledged.
In conclusion, we have described a one-pot reaction of N¢-
(2-alkynylbenzylidene)hydrazide, bromine, a,b-unsatur-
OMe
OMe
Ph
Br
N
N
N
N
Pd(PPh3)2Cl2 (10 mol%)
(1)
Ph B(OH)2
(2.2 equiv)
+
K2CO3, H2O–DMF
50 °C, 10 h
Ph
Ph
93% yield
Ph
Br
4i
3l
OMe
OMe
Ph
Ph
N
N
N
Pd(PPh3)2Cl2 (10 mol%)
On-Bu
O
N
+
(2)
Ph3P (40 mol%)
K2CO3, DMF, reflux, 24 h
80% yield
Ph
Ph
4j
Br
3a
COOn-Bu
Scheme 2 Palladium-catalyzed Suzuki–Miyaura coupling or Heck reaction of H-pyrazolo[5,1-a]isoquinoline 3
Synlett 2011, No. 7, 964–968 © Thieme Stuttgart · New York

968
Z. Chen et al.
LETTER
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