Three-component reaction of N′-(2-alkynylbenzylidene)hydrazide, α,β-unsaturated carbonyl compound, with bromine

Article abstract of DOI:10.1016/j.tet.2010.08.052

Different outcomes were generated under different conditions for the three-component reaction of N′-(2-alkynylbenzylidene)hydrazide, α,β-unsaturated carbonyl compound, with bromine. 6-BromoH-pyrazolo[5, 1-a]isoquinoline was obtained when the reaction was performed in NMP at 70 °C in the presence of DABCO as base, while 6-bromo-1,2,3,10b- tetrahydropyrazolo[5,1-a]isoquinoline was afforded when the reaction occurred in DMAc at 10 °C in the presence of K₃PO₄ as the base.

Full text of DOI:10.1016/j.tet.2010.08.052

Tetrahedron 66 (2010) 8242e8246
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Tetrahedron
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Three-component reaction of N0-(2-alkynylbenzylidene)hydrazide,
a,
b-unsaturated carbonyl compound, with bromine
,
Hui Ren a, Shengqing Ye a, Fen Liu b, Jie Wu a
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b Key Laboratory of Radioactive Geology and Exploration Technology Fundamental Science for National Defense, East China Institute of Technology, Fuzhou, Jiangxi 344000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2010
Received in revised form 17 August 2010
Accepted 19 August 2010
Available online 26 August 2010
Different outcomes were generated under different conditions for the three-component reaction of
N0-(2-alkynylbenzylidene)hydrazide,
a,b-unsaturated carbonyl compound, with bromine. 6-BromoH-
pyrazolo[5,1-a]isoquinoline was obtained when the reaction was performed in NMP at 70 ꢀC in the
presence of DABCO as base, while 6-bromo-1,2,3,10b-tetrahydropyrazolo[5,1-a]isoquinoline was afforded
when the reaction occurred in DMAc at 10 ꢀC in the presence of K3PO4 as the base.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N0-(2-Alkynylbenzylidene)hydrazide
Bromine
6-BromoH-pyrazolo[5,1-a]isoquinoline
6-Bromo-1,2,3,10b-tetrahydropyrazolo-
[5,1-a]isoquinoline
a,b-unsaturated carbonyl compound
1. Introduction
As mentioned above, we reported an efficient approach for
generation of H-pyrazolo[5,1-a]isoquinolines via silver triflate-
It is well recognized that the combination of methodology de-
velopment and library approaches is an efficient device for the
discovery of small-molecule enzyme inhibitors or receptor ligands.1
Usually, the natural product-like compounds with privileged scaf-
folds are considered as an important source of small molecules.
Among the skeletons, isoquinoline is a subunit in numerous natu-
rally occurring alkaloids that exhibit a wide range of biological
acitivities,2,3 such as inhibitor of human topoisomerase I4 and anti-
HIV activity.5 In continuation of our interest in the synthesis of
bioactive heterocycles using tandem reactions,6 we became in-
terested to construct a focused library of isoquinolines. Recently, we
have discovered several efficient strategies for the isoquinolines
generation.7,8 Among the compounds synthesized, H-pyrazolo[5,1-
a]isoquinolines are more attractive8 since in our preliminary bi-
ological assays, these particular analogues show promising activity
as PTP1B inhibitor. In order to search better hits, we need to rapidly
prepare the diverse H-pyrazolo[5,1-a]isoquinolines. The synthetic
route should have considerable flexibility to introduce a diversity of
functionalities in a high-throughput manner.
catalyzed three-component reaction of 2-alkynylbenzaldehyde,
sulfonohydrazide, and
a,b
-unsaturated carbonyl compound.8d In
this reaction process, 2-alkynylbenzaldehyde condensed with sul-
fonohydrazide firstly to afford the N0-(2-alkynylbenzylidene)hy-
drazide, which then underwent endo-cyclization catalyzed by
AgOTf to furnish the isoquinolinium-2-yl amide. After [3þ2] cy-
cloaddition of
a,b-unsaturated carbonyl compound and aromati-
zation, H-pyrazolo[5,1-a]isoquinoline would be afforded. Inspired
by this result, we envisioned that an electrophile might be involved
in the reaction of N0-(2-alkynylbenzylidene)hydrazide with
a,b-unsaturated carbonyl compound. As expected, the 6-bromoH-
pyrazolo[5,1-a]isoquinoline would be produced, which could be
further elaborated using palladium-catalyzed cross-coupling re-
actions to introduce more diversity into the H-pyrazolo[5,1-a]iso-
quinoline scaffold. Herein, we would like to disclose our recent
efforts for the three-component reaction9 of N0-(2-alkynylbenzyli-
dene)hydrazide,
a,b-unsaturated carbonyl compound, with bro-
mine. Interestingly, different outcomes were generated under
different conditions. The desired 6-bromoH-pyrazolo[5,1-a]iso-
quinoline was obtained when the reaction was performed in NMP
at 70 ꢀC in the presence of DABCO, while 6-bromo-1,2,3,10b-tetra-
hydropyrazolo[5,1-a]isoquinoline was afforded when the reaction
occurred in DMAc at 10 ꢀC in the presence of K3PO4.
* Corresponding author. Tel.: þ86 21 6510 2412; fax: þ86 21 6564 1740; e-mail
address: jie_wu@fudan.edu.cn (J. Wu).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.052

H. Ren et al. / Tetrahedron 66 (2010) 8242e8246
8243
Table 1
2. Results and discussion
Synthesis of 6-bromoH-pyrazolo[5,1-a]isoquinoline 3 via three-component reaction
of N0-(2-alkynylbenzylidene)hydrazide 1,
with bromine
a
,
b
-unsaturated carbonyl compound 2,
As described previously, N0-(2-alkynylbenzylidene)hydrazide
could be easily transferred to bromo-containing isoquinolinium-2-
yl amide in the presence of bromine.10 In order to simplify the re-
action optimization process, initial studies were carried out for the
reaction of bromo-containing isoquinolinium-2-yl amide A1 with
ethyl acrylate 2a (Scheme 1, Eq. 1). The reaction was complicated
when MeCN was used as the solvent at 70 ꢀC. To our delight, the
result could be improved dramatically when the reaction occurred
in DMAc, which afforded the desired product 3a in 63% yield.
Higher yield was obtained when DMF was utilized as a replacement
in the reaction (73% yield). Gratifyingly, compound 3a was isolated
in 90% yield when the reaction took place in NMP. With this
promising result in hand, we started to explore the three-compo-
nent reaction of N0-(2-alkynylbenzylidene)hydrazide 1a, ethyl ac-
rylate 2a, with bromine (Scheme 1, Eq. 2). Since HBr would be
generated during the reaction process, a base was added as
a scavenger. After screening different bases (LiOH, K3PO4, DABCO,
KOAc, Na2CO3, Et3N) for the above reaction in NMP at 70 ꢀC, we
realized that the reaction proceeded the most efficiently in the
presence of 2.0 equiv of DABCO, leading to the desired product 3a
in 65% yield.
O
R3
H
R3
N
N
Ts
DABCO
N
R1
(2.0 equiv)
NMP, 70 ο
N
2
+
O
R1
C
R2
R2
Br2
1
Br
3
Entry
1
Compound 1
Compound 2
Yielda (%)
65 (3a)
2
3
4
5
1a
1a
1a
61 (3b)
60 (3c)
55 (3d)
63 (3e)
O
EtO
H
N
OEt
N
N
N
Ts
N
Ts
Br2
ref. 10
O
2a
N
(1)
2a
Ph
solvent
Ph
Ph
N
Br
1a
A1
3a
Br
O
H
N
EtO
6
7
8
9
2a
2a
2a
2a
53 (3f)
50 (3g)
52 (3h)
31 (3i)
Ts
+
base
solvent
OEt
N
+
Br2
N
(2)
O
2a
3a
Ph
Ph
1a
Br
Scheme 1. Initial studies for the three-component reaction of N0-(2-alkynylbenzyli-
dene)hydrazide 1a, ethyl acrylate 2a, with bromine.
The optimized reaction condition mentioned above (DABCO
2.0 equiv in NMP at 70 ꢀC) led us to examine the generality of the
reaction for the synthesis of 6-bromoH-pyrazolo[5,1-a]isoquino-
lines (Table 1). As shown in Table 1, similar results were generated
when methyl acrylate 2b or n-butyl acrylate 2c was employed as
the substrate in the three-component reaction of N0-(2-alky-
nylbenzylidene)hydrazide 1a with bromine (Table 1, entries 2 and
3). When pent-1-en-3-one 2d was used as a partner in the above
reaction, the corresponding product 3d was obtained in 55% yield
(Table 1, entry 4). Reactions of chloro- or fluoro-substituted N0-(2-
alkynylbenzylidene)hydrazides 1 with ethyl acrylate 2a and bro-
mine were examined meanwhile, which gave rise to the desired
products in moderate yields (Table 1, entries 6e10). Substrates with
alkyl (n-butyl and cyclopropyl) groups attached to the triple bond
of N0-(2-alkynylbenzylidene)hydrazides 1 also worked well in the
transformation (Table 1, entries 9e10). However, N0-(2-alky-
nylbenzylidene)hydrazide with electron-donating groups attached
on the aromatic backbone effected the reaction remarkably,
resulting in diminished reactivity. For instance, only a trace amount
of product was detected when compound 1h was employed in the
reaction of ethyl acrylate 2a and bromine (Table 1, entry 11).
Similar to our previous report,8d for the reaction process we
conceived that the bromine-mediated 6-endo-cyclization would
occur firstly to generate the key intermediate isoquinolinium-2-yl
10
2a
2a
55 (3j)
11
Trace
a
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1.
release of tosyl group and aromatization would produce 6-bromoH-
pyrazolo[5,1-a]isoquinoline 3 (Scheme 2). To support the mecha-
nistic proposal and illustrate the reaction process, reaction of
bromo-containingisoquinolinium-2-yl amide A1 withethylacrylate
2a in different solvent was re-investigated. Indeed, under the stan-
dard conditions shown in Table 1, during the reaction process a new
compound, which might be the key intermediate 4 could be
amide A. After [3þ2] cycloaddition reaction with
a,b-unsaturated
carbonyl compound 2, compound 4 would be afforded. Subsequent

8244
H. Ren et al. / Tetrahedron 66 (2010) 8242e8246
detected. However, the effort for separation of the compound was
difficult since the compound was disappeared fast at 70 ꢀC. We
reasoned that the key intermediate might be isolated at lower
temperature. To our delight, we observed the formation of com-
pound 4awith a 92% isolatedyield when the reactionwas performed
in DMAc at 10 ꢀC. In addition, we found that three-component re-
room temperature under air atmosphere for 10 min. Then the
temperature was elevated to 70 ꢀC, and DABCO (0.3 mmol,1.5 equiv)
and a,b-unsaturated carbonyl compound (0.4 mmol, 2.0 equiv) were
added into the reaction mixture. After completion of the reaction as
indicated by TLC, the reaction was quenched with saturated NH4Cl
(aq), extracted with ethyl acetate (10 mLꢁ3). The organic layer was
washed with brine, dried over Na2SO4, and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy on silica gel to provide the desired product 3.
action of N0-(2-alkynylbenzylidene)hydrazide 1,
a,b-unsaturated
carbonyl compound 2, with bromine in the presence of K3PO4 as
a base in DMAc at 10 ꢀC proceeded efficiently to afford compound 4
in good yields (Scheme 3). However, compound 4 was not stable,
which was easily decomposed after several minutes of storage.
4.1.1. Ethyl 6-bromo-5-phenylpyrazolo[5,1-a]isoquinoline-1-carbox-
ylate (3a). White solid, 1H NMR (400 MHz, CDCl3):
d 9.97e9.94 (m,
O
1H), 8.38 (s,1H), 8.33e8.30 (m,1H), 7.77e7.73 (m, 2H), 7.62e7.57 (m,
O
R3
3H), 7.51e7.49 (m, 2H), 4.43 (q, J¼7.3 Hz, 2H),1.43 (t, J¼7.3 Hz, 3H).13C
2
NHTs
R2
NTs
R2
Br2
N
N
R3
R1
R1
N
NMR (100 MHz) d 163.7, 145.4, 138.4, 137.6, 134.1, 130.2, 130.0, 129.7,
Ts
6-endo
N
[3+2]
R1
129.6, 129.4, 128.7, 127.9, 127.4, 123.8, 112.0, 108.1, 60.6, 14.4. HRMS
cyclization
cycoaddition
1
A
Br
R2
(ESI) calcd for C20H15BrN2O2: 417.0215 (MþNaþ), found: 417.0204.
4
Br
4.1.2. Methyl 6-bromo-5-phenylpyrazolo[5,1-a]isoquinoline-1-car-
Compound 3
O
boxylate (3b). White solid, 1H NMR (400 MHz, CDCl3):
d 9.95e9.93
O
H
O
R3
R3
R3
H
(m, 1H), 8.37 (s, 1H), 8.32e8.28 (m, 1H), 7.78e7.73 (m, 2H),
aromatization
B
7.62e7.57 (m, 3H), 7.51e7.49 (m, 2H), 3.95 (s, 3H). 13C NMR
NH
N
N
N
N
N
R1
R1
R1
(100 MHz)
d 164.1, 145.4, 138.5, 137.6, 134.0, 130.3, 130.0, 129.7,
R2
R2
Br
R2
129.6, 128.7, 128.4, 127.9, 127.4, 123.7, 112.1, 107.7, 51.8. HRMS (ESI)
B
D
Br
C
Br
calcd for C19H13BrN2O2: 403.0058 (MþNaþ), found: 403.0050.
Scheme 2. Possible mechanism for the three-component reaction of N0-(2-alky-
nylbenzylidene)hydrazide,
a
,
b
-unsaturated carbonyl compound, with bromine.
4.1.3. Butyl 6-bromo-5-phenylpyrazolo[5,1-a]isoquinoline-1-carbox-
ylate (3c). White solid, 1H NMR (400 MHz, CDCl3):
d 9.97e9.94 (m,
O
1H), 8.37 (s, 1H), 8.31e8.28 (m, 1H), 7.76e7.75 (m, 2H), 7.62e7.57
(m, 3H), 7.51e7.49 (m, 2H), 4.37 (t, J¼6.6 Hz, 2H), 1.83e1.76 (m, 2H),
1.54e1.44 (m, 2H), 0.99 (t, J¼7.3 Hz, 3H). 13C NMR (100 MHz)
H
N
R3
R3
K3PO4
(2.0 equiv)
DMAc, rt
N
Ts
R1
NTs
R2
2
+
O
N
R1
d
163.9, 145.5, 138.6, 137.8, 134.2, 130.4, 130.2, 129.8, 129.7, 128.8,
R2
Br2
1
4
128.7, 128.1, 127.5, 124.0, 112.1, 108.3, 64.7, 30.9, 19.5, 13.9. HRMS
Br
p-PhC6H4
(ESI) calcd for C22H19BrN2O2: 445.0528 (MþNaþ), found: 445.0510.
O
O
O
O
n
Bu O
EtO
MeO
O
4.1.4. 1-(6-Bromo-5-phenylpyrazolo[5,1-a]isoquinolin-1-yl)propan-
Ts
1-one (3d). White solid, 1H NMR (400 MHz, CDCl3):
d 10.08e10.06
N
N
N
N
Ts
Ts
Ts
N
N
N
N
(m, 1H), 8.39 (s, 1H), 8.32e8.30 (m, 1H), 7.78e7.73 (m, 2H),
7.62e7.59 (m, 3H), 7.51e7.48 (m, 2H), 3.06 (q, J¼7.3 Hz, 2H), 1.30
Ph
Ph
Ph
Ph
Br
Br
4b: 64% yield
Br
Br
(t, J¼7.3 Hz, 3H). 13C NMR (100 MHz)
d 195.3, 145.0, 137.8, 137.4,
4a: 63% yield
4c: 70% yield
4d: 83% yield
134.1, 130.6, 130.0, 129.8, 129.7, 128.7, 128.6, 128.1, 127.3, 124.1, 116.6,
112.8, 34.7, 8.7. HRMS (ESI) calcd for C20H15BrN2O: 401.0265
(MþNaþ), found: 401.0247.
Scheme 3. Generation of 6-bromo-1,2,3,10b-tetrahydropyrazolo[5,1-a]-isoquinoline 4
via three-component reaction of N0-(2-alkynylbenzylidene)hydrazide 1,
saturated carbonyl compound 2, with bromine.
a,b-un-
4.1.5. Ethyl 6-bromo-5-p-tolylpyrazolo[5,1-a]isoquinoline-1-carbox-
3. Conclusions
ylate (3e). White solid, 1H NMR (400 MHz, CDCl3):
d 9.97e9.94 (m,
1H), 8.38 (s, 1H), 8.32e8.29 (m, 1H), 7.77e7.74 (m, 2H), 7.42e7.38
In summary, we have described a three-component reaction of
N0-(2-alkynylbenzylidene)hydrazide,
-unsaturated carbonyl
(m, 4H), 4.43 (q, J¼6.9 Hz, 2H), 2.49 (s, 3H),1.44 (t, J¼6.9 Hz, 3H). 13C
a,b
NMR (100 MHz) d 163.8, 145.4, 139.7, 138.5, 137.8,131.2, 130.2, 129.9,
compound, with bromine, which affords different results under
different conditions. 6-BromoH-pyrazolo[5,1-a]isoquinoline is
generated when the reaction is performed in NMP at 70 ꢀC in the
presence of DABCO, while 6-bromo-1,2,3,10b-tetrahydropyrazolo
[5,1-a]isoquinoline is obtained when the reaction occur in DMAc at
10 ꢀC in the presence of K3PO4. This temperature-controlled result
also gives us hits for the understanding of reaction process.
129.7, 129.5, 128.6, 127.9, 127.4, 123.8, 112.0, 108.1, 60.6, 21.6, 14.4.
HRMS (ESI) calcd for C21H17BrN2O2: 431.0371 (MþNaþ), found:
431.0352.
4.1.6. Ethyl 6-bromo-9-chloro-5-phenylpyrazolo[5,1-a]isoquinoline-
1-carboxylate (3f). White solid, 1H NMR (400 MHz, CDCl3):
d
10.05e10.04 (m, 1H), 8.38 (s, 1H), 8.24e8.21 (m, 1H), 7.70e7.68
(m, 1H), 7.60e7.58 (m, 3H), 7.50e7.47 (m, 2H), 4.44 (q, J¼7.3 Hz,
4. Experimental section
2H), 1.44 (t, J¼6.9 Hz, 3H). 13C NMR (100 MHz)
d 163.4, 145.5, 137.9,
137.3, 134.8, 133.7, 130.6, 130.0, 129.8, 128.9, 128.7, 128.0, 127.2,
124.6, 111.2, 108.6, 60.8, 14.4. HRMS (ESI) calcd for C20H14BrClN2O2:
429.0005 (MþHþ), found: 428.9992.
4.1. General procedure for synthesis of 6-bromoH-pyrazolo-
[5,1-a]isoquinoline 3 via three-component reaction of N0-(2-
alkynylbenzylidene)hydrazide 1,
compound 2, with bromine
a,b-unsaturated carbonyl
4.1.7. Ethyl 6-bromo-9-fluoro-5-phenylpyrazolo[5,1-a]isoquinoline-
1-carboxylate (3g). White solid, 1H NMR (400 MHz, CDCl3):
A mixture of N0-(2-alkynylbenzylidene)hydrazide 1 (0.2 mmol)
d
9.83e9.80 (m, 1H), 8.38 (s, 1H), 8.33e8.30 (m, 1H), 7.62e7.58
and bromine (0.24 mmol,1.2 equiv) in CH2Cl2 (0.5 mL) was stirred at
(m, 3H), 7.52e7.47 (m, 3H), 4.44 (q, J¼7.3 Hz, 2H), 1.44 (t, J¼7.4 Hz,

H. Ren et al. / Tetrahedron 66 (2010) 8242e8246
8245
3H). 13C NMR (100 MHz)
d
163.5, 162.0 (d, J(C,F)¼247.9 Hz), 145.4,
(m, 3H), 7.29e7.21 (m, 2H), 7.14 (d, J¼8.3 Hz, 3H), 6.96 (t, J¼7.8 Hz,
1H), 6.40 (d, J¼7.8 Hz, 1H), 5.17 (d, J¼8.7 Hz, 1H), 4.20 (dd, J¼9.2,
3.6 Hz, 1H), 3.72 (dd, J¼7.3, 5.1 Hz, 1H), 3.64e3.60 (m, 1H), 3.23
137.7, 137.1, 133.8, 130.0, 129.9, 129.8, 128.7, 126.3, 125.2
(d, J(C,F)¼11.4 Hz), 118.9 (d, J(C,F)¼23.8 Hz), 113.5 (d, J(C,F)¼26.7 Hz),
111.3, 108.5, 60.8, 14.4. HRMS (ESI) calcd for C20H14BrFN2O2:
435.0120 (MþNaþ), found: 435.0114.
(s, 3H), 2.47 (s, 3H). 13C NMR (100 MHz)
d 172.1, 145.1, 144.6, 136.3,
133.0,130.8, 129.6, 129.4,129.0, 128.7, 127.8, 127.7, 127.6, 126.1,101.4,
65.1, 52.9, 52.1, 47.0, 21.8. HRMS (ESI) calcd for C26H23BrN2O4S:
561.0460 (MþNaþ), found: 561.0422.
4.1.8. Ethyl 6-bromo-8-fluoro-5-phenylpyrazolo[5,1-a]isoquinoline-
1-carboxylate (3h). White solid, 1H NMR (400 MHz, CDCl3):
d
10.08e10.05 (m, 1H), 8.37 (s, 1H), 7.99e7.96 (m, 1H), 7.60e7.48
4.2.3. Butyl 6-bromo-5-phenyl-3-tosyl-1,2,3,10b-tetrahydropyrazolo-
(m, 6H), 4.42 (q, J¼6.9 Hz, 2H), 1.43 (t, J¼6.9 Hz, 3H). 13C NMR
[5,1-a]isoquinoline-1-carboxylate (4c). White solid, 1H NMR
(100 MHz)
d
163.7,163.2 (d, J(C,F)¼248.9 Hz),144.9,138.9,138.1,132.4,
(400 MHz, CDCl3): d 7.52e7.50 (m, 1H), 7.47e7.45 (m, 1H), 7.41e7.40
132.3, 130.9 (d, J(C,F)¼9.5 Hz), 130.0, 129.9, 128.8, 119.9, 116.5 (d,
J(C,F)¼22.9 Hz), 112.3 (d, J(C,F)¼25.7 Hz),110.7, 107.4, 60.6, 14.4. HRMS
(ESI) calcd for C20H14BrFN2O2: 435.0120 (MþNaþ), found: 435.0103.
(m, 2H), 7.37e7.29 (m, 3H), 7.24e7.22 (m, 1H), 7.18e7.16 (m, 3H),
6.98 (t, J¼7.3 Hz, 1H), 6.44 (d, J¼7.4 Hz, 1H), 5.17 (d, J¼8.2 Hz, 1H),
4.20 (dd, J¼8.7, 3.7 Hz, 1H), 3.75e3.66 (m, 2H), 3.62e3.52 (m, 2H),
2.47 (s, 3H), 1.36e1.28 (m, 2H), 0.94e0.87 (m, 2H), 0.83e0.79
4.1.9. Ethyl 6-bromo-5-cyclopropyl-8-fluoropyrazolo[5,1-a]isoquino-
line-1-carboxylate (3i). White solid, 1H NMR (400 MHz, CDCl3):
(m, 3H). 13C NMR (100 MHz)
d 171.8, 145.2, 144.5, 136.3, 133.0, 130.8,
129.6, 129.4, 129.3, 129.0, 128.7, 127.9, 127.8,127.7, 127.6, 127.2,126.1,
101.3, 65.3, 65.1, 52.8, 47.2, 30.1, 21.8, 19.0, 13.7. HRMS (ESI) calcd for
C29H29BrN2O4S: 603.0929 (MþNaþ), found: 603.0924.
d
9.97e9.94 (m, 1H), 8.46 (s, 1H), 7.93 (dd, J¼7.8, 2.8 Hz, 1H),
7.39e7.34 (m, 1H), 4.41 (q, J¼7.3 Hz, 2H), 2.38e2.33 (m, 1H),
1.45e1.35 (m, 3H), 1.26e1.24 (m, 4H). 13C NMR (100 MHz)
163.8,
d
163.3 (d, J(C,F)¼249.8 Hz), 145.0, 139.0, 138.2, 132.5, 131.1, 131.0,
119.9, 116.6 (d, J(C,F)¼22.9 Hz), 112.4 (d, J(C,F)¼25.8 Hz), 107.6, 60.6,
31.4, 30.2, 14.4, 10.4. HRMS (ESI) calcd for C17H14BrFN2O2: 399.0120
(MþNaþ), found: 399.0111.
4.2.4. Biphenyl-4-yl
dropyrazolo[5,1-a]isoquinoline-1-carboxylate (4d). White solid, 1H
NMR (400 MHz, CDCl3): 7.61e7.59 (m, 1H), 7.47e7.45 (m, 2H),
6-bromo-5-phenyl-3-tosyl-1,2,3,10b-tetrahy-
d
7.43e7.37 (m, 7H), 7.37e7.36 (m, 1H), 7.31e7.27 (m, 3H), 7.26e7.21
(m, 2H), 7.18e7.16 (m, 2H), 6.96 (dt, J¼7.4, 0.9 Hz, 1H), 6.44 (m, 3H),
5.35 (d, J¼9.2 Hz, 1H), 4.31 (dd, J¼8.7, 3.7 Hz, 1H), 3.89e3.83 (m,
4.1.10. Ethyl 6-bromo-5-butyl-8-fluoropyrazolo[5,1-a]isoquinoline-1-
carboxylate (3j). White solid, 1H NMR (400 MHz, CDCl3):
1H), 3.79e3.75 (m, 1H), 2.44 (s, 3H). 13C NMR (100 MHz)
d 171.0,
d
9.96e9.93 (m, 1H), 8.45 (s, 1H), 7.86 (dd, J¼8.2, 2.3 Hz, 1H),
149.6, 145.4, 144.8, 140.3, 139.2, 136.2, 133.0, 130.8, 129.7, 129.5,
129.4, 128.9, 128.6, 128.2, 127.9, 127.7, 127.6, 127.5, 127.3, 127.2,
126.4, 121.4, 101.3, 65.4, 52.8, 47.5, 21.8. HRMS (ESI) calcd for
C37H29BrN2O4S: 699.0929 (MþNaþ), found: 699.0923.
7.36e7.33 (m, 1H), 4.42 (q J¼7.3 Hz, 2H), 3.53 (t, J¼7.8 Hz, 2H),
1.78e1.73 (m, 2H),1.54 (q, J¼7.4 Hz, 2H),1.45 (t, J¼7.4 Hz, 3H),1.00 (t,
J¼7.3 Hz, 3H). 13C NMR (100 MHz)
163.8, 163.4 (d, J(C,F)¼249.8 Hz),
d
145.3, 140.6, 137.9, 132.1, 131.2, 131.1, 119.9, 116.4 (d, J(C,F)¼21.9 Hz),
112.3 (d, J(C,F)¼24.5 Hz),109.6,107.8, 60.7, 32.1, 28.9,14.5,14.0. HRMS
(ESI) calcd for C18H18BrN2O2: 393.0614 (MþHþ), found: 393.0615.
Acknowledgements
Financial support from National Natural Science Foundation of
China (20972030) and the Science & Technology Commission of
Shanghai Municipality (09JC1404902) is gratefully acknowledged.
4.2. General procedure for generation of 6-bromo-1,2,3,10b-
tetrahydropyrazolo[5,1-a]isoquinoline 4 via three-component
reaction of N0-(2-alkynylbenzylidene)hydrazide 1,
a,b-
unsaturated carbonyl compound 2, with bromine
Supplementary data
A mixture of N0-(2-alkynylbenzylidene)hydrazide 1 (0.2 mmol)
and bromine (0.24 mmol, 1.2 equiv) in CH2Cl2 (0.5 mL) was stirred
at room temperature under air atmosphere for 10 min. Then K3PO4
Experimental procedures, characterization data, 1H, and 13C
NMR spectra of compounds 3 and 4. Supplementary data associated
with this article can be found in online version at doi:10.1016/
j.tet.2010.08.052.
(0.3 mmol, 1.5 equiv) and
a,b-unsaturated carbonyl compound
(0.2 mmol, 1.0 equiv) were added into the reaction mixture. The
reaction mixture was stirred at 10 ꢀC until completion of the re-
action. The mixture was then quenched with saturated NH4Cl (aq),
extracted with ethyl acetate (10 mLꢁ3). The organic layer was
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel to provide the desired product 4.
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[5,1-a]isoquinoline-1-carboxylate (4a). White solid, 1H NMR
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4.17e4.10 (m, 1H), 3.73e3.63 (m, 3H), 3.59e3.53 (m, 1H), 2.44 (s,
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127.2, 126.1, 101.3, 65.1, 61.4, 52.7, 47.1, 21.8, 13.6. HRMS (ESI) calcd
for C27H25BrN2O4S: 575.0616 (MþNaþ), found: 575.0596.
4.2.2. Methyl
azolo[5,1-a]isoquinoline-1-carboxylate (4b). White solid, 1H NMR
(400 MHz, CDCl3): 7.51e7.49 (m, 1H), 7.43e7.37 (m, 2H), 7.35e7.29
6-bromo-5-phenyl-3-tosyl-1,2,3,10b-tetrahydropyr-
d

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