Synthesis of H-pyrazolo[5,1-a]isoquinolines via a silver triflate-catalyzed tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with alcohol

Article abstract of DOI:10.1016/j.tet.2013.08.049

A silver triflate-catalyzed tandem reaction of N′-(2- alkynylbenzylidene)hydrazide with alcohol is reported, which generates H-pyrazolo[5,1-a]isoquinoline derivatives in good yields under mild conditions.

Full text of DOI:10.1016/j.tet.2013.08.049

Tetrahedron 69 (2013) 9219e9223
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Tetrahedron
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Synthesis of H-pyrazolo[5,1-a]isoquinolines via a silver triflate-
catalyzed tandem reaction of N0-(2-alkynylbenzylidene)hydrazide
with alcohol
*
*
Wenyan Hao , Tinli Zhang, Mingzhong Cai
College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
a r t i c l e i n f o
a b s t r a c t
A silver triflate-catalyzed tandem reaction of N0-(2-alkynylbenzylidene)hydrazide with alcohol is re-
ported, which generates H-pyrazolo[5,1-a]isoquinoline derivatives in good yields under mild conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 16 June 2013
Received in revised form 8 August 2013
Accepted 20 August 2013
Available online 27 August 2013
Keywords:
N0-(2-Alkynylbenzylidene)hydrazide
Tandem reaction
Alcohol
1. Introduction
It is well-known that isoquinoline skeleton is found in
many bioactive natural products and pharmaceuticals.1,2 Among
groups of isoquinolines, H-pyrazolo[5,1-a]isoquinolines have been
recognized as the subjects of in-depth investigation in organic
synthesis due to their promising biological activities, such as the
inhibitor of PTP1B and CDC25B, TC-PTP.3 So far, continuous efforts
are dedicated for the constructions of these polycyclic com-
pounds.4 For instance, Wu and co-workers reported the synthesis
of H-pyrazolo[5,1-a]isoquinolines via copper(II)-catalyzed oxida-
tive reactions of tertiary amines with N0-(2-alkynylbenzylidene)
hydrazides in air.4 In the process, copper-catalyzed oxidation of
tertiary amines to enamines is shown to be an essential step
(Scheme 1).
On the other hand, alcohol is an important synthetic in-
termediate, and many related reactions are extensively studied,
such as nucleophilic addition, substitution, and oxidation.5 Among
these well-established reactions, selective oxidation of alcohols to
aldehydes is a type of classical transformation with long history. To
the best of our knowledge, this type of reaction could perform
under mild condition. Inspired by these results and considering the
advantages of tandem reactions,6,7 we hence anticipated that H-
pyrazolo[5,1-a]isoquinolines could be delivered from a one-pot
Scheme 1. Projected route for the synthesis of H-pyrazolo[5,1-a]isoquinolines via
a reaction of N0-(2-alkynylbenzylidene)hydrazide with alcohol.
reaction of N0-(2-alkynylbenzylidene)hydrazide with alcohol un-
der oxidative conditions (Scheme 1). In the reactions, we hypoth-
esized that the reactions might undergo a silver triflate-catalyzed
6-endo-cyclization of N0-(2-alkynylbenzylidene)hydrazide to gen-
erate a 1,3-dipoles species. In the meantime, the in situ selective
oxidation of alcohol would furnish aldehyde, which would go
through [3þ2] cycloaddition with 1,3-dipole species, and sub-
sequent aromatization to afford H-pyrazolo[5,1-a]isoquinolines.
2. Results and discussion
The starting N0-(2-alkynylbenzylidene)hydrazides were pre-
pared via the Sonogashira coupling of 2-bromobenzaldehydes
* Corresponding authors. Tel./fax: þ86 791 88120388; e-mail addresses:
wenyanhao@gmail.com (W. Hao), mzcai@jxnu.edu.cn (M. Cai).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.049

9220
W. Hao et al. / Tetrahedron 69 (2013) 9219e9223
Table 2
with terminal alkynes, followed by the condensation with sulfonyl
hydrazide according to the literature procedure.8 To test the feasi-
bility of the projected transformation, the reaction of N0-(2-
alkynylbenzylidene)hydrazide 1a and 2-phenylethanol 2a was
initially carried out in the presence of silver triflate and an oxidant,
and the experimental results are summarized in Table 1. As shown
in Table 1, the reactions failed when the reaction occurred by
PhI(OAc)2/air, PCC, DMP in DCE using K3PO4 as a base (Table 1,
entries 1e3). To our delight, by altering the solvent to dichloro-
methane (DCM), the desired H-pyrazolo[5,1-a]isoquinolines 3a was
obtained in 47% yield in the presence of DMP as an oxidant (Table 1,
entry 4). It is well-known that DCM is the classic solvent in the
DMP-mediated oxidative process.9 As a result, an array of co-
solvents was investigated (Table 1, entries 5e10). From the re-
sults, it was found that the co-solvent of dichloromethane and di-
chloroethane (1:1 v/v) was the best choice, leading to the final
product in 85% yield. Subsequently, we examined the effect of bases
in the reaction (Table 1, entries 11e17), however, no better result
was detected. Changing the temperature afforded inferior yields.
Synthesis of H-pyrazolo[5,1-a]isoquinolines through
a
reaction of N0-(2-
alkynylbenzylidene)hydrazide with alcohola
R3
AgOTf (10mol%)
DMP (2 equiv)
NHTs
+
N
N
N
R1
OH
K3PO4 (3 equiv)
R3
R1
DCE/DCM, 60 o
C
R2
R2
2
1
3
p-H3CC6H4
Ph
p-ClC6H4
p-H3COC6H4
N
N
N
N
N
N
N
N
Ph
3c, 90% yield
Ph
Ph
Ph
Ph
3b, 87% yield
3a, 85% yield
3d, 92% yield
Ph
Ph
o-BrC6H4
N
N
N
N
N
N
N
N
C6H4p-OCH3
3h, 73% yield
Ph
C6H4p-CH3
C6H4p-Cl
3f, 88% yield
Ph
3g, 78% yield
3e, 72% yield
Ph
Ph
Ph
N
N
N
N
N
N
F
F
N
N
n
Bu
Ph
3k, 61% yield
Ph
C6H4p-OCH3
Table 1
Initial studies for the silver triflate-catalyzed reaction of N0-(2-alkynylbenzylidene)
hydrazide 1a with 2-phenylethanol 2aa
3i, 69% yield
3j, 81% yield
3l, 70% yield
p-ClC6H4
Ph
Ph
Ph
Oxidant
N
N
N
N
N
F
NHTs
N
N
N
AgOTf (10mol%)
OH
N
N
N
+
Ph
3n, 57% yield
O
Ph
3o, 43% yield
C6H4p-CH3
3p, 84% yield
Base, Solvent,Temp.
3m, 69% yield
Ph
Ph
Oxidant
1a
2a
Base
3a
a
Reaction was performed with 1 (0.3 mmol), 2 (0.6 mmol) in DCE/DCM (4 mL, v/
Entry
Solventb
T (ꢀC)
Yield (%)c
v¼1:1). Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1.
1
2
3
4
5
6
7
8
PhI(OAc)2/air
PCC
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Et3N
DABCO
CsCO3
Na2CO3
DBU
K3PO4
K3PO4
DCE
DCE
DCE
DCM
60
60
60
Reflux
60
60
60
60
60
60
60
60
60
60
60
25
85
NR
Complex
NR
47
85
55
44
46
51
61
21
11
45
37
NR
9
40
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
DMP
alkynylbenzylidene)hydrazides with the substituted groups (elec-
tron-withdrawing groups or electron-donating groups) attached on
the aromatic ring were employed. As shown in the Table, the de-
sired product 3o was achieved in 43% when the reaction was per-
formed between N0-(4-methoxy-2-(phenylethynyl)benzylidene)-4-
methylbenzenesulfonohydrazide and 2-phenylethanol.
In order to further expand the scope of the substrates, we ex-
amined the reaction of N0-(2-alkynylbenzylidene)hydrazides with
aliphatic alcohols. To our surprise, the corresponding products
were not obtained in the present of DMP. After screening the oxi-
dants, it was found that the reaction of N0-(2-alkynylbenzylidene)
hydrazide with propanol could proceed smoothly in 84% yield
when PCC was used as the oxidant. The experimental results were
presented in Table 3. Inferior results were obtained when N0-(2-
alkynylbenzylidene)hydrazides 1 reacted with various aliphatic
alcohols, such as butanol, 2-methoxylethanol.
DCE/DCM
THF/DCM
Toluene/DCM
CH3CN/DCM
DMF/DCM
EtOH/DCM
DCE/DCM
DCE/DCM
DCE/DCM
DCE/DCM
DCE/DCM
DCE/DCM
DCE/DCM
9
10
11
12
13
14
15
16
17
a
Reaction was performed with 1a (0.3 mmol), 2a (0.6 mmol), base (0.9 mmol),
oxidant (0.6 mmol) in solvent (4 mL).
b
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide.
DMP: DesseMartin reagent.
c
We then started to investigate the tandem reaction of N0-(2-
alkynylbenzylidene)hydrazide with aromatic alcohol 2, catalyzed
by silver triflate under the optimized reaction conditions (DMP as
the oxidant, K3PO4, 1,2-dichloroethane/1,2-dichloroethane, 60 ꢀC).
The results are shown in Table 2. From Table 2, it was noticed that
a variety of H-pyrazolo[5,1-a]isoquinolines were furnished in good
to excellent yields. For example, reaction of N0-(2-alkynyl benzyli-
dene)hydrazide with 2-(4-methoxyphenyl)ethanol gave rise to the
desired product 3d in 92% yield under the standard conditions. The
product 3e was obtained in 72% yield when 2-(2-bromophenyl)
ethanol was utilized as a reaction partner. The reactions were
compatible with the substituent R2 including butyl and cyclopropyl
groups. Meanwhile, the reaction also worked well when R2 was
replaced by not only electron-rich but also electron-deficient aryl
groups. However, the yield drastically decreased when N0-(2-
Table 3
Synthesis of H-pyrazolo[5,1-a]isoquinolines through
a
reaction of N0-(2-
alkynylbenzylidene)hydrazides with aliphatic alcoholsa
R3
AgOTf (10mol%)
PCC (2 equiv)
NHTs
N
N
R1
OH
K3PO4 (3 equiv)
CH2ClCH2Cl, 60 o
R3
+
N
R1
R2
C
R2
2
1
3
n
H CO
Bu
3
Et
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
3r, 75% yield
3q, 84% yield
3t, 30% yield
3s, 36% yield
a
Reaction was performed with 1 (0.3 mmol), 2 (0.6 mmol) in DCE (2 mL). Isolated
yield based on N0-(2-alkynylbenzylidene)hydrazide 1.

W. Hao et al. / Tetrahedron 69 (2013) 9219e9223
9221
Based on the above results, we proposed a plausible mechanism
4.2. General experimental procedure for tandem reaction of
for this one-pot tandem reaction (Scheme 2). N0-(2-
Alkynylbenzylidene)hydrazide A through a 6-endo-cyclization re-
action would occur to generate the isoquinolinium-2-yl amide B in
the presence of suitable Lewis acid. In this step, the formation of
a p-complex via coordination of the alkynyl moiety of A to the Lewis
acid would be involved, thus activating the triple bond for further
cyclization. Meanwhile, the in situ formed enolate 3 (derived from
aldehyde 2, which was produced by the oxidation of alcohols 1 in
the presence of base) would attack the isoquinolinium-2-yl amide
B to produce intermediate C. Subsequent intramolecular conden-
sation and aromatization would give rise to the desired H-pyrazolo
[5,1-a]isoquinolines 4.
N0-(2-alkynylbenzylidene)hydrazide with aromatic alcohol
Silver trifluoromethanesulfonate (0.03 mmol), N0-(2-
alkynylbenzylidene)hydrazide 1 (0.30 mmol, 1.0 equiv), and anhy-
drous dichloroethane (2.0 mL) were added into a tube equipped
with a magnetic stirring bar under sealing plug. The mixture was
stirred at 60 ꢀC for 3 h. When N0-(2-alkynylbenzylidene)hydrazide 1
disappeared as indicated by TLC, the solution was cooled to rt, then
DMP (0.6 mmol, 2.0 equiv), aromatic alcohol 2 (0.6 mmol, 2.0 equiv),
K3PO4 (0.9 mmol, 3.0 equiv), and anhydrous dichloromethane
(2.0 mL) were added into the solution. The mixture was stirred at
60 ꢀC. After completion of the reaction as indicated by TLC, the re-
action was quenched with water (10 mL), extracted with EtOAc
(3ꢁ10 mL), dried by anhydrous Na2SO4. Evaporation of the solvent
followed by purification on silica gel provided the corresponding
product 3.
3
R
H
N
LA (Cat.)
N
Ts
1
N
R
R
OH
N
+
3
1
R
R
Oxidant
4.2.1. 1,5-Diphenyl-pyrazolo[5,1-a]isoquinoline (3a). Yield: 85%. 1H
2
2
R
1
A
4
NMR (400 MHz, CDCl3):
d
¼8.05 (d, J¼8.0 Hz, 1H), 7.94 (s, 1H), 7.89
(d, J¼7.2 Hz, 2H), 7.71 (d, J¼8.0 Hz, 1H), 7.42e7.59 (m, 8H), 7.31 (t,
aromatization
J¼7.6 Hz, 2H), 7.05 (s, 1H). 13C NMR (100 MHz, CDCl3):
¼141.65,
d
Oxidant
AgOTf
3
R
138.55, 134.62, 134.27, 133.99, 130.10, 129.75, 129.51, 129.33, 128.76,
128.44, 127.83, 127.47, 127.27, 126.93, 124.64, 123.25, 117.13, 113.02.
HRMS calcd for C23H17Nþ2 (MþHþ): 321.1386, Found: 321.1418.
H
B
NHTs
N
O
Ts
N
1
3
N
R
R
1
R
2
2
R
R
2
D
TfOAg
4.2.2. 1-(4-Chlorophenyl)-5-phenyl-pyrazolo[5,1-a]isoquinoline
Base
-H O
2
(3b). Yield: 87%. 1H NMR (400 MHz, CDCl3):
d
¼8.00 (d, J¼8.0 Hz,
3
R
1H), 7.92 (s, 1H), 7.88 (d J¼6.8 Hz, 2H), 7.75 (d, J¼7.6 Hz, 1H),
O
N
-
O
N
Ts
N
1
3
7.47e7.58 (m, 8H), 7.36 (t, J¼7.6 Hz, 1H), 7.08 (s, 1H). 13C NMR
R
R
+
N
Ts
1
R
2
R
(100 MHz, CDCl3):
d
¼141.46, 138.53, 134.65, 133.81, 133.43, 132.72,
2
R
3
B
131.37, 129.78, 129.47, 129.40, 128.98, 128.46, 128.01, 127.39, 127.04,
124.39, 123.08, 115.80, 113.16. HRMS calcd for C23H16ClNþ2 (MþHþ):
355.0997, Found: 355.0979.
C
Scheme 2. Proposed mechanistic pathway.
4.2.3. 5-Phenyl-1-(p-tolyl)-pyrazolo[5,1-a]isoquinoline (3c). Yield:
90%. 1H NMR (400 MHz, CDCl3):
d
¼8.07 (d, J¼8.0 Hz, 1H), 7.91 (s,
3. Conclusions
1H), 7.87 (d, J¼8.0 Hz, 2H), 7.68 (d, J¼8.0 Hz, 1H), 7.43e7.55 (m, 6H),
7.28e7.31 (m, 3H), 7.01 (s, 1H), 2.45 (s, 3H). 13C NMR (100 MHz,
In conclusion, we have described an efficient route for the
synthesis of H-pyrazolo[5,1-a]isoquinoline derivatives via a silver
triflate-catalyzed tandem reaction of N0-(2-alkynylbenzylidene)
hydrazides with alcohols. The reaction proceeds smoothly under
mild conditions, leading to the diverse products in good yields. The
efficiency of this method combined with the operational simplicity
of the present process makes it potential attractive for structure
construction.
CDCl3):
d
¼141.76, 138.59, 137.22, 134.61, 134.07, 131.23, 129.98,
129.75, 129.54, 129.34, 128.74, 128.46, 127.78, 127.26, 126.91, 124.78,
123.30, 117.10, 112.97, 21.39. HRMS calcd for C24H19Nþ2 (MþHþ):
335.1543, Found: 355.1571.
4.2.4. 1-(4-Methoxyphenyl)-5-phenyl-pyrazolo[5,1-a]isoquinoline
(3d). Yield: 92%.1H NMR (400 MHz, CDCl3):
d¼8.03 (d, J¼8.0 Hz,1H),
7.91 (s, 1H), 7.88 (d, J¼6.8 Hz, 2H), 7.70 (d, J¼6.8 Hz, 1H), 7.45e7.56
(m, 6H), 7.32 (t, J¼7.4 Hz,1H), 7.06 (s,1H), 7.03 (d, J¼2.4 Hz, 2H), 3.90
4. Experimental section
(s, 3H). 13C NMR (100 MHz, CDCl3):
d¼159.12, 141.74, 138.56, 134.65,
134.04, 131.23, 129.70, 129.51, 129.32, 128.45, 127.74, 127.25, 126.92,
126.39, 124.78, 123.20, 116.73, 114.23, 112.91, 55.41. HRMS calcd for
4.1. General
C
24H19N2Oþ (MþHþ) 351.1492, Found: 351.1492.
Unless otherwise stated, all commercial reagents and solvents
were used as received. Flash column chromatography was per-
4.2.5. 1-(2-Bromophenyl)-5-phenyl-pyrazolo[5,1-a]isoquinoline
(3e). Yield: 72%. 1H NMR (400 MHz, CDCl3):
ꢀ
formed using silica gel (60 A pore size, 32e63
mm, standard grade).
d¼7.93e7.94 (m, 2H),
Analytical thin-layer chromatography was performed using glass
plates pre-coated with 0.25 mm 230e400 mesh silica gel impreg-
nated with a fluorescent indicator (254 nm). Thin layer chroma-
tography plates were visualized by exposure to ultraviolet light.
Organic solutions were concentrated on rotary evaporators at
w20 Torr (house vacuum) at 25e35 ꢀC. Nuclear magnetic reso-
nance (NMR) spectra are recorded in parts per million from internal
7.92 (s, 1H), 7.79 (d, J¼7.6 Hz, 1H), 7.73 (d, J¼7.6 Hz, 1H), 7.43e7.61
(m, 7H), 7.24e7.36 (m, 2H), 7.09 (s, 1H). 13C NMR (100 MHz, CDCl3):
d
¼140.96, 138.03, 134.71, 134.66, 133.37, 132.63, 132.26, 129.24,
129.09, 129.01, 128.87, 127.94, 127.44, 127.15, 126.70, 126.65, 125.35,
123.97, 122.92, 114.89, 112.61. HRMS calcd for C23H16BrNþ2 (MþHþ):
399.0491, Found: 399.0497.
tetramethylsilane on the
d
scale. 1H and 13C NMR spectra were
4.2.6. 5-(4-Chlorophenyl)-1-phenyl-pyrazolo[5,1-a]isoquinoline
recorded in CDCl3 on a Bruker DRX-400 Spectrometer operating at
400 MHz and 100 MHz. High resolution mass spectrometry (HRMS)
spectra were obtained on a micrOTOF II Instrument.
(3f). Yield: 88%. 1H NMR (400 MHz, CDCl3):
1H), 7.94 (s,1H), 7.86 (d, J¼8.0 Hz, 2H), 7.74 (d, J¼8.0 Hz,1H), 7.59 (d,
J¼7.2 Hz, 2H), 7.44e7.54 (m, 6H), 7.34 (t, J¼7.6 Hz, 1H), 7.06 (s, 1H).
d
¼8.05 (d, J¼8.4 Hz,

9222
W. Hao et al. / Tetrahedron 69 (2013) 9219e9223
13C NMR (100 MHz, CDCl3):
d
¼140.59, 136.25, 134.23, 133.52,
0.92e0.95 (m, 2H). 13C NMR (100 MHz, CDCl3):
d
¼159.59 (d,
133.02, 131.26, 129.79, 128.99, 128.47, 127.72, 127.61, 126.85, 126.47,
126.25, 126.09, 123.63, 122.19, 116.19, 111.99. HRMS calcd for
1JCF¼244 Hz), 140.33, 139.01, 135.44, 132.64, 128.90, 127.81, 127.63
(d, 3JCF¼9 Hz), 126.64, 125.16, 123.96 (d, 3JCF¼10 Hz), 116.58, 115.20
23H16ClNþ2 (MþHþ): 355.0997, Found: 355.0995.
(d, JCF¼24 Hz), 107.49 (d, JCF¼24 Hz), 105.80, 10.46, 5.83. HRMS
calcd for C20H16FNþ2 (MþHþ): 303.1292, Found: 303.1261.
2
2
C
4.2.7. 1-Phenyl-5-(p-tolyl)-pyrazolo[5,1-a]isoquinoline (3g). Yield:
78%.1H NMR (400 MHz, CDCl3):
d
¼8.04 (d, J¼8.0 Hz,1H), 7.93 (s,1H),
4.2.14. 9-Methyl-1,5-diphenyl-pyrazolo[5,1-a]isoquinoline
7.77 (d, J¼8.0 Hz, 2H), 7.71 (d, J¼7.6 Hz, 1H), 7.59 (d, J¼7.6 Hz, 2H),
(3n). Yield: 57%. 1H NMR (400 MHz, CDCl3):
d
¼7.92 (s, 1H),
7.44e7.52 (m, 4H), 7.36 (d, J¼7.6 Hz, 2H), 7.30 (t, J¼7.6 Hz, 1H), 7.03
7.86e7.89 (m, 3H), 7.59e7.63 (m, 3H), 7.49e7.58 (m, 5H), 7.44e7.46
(s, 1H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3):
d¼141.61, 139.36,
(m, 1H), 7.30e7.32 (m, 1H), 7.02 (s, 1H), 2.32 (s. 3H). 13C NMR
138.66, 134.59, 134.34, 131.10, 130.11, 129.83, 129.41, 129.16, 128.76,
127.80, 127.45, 127.21, 126.79, 124.57, 123.25, 117.08, 112.64, 21.50.
HRMS calcd for C24H19Nþ2 (MþHþ): 335.1543, Found: 335.1553.
(100 MHz, CDCl3):
d
¼141.46, 137.70, 136.88, 134.35, 134.13, 130.07,
129.48, 129.39, 129.17, 128.63, 128.40, 127.48, 127.42, 127.14, 124.66,
123.10, 116.95, 112.93, 21.82. HRMS calcd for C24H19Nþ2 (MþHþ):
335.1543, Found: 335.1522.
4.2.8. 5-(4-Methoxyphenyl)-1-phenyl-pyrazolo[5,1-a]isoquinoline
(3h). Yield: 73%. 1H NMR (400 MHz, CDCl3):
d
¼8.04 (d, J¼8.0 Hz,
4.2.15. 8-Methoxy-1,5-diphenyl-pyrazolo[5,1-a]isoquinoline
1H), 7.94 (s,1H), 7.85 (d, J¼8.4 Hz, 2H), 7.71 (d, J¼8.4 Hz,1H), 7.59 (d,
J¼6.8 Hz, 2H), 7.44e7.53 (m, 4H), 7.30 (t, J¼7.6 Hz, 1H), 7.08 (d,
J¼8.4 Hz, 2H), 7.02 (s, 1H), 3.90 (s, 3H). 13C NMR (100 MHz, CDCl3):
(3o). Yield: 43%. 1H NMR (400 MHz, CDCl3):
d
¼7.99 (d, J¼8.0 Hz,
1H), 7.92 (s, 1H), 7.88e7.92 (m, 2H), 7.50e7.61 (m, 7H), 7.42e7.47
(m, 1H), 7.13 (d, J¼4.0 Hz, 1H), 7.00 (s, 1H), 6.95e6.98 (m, 1H), 3.91
d
¼160.37, 141.56, 138.34, 134.63, 134.33, 130.90, 130.11, 129.88,
(s, 3H). 13C NMR (100 MHz, CDCl3):
d
¼159.09. 141.74, 138.93, 134.40,
128.76, 127.81, 127.45, 127.15, 126.70, 126.32, 124.45, 123.24, 117.09,
134.01, 131.49, 130.07, 129.48, 129.31, 128.74, 128.42, 127.32, 124.86,
118.72, 116.44, 115.82, 112.69, 108.36, 55.40. HRMS calcd for
113.90, 112.43, 55.45. HRMS calcd for
351.1492, Found: 351.1509.
C
24H19N2Oþ (MþHþ):
C
24H19N2Oþ (MþHþ): 351.1492, Found: 351.1481.
4.2.9. 5-Cyclopropyl-1-phenyl-pyrazolo[5,1-a]isoquinoline
(3i). Yield: 69%.1H NMR (400 MHz, CDCl3):
4.2.16. 1-(4-Chlorophenyl)-5-(p-tolyl)-pyrazolo[5,1-a]isoquinoline
(3p). Yield: 84%. 1H NMR (400 MHz, CDCl3):
d
¼8.01 (d, J¼5.2 Hz,1H),
d
¼7.99 (d, J¼8.0 Hz,
8.01 (s, 1H), 7.63 (d, J¼8.0 Hz, 1H), 7.58 (d, J¼7.2 Hz, 2H), 7.42e7.52
1H), 7.90 (s, 1H), 7.73e7.78 (m, 3H), 7.47e7.54 (m, 5H), 7.33e7.38
(m, 4H), 7.24e7.28 (m,1H), 6.71 (s,1H), 2.70e2.74 (m,1H),1.21e1.25
(m, 3H), 7.06 (s, 1H), 2.46 (s, 3H). 13C NMR (100 MHz, CDCl3):
(m, 2H), 0.93e0.97 (m, 2H). 13C NMR (100 MHz, CDCl3):
d¼141.41,
d
¼141.44, 139.45, 138.65, 134.64, 133.40, 132.82, 131.39, 130.95,
140.76, 134.36, 134.19, 130.09, 129.71, 128.73, 127.64, 127.40,
126.68, 126.22, 123.95, 123.17, 117.14, 107.44, 11.61, 6.96. HRMS
calcd for C20H17Nþ2 (MþHþ): 285.1386, Found: 285.1386.
129.88, 129.39, 129.17, 128.99, 127.98, 127.34, 126.91, 124.34, 123.08,
115.76, 112.78, 21.50. HRMS calcd for
369.1153, Found: 369.1134.
C
24H18ClNþ2 (MþHþ):
4.2.10. 5-Butyl-1-phenyl-pyrazolo[5,1-a]isoquinoline
(3j). Yield:
¼7.93 (d, J¼8.4 Hz, 1H), 7.87 (s,
4.3. General experimental procedure for tandem reaction of
81%. 1H NMR (400 MHz, CDCl3):
d
N0-(2-alkynylbenzylidene)hydrazide with aliphatic alcohol
1H), 7.56 (d, J¼7.6 Hz, 1H), 7.48 (d, J¼6.8 Hz, 2H), 7.31e7.42 (m, 3H),
7.17 (t, J¼8.0 Hz, 2H), 6.77 (s, 1H), 3.12 (t, J¼7.8 Hz, 2H), 1.81e1.85
(m, 2H), 1.43e1.49 (m, 2H), 0.93 (t, J¼7.4 Hz, 3H). 13C NMR
Silver trifluoromethanesulfonate (0.03
mmol), N0-(2-
alkynylbenzylidene)hydrazide 1 (0.30 mmol, 1.0 equiv), anhy-
drous dichloroethane (2 mL) were placed into a tube equipped with
a magnetic stirring bar under sealing plug. The mixture was stirred
at 60 ꢀC for 3 h. When N0-(2-)hydrazide 1 disappeared as indicated
by TLC, the solution was cooled to 0 ꢀC, then PCC (0.6 mmol,
2.0 equiv), aliphatic alcohol 2 (0.6 mmol, 2.0 equiv), K3PO4
(0.9 mmol, 3.0 equiv) were added into the solution for stirring
about 2 h, the solution was heated to 60 ꢀC again. After completion
of the reaction as indicated by TLC, the reaction was quenched with
water (10 mL), extracted with EtOAc (3ꢁ10 mL), dried by anhydrate
Na2SO4. Evaporation of the solvent followed by purification on
silica gel provided the corresponding product 3.
(100 MHz, CDCl3):
d
¼141.24, 139.49, 134.44, 134.16, 130.10, 129.74,
128.73, 127.62, 127.38, 126.62, 126.15, 124.08, 123.16, 116.98, 109.98,
30.91, 29.08, 22.69, 14.07. HRMS calcd for C21H21Nþ2 (MþHþ):
301.1699, Found: 301.1671.
4.2.11. 9-Fluoro-1,5-diphenyl-pyrazolo[5,1-a]isoquinoline
(3k). Yield: 61%. 1H NMR (400 MHz, CDCl3):
d
¼7.94 (s, 1H), 7.87 (d,
J¼7.2 Hz, 2H), 7.67e7.72 (m, 2H), 7.46e7.58 (m, 8H), 7.20e7.25 (m,
1H),7.03(s,1H).13CNMR(100MHz,CDCl3):
d
¼161.11(d,1JCF¼246 Hz),
141.60,137.91,133.90,133.86,133.73,133.57,129.97,129.45,129.35 (d,
3JCF¼9 Hz),128.91,128.46,127.78,126.29,125.80 (d, 3JCF¼9 Hz),117.65,
116.50 (d, 2JCF¼24 Hz), 112.29, 108.74 (d, 2JCF¼24 Hz). HRMS calcd for
C
23H16FNþ2 (MþHþ): 339.1292, Found: 339.1280.
4.3.1. 1-Methyl-5-phenyl-pyrazolo[5,1-a]isoquinoline10 (3q). Yield:
84%. 1H NMR (400 MHz, CDCl3):
d
¼8.28 (d, J¼7.6 Hz, 1H), 7.85 (d,
J¼6.8 Hz, 2H), 7.81 (s, 1H), 7.72 (d, J¼6.8 Hz, 1H), 7.50e7.57 (m, 5H),
6.97 (s, 1H), 2.66 (s, 3H). 13C NMR (100 MHz, CDCl3):
4.2.12. 9-Fluoro-5-(4-methoxyphenyl)-1-phenyl-pyrazolo[5,1-a]iso-
quinoline (3l). Yield: 70%. 1H NMR (400 MHz, CDCl3):
d¼7.94 (s,1H),
d
¼142.04,
7.83 (d, J¼8.8 Hz, 2H), 7.66e7.70 (m, 2H), 7.45e7.57 (m, 5H),
138.63, 135.23, 134.06,129.49,129.42, 129.25, 128.42, 127.16,125.69,
123.23, 112.40, 110.13, 11.93.
7.20e7.23 (m, 1H), 7.07 (d, J¼8.8 Hz, 2H), 6.99 (s, 1H), 3.89 (s, 3H).
1
13C NMR (100 MHz, CDCl3):
d
¼160.99 (d, JCF¼245 Hz), 141.53,
137.73, 133.94, 133.90, 133.67, 130.86, 130.00, 129.20 (d, 3JCF¼9 Hz),
128.93, 127.77, 126.44, 126.08, 125.60 (d, 3JCF¼10 Hz), 117.62, 116.46
(d, 2JCF¼24 Hz), 113.91, 111.70, 108.71 (d, 2JCF¼24 Hz), 55.44. HRMS
calcd for C24H18FN2Oþ (MþHþ): 369.1398, Found: 369.1394.
4.3.2. 1-Ethyl-5-phenyl-pyrazolo[5,1-a]isoquinoline11
75%. 1H NMR (400 MHz, CDCl3):
(3r). Yield:
¼8.25 (d, J¼8.0 Hz, 1H), 7.84e7.86
d
(m, 3H), 7.72 (d, J¼7.6 Hz, 1H), 7.48e7.57 (m, 5H), 6.97 (s, 1H),
3.09e3.14 (m, 2H),1.46 (t, J¼7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
¼139.31, 137.61, 133.48, 133.08, 128.50, 128.37, 128.15, 127.33,
4.2.13. 5-Cyclopropyl-9-fluoro-1-phenyl-pyrazolo[5,1-a]isoquinoline
126.18, 126.13, 126.07, 124.43, 122.19, 116.10, 111.39, 18.45, 13.10.
(3m). Yield: 69%. 1H NMR (400 MHz, CDCl3):
d
¼8.02 (s, 1H),
7.60e7.67 (m, 2H) 7.50e7.57 (m, 4H), 7.46e7.47 (m, 1H), 7.17e7.22
(m, 1H), 6.70 (s, 1H), 2.65e2.70 (m, 1H), 1.21e1.25 (m, 2H),
4.3.3. 1-Butyl-5-phenyl-pyrazolo[5,1-a]isoquinoline
(3s). Yield:
36%. 1H NMR (400 MHz, CDCl3):
d
¼8.18 (d, J¼8.0 Hz, 1H), 7.77 (d,

W. Hao et al. / Tetrahedron 69 (2013) 9219e9223
9223
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J¼8.0 Hz, 2H), 7.76 (s, 1H), 7.66 (d, J¼7.8 Hz, 1H), 7.39e7.53 (m,
5H), 6.90 (s, 1H), 3.00 (t, J¼7.6 Hz, 2H), 1.73e1.76 (m, 2H),
1.43e1.48 (m, 2H), 0.94 (t, J¼7.4 Hz, 3H). 13C NMR (100 MHz,
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CDCl3):
d
¼140.07, 137.64, 133.55, 133.09, 128.52, 128.38, 128.16,
127.33, 126.21, 126.12, 126.08, 124.45, 122.18, 114.65, 111.34, 30.70,
28.68, 21.67, 13.11. HRMS calcd for C21H21Nþ2 (MþHþ): 301.1699,
Found: 301.1650.
4.3.4. 1-Methoxy-5-phenyl-pyrazolo[5,1-a]isoquinoline (3t). Yield:
30%. 1H NMR (400 MHz, CDCl3):
d
¼8.52 (d, J¼8.0 Hz, 1H), 7.85 (d,
J¼7.8 Hz, 1H), 7.84 (s, 1H), 7.68e7.73 (m, 2H), 7.47e7.57 (m, 5H),
6.94 (s, 1H), 4.06 (s, 3H). 13C NMR (100 MHz, CDCl3):
d
¼141.29,
138.12, 133.44, 130.93, 129.42, 129.31, 128.85, 128.42, 127.32, 127.02,
126.55, 126.34, 124.88, 123.14, 112.65, 59.21. HRMS calcd for
C
18H15N2Oþ (MþHþ): 275.1179, Found: 275.1192.
Acknowledgements
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Financial support from National Natural Science Foundation of
China (no 20862008), is gratefully acknowledged.
References and notes
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