[Cu(maloNHC)]-catalyzed synthesis of 2-aryl pyrazolo[5,1-a]isoquinolines by annulation of N′-(2-((trimethylsilyl)ethynyl)benzylidene)hydrazides with terminal aromatic alkynes

Article abstract of DOI:10.1016/j.tet.2017.09.037

A [Cu(maloNHC)]-catalyzed synthesis of 2-aryl pyrazolo[5,1-a]isoquinolines via annulation of N′-(2-((trimethylsilyl)ethynyl)benzylidene)hydrazides with terminal aromatic alkynes was developed.

Full text of DOI:10.1016/j.tet.2017.09.037

Accepted Manuscript
[Cu(maloNHC)]-catalyzed synthesis of 2-aryl pyrazolo[5,1-a]isoquinolines by
annulation of N′-(2-((trimethylsilyl)ethynyl)benzylidene)hydrazides with terminal
aromatic alkynes
Huixin Liu, Le Lu, Ruimao Hua
PII:
S0040-4020(17)30966-3
10.1016/j.tet.2017.09.037
TET 28988
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 August 2017
Revised Date: 17 September 2017
Accepted Date: 19 September 2017
Please cite this article as: Liu H, Lu L, Hua R, [Cu(maloNHC)]-catalyzed synthesis of 2-aryl
pyrazolo[5,1-a]isoquinolines by annulation of N′-(2-((trimethylsilyl)ethynyl)benzylidene)hydrazides with
terminal aromatic alkynes, Tetrahedron (2017), doi: 10.1016/j.tet.2017.09.037.
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ACCEPTED MANUSCRIPT
Graphical Abstract
[Cu(maloNHC)]-catalyzed synthesis of 2-aryl pyrazolo[5,1-a]isoquinolines by annulation
of N′-(2-((trimethylsilyl)ethynyl)benzylidene)hydrazides with terminal aromatic alkynes
1

ACCEPTED MANUSCRIPT
[Cu(maloNHC)]-catalyzed synthesis of 2-aryl pyrazolo[5,1-a]isoquinolines by annulation
of N′-(2-((trimethylsilyl)ethynyl)benzylidene)hydrazides with terminal aromatic alkynes
Huixin Liu, Le Lu and Ruimao Hua*
Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics &
Molecular Engineering of Ministry of Education, Beijing 100084, China
E-mail: ruimao@mail.tsinghua.edu.cn
Abstract: A [Cu(maloNHC)]-catalyzed synthesis of 2-aryl pyrazolo[5,1-a]isoquinolines via
annulation of N′-(2-((trimethylsilyl)ethynyl)benzylidene)hydrazides with terminal aromatic
alkynes was developed.
Keywords: annulation; alkynes; pyrazolo[5,1-a]isoquinolines; N-heterocyclic carbene.
1. Introduction
It is one of the interesting and important research topics to synthesize the fused
N-heterocyclic compounds due to their potential physiological and biological activity.1
Pyrazoles2 and isoquinolines3 are the important classes of N-heterocyclic compounds.
Pyrazolo[5,1-a]isoquinolines, incorporated both isoquinoline and pyrazole skeletons,
represent one of the interesting structures of the fused N-heterocyclic compounds, which may
show the promising biological activity.4
Wu’s group has well-studied and reported the construction of pyrazolo[5,1-a]isoquinoline
skeleton bearing multi-substituents by AgOTf-catalyzed tandem reactions of
N′-(2-alkynylbenzylidene)hydrazides (or generated in situ, R ≠ H, SiMe3) (Scheme 1) with a
variety of other reactants,5 and the reactive intermediate is proposed to be the N-tosyl
isoquinolinium-2-yl amide, generated via 6-endo-cyclization by intramolecular nucleophilic
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attack of hydrazide group to carbon-carbon triple bond. The reaction of
N′-(2-alkynylbenzylidene)hydrazides with terminal alkynes provides an efficient method for
the synthesis of 2,5-disubstituted pyrazolo[5,1-a]isoquinolines (Scheme 1, eq. 1).5a The
similar intermediates of N-benzoylpyridinium imides have been also well used in the
synthesis of pyrazolo[1,5-a]pyridines via a [3+2] cycloaddition with alkynes under different
conditions.6
On the other hand, Cu/NHC (N-heterocyclic carbene)-catalyzed transformation has
attracted widespread attention,7 but the application of Cu/NHC as catalyst in the synthesis of
N-heterocycles is limited to the [3+2] cycloaddition of azides with alkynes for the synthesis of
1,2,3-triazoles.8 With several Cu/NHC complexes in hand, and in continuation of our previous
work on the synthesis of N-heterocycles via annulation reactions using alkynes as one of the
reactants,9 we explored the possibility to extend the application of Cu/NHC complexes as
catalysts to catalyze the annulation of N′-(2-alkynylbenzylidene)hydrazide (R = H) (Scheme 1,
eq. 2) with terminal aromatic alkynes for the synthesis of 2-aryl pyrazolo[5,1-a]isoquinolines.
Scheme 1. Synthesis of pyrazolo[5,1-a]isoquinolines
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2. Results and discussion
At first, we carried out the reaction of N'-(2-ethynylbenzylidene)hydrazide (1a’) (R = H,
as shown in Scheme 1) with phenylacetylene (2a) in the presence of [Cu(maloNHC)] (A)
([(maloNHC)CuCl]·Li(THF)2,10 5 mol%), CuI (10 mol%), 3.0 equivalent of KOtBu and 1.0
equivalent of NH2NHTs in 1,4-dioxane at 90 °C under N2 for 4 h, and the desired product of
2-phenyl pyrazolo[5,1-a]isoquinoline (3a) could be isolated from the reaction mixture in 90%
yield (Scheme 2).11 Because 1a (R = SiMe3, in Scheme 1) is the precursor of 1a’, which can
be converted into 1a’ under basic conditions, we therefore performed the reaction of 1a with
2a under the same reaction conditions, and fortunately 3a could be obtained in 85% yield
(Table 1, entry 1).
Screening of other [Cu(NHC)] complexes in the reaction of 1a with 2a under the similar
conditions revealed that B showed the similar catalytic activity as A (Table 1, entry 2). The
use of C and D complexes gave low yields of 3a (Table 1, entries 3-4). In case of either
without Cu(NHC) complex or without CuI, no product formed at all (Table 1, entries 5 and
6).12 Other solvents such as toluene, DCE and MeCN are less effective and afforded 3a in low
yields (Table 1, entries 7-9). In addition, no desired product could be obtained without use of
KOtBu (Table 1, entry 10).
Scheme 2. Synthesis of 2-phenylpyrazolo[5,1-a]isoquinoline from 1a’
3

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Table 1
Reaction optimization for the synthesis of 3a a
Entry Cu(NHC)
Solvent
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
Yield (%)b
1
2
85
88
20
35
0
A
B
C
D
3
4
5
6c
0
B
B
B
B
B
7
31
43
18
0
8
DCE
9
10d
MeCN
1,4-dioxane
a
o
The reactions were carried out at 90 C for 4 h by using 1a (0.25 mmol), 2a (0.2
mmol), Cu(NHC) (5 mol%), CuI (10 mol%), KOtBu (3 equiv) and NH2NHTs (1
equiv) in solvent (5 mL) under N2.
b Isolated yield.
c Without CuI.
d Without base.
Under the optimized reaction conditions (indicated in entry 2 of Table 1), we then
examined the scope of the reactants, and Table 2 shows the effect of substituents in starting
material 1, when it was allow to react with 2a. Neither significant electron effect nor steric
hindrance effect could be observed by using 1 bearing electron-withdrawing groups or
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electron-donating groups at different position, and the corresponding products 3b-e and 3g-h
were obtained good yields. Only in the case of 1 having chloro group at 4-position of phenyl
ring used, the corresponding product 3f was formed in a declined yield (77%).
Table 2
Substrate scope of 1a
Ph
B (5 mol %), KOtBu (3 equiv)
NNHTs
R'
CuI (10 mol %)
NH2NHTs (1 equiv)
1,4-dioxane, 90 oC, 4 h
N
Ph
+
N
R'
TMS
F
2a
3
1
Ph
N
Ph
Ph
N
Ph
N
F
N
MeO
Cl
N
N
N
N
3b 86%
3c 83%
3d 80%
3e 93%
Ph
N
Ph
N
Ph
MeO
MeO
N
N
MeO
MeO
N
N
Cl
OMe
3h 81%
3f 74%
3g 89%
a Reactions were carried out with 1 (0.25 mmol), 2a (0.2 mmol), B (5 mol%), CuI (10
mol%), KOtBu (3 equiv) and NH2NHTs (1 equiv) in 1,4-dioxane (5 mL) at 90 oC for 4 h.
Table 3 summaries the results from the reaction of 1a with various terminal aromatic
alkynes (2), and various 2-arylpyrazolo[5,1-a]isoquinoline (3i-q) were obtained in good to
excellent yields. The effects of substituent(s) in aryl group of alkynes are apparently observed.
Terminal aromatic alkynes bearing electron-withdrawing group (Cl group) at meta-position
showed higher reactivity than that having electron-donating group (Me) at the same position,
and the corresponding products 3i and 3j formed in 92% and 84%, respectively. However, in
the cases of para-substituted aromatic alkynes employed, alkynes having electron-donating
group showed higher reactivity (products 3l and 3m) than those bearing electron-withdrawing
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groups (products 3k and 3n). Noted that 1,4-diethynylbenzene also showed good reactivity to
give 3n with one alkynyl group untouched, which is expected to be the interesting
intermediate for further transformation. In addition, the use of 4-fluoro-3-
methylphenylacetylene and 1-ethynylnaphthalene led to relative low yields of the expected
products 3o and 3p. The reaction of 3-ethynylthiophene afforded 3q in 85% yield. Moreover,
the structures of 3k and 3q were further confirmed by x-ray diffraction (see SI for details).
However, all attempts to realize the annulation of terminal aliphatic alkynes under similar
conditions have been unsuccessful to date.
Table 3
Substrate scope of alkynesa
Ar
NNHTs
B (5 mol %), CuI (10 mol %)
KOtBu (3 equiv)
N
+
N
Ar
NH2NHTs (1 equiv)
1, 4-dioxane, 90 oC, 4 h
TMS
1a
3
2
R
R
R = Br, 3k 75%
R = Me, 3l 90%
R = OMe, 3m 89%
R = alkynyl, 3n 78%
N
N
N
N
R = Cl, 3i 92%
R = Me, 3j 84%
F
S
N
N
N
N
N
N
3o 52%
3p 70%
3q 85%
a Reactions were carried out with 1a (0.25 mmol), 2 (0.2 mmol), B (5 mol%), CuI (10
mol%), KOtBu (3 equiv) and NH2NHTs (1 equiv) in 1,4-dioxane (5 mL) at 90 oC for 4 h.
Since the transformation of aldehydes to the corresponding tosylhydrazones is highly
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efficient, and then a one-pot/two steps process for the synthesis of 3 using
2-((trimethylsilyl)ethynyl)benzaldehyde as one of the starting materials was also studied. As
shown in Table 4, the reaction occurred smoothly to afford the corresponding products in
acceptable yields.
Table 4
One-pot synthesis of pyrazolo[5,1-a]isoquinoline a
a Reactions were carried out with 4 (0.25 mmol), NH2NHTs (2.5 equiv), 2a (0.2
mmol), B (5 mol%), CuI (10 mol%) and KOtBu (3 equiv) in 1,4-dioxane (5 mL).
To investigate the potential applications of this transformation, a gram-scale reaction of
1e (5.4 mmol) with 2b (4.5 mmol) under standard conditions was conducted, and the desired
3r was obtained in 79% yield (1.095 g) (eq 3).
The mechanism of the present annulation in the presence of [Cu(maloNHC)] is considered
to be essentially similar to AgOTf-catalyzed reaction of N′-(2-alkynylbenzylidene)hydrazides
7

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with terminal alkynes.5a
3. Conclusion
In conclusion, we have developed an efficient [Cu(maloNHC)]-catalyzed synthesis of
2-arylpyrazolo[5,1-a]isoquinolines by the annulation of N′-(2-((trimethylsilyl)ethynyl)-
benzylidene)hydrazides with terminal aromatic alkynes. The present work not only extends
the application of Cu/NHC as catalyst in the synthesis of N-heterocyclic compounds with the
use of alkyne as one of the reactants, but also broadens the molecular library of 2-substituted
pyrazolo[1,5-a]isoquinolines.13 Further investigations on the application of the products as the
ligands of organic phosphorescent materials are in progress.
4. Experimental section
4.1 General methods
All organic compounds and inorganic salts were analytically pure and used directly after
1
purchased. Nuclear magnetic resonance (NMR) spectra were recorded at 298 K. H NMR
(400 MHz) chemical shifts (δ) were referenced to internal standard TMS (δ = 0.00 ppm). 13C
NMR (100 MHz) chemical shifts were referenced to internal solvent CDCl3 (δ = 77.16 ppm).
HRMS spectra were obtained on a microTOF-Q 10142 spectrometer with electron spray
ionization (ESI) source. The melting points were uncorrected. Single crystal X-ray diffraction
data were collected on a diffraction meter.
4.2 A typical experiment procedure for synthesis of 3a
A mixture of N'-(2-((trimethylsilyl)ethynyl)-benzylidene)-4-methylbenzenesulfono-
hydrazide (1a, 92.5 mg, 0.25 mmol), phenylacetylene (2a, 20.2 mg, 0.2 mmol),
[Cu(maloNHC)] B (6.9 mg, 0.01 mmol, 5 mol %), CuI (3.8 mg, 0.02 mmol, 10 mol %),
KOtBu (67.2 mg, 0.6 mmol, 3 equiv) and NH2NHTs (37.2 mg, 0.2 mmol, 1 equiv) and
1,4-dioxane (5.0 mL) was heated at 90 °C (oil bath temperature) with stirring in a 25 mL
screw-capped thick-walled Pyrex tube under nitrogen atmosphere. When TLC control showed
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the completion of the reaction (after 4 h), the mixture was extracted with dichloromethane
(DCM) three times, and dried over Na2SO4. The solvent was evaporated and the crude residue
was purified by column chromatography on silica gel to afford 3a as a white solid in 88%
yield (42.9 mg).
4.3 Characterization data of new starting materials and products
1
The new starting materials and all the products were characterized by H-NMR,
13C-NMR and HRMS (for new compounds). The copies of NMR charts were reported in
supplementary data.
N'-(2-Fluoro-2-((trimethylsilyl)ethynyl)benzylidene)-4-methylbenzenesulfonohydrazide (1b).
o
1
White solid; mp 152-154 C; H-NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.22 (s, 1H), 7.92
(dd, J = 8.0, 1.6 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.26-7.21 (m, 2H), 7.04-6.99 (m, 1H), 2.40
(s, 3H), 0.23 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 160.3 (d, J = 258 Hz), 144.3, 143.0 (d, J
= 4 Hz), 135.2, 130.5 (d, J = 9 Hz), 129.6, 129.1 (d, J = 3 Hz), 128.1, 125.2 (d, J = 4 Hz),
122.5 (d, J = 10 Hz), 117.1 (d, J = 21 Hz), 102.3, 100.8 (d, J = 4 Hz), 21.7, -0.2; HRMS (ESI)
calcd for C19H22FN2O2SSi m/z [M+H]+: 389.1155; found: 389.1149.
N'-(5-Fluoro-2-((trimethylsilyl)ethynyl)benzylidene)-4-methylbenzenesulfonohydrazide (1c).
o
1
White solid; mp 171-173 C; H-NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 8.23 (s, 1H), 7.89
(d, J = 8.0 Hz, 2H), 7.55 (dd, J = 9.6, 2.6 Hz, 1H), 7.42-7.38 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H),
2.42 (s, 3H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 162.5 (d, J = 248 Hz), 144.6, 144.5
(d, J = 3 Hz), 136.9 (d, J = 8 Hz), 135.3, 134.8 (d, J = 8 Hz), 129.9, 128.1, 119.4 (d, J = 3 Hz),
117.5 (d, J = 23 Hz), 111.9 (d, J = 24 Hz), 100.7, 100.5, 21.7, -0.06; HRMS (ESI) calcd for
C19H22FN2O2SSi m/z [M+H]+: 389.1155; found: 389.1159.
N'-(5-Chloro-2-((trimethylsilyl)ethynyl)benzylidene)-4-methylbenzenesulfonohydrazide (1d).
o
1
White solid; mp 141-144 C; H-NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.20 (s, 1H), 7.88
(d, J = 8.0, 2H), 7.85 (d, J = 2.4 Hz, 1H), 7.35 (s, 1H), 7.34 (d, J = 8.0, 2H), 7.26-7.22 (m,
13
1H), 2.43 (s, 3H), 0.23 (s, 9H); C-NMR (100 MHz, CDCl3): δ 144.6, 144.3, 135.9, 135.3,
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135.0, 134.0, 130.0, 129.9, 128.1, 125.2, 121.6, 102.1, 100.4, 21.7, -0.08; HRMS (ESI) calcd
for C19H22ClN2O2SSi m/z [M+H]+: 405.0860; found: 405.0853.
N'-(5-Methoxy-2-((trimethylsilyl)ethynyl)benzylidene)-4-methylbenzenesulfonohydrazide (1e).
o
1
White solid; mp 148-150 C; H-NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.26 (s, 1H), 7.89
(d, J = 8.0 Hz, 2H), 7.37-7.30 (m, 4H), 6.83 (dd, J = 7.4, 1.8 Hz, 1H), 3.82 (s, 3H), 2.40 (s,
13
3H), 0.21 (s, 9H); C-NMR (100 MHz, CDCl3): δ 159.7, 145.8, 144.4, 136.0, 135.4, 134.2,
129.8, 128.0, 117.2, 115.9, 108.9, 101.6, 99.1, 55.5, 21.6, 0.03; HRMS (ESI) calcd for
C20H25N2O3SSi m/z [M+H]+: 401.1355; found: 401.1362.
N'-(4-Chloro-2-((trimethylsilyl)ethynyl)benzylidene)-4-methylbenzenesulfonohydrazide (1f).
o
1
White solid; mp 137-139 C; H-NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 8.23 (s, 1H), 7.89
(d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H),
13
7.21 (dd, J = 8.6, 1.9 Hz, 1H), 2.40 (s, 3H), 0.22 (s, 9H); C-NMR (100 MHz, CDCl3): δ
144.7, 144.5, 135.6, 135.3, 133.0, 132.3, 129.8, 129.2, 128.0, 126.6, 124.5, 102.4, 99.9, 21.7,
-0.18; HRMS (ESI) calcd for C19H22ClN2O2SSi m/z [M+H]+: 405.0860; found: 405.0860.
N'-(4,5-Dimethoxy-2-((trimethylsilyl)ethynyl)benzylidene)-4-methylbenzenesulfonohydrazide
o
1
(1g). White solid; mp 161-163 C; H-NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 8.22 (s, 1H),
7.88 (d, J = 8.1 Hz, 2H), 7.34 (s, 1H), 7.30 (d, J = 8.1 Hz, 2H), 6.84 (s, 1H), 3.90 (s, 3H), 3.86
(s, 3H), 2.41 (s, 3H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 150.6, 149.8, 146.2, 144.3,
135.5, 129.7, 128.4, 128.1, 116.6, 114.1, 106.9, 101.5, 99.4, 56.1, 56.0, 21.7, 0.02; HRMS
(ESI) calcd for C21H27N2O4SSi m/z [M+H]+: 431.1461; found: 431.1455.
o
4-Fluoro-5-methoxy-2-((trimethylsilyl)ethynyl)benzaldehyde (1h’). white solid; mp 90-93 C;
1H-NMR (400 MHz, CDCl3): δ 10.3 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.6 Hz, 1H),
3.86 (s, 3H), 0.20 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 190.0, 152.2 (d, J = 256 Hz), 148.8
(d, J = 11 Hz), 133.5 (d, J = 3 Hz), 120.5, 120.4 (d, J = 20 Hz), 110.4 (d, J = 4 Hz), 101.8,
98.7 (d, J = 2 Hz), 56.2, -0.3; HRMS (ESI) calcd for C13H16FO2Si m/z [M+H]+: 251.0904;
found: 251.0910.
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N'-(4-Fluoro-5-methoxy-2-((trimethylsilyl)ethynyl)benzylidene)-4-methylbenzenesulfonohydra
o
1
zide (1h). White solid; mp 131-134 C; H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.20 (s,
1H), 7.88 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.10 (d, J =
8.0 Hz, 1H), 3.91 (s, 3H), 2.41 (s, 3H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 153.1 (d,
J = 251 Hz), 148.7, (d, J = 12 Hz), 145.2, 144.6, 135.4, 131.7, 129.9, 128.1, 119.8 (d, J = 20
Hz), 116.4 (d, J = 8 Hz), 109.2, 100.4, 100.3, 56.4, 21.7, -0.04; HRMS (ESI) calcd for
C20H24FN2O3SSi m/z [M+H]+: 419.1261; found: 419.1263.
N'-(4,5,6-Trimethoxy-2-((trimethylsilyl)ethynyl)benzylidene)-4-methylbenzenesulfonohydrazid
e (1i). Yellow solid; mp 129-131 oC; 1H-NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.21 (s, 1H),
7.87 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.18 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86
(s, 3H), 2.40 (s, 3H), 0.22 (s, 9H); 13C-NMR (100 MHz, CDCl3): δ 155.0, 154.1, 145.7, 144.4,
144.1, 135.5, 130.8, 129.7, 128.0, 111.9, 104.0, 103.6, 97.3, 61.2, 56.2, 21.7, -0.00; HRMS
(ESI) calcd for C22H29N2O5SSi m/z [M+H]+: 461.1566; found: 461.1554.
2-Phenylpyrazolo[5,1-a]isoquinoline (3a).12 White solid (42.9 mg, 88% yield); mp 109-111
1
oC ; H-NMR (400 MHz, CDCl3): δ 8.30 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H),
8.03-8.01 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.61-7.53 (m, 2H), 7.51-7.47 (m, 2H), 7.39 (dd, J
13
= 7.2, 1.6 Hz, 1H), 7.29 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H); C-NMR (100 MHz, CDCl3): δ
152.9, 139.8, 133.0, 128.9, 128.5, 128.1, 127.7, 127.3, 126.4, 126.3, 124.4, 123.8, 112.2, 94.7;
HRMS (ESI) calcd for C17H13N2 m/z [M+H]+: 245.1079; found: 245.1091.
10-Fluoro-2-phenylpyrazolo[5,1-a]isoquinoline (3b). White solid (45.1 mg, 86% yield); mp
o
1
129-130 C ; H-NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.0 Hz, 1H), 7.95-7.92 (m, 2H),
7.41-7.35 (m, 5H), 7.32-7.30 (m, 1H), 7.22-7.17 (m, 1H), 6.88 (dd, J = 7.8, 1.7 Hz, 1H);
13C-NMR (100 MHz, CDCl3): δ 158.7 (d, J = 251 Hz), 153.5, 134.9, 133.0, 131.3 (d, J = 4
Hz), 128.9, 128.6, 128.5 (d, J = 9 Hz), 127.4, 126.6, 122.8 (d, J = 4 Hz), 114.3 (d, J = 15 Hz),
113.4 (d, J = 20 Hz), 111.4 (d, J = 3 Hz), 99.4 (d, J = 10 Hz); HRMS (ESI) calcd for
C17H12N2F m/z [M+H]+: 263.0985; found: 263.0989.
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9-Fluoro-2-phenylpyrazolo[5,1-a]isoquinoline (3c). Yellow solid (43.5 mg, 83% yield); mp
o
1
130-132 C ; H-NMR (400 MHz, CDCl3): δ 8.26 (d, J = 8.0 Hz, 1H), 8.01 (dd, J = 8.2, 2.6
Hz, 2H), 7.75 (dd, J = 9.2, 2.6 Hz, 1H), 7.70 (dd, J = 8.8, 5.4 Hz, 1H), 7.49-7.47 (m, 2H),
7.42-7.40 (m, 1H), 7.29-7.27 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3):
δ 162.0 (d, J = 247 Hz), 153.1, 139.2, 132.9, 129.7 (d, J = 9 Hz), 129.0, 128.7, 126.5, 125.9 (d,
J = 10 Hz), 125.7 (d, J = 3 Hz), 125.5 (d, J = 2 Hz), 116.8 (d, J = 24 Hz), 111.7, 109.2 (d, J =
23 Hz), 95.3; HRMS (ESI) calcd for C17H12N2F m/z [M+H]+: 263.0985; found: 263.0986.
9-Chloro-2-phenylpyrazolo[5,1-a]isoquinoline (3d). White solid (44.5 mg, 80% yield); mp
158-160 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.20 (d, J = 7.4 Hz, 1H), 8.01 (d, J = 1.9 Hz, 1H),
7.93-7.91 (m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.42-7.39 (m, 3H), 7.34-7.30 (m, 1H), 7.18 (s,
13
1H), 6.87 (d, J = 7.4 Hz, 1H); C-NMR (100 MHz, CDCl3): δ 153.4, 138.8, 133.6, 132.8,
128.9, 128.8, 128.7, 128.6, 127.3, 126.6, 126.5, 125.6, 123.4, 111.6, 95.3; HRMS (ESI) calcd
for C17H12N2Cl m/z [M+H]+: 279.0689; found: 279.0685.
9-Methoxy-2-phenylpyrazolo[5,1-a]isoquinoline (3e). Yellow liquid (51.0 mg, 93% yield);
1H-NMR (400 MHz, CDCl3): δ 8.18 (d, J = 7.3 Hz, 1H), 8.03-8.00 (m, 2H), 7.61 (d, J = 8.7
Hz, 1H), 7.49-7.46 (m, 3H), 7.40-7.36 (m, 1H), 7.20 (s, 1H), 7.15 (dd, J = 8.7, 2.5 Hz, 1H),
13
6.92 (d, J = 7.3 Hz, 1H), 3.96 (s, 3H); C-NMR (100 MHz, CDCl3): δ 159.2, 152.6, 139.5,
133.2, 128.9, 128.4, 126.4, 125.7, 124.2, 123.0, 117.8, 112.0, 105.1, 94.5, 55.6; HRMS (ESI)
calcd for C18H15N2O m/z [M+H]+: 275.1184; found: 275.1190.
8-Chloro-2-phenylpyrazolo[5,1-a]isoquinoline (3f). White solid (41.1 mg, 74% yield); mp
o
1
161-163 C ; H-NMR (400 MHz, CDCl3): δ 8.39 (d, J = 7.4 Hz, 1H), 8.04-87.98 (m, 3H),
7.69 (d, J = 1.5 Hz, 1H), 7.53-7.46 (m, 3H), 7.41-7.31 (m, 1H), 7.24 (s, 1H), 6.90 (d, J = 7.4
Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 153.4, 139.3, 134.0, 132.9, 130.2, 128.9, 128.7,
128.2, 127.4, 126.6, 126.5, 125.3, 122.9, 111.2, 95.0; HRMS (ESI) calcd for C17H12N2Cl m/z
[M+H]+: 279.0689; found: 279.0689.
8,9-Dimethoxy-2-phenylpyrazolo[5,1-a]isoquinoline (3g). Yellow solid (54.1 mg, 89% yield);
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o
1
mp 171-174 C ; H-NMR (400 MHz, CDCl3): δ 8.14 (d, J = 7.3 Hz, 1H), 7.92 (dd, J = 8.3,
1.2 Hz, 2H), 7.40-7.36 (m, 2H), 7.31-7.29 (m, 2H), 7.11 (s, 1H), 7.05 (s, 1H), 5.88 (d, J = 7.3
Hz, 1H), 4.13 (s, 3H), 4.07 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 152.6, 150.2, 150.0,
139.6, 133.1, 128.8, 128.5, 126.4, 124.7, 123.7, 118.7, 111.7, 107.7, 104.4, 93.2, 56.2, 56.1;
HRMS (ESI) calcd for C19H17N2O2 m/z [M+H]+: 305.1290; found: 305.1293.
7,8,9-Trimethoxy-2-phenylpyrazolo[5,1-a]isoquinoline (3h). White solid (54.1 mg, 81% yield);
mp 178-181 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.18 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.1 Hz,
2H), 7.48-7.45 (m, 2H), 7.39-7.35 (m, 1H), 7.25 (s, 2H), 7.17 (s, 1H), 4.05 (s, 3H), 4.03 (s,
13
3H), 3.98 (s, 3H); C-NMR (100 MHz, CDCl3): δ 154.1, 152.8, 149.0, 142.2, 139.3, 133.3,
128.8, 128.4, 126.3, 124.5, 121.1, 118.4, 106.4, 100.5, 94.0, 61.7, 61.3, 56.3; HRMS (ESI)
calcd for C20H19N2O3 m/z [M+H]+: 335.1396; found: 335.1392.
2-(3-Chlorophenyl)pyrazolo[5,1-a]isoquinoline (3i). White solid (51.2 mg, 92% yield); mp
162-165 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.4 Hz, 1H), 8.10-8.08 (m, 1H), 8.00
(t, J = 1.7 Hz, 1H), 7.88-7.86 (m, 1H), 7.71-7.69 (m, 1H), 7.60-7.52 (m, 2H), 7.41-7.32 (m,
1H), 7.23 (s, 1H), 7.69 (d, J = 7.4 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 151.6, 139.9,
135.1, 134.9, 130.1, 128.9, 128.4, 128.2, 127.9, 127.4, 126.5, 126.3, 124.5, 123.8, 112.6, 94.9;
HRMS (ESI) calcd for C17H12N2Cl m/z [M+H]+: 279.0689; found: 279.0691.
2-(3-Methylphenyl)pyrazolo[5,1-a]isoquinoline (3j). White solid (43.4 mg, 84% yield); mp
112-115 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.35 (d, J = 7.4 Hz, 1H), 8.12 (d, J = 7.4 Hz, 1H),
7.87 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.73-7.70 (m, 1H), 7.61-7.53 (m, 2H), 7.39-7.35 (m,
13
1H), 7.28 (s, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 2.46 (s, 3H); C-NMR
(100 MHz, CDCl3): δ 152.8, 139.8, 138.6, 132.5, 129.5, 129.0, 128.8, 128.3, 127.9, 127.4,
127.1, 126.1, 124.4, 123.9, 123.7, 112.4, 94.8, 21.6; HRMS (ESI) calcd for C18H15N2 m/z
[M+H]+: 259.1235; found: 259.1236.
2-(4-Bromophenyl)pyrazolo[5,1-a]isoquinoline (3k). Yellow solid (48.3 mg, 75% yield); mp
176-179 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.28 (d, J = 7.4 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H),
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7.88 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 7.2 Hz, 1H), 7.62-7.56 (m, 4H), 7.26-7.25 (m, 1H), 7.02
(d, J = 7.4 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 151.7, 140.0, 132.1, 131.9, 129.9, 129.0,
128.3, 128.0, 127.5, 126.2, 124.4, 123.9, 122.6, 112.7, 94.7; HRMS (ESI) calcd for C17H12N2
Br m/z [M+H]+: 323.0184; found: 323.0179.
2-(4-Methylphenyl)pyrazolo[5,1-a]isoquinoline (3l). White solid (46.4 mg, 90% yield); mp
144-146 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.4 Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H),
7.84-7.82 (m, 2H), 7.65-7.62 (m, 1H), 7.52-7.44 (m, 2H), 7.22-7.17 (m, 3H), 6.91 (d, J = 7.4
Hz, 1H), 2.33 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 153.0, 139.9, 138.5, 130.2, 129.6,
129.0, 128.1, 127.8, 127.4, 126.4, 126.3, 124.5, 123.9, 112.2, 94.6, 21.5; HRMS (ESI) calcd
for C18H15N2 m/z [M+H]+: 259.1235; found: 259.1236.
2-(4-Methoxyphenyl)pyrazolo[5,1-a]isoquinoline (3m). White solid (48.8 mg, 89% yield); mp
124-127 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.30 (d, J = 6.9 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H),
7.95 (d, J = 8.6 Hz, 2H), 7.72-7.70 (m, 1H), 7.59-7.54 (m, 2H), 7.21 (s, 1H), 7.02-6.97 (m,
13
3H), 3.87 (s, 3H); C-NMR (100 MHz, CDCl3): δ 160.1, 139.9, 133.5, 129.0, 128.1, 127.8,
127.4, 126.2, 125.7, 124.5, 123.9, 114.4, 113.4, 112.0, 94.3, 55.5; HRMS (ESI) calcd for
C18H15N2O m/z [M+H]+: 275.1184; found: 275.1190.
2-(4-Ethynylphenyl)pyrazolo[5,1-a]isoquinoline (3n). White solid (41.8 mg, 78% yield); mp
160-163 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.27 (d, J = 7.4 Hz, 1H), 8.11 (d, J = 7.4 Hz, 1H),
7.97 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 7.2 Hz, 1H), 7.61-7.53 (m, 4H), 7.27 (s, 1H), 7.01 (d, J =
13
7.4 Hz, 1H), 3.16 (s, 1H); C-NMR (100 MHz, CDCl3): δ 152.0, 139.9, 133.5, 132.7, 128.9,
128.2, 127.9, 127.4, 126.3, 126.3, 124.5, 123.8, 122.1, 112.6, 95.0, 83.8, 78.1; HRMS (ESI)
calcd for C19H13N2 m/z [M+H]+: 269.1079; found: 269.1087.
2-(4-Fluoro-3-methylphenyl)pyrazolo[5,1-a]isoquinoline (3o). White solid (28.7 mg, 52%
o
yield); mp 164-166 C ; 1H-NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.0 Hz, 1H), 8.11 (d, J =
8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79-7.75 (m, 1H), 7.73-7.71 (m, 1H), 7.63-7.53 (m,
13
2H), 7.22 (s, 1H), 7.12-7.07 (m, 1H), 7.00 (d, J = 7.2 Hz, 1H), 2.40 (s, 3H); C-NMR (100
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MHz, CDCl3): δ 161.8 (d, J = 245 Hz), 140.0, 129.6 (d, J = 5 Hz), 129.0, 128.9, 128.2, 127.9,
127.4, 126.2, 125.6, 125.5, 125.3, 124.4, 123.8, 115.5 (d, J = 23 Hz), 112.3, 94.7, 14.8 (d, J =
4 Hz); HRMS (ESI) calcd for C18H14N2F m/z [M+H]+: 277.1141; found: 277.1146.
2-(Naphthalen-1-yl)pyrazolo[5,1-a]isoquinoline (3p). Yellow liquid (41.2 mg, 70% yield);
1H-NMR (400 MHz, CDCl3): δ 8.54 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 7.4 Hz, 1H), 8.15 (d, J =
7.3 Hz, 1H), 7.96-7.92 (m, 2H), 7.87 (d, J = 7.1 Hz, 1H), 7.75-7.74 (m, 1H), 7.61-7.55 (m,
5H), 7.29 (s, 1H), 7.04 (d, J = 7.4 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 152.9, 139.1,
134.1, 131.6, 131.2, 129.0, 128.9, 128.5, 128.1, 128.0, 127.8, 127.4, 126.6, 126.4, 126.2,
126.0, 125.5, 124.5, 123.9, 112.3, 98.8; HRMS (ESI) calcd for C21H15N2 m/z [M+H]+:
292.1235; found: 292.1235.
2-(Thiophen-3-yl)pyrazolo[5,1-a]isoquinoline (3q). Yellow solid (42.5 mg, 85% yield); mp
o
1
119-122 C ; H-NMR (400 MHz, CDCl3): δ 8.23 (d, J = 7.4 Hz, 1H), 8.07-8.05 (m,1H),
7.81-7.80 (m, 1H), 7.69-7.64 (m, 2H), 7.55-7.51 (m, 2H), 7.43-7.41 (m, 1H), 7.12 (s, 1H),
13
6.94 (d, J = 7.4 Hz, 1H); C-NMR (100 MHz, CDCl3): δ 149.2, 139.6, 134.9, 128.9, 128.0,
127.7, 127.3, 126.4, 126.2, 126.2, 124.4, 123.8, 121.9, 112.1, 95.0; HRMS (ESI) calcd for
C15H11N2S m/z [M+H]+: 251.0648; found: 251.0643.
2-(3-Chlorophenyl)-9-methoxypyrazolo[5,1-a]isoquinoline (3r). White solid (1.10 g, 79%
yield); mp 145-147 oC ; 1H-NMR (400 MHz, CDCl3): δ 8.12 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H),
7.86 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.42 (s, 1H), 7.39-7.32 (m, 2H), 7.18 (s,
1H), 7.4 (dd, J = 8.7, 2.4 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 3.95 (s, 3H); 13C-NMR (100 MHz,
CDCl3): δ 159.3, 151.3, 139.6, 135.2, 134.8, 130.1, 128.9, 128.3, 126.4, 124.4, 124.3, 117.8,
112.3, 105.0, 94.6, 55.6; HRMS (ESI) calcd for C18H13ClN2O m/z [M+H]+: 309.0795; found:
309.0793.
Acknowledgements
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This project was supported by the National Natural Science Foundation of China (Nos.
21473097 and 21673124). Miss H. Liu thanks China Scholarship Council (CSC) for generous
support for her study in Nanyang Technological University, Singapore (No. 201506210176).
Supplementary data
Copies of 1H-NMR, 13C-NMR charts of new starting materials and all the products, as well as
the x-ray structural details for 3k and 3q associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.xxxx.
References and notes:
1. Selected reports, see: (a) Deady, L. W.; Loria, P. M.; Quazi, N. H. Aust. J. Chem. 1996, 49,
485–488. (b) Rashad, A. E.; Hegab, M. I.; Abdel-Megeid, R. E.; Fathalla, N.;
Abdel-Megeid, F. M. E. Eur. J. Med. Chem. 2009, 44, 3285–3292. (c) Kato, J.-y.;
Aoyama, H.; Yokomatsu, T. Org. Biomol. Chem. 2013, 11, 1171–1178. (c) Schenone, S.;
Radi, M.; Musumeci, F.; Brullo, C.; Botta, M. Chem. Rev. 2014, 114, 7189−7238. (d)
Shekarrao, K.; Kaishap, P. P.; Saddanapu, V.; Addlagatta, A.; Gogoi, S.; Boruah, R. C.
RSC Adv. 2014, 4, 24001–24006.
2. Selected reports, see: (a) Bekhit, A. A.; Abdel-Aziem, T. Bioorg. Med. Chem. 2004, 12,
1935–1945. (b) Manna, F.; Chimenti, F.; Fioravanti, R.; Bolasco, A.; Secci, D.; Chimenti,
P.; Ferlini, C.; Scambia, G. Bioorg. Med. Chem. Lett. 2005, 15, 4632–4635. (c) Nitulescu,
G. M.; Draghici, C.; Missir, A. V. Eur. J. Med. Chem. 2010, 45, 4914–4919. (d) Fustero,
S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A. Chem. Rev. 2011, 111, 6984–7034.
(e) Sharshira, E. M.; Hamada, N. M. M. Molecules 2012, 17, 4962–4971.
3. Selected reports, see: (a) Casellas, P.; Galiegue, S.; Basile, A. S. Neurochem. Int. 2002, 40,
475–486. (b). Croisy-Delcey, M.; Croisy, A.; Carrez, D.; Huel, C.; Chiaroni, A.; Ducrot,
P.; Bisagnia, E.; Jin, L; Leclercq, G. Bioorg. Med. Chem. 2000, 8, 2629–2641. (c) Kartsev,
V. G. Med. Chem. Res. 2004, 13, 325–336.
16

ACCEPTED MANUSCRIPT
4. Chen, Z.; Wu, J. Org. Lett. 2010, 12, 4856–4859.
5. (a) Chen, Z.; Yang, X.; Wu, J. Chem. Commun. 2009, 3469–3471. (b) Chen, Z.; Su, M.;
Yu, X.; Wu, J. Org. Biomol. Chem. 2009, 7, 4641–4646. (c) Yu, X.; Ye, S.; Wu, J. Adv.
Synth. Catal. 2010, 352, 2050–2056. (d) Ye, S.; Yang, X.; Wu, J. Chem. Commun. 2010,
46, 5238–5240. (e) Chen, Z.; Gao, L.; Ye, S.; Ding, Q.; Wu, J. Chem. Commun. 2012, 48,
3975–3977. (f) Li, S.; Wu, J. Org. Lett. 2011, 13, 712–715. (g) Li, S.; Luo, Y.; Wu, J. Org.
Lett. 2011, 13, 4312–4315. (h) Gong, X.; Wu, J. Org. Biomol. Chem. 2015, 13,
11657–11662.
6. (a) Mousseau, J. J.; Bull, J. A.; Ladd, C. L.; Fortier, A.; Roman, D. S.; Charette, A. B. J.
Org. Chem. 2011, 76, 8243–8261. (b) Ding, S.; Yan, Y.; Jiao, N. Chem. Commun. 2013,
49, 4250–4252. (c) Ling, L.; Chen, J.; Song, J.; Zhang, Y.; Li, X.; Song, L.; Shi, F.; Li, Y.;
Wu, C. Org. Biomol. Chem. 2013, 11, 3894–3902.
7. (a) Lin, J. C. Y.; Huang, R. T. W.; Lee, C. S.; Bhattacharyya, A.; Hwang, W. S.; Lin, I. J.
B. Chem. Rev. 2009, 109, 3561–3598. (b) Díez-González, S.; Marion, N.; Nolan, S. P.
Chem. Rev. 2009, 109, 3612–3676. (c) Egbert, J. D.; Cazin, C. S. J.; Nolan, S. P. Catal.
Sci. Technol. 2013, 3, 912–926. (d) Levin, E.; Ivry, E.; Diesendruck, C. E.; Lemcoff , N.
G. Chem. Rev. 2015, 115, 4607−4692. (e) Lazreg, F.; Nahra, F.; Cazin, C. S. J. Coord.
Chem. Rev. 2015, 293-294, 48–79.
8. (a) Díez-González, S.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem. Eur. J. 2006, 12,
7558−7564. (b) Díez-González, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2008, 47,
8881−8884. (c) Candelon, N.; Lastécouères, D.; Diallo, A. K.; Ruiz Aranzaes, J.; Astruc,
D.; Vincent, J.-M. Chem. Commun. 2008, 741–743. (d) Díez-González, S.; Stevens, E.
D.; Nolan, S. P. Chem. Commun. 2008, 4747−4749. (e) Li, P.; Wang, L.; Zhang, Y.
Tetrahedron 2008, 64, 10825−10830. (f) Wang, W.; Wu, J.; Xia, C.; Li, F. Green Chem.
2011, 13, 3440−3445. (g) Teyssot, M.-L.; Chevry, A.; Traïkia, M.; El-Ghozzi, M.;
Avignant, D.; Gautier, A. Chem. Eur. J. 2009, 15, 6322−6326. (h) Collinson, J.-M.;
17

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Wilton-Ely, J. D. E. T.; Díez-González, S. Chem. Commun. 2013, 49, 11358−11360.
9. Selected reports, see: (a) Zheng, Q.; Hua, R. Tetrahedron Lett. 2010, 51, 4512−4514. (b)
Su, J.; Hua, R. Curr. Org. Synth. 2012, 9, 273−277. (c) Su, J.; Ju, J.; Hua, R. Curr. Org.
Synth. 2012, 9, 898−902. (d) Zheng, L.; Ju, J.; Bin, Y.; Hua, R. J. Org. Chem. 2012, 77,
5794−5800. (e) Ju, J.; Hua, R. Curr. Org. Synth. 2013, 10, 328−332. (f) Yang, L.; Hua, R.
Chem. Lett. 2013, 42, 769−771. (g) Zheng, L.; Hua, R. Chem. Eur. J. 2014, 20,
2352−2356. (h) Zheng, L.; Hua, R. J. Org. Chem. 2014, 79, 3930−3936. (i) Zhang, L.;
Zheng, L.; Guo, B.; Hua, R. J. Org. Chem. 2014, 79, 11541−11548. (j) Zheng, Q.; Hua,
R.; Jiang, J.; Zhang, L. Tetrahedron 2014, 70, 8252−8256. (k) Su, J.; Liu, H.; Hua, R. Int.
J. Mol. Sci. 2015, 16, 3599−3608. (l) Zhang, Z.; Guo, B.; Zhou, Y.; Hua, R. Tetrahedron
2016, 72, 7613−7619. (m) Zheng, L.; Bin, Y.; Wang, Y.; Hua, R. J. Org. Chem. 2016, 81,
8911−8919.
10. The synthesis, structure and catalytic applications of [(maloNHC)CuCl].Li, see: César, V.;
Barthes, C.; Farré, Y. C.; Cuisiat, S. V.; Vacher,B. Y.; Brousses, R.; Lugan, N.; Lavigne, G.
Dalton Trans. 2013, 42, 7373–7385.
11. The structures of all the products were identified by their 1H-NMR, 13C-NMR and HRMS
(ESI). 3k and 3q were further confirmed by x-ray crystallography (see supplementary
data). The supplementary crystallographic data of 3k, CCDC 1566482 and 3q, CCDC
1566483, can be obtained free of charge via www.ccdc.cam.ac.uk
12. Although it is not clear to know the role of CuI in the present annulations, we have noted
that the presence of iodide anion is crucial to promote the catalytic activation of Cu(NHC)
B in another reaction, due possible to the halogen exchange. The results will be
concluded and published in the near future.
13. The reported most of pyrazolo[5,1-a]isoquinoline derivatives bear substituent at the
position 5, and only 2-phenyl pyrazolo[5,1-a]isoquinoline was reported in two literatures
via different processes. (a) AgOTf-catalyzed cascade bicyclization of propargylic
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alcohols with p-tolylsulfonohydrazide: Xu, S.; Hao, L.; Wang, T.; Ding, Z.; Zhan, Z. Org.
Biomol. Chem. 2013, 11, 294–298. (b) CuCl-catalyzed reaction of
3-(2-bromophenyl)pyrazoles with terminal alkynes: Yang, Y.; Ren, H.; Wang, D.; Shi, F.;
Wu, C. RSC Adv. 2013, 3, 10434–10441.
19