Nickel-Catalyzed Tandem Knoevenagel Condensation and Intramolecular Direct Arylation: Synthesis of Pyrazolo[5,1-a]-isoquinoline Derivatives

Article abstract of DOI:10.1002/adsc.201701519

A simple and efficient method for the synthesis of pyrazolo[5,1-a]isoquinoline derivatives has been developed using the nickel-catalyzed reaction of 1-aryl-2-(1H-pyrazol-1-yl)ethan-1-ones and 2-bromo aldehydes. The overall transformation involves tandem K

Full text of DOI:10.1002/adsc.201701519

Title: Nickel-Catalyzed Tandem Knoevenagel Condensation and
Intramolecular Direct Arylation: Synthesis of Pyrazolo[5,1-
a]isoquinoline Derivatives
Authors: Shiv Dhiman, Nitesh Nandwana, Dalip Kumar, Hitesh K Saini,
Krishnan Rangan, Mukund Jha, Katherine N Robertson, and
Anil Kumar
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701519
Link to VoR: http://dx.doi.org/10.1002/adsc.201701519

Advanced Synthesis & Catalysis
10.1002/adsc.201701519
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Nickel-Catalyzed Tandem Knoevenagel Condensation and
Intramolecular Direct Arylation: Synthesis of Pyrazolo[5,1-a]-
isoquinoline Derivatives
a
a
a
a
Shiv Dhiman, Nitesh Kumar Nandwana, Hitesh Kumar Saini, Dalip Kumar,
b
c
d
a,
Krishnan Rangan, Katherine N. Robertson, Mukund Jha and Anil Kumar *
a
Department of Chemistry, BITS Pilani, Pilani Campus, Pilani 333031, Rajasthan, India
Department of Chemistry, BITS Pilani, Hyderabad Campus, Secunderabad 500078, Telangana, India
Department of Chemistry, Saint Mary’s University, Halifax, NS, B3H 3C3, Canada
Department of Biology and Chemistry, Nipissing University, North Bay, ON, P1B 8L7, Canada
b
c
d
*E-mail: anilkumar@pilani.bits-pilani.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A simple and efficient method for the synthesis of aroyl‒substituted pyrazolo[5,1-a]isoquinolines have been
pyrazolo[5,1-a]isoquinoline derivatives has been developed synthesized in moderate to good yields.
using the nickel-catalyzed reaction of 1-aryl-2-(1H-pyrazol-
1
-yl)ethan-1-ones and 2-bromo aldehydes. The overall Keywords: Nickel; tandem reaction; Knoevenagel
transformation involves tandem Knoevenagel condensation condensation, C-H functionalization, direct arylation,
and intramolecular direct arylation via activation of the C5‒H pyrazolo[5,1-a]isoquinoline.
bond of the pyrazole ring. A series of 27 drug-like
Introduction
present in a significant number of pharmaceutically
relevant molecules that exhibit remarkable biological
[9]
Formation of carbon-carbon and carbon-heteroatom
bonds through transition metal‒catalyzed C‒H
functionalization has attracted much attention in
activities (Figure 1).
[1]
comparison to traditional methods in last decade. It
avoids pre-functionalization of substrates and provides
straightforward access to structurally diverse and
complex molecules from simple substrates under eco-
benign conditions. Most of the C-H functionalization
reactions have been catalyzed by palladium and
ruthenium catalysts.[ However, in recent years focus
of the researchers has drifted towards the use of
nonprecious metals such as nickel[3] and cobalt for
these reactions mainly due to the cost and toxicity of
noble metals. Moreover, development of novel
synthetic transformations involving tandem C‒C and
C‒heteroatom bonds, generating complex structural
frameworks in one-pot have become very attractive
and highly desirable in organic synthesis as they avoid
generation of chemical waste and reduce reaction
times dramatically.[
2]
[4]
Figure 1. Selected bioactive pyrazolo[5,1-a]isoquinoline
derivatives.
Several synthetic methods have been developed for
5]
the preparation of pyrazolo[5,1-a]isoquinolines due to
Compounds containing the isoquinoline framework
are among the most common aza-heterocycles
[10]
their biological significance.
In particular,
development of straightforward methods for their
synthesis using transition metal catalyzed tandem
reactions has received more attention of chemists. For
example, Wu group achieved synthesis of
pyrazolo[5,1-a]isoquinolines derivatives using the
[6]
encountered in natural products, pharmaceutical
drugs[ and functional materials. In particular, the
pyrazolo[5,1-a]isoquinoline scaffold which is
embedded with two privileged structural motifs,
isoquinoline and pyrazolo[1,5-a]pyridine has attracted
special interest of chemists as these two motifs are
7]
[8]
multicomponent
tandem
reaction
of
2-
alkynylbenzaldehyde/
N′-(2-alkynylbenzylidene)-
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201701519
hydrazide/ 2-alkynylbromobenzene.[10c, 11] Fu et al.
reported their synthesis via the CuI catalyzed one pot
reaction of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-
one, hydrazine and ethyl 2-cyanoacetate.[ Li group
reported synthesis of substituted pyrazolo[5,1-
a]isoquinolines from 5-(2-bromoaryl)-N-aryl-1H-
pyrazole-3-amines using active methylene acetonitrile
following our previous work on synthesis of aza-fused
[19f]
isoquinolines.
However, only traces of
phenyl(pyrazolo[1,5-a]isoquinolin-5yl)methanone
(3aa) was observed on TLC. We then examined model
12]
reaction using Co(acac)
2
and Ni(acac) as catalysts
2
under similar conditions and to our satisfaction both
the catalysts resulted 3aa in 28% and 35% yields,
respectively (Table 1, entries 2-3). With our initial
success in the synthesis of 3aa, we proceeded to
examine the effect of solvents on the yield of 3aa using
in the presence of CuI and heterocyclic ketene aminals
(
HKAs) as ligands.[ Zhang et al. described an
13]
efficient method to access these heterocycles via the
multi-component palladium-catalyzed reaction of 1-
Ni(acac) as catalyst of choice. The best yield of 3aa
2
(
2-bromophenyl)buta-2,3-dien-1-ones with hydrazine
(52%) was obtained in DMSO (Table 1, entries 4-6).
In the case of toluene, only Knoevenagel product
4a/4a (45%) was isolated from the reaction mixture
(Table 1, entry 6). Next, we studied effect of different
[14]
[15]
hydrate and terminal alkynes.
Ackermann
and
Li[
16]
groups have independently synthesized
pyrazolo-fused isoquinolines from 5-aryl-1H-
pyrazoles and alkynes via Rh‒catalyzed oxidative
coupling. Very recently, Yang and coworkers
achieved synthesis of substituted pyrazolo[5,1-
a]isoquinolines from 3,5-disubstituted-1H-pyrazoles
and -diazocarbonyl compounds via a Rh-catalyzed
ligands such as PCy
PCy HBF and PPh
3
, 1,10-phenanthroline, xanthphos,
in the catalysis of the reaction
3
4
3
under investigation (Table 1, entries 7-11). The
reaction efficiency improved significantly with the use
of PCy
in 68% yield (Table 1, entry 7). Subsequently, a
variety of nickel salts (Ni(OAc)2•4H O, Ni(PPh Cl
and NiCl •6H O) were examined, however, rather
3
compared to the other ligands, furnishing 3aa
[17]
sequential C‒H activation and annulation reaction.
Although, these synthetic methods are efficient, the
requirement of expensive catalysts, excess use of
oxidants and uneconomical building blocks limit their
practical applications. Thus, developing economically
efficient routes to pyrazolo[5,1-a]isoquinolines
remains an important objective in synthetic organic
chemistry. Also, aroyl functionality has been reported
to be crucial for the potential bio-activities of various
2
3
)
2
2
2
2
disappointing results were obtained (Table 1, entries
12-14). The efficacy of the reaction was found to
dramatically decrease in the presence of these salts. To
further fine-tune the reaction conditions, we then
shifted our focus on the effect of base and temperature
on the reaction outcome. A number of inorganic
[18]
heterocycles. For the past few years, we have been
interested in the synthesis of various N-fused
heterocycles through transition metal catalyzed
(K
were screened in the presence of the Ni(acac)
and PCy ligand mixture (Table 1, entries 15-18). As
3
4
PO , Cs
2
CO
3
, NaOMe) and organic (DIPEA) bases
2
catalyst
3
[19]
tandem C-C/C-heteroatom bond forming reactions.
indicated in Table 1, poor yields of the desired product
3aa were obtained in the presence of other inorganic
bases (entries 15-17). Only Knoevenagel product was
obtained in 28% yield in the presence of the DIPEA
In continuation of our interest, herein we report Ni-
catalyzed tandem reactions to prepare pyrazolo[5,1-
a]isoquinolines
using
1-aryl-2-(1H-pyrazol-1-
[20]
yl)ethan-1-one with 2-bromo aldehydes (Scheme 1). (Table 1, entry 18). Reaction did not take place in the
The proposed strategy involves Knoevenagel
condensation followed by Ni-catalyzed direct
arylation via C-H activation.
absence of base (Table 1, entry 19). Decreasing the
reaction temperature to 80 °C resulted in the formation
of 3aa in low yield (18%) along with the Knoevenagel
adduct (4a/4a) in 61% yield after 24 h (Table 1,
footnote e). It is worthwhile to mention that decreasing
the catalyst loading to 10 mol % and the ligand to 20
mol % diminished the yield of 3aa (Table 1, footnote
f). Whereas, formation of 3aa was not detected in the
absence of Ni(acac) under the optimized conditions
2
and only Knoevenagel product was obtained in 68%
yield (Table 1, entry 20). Thus, through our
optimization studies we established that use of
Scheme 1. Synthesis of pyrazolo[5,1-a]isoquinolines by
nickel-catalyzed tandem reaction
Ni(acac)
2
(20 mol %), PCy
3
(30 mol %), and K
2
CO (3
3
equiv.) in DMSO at 150 °C under a nitrogen
atmosphere are the optimal condition for the synthesis
of pyrazolo[5,1-a]-isoquinolines.
Having optimized the reaction conditions to prepare
pyrazolo[5,1-a]isoquinoline, we turned our attention
to study the scope and limitations of this methodology.
Initial efforts were made to explore the reactions of 2-
bromobenzaldehyde (2a) with various substituted 1-
Results and Discussion
At the outset, we chose 1-phenyl-2-(1H-pyrazol-1-
yl)ethan-1-one (1a) and 2-bromobenzaldeyde (2a) as
model substrates to optimize the reaction conditions
for the proposed tandem reaction. The results of the
optimization experiments are summarized in Table 1.
The reaction of 1a and 2a was initiated in the presence
aryl-2-(1H-pyrazol-1-yl)ethan-1-ones
furnish the corresponding
(1a-n)
to
pyrazolo[5,1-
a]isoquinolines. As depicted in Table 2, we were
of Pd(OAc)
2
and K
2
CO in N,N-dimethyl acetamide
3
delighted to achieve the synthesis of the compounds
(
DMAC) at 150 C under a nitrogen atmosphere
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201701519
3
aa-3na in decent yields using the optimized reaction
pyrazolo[5,1-a]isoquinolines (3aa-ha) in moderate to
good (43-72%) yields. However, 1-aryl-2-(1H-
pyrazol-1-yl)ethan-1-ones 1i and 1j with electron-
withdrawing on the 1-aryl ring gave corresponding
products 3ia (18%) and 3ja (32%) in poor yields.
conditions. Our results suggested that 1-aryl-2-(1H-
pyrazol-1-yl)ethan-1-ones (1a-h) with neutral or
electron-releasing substituents on the 1-aryl ring
reacted smoothly to furnish corresponding
Table 1. Optimization of reaction condition for the synthesis of pyrazolo[5,1-a]isoquinoline.a
Entry
Catalyst
Pd(OAc)
Co(acac)
Ligand
Base
Solvent
DMAC
DMAC
DMAC
DMSO
DMF
% Yield of 3aa
1
2
3
4
5
6
7
8
9
2
2
-
-
-
-
-
-
K
K
K
K
K
K
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
traces
28
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
2
35
2
52
2
2
39
Toluene
DMSO
DMSO
DMSO
DMSO
DMF
45c
68e-h
40
Ni(acac)
2
PCy d
1,10-Phend
PCy ·HBF
Xanthphos
PPh
3
K
2
CO
3
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
2
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
3
CO
CO
CO
CO
CO
CO
CO
3
2
3
4
3
20
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
2
2
3
3
3
3
3
12
3
34
Ni(OAc)
Ni(PPh
NiCl •6H
2
•4H
Cl
2
O
PCy
PCy
PCy
PCy
PCy
PCy
PCy
PCy
PCy
3
3
3
3
3
3
3
3
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
15
3
)
2
2
trace
12
2
2
O
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
Ni(acac)
-
2
2
2
2
2
PO
4
7
Cs
2
CO
3
19
NaOMe
DIPEAd
-
15
28c
NRi
68c
2 3
K CO
a)
Reaction condition: 1a (0.537 mmol), 2a (0.590 mmol), base (3.0 equiv.), catalyst (20 mol %), ligand (30 mol %) at 150
b)
c)
d)

C, 16 h under N
=
2
atmosphere. Isolated yield. Yield for mixture of 4a/4a. PCy
3
= tricyclohexyl phosphine, 1,10-Phen
e)
1,10‒Phenanthroline, DIPEA = N,N-Diisopropylethylamine. At 80 C 3aa was obtained in 18% yield along with 4a/4a
f)
g)
2 3
in 61% yield after 24 h. Yield of 3aa was 40% when10 mol % Ni(acac) and 20 mol % PCy were used. 3aa was obtained
in 10% yield along with 4a/4a under air atm. after 16 h. 3aa was observed in traces along with 4a/4a under oxygen atm.
after 16 h. NR = no reaction.
h)
i)
The reactions of 1 having substituents on the
pyrazole ring with 2a yielded some interesting results.
substituents participated well in the reaction to furnish
corresponding pyrazolo[5,1-a]isoquinolines (3ab-kf)
in moderate to good yields (30-70%). Interestingly, 2-
bromo heteroaromatic aldehydes such as 2-bromo-3-
pyridinecarboxaldehyde (2h) and 2-bromothiophene-
3-carbaldehyde (2i) also reacted smoothly with 1a to
give corresponding products 3ah and 3ai in 66% and
56% yield, respectively. It is worth mentioning that the
reaction of 1-(2-bromophenyl)ethanone with 1a under
the optimized reaction resulted in a complex reaction
mixture and pure desired product could not be isolated.
However, peak at m/z 287.1166 in the HRMS analysis
of the reaction mixture confirmed formation of the
desired product. Structural confirmation of all the
1
-Aryl-2-(1H-pyrazol-1-yl)ethan-1-ones (1k and 1l)
2
with bulky substituents (R = isopropyl and Ph) at the
C-3 and C-4 positions of the pyrazole ring reacted with
2
a
to give the corresponding pyrazolo[5,1-
a]isoquinolines 3ka and 3la in 75% and 35% yields,
respectively. 1-Aryl-2-(1H-pyrazol-1-yl)ethan-1-one
(
1m) with a bromo and (1n) with chloro substituent at
the C-4 position of the pyrazole ring gave
corresponding product 3ma and 3na in 21% and 18%
yields, respectively. In the next series of experiments,
the reactions of 1a and 1k with substituted 2-
bromobenzaldehydes (2b-i) was investigated under
the optimized reaction conditions (Table 2). It was
found that 2-bromobenzaldehydes having either
1
synthesized compounds was done using IR, H NMR,
1
3
C NMR and HRMS data (supporting information).
electron-releasing
or
electron-withdrawing
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201701519
Table 2. Optimization of reaction condition for the synthesis of pyrazolo[5,1-a]isoquinoline.a
a)
Reaction condition: 1 (0.537 mmol), 2 (0.590 mmol), K
atm.
2 3 2 3
CO (3.0 equiv.), Ni(acac) (20 mol %) and PCy (30 mol %), 150
C, 16 h, N
2
The structure of 3ae was unambiguously confirmed
by the single crystal X-ray analysis, the single crystal
structure ORTEP diagram of 3ae with 50% thermal
[21]
ellipsoids is given in Figure 2A. The three fused
cyclic rings of the pyrazolo[5,1-a]isoquinoline moiety
are nearly planar, however the phenyl ring of the
benzoyl group (-COPh) substitution deviates by
A
B
7
3.04° with respect to the main heterocyclic plane. The
Figure 2. ORTEP diagrams of A) 3ae and B) 4a.[21]
torsion angles of N1-C11-C12-C13 and C11-C12-
C13-C18 are 43.77° and 29.27°, respectively. The
carbonyl group C=O is not in the plane of either of the
two adjacent rings and deviates from these planes with
torsion angles of C10-C11-C12-O1 = 39.01°, and C14-
C13-C12-O1 = 27.35°.
The compatibility of the developed method was
further explored by reacting 1a and 1k with 3-bromo-
3
-phenylacrylaldehydes (5) to give pyrazolo[1,5-
a]pyridines 6aa and 6ak in 70% and 67% yields,
respectively (Scheme 2).
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201701519
On the basis of the current results and literature
[
3b,3d]
reports,
a plausible mechanism invoking a
cascade-type cyclization is presented in Scheme 4.
Firstly, the reaction of 1a with 2a in presence of
K
2
CO
3
generates the Knoevenagel condensation
Simultaneously, Ni(acac) reacts with PCy
product 4
.
2
3
to form the active catalyst Ni(0), which undergoes
oxidative addition with the Knoevenagel product 4 to
form the organo-nickel complex A. The formation of
complex A, in turn, leads to intramolecular C‒H
activation at the C‒5 position of the azole to produce
the cyclic complex B. Finally, the reductive
elimination of the complex B affords the product 3aa,
along with the concomitant release of the active Ni(0)
for the next catalytic cycle.
Scheme 2. Synthesis of pyrazolo[1,5-a]pyridines.
Next, in order to obtain experimental support for
elucidating the reaction pathway, some control
experiments were performed (Scheme 3). Initially,
reaction of 1a with 2a was carried out under the
optimized reaction conditions but at lower temperature
(
80 C). This resulted in a mixture of two isomeric
Knoevenagel condensation products 4a (E-isomer,
4
7%) and 4a (Z-isomer, 19%) (Scheme 3A). The
configuration of 4a was confirmed by X‒ray
crystallography, and the crystal structure ORTEP
diagram with 50% thermal ellipsoids is given in Figure
21]
2
B.[ Further, pure forms of both of these isomers, 4a
and 4a′ were heated separately in the presence of
Ni(acac) under the optimized conditions and cyclized
2
product 3aa was observed from both the isomers in
good yields (Scheme 3B). It is quite likely that
intramolecular cyclization might actually be
happening via 4a (Z-isomer) due to the spatial
proximity of the reaction sites. It appears, that high
temperature not only aids the catalytic process but also
facilitates the isomerization of 4a (E-isomer) to 4a. In
another experiment, the reaction of 1a with 2a was
Scheme 4. The proposed mechanism for the Ni-catalyzed
cascade reaction.
carried out in the presence of NiCl
2
•6H
2
O, PCy
3
and
acetyl acetone (30 mol %) under conditions analogous
to the optimized conditions, which afforded 3aa in Conclusion
4
7% yield (Scheme 3C). The increase in the yield of
3
aa from 12% (Table 1, entry 14) to 47% when using
In conclusion, we have successfully developed a
simple one-pot synthesis of 5-substituted
pyrazolo[5,1-a]isoquinolines from 1-aryl-2-(1H-
pyrazol-1-yl)ethan-1-ones via nickel-catalyzed
acetyl acetone along with NiCl
2
•6H O suggests
2
involvement of Ni(0) in the catalysis of the reaction
under investigation.[
22]
tandem Knoevenagel condensation and intramolecular
carbon-carbon bond formation through C‒H activation.
The easily accessible substrates, cheaper catalyst, ease
of operation and good yields make this method very
practical for the synthesis of the biologically useful 5-
substituted pyrazolo[5,1-a]isoquinoline derivatives.
Experimental Section
General information
Melting points were measured using an automatic melting
point apparatus and are uncorrected. The thin layer
chromatography to monitor the progress of the reactions
1
was performed on 0.25 mm silica gel 60-F254. The H
13
and C NMR spectra were obtained on a 400 MHz
spectrometer. Coupling constant and chemical shifts were
reported in hertz (Hz) and parts per million (ppm),
respectively downfield from tetramethylsilane as an internal
Scheme 3. Control experiments.
-
1
3
with CDCl . IR spectral values are expressed in cm . The
HRMS spectra were recorded on a Q-TOF mass
spectrometer in ESI mode.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201701519
Representative procedure for the synthesis of 1-aryl-2-
1.7 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.97 – 7.90 (m, 2H),
7.69 – 7.61 (m, 3H), 7.58 (d, J = 2.2 Hz, 1H), 6.42 (t, J =
(
1H-pyrazol-1-yl)ethan-1-one: An oven dried RB flask
13
was charged with 1H- pyrazole (0.500 g, 7.34 mmol) and
3
2.1 Hz, 1H), 5.77 (s, 2H); C NMR (100 MHz, CDCl ) δ
K
2
CO
3
(2.02 g, 14.68 mmol) and was kept under a nitrogen
192.4, 140.0, 136.0, 132.4, 131.9, 130.9, 130.1, 129.7, 129.1,
atmosphere. Phenacyl bromide (1.46 g, 7.35 mmol) was
added portion wise. The reaction mixture was heated at 60
129.0, 127.9, 127.1, 123.5, 106.6, 57.8; FT-IR vmax (neat)
-
1
3084, 1662, 1455, 1288, 1107, 730 cm

C for 5 h. Reaction progress was monitored by TLC. After
completion of the reaction, 1,4-dioxane was evaporated and
reaction mixture was diluted with water (100 mL) and
extracted by ethyl acetate (20 mL × 2). Combined organic
2
-(1H-Pyrazol-1-yl)-1-(thiophen-2-yl)ethan-1-one (1h):
1
Brown oil (0.86 g, 60%); H NMR (400 MHz, CDCl
7.74 (m, 1H), 7.73 (bs, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.55
d, J = 2.3 Hz, 1H), 7.19 – 7.16 (m, 1H), 6.39 (t, J = 2.1 Hz,
3
) δ 7.75
–
(
2
layer was dried over anhydrous Na SO4, filtered and
evaporated the ethyl acetate layer. Crude solid compound
was triturated with cold diethyl ether to provide pure 1-
phenyl-2-(1H-pyrazol-1-yl)ethan-1-one (1a) in 67% (0.92
g) yield as off white solid.
13
1
1
H), 5.51 (s, 2H); C NMR (100 MHz, CDCl
3
) δ 185.6,
41.0, 140.1, 135.1, 132.8, 130.9, 128.5, 106.7, 57.9; FT-IR
-1
v
max (neat) 3086, 1662, 1450, 1292, 1099, 729 cm
1
-(4-Chlorophenyl)-2-(1H-pyrazol-1-yl)ethan-1-one
1
-Phenyl-2-(1H-pyrazol-1-yl)ethan-1-one (1a): Off white
1
(
1i): White crystalline solid (1.10 g, 68 %); mp. 134 ‒ 136
solid (0.92 g, 67%); mp. 90 ‒ 91 C; H NMR (400 MHz,
CDCl ) δ 8.01 – 7.99 (m, 2H), 7.67 – 7.63 (m, 1H), 7.62 (d,
1

C; H NMR (400 MHz, CDCl
3
) δ 7.96 – 7.93 (m, 2H), 7.62
3
(
d, J = 1.6 Hz, 1H), 7.53 – 7.51 (m, 2H), 7.50 – 7.49 (m,
J = 1.6 Hz, 1H), 7.55 – 7.51 (m, 3H), 6.40 (t, J = 2.1 Hz,
13
1
H), 6.40 (t, J = 2.1 Hz, 1H), 5.60 (s, 2H); C NMR (100
) δ 191.4, 140.7, 140.1, 132.8, 130.8, 129.6,
1
3
1
1
H), 5.64 (s, 2H); C NMR (100 MHz, CDCl
3
) δ 192.5,
MHz, CDCl
3
40.0 134.5, 134.1, 130.9, 129.0, 128.1, 106.6, 57.7; FT-IR
1
1
29.4, 106.8, 57.6; FT-IR vmax (neat) 3109, 1705, 1581, 1211,
-
1
v
max (neat) 3140, 1697, 1597, 1211, 1087, 748 cm .
-1
087, 763 cm .
2
-(1H-pyrazol-1-yl)-1-(p-tolyl)ethan-1-one (1b): White
1
2
-(1H-Pyrazol-1-yl)-1-(4-(trifluoromethyl)phenyl)-
crystalline solid (1.04 g, 71%); mp. 136 ‒ 138 C; H NMR
ethan-1-one (1j): White crystalline (152 mg, 32%); mp 140
(
400 MHz, CDCl
3
) δ 7.90 (d, J = 8.3 Hz, 2H), 7.62 (d, J =
1
‒
141 C; H NMR (400 MHz, CDCl
3
) δ 8.11 (d, J = 8.2 Hz,
1
2
.6 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 8.0 Hz,
2
H), 7.80 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 1.7 Hz, 1H), 7.54
1
3
H), 6.40 (t, J = 2.1 Hz, 1H), 5.61 (s, 2H), 2.45 (s, 3H);
C
(
d, J = 2.3 Hz, 1H), 6.41 (t, J = 2.1 Hz, 1H), 5.64 (s, 2H);
NMR (100 MHz, CDCl
1
3
3
) δ 192.0, 145.1, 139.9, 132.0,
30.9, 129.7, 128.2, 106.5, 57.6, 21.8; FT-IR vmax (neat)
13
3
C NMR (100 MHz, CDCl ) δ 191.7, 140.3, 137.2, 137.2,
1
1
35.3 (q, J = 33 Hz), 130.8, 128.6, 126.0 (q, J = 3.7 Hz),
-1
124, 1689, 1597, 1288, 1188, 756 cm .
19
23.3 (q, J = 271 Hz), 106.9, 57.9; F NMR (375 MHz,
CDCl
3
) δ -63.3; FT-IR vmax (neat) 3109, 1705, 1404, 1327,
-
1
2
-(1H-Pyrazol-1-yl)-1-(o-tolyl)ethan-1-one (1c): An oven
1111, 763 cm .
dried RB flask was charged with 1H- pyrazole (200 mg,
2
.94 mmol), DMF (5 mL) and stirred at room temperature.
2
-(3-Isopropyl-1H-pyrazol-1-yl)-1-phenylethan-1-one
1
To the reaction mixture was added KOH (247 mg, 4.4
mmol) portion wise and after 20 min, 2-bromo-1-(o-
tolyl)ethan-1-one (0.751 g, 3.52 mmol) was added portion
wise. Reaction progress was monitored by TLC. After
completion of the reaction, reaction mixture was diluted
with ice-cold water (50 mL) and extracted with ethyl acetate
(
1k): Yellow solid (0.71 g, 69%); mp. 95 ‒ 96 C; H NMR
400 MHz, CDCl ) δ 8.01 – 7.99 (m, 2H), 7.67 – 7.62 (m,
H), 7.54 – 7.50 (m, 2H), 7.43 (d, J = 2.3 Hz, 1H), 6.21 (d,
(
3
1
J = 2.3 Hz, 1H), 5.59 (s, 2H), 3.10 – 2.99 (m, 1H), 1.31 (d,
13
3
J = 6.9 Hz, 6H); C NMR (100 MHz, CDCl ) δ 192.7, 159.7,
1
34.6, 134.0, 131.40, 128.9, 128.1, 103.4, 57.5, 27.8, 22.9;
(
2 × 20 mL). Combined organic layer was dried over
FT-IR vmax (neat) 3209, 2970, 1705, 1257, 1211, 1026, 717
anhydrous Na
2
SO4, filtered and evaporated the ethyl acetate
-1
cm .
layer. Crude solid compound was purified by column
chromatography over silica (25% v/v EtOAc: Hexane) to
obtain 2-(1H-pyrazol-1-yl)-1-(o-tolyl)ethan-1-one (1j) as
1
-Phenyl-2-(4-phenyl-1H-pyrazol-1-yl)ethan-1-one (1l):
1
1
Off white solid (0.232 g, 64%); mp.121 ‒ 122 C; H NMR
light yellow solid (59%, 110 mg); mp. 75 ‒ 77 C; H NMR
(
(
3
400 MHz, CDCl ) δ 8.06 – 8.01 (m, 2H), 7.90 (s, 1H), 7.79
(
3
400 MHz, CDCl ) δ 7.78 (d, J = 7.7 Hz, 1H), 7.62 (d, J =
s, 1H), 7.67 (t, J = 7.4 Hz, 1H), 7.58 – 7.51 (m, 4H), 7.39
1
1
.4 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.47 (t, J = 7.5 Hz,
H), 7.34 (t, J = 8.5 Hz, 2H), 6.40 (t, J = 2.0 Hz, 1H), 5.54
(
t, J = 7.7 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 5.65 (s, 2H);
1
3
1
3
3
C NMR (100 MHz, CDCl ) δ 192.2, 137.5, 134.5, 134.2,
32.4, 129.0, 128.8, 128.2, 127.8, 126.5, 125.7, 124.1, 57.9;
(
s, 2H), 2.56 (s, 3H); C NMR (100 MHz, CDCl
3
) δ 195.4,
40.0, 139.8, 134.3, 132.5, 130.9, 128.5, 125.9, 106.5, 59.2,
1.6; FT-IR vmax (neat) 2927, 1666, 1597, 1242, 1035, 742
1
1
2
-1
FT-IR vmax (neat) 3102, 1658, 1450, 1282, 1078, 728 cm .
-
1
cm .
2
-(4-Bromo-1H-pyrazol-1-yl)-1-phenylethan-1-one
(
1m): White crystalline solid (0.54 g, 60%); mp. 138 ‒ 139
1
-(4-Methoxyphenyl)-2-(1H-pyrazol-1-yl)ethan-1-one
1

C; H NMR (400 MHz, CDCl
3
) δ 8.02 – 7.99 (m, 2H), 7.71
(
1d): White crystalline solid (1.08 g, 68%); mp. 140 ‒ 141
1
– 7.65 (m, 1H), 7.57 (s, 2H), 7.57 – 7.52 (m, 2H), 5.61 (s,

3
C; H NMR (400 MHz, CDCl ) δ 8.01 – 7.98 (m, 2H), 7.61
13
2
H); C NMR (100 MHz, CDCl ) δ 191.7, 140.6, 134.4,
3
(
d, J = 1.6 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.01 – 6.98 (m,
1
3
134.2, 131.1, 129.1, 128.1, 94.1, 58.2; FT-IR vmax (neat)
2
H), 6.39 (t, J = 2.1 Hz, 1H), 5.59 (s, 2H), 3.91 (s, 3H);
C
-1
3
125, 1697, 1597, 1219, 1088, 687 cm .
NMR (100 MHz, CDCl
3
) δ 190.8, 164.2, 139.9, 130.8,
30.5, 127.5, 114.2, 106.5, 57.4, 55.6; FT-IR vmax (neat)
1
3
-1
140, 1681, 1597, 1265, 1066, 756 cm .
2-(4-Chloro-1H-pyrazol-1-yl)-1-phenylethan-1-one (1n):
White crystalline solid (0.225 g, 52%); mp. 129 ‒ 130 C;
1
3
H NMR (400 MHz, CDCl ) δ 8.00 (dd, J = 8.4, 1.2 Hz, 2H),
1
-(3-Methoxyphenyl)-2-(1H-pyrazol-1-yl)ethan-1-one1
7.68 (tt, J = 7.6, 1.2 Hz, 1H), 7.57 – 7.53 (m, 4H), 5.58 (s,
(
1e): Light yellow solid (114 mg, 61%); mp 67 ‒ 68 C; H
1
3
2
1
3
H); C NMR (101 MHz, CDCl
3
) δ 191.7, 138.5, 134.3,
3
NMR (400 MHz, CDCl ) δ 7.61 (d, J = 1.1 Hz, 1H), 7.56 (d,
J = 7.6 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.50 (bs, 1H), 7.42
34.2, 129.1, 129.0, 128.9, 128.2, 58.3; FT-IR vmax (neat)
124, 1697, 1597, 1219, 1087, 748 cm .
-
1
(
t, J = 7.9 Hz, 1H), 7.18 (dd, J = 8.2, 2.2 Hz, 1H), 6.39 (s,
1
3
1
3
H), 5.60 (s, 2H), 3.86 (s, 3H); C NMR (100 MHz, CDCl )
δ 192.3, 160.0, 139.9, 135.8, 130.9, 129.9, 120.6, 112.4,
1
1
Representative procedure for the synthesis of
pyrazolo[5,1-a]isoquinoline derivatives (3aa‒3kf): An
oven-dried sealed tube with a rubber septum was charged
with 1-phenyl-2-(1H-pyrazol-1-yl)ethan-1-one (0.100 g,
06.6, 57.8, 55.5; FT-IR vmax (neat) 2933, 1689, 1597, 1257,
-1
165, 756 cm .
0
.537 mmol), 2‒bromobenzaldehyde (0.109 g, 0.590 mmol),
1
-(Naphthalen-2-yl)-2-(1H-pyrazol-1-yl)ethan-1-one
1
2 3 3
K CO (0.222 g, 1.61 mmol), P(Cy) (0.045 g, 0.161 mmol)
(
1g): Off white solid (0.89 g, 52%); mp.134 ‒ 136 C;
H
and dry DMSO (2 mL). The resulting slurry was evacuated
NMR (400 MHz, CDCl
3
) δ 8.54 (s, 1H), 8.04 (dd, J = 8.6,
6
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701519
1
and backfilled with nitrogen gas. After 10 min, Ni(acac)
2
3
‒ 137 C; H NMR (400 MHz, CDCl ) δ 8.18 (d, J = 7.9 Hz,
(
0.027 g, 0.107 mmol) was added then septum was replaced
1H), 8.04 – 8.02 (m, 3H), 7.99 (d, J = 1.9 Hz, 1H), 7.84 –
7.78 (m, 4H), 7.70 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.5 Hz,
1H), 7.28 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.53 (t, J = 1.6
with screw cap to sealed vial tightly and reaction mixture
was heated at 150 C for 16 h. The reaction mass was
allowed to cool to ambient temperature, diluted with ice
cold water (20 mL) and extracted by EtOAc (2 × 30 mL).
The combined organic layer was dried over anhydrous
1
3
3
Hz, 1H); C NMR (100 MHz, CDCl ) δ 188.1, 143.9, 142.2,
141.7, 139.1, 134.8, 133.9, 131.8, 129.1, 128.4, 128.2, 127.7,
126.9, 125.32, 123.8, 118.4, 114.5, 108.7, 97.9; FT-IR vmax
-
1
Na
2
SO
4
and evaporated to dryness under reduced pressure
(neat) 3016, 1659, 1435, 1265, 1033, 741 cm ; HRMS
15 4
H N
O [M+H]+ 339.1240, found
on a rotatory evaporator. The crude residue was purified by
column chromatography (12% EtOAc: Hexane) to afford
(ESI) calcd. for C21
339.1244.
3
aa in 68% (100 mg) yield.
Naphthalen-2-yl(pyrazolo[5,1-a]isoquinolin-5-
Phenyl(pyrazolo[5,1-a]isoquinolin-5-yl)methanone
yl)methanone (3ga): Light yellow solid (90 mg, 66%);
1
(
3aa): Light yellow solid (100 mg, 68%); mp. 134 ‒ 136 C;
mp.156 ‒ 158 C; H NMR (400 MHz, CDCl
3
) δ 8.42 (s,
1
H NMR (400 MHz, CDCl
3
) δ 8.19 (d, J = 7.9 Hz, 1H), 8.00
1H), 8.21 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.00
(s, 1H), 7.98 – 7.85 (m, 3H), 7.82 (d, J = 7.8 Hz, 1H), 7.72
(
d, J = 2.0 Hz, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.80 (d, J = 7.8
Hz, 1H), 7.72 – 7.67 (m, 1H), 7.67 – 7.59 (m, 2H), 7.50 (t,
(t, J = 7.5 Hz, 1H), 7.64 (t, J = 6.5 Hz, 2H), 7.58 – 7.51 (m,
13
13
J = 7.7 Hz, 2H), 7.26 (s, 1H), 7.10 (d, J = 2.1 Hz, 1H);
NMR (100 MHz, CDCl
C
1H), 7.31 (s, 1H), 7.12 (s, 1H); C NMR (100 MHz, CDCl
3
)
3
) δ 189.4, 141.8, 139.1, 136.3,
δ 189.4, 141.8, 139.1, 136.1, 135.1, 133.7, 132.6, 132.4,
1
1
1
2
34.9, 134.0, 130.1, 129.1, 128.7, 128.4, 128.2, 127.7, 125.3, 129.8, 129.1, 129.0, 128.7, 128.4, 128.2, 127.9, 127.8, 126.9,
23.8, 114.6, 97.8: FT-IR vmax (neat) 3055, 1659, 1435, 1257, 125.3, 124.9, 123.8, 114.6, 98.0; FT-IR vmax (neat) 3059,
-
1
O [M+H]+
-1
172, 756 cm ; HRMS (ESI) calcd. for C18
73.1022, found 273.1023.
H
13
N
2
1678, 1469, 1257, 1184, 744 cm ; HRMS (ESI) calcd. for
+
C
22
H
15
N
2
O [M+H] 323.1179, found 323.1158.
Pyrazolo[5,1-a]isoquinolin-5-yl(p-tolyl)methanone
Pyrazolo[5,1-a]isoquinolin-5-yl(thiophen-2-
yl)methanone (3ha): Light yellow oil (85 mg, 59%); H
1
(
3ba): Light yellow solid (102 mg, 72%); mp.158 ‒ 159 C;
1
H NMR (400 MHz, CDCl
3
) δ 8.16 (d, J = 8.0 Hz, 1H), 7.99
3
NMR (400 MHz, CDCl ) δ 8.16 (d, J = 7.9 Hz, 1H), 8.04 (d,
(
d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 7.9
J = 2.0 Hz, 1H), 7.82 (dd, J = 4.9, 0.8 Hz, 1H), 7.79 (d, J =
7.9 Hz, 1H), 7.71 – 7.66 (m, 2H), 7.60 (t, J = 7.5 Hz, 1H),
Hz, 1H), 7.69 – 7.63 (m, 1H), 7.62 – 7.56 (m, 1H), 7.28 (d,
J = 8.0 Hz, 2H), 7.21 (s, 1H), 7.08 (d, J = 2.1 Hz, 1H), 2.44
7.32 (s, 1H), 7.16 (t, J = 4.0 Hz, 1H), 7.09 (d, J = 2.1 Hz,
13
13
(
s, 3H); C NMR (100 MHz, CDCl
3
) δ 189.1, 145.2, 141.7,
1H); C NMR (100 MHz, CDCl
3
) δ 181.0, 143.30, 141.8,
1
1
1
39.0, 135.1, 133.7, 130.2, 129.5, 129.0, 128.3, 128.1, 127.8, 139.2, 136.2, 135.7, 134.4, 129.2, 128.4, 128.2, 127.5, 125.3,
25.2, 123.8, 114.1, 97.8, 21.9; FT-IR vmax (neat) 3140, 1657, 123.8, 114.4, 98.0; FT-IR vmax (neat) 3059, 1666, 1477, 1242,
-
1
-1
435, 1249, 1173, 740 cm ; HRMS (ESI) calcd. for
1108, 725 cm ; HRMS (ESI) calcd. for C16
H
11
N
2
OS
+
+
C
19
H
15
N
2
O [M+H] 287.1179, found 287.1203.
[M+H] 279.0587, found 279.0587.
(
Pyrazolo[5,1-a]isoquinolin-5-yl(o-tolyl)methanone
(4-Chlorophenyl)(pyrazolo[5,1-a]isoquinolin-5-
1
(
3ca): Light yellow solid (103 mg, 72%); mp 154 ‒ 156 C;
yl)methanone (3ia): Light yellow oil (25 mg, 18%); H
1
H NMR (400 MHz, CDCl
3
) δ 8.13 (d, J = 7.9 Hz, 1H), 8.02
3
NMR (400 MHz, CDCl ) δ 8.18 (d, J = 8.0 Hz, 1H), 7.99 (d,
(
bs, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H),
.56 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.45 (t, J
7.4 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.24 – 7.19 (m, 2H),
J = 1.8 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 7.8
Hz, 1H), 7.72 – 7.68 (m, 1H), 7.64 – 7.60 (m, 1H), 7.46 (d,
7
13
=
J = 8.6 Hz, 2H), 7.26 (s, 1H), 7.10 (d, J = 1.9 Hz, 1H); C
1
3
7
1
1
2
.07 (s, 1H), 2.61 (s, 3H); C NMR (100 MHz, CDCl
3
) δ
3
NMR (100 MHz, CDCl ) δ 188.2, 141.8, 140.5, 139.0,
91.0, 141.8, 139.6, 139.2, 136.6, 135.8, 132.1, 131.9, 130.8, 134.7, 134.6, 131.3, 129.3, 129.1, 128.4, 128.3, 127.6, 125.3,
29.4, 128.4, 128.3, 127.5, 125.6, 125.6, 123.7, 116.5, 97.8,
123.8, 114.7, 97.9; FT-IR vmax (neat) 2954, 1666, 1597, 1249,
-1
1.0; FT-IR vmax (neat) 3016, 1659, 1589, 1265, 1033, 741
1165, 694 cm ; HRMS (ESI) calcd. for C18
H
12ClN
2
O
-
1
+
+
cm ; HRMS (ESI) calcd. for C19
H
15
N
2
O [M+H] 287.1179,
[M+H] 307.0633, found 307.0639.
found 287.1194.
Pyrazolo[5,1-a]isoquinolin-5-yl(4-(trifluoromethyl)-
phenyl)methanone (3ja): Off white solid (43 mg, 32%);
(
4-Methoxyphenyl)(pyrazolo[5,1-a]isoquinolin-5-
1
yl)methanone (3da): Light yellow solid (91 mg, 65%); mp.
3
mp 143 ‒ 145 C; H NMR (400 MHz, CDCl ) δ 8.20 (d, J
1
1
32 ‒ 134 C; H NMR (400 MHz, CDCl
3
) δ 8.16 (d, J = 7.9
= 7.8 Hz, 1H), 8.01 – 7.98 (m, 3H), 7.83 (d, J = 7.7 Hz, 1H),
7.76 – 7.71 (m, 3H), 7.64 (t, J = 7.3 Hz, 1H), 7.30 (s, 1H),
Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.96 – 7.90 (m, 2H), 7.77
13
(
d, J = 7.6 Hz, 1H), 7.69 – 7.63 (m, 1H), 7.61 – 7.56 (m,
7.11 (s, 1H); C NMR (100 MHz, CDCl3) δ 188.4, 141.8,
139.2, 139.1, 135.1 (q, J = 33 Hz), 134.4, 130.1, 129.5,
128.5, 128.4, 125.7 (q, J = 3.6 Hz), 125.5, 124.9, 123.5 (q,
1
2
1
1
H), 7.19 (s, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.98 – 6.92 (m,
13
3
H), 3.88 (s, 3H); C NMR (100 MHz, CDCl ) δ 188.0,
19
3
64.4, 141.7, 139.0, 135.3, 132.6, 129.1, 128.8, 128.3, 128.0, J = 271 Hz), 115.5, 98.0; F NMR (375 MHz, CDCl ) δ -
27.8, 125.1, 123.8, 114.0, 113.6, 97.8, 55.6; FT-IR vmax
63.2; FT-IR vmax (neat) 2954, 1674, 1442, 1319, 1111, 748
-
1
-1
O [M+H]+
(
(
neat) 3132, 1659, 1435, 1257, 1172, 756 cm ; HRMS
cm ; HRMS (ESI) calcd. for C19
H
12
F
3
N
2
+
ESI) calcd. for C19
03.1149.
H
15
N
2
O
2
[M+H] 303.1128, found
341.0896, found 341.0901.
3
(
2-Isopropylpyrazolo[5,1-a]isoquinolin-5-
(
3-Methoxyphenyl)(pyrazolo[5,1-a]isoquinolin-5-
yl)(phenyl)methanone (3ka): Off white solid (103 mg,
1
yl)methanonemethanone (3ea): Light yellow solid (60 mg, 75%); mp. 140 ‒ 142 C; H NMR (400 MHz, CDCl
3
) δ 8.13
1
4
3%); mp 186 ‒ 187 C; H NMR (400 MHz, CDCl
3
) δ 8.18
(d, J = 8.0 Hz, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.75 (d, J = 7.8
(
d, J = 7.9 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 7.8
Hz, 1H), 7.70 – 7.60 (m, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.48
(t, J = 7.7 Hz, 2H), 7.16 (s, 1H), 6.91 (s, 1H), 3.22 – 3.12
Hz, 1H), 7.71 – 7.67 (m, 1H), 7.63 – 7.59 (m, 1H), 7.58 –
13
7
1
1
1
1
.57 (m, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.9 Hz,
H), 7.24 (s, 1H), 7.21 – 7.18 (m, 1H), 7.09 (d, J = 2.1 Hz,
(m, 1H), 1.31 (d, J = 6.9 Hz, 6H); C NMR (100 MHz,
3
CDCl ) δ 189.6, 161.9, 139.6, 136.5, 134.9, 133.7, 130.2,
1
3
H), 3.87 (s, 3H); C NMR (101 MHz, CDCl
3
) δ 189.19,
128.8, 128.4, 128.1, 128.0, 127.7, 125.2, 123.6, 113.6, 94.4,
41.75, 139.0, 137.5, 134.9, 129.6, 129.0, 128.3, 128.2,
27.7, 125.3, 123.8, 123.1, 120.8, 114.4, 113.6, 97.8, 55.5;
28.1, 23.0; FT-IR vmax (neat) 3132, 2970, 1659, 1234, 1080,
-
1
19 2
H N
O [M+H]+
679 cm ; HRMS (ESI) calcd. for C21
315.1492, found 315.1494.
-
1
FT-IR vmax (neat) 3132, 1651, 1597, 1311, 1041, 748 cm ;
+
HRMS (ESI) calcd. for C19
found 303.1145.
15 2 2
H N O [M+H] 303.1128,
Phenyl(1-phenylpyrazolo[5,1-a]isoquinolin-5-
yl)methanone (3la): Light yellow solid (46 mg, 35%);
1
(
5
4-(1H-Pyrazol-1-yl)phenyl)(pyrazolo[5,1-a]isoquinolin-
-yl)methanone (3fa): Yellow solid (78 mg, 48%); mp 135
3
mp.162 ‒ 164 C; H NMR (400 MHz, CDCl ) δ 8.10 (d, J
= 8.2 Hz, 1H), 8.01 – 7.93 (m, 2H), 7.93 (s, 1H), 7.78 (d, J
7
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701519
=
7.8 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.61 – 7.57 (m, 2H),
151.2, 150.3, 141.6, 138.9, 136.7, 133.7, 133.3, 130.1, 128.6,
7
1
.57 – 7.51 (m, 4H), 7.51 – 7.49 (m, 1H), 7.48 – 7.45 (m,
122.1, 120.2, 115.3, 108.4, 104.3, 96.3, 56.3, 56.1; FT-IR
1
3
-1
H), 7.46 – 7.42 (m, 1H), 7.24 (s, 1H); C NMR (100 MHz,
) δ 189.5, 142.5, 136.2, 135.0, 134.3, 134.1, 133.7,
30.1, 130.0, 128.8, 128.7, 128.6, 128.4, 128.3, 128.2, 127.7, 333.1230.
25.8, 123.5, 117.0, 114.4; FT-IR vmax (neat) 3059, 1643,
v
max (neat) 3132, 1651, 1496, 1242, 1157, 732 cm ; HRMS
3
17 2 3
(ESI) calcd. for C20H N O
[M+H]+ 333.1234, found
CDCl
1
1
1
-
1
408, 1238, 1091, 725 cm ; HRMS (ESI) calcd. for
[
1,3]Dioxolo[4,5-g]pyrazolo[5,1-a]isoquinolin-5-
+
C
24
H
17
N
2
O [M+H] 349.1335, found 349.1358.
yl(phenyl)methanone (3af): Yellow solid (102 mg, 60%);
1
3
mp. 172 ‒ 173 C; H NMR (400 MHz, CDCl ) δ 7.94 (d, J
(
1-Bromopyrazolo[5,1-a]isoquinolin-5-yl)(phenyl)-
= 2.0 Hz, 1H), 7.91 (d, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz,
methanone (3ma): Yellow solid (28 mg, 21%); mp 183 ‒
1H), 7.49 – 7.46 (m, 3H), 7.14 (s, 1H), 7.10 (s, 1H), 6.89 (d,
1
13
1
1
1
7
1
1
(
(
3
85 C; H NMR (400 MHz, CDCl
3
) δ 9.10 (d, J = 8.1 Hz,
J = 2.0 Hz, 1H), 6.12 (s, 2H); C NMR (100 MHz, CDCl
3
)
H), 7.94 (s, 1H), 7.92 – 7.90 (m, 2H), 7.81 (d, J = 7.8 Hz,
H), 7.76 – 7.72 (m, 1H), 7.68 – 7.63 (m, 2H), 7.49 (t, J =
δ 189.4, 149.6, 148.8, 141.6, 139.1, 136.5, 133.8, 133.4,
130.0, 128.6, 123.5, 121.5, 115.1, 106.0, 102.2, 102.0, 96.6;
1
3
-1
.8 Hz, 2H), 7.26 (s, 1H); C NMR (100 MHz, CDCl
3
) δ
FT-IR vmax (neat) 3063, 1666, 1450, 1219, 1039, 687 cm ;
+
88.9, 142.9, 136.1, 134.9, 134.2, 133.8, 129.9, 129.0, 128.8, HRMS (ESI) calcd. for C19
H
13
N
2
O
3
[M+H] 317.0921,
28.7, 128.3, 128.2, 125.1, 123.4, 115.0, 87.4; FT-IR vmax
found 317.0944.
-
1
neat) 2924, 1659, 1435, 1311, 1249, 679 cm ; HRMS
+
ESI) calcd. for C18
2
H12BrN O [M+H] 351.0128, found
+
(
8-Methoxypyrazolo[5,1-a]isoquinolin-5-
51.0143 and [M+H+2] 353.0124.
yl)(phenyl)methanone (3ag): Light yellow solid (107 mg,
1
6
3
6%); mp. 176 ‒ 177 C; H NMR (400 MHz, CDCl ) δ 8.09
(
1-Chloropyrazolo[5,1-a]isoquinolin-5-yl)(phenyl)-
(d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.0 Hz, 3H), 7.65 (t, J = 7.2
Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 8.2 Hz, 1H),
methanone (3na): Yellow solid (25 mg, 18%); mp 170 ‒
1
13
1
1
7
7
1
1
1
72 C; H NMR (400 MHz, CDCl
3
) δ 8.93 (d, J = 8.1 Hz,
7.18 (s, 2H), 6.97 (s, 1H), 3.95 (s, 3H); C NMR (100 MHz,
H), 7.93 – 7.91 (m, 3H), 7.82 (d, J = 8.1 Hz, 1H), 7.77 –
.73 (m, 1H), 7.69 – 7.64 (m, 2H), 7.50 (t, J = 7.8 Hz, 2H),
3
CDCl ) δ 189.5, 159.6, 141.9, 139.2, 136.2, 135.3, 134.0,
130.1, 129.3, 128.7, 125.4, 119.4, 118.9, 114.2, 109.0, 96.6,
13
.25 (s, 1H); C NMR (101 MHz, CDCl
3
) δ 188.9, 140.6,
55.6; FT-IR vmax (neat) 3063, 1666, 1604, 1242, 1165, 687
-
1
+
15 2 2
36.1, 134.9, 134.2, 132.8, 129.9, 129.1, 128.8, 128.2, 128.1, cm ; HRMS (ESI) calcd. for C19H N O [M+H] 303.1128,
25.0, 123.4, 115.0, 104.3; FT-IR vmax (neat) 3055, 1659,
found 303.1154.
-
1
435, 1319, 1249, 756 cm ; HRMS (ESI) calcd. for
+
18 2
C H12ClN O [M+H] 307.0633, found 307.0627.
Phenyl(pyrazolo[1,5-h][1,7]naphthyridin-6-
yl)methanone (3ah): Light yellow solid (96 mg, 66%);
1
(
8-Fluoropyrazolo[5,1-a]isoquinolin-5-
mp.161 ‒ 162 C; H NMR (400 MHz, CDCl
3
) δ 8.97 (dd,
yl)(phenyl)methanone (3ab): Yellow solid (70 mg, 45%);
J = 4.5, 1.5 Hz, 1H), 8.11 (dd, J = 8.0, 1.5 Hz, 1H), 8.05 (d,
J = 2.0 Hz, 1H), 7.93 (d, J = 7.3 Hz, 2H), 7.66 (t, J = 7.4 Hz,
1H), 7.55 (dd, J = 8.0, 4.6 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H),
1
3
mp. 154 ‒ 155 C; H NMR (400 MHz, CDCl ) δ 8.16 (dd,
J = 8.2, 5.3 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J = 7.5 Hz, 2H),
13
7
.65 (t, J = 7.1 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.42 (dd, J
7.44 (d, J = 2.1 Hz, 1H), 7.19 (s, 1H); C NMR (100 MHz,
13
=
16.4, 8.5 Hz, 2H), 7.16 (s, 1H), 7.03 (s, 1H); C NMR
CDCl
3
) δ 189.0, 150.9, 142.7, 142.3, 139.7, 135.9, 135.8,
(
100 MHz, CDCl
3
) δ 189.2, 162.1 (d, J = 249.0 Hz),, 142.1,
135.5, 134.3, 130.0, 128.8, 123.6, 123.2, 112.2, 100.2; FT-
-
1
1
1
38.7, 136.0, 135.9, 134.2, 130.0, 129.5 (d, J = 9.2 Hz),
28.8, 126.12 (d, J = 8.9 Hz), 121.7 (d, J = 2.0 Hz), 117.7
IR vmax (neat) 3062, 1659, 1473, 1273, 1180, 729 cm ;
+
HRMS (ESI) calcd. for C17
found 274.0977.
12 3
H N O [M+H] 274.0975,
(
d, J = 23.8 Hz), 113.10, 113.07, 113.0 (d, J = 22.0 Hz),
19
9
3
7.6; F NMR (375 MHz, CDCl ) δ -111.2; FT-IR vmax
-1
(
(
neat) 3124, 1659, 1442, 1234, 1141, 679 cm ; HRMS
Phenyl(pyrazolo[1,5-a]thieno[2,3-c]pyridin-5-
yl)methanone (3ai): Light brown oil (86 mg, 56%); H
+
ESI) calcd. for C18
91.0929.
H
12FN
2
O [M+H] 291.0928, found
1
2
3
NMR (400 MHz, CDCl ) δ 8.01 (d, J = 1.6 Hz, 1H), 7.90 (d,
J = 7.5 Hz, 2H), 7.68 (dd, J = 19.5, 5.3 Hz, 2H), 7.63 (t, J =
7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.43 (s, 1H), 6.85 (d,
(
8-Chloropyrazolo[5,1-a]isoquinolin-5-
13
yl)(phenyl)methanone (3ac): Off white solid (50 mg,
3
J = 1.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ 189.3, 142.0,
1
3
0%); mp.172 ‒ 174 C; H NMR (400 MHz, CDCl
3
) δ 8.10
137.7, 136.3, 133.9, 133.3, 133.1, 130.3, 130.0, 129.8, 128.7,
(
d, J = 8.5 Hz, 1H), 7.99 (s, 1H), 7.93 (d, J = 7.4 Hz, 2H),
122.5, 109.7, 95.9; FT-IR vmax (neat) 3059, 1655, 1446,
-
1
7
7
.77 (s, 1H), 7.69 – 7.60 (m, 2H), 7.49 (t, J = 7.6 Hz, 2H),
1276, 1180, 725 cm ; HRMS (ESI) calcd. for C16
H
11
N
2
OS
1
3
+
.14 (s, 1H), 7.07 (d, J = 1.7 Hz, 1H); C NMR (100 MHz,
) δ 189.1, 142.1, 138.5, 135.9, 135.9, 134.2, 134.2,
30.0, 129.4, 128.9, 128.8, 127.3, 125.2, 123.5, 112.9, 98.1;
[M+H] 279.0587, found 279.0588.
CDCl
3
1
(
8-Fluoro-2-isopropylpyrazolo[5,1-a]isoquinolin-5-
-
1
FT-IR vmax (neat) 3063, 1662, 1435, 1288, 1083, 721 cm ;
yl)(phenyl)methanone (3kb): Light yellow solid (77 mg,
+
HRMS (ESI) calcd. for C18
found 307.0631.
H
12ClN
2
O [M+H] 307.0633,
1
5
8
7
3
3%); mp. 151 ‒ 152 C; H NMR (400 MHz, CDCl ) δ
.13 – 8.10 (m, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.64 (t, J =
.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.39 (ddd, J = 15.8,
(
9-Methylpyrazolo[5,1-a]isoquinolin-5-
8.9, 2.4 Hz, 2H), 7.07 (s, 1H), 6.86 (s, 1H), 3.20 – 3.10 (m,
13
yl)(phenyl)methanone (3ad): Off white solid (52 mg,
3
1H), 1.30 (d, J = 6.9 Hz, 6H); C NMR (100 MHz, CDCl )
1
3
4%); mp. 173 ‒ 175 C; H NMR (400 MHz, CDCl
3
) δ 7.98
δ 189.4, 162.3, 161.9 (d, J = 248.3 Hz), 139.3, 136.2, 135.9,
133.9, 130.1, 129.5 (d, J = 9.2 Hz), 128.5, 125.9 (d, J = 8.9
Hz), 121.8 (d, J = 2.1 Hz), 117.3 (d, J = 23.8 Hz), 112.9 (d,
(
d, J = 6.7 Hz, 2H), 7.94 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 8.0
Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H),
19
7
1
1
1
.43 (d, J = 7.8 Hz, 1H), 7.23 (s, 1H), 7.06 (d, J = 1.4 Hz,
J = 21.9 Hz), 112.2, 112.1, 94.2, 28.1, 22.9; F NMR (375
1
3
H), 2.60 (s, 3H); C NMR (100 MHz, CDCl
3
) δ 189.5,
MHz, CDCl ) δ -111.9; FT-IR vmax (neat) 3132, 2947, 1659,
3
-1
41.6, 139.6, 139.0, 136.5, 134.1, 133.9, 130.1, 130.0, 128.7, 1234, 1141, 687 cm ; HRMS (ESI) calcd. for C21
H
2
18FN O
+
28.1, 125.4, 125.4, 123.6, 115.0, 97.6, 21.9; FT-IR vmax
[M+H] 333.1398, found 333.1420.
-
1
(
(
neat) 3063, 1665, 1447, 1226, 1187, 663 cm ; HRMS
+
ESI) calcd. for C19
87.1201.
15 2
H N O [M+H] 287.1179, found
(
8-Chloro-2-isopropylpyrazolo[5,1-a]isoquinolin-5-
2
yl)(phenyl)methanone (3kc): Off white solid (52 mg,
1
3
3
4%); mp.164 ‒ 166 C; H NMR (400 MHz, CDCl ) δ 8.05
(
8,9-Dimethoxypyrazolo[5,1-a]isoquinolin-5-
(d, J = 8.6 Hz, 1H), 7.92 (dd, J = 8.3, 1.1 Hz, 2H), 7.73 (d,
J = 2.0 Hz, 1H), 7.66 – 7.61 (m, 1H), 7.58 (dd, J = 8.6, 2.1
Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.04 (s, 1H), 6.88 (s, 1H),
yl)(phenyl)methanone (3ae): Yellow solid (112 mg, 63%);
1
mp. 144 ‒ 146 C; H NMR (400 MHz, CDCl
3
) δ 7.99 (s,
H), 7.94 (d, J = 7.4 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.53
7.46 (m, 3H), 7.21 (s, 1H), 7.16 (s, 1H), 6.95 (s, 1H), 4.12
13
1
3.21 – 3.10 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H); C NMR (100
MHz, CDCl ) δ 189.1, 162.3, 139.1, 136.1, 135.9, 133.9,
3
–
1
3
(
s, 3H), 4.02 (s, 3H); C NMR (100 MHz, CDCl
3
) δ 189.4,
133.7, 130.1, 129.1, 129.0, 128.5, 127.2, 125.1, 123.4, 111.9,
8
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701519
9
1
4.7, 28.1, 22.9; FT-IR vmax (neat) 3130, 2960 1662, 1253,
(2-Isopropyl-4-phenylpyrazolo[1,5-a]pyridin-7-
-
1
053, 725 cm ; HRMS (ESI) calcd. for C21
H
18ClN
2
O
yl)(phenyl)methanone (6ka): Light yellow solid (99 mg,
+
1
[
M+H] 349.1102, found 349.1092.
67%); mp.76 ‒ 78 C; H NMR (400 MHz, CDCl
3
) δ 7.93
(
d, J = 7.4 Hz, 2H), 7.74 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.4
Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H), 7.52 – 7.47 (m, 3H), 7.17
(
2-Isopropyl-9-methylpyrazolo[5,1-a]isoquinolin-5-
(
d, J = 7.1 Hz, 1H), 7.02 (d, J = 7.1 Hz, 1H), 6.59 (s, 1H),
13
yl)(phenyl)methanone (3kd): Off white solid (57 mg,
1
3.21 – 3.11 (m, 1H), 1.28 (d, J = 6.9 Hz, 6H); C NMR (100
MHz, CDCl3) δ 189.6, 162.9, 141.2, 137.9, 136.4, 135.2,
4
–
7
1
6
1
1
3
3
0%); mp. 173 ‒ 175 C; H NMR (400 MHz, CDCl ) δ 7.94
7.92 (m, 2H), 7.66 – 7.61 (m, 2H), 7.48 (t, J = 7.4 Hz, 2H),
.40 (d, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.15 (s, 1H), 6.89 (s,
H), 3.23 – 3.12 (m, 1H), 2.59 (s, 3H), 1.31 (d, J = 6.8 Hz,
1
9
34.1, 133.7, 130.1, 128.9, 128.7, 128.4, 128.1, 120.9, 113.8,
4.2, 28.1, 23.0; FT-IR vmax (neat) 3059, 2962, 1666, 1477,
-
1
13
1253, 1176, 698 cm ; HRMS (ESI) calcd. for C23
H
21
N
2
O
3
H); C NMR (100 MHz, CDCl ) δ 189.6, 161.7, 139.5,
+
[
M+H] 341.1648, found 341.1658.
39.2, 136.7, 134.1, 133.6, 130.3, 129.6, 128.4, 128.0, 125.4,
25.3, 123.4, 114.2, 94.3, 28.1, 23.0, 21.9; FT-IR vmax (neat)
-
1
155, 2955, 1658, 1235, 1187, 671 cm ; HRMS (ESI) calcd.
+
for C22
H
21
N
2
O [M+H] 329.1648, found 329.1672.
Acknowledgements
(
2-Isopropyl-8,9-dimethoxypyrazolo[5,1-a]isoquinolin-
The authors sincerely acknowledge financial support [Project
EMR/2016/002242] by Science and Engineering Research Board
5
7
7
3
3
-yl)(phenyl)methanone (3ke): Yellow solid (115 mg,
1
3
0%); mp. 154 ‒ 155 C; H NMR (400 MHz, CDCl ) δ
(
SERB), New Delhi to carry out this work, DST-FIST
.93 – 7.92 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.49 – 7.45 (m,
[
SR/FST/CSI-270/2015] for HRMS facility and Central Analytical
H), 7.12 (s, 2H), 6.78 (s, 1H), 4.11 (s, 3H), 4.01 (s, 3H),
1
3
Lab, BITS Pilani for NMR and single crystal XRD facility. HKS is
thankful to CSIR New Delhi, BITS Pilani for the research
fellowship.
.20 – 3.15 (m, 1H), 1.32 (d, J = 6.5 Hz, 6H); C NMR (100
MHz, CDCl
3
) δ 189.5, 161.8, 151.0, 150.0, 139.4, 136.8,
33.4, 133.3, 130.2, 128.3, 122.1, 120.0, 114.4, 108.3, 104.2,
2.8, 56.2, 56.1, 28.1, 23.1; FT-IR vmax (neat) 3155, 2962,
1
9
1
-
1
667, 1242, 1149, 686 cm ; HRMS (ESI) calcd. for
+
C
23
H
23
N
2
O
3
[M+H] 375.1703, found 375.1730.
References
(
2-Isopropyl-[1,3]dioxolo[4,5-g]pyrazolo[5,1-
[
1]
a) Y. Wei, P. Hu, M. Zhang, W. Su, Chem. Rev.
2017, 117, 8864–8907; b) X.-X. Guo, D.-W. Gu,
Z. Wu, W. Zhang, Chem. Rev. 2015, 115, 1622-
a]isoquinolin-5-yl)(phenyl)methanone (3kf): Off white
1
solid (97 mg, 62%); mp.160 ‒ 162 C; H NMR (400 MHz,
CDCl
3
) δ 7.91 (d, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H),
7
6
.48 – 7.45 (m, 3H), 7.09 (s, 1H), 7.06 (s, 1H), 6.72 (s, 1H),
.13 (s, 2H), 3.21 – 3.10 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H);
1
651; c) C. Liu, H. Zhang, W. Shi, A. Lei, Chem.
13
Rev. 2011, 111, 1780-1824; d) Y. Yamamoto,
Chem. Soc. Rev. 2014, 43, 1575-1600; e) G. Song,
F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651-
3678; f) R. Rossi, F. Bellina, M. Lessi, C. Manzini,
Adv. Synth. Catal. 2014, 356, 17-117; g) J.
Yamaguchi, A. D. Yamaguchi, K. Itami, Angew.
Chem. Int. Ed. 2012, 51, 8960-9009; h) L.
Ackermann, Chem. Rev. 2011, 111, 1315-1345; i)
I. Nakamura, Y. Yamamoto, Chem. Rev. 2004,
104, 2127-2198; j) N. K. Mishra, S. Sharma, J.
Park, S. Han, I. S. Kim, ACS Catal. 2017, 7, 2821-
3
C NMR (100 MHz, CDCl ) δ 189.5, 161.8, 149.4, 148.5,
1
1
2
39.7, 136.7, 133.5, 133.4, 130.1, 128.3, 123.5, 121.4, 114.2,
05.9, 102.1, 101.8, 93.1, 28.1, 23.0; FT-IR vmax (neat) 3130,
-
1
950, 1662, 1258, 1061, 728 cm ; HRMS (ESI) calcd. for
+
C
22
H
19
N
2
O
3
[M+H] 359.1390, found 359.1364.
(
Z)-3-(2-Bromophenyl)-1-phenyl-2-(1H-pyrazol-1-
yl)prop-2-en-1-one (4a′): Light yellow solid (0.18 g, 19%);
1
mp.104 ‒ 105C; H NMR (400 MHz, CDCl
3
) δ 7.86 – 7.82
(
–
m, 2H), 7.66 (d, J = 1.7 Hz, 1H), 7.64 – 7.62 (m, 1H), 7.61
7.57 (m, 1H), 7.55 (s, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.41
(
d, J = 2.4 Hz, 1H), 7.20 (td, J = 7.7, 1.8 Hz, 1H), 7.14 (td,
J = 7.6, 1.3 Hz, 1H), 6.72 (dd, J = 7.6, 1.7 Hz, 1H), 6.35 (t,
1
3
J = 2.0 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ 191.1, 141.2,
2
1
847; k) R. F. Heck, Acc. Chem. Res. 1979, 12,
46-151; l) T. Hiyama, E. Shirakawa, Cross-
1
37.2, 136.7, 134.3, 133.1, 133.0, 132.9, 131.5, 131.0, 130.1,
1
29.3, 128.5, 127.4, 125.3, 107.4; HRMS (ESI) calcd. for
+
+
C
18
H
14BrN
2
O [M+H] 353.0284, found 353.0301 [M + H]
Coupling Reactions 2002, 61-85; m) J. K. Stille,
Angew. Chem. Int. Ed. 1986, 25, 508-524; n) K.
Sonogashira, J. Organomet. Chem. 2002, 653, 46-
+
and 355.0280. [M + H + 2] .
(
E)-3-(2-Bromophenyl)-1-phenyl-2-(1H-pyrazol-1-
4
9
9; o) N. Miyaura, A. Suzuki, Chem. Rev. 1995,
5, 2457-2483; p) E.-i. Negishi, Bull. Chem. Soc.
yl)prop-2-en-1-one (4a): Light brown oil (0.45 g, 47%); 1H
NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 2H), 7.71
(
d, J = 2.4 Hz, 2H), 7.58 (s, 1H), 7.45 (t, J = 7.6 Hz, 2H),
Jpn. 2007, 80, 233-257.
7
.33 (t, J = 7.7 Hz, 2H), 7.23 (dd, J = 7.5, 1.2 Hz, 1H), 7.03
[
[
2]
3]
a) A. Dey, S. Agasti, D. Maiti, Org. Biomol. Chem.
2016, 14, 5440-5453; b) H. M. L. Davies, D.
Morton, J. Org. Chem. 2016, 81, 343-350; c) J. F.
Hartwig, M. A. Larsen, ACS Cent. Sci. 2016, 2,
(
(
td, J = 7.4, 1.0 Hz, 1H), 6.98 (td, J = 7.6, 1.6 Hz, 1H), 6.43
1
3
t, J = 2.0 Hz, 1H); C NMR (100MHz, CDCl
3
) δ 191.8,
41.8, 136.6, 136.0, 134.1, 133.9, 132.6, 130.7, 129.8, 129.4,
28.7, 128.6, 127.3, 124.3, 120.8, 107.8; HRMS (ESI) calcd.
1
1
+
for C18
H
14BrN
2
O [M+H] 353.0284, found 353.0295 [M +
2
81-292.
+
+
H] and 355.0272 [M + H + 2] .
a) J.-N. Desrosiers, X. Wei, O. Gutierrez, J. Savoie,
B. Qu, X. Zeng, H. Lee, N. Grinberg, N. Haddad,
N. K. Yee, F. Roschangar, J. J. Song, M. C.
Kozlowski, C. H. Senanayake, Chem. Sci. 2016, 7,
Phenyl(4-phenylpyrazolo[1,5-a]pyridin-7-yl)methanone
(
6aa): Light yellow solid (112 mg, 70%); mp.104 ‒ 105 C;
1
H NMR (400 MHz, CDCl
3
) δ 8.03 (d, J = 1.8 Hz, 1H), 7.94
(
d, J = 7.4 Hz, 2H), 7.74 (d, J = 7.1 Hz, 2H), 7.65 (t, J = 7.4
5
1
581-5586; b) X.-h. Cai, B. Xie, ARKIVOC 2015,
84-211; c) M. Tobisu, N. Chatani, Acc. Chem.
Hz, 1H), 7.57 (t, J = 6.9 Hz, 2H), 7.50 (t, J = 7.7 Hz, 3H),
7
.25 (d, J = 7.1 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.81 (d, J
13
=
1.9 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ 189.4, 142.5,
Res. 2015, 48, 1717-1726; d) S. Z. Tasker, E. A.
Standley, T. F. Jamison, Nature 2014, 509, 299-
309; e) J. Yamaguchi, K. Muto, K. Itami, Eur. J.
Org. Chem. 2013, 2013, 19-30; f) B. M. Rosen, K.
W. Quasdorf, D. A. Wilson, N. Zhang, A.-M.
1
1
1
40.4, 137.5, 136.2, 135.5, 134.8, 134.0, 130.0, 129.0, 128.9,
28.7, 128.1, 121.3, 114.6, 97.9; FT-IR vmax (neat) 3055,
-
1
659, 1450, 1296, 1180, 721 cm ; HRMS (ESI) calcd. for
+
C
20
H
15
N
2
O [M+H] 299.1179, found 299.1183.
9
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Advanced Synthesis & Catalysis
10.1002/adsc.201701519
Resmerita, N. K. Garg, V. Percec, Chem. Rev.
011, 111, 1346-1416.
M. Moselage, J. Li, L. Ackermann, ACS Catal.
016, 6, 498-525.
a) J. Keilitz, H. A. Malik, M. Lautens, in Synthesis
of Heterocycles via Metal-Catalyzed Reactions
that Generate One or More Carbon-Heteroatom
Bonds (Ed.: J. P. Wolfe), Springer Berlin
Heidelberg, Berlin, Heidelberg, 2013, pp. 187-223;
b) C. Bressy, D. Alberico, M. Lautens, J. Am.
Chem. Soc. 2005, 127, 13148-13149.
[13]
[14]
[15]
[16]
[17]
[18]
L.-R. Wen, X.-J. Jin, X.-D. Niu, M. Li, J. Org.
Chem. 2014, 80, 90-98.
X. Fan, M. Yan, Y. Wang, X. Zhang, J. Org. Chem.
2015, 80, 10536-10547.
W. Ma, K. Graczyk, L. Ackermann, Org. Lett.
2012, 14, 6318-6321.
X. Li, M. Zhao, J. Org. Chem. 2011, 76, 8530-
8536.
2
[
[
4]
5]
2
J. Jie, H. Li, S. Wu, Q. Chai, H. Wang, X. Yang,
RSC Adv. 2017, 7, 20548-20552.
a) Y.-S. Tung, M. S. Coumar, Y.-S. Wu, H.-Y.
Shiao, J.-Y. Chang, J.-P. Liou, P. Shukla, C.-W.
Chang, C.-Y. Chang, C.-C. Kuo, T.-K. Yeh, C.-Y.
Lin, J.-S. Wu, S.-Y. Wu, C.-C. Liao, H.-P. Hsieh,
J. Med. Chem. 2011, 54, 3076-3080; b) M. B.
Hadimani, M. T. MacDonough, A. Ghatak, T. E.
Strecker, R. Lopez, M. Sriram, B. L. Nguyen, J. J.
Hall, R. J. Kessler, A. R. Shirali, L. Liu, C. M.
Garner, G. R. Pettit, E. Hamel, D. J. Chaplin, R. P.
Mason, M. L. Trawick, K. G. Pinney, J. Nat. Prod.
2013, 76, 1668-1678; c) D. Kumar, M. Pilania, V.
Arun, B. Mishra, Synlett 2014, 25, 1137-1141.
a) M. Jha, S. Dhiman, T. S. Cameron, D. Kumar,
A. Kumar, Org. Lett. 2017, 19, 2038-2041; b) N.
K. Nandwana, S. Dhiman, H. K. Saini, I. Kumar,
A. Kumar, Eur. J. Org. Chem. 2017, 2017, 514-
522; c) N. K. Nandwana, S. Dhiman, G. M. Shelke,
A. Kumar, Org. Biomol. Chem. 2016, 14, 1736-
1741; d) H. K. Saini, P. Kaswan, K. Pericherla, A.
Kumar, Asian J. Org. Chem. 2015, 4, 1380-1385;
e) P. Kaswan, A. Porter, K. Pericherla, M. Simone,
S. Peters, A. Kumar, B. DeBoef, Org. Lett. 2015,
17, 5208-5211; f) S. Dhiman, K. Pericherla, N. K.
Nandwana, D. Kumar, A. Kumar, J. Org. Chem.
2014, 79, 7399-7404; g) K. Pericherla, A. Jha, B.
Khungar, A. Kumar, Org. Lett. 2013, 15, 4304-
4307.
[
[
6]
7]
K. W. Bentley, Isoquinoline Alkaloids, CRC Press,
1
998.
a) E. Marco, W. Laine, C. Tardy, A. Lansiaux, M.
Iwao, F. Ishibashi, C. Bailly, F. Gago, J. Med.
Chem. 2005, 48, 3796-3807; b) D. Pla, A. Marchal,
C. A. Olsen, A. Francesch, C. Cuevas, F. Albericio,
M. Álvarez, J. Med. Chem. 2006, 49, 3257-3268;
c) C. Marchand, S. Antony, K. W. Kohn, M.
Cushman, A. Ioanoviciu, B. L. Staker, A. B.
Burgin, L. Stewart, Y. Pommier, Mol. Cancer
Ther. 2006, 5, 287-295.
[
[
8]
9]
L. Zheng, R. Hua, J. Org. Chem. 2014, 79, 3930-
[19]
3
936.
a) S. Löber, H. Hübner, P. Gmeiner, Bioorg. Med.
Chem. Lett. 1999, 9, 97-102; b) X.-H. Liu, P. Cui,
B.-A. Song, P. S. Bhadury, H.-L. Zhu, S.-F. Wang,
Bioorg. Med. Chem. 2008, 16, 4075-4082; c) A.
Dore, B. Asproni, A. Scampuddu, G. A. Pinna, C.
T. Christoffersen, M. Langgård, J. Kehler, Eur. J.
Med. Chem. 2014, 84, 181-193; d) C. Custodi, R.
Nuti, T. I. Oprea, A. Macchiarulo, J. Mol. Graph.
Modell. 2012, 38, 70-81.
a) Y.-H. Zhao, Y. Li, T. Guo, Z. Tang, W. Xie, G.
Zhao, Tetrahedron Lett. 2016, 57, 2257-2261; b)
X. Zhou, M. Liu, P. Luo, Y. Lai, T. Yang, Q. Ding,
Beilstein J. Org. Chem. 2014, 10, 2286-2292; c) Z.
Chen, J. Wu, Org. Lett. 2010, 12, 4856-4859; d) G.
Qiu, J. Wu, Chem. Rec. 2016, 16, 19-34.
[
[
10]
11]
[20]
[21]
M. Ghosh, J. K. Ray, Tetrahedron 2017, 73, 3731-
3799.
a) X. Yu, Q. Yang, H. Lou, Y. Peng, J. Wu, Org.
Biomol. Chem. 2011, 9, 7033-7037; b) X. Yu, S.
Ye, J. Wu, Adv. Synth. Catal. 2010, 352, 2050-
CCDC-1569506 (3ae) and CCDC-1575940 (4a)
contain the supplementary crystallographic data
for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
2
4
056; c) S. Li, Y. Luo, J. Wu, Org. Lett. 2011, 13,
312-4315; d) Z. Chen, L. Gao, S. Ye, Q. Ding, J.
Wu, Chem. Commun. 2012, 48, 3975-3977; e) X.
Pan, Y. Luo, J. Wu, J. Org. Chem. 2013, 78, 5756-
[
22]
M. N. Bhattacharjee, M. K. Chaudhuri, S. K.
Ghosh, Z. Hiese, N. Roy, J. Chem. Soc., Dalton
Trans. 1983, 2561-2562.
5
760.
[
12]
X. Yang, Y. Luo, Y. Jin, H. Liu, Y. Jiang, H. Fu,
RSC Adv. 2012, 2, 8258-8261.
1
0
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Advanced Synthesis & Catalysis
10.1002/adsc.201701519
FULL PAPER
Nickel-Catalyzed Tandem Knoevenagel
Condensation and Intramolecular Direct
Arylation: A Convenient Route to Pyrazolo[5,1-
a]isoquinoline Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Shiv Dhiman, Nitesh K. Nandwana, Hitesh K.
Saini, Dalip Kumar, Krishnan Rangan, Katherine
N. Robertson, Mukund Jha and Anil Kumar*
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1
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