Synthesis of poly-substituted pyrazolo[1,5-a]quinolines through one-pot two component cascade reaction

Article abstract of DOI:10.1016/j.tet.2014.02.081

A diversity-oriented method for the synthesis of novel poly-substituted pyrazolo[1,5-a]quinolines has been developed on the basis of an S _NAr/Knoevenagel cyclization cascade reaction or an S _NAr/Dieckmann-Thorpe cyclization cascade reaction. The methods provide a variety of poly-substituted pyrazolo[1,5-a]quinolines bearing an amino, alkyl or aryl substituent at the 5-position. In addition, a diversity-oriented method for the synthesis of 2-substituted pyrazolo[1,5-a]quinolines from a readily available 2-[[(trifluoromethyl) sulfonyl]oxy]pyrazolo[1,5-a]quinoline has also been disclosed.

Full text of DOI:10.1016/j.tet.2014.02.081

Tetrahedron 70 (2014) 2766e2775
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of poly-substituted pyrazolo[1,5-a]quinolines through
one-pot two component cascade reaction
*
Jun-ya Kato, Ryosuke Ijuin, Hiroshi Aoyama, Tsutomu Yokomatsu
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A diversity-oriented method for the synthesis of novel poly-substituted pyrazolo[1,5-a]quinolines has
been developed on the basis of an SNAr/Knoevenagel cyclization cascade reaction or an SNAr/Die-
ckmanneThorpe cyclization cascade reaction. The methods provide a variety of poly-substituted pyr-
azolo[1,5-a]quinolines bearing an amino, alkyl or aryl substituent at the 5-position. In addition,
a diversity-oriented method for the synthesis of 2-substituted pyrazolo[1,5-a]quinolines from a readily
available 2-[[(trifluoromethyl)sulfonyl]oxy]pyrazolo[1,5-a]quinoline has also been disclosed.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 27 January 2014
Received in revised form 24 February 2014
Accepted 26 February 2014
Available online 5 March 2014
Keywords:
Pyrazolo[1,5-a]quinolones
SNAr reaction
Knoevenagel cyclization
DieckmanneThorpe cyclization
Cascade reaction
Diversity
1. Introduction
A facile preparation of a structurally diverse small-molecule li-
brary plays a crucial role in drug discovery. Heterocyclic privileged
scaffolds have recently emerged as one of the most guiding prin-
ciples of modern drug discovery.1 A number of fused aza-hetero-
cycles, such as indoles, quinolines, benzodiazepines and pyrazolo
[1,5-a]pyridines 1 are known to act as privileged scaffolds. There-
fore, many diversity-oriented synthesis of these aza-heterocycles
have been developed.2 Apart from these fused aza-heterocycles,
pyrazolo[1,5-a]quinoline, benzo-fused analogues of pyrazolo[1,5-
a]pyridines 2, are also expected to act as a potential privileged
scaffold of promise.3 This expectation is based upon the previous
works, in which 3-substituted pyrazolo[1,5-a]quinoline derivatives
have been reported to bind to two independent proteins with high
affinities exhibiting dopamine D4 antagonistic and GPR109a ago-
nistic activities, respectively, upon fine-tuning substituents at the
3-position of the pyrazolo[1,5-a]quinolines 1 (Fig. 1).4,5 However,
besides these two examples, the pyrazolo[1,5-a]quinoline subunit
has not been applied to seek further biologically active compounds
as a privileged scaffold, which might be due to the lack of diversity-
oriented methods for the synthesis of pyrazolo[1,5-a]quinoline
derivatives.3
Fig. 1. Structures of pyrazolo[1,5-a]quinoline and pyrazolo[1,5-a]pyridine.
In our study directed on the development of novel synthetic
methods of fused aza-heterocycles with high diversity,6 we re-
cently disclosed a one-pot, two-step cascade synthesis of pyrazolo
[1,5-a]quinolines.6a This cascade reaction involves a sequential
intermolecular aromatic nucleophilic substitution (SNAr) and
intramolecular Knoevenagel condensation,7 and substituted pyr-
azolo[1,5-a]quinoline derivatives having a variety of substituents
at varied positions that could be synthesized, upon selecting two
readily available substrates (Scheme 1). However, there is still in
the possibility of extending this methodology to applying the
facile introduction of substituents to the 5-position. The purpose
of this paper is to demonstrate a new cascade process leading to
novel pyrazolo[1,5-a]quinolines having representative sub-
stituents at the 5-position. In addition to this process, we have
also developed a versatile intermediate useful for the synthesis of
pyrazolo[1,5-a]quinolines possessing a variety of substituents at
the 2-poisition.
* Corresponding author. Tel./fax: þ81 42 676 3239; e-mail address: yokomatu@
toyaku.ac.jp (T. Yokomatsu).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.081

J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
2767
fluoroarylketones 3c and 3d rapidly decomposed under the con-
ditions8 and a large amount of 1H-pyrazole 4 remained unreacted.
On the contrary, Cs2CO3 was determined to be the better base to
induce the cascade reaction with electron-sufficient 2-
fluoroarylketone 3e and 2-fluorobenzophenone (3f). In these
cases, dramatic improvement in yield was observed upon re-
placement of K2CO3 with Cs2CO3 (entries 5 and 6).
2.2. Synthesis of 5-aminopyrazolo[1,5-a]quinoline derivatives
Scheme 1. A cascade synthesis of pyrazolo[1,5-a]quinolines.
The amines possess versatile functions to elaborate a variety of
chemical structures through amide formations and reductive al-
kylation sequences, and have been used as key intermediates in
drug discovery.9 Therefore, we next focused on introduction of the
amino functionality to the 5-position of pyrazolo[1,5-a]quinoline
skeleton. In this context, we examined the reactions of 1H-pyrazole
4 with 2-fluorobenzonitriles 6, instead of 2-fluorobenz-aldehydes
and -ketones. The attempted reaction is expected to proceed
through the sequential SNAr reaction and the DieckmanneThorpe
cyclization10 (SNAr/DieckmanneThorpe cyclization cascade re-
action) to give 5-aminopyrazolo[1,5-a]quinolines. The results are
shown in Table 2.
Initially, a mixture of 2-fluorobenzonitrile (6a) and 1H-pyrazole
4 was heated at 120 ꢀC in DMF in the presence of Cs2CO3 for 16 h as
a model reaction (entry 1). This reaction gave the expected cascade
product 7a in a 46% yield. The yield significantly increased to 65%,
upon switching the solvent to DMSO (entry 1). In an effort to survey
the scope of the present cascade reaction, a variety of fluoroar-
ylnitriles were used as a substrate. Although almost all of the tested
combinations successfully produced the desired 5-aminopyrazolo
[1,5-a]quinolines 7aef, the yields varied depending on the sol-
vent applied. For example, in the case of 2-fluorobenzonitriles 6e
and 6f bearing an electron-donating group, these substrates
showed poor reactivity in DMF under the conditions to give trace
amounts of desired products 7e and 7f (entries 5 and 6). In these
reactions, the SNAr adducts 8 and 9 were isolated in 38% and 29%
yields, respectively (Scheme 2). These results suggest to us that the
DieckmanneThorpe cyclization of 8 and 9 is inert to the conditions
using Cs2CO3 in DMF at 120 ꢀC. Yields of the cascade products 7e
and 7f dramatically increased to moderate yields, upon switching
the solvent to DMSO (entries 5 and 6). The structures of the new
compounds 7aef were readily confirmed by the conventional
spectroscopic analysis. The structure of 7d was further confirmed
by X-ray crystallographic analysis (Fig. 2).
2. Results and discussion
2.1. Synthesis of 5-methyl and 5-phenyl pyrazolo[1,5-a]
quinolines
To verify the validity of our cascade reaction for the synthesis of
5-substituted pyrazolo[1,5-a]quinolines, first, we chose 2-
fluoroarylketones 3aef as one of the substrates in our cascade re-
action from 1H-pyrazole 4. These cascade reactions are expected to
introduce a variety of alkyl or aryl substituents at the 5-position
upon fine-tuning the 2-fluoroarylketones. In our previous studies
on the cascade reaction from 2-fluoroarylaldehydes and 3,5-
disubstituted 1H-pyrazoles (Scheme 1), K2CO3 was found to be
the best base promoting this reaction in DMF at 120 ꢀC.6a We also
found the reaction was accelerated upon using Cs2CO3 instead of
K2CO3 as a base in our related cascade reaction providing benzi-
midazo[1,2-a]quinolines.6b With these findings in mind, the re-
action of 4 with 2-fluoroarylketones was examined under two
representative conditions. The results are summarized in Table 1.
As shown in Table 1, almost all of the tested reactions under the
conditions using either K2CO3 or Cs2CO3 successfully produced the
desired pyrazolo[1,5-a]quinoline derivatives 5aef having a methyl
or phenyl substituent at the 5-position in modest to excellent iso-
lated yield. It should be noted that K2CO3 is a better base than
Cs2CO3 for the cascade reaction with electron-deficient 2-
fluoroarylketones (entries 3 and 4). When the reactions were car-
ried out with K2CO3 in DMF, the cascade products 5c and 5d were
isolated in 80% and 99% yields, respectively (entries 3 and 4).
However, 5c and 5d were obtained in modest yield upon using
Cs2CO3 as
a base (entries 3 and 4). In these reactions,
Table 1
The cascade reaction toward 5-alkyl and 5-aryl pyrazolo[1,5-a]quinolines
a
b
Entry
Arylketone
Product 5
Yield % with K2CO3
Yield % with Cs2CO3
3
R1
R2
R3
X
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
H
F
CF3
H
H
H
H
H
H
CH3O
H
CH3
CH3
CH3
CH3
CH3
C6H5
CH
CH
CH
N
CH
CH
5a
5b
5c
5d
5e
5f
34
35
80
99
13
1
78
44
45
31
55
45
H
a
Arylketone (1.0 mmol) and pyrazole (1.0 mmol) were reacted in DMF(5.0 mL) in the presence of K2CO3 (3.0 mmol) at 120 ꢀC for 16 h.
Arylketone (1.0 mmol) and pyrazole (1.0 mmol) were reacted in DMF (5.0 mL) in the presence of Cs2CO3 (3.0 mmol) at 120 ꢀC for 16 h.
b

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J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
Table 2
The cascade reaction of 1H-pyrazole 4 with fluoroarylnitriles
Entry
Arylnitrile
Product 7
Yield % in DMFa
Yield % in DMSOb
6
R
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
H
Cl
Br
CF3
CH3
CH3O
7a
7b
7c
7d
7e
7f
46
51
NEc
38
1
65
30
70
31
39
55
1
a
Arylnitrile (1.00 mmol) and pyrazole (1.00 mmol) were reacted in DMF(5.0 mL) in the presence of Cs2CO3 (3.00 mmol) at 120 ꢀC for 16 h.
Arylnitrile (1.00 mmol) and pyrazole (1.00 mmol) were reacted in DMSO (5.0 mL) in the presence of Cs2CO3 (3.00 mmol) at 120 ꢀC for 16 h.
Not examined.
b
c
desired 5-aminopyrazolo[1,5-a]quinoline 11a was obtained in
a 78% yield upon using DMF as a solvent. It may be of worth noting
that 2-chloronicotinonitrile (10c) reacted with 4 to give 11b in
N
R
CH3
6e or 6f
Cs2CO3
CO2Et
N
N
a
comparable yield to that with the reaction from 2-
+
DMF
fluoronicotinonitrile (10b) (entry 2 vs 3).
4
120 °C
CH3
R = CH
8:
R = CH3O
2.3. Reaction of 2-fluorobenzonitrile 6a with various un-
symmetrical 1H-pyrazoles
9:
3
Scheme 2. Isolation of SNAr adducts from the reaction between 6e (or 6f) and 4.
Unsymmetrical 1H-pyrazoles, such as I exist as an equilibrium
mixture of their tautomers I and II (Scheme 3). Therefore, the SNAr
sequence of our cascade reaction with unsymmetrical 1H-pyrazoles
theoretically provides a regioisomeric mixture of the correspond-
ing adducts III and IV. The regiochemical outcome of the SNAr ad-
ducts are highly affected by the steric and electronic nature of the
substituents. In the case that both substituents (R1 and R2) of SNAr
adducts III and IV can participate in the DieckmanneThorpe cy-
clization, two types of the corresponding cascade products would
be produced. With these hypotheses in mind, we next examined
the reaction of 2-fluorobenzonitorile (6a) with unsymmetrical
pyrazoles 12aeg having substituents at the varied positions to
extend the scope and diversity for the present cascade reaction.
These results are listed in Table 4.
Fig. 2. ORTEP drawing of 7d.
Halogenated heteroaromatic nitriles were also available to the
SNAr/DieckmanneThorpe cyclization cascade reaction (Table 3). In
these reactions, DMF was found to be a better solvent than DMSO to
induce the reaction with 3-fluoropicolinonitrile (10a) (entry 1). The
Initially, the reaction of 6a with unsymmetrical 1H-pyrazoles
12aec was examined (entries 1e3). In these 1H-pyrazoles, one
substituent can participate in the DieckmanneThorpe cyclization
but the other substituents are inert to these cyclization. From these
Table 3
The cascade reaction of 1H-pyrazole 4 with halogenated heteroaromatic nitriles
Entry
Arylnitrile
Product 11
Yield % in DMFa
Yield % in DMSOb
10
X
Y
Z
1
2
3
10a
10b
10c
F
F
Cl
CH2
N
N
N
CH2
CH2
11a
11b
11b
78
35
38
36
NEc
NEc
a
Heteroaromatic nitrile (1.00 mmol) and pyrazole (1.00 mmol) were reacted in DMF (5.0 mL) in the presence of Cs2CO3 (3.00 mmol) at 120 ꢀC for 16 h.
Heteroaromatic nitrile (1.00 mmol) and pyrazole (1.00 mmol) were reacted in DMSO (5.0 mL) in the presence of Cs2CO3 (3.00 mmol) at 120 ꢀC for 16 h.
Not examined.
b
c

J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
2769
cascade product 13ad was determined to be a separable product in
a low yield (23%) (entry 4). In this reaction, the isomer 13
(R2¼R3¼Me, X¼CO2Et) was not detected. The results suggest to us
that the SNAr reaction preferably occurs at the sterically less con-
gested nitrogen of 1H-pyrazole 12d. It should be noted that our
cascade reaction does not require the carboethoxy group at the 4-
position (entries 5e7). Thus, symmetrical pyrazole 12e bearing
a bromo group instead of the carboethoxy group reacted with 6a to
give the desired cascade product 13ae in a 46% yield (entry 5). In
cases where 1H-pyrazoles possess a CF3 group at the 3-position,
electron-withdrawing substituents, such as carboethoxy and
bromo groups at the 4-position can be replaced with a hydrogen
atom to give the desired cascade products 13af and 13ag in mod-
erate yields (entries 6 and 7).12
2.4. Synthesis of versatile intermediates for diverse-oriented
Scheme 3. Tautomerism of 3,5-disubstituted unsymmetrical 1H-pyrazoles.
synthesis of 2-substituted pyrazolo[1,5-a]quinolines
In our previous paper,6a we reported on the facile and high yield
synthesis of ethyl 2-(methylthio)pyrazolo[1,5-a]quinoline-3-
carboxylate (14) through our SNAr/Knoevenagel cyclization cas-
cade reaction. In this section, we describe the transformation of 14
to the versatile triflate 18 and its applications to the diversity-
oriented synthesis of 2-substituted pyrazolo[1,5-a]quinolines. The
required triflate 18 was readily synthesized by the sequences
shown in Scheme 4. Thus, compound 14 was first transformed to
sulfone 15 in a 94% yield though oxidation with OxoneÒ under
standard conditions. The sulfone 15 was briefly treated with
NaOEt in refluxing THF to give 16 in a 64% yield.13 The selective
deethylation of 16 with BBr3 in CH2Cl2, followed by tri-
fluoromethansulfonylation of the resulting alcohol 17, gave triflate
18 in a 71% yield for two steps.
Table 4
Scope of 1H-pyrazoles in the SNAr/DieckmanneThorpe cyclization sequences
Entrya
Pyrazole
Product
12
R1
R2
X
13
R3
Yield %
1b
2
12a
12b
12c
12d
12e
12f
CH3
CH3
CH3CH2
CH3
CH3
C6H5
CH3S
CH3S
CH3CH2
CH3
CO2Et
CO2Et
CO2Et
CO2Et
Br
13aa
13ab
13ac
13ad
13ae
13af
13ag
H
H
CH3
H
H
41
41
31
23
46
49
28
3
4c
5
With triflate 18 in hand, several cross-coupling reactions were
examined to show their efficacy with introduction of a variety of
functionalized substituents to the 2-position (Scheme 5).
6
7
CH3
CH3CH2
CF3
CF3
H
H
H
CH3
12g
a
All reaction were carried out in the presence of 2-fluorobenzonitrile (6a)
(1.00 mmol), pyrazole11 (1.00 mmol) and Cs2CO3 (3.00 mmol) in DMSO (5 mL) at
120 ꢀC for 16 h unless otherwise noted.
The Heck reaction of triflate 18 with tert-butyl acrylate in the
presence of PdCl2(PPh3)2 in DMF containing TEA gave cross-cou-
pling product 19 in a 26% yield.14 The Suzuki coupling reaction of 18
with phenylboronic acid was catalyzed by Pd(PPh3)4 in refluxing
dioxane in the presence of K3PO4 and KBr to give 20 in a 46% yield.14
The Negishi coupling reaction with (4-ethoxy-4-oxobutyl)zinc(II)
bromide was carried out in THF in the presence of Pd(OAc)2 and
Xphos for 16 h to give 21 in a 68% yield.15 Although, the Buchwald
amination of 18 with morpholine using a palladium catalyst under
the representative conditions failed,16 it was found that the ami-
nation proceed rapidly to give 22 in a 58% yield through an aromatic
nucleophilic substitution upon heating a mixture of 18 and a large
excess of morpholine.
b
An excess (1.20 mmol) of pyrazole 12a was used.
A large excess (2.00 mmol) of pyrazole 12d was used.
c
reactions with 12a and 12b, the desired cascade products 13aa and
13ab were obtained with virtually the same yields (41%) (entries 1
and 2). In these reactions, the SNAr adducts for either type III or type
IV shown in Scheme 3 were not detected. The yields of 13aa and
13ab were slightly poorer than that of 8a from the symmetrical 1H-
pyrazole 4 under the same conditions (cf. Table 2, entry 1). The
modest yields of 13aa and 13ab may have arisen from the modest
distribution ratio of the SNAr adducts leading to the desired cascade
product.11 The reaction of 6a with 12c, ethyl analogue of 12b, gave
4-methyl-5-aminopyrazolo[1,5-a]quinoline (13ac) in a 31% yield
(entry 3). Although both substituents of unsymmetrical 1H-pyr-
azole 12d having methyl and ethyl substituents at 3- and 5-position
can be participate in the DieckmanneThorpe cyclization, the
3. Conclusions
In conclusion, we have demonstrated diversity-oriented ap-
proaches for the effective preparation of poly-substituted pyrazolo
Reagents and conditions: a) Oxone®, THF-MeOH-H2O, rt, 16 h (94%); b) NaOEt, THF, 20 min
(64%); c) BBr3, CH2Cl2, rt, 16 h, (85%); d) Tf2O, Et3N, CH2Cl2, 16 h, (83%).
Scheme 4. Synthesis of versatile intermediate 18.

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J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
Scheme 5. Cross-coupling reactions of 18 with various reagents.
[1,5-a]quinolines through novel SNAr/Knoevenagel cyclization cas-
cade reactions or SNAr/DieckmanneThorpe cyclization cascade re-
actions. A characteristic feature of these syntheses is that a variety of
substituents including an alkyl, aryl or amino functional group can
be readily introduced to the 5-position upon fine-tuning 2-
fluoroarylketones or 2-fluoroarylnitriles. In addition to these re-
sults, a versatile intermediate applicable to the diversity-oriented
synthesis of 2-substituted pyrazolo[1,5-a]quinolines has been de-
veloped. The present methods are complementary to our SNAr/
Knoevenagel cyclization cascade reaction using 2-fluoro
arylaldehydes6a to synthesize a variety of poly-substituted pyrazolo
[1,5-a]quinolines, and should be useful to prove that pyrazolo[1,5-a]
quinoline skeleton acts as a potential privileged scaffold for the
discovery of potential biological active compounds. The study about
this issue is now in progress and will be reported in due course.
ionization. NMR spectra were obtained on a JEOL JNM-ECP400 NMR
Spectrometer (1H NMR: 400 MHz), a Bruker DPX400 NMR Spec-
trometer (1H NMR: 400 MHz and 13C NMR: 100 MHz) or a Bruker
AVANCE III NMR spectrometer (1H NMR: 400 MHz and 13C NMR:
100 MHz). The chemical shift data for each signal on 1H NMR were
given in units of
and to DMSO (
d
relative to CHCl3 (
d
¼7.26 ppm) for CDCl3 solution
d
¼2.50 ppm) for DMSO-d6 solution. For 13C NMR
spectra, the chemical shifts in CDCl3 were relative to CDCl3
(d
¼77.0 ppm) resonances and the chemical shifts in DMSO-d6 were
relative to DMSO-d6
¼39.5 ppm) resonances. Column chroma-
tography was carried out using 63e210 m silica gel 60N (Kanto
(d
m
Chemical Co., Inc.). Analytical TLC was carried out with Merck
plates precoated with silica gel 60F254 plates (0.25 mm). Crystal-
lographic data (excluding structure factors) for the X-ray crystal
structure analysis reported in this paper have been deposited with
the Cambridge Crystallographic Data Center (CCDC) as supple-
mentary publication No. CCDC 982642, copies of these data can be
obtained, free of charge, upon application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax:þ44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
4. Experimental
4.1. General
All reagents and solvents were pure analytical-grade materials
purchased from commercial sources and were used without further
purification except for the 1H-pyrazoles 12bec and 12d. Com-
pounds 12bec17 and 12d18 were synthesized by a known method.
All melting points were taken on a Yanagimoto micromelting point
apparatus and were uncorrected. IR spectra were recorded on
a JASCO FTIR-620. Mass spectra were measured on JEOL GCmate by
electron ionization and Micromass Autospec by electrospray
4.2. General procedures for the preparation of pyrazolo[1,5-a]
quinolines 5
4.2.1. Ethyl 2,5-dimethylpyrazolo[1,5-a]quinoline-3-carboxylate
(5a). Condition A:
(138 mg, 1.00 mmol), 1H-pyrazole 2a (202 mg, 1.20 mmol) and
K2CO3 (420 mg, 3.00 mmol) in DMF (5.0 mL) was stirred at 120 ꢀ
A
mixture of 2-fluoroacetophenone 3a
C

J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
2771
for 16 h. After monitoring the end of the reaction on TLC, the
mixture was cooled to room temperature and diluted with water.
The resulting mixture was extracted with ethyl acetate twice. The
combined organic layers were washed with water twice, dried over
MgSO4 and the solvent was removed in vacuo to afford a residue.
The residue was purified by flash column chromatography
(hexane:EtOAc¼5:1) on silica gel to afford 5a (92.0 mg, 34% yield).
Condition B: The reaction was carried out with Cs2CO3 instead of
K2CO3 under the same conditions as that of Condition A to afford 5a
(210 mg, 78% yield).
2.7 Hz, 1H), 4.40 (q, J¼7.3 Hz, 2H), 4.01 (s, 3H), 2.71 (s, 3H), 2.63 (d,
J¼1.2 Hz, 3H), 1.44 (t, J¼7.3 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d
164.48, 161.01, 154.09, 140.72, 135.47, 134.94, 126.47, 117.68,
115.48, 113.66, 102.70, 97.35, 59.67, 55.83, 19.36, 14.64, 14.53; HR-
MS (ESI) calcd for C17H19N2O3 (MþH)þ requires 299.1396, found
299.1390.
4.2.6. Ethyl 2-methy-5-phenyllpyrazolo[1,5-a]quinoline-3-
carboxylate (5f). Prepared from 3f and 4 in an analogous man-
ner for preparation of 5a. Yield: trace for condition A, 45% for
Pale yellow solid, mp 121e123 ꢀC; IR (neat): nmax/cmꢁ1 1697,
condition B; Pale yellow solid, mp 147e148 ꢀC; IR (neat): nmax
/
1624, 1126, 1090; 1H NMR (CDCl3, 400 MHz)
d
8.59 (d, J¼8.5 Hz, 1H),
cmꢁ1 1698, 1611, 1113; 1H NMR (CDCl3, 400 MHz)
d 8.68 (dd,
7.91e7.89 (m, 2H), 7.70 (td, J¼8.1 Hz, 1.2 Hz, 1H), 7.51 (td, J¼8.1 Hz,
1.2 Hz,1H), 4.40 (q, J¼7.0 Hz, 2H), 2.71 (s, 3H), 2.66 (d, J¼0.8 Hz, 3H),
J¼8.5 Hz, 0.7 Hz, 1H), 8.01 (s, 1H), 7.81 (dd, J¼8.3 Hz, 0.92 Hz, 1H),
7.73 (td, J¼7.2 Hz, 1.3 Hz, 1H), 7.54e7.50 (m, 5H), 7.43 (td,
J¼8.3 Hz, 1.2 Hz), 4.40 (q, J¼7.1 Hz, 2H), 2.77 (s, 3H), 1.41 (t,
1.44 (t, J¼7.0 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d 164.41, 153.96,
140.08, 135.36, 133.57, 129.60, 125.03, 124.91, 123.62, 116.20,
116.042, 103.11, 59.72, 19.37, 14.59, 14.51; HR-MS (ESI) calcd for
J¼7.1 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d 164.32, 154.38, 140.45,
139.73, 138.27, 133.98, 129.87, 129.63 (2C), 128.53 (2C), 128.26,
127.31, 124.96, 122.74, 116.83, 116.07, 104.09, 59.82, 14.63, 14.52;
HR-MS (ESI) calcd for C21H19N3O2 (MþH)þ requires 331.1447,
found 331.1449.
C
16H17N2O2 (MþH)þ requires 269.1290, found 269.1294.
4.2.2. Ethyl 7-fluoro-2,5-dimethylpyrazolo[1,5-a]quinoline-3-
carboxylate (5b). Prepared from 3b and 4 in an analogous man-
ner for preparation of 5a. Yield: 35% for Condition A, 44% for Con-
dition B; Pale yellow solid, mp 143e144 ꢀC; IR (neat): nmax/cmꢁ1
4.3. General procedure for the preparation of 5-aminopyrazolo
[1,5-a]quinolone derivatives 7 and the related compounds 10
1698, 1566, 1235, 1147; 1H NMR (CDCl3, 400 MHz)
d 8.59 (dd,
J¼9.2 Hz, 5.0 Hz, 1H), 7.94 (s, 1H), 7.55 (dd, J¼9.6 Hz, 2.7 Hz, 1H),
4.3.1. Ethyl 5-amino-2-methylpyrazolo[1,5-a]quinoline-3-
carboxylate (7a). Condition C: A mixture of 2-fluorobenzonitrile
6a (121 mg, 1.00 mmol), 1H-pyrazole 4 (202 mg, 1.20 mmol) and
Cs2CO3 (980 mg, 3.00 mmol) in DMF (5.0 mL) was stirred at 120 ꢀC
for 16 h. After monitoring the end of the reaction on TLC, the
mixture was cooled to room temperature and diluted with water.
The resulting mixture was extracted with ethyl acetate twice. The
combined organic layers were washed with water twice, dried over
MgSO4 and the solvent was removed in vacuo to afford a residue.
The residue was purified by flash column chromatography
(hexane:EtOAc¼1:1) on silica gel to afford 7a (124 mg, 46% yield).
Condition D: The reaction was carried out in DMSO instead of DMF
under the same conditions as that of condition C to afford 7a
(175 mg, 65% yield).
7.46e7.41 (m, 1H), 4.40 (q, J¼7.3 Hz, 2H), 2.70 (s, 3H), 2.62 (d,
J¼0.8 Hz, 3H), 1.44 (t, J¼7.4 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
1
d
164.30, 159.78 (d, JCF¼243.4 Hz), 153.97, 139.60, 134.54 (d,
4JCF¼3.6 Hz), 130.24, 125.0 (d, JCF¼8.4 Hz), 118.14 (d, JCF¼8.9 Hz),
3
3
2
117.84, 117.38, 110.13 (d, JCF¼23.0 Hz), 103.34, 59.82, 19.33, 14.51
(2C); HR-MS (ESI) calcd for C16H16FN2O2 (MþH)þ requires 287.1196,
found 287.1191.
4.2.3. Ethyl 7-trifluoromethyl-2,5-dimethylpyrazolo[1,5-a]quinoline-
3-carboxylate (5c). Prepared from 3c and 4 in an analogous man-
ner for preparation of 5a. Yield: 80% for condition A, 45% for con-
dition B; Pale yellow solid, mp 130e131 ꢀC; IR (neat): nmax/cmꢁ1
1696, 1624, 1541, 1313, 1159, 1119; 1H NMR (CDCl3, 400 MHz)
d 8.68
(d, J¼8.8 Hz, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.90 (dd, J¼8.8 Hz, 1.5 Hz,
Yellow solid, mp 166e168 ꢀC; IR (neat): nmax/cmꢁ1 3207, 1649,
1H), 4.41 (q, J¼7.3 Hz, 2H), 2.71 (s, 3H), 2.69 (d, J¼0.8 Hz, 3H), 1.45
1604, 1097; 1H NMR (CDCl3, 400 MHz)
d
8.56 (d, J¼8.2 Hz, 1H),
(t, J¼7.4 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d
164.07, 154.72,
7.75e7.69 (m, 2H), 7.46 (td, J¼8.2 Hz, 1.1 Hz, 1H), 7.25 (d, J¼4.1 Hz,
2
140.52, 135.10, 134.92, 126.97 (q, JCF¼32.0 Hz), 125.82 (q,
1H), 4.37 (q, J¼7.2 Hz, 2H), 2.66 (s, 3H), 1.42 (t, J¼7.2 Hz, 3H), 13
C
1
3JCF¼3.0 Hz), 124.00 (q, JCF¼270.0 Hz), 123.21, 122.66 (q,
NMR (CDCl3, 100 MHz) d 164.76, 154.22, 142.38, 142.14, 134.09,
3JCF¼4.0 Hz), 117.59, 116.94, 103.99, 59.97, 19.25, 14.57, 14.48; HR-
MS (ESI) calcd for C17H16F3N2O2 (MþH)þ requires 337.1164, found
337.1165.
130.15, 124.44, 121.69, 116.75, 116.53, 101.10, 95.75, 59.46, 14.72,
14.59; HR-MS (ESI) calcd for
270.1243, found 270.1242.
C
15H16N3O2 (MþH)þ requires
4.2.4. Ethyl 2,5-dimethylpyrazolo[1,5-a][1,8]naphthyridine-3-
carboxylate (5d). Prepared from 3d and 4 in an analogous man-
ner for preparation of 5a. Yield: 99% for condition A, 31% for
4.3.2. Ethyl
5-amino-7-chloro-2-methyl-2-methylpyrazolo[1,5-a]
quinoline-3-carboxylate (7b). Prepared from 6b and 4 in an analo-
gous manner for preparation of 7a. Yield: 51% for condition C, 30%
for condition D; Yellow solid, mp 251e253 ꢀC; IR (neat): nmax/cmꢁ1
3438, 3196, 1650, 1603, 1552, 1344, 1123; 1H NMR (DMSO-d6,
condition B; Pale yellow solid, mp 172e174 ꢀC; IR (neat): nmax
/
cmꢁ1 1693, 1626; 1H NMR (CDCl3, 400 MHz)
d
8.87 (dd, J¼4.6 Hz,
1.9 Hz, 1H), 8.27 (dd, J¼8.1 Hz, 1.6 Hz, 1H), 7.98 (d, J¼0.8 Hz, 1H),
7.52 (dd, J¼8.1 Hz, 4.6 Hz, 1H), 4.41 (q, J¼7.3 Hz, 2H), 2.76 (s, 3H),
2.66 (d, J¼1.2 Hz, 3H), 1.44 (t, J¼7.3 Hz, 3H), 13C NMR (CDCl3,
400 MHz)
d
8.35e8.33 (m, 2H), 7.76 (dd, J¼9.0 Hz, 1.6 Hz, 1H), 7.03
(s, 1H), 4.24 (q, J¼7.0 Hz, 2H), 2.49 (s, 3H), 1.34 (t, J¼7.0 Hz, 3H), 13
C
NMR (DMSO-d6, 100 MHz)
d 163.45, 153.23, 144.41, 142.30, 132.06,
100 MHz)
d
164.24, 155.24, 150.28, 143.63, 141.92, 134.63, 134.19,
130.25, 128.85, 123.07, 117.63(2C), 99.09, 92.44, 58.82, 14.40 (2C);
HR-MS (ESI) calcd for C15H15N3O2Cl (MþH)þ requires 304.0853,
found 304.0854.
121.14, 118.97, 117.30, 104.56, 60.02, 18.71, 14.76, 14.51; HR-MS
(ESI) calcd for C15H16N3O2 (MþH)þ requires 270.1243, found
270.1237.
4.3.3. Ethyl 5-amino-7-bromo-2-methylpyrazolo[1,5-a]quinoline-3-
carboxylate (7c). Prepared from 6c and 4 in an analogous manner
for preparation of 7a. Yield: 70% for condition D; Yellow solid, mp
244e246 ꢀC; IR (neat): nmax/cmꢁ1 3453, 3340, 3202, 1649, 1617,
4.2.5. Ethyl 8-methoxy-2,5-dimethylpyrazolo[1,5-a]quinoline-3-
carboxylate (5e). Prepared from 3e and 4 in an analogous manner
for preparation of 5a. Yield: 13% for condition A, 55% for condition B;
Pale yellow solid, mp 150e152 ꢀC; IR (neat): nmax/cmꢁ1 1697, 1617,
1546, 1148, 1124, 1104, 1103; 1H NMR (CDCl3, 400 MHz)
d 8.48 (d,
1541, 1223, 1127; 1H NMR (CDCl3, 400 MHz)
d
7.98 (d, J¼2.7 Hz, 1H),
J¼2.0 Hz, 1H), 8.28 (d, J¼9.0 Hz, 1H), 7.88 (dd, J¼9.0 Hz, 2.0 Hz, 1H),
7.79 (d, J¼8.9 Hz, 1H), 7.75 (d, J¼1.2 Hz, 1H), 7.10 (dd, J¼8.8 Hz,
7.03 (s,1H), 6.72 (s,1H), 4.24 (q, J¼7.1 Hz, 2H), 2.50 (d, J¼2.7 Hz, 3H),

2772
J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
1.34 (t, J¼7.1 Hz, 3H), 13C NMR (DMSO-d6, 100 MHz)
d
163.46,
[M]þ, 254 [base]þ, HR-MS (ESI) calcd for C16H18N3O2 (MþH)þ re-
153.28, 144.36, 142.34, 133.02, 132.38, 126.10, 118.04, 117.84, 116.97,
99.12, 92.42, 58.84, 14.42 (2C); HR-MS (ESI) calcd for C15H15N3O2Br
(MþH)þ requires 348.0348, found 348.0346.
quires 300.1348, found 300.1343.
4.3.9. Ethyl 2-amino-5-methylpyrazolo[1,5-a][1,5]naphthyridine-3-
carboxylate (11a). Prepared from 10a and 4 in an analogous man-
ner for preparation of 7a. Yield:78% for condition C, 36% for condi-
tion D; Yellow solid, mp 186e188 ꢀC; IR (neat): nmax/cmꢁ1 3473,
3351, 1678, 1643, 1625, 1557, 1422, 1363, 1336, 1298, 1138; 1H NMR
4.3.4. Ethyl 5-amino-7-trifluoromethyl-2-methyl-2-methylpyrazolo
[1,5-a]quinoline-3-carboxylate (7d). Prepared from 6d and 4 in an
analogous manner for preparation of 7a. Yield: 38% for condition C,
31% for condition D; Yellow solid, mp 249e251 ꢀC; IR (neat): nmax
/
(CDCl3, 400 MHz)
d
8.79 (d, J¼8.4 Hz, 1.2 Hz, 1H), 8.74 (d, J¼4.4 Hz,
cmꢁ1 3335, 3228, 1655, 1630, 1611, 1129; 1H NMR (CDCl3,
400 MHz)
1.6 Hz, 1H), 7.64 (dd, J¼8.4 Hz, 4.4 Hz, 1H), 7.32 (s, 1H), 4.38 (q,
d
8.66 (d, J¼8.8 Hz, 1H), 8.02 (s, 1H), 7.91 (dd, J¼8.8 Hz,
J¼7.2 Hz, 2H), 2.65 (s, 3H), 1.43 (t, J¼7.2 Hz, 3H), 13C NMR (DMSO-d6,
1.9 Hz, 1H), 7.39 (s, 1H), 4.49 (br s, 2H), 4.38 (q, J¼7.3 Hz, 2H), 2.66
100 MHz) d 163.45, 153.73, 146.19, 145.04, 142.34, 132.58, 129.66,
(s, 3H), 1.42 (t, J¼7.3 Hz, 3H), 13C NMR (DMSO-d6, 100 MHz)
125.23, 123.60, 99.26, 92.21, 58.88, 14.44, 14.39; HR-MS (ESI)
3
d
163.41, 153.90, 145.12, 143.12, 135.18, 126.31 (q, JCF¼3.0 Hz),
calcd for C14H15N4O2 (MþH)þ requires 271.1195, found 271.1197.
2
1
124.85 (q, JCF¼32.0 Hz), 124.26 (q, JCF¼271.0 Hz), 121.86 (q,
3JCF¼4.0 Hz), 116.83, 116.15, 99.32, 92.55, 58.92, 14.44, 14.48; HR-
4.3.10. Ethyl 2-amino-5-methylpyrazolo[1,5-a][1,8]naphthyridine-3-
carboxylate (11b). Prepared by condition C from 10b (or 10c) and 4
in an analogous manner for preparation of 7a. Yield: 30% from 10b,
38% from 10c; Yellow solid, mp 245e247 ꢀC; IR (neat): nmax/cmꢁ1
3473, 3351, 1678, 1643, 1625, 1557, 1422, 1363, 1336, 1298, 1138; 1H
MS (ESI) calcd for
found 338.1118.
C
16H15N3O2F3 (MþH)þ requires 338.1116,
4.3.5. Ethyl
5-amino-2,7-dimethyl-2-methylpyrazolo[1,5-a]quino-
line-3-carboxylate (7e). Prepared from 6e and 4 in an analogous
manner for preparation of 7a. Yield: trace for condition C, 39% for
condition D; Yellow solid, mp 221e223 ꢀC; IR (neat): nmax/cmꢁ1
3477, 3339, 3230, 1668, 1639, 1609, 1126, 1103; 1H NMR (DMSO-
NMR (CDCl3, 400 MHz)
d
8.88 (d, J¼3.9 Hz,1H), 8.16 (d, J¼8.1 Hz,1H),
7.50 (dd, J¼8.1 Hz, 4.5 Hz,1H), 7.33 (s,1H), 4.39 (q, J¼7.1 Hz, 2H), 2.72
(d, J¼3.3 Hz, 3H),1.43 (t, J¼7.1 Hz, 3H),13C NMR (DMSO-d6,100 MHz)
d
163.55, 153.53, 150.55, 144.95, 144.28, 143.30, 133.07, 120.49,
d6, 400 MHz)
d
8.27 (d, J¼8.5 Hz, 1H), 8.04 (s, 1H), 7.59 (d,
112.05, 99.46, 91.88, 58.91, 14.61, 14.42; HR-MS (ESI) calcd for
C
J¼7.8 Hz, 1H), 7.01 (s, 1H), 6.60 (br s, 2H), 4.26 (q, J¼7.1 Hz, 2H),
14H15N4O2 (MþH)þ requires 271.1195, found 271.1191.
2.51 (s, 3H), 1.35 (t, J¼7.1 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d
164.67, 153.87, 142.33, 141.68, 134.39, 132.12, 131.72, 121.36,
4.4. General procedure for one-pot reaction of 2-fluorobenzo
nitrile (6a) with substituted 1H-pyrazoles 12
116.68, 116.42, 100.97, 95.75, 59.49, 21.43, 14.59 (2C); HR-MS (ESI)
calcd for C16H18N3O2 (MþH)þ requires 284.1399, found 284.1391.
In the experiment through condition C, the SNAr adduct 8 was
isolated in 38% yield.
4.4.1. Ethyl 5-amino-2-phenylpyrazolo[1,5-a]quinoline-3-
carboxylate (13aa). A mixture of 2-fluorobenzonitrile 6a (121 mg,
1.00 mmol), 12a (280 mg, 1.20 mmol) and Cs2CO3 (980 mg,
3.00 mmol) in DMSO (5.0 mL) was stirred at 120 ꢀC for 16 h. After
monitoring the end of the reaction on TLC, the mixture was cooled
to room temperature and diluted with water. The resulting mixture
was extracted with ethyl acetate twice. The combined organic
layers were washed with water twice, dried over MgSO4 and the
solvent was removed in vacuo to afford a residue. The residue was
purified by flash column chromatography (hexane:EtOAc¼1:1) on
silica gel to afford pyrazolo[1,5-a]quinoline 13aa (137 mg, 41%
yield).
4.3.6. Ethyl 1-(cyano-4-methylphenyl)-3,5-dimethyl-1H-pyrazole-4-
carboxylate (8). White solid, mp 92e93 ꢀC; IR (neat): nmax/cmꢁ1
2980, 2930, 2232, 1702, 1556, 1518, 1479, 1427, 1256, 1120; 1H NMR
(CDCl3, 400 MHz)
d
7.59 (s, 1H), 7.52 (dd, J¼8.5 Hz, 1.9 Hz, 1H), 7.35
(d, J¼8.5 Hz, 1H), 4.32 (q, J¼7.3 Hz, 2H), 2.49 (s, 3H), 2.47 (s, 3H),
2.44 (s, 3H), 1.37 (t, J¼7.3 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d
164.16, 152.34, 145.80, 140.21, 138.39, 134.42, 133.81, 128.34,
115.53, 111.37, 111.17, 59.82, 20.90, 14.34, 14.26, 12.15; MS (EIþ) m/z
283 [M]þ, HR-MS (ESI) calcd for C16H18N3O2 (MþH)þ requires
284.1399, found 284.1397.
Pale yellow solid, mp 212e214 ꢀC; IR (neat): nmax/cmꢁ1 3365,
1680, 1618, 1556, 1438, 1167, 1066; 1H NMR (CDCl3, 400 MHz)
d 8.69
4.3.7. Ethyl 5-amino-7-methoxy-2-methylpyrazolo[1,5-a]quinoline-
3-carboxylate (7f). Prepared from 6e and 4 in an analogous manner
for preparation of 7a. Yield: trace for condition C, 55% for condition
D; Pale yellow solid, mp 257e259 ꢀC; IR (neat): nmax/cmꢁ1 3213,
(d, J¼8.3 Hz, 1H), 7.81e7.77 (m, 3H), 7.74 (td, J¼7.3 Hz, 1.1 Hz, 1H),
7.53 (dt, J¼8.2 Hz, 1.0 Hz, 1H), 7.45e7.42 (m, 3H), 7.36 (s, 1H), 4.50
(br s, 2H), 4.29 (q, J¼7.1 Hz, 2H), 1.27 (t, J¼7.1 Hz, 3H), 13C NMR
(DMSO-d6, 100 MHz)
d 163.09, 154.75, 145.55, 143.09, 133.52,
1653, 1607, 1348, 1239, 839; 1H NMR (DMSO-d6, 400 MHz)
d
8.29 (d,
133.30, 130.49 (2C), 129.70, 128.29, 127.42 (2C), 124.71, 123.71,
116.74, 115.74, 98.14, 91.57, 58.92, 14.14; HR-MS (ESI) calcd for
J¼8.9 Hz, 1H), 7.66 (d, J¼2.5 Hz, 1H), 7.37 (dd, J¼9.2 Hz, 2.5 Hz, 1H),
7.00 (s, 1H), 6.61 (br s, 2H), 4.24 (q, J¼7.1 Hz, 2H), 3.89 (s, 3H), 2.49
C
20H18N3O2 (MþH)þ requires 332.1399, found 332.1406.
(s, 3H),1.34 (t, J¼7.1 Hz, 3H), 13C NMR (DMSO-d6,100 MHz)
d 163.63,
156.16, 152.42, 144.93, 141.25, 128.30, 119.60, 117.37, 117.09, 105.16,
98.51, 91.82, 58.67, 55.80, 14.45, 14.40; HR-MS (ESI) calcd for
4.4.2. Ethyl 5-amino-2-(methylthio)pyrazolo[1,5-a]quinoline-3-
carboxylate (13ab). Prepared from 6a (1.00 mmol) and 12b
(1.00 mmol) in an analogous manner for preparation of 13aa. Yield:
41%; Yellow solid, mp 174e176 ꢀC; IR (neat): nmax/cmꢁ1 3365, 1672,
C
16H18N3O3 (MþH)þ requires 300.1348, found 300.1338. In the
experiment through condition C, the SNAr adduct 9 was isolated in
29% yield.
1618, 1557, 1450, 1312, 1072; 1H NMR (CDCl3, 400 MHz)
d 8.56 (d,
J¼8.4 Hz, 1H), 7.75e7.70 (m, 2H), 7.48 (t, J¼7.4 Hz, 1H), 7.18 (s, 1H),
4.3.8. Ethyl 1-(cyano-4-methoylphenyl)-3,5-dimethyl-1H-pyrazole-
4.48 (br s, 2H), 4.39 (q, J¼7.1 Hz, 2H), 2.30 (s, 3H), 1.44 (t, J¼7.1 Hz,
4-carboxylate (9). Pale yellow solid, mp 81e83 ꢀC; IR (neat): nmax
/
3H), 13C NMR (DMSO-d6, 100 MHz)
d 162.81, 153.63, 145.88, 143.01,
133.25, 130.56, 124.21, 123.68, 115.90, 115.44, 97.94, 90.84, 58.99,
14.46, 12.90; HR-MS (ESI) calcd for C15H16N3O2S (MþH)þ requires
302.0963, found 302.0953.
cmꢁ1 2979, 2937, 2233, 1702, 1518, 1310, 1284, 1097; 1H NMR
(CDCl3, 400 MHz)
d
7.37 (d, J¼8.5 Hz, 1H), 7.24 (d, J¼2.7 Hz, 1H), 7.21
(dd, J¼8.5 Hz, 2.7 Hz, 1H), 4.32 (q, J¼7.4 Hz, 2H), 3.89 (s, 3H), 2.48 (s,
3H), 2.43 (s, 3H), 1.37 (t, J¼7.3 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d
164.18, 159.77, 152.23, 145.97, 133.70, 129.88, 119.63, 117.87, 115.24,
4.4.3. Ethyl 5-amino 4-methyl-2-(methylthio)pyrazolo[1,5-a]quino-
line-3-carboxylate (13ac). Prepared from 6a (1.00 mmol) and 12c
112.58, 111.01, 59.81, 56.02, 14.35, 14.27, 12.10; MS (EIþ) m/z 299

J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
2773
(1.0 mmol) in an analogous manner for preparation of 13aa. Yield:
31%; Yellow solid, mp 152e154 ꢀC; IR (neat): nmax/cmꢁ1 3388, 1683,
dried over MgSO4 and the solvent was removed in vacuo to afford
to afford analytically pure 15 (1.60 g, 94% yield).
1629, 1525, 1308, 1065; 1H NMR (CDCl3, 400 MHz)
d
8.57 (d,
White solid, mp 173e175 ꢀC; IR (neat): nmax/cmꢁ1 1707, 1615,
J¼8.4 Hz, 1H), 7.72 (d, J¼8.4 Hz, 1H), 7.66 (t, J¼7.6 Hz, 1H), 7.46 (t,
1321, 1245, 1148, 1109; 1H NMR (DMSO-d6, 400 MHz)
d 8.58 (d,
J¼7.6 Hz, 1H), 4.38 (q, J¼7.2 Hz, 2H), 2.68 (s, 3H), 2.56 (s, 3H), 1.45 (t,
J¼8.5 Hz, 1H), 8.17e8.15 (m, 2H), 8.09 (d, J¼9.6 Hz, 1H), 7.76 (td,
J¼7.2 Hz, 3H), 13C NMR (DMSO-d6, 100 MHz)
d 162.98, 153.90,
J¼8.1 Hz, 1.2 Hz, 1H), 4.42 (q, J¼7.3 Hz, 2H), 3.59 (s, 3H), 1.41 (t,
142.39, 142.23, 132.16, 129.51, 124.32, 123.12, 115.74, 115.57, 100.47,
98.72, 59.55, 14.33, 14.21, 13.45; HR-MS (ESI) calcd for C16H18N3O2S
(MþH)þ requires 316.1120, found 316.1125.
J¼7.4 Hz, 3H), 13C NMR (DMSO-d6, 100 MHz)
d 160.66, 152.72,
140.28, 132.87, 131.19, 130.51, 129.19, 127.18, 123.73, 116.19, 115.45,
103.58, 60.90, 42.62, 13.95; HR-MS (ESI) calcd for C15H14N2O4NaS
(MþNa)þ requires 341.0572, found 341.0567.
4.4.4. Ethyl 5-amino-2-ethylpyrazolo[1,5-a]quinoline-3-carboxylate
(13ad). Prepared from 6a (1.00 mmol) and 12d (2.00 mmol) in an
analogous manner for preparation of 13aa. Yield: 23%; White solid,
mp 178e180 ꢀC; IR (neat): nmax/cmꢁ1 3336, 3203, 1655, 1607, 1558,
4.5.2. Ethyl 2-ethoxypyrazolo[1,5-a]quinoline-3-carboxylate (16). A
solution of 15 (2.78 g, 8.74 mmol) and sodium ethoxide (9.00 g of
a 20 wt % solution in ethanol, 26.3 mmol) in THF (75 mL) was stirred
at reflux for 20 min. The mixture was diluted with water. The
resulting mixture was extracted with ethyl acetate twice. The
combined organic layers were washed with water twice, dried over
MgSO4 and the solvent was removed in vacuo to afford a residue.
The residue was purified by flash column chromatography
(hexane:EtOAc¼3:1) on silica gel to afford 16 (1.58 g, 64% yield).
Pale yellow solid, mp 83e85 ꢀC; IR (neat): nmax/cmꢁ1 2979, 1709,
1618, 1563, 1550, 1510, 1442, 1290, 1106, 814; 1H NMR (CDCl3,
1121; 1H NMR (CDCl3, 400 MHz)
d
8.62 (d, J¼8.4 Hz, 1H), 7.77e7.70
(m, 2H), 7.50 (t, J¼8.0 Hz, 1H), 7.26 (s, 1H), 4.41e4.45 (m, 2H), 3.11
(q, J¼7.6 Hz, 2H), 1.45e1.36 (m, 6H), 13C NMR (DMSO-d6, 100 MHz)
d
163.45, 158.11, 145.32, 142.55, 133.54, 130.32, 124.20, 123.64,
116.42, 115.60, 97.94, 91.59, 58.74, 21.55, 14.41, 13.26; HR-MS (ESI)
calcd for C16H18N3O2 (MþH)þ requires 284.1399, found 284.1389.
4.4.5. 3-Bromo-2-methylpyrazolo[1,5-a]quinolin-5-amine
(13ae). Prepared from 6a (1.00 mmol) and 12e (1.00 mmol) in an
analogous manner for preparation of 13aa. Yield: 46%; Yellow solid,
mp 168e170 ꢀC; IR (neat): nmax/cmꢁ1 3303, 3189, 1640, 1619, 1561,
400 MHz)
d
8.44 (d, J¼8.5 Hz, 1H), 7.98 (d, J¼9.3 Hz, 1H), 7.78 (d,
J¼8.1 Hz, 1H), 7.72e7.64 (m, 2H), 7.45 (td, J¼8.1 Hz, 1.2 Hz, 1H), 4.59
(q, J¼7.3 Hz, 2H), 4.39 (q, J¼6.9 Hz, 2H), 1.55 (t, J¼6.9 Hz, 3H), 1.43 (t,
1480,1244,1062; 1H NMR (CDCl3, 400 MHz)
d
8.50 (d, J¼8.4 Hz,1H),
J¼7.3 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d 164.30, 163.32, 140.48,
7.72 (d, J¼8.2 Hz, 1H), 7.67 (t, J¼8.2 Hz, 1H), 7.44 (td, J¼8.1 Hz,
133.94, 129.99, 128.39, 128.11, 124.51, 122.99, 116.51, 115.57, 91.34,
65.48, 59.75, 14.69, 14.49; HR-MS (ESI) calcd for C16H17N2O3
(MþH)þ requires 285.1239, found 285.1247.
0.9 Hz, 1H), 6.49 (s, 1H), 4.26 (br s, 2H), 2.46 (s, 3H), 13C NMR
(DMSO-d6, 100 MHz) d 148.19, 142.79, 138.13, 134.01, 129.93, 123.86,
123.80, 116.86, 114.52, 88.64, 80.94, 12.32, HR-MS (ESI) calcd for
C
12H11N3Br (MþH)þ requires 276.0136, found 276.0134.
4.5.3. Ethyl 2-hydroxypyrazolo[1,5-a]quinoline-3-carboxylate
(17). To a stirred solution of 16 (400 mg, 1.41 mmol) in CH2Cl2
(20 mL) was dropwise added boron tribromide (7.0 mL of a 1.0 M
solution in CH2Cl2, 7.00 mmol) under ice-cooling. The ice bath was
removed and the mixture was stirred at ambient temperature for
16 h. After monitoring the end of the reaction on TLC, the reaction
was quenched with saturated aqueous NaHCO3, and diluted with
water. The resulting mixture was extracted with CHCl3 twice. The
combined organic layers were washed with water twice, dried over
MgSO4 and the solvent was removed in vacuo to afford a residue.
The residue was purified by flash column chromatography
(hexane:EtOAc¼1:1) on silica gel to afford 17 (305 mg, 85% yield).
Pale pink solid, mp 157e159 ꢀC; IR (neat): nmax/cmꢁ1 3338, 1665,
4.4.6. 2-(Trifluoromethyl)pyrazolo[1,5-a]quinolin-5-amine
(13af). Prepared from 6a (1.00 mmol) and 12f (1.00 mmol) in an
analogous manner for preparation of 13aa. Yield: 49%; Yellow solid,
mp 159e161 ꢀC; IR (neat): nmax/cmꢁ1 3333, 3220, 1642, 1443, 1252,
1160, 1114, 970; 1H NMR (CDCl3, 400 MHz)
d
8.64 (d, J¼8.0 Hz, 1H),
7.77e7.70 (m, 2H), 7.54 (t, J¼7.6 Hz, 1H), 6.61 (s, 1H), 6.52 (s, 1H),
4.26 (br s, 2H), 13C NMR (DMSO-d6, 100 MHz)
d 142.81, 142.24 (q,
2JCF¼36.5 Hz), 141.05, 133.68, 130.03, 125.20, 123.87, 121.92 (q,
1JCF¼267.2 Hz), 117.81, 115.56, 93.18, 90.74; HR-MS (ESI) calcd for
C
12H9N3F3 (MþH)þ requires 252.0749, found 252.0742.
4.4.7. 4-Methyl-2-(trifluoromethyl)pyrazolo[1,5-a]quinolin-5-amine
(13ag). Prepared from 6a (1.00 mmol) and 12g (1.00 mmol) in an
analogous manner for preparation of 13aa. Yield: 28%; Brown solid,
mp 113e115 ꢀC; IR (neat): nmax/cmꢁ1 3397, 1634, 1506, 1455, 1248,
1418, 1137, 815; 1H NMR (CDCl3, 400 MHz)
d 8.90 (br s, 1H), 8.50 (d,
J¼8.5 Hz, 1H), 7.80 (dd, J¼8.1 Hz, 1.2 Hz, 1H), 7.76e7.00 (m, 3H), 7.48
(td, J¼8.1 Hz, 1.2 Hz,1H), 4.47 (q, J¼7.3 Hz, 2H), 1.47 (t, J¼7.3 Hz, 3H),
13C NMR (CDCl3, 100 MHz)
d 166.15, 165.61, 137.97, 133.91, 130.42,
1125, 970; 1H NMR (CDCl3, 400 MHz)
d
8.63 (dd, J¼8.4 Hz, 0.4 Hz,
128.81, 128.44, 124.92, 123.19, 115.97, 115.38, 89.29, 60.63, 14.44;
HR-MS (ESI) calcd for C14H12N2O3Na (MþNa)þ requires 279.0746,
found 279.0741.
1H), 7.77 (d, J¼8.0 Hz, 1H), 7.68 (td, J¼8.4 Hz, 1.2 Hz, 1H), 7.53 (td,
J¼8.4 Hz, 1.2 Hz, 1H), 6.60 (s, 1H), 4.43 (br s, 2H), 13C NMR (DMSO-
2
d6, 100 MHz)
d
142.46, 142.28 (q, JCF¼36.6 Hz), 138.33, 132.51,
1
128.93, 125.24, 123.51, 121.95 (q, JCF¼267.2 Hz), 117.95, 115.37,
4.5.4. Ethyl 2-[[(trifluoromethyl)sulfonyl]oxy]pyrazolo[1,5-a]quino-
line-3-carboxylate (18). Compound 17 (550 mg, 2.15 mmol), tri-
fluoromethanesulfonic anhydride (2.42 g, 8.58 mmol) and
triethylamine (1.5 mL, 10.8 mmol) were dissolved in CH2Cl2
(20 mL), and the mixture was stirred at ambient temperature for
16 h. After monitoring the end of the reaction on TLC, the mixture
was diluted with water. The resulting mixture was extracted with
ethyl acetate twice. The combined organic layers were washed with
water twice, dried over MgSO4 and the solvent was removed in
vacuo to afford a residue. The residue was purified by flash column
chromatography (hexane:EtOAc¼6:1) on silica gel to afford 18
(693 mg, 83% yield).
3
98.27, 93.04 (q, JCF¼1.8 Hz), 12.53; HR-MS (ESI) calcd for
C
13H11N3F3 (MþH)þ requires 266.0905, found 266.0898.
4.5. Diverse-oriented synthesis of 2-substituted pyrazolo
[1,5-a]quinolines
4.5.1. Ethyl 2-(methylsulfonyl)pyrazolo[1,5-a]quinoline-3-
carboxylate (15). To a stirred solution of 146a (1.50 g, 5.24 mmol)
in a mixture of THF (100 mL), MeOH (100 mL) and H2O (100 mL),
was added OxoneÒ (14 g, 22.0 mmol) in one potion. After being
stirred at an ambient temperature for 16 h, the mixture was diluted
with water. The resulting mixture was extracted with ethyl acetate
twice. The combined organic layers were washed with water twice,
White solid, mp 129e131 ꢀC; IR (neat): nmax/cmꢁ1 1704, 1426,
1240, 1221, 1204, 1138; 1H NMR (CDCl3, 400 MHz)
d
8.51 (d,
J¼8.5 Hz,1H), 8.10 (d, J¼9.2 Hz,1H), 7.87 (d, J¼7.7 Hz,1H), 7.83e7.76

2774
J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
(m, 2H), 7.59 (td, J¼8.1 Hz, 1.2 Hz, 1H), 4.46 (q, J¼7.3 Hz, 2H), 1.45 (t,
400 MHz)
d
8.60 (d, J¼8.5 Hz, 1H), 8.06 (d, J¼9.2 Hz, 1H), 7.81 (d,
J¼7.4 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
d
161.24, 153.37, 140.57,
J¼8.1 Hz, 1H), 7.71 (td, J¼8.5 Hz, 1.6 Hz, 1H), 7.65 (d, J¼9.6 Hz, 1H),
7.49 (td, J¼8.1 Hz, 0.8 Hz, 1H), 4.40 (q, J¼7.3 Hz, 2H), 4.12 (q,
J¼7.3 Hz, 2H), 3.2 (t, J¼7.3 Hz, 2H), 2.46 (t, J¼7.3 Hz, 2H), 2.18 (quin,
J¼7.4 Hz, 2H), 1.45 (t, J¼7.3 Hz, 3H), 1.24 (t, J¼7.3 Hz, 3H), 13C NMR
133.64, 130.79, 129.68, 128.75, 126.42, 123.76, 118.74 (q,
1JCF¼319.2 Hz), 116.28, 116.01, 96.78, 60.94, 14.23; HR-MS (ESI)
calcd for C15H11N2O5F3NaS (MþNa)þ requires 341.0572, found
341.0567.
(CDCl3, 100 MHz)
d 173.55, 164.07, 157.04, 140.30, 134.06, 129.98,
128.34, 127.84, 125.23, 123.44, 117.04, 116.02, 103.57, 60.19, 59.89,
34.03, 27.75, 24.23, 14.48, 14.23; HR-MS (ESI) calcd for C20H23N2O4
(MþH)þ requires 355.1658, found 355.1659.
4.5.5. (E)-Ethyl
2-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)pyrazolo
[1,5-a]quinoline-3-carboxylate (19). The triflate 18 (100 mg,
0.26 mmol), triethylamine (0.4 mL, 2.60 mmol), tert-butyl acrylate
(0.4 mL, 2.60 mmol) and PdCl2(PPh3)2 (30 mg, 0.03 mmol) were
sequentially added to a sealed tube. The resulting mixture was
stirred at 120 ꢀC for 16 h and diluted with water. The resulting
mixture was extracted with ethyl acetate twice. The combined or-
ganic layers were washed with water twice, dried over MgSO4 and
the solvent was removed in vacuo to afford a residue. The residue
was purified by flash column chromatography (hexane:EtOAc¼4:1)
on silica gel to afford 19 (24.5 mg, 26% yield).
4.5.8. Ethyl 2-molpholinopyrazolo[1,5-a]quinoline-3-carboxylate
(22). The triflate 18 (82.0 mg, 0.12 mmol) was dissolved in mor-
pholine (1.0 mL) and the mixture was stirred at 100 ꢀC for 1 h. After
cooling to ambient temperature, the reaction mixture was directly
purified by flash column chromatography (hexane:EtOAc¼4:1) on
silica gel to afford 22 (40.0 mg, 58% yield).
Pale yellow solid, mp 102e104 ꢀC; IR (neat): nmax/cmꢁ1 2960,
2854, 1695, 1615, 1561, 1497, 1115, 1068, 935, 813; 1H NMR (CDCl3,
White solid, mp 96e98 ꢀC; IR (neat): nmax/cmꢁ11703,1616,1559,
400 MHz)
d
8.50 (d, J¼8.1 Hz, 1H), 8.02 (d, J¼9.2 Hz, 1H), 7.79 (d,
1151, 1112, 1075; 1H NMR (CDCl3, 400 MHz)
d
8.67 (d, J¼8.5 Hz, 1H),
J¼7.7 Hz, 1H), 7.69 (td, J¼8.5 Hz, 1.2 Hz, 1H), 7.65 (d, J¼9.6 Hz, 1H),
7.46 (td, J¼8.1 Hz, 0.8 Hz, 1H), 4.40 (q, J¼7.3 Hz, 2H), 3.94 (t,
J¼4.6 Hz, 4H), 3.54 (t, J¼4.6 Hz, 4H), 1.45 (t, J¼7.3 Hz, 3H), 13C NMR
8.30 (d, J¼16.2 Hz, 1H), 8.12 (d, J¼9.2 Hz, 1H), 7.83 (d, J¼8.1 Hz, 1H),
7.75 (td, J¼8.5 Hz, 1.2 Hz, 1H), 7.68 (d, J¼9.6 Hz, 1H), 7.55 (td,
J¼8.1 Hz, 1.2 Hz, 1H), 7.03 (d, J¼15.8 Hz, 1H), 4.45 (q, J¼7.3 Hz, 2H),
1.56 (s, 9H), 1.48 (t, J¼7.3 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
(CDCl3, 100 MHz)
d 163.46, 161.17, 141.20, 133.87, 130.03, 128.31,
128.02, 124.78, 123.14, 116.94, 115.87, 94.87, 66.81 (2C), 59.97, 50.58
(2C), 14.53; HR-MS (ESI) calcd for C18H20N3O3 (MþH)þ requires
326.1505, found 326.1497.
d
165.94, 163.51, 149.46, 140.70, 133.91, 133.49, 130.16, 128.44,
128.05, 126.00, 125.16, 123.99, 117.04, 116.31, 105.06, 80.55, 60.40,
28.20 (3C), 14.44; HR-MS (ESI) calcd for C21H22N2O4Na (MþNa)þ
requires 285.1239, found 285.1247.
Acknowledgements
4.5.6. Ethyl 2-phenylpyrazolo[1,5-a]quinoline-3-carboxylate (20). To
a solution of the triflate 18 (100 mg, 0.26 mmol) in 1,4-dioxane
(5 mL) were added anhydrous K3PO4 (170 mg, 0.78 mmol), phe-
nylboronic acid (95 mg, 0.78 mmol), Pd(PPh3)4 (40 mg,
0.03 mmol) and KBr (35 mg, 0.29 mmol) under an argon atmo-
sphere. The mixture was stirred at reflux for 16 h and diluted with
water. The resulting mixture was extracted with ethyl acetate twice.
The combined organic layers were washed with water twice, dried
over MgSO4 and the solvent was removed in vacuo to afford a resi-
due. The residue was purified by flash column chromatography
(hexane:EtOAc¼6:1) on silica gel to afford 20 (38.0 mg, 46% yield).
White solid, mp 121e123 ꢀC; IR (neat): nmax/cmꢁ1 1704, 1615,
The authors wish to thank Mr. Haruhiko Fukaya (the Analytical
Center, Tokyo University of Pharmacy and Life Sciences) for the X-
ray crystallographic analysis.
Supplementary data
These data include X-ray data for compound 7d and 1H/13C NMR
spectra of all new compounds described in this article. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2014.02.081. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
1456, 1179, 1097, 1066, 815; 1H NMR (CDCl3, 400 MHz)
d 8.70 (d,
J¼8.5 Hz, 1H), 8.16 (d, J¼9.2 Hz, 1H), 7.86e7.82 (m, 3H), 7.75e7.70
(m, 2H), 7.53 (td, J¼8.1 Hz, 0.8 Hz, 1H), 7.49e7.44 (m, 3H), 4.34 (q,
J¼7.3 Hz, 2H), 1.32 (t, J¼7.3 Hz, 3H), 13C NMR (CDCl3, 100 MHz)
References and notes
d
163.74, 155.67, 140.77, 134.11, 132.95, 130.07 (2C), 130.05, 128.71,
1. a) O’Connel, K. M. G.; Galloway, W. R. J. D.; Spring, D. R. In Diversity-oriented
Synthesis: Basics and Applications in Organic Synthesis, Drug Discovery, and
Chemical Biology; Trabocchi, A., Ed.; Wiley & Sons: New Jersey, NJ, 2013;
pp 1e26; b) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol.
2010, 14, 347; c) Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65; d)
DeSimone, R. W.; Currie, K. S.; Darow, J. W.; Pippin, D. A. Comb. Chem. High
Throughput Screening 2004, 7, 473; e) Muller, G. Drug Discovery Today 2003, 8,
681.
2. (a) LaPorte, M. G.; Goodell, J. R.; Tsegy, S.; Wip, P. In Diversity-oriented Synthesis:
Basics and Applications in Organic Synthesis, Drug Discovery, and Chemical Bi-
ology; Trabocchi, A., Ed.; Wiley & Sons: New Jersey, NJ, 2013; pp 135e176; (b)
Horton, D. A.; Bourene, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
3. Barrett, D. Heterocycles 1997, 45, 1839.
4. Lober, S.; Hubuner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999, 9, 97.
5. Shen, H. C.; Ding, F.-X.; Deng, Q.; Wilsie, L. C.; Krsmanovic, M. L.; Taggart, A. K.;
Carballo-Jane, E.; Ren, N.; Cai, T.-Q.; Wu, T.-J.; Wu, K. K.; Cheng, K.; Chen, Q.;
Wolff, M. S.; Tong, X.; Holt, T. G.; Waters, M. G.; Hammond, M. L.; Tata, J. R.;
Colletti, S. L. J. Med. Chem. 2009, 52, 2587.
6. (a) Kato, J.; Aoyama, H.; Yokomatsu, T. Org. Biomol. Chem. 2013, 11, 1171; (b)
Kato, J.; Ito, Y.; Ijuin, R.; Aoyama, H.; Yokomatsu, T. Org. Lett. 2013, 15, 3794.
7. For a review of domino reactions based on Knoevenagel condensation in the
synthesis of heterocyclic compounds: Voskressensky, L. G.; Festa, A. A.; Varla-
mov, A. V. Tetrahedron 2014, 70, 551.
128.36, 128.04, 127.73 (2C), 125.56, 123.66, 117.33, 116.20, 103.58,
60.04, 14.22; HR-MS (ESI) calcd for C20H17N2O2 (MþH)þ requires
317.1290, found 317.1290.
4.5.7. Ethyl 2-(4-ethoxy-4-oxobutyl)pyrazolo[1,5-a]quinoline-3-
carboxylate (21). Under an inert and anhydrous condition,
Pd(OAc)2 (7.00 mg, 0.03 mmol) and Xphos (29.0 mg, 0.06 mmol)
were dissolved in THF (0.5 mL), and the mixture was stirred at
ambient temperature for 15 min. To this mixture were sequentially
added a solution of the triflate 18 (100 mg, 0.26 mmol) in THF
(0.4 mL) and (4-ethoxy-4-oxobutyl)zinc(II) bromide (0.5 M in THF,
1.6 mL, 0.78 mmol). After being stirred at 50 ꢀC for 16 h, the mixture
was cooled to an ambient temperature. The resulting mixture was
filtered through CeliteÒ. The CeliteÒ was washed with EtOAc and
combined washings and filtrate were dried over MgSO4 and the
solvent was removed in vacuo to afford a residue. The residue was
purified by flash column chromatography (hexane:EtOAc¼6:1) on
silica gel to afford pyrazolo[1,5-a]quinoline 21 (63.0 mg, 68% yield).
Pale yellow solid, mp 43e44 ꢀC; IR (neat): nmax/cmꢁ1 2978, 1731,
1698, 1616, 1560, 1440, 1267, 1167, 1106, 815; 1H NMR (CDCl3,
8. Although decomposition products could not be identified clearly, it may be
conceivable that self-aldol condensation of electron-deficient fluoroarylketones
3c and 3d occurs prior to the SNAr reaction.

J.-ya Kato et al. / Tetrahedron 70 (2014) 2766e2775
2775
9. (a) Lawrence, S. A. Amine: Synthesis, Properties and Applications; Cambridge
University Press: Cambridge, UK, 2004; (b) Amino Group Chemistry: From Syn-
thesis to the Life Sciences; Ricci, A., Ed.; Wiley-VCH: Weinheim, Germany, 2008.
10. Rochais, C.; Yougnia, R.; Cailly, T.; Santos, J. S. O.; Rault, S.; Dallemagne, P. Tet-
rahedron 2011, 67, 5806.
the DieckmanneThorpe cyclization in our cascade sequence. The similar results
are observed in our SNAr/Knoevenagel cyclization cascade reaction from 2-
fluorobenzaldehyde (6a) and 1H-pyrazoles 12 (X¼H or CH3, R1¼R2¼CH3)
without having an electron-withdrawing group.6a
13. Prolonged heating over 20 min resulted in significant loss of the product 16 due
to hydrolysis of the carboethoxy functionality.
11. From the reaction with 12b, the SNAr adduct derived from 6a and 13ab was
isolated in an 14% yield. This side reaction also reduced the yield of 13ab.
14. Arbaciauskiene, E.; Vilkauskaite, G.; Eller, G. E.; Holzer, W.; Sackus, A. Tetrahe-
dron 2009, 65, 7817.
15. Zang, T.; Gao, X.; Wood, H. B. Tetrahedron Lett. 2011, 52, 311.
16. Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 4720.
17. Taylor, E. C.; Purdum, W. R. Heterocycles 1977, 6, 1865.
12.
A
reaction between 2-fluorobenzonitrile (6a) and 1H-pyrazole 12 (X¼H,
R1¼R2¼CH3) without having an electron-withdrawing groups at the pyrazole
ring was examined under the conditions using Cs2CO3 in DMSO at 120 ꢀC.
Although this reaction gave the corresponding SNAr product in 38% yield, no
desired cascade products were detected. These results suggest to us that
electron-withdrawing substituents at the pyrazole ring are necessary to induce
18. Betard, A.; Wannapaiboon, S.; Fischer, R. A. Chem. Commun. 2012, 10495.