Development of a new cascade reaction for convergent synthesis of pyrazolo[1,5-a]quinoline derivatives under transition-metal-free conditions

Article abstract of DOI:10.1039/c2ob27050a

A novel method for the synthesis of pyrazolo[1,5-a]quinolines under the transition-metal-free conditions has been developed. This method involves a novel combination of aromatic nucleophilic substitution and Knoevenagel condensation reactions to give pyrazolo[1,5-a]quinolines.

Full text of DOI:10.1039/c2ob27050a

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Development of a new cascade reaction for convergent
synthesis of pyrazolo[1,5-a]quinoline derivatives under
transition-metal-free conditions†
Cite this: Org. Biomol. Chem., 2013, 11,
1171
Jun-ya Kato, Hiroshi Aoyama and Tsutomu Yokomatsu*
Received 20th October 2012,
Accepted 10th December 2012
A novel method for the synthesis of pyrazolo[1,5-a]quinolines under the transition-metal-free conditions
has been developed. This method involves a novel combination of aromatic nucleophilic substitution and
Knoevenagel condensation reactions to give pyrazolo[1,5-a]quinolines.
DOI: 10.1039/c2ob27050a
www.rsc.org/obc
Introduction
Recently, the pyrazolo[1,5-a]quinoline subunit has been
applied to useful compounds that display a biological and
material function. In particular, 3-substituted pyrazolo[1,5-a]-
quinoline derivatives have been developed for dopamine D4
antagonist agents,1 GPR109a agonist agents,2 and organic
light-emitting device agents.3 These reports suggest to us that
the pyrazolo[1,5-a]quinoline skeleton may be a potentially
useful privileged scaffold in the discovery of biologically and
materially active compounds.4 However, besides these
examples, the pyrazolo[1,5-a]quinoline subunit has not been
applied to seek further biologically and materially active com-
pounds, which might be due to the lack of general methods
for the synthesis of pyrazolo[1,5-a]quinoline derivatives.
Previous methods for the synthesis of pyrazolo[1,5-a]quino-
lones involve (1) a 1,3-dipolar cycloaddition reaction of N-imino-
quinolines with acetylene esters;5 (2) a nucleophilic reaction of
N-iminoquinolines with ketene dithioacetals;6 (3) an alkenyla-
tion/cyclization reaction of N-iminoquinolines with alkenyl
iodides;7 (4) a direct oxidative coupling reaction of phenylpyra-
zoles with internal alkynes;8 and other approaches.9 These
methods require an inconvenient multi-step synthesis for the
required substrates. Therefore, to develop medicinally and
materially significant compounds possessing a pyrazolo[1,5-a]-
quinoline subunit, a general and more facile approach to the
synthesis of pyrazolo[1,5-a]quinolines and related compounds
has become more desirable.
Scheme 1 New cascade reaction for synthesis of pyrazolo[1,5-a]quinoline.
In this context, we envisaged a new cascade reaction as
shown in Scheme 1. In this cascade reaction, the intermolecu-
lar aromatic nucleophilic substitution (SNAr) of 2-fluorobenz-
aldehyde (1a) with 3,5-dimethyl-1H-pyrazole (2a) having a
carboethoxy group at the 4-position is first conducted in the
presence of a base to give the expected 1-substituted 3,5-
dimethylpyrazole (3aa). In these intermediates, the 5-methyl
group would be anionically more activated than the 3-methyl
group under the conditions, since the trace anion generated at
the 5-methyl group is favourably conjugated to the carboethoxy
group.10 The trace anions of 3aa are successfully expected to
proceed through the intramolecular Knoevenagel conden-
sation reaction to give the desired pyrazolo[1,5-a]quinoline
4aa. This SNAr/Knoevenagel cyclization cascade reaction allows
us to synthesize a variety of pyrazolo[1,5-a]quinolines without
using any transition metal catalysts upon fine-tuning a combi-
nation of two substrates. In this paper, we describe the pre-
liminary results of our studies.
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail: yokomatu@toyaku.ac.jp;
Fax: +81-42-676-3239; Tel: +81-42-676-3239
Results and discussion
Optimization of the reaction conditions
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all new compounds; X-ray analysis data for compound 9ca.
CCDC 900469. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob27050a
First, we examined the SNAr/Knoevenagel cyclization cascade
reaction utilizing 1a and 2a as model substrates to optimize
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Table 1 Optimization of the SNAr/Knoevenagel cyclization cascade reactiona
Scheme 2 Knoevenagel condensation of 3aa.
Entry
Base
Solvent
Temp. (°C)
Yieldb (%) of 4aa
upon arylating at the nitrogen of the pyrazoles through the
SNAr substitution.11
1
2
3
4
5
6
7
8
9
K2CO3
Na2CO3
Cs2CO3
K3PO4
KF
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
120
120
120
120
120
120
100
80
80
Trace
64
58
Not detected
76
59
Scope of 2-fluorobenzaldehydes
With the optimized conditions in hand, the scope and general-
ity of the one-pot cascade reactions were investigated. First, 2a
was reacted with a variety of 2-fluorobenzaldehydes possessing
a representative functional group on the aromatic ring. The
results are shown in Table 2. Almost all of the tested combi-
nations successfully produced the desired pyrazolo[1,5-a]qui-
nolines 4ba–4na with low to good isolated yields.
Trace
120
37c,d
a All reactions were carried out in the presence of pyrazole (2a)
(1.2 mmol), 2-fluorobenzaldehyde (1a) (1.0 mmol), and base
(3.0 mmol) in the indicated solvent (5 mL) for 8 h. b Isolated yield.
c The reaction was carried out for 1 h. d The intermediate 3aa was
isolated in a 7% yield.
The results suggest that the electronic density of the corre-
sponding 2-fluorobenzaldehydes might have some influence
on this cascade reaction. 2-Fluorobenzaldehydes having an
electron-withdrawing group were preferred substrates to those
with an electron-donating group (Table 2, entries 1–13). Thus,
when the cascade reaction was carried out with 2-fluorobenz-
aldehyde possessing a methoxy or methyl group under opti-
mized conditions using K2CO3 as a base, the yield was
significantly decreased (Table 2, entries 8–13). For instance,
only 15% of the desired product was isolated upon reacting 1i
with 2a using K2CO3 as a base (Table 2, entry 8). However, the
suitable bases and solvents. The results are shown in Table 1.
When 1a was treated with 2a in the presence of an excess of
K2CO3 (3 equiv.) in DMF at 120 °C for 8 h, the desired pyrazolo-
[1,5-a]quinoline 4aa was obtained with 80% yield as expected
(Table 1, entry 1). Although a very slow reaction was observed
when the reaction was carried out with Na2CO3 in place of
K2CO3 (Table 1, entry 2), it was found that Cs2CO3 and K3PO4
are also effective bases for this cascade reaction in DMF at
120 °C to give 4aa in slightly lower yields (Table 1, entries 3
and 4). It is noteworthy that organic bases such as Et3N and
DBU were highly detrimental to this reaction and no desired
products were detected for this reaction. No reaction occurred
without a base in DMF at 120 °C.
Table 2 Scope of 2-fluorobenzaldehydesa
Choice of the solvents is critical for this cascade reaction.
When the reaction was carried out in the presence of K2CO3 at
reflux upon switching the solvents from DMF to dioxane or
toluene, no desired product was detected. However, DMSO was
found to also be an efficient solvent to give 4aa in a compara-
tive yield (Table 1 entry 1 vs. 6). The cascade reaction was
highly affected by the reaction temperature; the yield signifi-
cantly decreased when the reaction was conducted below
120 °C (Table 1, entry 1 vs. 7, 8). Based on these results, at this
stage, the optimal conditions for the cascade reaction were
determined to be as conducted with 300 mol% of inexpensive
K2CO3 in DMF at 120 °C for 8 h.
When the reaction was stopped within 1 h for the con-
ditions of entry 1, 3aa was isolated in a 7% yield along with
37% of 4aa (Table 1, entry 9 and Scheme 1). The obtained 3aa
was resubmitted to the same conditions to entry 1 for 8 h to
give 4aa in a 31% isolated yield (Scheme 2). These experiments
show that the proposed cascade reaction works well as
expected (Scheme 1). We believe that the present cascade reac-
tion is the first example in which the inactivated methyl group
of the pyrazoles participates in the Knoevenagel cyclization
Aldehyde
Product
Entry
1
R
X
4
R
Yieldb (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
3-F
5-F
6-F
5-Br
F
F
F
F
4ba
4ca
4da
4ea
9-F
7-F
6-F
7-Br
61
64
12c
63
6-Cl
Cl 4fa
6-Cl
(24)d
47
5-CN
5-CF3
5-CH3
3-CH3O
4-CH3O
5-CH3O
F
F
F
F
F
F
F
F
4ga
4ha
4ia
4ja
4ka
4la
7-CN
7-CF3
7-CH3
9-CH3O
8-CH3O
7-CH3O
71
15(50)d
(52)d
(61)d
(63)d
(38)d
9
1j
1k
1l
10
11
12
13
1m 6-CH3O
1n 4,5-dimethoxy
4ma 6-CH3O
4na
7,8-dimethoxy (36)d
a All reactions were carried out in the presence of pyrazole (2a)
(1.2 mmol), 2-fluorobenzaldehydes (1.0 mmol), and K2CO3 (3.0 mmol)
in DMF (5 mL) for 8 h. b Isolated yields. c An adduct of 4da with 2a was
obtained in a 36% yield (see Experimental section). d Cs2CO3 was used
instead of K2CO3.
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Table 3 Scope of pyrazolesa
Entry
Pyrazole 2
Product 4
Yieldb (%)
1
2b
2c
2d
2e
2f
X = H, R1 = CH3, R2 = CH3
X = CH3, R1 = CH3, R2 = CH3
X = CN, R1 = CH3, R2 = CH3
X = F, R1 = CH3, R2 = CH3
X = Cl, R1 = CH3, R2 = CH3
X = Br, R1 = CH3, R2 = CH3
X = I, R1 = CH3, R2 = CH3
4ab
R3 = H
4ac
R3 = H
4ad
R3 = H
4ae
R3 = H
4af
R3 = H
4ag
R3 = H
4ah
R3 = H
4ai
R3 = H
4aj
R3 = H
4ak
R3 = CH3
4al
Not detected
2
Not detected
3
34
4
Not detected
5
6c
6
2g
2h
2i
58c
12c
10
7
8
X = CO2Et, R1 = CH3, R2 = H
X = CO2Et, R1 = CH3, R2 = SCH3
X = CO2Et, R1 = CH2CH3, R2 = SCH3
X = H, R1 = CH3, R2 = CF3
9
2j
79
10
11
2k
2l
47c
71c,d
R3 = H
a All reactions were carried out in the presence of pyrazoles (1.2 mmol), 2-fluorobenzaldehyde (1a) (1.0 mmol), and K2CO3 (3.0 mmol) in DMF
(5 mL) for 8 h. b Isolated yields. c Cs2CO3 was used instead of K2CO3. d Reaction time was 4 days.
yield was significantly improved to 50% when Cs2CO3 was product 4ag with a good yield, though pyrazoles 2f and 2h,
used instead of K2CO2.12 Using Cs2CO3 as a base, 2-fluorobenz- possessing other halogen atoms, did not react well (Table 3,
aldehyde possessing a methoxy functional group at either of entries 4–7).
the positions of the aromatic ring reacted with the pyrazole to
The substituent at the 3-position of the pyrazoles also
give the desired compounds 4ja–4na in modest yields (Table 2, strongly affected the present cascade reaction. When pyrazole
entries 9–13). Although the less reactive 2-chlorobenzaldehyde 2i, not having a methyl group at the 3-position, was used
could not react with 2a (data not shown), the more electron- instead of 2a, the corresponding cascade product 4ai was
deficient 2,6-dichlorobenzaldehyde 1f reacted with 2a under obtained in a very low yield (Table 3, entry 8). However, pyra-
the modified conditions using Cs2CO3 instead of K2CO3 to give zoles 2j and 2k bearing –SCH3 at the 3-position was able to
the cascade product 4fa in a low yield (Table 2, entry 5).
react with 1a to afford the desired product 4aj5 and 4ak with a
good yield (Table 3, entries 9 and 10). It should be pointed out
that pyrazole 2l bearing a CF3 functional group at the 3-posi-
tion reacts with 1a to afford the desired product 4al with a
good yield (Table 3, entry 11). This experiment suggests to us
that an electron-withdrawing group at the 4 position of the pyr-
azole is not necessary to induce the present cascade reaction.
Scope of pyrazoles
To extend the scope of the pyrazole substrates for the SNAr/
Knoevenagel cyclization cascade reaction, we next examined
the reactions of 2-fluorobenzaldehyde 1a with a variety of pyra-
zole derivatives 2b–l. The results are shown in Table 3.
Although pyrazoles 2b and 2c bearing electron-rich or elec-
tron-neutral groups at the 4-position such as –CH3 or –H could
not react with 1a (Table 3, entries 1 and 2), pyrazole 2d
Application to synthesis of new heterocycles related to
pyrazolo[1,5-a]quinolines
bearing an electron-deficient cyano group (–CN) at the 4-posi- In an effort to apply the present cascade reaction to the syn-
tion was able to react with 1a to afford the desired products thesis of new heterocycles related to pyrazolo[1,5-a]quinolines,
4ad with a moderate yield (Table 3, entry 3). We found that we finally examined the cascade reaction of 1a with heteroaro-
halogen atoms, except a fluorine atom, also function as avail- matic aldehydes 6 and 7 (Tables 4 and 5).
able as an electron-deficient functional group at the 4-position
As shown in Table 4, both 2-fluoro- and 2-chloropyridin-3-
(Table 3, entries 4–7). It is noteworthy that the cascade reac- aldehydes 6a and 6b reacted with the pyrazole 2a to give the
tion with pyrazole 2g substituted by a bromo group at the expected adduct 8aa in comparative yields (Table 4, entries 1
4-position remarkably reacted with 1a to give the desired and 2). 3-Fluoropyridin-4-aldehyde 6c reacted with the pyrazole
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Table 4 The cascade reaction of 2a with pyridyl aldehydes 6 for synthesis of
new heterocyclesa
Conclusions
A convenient and general method for the synthesis of pyrazolo
[1,5-a]quinolines and the related heterocycles has been devel-
oped. The method is based upon a cascade reaction through
an aromatic nucleophilic substitution of 1H-pyrazoles with
2-fluorobenzaldehyde derivatives, followed by Knoevenagel
cyclization of the resulting adducts. Our method potentially
provides a variety of pyrazolo[1,5-a]quinolines and the related
heterocycles without using any transition metal catalysts upon
fine-tuning a combination of two readily available substrates.
Entry
Heteroaromatic aldehyde
Product
Yieldb (%)
1
2
3
6a
6b
6c
X = F, A = N, B = CH
X = Cl, A = N, B = CH
X = F, A = CH, B = N
8aa
8aa
8ca
51
41c
2 (30)d
a All reactions were carried out in the presence of 2a (1.2 mmol), 6
(1.0 mmol), and K2CO3 (3.0 mmol) in DMF (5 mL) for 8 h. b Isolated
yields. c Cs2CO3 was used instead of K2CO3. d DMSO was used instead
of DMF.
Experimental section
General information
All reagents and solvents were pure analytical-grade materials
purchased from commercial sources and were used without
further purification except for 1H-pyrazoles 2d, 2j and 2k.
Compounds 2d, 2j and 2k were synthesized by a known
method.13,14 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 a JEOL GCmate by electron ionization and a
Micromass Autospec by electrospray ionization. Elemental
analysis was performed on an Elemental Vavio EL. NMR
spectra were obtained on a JEOL JNM-ECP400 NMR spec-
trometer (1H NMR: 400 MHz), a Bruker DPX400 NMR spec-
trometer (1H NMR: 400 MHz) or a Bruker AVANCE III NMR
spectrometer (1H NMR: 400 MHz and 13C NMR: 100 MHz).
Table 5 The cascade reaction of 2a with pyrazolyl aldehydes 7 for synthesis of
new heterocyclesa
Entry
Heteroaromatic aldehyde
Product
Yieldb (%)
1
2
3
7a
7b
7c
R1 = CH3, R2 = CH3
R1 = CH3, R2 = CH2Ph
R1 = CF3, R2 = CH3
9aa
9ba
9ca
49c
27c
64
a All reactions were carried out in the presence of 2a (1.2 mmol), 7
(1.0 mmol), and K2CO3 (3.0 mmol) in DMF (5 mL) for 8 h. b Isolated
yields. c Cs2CO3 was used instead of K2CO3.
1
The chemical shift data for each signal on H NMR were given
in units of δ relative to CHCl3 (δ = 7.26) for CDCl3 solution. For
13C NMR spectra, the chemical shifts in CDCl3 were relative to
CDCl3 (δ = 77.0) resonances. Column chromatography was
carried out using 63–210 μm silica gel 60N (Kanto Chemical
Co., Inc.). Analytical TLC was carried out with Merck plates
precoated with silica gel 60F254 plates (0.25 mm). Crystallo-
graphic 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
supplementary publication No. CCDC 900469.
Fig. 1 ORTEP drawing of 9ca.
Typical procedure for the preparation of pyrazolo[1,5-a]
quinolone 4aa
2a to give the expected adduct 8ca in very low yields (Table 4,
entry 3). However, the yield was significantly improved to 30%
when DMSO was used instead of DMF.
5-Chloropyrazoles 7a–c having a substituent at the 1-posi-
tion also reacted with 2a under these conditions to give new
heterocycles 9aa–9ca in varied yields. We wish to point out
that pyrazole 8c having an electron-withdrawing CF3 group
gave 9ca in a good yield (Table 5).
A mixture of 2-fluorobenzaldehyde 1a (202 mg, 1.0 mmol), 3,5-
dimethyl-1H-4-pyrazolecarboxylate 2a (125 mg, 1.2 mmol), and
K2CO3 (420 mg, 3 mmol) in DMF (5 mL) was stirred at 120 °C
for 8 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 : EtOAc = 5 : 1) on silica gel to afford
pyrazolo[1,5-a]quinolone 4aa (203 mg, 80% yield).
All new heterocycles 9aa–9ca were identified by convention-
al spectroscopic means. The structure of 9ca was further con-
firmed by X-ray crystallographic analysis (Fig. 1).
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HR-MS (ESI) calcd for C15H14N2O2F [M + H]+ requires 273.1039,
found 273.1034. Anal. Calcd for C15H13N2O2F: C, 66.17; H, 4.81;
N, 10.29. Found: C, 66.06; H, 4.92; N, 10.26.
Ethyl 7-fluoro-2-methylpyrazolo[1,5-a]quinoline-3-carboxy-
late (4ca). Yield: 64%. White solid. Mp. 145–146 °C. IR (neat):
1
νmax/cm−1 1700, 1566, 1436, 1241, 1123, 808. H-NMR (CDCl3,
400 MHz) δ 8.59 (dd, J = 9.1 Hz, 4.8 Hz, 1H), 8.10 (d, J = 9.5 Hz,
1H), 7.59 (d, J = 9.5 Hz, 1H), 7.49–7.42 (m, 2H), 4.41 (q, J = 7.1
Hz, 2H), 2.74 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3,
Fig. 2 Structure of 4daa.
1
100 MHz) δ 164.17, 159.77 (d, JCF = 245.6 Hz), 154.26, 139.74,
Reaction of 2,6-difluorobenzaldehyde (1d) with 2a (Table 2,
entry 3)
4
3
130.66, 126.94 (d, JCF = 3.1 Hz), 124.56 (d, JCF = 8.9 Hz),
2
3
118.46 (d, JCF = 24.8 Hz), 118.30, 118.00 (d, JCF = 8.7 Hz),
2
Compound 1d (143 mg, 1 mmol) was treated with 2a (202 mg,
1 mmol) in the presence of K2CO3 (420 mg, 3 mmol) in DMF
(5 mL) for 8 h at 120 °C in a similar manner for the prep-
aration of 4aa. The crude product was purified by silica gel
column chromatography. Elution with a mixture of hexane :
EtOAc = 5 gave 4da (33 mg, 12.1%). Successive elution with
EtOAc afforded the adduct 4daa (149 mg, 35.5%). The struc-
ture of 4daa is shown in Fig. 2.
112.88 (d, JCF = 22.6 Hz), 104.32, 59.93, 14.50, 14.47. HR-MS
(ESI) calcd for C15H14N2O2F [M + H]+ requires 273.1039, found
273.1035. Anal. Calcd for C15H13N2O2F: C, 66.17; H, 4.81; N,
10.29. Found: C, 66.04; H, 5.06; N, 10.51.
Ethyl 6-fluoro-2-methylpyrazolo[1,5-a]quinoline-3-carboxy-
late (4da). Yield: 12%. Pale yellow solid. Mp. 102–104 °C. IR
(neat): νmax/cm−1 1699, 1615, 1454, 1268, 1108, 791. 1H-NMR
(CDCl3, 400 MHz) δ 8.35 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 9.4 Hz,
1H), 7.89 (d, J = 9.4 Hz, 1H), 7.66–7.61 (m, 1H), 7.18 (t, J =
8.7 Hz, 1H), 4.41 (q, J = 7.3 Hz, 2H), 2.73 (s, 3H), 1.45 (t, J =
7.3 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 164.12, 158.85 (d, 1JCF
Ethyl 2-methylpyrazolo[1,5-a]quinoline-3-carboxylate (4aa).
Yield: 80%. Pale yellow solid. Mp. 84–85 °C. IR (neat): νmax
/
cm−1 1698, 1617, 1561, 1549, 1272, 1124. 1H-NMR (CDCl3,
400 MHz) δ 8.56 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 9.3 Hz, 1H),
7.79 (d, J = 7.7 Hz, 1H), 7.72–7.67 (m, 1H), 7.63 (d, J = 9.3 Hz,
1H), 7.49–7.45 (m, 1H), 4.40 (q, J = 7.3 Hz, 2H), 2.74 (s, 3H),
1.44 (t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 164.31,
154.25, 140.25, 133.98, 129.99, 128.37, 127.84, 125.15, 123.42,
116.94, 115.85, 104.06, 59.85, 14.56, 14.51. MS (EI+) m/z 254
[M]+, 209 [base]+. HR-MS (ESI) calcd for C15H15N2O2 [M + H]+
requires 255.1134, found 255.1134. Anal. Calcd for
C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C, 70.72; H,
5.62; N, 10.91.
3
= 253 Hz), 154.66, 140.32, 134.85 (d, JCF = 6.2 Hz), 130.22 (d,
3JCF = 9.2 Hz), 120.14 (d, 3JCF = 5.4 Hz), 117.32 (d, 4JCF = 1.3 Hz),
113.66 (d, 2JCF = 19.3 Hz), 111.74 (d, 3JCF = 4.0 Hz), 110.14 (d, 2JCF
= 19.9 Hz), 104.68, 60.00, 14.53, 14.50. MS (EI+) m/z 272 [M]+, 227
[base]+. HR-MS (ESI) calcd for C15H14N2O2F (M + H)+ requires
273.1039, found 273.1034. Anal. Calcd for C15H13N2O2F: C,
66.17; H, 4.81; N, 10.29. Found: C, 66.01; H, 5.00; N, 10.13.
Ethyl 6-{4-(ethoxycarbonyl)-3,5-dimethyl-1H-pyrazol-1-yl}-2-
methylpyrazolo[1,5-a]quinoline-3-carboxylate (4daa, an adduct
of 4da with 2a). Yield: 36%. Pale yellow solid. Mp. 161–164 °C.
IR (neat): νmax/cm−1 1703, 1263, 1108. 1H-NMR (CDCl3,
400 MHz) δ 8.74 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H),
7.80 (t, J = 8.5 Hz, 1H), 7.46–7.43 (m, 1H), 7.12 (d, J = 9.6 Hz,
1H), 4.41–4.33 (m, 4H), 2.75 (s, 3H), 2.54 (s, 3H), 2.34 (s, 3H),
1.43–1.38 (m, 6H). 13C-NMR (CDCl3, 100 MHz) δ 164.39,
164.00, 154.88, 152.06, 146.52, 140.02, 135.78, 134.67, 129.52,
124.46, 122.34, 121.18, 118.76, 117.49, 110.70, 104.79, 60.02,
59.94, 14.53, 14.45, 14.39, 12.09. MS (EI+) m/z 420 [M]+. HR-MS
(ESI) calcd for C23H25N4O4 [M + H]+ requires 421.1876, found
421.1876. Anal. Calcd for C23H24N4O4: C, 65.70; H, 5.75; N,
13.33. Found: C, 65.75; H, 5.72; N, 13.05.
Ethyl 1-(2-formylphenyl)-3,5-dimethyl-1H-pyrazole-4-carboxy-
late (3aa). Yield: 7%. Pale yellow solid. Mp. 100–102 °C. IR
(neat): νmax/cm−1 1701. 1H-NMR (CDCl3, 400 MHz) δ 9.64 (s,
1H), 8.07 (dd, J = 7.7 Hz, 7.7 Hz, 1H), 7.74 (td, J = 7.7 Hz, 1.5
Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 4.35
(q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 2.43 (s, 3H), 1.39 (t, J = 7.1 Hz,
3H). 13C-NMR (CDCl3, 100 MHz) δ 188.89, 164.22, 152.11,
146.40, 140.38, 134.47, 132.51, 129.80, 128.87, 128.03, 111.13,
59.96, 14.39, 14.25, 12.26. HR-MS (ESI) calcd for C15H17N2O3
[M + H]+ requires 273.1239, found 273.1234. Anal. Calcd for
C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.04; H,
5.98; N, 10.01.
Ethyl 9-fluoro-2-methylpyrazolo[1,5-a]quinoline-3-carboxy-
late (4ba). Yield: 61%. White solid. Mp. 121–126 °C. IR (neat):
νmax/cm−1 1696, 1571, 1551, 1324, 1272, 1228, 1105. 1H-NMR
(CDCl3, 400 MHz) δ 8.13 (d, J = 9.3 Hz, 1H), 7.63 (dd, J = 1.9 Hz,
9.3 Hz, 1H), 7.59 (d, J = 6.9 Hz, 1H), 7.49–7.46 (m, 1H),
7.44–7.38 (m, 1H), 4.41 (q, J = 7.3 Hz, 2H), 2.76 (s, 3H), 1.45 (t,
J = 7.3 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 164.09, 154.68 (d,
3JCF = 5.0 Hz), 152.20 (d, 1JCF = 256.6 Hz), 141.45, 127.46 (d, 4JCF
Ethyl 7-bromo-2-methylpyrazolo[1,5-a]quinoline-3-carboxy-
late (4ea). Yield: 63%. Pale yellow solid. Mp. 164–167 °C. IR
1
(neat): νmax/cm−1 1699, 1122, 813. H-NMR (CDCl3, 400 MHz)
δ 8.46 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 9.5 Hz, 1H), 7.95 (d, J =
2.0 Hz, 1H), 7.79 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.55 (d, J =
9.5 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.73 (s, 3H), 1.45 (t, J =
7.1 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 164.07, 154.54,
140.04, 132.94, 132.74, 130.51, 126.52, 124.81, 118.47, 118.23,
117.66, 104.54, 59.99, 14.51, 14.49. HR-MS (ESI) calcd for
C15H14N2O2Br [M + H]+ requires 333.0239, found 333.0239.
Anal. Calcd for C15H13N2O2Br: C, 54.07; H, 3.93; N, 8.41.
Found: C, 54.19; H, 3.97; N, 8.61.
3
4
= 2.0 Hz), 126.43, 125.01 (d, JCF = 7.6 Hz), 124.08 (d, JCF = 4.2
2
2
Hz), 123.39 (d, JCF = 7.9 Hz), 117.88, 116.97 (d, JCF = 20.5 Hz),
103.64, 59.99, 14.70, 14.45. MS (EI+) m/z 272 [M]+, 227 [base]+.
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Ethyl 6-chloro-2-methylpyrazolo[1,5-a]quinoline-3-carboxy- 100 MHz) δ 164.35, 154.04, 150.34, 141.96, 128.39, 126.28,
late (4fa). Yield: 24%. White solid. Mp. 116–118 °C. IR (neat): 125.30, 125.21, 121.07, 117.34, 112.82, 102.93, 59.87, 57.24,
νmax/cm−1 1705, 1613, 1127, 1092, 791. 1H-NMR (CDCl3, 15.02, 14.46. HR-MS (ESI) calcd for C16H17N2O3 [M + H]+
400 MHz) δ 8.54 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), requires 285.1239, found 285.1239. Anal. Calcd for
8.07 (d, J = 9.7 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.56 (dd, J = C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.51; H,
8.0 Hz, 1.2 Hz, 1H), 4.42 (q, J = 7.3 Hz, 2H), 2.74 (s, 3H), 1.46 5.58; N, 10.04.
(t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 164.05, 154.76,
Ethyl 8-methoxy-2-methylpyrazolo[1,5-a]quinoline-3-carboxy-
140.03, 134.91, 132.65, 129.82, 125.60, 123.93, 121.45, 117.87, late (4ka). Yield: 61%. Pale yellow solid. Mp. 122–124 °C. IR
114.84, 104.47, 59.98, 14.51, 14.48. HR-MS (ESI) calcd for (neat): νmax/cm−1 1697, 1616, 1549, 1217, 1108. 1H-NMR
C15H14N2O2Cl [M + H]+ requires 289.0744, found 289.0740.
(CDCl3, 400 MHz) δ 8.00 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 9.2 Hz,
Ethyl 7-cyano-2-methylpyrazolo[1,5-a]quinoline-3-carboxylate 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.10 (dd,
(4ga). Yield: 47%. Pale brown solid. Mp. 220–224 °C. IR (neat): J = 8.7 Hz, 2.5 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H),
νmax/cm−1 2227, 1697, 1613, 1542, 1431, 1324, 1270, 1159, 2.76 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3,
1124, 814. 1H-NMR (CDCl3, 400 MHz) δ 8.68 (d, J = 8.8 Hz, 1H), 100 MHz) δ 164.33, 161.37, 154.33, 140.67, 135.25, 129.64,
8.16 (d, J = 9.4 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.91 (dd, J = 127.61, 117.48, 115.93, 114.02, 103.55, 97.13, 59.75, 55.86,
8.8 Hz, 1.8 Hz, 1H), 7.64 (d, J = 9.4 Hz, 1H), 4.43 (q, J = 7.2 Hz, 14.57, 14.50. HR-MS (ESI) calcd for C16H17N2O3 [M + H]+
2H), 2.75 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). 13C-NMR (CDCl3, requires 285.1239, found 285.1242. Anal. Calcd for
100 MHz) δ 163.81, 155.49, 140.83, 135.73, 133.36, 132.02, C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.76; H,
126.55, 123.21, 119.13, 118.21, 117.22, 108.92, 105.47, 60.22, 5.46; N, 9.88.
14.57, 14.47. HR-MS (ESI) calcd for C16H14N3O2 [M + H]+
Ethyl 7-methoxy-2-methylpyrazolo[1,5-a]quinoline-3-carboxy-
requires 280.1086, found 280.1081. Anal. Calcd for late (4la). Yield: 63%. Pale yellow solid. Mp. 119–122 °C. IR
C16H13N3O2: C, 68.81; H, 4.69; N, 15.05. Found: C, 68.79; H, (neat): νmax/cm−1 1690, 1272, 1127, 806. 1H-NMR (CDCl3,
4.76; N, 15.09.
400 MHz) δ 8.49 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H),
Ethyl 2-methyl-7-(trifluoromethyl) pyrazolo[1,5-a]quinoline- 7.58 (d, J = 9.2 Hz, 1H), 7.32 (dd, J = 8.9 Hz, 2.7 Hz, 1H), 7.18
3-carboxylate (4ha). Yield: 71%. Yellow solid. Mp. 135–139 °C. (d, J = 2.7 Hz, 1H), 4.40 (q, J = 7.3 Hz, 2H), 3.92 (s, 3H), 2.72 (s,
IR (neat): νmax/cm−1 1702, 1316, 1113. 1H-NMR (CDCl3, 3H), 1.44 (t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3, 100 MHz)
400 MHz) δ 8.68 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 9.4 Hz, 1H), δ 164.33, 156.94, 153.86, 139.26, 128.88, 127.32, 124.43,
8.09 (s, 1H), 7.91 (dd, J = 8.8 Hz, 1.5 Hz, 1H), 7.67 (d, J = 119.68, 117.35, 117.24, 108.78, 103.61, 59.74, 55.61, 14.50,
9.4 Hz, 1H), 4.41 (q, J = 7.3 Hz 2H), 2.75 (s, 3H), 1.45 (t, J = 7.3 14.47. MS (EI+) m/z 284 [M]+. HR-MS (ESI) calcd for
Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 163.95, 155.02, 140.67, C16H17N2O3 [M + H]+ requires 285.1239, found 285.1238. Anal.
2
3
135.44, 127.32 (q, JCF = 33.0 Hz), 127.27, 126.17 (q, JCF = 3.2 Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C,
3
1
Hz), 125.92 (q, JCF = 4.0 Hz), 125.23 (q, JCF = 272.0 Hz), 67.69; H, 5.70; N, 9.83.
122.83, 118.52, 116.79, 104.97, 60.08, 14.54, 14.47. MS (EI+)
Ethyl 6-methoxy-2-methylpyrazolo[1,5-a]quinoline-3-carboxy-
m/z 322 [M ]+, 277 [base]+. HR-MS (ESI) calcd for C16H14N2O2F3 late (4ma). Yield: 38%. White solid. Mp. 132–133 °C. IR (neat):
[M + H]+ requires 323.1007, found 323.1007. Anal. Calcd for νmax/cm−1 1701, 1617, 1105, 789. 1H-NMR (CDCl3, 400 MHz)
C16H13N2O2F3: C, 59.63; H, 4.07; N, 8.09. Found: C, 59.66; H, δ 8.16 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 9.6 Hz, 1H), 8.00 (d, J =
4.35; N, 8.28.
9.6 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H),
Ethyl 2,7-dimethyl-2-methylpyrazolo[1,5-a]quinoline-3-car- 4.41 (q, J = 7.4 Hz, 2H), 4.02 (s, 3H), 2.74 (s, 3H), 1.45 (t, J =
boxylate (4ia). Yield: 15% (using K2CO3), 50% (using Cs2CO3). 7.4 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 164.49, 156.19,
White solid. Mp. 103–104 °C. IR (neat): νmax/cm−1 1697, 823. 154.45, 140.62, 134.87, 130.51, 122.43, 115.62, 114.82, 108.22,
1H-NMR (CDCl3, 400 MHz) δ 8.45 (d, J = 8.5 Hz, 1H), 8.01 (d, 104.87, 103.81, 59.90, 56.00, 14.67, 14.62. HR-MS (ESI) calcd
J = 9.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.58 (s, 1H), 7.53 (dd, for C16H17N2O3 [M + H]+ requires 285.1239, found 285.1230.
J = 8.5 Hz, 1.5 Hz, 1H), 4.40 (q, J = 7.3 Hz, 2H), 2.73 (s, 3H),
Ethyl 7,8-dimethoxy-2-methylpyrazolo[1,5-a]quinoline-3-car-
2.51 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3, boxylate (4na). Yield: 36%. White solid. Mp. 150–152 °C. IR
100 MHz) δ 164.33, 154.01, 139.90, 134.90, 132.14, 131.46, (neat): νmax/cm−1 1692, 1247, 1112. H-NMR (CDCl3, 400 MHz)
1
127.83, 127.62, 123.43, 116.80, 115.60, 103.75, 59.76, 21.12, δ 8.00 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H),
14.50, 14.49. MS (EI+) m/z 268 [M]+, 223 [base]+. HR-MS (ESI) 7.26 (s, 1H), 7.16 (s, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.11 (s, 3H),
calcd for C16H17N2O2 (M + H)+ requires 285.1290, found 4.01 (s, 3H), 2.75 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). 13C-NMR
269.1292. Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, (CDCl3, 100 MHz) δ 164.41, 154.11, 152.09, 147.86, 139.77,
10.44. Found: C, 71.41; H, 5.88; N, 10.42.
129.46, 127.01, 117.29, 114.67, 107.84, 103.10, 97.43, 59.69,
Ethyl 9-methoxy-2-methylpyrazolo[1,5-a]quinoline-3-carboxy- 56.50, 56.12, 14.53. HR-MS (ESI) calcd for C17H19N2O4 [M + H]+
late (4ja). Yield: 52%. White solid. Mp. 101–105 °C. IR (neat): requires 315.1345, found 315.1345. Anal. Calcd for
1
νmax/cm−1 1697, 1566, 1271, 1098. H-NMR (CDCl3, 400 MHz) C17H20N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C, 64.71; H,
δ 8.15 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.44–7.43 (m, 5.79; N, 8.74.
2H), 7.28–7.25 (m, 1H), 4.41 (q, J = 7.2 Hz, 2H), 4.14 (s, 3H),
3-Cyano-2-methylpyrazolo[1,5-a]quinoline (4ad). Yield: 34%.
2.79 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). 13C-NMR (CDCl3, White solid. Mp. 160–161 °C. IR (neat): νmax/cm−1 1614, 1471,
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1
1304, 804, 756, 744. H-NMR (CDCl3, 400 MHz) δ 8.55 (d, J = 133.81, 130.10, 128.38, 128.17, 125.12, 123.05, 116.34, 115.83,
8.5 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.78–7.73 (m, 1H), 7.71 (d, 103.25, 60.15, 14.52, 13.75. MS (EI+) m/z 286 [M] +. HR-MS
J = 9.2 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.56–7.51 (m, 1H), 2.64 (ESI) calcd for C15H15N2O2S [M + H]+ requires 286.0864, found
(s, 3H). 13C-NMR (CDCl3, 100 MHz) δ 152.73, 139.75, 134.77, 287.0854. Anal. Calcd for C15H14N2O2S: C, 62.92; H, 4.93; N,
129.61, 128.53, 125.84, 124.65, 123.23, 115.98, 114.81, 77.21, 9.78. Found: C, 62.73; H, 4.91; N, 9.87.
54.96, 14.35. MS (EI+) m/z 207 [M] +. HR-MS (ESI) calcd for
Ethyl 2-(methylthio)-4-methyl-pyrazolo[1,5-a]quinoline-3-car-
boxylate (4ak). Yield: 47%. Pale yellow solid. Mp. 112–114 °C.
C13H10N3 [M + H]+ requires 208.0875, found 208.0880.
3-Chloro-2-methylpyrazolo[1,5-a]quinoline (4af). Yield: 6%. IR (neat): νmax/cm−1 1713, 11525, 1078. 1H-NMR (CDCl3,
White solid. Mp. 91–95 °C. IR (neat): νmax/cm−1 1487, 1310, 400 MHz) δ 8.56 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H),
1
801, 747. H-NMR (CDCl3, 400 MHz) δ 8.48 (d, J = 8.5 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H),
7.74 (d, J = 7.7 Hz, 1H), 7.67–7.63 (m, 1H), 7.45–7.34 (m, 2H), 4.41 (q, J = 7.2 Hz, 2H), 2.77 (s, 3H), 2.72 (s, 3H), 1.45 (t, J =
7.35 (d, J = 9.2 Hz, 1H), 2.51 (s, 3H). 13C-NMR (CDCl3, 7.2 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ 163.48, 154.91,
100 MHz) δ 147.82, 135.00, 134.55, 129.65, 128.55, 125.03, 140.51, 132.73, 129.02, 127.85, 127.16, 126.73, 125.08, 122.98,
124.66, 123.06, 114.75, 114.02, 102.13, 11.67. MS (EI+) m/z 216 115.88, 105.07, 60.54, 21.85, 14.39, 14.26. HR-MS (ESI) calcd
[M]+, 140 [base]+. HR-MS (ESI) calcd for C12H10N2Cl [M + H]+ for C16H17N2O2S [M + H]+ requires 301.1011, found 301.1012.
requires 217.0533, found 217.0532.
Anal. Calcd for C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33. Found:
3-Bromo-2-methylpyrazolo[1,5-a]quinoline
(4ag). Yield: C, 63.91; H, 5.32; N, 9.35.
58%. White solid. Mp. 116–118 °C. IR (neat): νmax/cm−1 1478,
Ethyl 2-trifluoromethyl-pyrazolo[1,5-a]quinoline-3-carboxy-
1305, 802, 743. 1H-NMR (CDCl3, 400 MHz) δ 8.49 (d, J = 8.5 Hz, late (4al). Yield: 71%. Pale yellow solid. Mp. 78–79 °C. IR
1H), 7.74 (d, J = 7.7 Hz, 1H), 7.67–7.63 (m, 1H), 7.45–7.40 (m, (neat): νmax/cm−1 1124, 811. H-NMR (CDCl3, 400 MHz) δ 8.63
1
2H), 7.33 (d, J = 9.6 Hz, 1H), 2.51 (s, 3H). 13C-NMR (CDCl3, (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 7.9 Hz, 1.1 Hz, 1H), 7.73–7.69
100 MHz) δ 149.35, 136.59, 134.54, 129.61, 128.51, 125.35, (m, 1H), 7.547.25 (m, 3H), 6.86 (s, 1H). 13C-NMR (CDCl3,
124.63, 123.07, 114.74, 114.62, 87.81, 12.60. MS (EI+) m/z 260 100 MHz) δ 143.89 (q, JCF, 38.2 Hz), 138.63, 134.45, 129.80,
2
[M − 1]+, 140 [base]+. HR-MS (ESI) calcd for C12H10N2Br [M + 128.45, 125.98, 125.86, 123.66, 121.60 (q, JCF, 272.0 Hz),
1
H]+ requires 261.0027, found 261.0032. Anal. Calcd for 116.38, 116.00, 98.01 (q, JCF, 2.0 Hz). HR-MS (ESI) calcd for
3
C12H9N2Br: C, 55.20; H, 3.47; N, 10.73. Found: C, 55.28; H, C12H8N2F3 [M + H]+ requires 237.0640, found 237.0643.
3.58; N, 10.74.
Ethyl 2-methylpyrazolo[1,5-a][1,8]naphthyridine-3-carboxy-
3-Iodo-2-methylpyrazolo[1,5-a]quinoline (4ah). Yield: 12%. late (8aa). Yield: 51% (for 6a), 41% (for 6b). White solid.
White solid. Mp. 135–138 °C. IR (neat): νmax/cm−1 1614, 1472, Mp. 125–129 °C. IR (neat): νmax/cm−1 1700, 1619, 1550, 1414,
1
1
1303, 803, 755, 743. H-NMR (CDCl3, 400 MHz) δ 8.50 (d, J = 1109. H-NMR (CDCl3, 400 MHz) δ 8.88 (dd, J = 4.6 Hz, 1.9 Hz,
8.5 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.67–7.62 (m, 1H), 1H), 8.18 (dd, J = 7.7 Hz, 1.9 Hz, 1H), 8.15 (d, J = 9.5 Hz, 1H),
7.46–7.39 (m, 2H), 7.29 (d, J = 9.2 Hz, 1H), 2.53 (s, 3H). 7.61 (d, J = 9.5 Hz, 1H), 7.51 (dd, J = 9.4 Hz, 4.6 Hz, 1H), 4.42 (q,
13C-NMR (CDCl3, 100 MHz) δ 154.72, 141.61, 134.17, 130.69, J = 7.3 Hz, 2H), 2.79 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H). 13C-NMR
128.74, 128.71, 125.80, 123.37, 115.94, 114.16, 85.03, 13.14. MS (CDCl3, 100 MHz) δ 163.98, 155.37, 150.58, 143.87, 142.03,
(EI+) m/z 308 [M]+. HR-MS (ESI) calcd for C12H10N2I [M + H]+ 137.11, 126.55, 121.37, 118.38, 118.26, 105.37, 60.05, 14.63,
requires 308.9889, found 308.9893. Anal. Calcd for C12H9N2I: 14.41. MS (EI+) m/z 255 [M]+, 210 [base]+. HR-MS (ESI) calcd for
C, 46.78; H, 2.94; N, 9.09. Found: C, 46.63; H, 3.13; N, 9.11.
C14H13N3O2Na [M + H]+ requires 278.0905, found 278.0903.
Ethyl pyrazolo[1,5-a]quinoline-3-carboxylate (4ai). Yield:
Ethyl 2-methylpyrazolo[1,5-a][1,7]naphthyridine-3-carboxy-
10%. Pale yellow solid. Mp. 101–102 °C. IR (neat): νmax/cm−1 late (8ca). Pale brown solid. Mp. 118–120 °C. IR (neat): νmax
/
1
1
1703, 1244, 1218, 1097. H-NMR (CDCl3, 400 MHz) δ 8.62 (d, cm−1 1695, 1549, 1431, 1276, 1128. H-NMR (CDCl3, 400 MHz)
J = 8.5 Hz, 1H), 8.44 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.84 (d, J = δ 9.94 (s, 1H), 8.68 (d, J = 5.4 Hz, 1H), 8.24 (d, J = 9.3 Hz, 1H),
8.0 Hz, 1H), 7.76–7.72 (m, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.53 (t, 7.64 (d, J = 5.4 Hz, 1H), 7.59 (d, J = 9.3 Hz, 1H), 4.41 (q, J = 7.3
J = 7.3 Hz, 1H), 4.41 (q, J = 7.3 Hz, 2H), 1.43 (t, J = 7.3 Hz, 3H). 2H), 2.75 (s, 3H), 1.45 (t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3,
13C-NMR (CDCl3, 100 MHz) δ 163.57, 143.52, 139.08, 134.40, 100 MHz) δ 163.82, 154.86, 144.47, 140.28, 139.68, 129.33,
130.15, 128.47, 128.13, 125.61, 123.60, 116.72, 116.01, 106.55, 127.81, 125.53, 121.89, 120.54, 105.34, 60.13, 14.46, 14.45; EI+
60.12, 14.50. MS (EI+) m/z 240 [M]+, 195 [base]+; HR-MS (ESI) m/z 255 [M]+, 210 [base]+; HR-MS (ESI) calcd for C14H14N3O2
calcd for C14H13N2O2 [M + H]+ requires 241.0977, found (M + H)+ requires 256.1086, found 256.1085.
241.0972. Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N,
11.66. Found: C, 69.96; H, 4.93; N, 11.73.
Ethyl 1,3,7-trimethyl-1H-dipyrazolo[1,5-a:4′,3′-e]pyridine-6-
carboxylate (9aa). Yield: 49%. White solid. Mp. 140–142 °C. IR
Ethyl 2-(methylthio)pyrazolo[1,5-a]quinoline-3-carboxylate (neat): νmax/cm−1 1698, 1632, 1505, 1267, 1106. 1H-NMR
(4aj). Yield: 79%. Pale yellow solid. Mp. 115–117 °C. IR (neat): (CDCl3, 400 MHz) δ 7.72 (d, J = 9.3 Hz, 1H), 7.50 (d, J = 9.3 Hz,
1
νmax/cm−1 1695, 1614, 1105. H-NMR (CDCl3, 400 MHz) δ 8.57 1H), 4.50 (s, 3H), 4.40 (q, J = 7.3 Hz, 2H), 2.70 (s, 3H), 2.52 (s,
(d, J = 8.5 Hz, 1H), 8.00 (d, J = 9.4 Hz, 1H), 7.81 (d, J = 7.7 Hz, 3H), 1.44 (t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3, 100 MHz)
1H), 7.73–7.69 (m, 1H), 7.66 (d, J = 9.4 Hz, 1H), 7.50–7.47 (m, δ 164.29, 155.08, 142.95, 142.50, 135.62, 121.51, 110.53,
1H), 4.42 (q, J = 7.3 Hz, 2H), 2.73 (s, 3H), 1.45 (t, J = 7.3 Hz, 110.08, 102.00, 64.00, 59.83, 38.05, 14.58, 14.49, 12.09. MS
3H). 13C-NMR (CDCl3, 100 MHz) δ 163.59, 154.87, 140.75, (EI+) m/z 272 [M]+. HR-MS (ESI) calcd for C14H17N4O2 [M + H]+
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requires 273.1352, found 273.1349. Anal. Calcd for
C14H16N4O2: C, 61.75; H, 5.92; N, 20.58. Found: C, 61.73; H,
5.76; N, 20.54.
M. L. Hammond, J. R. Tata and S. L. Colletti, J. Med. Chem.,
2009, 52, 2587.
3 S. Philipp, H. Holger, J. Dominik. D. Christof, G. Anja and
B. Esther, (Merck Patent GmbH., Germany). PCT Int. Appl.,
WO 2010086089 A1 20100805, 2010.
Ethyl 1-benzyl-3,7-dimethyl-1H-dipyrazolo[1,5-a:4′,3′-e]pyri-
dine-6-carboxylate
(9ba). Yield:
27%.
White
solid.
Mp. 128–130 °C. IR (neat): νmax/cm−1 1699, 1627, 1505, 1252,
1119, 1088. 1H-NMR (CDCl3, 400 MHz) δ 7.75 (d, J = 9.2 Hz,
1H), 7.52(d, J = 9.2 Hz, 1H), 7.40 (d, J = 7.7 Hz, 2H), 7.30–7.21
(m, 3H), 6.13 (s, 2H), 4.40 (q, J = 7.3 Hz, 2H), 2.71 (s, 3H), 2.52
(s, 3H), 1.43 (t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3, 100 MHz)
δ 164.35, 155.12, 143.80, 142.62, 137.31, 135.29, 128.55,
128.18, 127.73, 121.52, 110.74, 110.35, 102.74, 59.85, 53.85,
14.68, 14.52, 12.18. MS (EI+) m/z 348 [M]+, 91 [base]+; HR-MS
(ESI) calcd for C20H21N4O2 [M + H]+ requires 349.1665, found
349.1663. Anal. Calcd for C20H20N4O2: C, 68.95; H, 5.79; N,
16.08. Found: C, 69.03; H, 5.78; N, 16.08.
4 M. W. Welsch, S. A. Snyder and B. R. Stockwell, Curr. Opin.
Chem. Biol., 2010, 14, 1.
5 (a) Y. Tamura, Y. Miki and M. Ikeda, J. Heterocycl. Chem.,
1975, 12, 119; (b) R. J. Sundberg and J. E. Ellis, J. Heterocycl.
Chem., 1982, 19, 573; (c) Y. Tominaga, Y. Ichihara, T. Mori,
C. Kamio and A. Hosomi, J. Heterocycl. Chem., 1990, 27,
263.
6 Y. Tominaga and A. Hosomi, J. Heterocycl. Chem., 1987, 25,
119.
7 (a) J. J. Mousseau, A. Fortier and A. B. Charette, Org. Lett.,
2010, 12, 516; (b) J. J. Mousseau, J. A. Bull, C. L. Ladd,
A. Fortier, D. S. Roman and A. B. Charette, J. Org. Chem.,
2011, 76, 8243.
Ethyl
1,7-dimethyl-3-(trifluoromethyl)-1H-dipyrazolo[1,5-
a:4′,3′-e]pyridine-6-carboxylate (9ca). Yield: 64%. White solid.
Mp. 148–150 °C. IR (neat): νmax/cm−1 1702, 1509, 1266, 1180,
1120, 1091. 1H-NMR (CDCl3, 400 MHz) δ 7.90 (d, J = 9.6 Hz,
1H), 7.64 (d, J = 9.6 Hz, 1H), 4.63 (s, 3H), 4.41 (q, J = 7.3 Hz,
8 N. Umeda, K. Hirano, T. Satoh, N. Shibata, H. Sato and
M. Miura, J. Org. Chem., 2011, 76, 13.
9 (a) D. Csanyi, G. Timari and G. Hajos, Synth. Commun.,
1999, 29, 3959; (b) J. Zhao, C. Wu, P. Li, W. Ai, H. Chen,
C. Wang, R. C. Larock and F. Shi, J. Org. Chem., 2011, 76,
6837; (c) H. Gnichtel and B. Moeller, Liebigs Ann. Chem.,
1981, 10, 1751.
2H), 2.72 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3,
2
100 MHz) δ 163.84, 155.60, 142.35, 135.64, 135.33 (q, JCF
=
1
39.3 Hz), 121.05 (q, JCF = 269.3 Hz), 120.12, 113.92, 107.93,
103.86, 60.16, 39.47, 14.49, 14.42. MS (EI+) m/z 326 [M]+, 281
[base]+. HR-MS (ESI) calcd for C14H14N4O2F3 [M + H]+ requires 10 A. R. Katritzky, C. A. Ramsden, J. A. Joule and J. A. V.
327.1069, found 327.1064. Anal. Calcd for C14H13N4O2F3: C,
51.54; H, 4.02; N, 17.17. Found: C, 51.36; H, 4.28; N, 17.16.
V. Zhdankin, Reactions of Alkylazoles Involving Traces of
Reactive Anions: Handbook of Heterocyclic Chemistry, Else-
vier, The Netherlands, 3rd edn, 2010, pp. 564–565.
11 Although several new syntheses of aza- or oxa-fused hetero-
cycles based on Knoevenagel condensation have been
reported, most of the methods are required to introduce a
direct-activating group such as –CO2Et and –CN into the
α-position to the reacting methylene for inducing the Knoe-
venagel condensation.15.
Acknowledgements
The authors thank Mr Haruhiko Fukaya (the Analytical Center,
Tokyo University of Pharmacy and Life Sciences) for the X-ray
crystallographic analysis.
12 Recently, Cs2CO3 was reported to be a better base than
K2CO3 in an SNAr reaction of inactivated 2-fluorobenzenes
with 1H-pyrazoles: F. Diness and P. D. Fairlie, Angew.
Chem., Int. Ed., 2012, 51, 8012.
Notes and references
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14 A. Alberola, L. F. Antolin, A. M. Gonzalez, M. A. Laguna and
F. J. Pulido, J. Heterocycl. Chem., 1986, 24, 1035.
15 (a) Q. Cai, Z. Li, L. Fu, D. Pei and K. Ding, Org. Lett., 2010,
12, 1500; (b) Y. L. Choi, H. S. Lim and J.-N. Heo, Org. Lett.,
2012, 14, 5102.
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1178 | Org. Biomol. Chem., 2013, 11, 1171–1178
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