La(OTf)3 catalyzed reaction of salicylaldehyde phenylhydrazones with β-ketoesters and activated alkynes: Facile approach for the preparation of chromenopyrazolones

Article abstract of DOI:10.1039/c6ra21717f

A facile approach has been developed for the preparation of chromenopyrazolones (5a-o, 7a-k) by the reaction of salicylaldehyde phenylhydrazones (3a-o) with β-ketoesters (4a, 4f-g) and activated alkynes (6a-e) in the presence of La(OTf)₃ with good yields. However, the reaction of salicylaldehyde phenylhydrazones (3a, 3c, 3j-k, 3n) with ethyl 4-chloro-3-oxobutanoate (4e) underwent cyclization with reductive dechlorination and provided the methyl chromenopyrazolones instead of chloromethyl chromenopyrazolones. The present solvent free protocol provided the novel heterocyclic compounds.

Full text of DOI:10.1039/c6ra21717f

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ARTICLE TYPE
La(OTf)3 catalyzed reaction of salicylaldehyde phenylhydrazones with
βꢀketoesters and activated alkynes: Facile approach for the preparation
of chromenopyrazolones†
5
Kurma Siva Hariprasadab, Kasagani Veera Prasada, and Bhimapaka China Raju*ab
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
research on βꢀketoesters, we have studied the reactions between
55 salicylaldehydes and βꢀketoesters and described below.
Condensation of salicylaldehydes and ethyl 4ꢀchloroꢀ3ꢀ
oxobutanoate in the presence of piperidine provided 2Hꢀ
chromenes,6a interim these derivatives were successfully
converted to useful heterocyclic compounds.6bꢀe
A facile approach has been developed for the preparation of
chromenopyrazolones (5aꢀo, 7aꢀk) by the reaction of
10 salicylaldehyde phenylhydrazones (3aꢀo) with βꢀketoesters (4a,
4fꢀg) and activated alkynes (6aꢀe) in the presence of La(OTf)3
with good yields. However, the reaction of salicylaldehyde
phenylhydrazones (3a, 3c, 3jꢀk, 3n) with ethyl 4ꢀchloroꢀ3ꢀ
oxobutanoate (4e) underwent cyclization with reductive
15 dechlorination and provided the methyl chromenopyrazolones
instead of chloromethyl chromenopyrazolones. The present
solvent free protocol provided the novel heterocyclic compounds.
60
Further, a systematic study has been conducted for the
preparation of 1Hꢀbenzimidazoles, pyrazolones and pyrazoles by
the
phenylhydrazines
Condensation of salicylaldehydes with ethyl 4,4,4ꢀtrichloroꢀ3ꢀ
condensation
of
with
orthoꢀphenylenediamines
ethyl
and
4ꢀchloroꢀ3ꢀoxobutanoate.6f
65 oxobutanoate in the presence of piperidine provided 2Hꢀ
chromeneꢀ3ꢀcarboxylates.6g Carbonyl compounds with ethyl
Introduction
4,4,4ꢀtrifluoroꢀ3ꢀoxobutanoate provided
a series of (E)ꢀα,βꢀ
unsaturated esters and ketones.6h
20
Activated alkynes7 are also an important reagents and have
70 been utilized for the preparation of various natural products,
carbocyclic and heterocyclic compounds. As part of our work on
Coumarin and its derivatives have been found in many natural
products.1 Coumarin is important heterocycle and is known for
their pharmaceutical and medicinal properties.2 Further, coumarin
compounds commercially exploited as optical brighteners and
25 laser dyes.3 On the other hand, chromenopyrazolones are
activated
alkynes,
we
prepared
2ꢀoxoꢀ2Hꢀ
chromenylpyrazolecarboxylates by [3+2] cycloaddition of 2Hꢀ
chromenophenylhydrazones with diethyl/dimethyl butꢀ2ꢀ
75 ynedioates.8 Aforesaid importance of βꢀketoesters, activated
alkynes and our previous work prompted us to study the reaction
of salicylaldehyde phenylhydrazones with βꢀketoesters and
activated alkynes to prepare novel chromenopyrazolones
(Scheme 1).
important
tricyclic
heteroaromatic
compounds4a
and
benzodiazepine receptor (BZR) ligands. Benzodiazepine
receptors are important tools to find out the physiological
properties and structural requirements for the recognition site of
30 the receptor. Previously, arylpyrazoloquinolinꢀ4ꢀones have been
reported as benzodiazepine receptors.4c A series of 1,4ꢀdihydroꢀ1ꢀ
80
R1
arylꢀ3ꢀmethylbenzopyrano[3,4ꢀd]ꢀpyrazoloꢀ4ꢀones
dihydroꢀ2ꢀarylꢀ3ꢀmethylbenzopyrano[4,3ꢀc]ꢀpyrazoloꢀ4ꢀones
and
2,4ꢀ
O
O
R2
OR4
N
N
R3
have been reported by the reaction of arylhydrazones of 3ꢀacetylꢀ
35 4ꢀhydroxycoumarin.4bꢀd These benzopyranopyrazoloꢀ4ꢀones are
identified as BZR receptors. Wang et al4eꢀf reported 3ꢀmethylꢀ1ꢀ
phenylchromeno[4,3ꢀc]pyrazolꢀ4(1H)ꢀones by the oxidative
cyclization of 3ꢀacylcoumarin hydrazones using CuSO4.5H2O.
Therefore, benzopyranopyrazolones continues to draw
40 considerable attention of synthetic and medicinal chemists.
βꢀKetoesters5 are important reagents utilized for the
preparation of various biologically important heterocyclic
R2
4a, 4f-g
R
O
5a-o
O
R1
85
O
O
NHNH2
R1
N
H
N
O
Cl
CHO
N
OC2H5
CH3
N
4e
R
R
+
R1
R
OH
OH
3a-o
O
1a-i
2a-g
5a, 5c, 5j-k, 5n
R1
R4
90
compounds. βꢀKetoesters bearing electron withdrawing
substituents such as chloro, trichloro and trifluoro groups have
45 the influence in promoting the reactions. As part of our ongoing
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
aNatural Products Chemistry Division, CSIRꢀIndian Institute of Chemical
Technology, Hyderabadꢀ500 007, India. Fax: (+91)ꢀ4027160512,
Eꢀmail: chinaraju@iict.res.in Homepage: http://www.iictindia.org
50 bAcSIRꢀIndian Institute of Chemical Technology, Hyderabadꢀ500 007,
India.
N
N
CO2R5
6a-e
R4
R
O
7a-k
O
95
Scheme 1 Synthesis of chromenopyrazolones 5aꢀo and 7aꢀk.
†Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
100
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Lewis acids such as ZrOCl2 and Cu(OAc)2 did not promote
the reaction (entry 8ꢀ9). Further, we have investigated the effect
of the amount of [20 and 50 mol%] La(OTf)3 at 130 0C. Moderate
yield was obtained when less than 30 mol% of the catalyst was
45 used (entry 12). There is no further improvement in the yield with
an excess mol% of catalyst (entry 14). Next, the reaction of 3a
and 4a was investigated with various solvents (toluene, DCM,
C2H5OH and CH3CN) under reflux conditions in the presence of
La(OTf)3 (30 mol%, Table 1, entry 15ꢀ18). The results of this
Results and discussion
To optimize the reaction conditions, the reaction was studied
by employing a series of catalysts with solvents and under solvent
free conditions. In an initial experiment, we conducted the threeꢀ
component, oneꢀpot reaction of salicylaldehyde (1a, 1 mmol),
phenylhydrazine (2a, 1 mmol) and ethyl 3ꢀoxobutanoate (4a, 1
5
0
mmol) at 130 C without any catalyst. The expected compound
did not formed; however, salicylaldehyde phenylhydrazone was
0
50 study indicated that the conventional heating at 130 C was more
10 obtained. Then the reaction was carried out in the presence of
La(OTf)3 (30 mol%)9 at 130 0C for 8ꢀ10 h. This provided 3ꢀ
methylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀone 5a in 20%
yield.4a The structure of the chromenopyrazolone 5a was well
characterized by FTꢀIR, 1H NMR, 13C NMR and HRMS
15 spectroscopies. The threeꢀcomponent, oneꢀpot reaction provided
the desired compound 5a in fewer yields. Then, we investigated
the reaction of salicylaldehyde phenylhydrazone 3a with ethyl 3ꢀ
oxobutanoate 4a. Accordingly, salicylaldehyde phenylhydrazone
3a was prepared by the reaction of salicylaldehyde (1a, 1 mmol)
20 and phenylhydrazine (2a, 1 mmol) in acetonitrile at room
temperature. The hydrazone 3a (1 mmol) and ethyl 3ꢀ
oxobutanoate 4a (1.2 mmol) were heated at 130 0C in the
presence of La(OTf)3 (30 mol%, Scheme 2). The reaction was
smoothly underwent and provided the chromenopyrazolone 5a in
25 69% yield.
efficient with respect to the reaction time and yield of the product
5a than using organic solvents.
To study the scope and efficiency of this methodology, we
prepared various salicylaldehyde phenylhydrazones 3bꢀo by the
55 reaction of substituted salicylaldehydes (5ꢀmethyl 1b, 4ꢀmethoxy
1c, 5ꢀfluoro 1d, 5ꢀchloro 1e, 5ꢀbromo 1f, 3,5ꢀdichloro 1g, 3,5ꢀ
dibromo 1h and 3ꢀbromoꢀ5ꢀchloro 1i) with phenylhydrazine
hydrochlorides (4ꢀmethoxy 2b, 2ꢀmethyl 2c, 4ꢀmethyl 2d, 3,4ꢀ
dimethyl 2e, 4ꢀchloro 2f and 3,4ꢀdichloro 2g). Thus, obtained
60 hydrazones 3bꢀo were reacted with ethyl 3ꢀoxobutanoate 4a in
the presence of La(OTf)3 at 130 0C to provide corresponding
chromenopyrazolones 5bꢀo (Table 2). The newly prepared
compounds 5bꢀo are well characterized by spectral data (see
ESI). Under these conditions, salicylaldehyde phenylhydrazones
65 such as 2,4ꢀdihydroxy 3p, 2ꢀhydroxyꢀ5ꢀnitro 3q, 4ꢀ(benzyloxy)ꢀ
2ꢀhydroxy 3r and 4ꢀ(allyloxy)ꢀ2ꢀhydroxy 3s did not provided the
corresponding chromenopyrazolones.
Scheme 2 Preparation of chromenopyrazolone 5a.
In order to find out the best catalyst to provide target
30 compound 5a, the reaction of 3a (1 mmol) and 4a (1.2 mmol)
have been investigated with various catalysts such as protic acids
(Table 1, entries 1ꢀ2), pꢀTsOH (entry 3) and Lewis acids (entries
0
4ꢀ14) at 130 C. La(OTf)3 provided the compound 5a in better
yield when compared to other Lewis acids (entry 13). Lanthanide
35 triflates9 are new type of Lewis acids different from typical Lewis
acids such as AlCl3, BF3, and SnCl4 etc. La(OTf)3 is quite stable,
highly effective even in aqueous media and reusable catalyst for
several important carbonꢀcarbon bond forming reactions.
Table 1 Optimization of reaction conditions for the preparation of 5a
___________________________________________________________________
N
H
O
O
N
N
N
O
+
H3C
OC2H5
CH3
OH
3a
O
4a
5a
__________________________________________________________________
Entry
Catalyst
Quantity (equiv.)
Time (h)
Yield (%)e
Solvent
70
___________________________________________________________________
A plausible mechanism was depicted in scheme 3. The enol
formation of βꢀketoesters could significantly catalyze by
Lanthanide triflates.9 The addition reaction between enol of βꢀ
ketoesters and salicylaldehyde phenylhydrazone provides the
---
1
AcOH
H2SO4
2.0
---a
10
---b
---
---
54
57
51
49
---
---
53
45
52
69
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
0.3
0.3
0.3
1.0
0.3
0.3
0.2
0.3
18
24
10
10
10
10
24
24
10
10
10
08
---c
---c
p-TsOH
AlCl3
FeCl3
InCl3
---c
---c
---c
75 intermediate
ethyl
2ꢀ((2ꢀhydroxyphenyl)(2ꢀ
SnCl2
phenylhydrazinyl)methyl)ꢀ3ꢀoxobutanoate by the elimination of
ethyl alcohol. Further, the La(OTf)3 coꢀordinates between the
amine and carbonyl carbon. Finally, intramolecular cyclization
and aromatization provides the chromenopyrazolones by the
80 elimination of hydrogen and water.
---c
ZrOCl2.8H2O
Cu(OAc)2
Sc(OTf)3
Bi(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
---c
---c
---c
9
10
11
12
13
14
15
16
17
18
---c
---c
---c
0.5
0.3
0.3
0.3
10
24
24
24
69
59
53
60
Toluened
DCMd
Ethanold
CH3CNd
La(OTf)3
0.3
24
48
__________________________________________________________________
a110 oC, broom temperature, c130 oC, dreflux, eisolated yields
40
2
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50 Scheme 5 Reaction of 3a with βꢀketoesters 4bꢀh.
The cyclization and reductive dechlorination reaction
prompted us to investigate further with various salicylaldehyde
phenylhydrazones. Accordingly, we have carried out the reaction
55 of various salicylaldehyde phenylhydrazones (3a, 3c, 3jꢀk, 3n)
with ethyl 4ꢀchloroꢀ3ꢀoxobutanoate 4e in the presence of
La(OTf)3 at 130 C. All these reactions were preceded smoothly
and provided the corresponding chromenopyrazolones (5a, 5c,
5jꢀk, 5n) in good yields (Table 3).
Scheme 3 Plausible catalytic cycle for the preparation of 5a.
5
Having achieved the preparation of chromenopyrazolone 5a
under conventional method, next, we attempted the reaction of 3a
with 4a under microwave conditions. Accordingly,
salicylaldehyde phenylhydrazone 3a (1 mmol), ethyl 3ꢀ
oxobutanoate 4a (1.2 mmol) and La(OTf)3 (30 mol%) were
10 adsorbed on neutral Al2O3 and subjected to microwave irradiation
(180 W, Scheme 4). The progress of the reaction was monitored
by TLC (16 min). The usual work up and after column
chromatography purification compound 5a afforded in 55% yield.
0
60
15
Scheme
4
Microwave
assisted
preparation
of
chromenopyrazolone 5a.
20
Further, we have investigated the electron donating 3b, 3c and
withdrawing substitutents 3dꢀf present on salicylaldehyde moiety
of salicylaldehyde phenylhydrazones with 4a under microwave
conditions (8ꢀ20 mins). The chromenopyrazolones 5b (48%), 5c
(52%), 5d (64%), 5e (65%) and 5f (64%) were obtained in good
Having achieved the preparation of chromenopyrazolones 5aꢀ
o, next, we extended this protocol to investigate 3a with activated
65 alkyne such as diethyl butꢀ2ꢀynedioate 6a. Accordingly,
salicylaldehyde phenylhydrazone 3a and diethyl butꢀ2ꢀynedioate
25 to moderate yields. Next, we have investigated the electron
donating 3j, 3l and withdrawing substitutents 3n present on
phenylhydrazone moiety of salicylaldehyde phenylhydrazones
with 4a. However, these reactions did not go smoothly and
moreover multiple spots were observed. Therefore, we have
30 chosen the conventional method for the preparation of
chromenopyrazolones by the reaction of salicylaldehyde
phenylhydrazones with other βꢀketoesters and activated alkynes
were discussed below.
0
6a were heated at 130 C in the presence of La(OTf)3 (30 mol%,
Scheme 6). The reaction proceeded smoothly and provided ethyl
4ꢀoxoꢀ2ꢀphenylꢀ2,4ꢀdihydrochromeno[4,3ꢀc]pyrazoleꢀ3ꢀ
70 carboxylate 7a. The compound 7a is new and well characterized
by spectral data.
35
The reaction of salicylaldehyde phenylhydrazone 3a with
various βꢀketoesters such as ethyl 3ꢀoxoꢀ3ꢀphenylpropanoate 4b,
ethyl 4,4,4ꢀtrifluoroꢀ3ꢀoxobutanoate 4c, ethyl 4,4,4ꢀtrichloroꢀ3ꢀ
oxobutanoate 4d, ethyl 4ꢀchloroꢀ3ꢀoxobutanoate 4e, ethyl 2ꢀ
chloroꢀ3ꢀoxobutanoate 4f, 2ꢀmethoxy ethyl 3ꢀoxobutanoate 4g
Scheme 6 Preparation of chromenopyrazoleꢀ3ꢀcarboxylate 7a.
40 and diethyl malonate 4h in the presence of La(OTf)3 (30 mol%) at
130 C (Scheme 5). The βꢀketoesters 4e, 4f and 4g facilitated the
0
75
The result encouraged us to carry out the reaction of
salicylaldehyde phenylhydrazones with various activated alkynes
6aꢀe (Table 4). Accordingly, salicylaldehyde phenylhydrazone 3a
reacted with alkynes such as diethyl butꢀ2ꢀynedioate 6a, dimethyl
butꢀ2ꢀynedioate 6b, ethyl propiolate 6c, ethyl butꢀ2ꢀynoate 6d
reaction and provided the chromenopyrazolone 5a in good yield.
However, phenyl, trifluoro and trichloro oxobutanoates 4bꢀd and
diethyl malonate 4h did not provided the chromenopyrazolones.
45 Interestingly, the reaction of 3a with ethyl 4ꢀchloroꢀ3ꢀ
oxobutanoate 4e underwent cyclization with reductive
dechlorination and provided 5a.
80 and ethyl 3ꢀphenylpropiolate 6e under optimized conditions. All
these reactions provided the chromenopyrazoleꢀ3ꢀcarboxylates
7bꢀe. Next, we have carried out the reaction of salicylaldehyde
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phenylhydrazones 3bꢀc, 3fꢀg, 3l and 3n with diethyl butꢀ2ꢀ
ynedioate 6a under optimized conditions provided 7fꢀk. All these
on Avance 300, 400 and 500 MHz spectrometer in CDCl3 using
TMS as internal standard. IR spectra were recorded on Nicollet
reactions underwent smoothly and provided the corresponding 45 Nexus 670 FT spectrometer. ESIꢀMS obtained on quarto micro
chromenopyrazoleꢀ3ꢀcarboxylates 7bꢀk. All the compounds are
well characterized by spectral data.
spectrometer. HRMS were measured on Agilent Technologies
6510, QꢀTOFLC/MS ESIꢀTechnique. Melting points were
determined in open glass capillary tubes on a Stuart melting point
apparatus and are uncorrected.
General procedure for the preparation of 2ꢀ((2ꢀ
phenylhydrazono)methyl)phenols (3aꢀo). Phenylhydrazine (2a,
1 equiv.) was added to a stirred solution of salicylaldehyde (1a, 1
equiv.) in CH3CN at room temperature. The contents were stirred
at the same temperature. The reaction was monitored by TLC,
5
Table 4 Preparation of chromenopyrazole-3-carboxylates 7a-k
_______________________________________________________________________
R
50
COOR2
H
N
N
N
R1
La(OTf)3
130 o
N
R
+
O
OH
3a-c, 3f-g, 3l, 3n
R1
C
R3
R3
7a-k
O
6a-e
_______________________________________________________________________
55 after the completion of the reaction (2 h); the solvent was
removed under reduced pressure. The residue was purified by
Compound Yield(%)a
R1
R2
R3
Entry
_______________________________________________________________________
R
recrystallization
with
hexane
afforded
2ꢀ((2ꢀ
C2H5
CH3
CO2C2H5
CO2CH3
1
2
7a
7b
64
65
H
H
H
H
phenylhydrazono)methyl)phenol 3a as colourless solid in 95%
yield. The salicylaldehyde phenylhydrazones 3bꢀo were prepared
60 by the reaction of substituted salicylaldehydes 3aꢀi with
phenylhydrazines 2aꢀg.
C2H5
C2H5
3
4
7c
68
65
H
H
H
H
H
CH3
7d 5a
/
General procedure for the preparation of 3ꢀmethylꢀ2ꢀ
phenylchromenoꢀ[4,3-c]pyrazolꢀ4(2H)ꢀones (5aꢀo). La(OTf)3
C2H5
C2H5
5
6
7e
7f
67
51
H
H
H
Ph
4-OCH3
CO2C2H5
(0.3
equiv.)
was
added
to
the
2ꢀ((2ꢀ
5-CH3
C2H5
CO2C2H5
7g
7
H
H
54
65 phenylhydrazono)methyl)phenol (3a, 1 equiv.) and ethyl 3ꢀ
oxobutanoate (4a, 1.2 equiv.) at room temperature. The contents
were heated to 130 °C for 8ꢀ10 h. After completion of the
reaction (TLC), the residue was purified by column
chromatography by using silica gel (60:120, ethyl acetate/hexane
C2H5
C2H5
C2H5
C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
7h
7i
8
5-Br
5-Cl
H
67
65
74
77
9
H
10
Cl
7j
70 5:95)
afforded
3ꢀmethylꢀ2ꢀphenylchromenoꢀ[4,3ꢀc]pyrazolꢀ
CH3
11
7k
H
_______________________________________________________________________
4(2H)ꢀone 5a as colourless solid. The substituted 3ꢀmethylꢀ2ꢀ
phenylchromenoꢀ[4,3ꢀc]pyrazolꢀ4(2H)ꢀones 5bꢀo were prepared
by the reaction of 2ꢀ((2ꢀphenylhydrazono)methyl)phenols 3aꢀo
with ethyl 3ꢀoxobutanoate 4a under optimized conditions.
aIsolated yields
Conclusions
10
75
3ꢀMethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀone
(5a).
In summary, a facile and solvent free method was developed
for the preparation of chromenopyrazolones by the reaction of
salicylaldehyde phenylhydrazones with βꢀketoesters and activated
alkynes. The interesting reaction between salicylaldehyde
Yield: 69%, 8 h; colorless solid; mp 208ꢀ210 °C; FTꢀIR (KBr):
1
3059, 1741, 1594, 1485, 1456, 1197, 1041, 754, 700 cmꢀ1; H
NMR (500 MHz, CDCl3): δ 8.12 (dd, J = 7.8, 1.6 Hz, 1H
aromatic), 7.61ꢀ7.51 (m, 5H, aromatic), 7.48 (ddd, J = 8.7, 7.3,
15 phenylhydrazones and ethyl 4ꢀchloroꢀ3ꢀoxobutanoate underwent
cyclization with reductive dechlorination and provided the methyl
80 1.6 Hz, 1H, aromatic), 7.39 (dd, J = 8.3, 0.9 Hz, 1H, aromatic),
7.31 (td, J = 7.6, 1.1 Hz, 1H, aromatic), 2.75 (s, 3H, CH3) ppm;
13C NMR (75 MHz, CDCl3): δ 158.9, 153.13, 148.70, 144.52,
138.45, 130.42, 129.59, 129.42, 125.60, 124.44, 122.80, 117.55,
115.00, 106.49, 12.07 ppm; MS (ESI): (m/z) 277 [M+H]+; HRMS
85 (ESI): (m/z) calcd for C17H13N2O2 [M+H]+ 277.0971, Found:
277.0966.
7ꢀMethoxyꢀ3ꢀmethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀ
one (5b). Yield: 62%, 9 h; colorless solid; mp 204ꢀ206 °C; FTꢀIR
(KBr): 3074, 2966, 2841, 1744, 1514, 1491, 1250, 1199, 1171,
90 1043, 975, 759 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J =
8.8 Hz, 1H, aromatic), 7.61ꢀ7.49 (m, 5H, aromatic), 6.91ꢀ6.86 (m,
2H, aromatic), 3.88 (s, 3H, OCH3), 2.73 (s, 3H, CH3) ppm; 13C
NMR (75 MHz, CDCl3): δ 161.54, 159.10, 154.46, 148.85,
144.39, 138.48, 129.42, 125.57, 123.67, 113.89, 112.03, 107.94,
95 105.52, 101.89, 55.65, 12.03 ppm; MS (ESI): (m/z) 307 [M+H]+;
HRMS (ESI): (m/z) calcd for C18H15N2O3 [M+H]+ 307.1077,
Found: 307.1075.
chromenopyrazolone
instead
of
chloromethyl
chromenopyrazolone. This is the first report for the preparation of
chromenopyrazolones by the reaction of salicylaldehyde
20 phenylhydrazones with 3ꢀoxobutanoates and activated alkynes.
The chromenopyrazolones are an important heterocyclic
compounds especially in pharmaceutical and medicinal
chemistry.
25
Experimental section
General
30 Salicylaldehydes, ethyl 3ꢀoxoꢀ3ꢀphenylpropanoate, ethyl 4,4,4ꢀ
trifluoroꢀ3ꢀoxobutanoate, ethyl 4,4,4ꢀtrichloroꢀ3ꢀoxobutanoate,
ethyl 4ꢀchloroꢀ3ꢀoxobutanoate, ethyl 2ꢀchloroꢀ3ꢀoxobutanoate, 2ꢀ
methoxy ethyl 3ꢀoxobutanoate, diethyl butꢀ2ꢀynedioate, dimethyl
butꢀ2ꢀynedioate, ethyl propiolate, ethyl butꢀ2ꢀynoate, ethyl 3ꢀ
35 phenylpropiolate, La(OTf)3, Bi(OTf)3, Sc(OTf)3, and InCl3 were
3,8ꢀDimethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀone
(5c). Yield: 64%, 9 h; colorless solid; mp 197ꢀ199 °C; FTꢀIR
100 (KBr): 2923, 2363, 1740, 1595, 1498, 1199, 1011, 813, 776, 697
1
cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.11 (dd, J = 7.8, 1.5 Hz,
procured
from
SigmaꢀAldrich.
Ethyl
3ꢀoxobutanoate,
1H, aromatic), 7.47 (tt, J = 8.9, 4.5 Hz, 1H, aromatic), 7.43ꢀ7.35
(m, 5H, aromatic), 7.32ꢀ7.28 (m, 1H, aromatic), 2.72 (s, 3H,
CH3), 2.47 (s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δ
105 159.09, 151.16, 148.72, 144.45, 138.43, 134.14, 131.30, 129.47,
125.58, 122.65, 117.21, 114.47, 106.46, 20.86, 12.06 ppm; MS
phenylhydrazine hydrochlorides, Lewis acid catalysts and
solvents were obtained from local suppliers. All the reactions
were monitored by thin layer chromatography (TLC) on preꢀ
40 coated silica gel 60 F254 (mesh); spots were visualized under UV
light. Merck silica gel (100ꢀ200 mesh) was used for column
1
chromatography. H NMR and 13C NMR spectra were recorded
4
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DOI: 10.1039/C6RA21717F
(ESI): (m/z) 291 [M+H]+; HRMS (ESI): (m/z) calcd for 65 (m/z) calcd for C17H11N2O2BrCl [M+H]+ 388.9687, Found:
C18H15N2O2 [M+H]+ 291.1128, Found: 291.1120.
388.9679.
2ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀmethylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀ
one (5j). Yield: 57%, 8.5 h; colorless solid; mp 211ꢀ213 °C; FTꢀ
8ꢀFluoroꢀ3ꢀmethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀ
one (5d). Yield: 71%, 8 h; colorless solid; mp 184ꢀ186 °C; FTꢀIR
(KBr): 3448, 1748, 1598, 1570, 1497, 1465, 1398, 1256, 1130,
5
IR (KBr): 2927, 1740, 1624, 1595, 1501, 1274, 1146, 1117, 1028,
840, 763, 696 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.78 (dd, J = 70 975, 773 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.10 (d, J = 7.8
1
8.2, 3.0 Hz, 1H, aromatic), 7.63ꢀ7.51 (m, 5H, aromatic), 7.36 (dd,
J = 9.1, 4.4 Hz, 1H, aromatic), 7.18 (ddd, J = 9.1, 8.0, 3.0 Hz, 1H,
aromatic), 2.75 (s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δ
Hz, 1H, aromatic), 7.50ꢀ7.41 (m, 3H, aromatic), 7.38 (d, J = 8.3
Hz, 1H, aromatic), 7.29 (dd, J = 13.8, 6.2 Hz, 1H, aromatic),
7.09ꢀ7.03 (m, 2H, aromatic), 3.90 (s, 3H, OCH3), 2.70 (s, 3H,
CH3) ppm; 13C NMR (75 MHz, CDCl3): δ 160.22, 158.95,
10 160.64, 158.51, 157.41, 149.16, 148.05, 144.74, 138.27, 129.60,
125.53, 119.06, 117.77, 117.44, 116.07, 108.73, 106.32, 12.07 75 153.08, 148.45, 144.53, 131.30, 130.33, 126.97, 124.41, 122.75,
ppm; MS (ESI): (m/z) 295 [M+H]+; HRMS (ESI): (m/z) calcd for
C17H12FN2O2 [M+H]+ 295.0877, Found: 295.0869.
8ꢀChloroꢀ3ꢀmethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀ
15 one (5e). Yield: 70%, 8 h; colorless solid; mp 180ꢀ182 °C; FTꢀIR
117.52, 115.03, 114.68, 106.15, 55.72, 11.97 ppm; MS (ESI):
(m/z) 307 [M+H]+; HRMS (ESI): (m/z) calcd for C18H15N2O3
[M+H]+ 307.1077, Found: 307.1074.
3ꢀMethylꢀ2ꢀoꢀtolylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀone
(5k).
(KBr): 3456, 1740, 1595, 1497, 1460, 1396, 1199, 989, 807, 772 80 Yield: 52%, 8.5 h; colorless solid; mp 161ꢀ163 °C; FTꢀIR (KBr):
1
cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.08 (d, J = 2.5 Hz, 1H,
aromatic), 7.62ꢀ7.52 (m, 5H, aromatic), 7.41 (dd, J = 8.8, 2.5 Hz,
1H, aromatic), 7.31 (d, J = 8.8 Hz, 1H, aromatic), 2.74 (s, 3H,
20 CH3) ppm; 13C NMR (75 MHz, CDCl3): δ 158.2, 151.39, 147.58,
3061, 2927, 1729, 1593, 1485, 1502, 1322, 1195, 1168, 1039,
975, 756 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.09 (dd, J = 7.8,
1.6 Hz, 1H, aromatic), 7.48 (ddt, J = 8.8, 7.5, 1.6 Hz, 2H,
aromatic), 7.44ꢀ7.37 (m, 3H, aromatic), 7.33ꢀ7.28 (m, 2H,
144.77, 138.25, 130.36, 129.83, 125.51, 122.42, 118.90, 116.14, 85 aromatic), 2.52 (s, 3H, CH3), 2.11 (s, 3H, CH3) ppm; 13C NMR
106.31, 12.07 ppm; MS (ESI): (m/z) 311 [M+H]+; HRMS (ESI):
(m/z) calcd for C17H12N2O2Cl [M+H]+ 311.0581, Found:
311.0580.
(75 MHz, CDCl3): δ 158.96, 153.11, 148.68, 145.38, 137.16,
135.72, 131.48, 130.43, 127.42, 127.13, 124.44, 122.77, 117.56,
115.08, 17.28, 11.25 ppm; MS (ESI): (m/z) 291 [M+H]+; HRMS
(ESI): (m/z) calcd for C18H15N2O2 [M+H]+ 291.1128, Found
25
8ꢀBromoꢀ3ꢀmethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀ
one (5f). Yield: 71%, 8 h; colorless solid; mp 202ꢀ204 °C; FTꢀIR 90 291.1120.
(KBr): 3061, 2925, 1758, 1592, 1493, 1257, 1199, 1030 983, 810,
762 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.25 (d, J = 2.4 Hz, 1H,
aromatic), 7.61ꢀ7.53 (m, 5H, aromatic), 7.52 (dd, J = 3.5, 2.2 Hz,
3ꢀMethylꢀ2ꢀpꢀtolylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀone
(5l).
Yield: 48%, 8 h; colorless solid; mp 209ꢀ211 °C; FTꢀIR (KBr):
2921, 1735, 1593 1511, 1486, 1450, 1396, 1325, 1199, 1041,
975, 825, 765 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.11 (dd, J =
30 1H, aromatic), 7.28ꢀ7.26 (m, 1H, aromatic), 2.74 (s, 3H, CH3)
ppm; 13C NMR (75 MHz, CDCl3): δ 158.24, 151.91, 147.50, 95 7.8, 1.5 Hz, 1H, aromatic), 7.49ꢀ7.44 (m, 1H, aromatic), 7.43ꢀ
144.79, 138.24, 133.18, 129.61, 125.51, 119.24, 117.26, 116.62,
106.35, 12.08 ppm; MS (ESI): (m/z) 355 [M+H]+; HRMS (ESI):
(m/z) calcd. for C17H12N2O2Br [M+H]+ 355.0076, Found:
35 355.0075.
7.35 (m, 5H, aromatic), 7.32ꢀ7.27 (m, 1H, aromatic), 2.72 (s, 3H,
CH3), 2.47 (s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δ
158.93, 153.06, 148.50, 144.43, 139.6, 135.91, 130.21, 125.38,
124.39, 122.76, 117.50, 115.01, 106.27, 21.29, 12.03 ppm; MS
100 (ESI): (m/z) 291 [M+H]+; HRMS (ESI): (m/z) calcd for
C18H15N2O2 [M+H]+ 291.1128, Found: 291.1123.
6,8ꢀDichloroꢀ3ꢀmethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ
4(2H)ꢀone (5g). Yield: 74%, 8 h; colorless solid; mp 205ꢀ207 °C;
FTꢀIR (KBr): 3071, 2923, 1744, 1589, 1552, 1496, 1400, 1001,
2ꢀ(3,4ꢀDimethylphenyl)ꢀ3ꢀmethylchromeno[4,3ꢀc]pyrazolꢀ
4(2H)ꢀone (5m). Yield: 57%, 8 h; colorless solid; mp 158ꢀ160 °C;
FTꢀIR (KBr): 3075, 2922, 1737, 1595, 1501, 457, 1383, 1197,
1
862, 767, 693 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.01 (d, J =
40 2.4 Hz, 1H, aromatic), 7.61ꢀ7.53 (m, 6H, aromatic), 2.75 (s, 3H,
CH3) ppm; 13C NMR (75 MHz, CDCl3): δ 156.89, 147.33, 105 1154, 820, 746 cmꢀ1; 1H NMR (300 MHz, CDCl3); δ 8.11 (dd, J =
145.11, 138.14, 130.50, 129.67, 125.50, 123.23, 120.94, 117.23,
106.23, 12.12 ppm; MS (ESI): (m/z) 345 [M+H]+; HRMS (ESI):
(m/z) calcd for C17H11N2O2Cl2 [M+H]+ 345.0192, Found:
45 345.0190.
7.7, 1.4 Hz, 1H, aromatic), 7.52ꢀ7.43 (m, 1H, aromatic), 7.38 (d,
J = 7.5 Hz, 1H, aromatic), 7.32ꢀ7.21 (m, 4H, aromatic), 2.71 (s,
3H, CH3), 2.36 (s, 6H, 2CH3) ppm; 13C NMR (75 MHz, CDCl3):
δ 159.04, 153.09, 144.43, 136.10, 130.43, 130.30, 126.62,
110 122.79, 117.52, 115.08, 106.19, 19.93, 19.63, 12.25 ppm; MS
(ESI): (m/z) 305 [M+H]+; HRMS (ESI): (m/z) calcd for
C19H17N2O2 [M+H]+ 305.1284, Found: 305.1277.
6,8ꢀDibromoꢀ3ꢀmethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ
4(2H)ꢀone (5h). Yield: 76%, 8 h; colorless solid; mp 237ꢀ239 °C;
FTꢀIR (KBr): 2924, 1761, 1576, 1545, 1495, 1454, 1395, 1217,
1
1183, 981, 855, 768 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.24ꢀ
2ꢀ(4ꢀChlorophenyl)ꢀ3ꢀmethylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀ
one (5n). Yield: 50%, 9 h; colorless solid; mp 205ꢀ207 °C; FTꢀIR
50 8.12 (m, 1H, aromatic), 7.86ꢀ7.79 (m, 1H, aromatic), 7.61ꢀ7.52
(m, 5H, aromatic), 2.75 (s, 3H, CH3) ppm; 13C NMR (75 MHz, 115 (KBr): 3074, 2921, 1745, 1597, 1495, 1448, 1393, 1198, 1039,
1
CDCl3): δ 145.07, 138.13, 136.08, 129.68, 125.48, 124.61,
117.58, 117.12, 106.28, 12.14 ppm; MS (ESI): (m/z) 433
[M+H]+; HRMS (ESI): (m/z) calcd for C17H11N2O2Br2 [M+H]+
55 432.9181, Found: 432.9181.
829, 748 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.10 (dd, J = 7.8,
1.5 Hz, 1H, aromatic), 7.58ꢀ7.54 (m, 2H, aromatic), 7.53ꢀ7.47 (m,
3H, aromatic), 7.41ꢀ7.37 (m, 1H, aromatic), 7.35ꢀ7.29 (m, 1H,
aromatic), 2.75 (s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δ
6ꢀBromoꢀ8ꢀchloroꢀ3ꢀmethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ 120 158.76, 153.13, 148.89, 144.56, 136.93, 135.40, 130.61, 129.81,
4(2H)ꢀone (5i). Yield: 79%, 7.5 h; colorless solid; mp 202ꢀ204
°C; FTꢀIR (KBr): 3059, 1747, 1580, 1550, 1500, 1482, 1398,
1225, 1190, 1007, 859, 769 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ
60 8.05 (d, J = 2.4 Hz, 1H, aromatic), 7.69 (d, J = 2.4 Hz, 1H,
126.77, 124.52, 122.80, 117.60, 114.80, 106.74, 12.10 ppm; MS
(ESI): (m/z) 311 [M+H]+; HRMS (ESI): (m/z) calcd for
C17H12N2O2Cl [M+H]+ 311.0581, Found: 311.0578.
2ꢀ(3,4ꢀDichlorophenyl)ꢀ3ꢀmethylchromeno[4,3ꢀc]pyrazolꢀ
aromatic), 7.60ꢀ7.53 (m, 5H, aromatic), 2.75 (s, 3H, CH3) ppm; 125 4(2H)ꢀone (5o). Yield: 46%, 10 h; colorless solid; mp 171ꢀ173
13C NMR (75 MHz, CDCl3): δ 156.92, 148.47, 147.18, 145.06,
138.16, 133.39, 129.97, 129.66, 125.51, 121.58, 117.07, 111.70,
106.22, 12.12 ppm; MS (ESI): (m/z) 389 [M+H]+; HRMS (ESI):
°C; FTꢀIR (KBr): 3069, 2924, 2854, 1745, 1595, 1566, 1482,
1
1320, 1196,1036, 975, 754 cmꢀ1; H NMR (500 MHz, CDCl3): δ
8.07 (dd, J = 7.8, 1.6 Hz, 1H, aromatic), 7.65 (d, J = 2.0 Hz, 1H,
aromatic), 7.51ꢀ7.46 (m, 3H, aromatic), 7.39 (dd, J = 8.4, 1.0 Hz,
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DOI: 10.1039/C6RA21717F
1H, aromatic), 7.33ꢀ7.29 (m, 1H, aromatic), 2.59 (s, 3H, CH3)
ppm; 13C NMR (75 MHz, CDCl3): δ 158.6, 153.19, 146.60,
137.25, 134.61, 133.12, 130.64, 130.30, 128.48, 124.54, 122.88,
117.63, 114.74, 106.10, 11.26 ppm; MS (ESI): (m/z) 345
[M+H]+; HRMS (ESI): (m/z) calcd for C17H11N2O2Cl2 [M+H]+
345.0192, Found: 345.0190.
157.87, 153.07, 149.91, 139.18, 130.67, 129.82, 129.45, 128.59,
124.60, 122.95, 120.39, 117.63, 114.60, 109.43 ppm; MS (ESI):
(m/z) 263 [M+H]+; HRMS (ESI): (m/z) calcd for C16H11N2O2
[M+H]+ 263.0815, Found: 263.0819.
5
70
3ꢀMethylꢀ2ꢀphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀone
(7d).
Yield: 65%, 8 h; colorless solid; mp 208ꢀ210 °C; FTꢀIR (KBr):
1
3059, 1741, 1594, 1485, 1456, 1197, 1041, 754, 700 cmꢀ1; H
General
procedure
for
the
preparation
of
chromenopyrazolones (5a, 5c, 5jꢀk, 5n) by the reaction of
salicylaldehyde phenylhydrazones (3a, 3c, 3jꢀk, 3n) with ethyl
NMR (500 MHz, CDCl3): δ 8.12 (dd, J = 7.8, 1.6 Hz, 1H
aromatic), 7.61ꢀ7.51 (m, 5H, aromatic), 7.48 (ddd, J = 8.7, 7.3,
10 4ꢀchloroꢀ3ꢀoxobutanoate (4e). La(OTf)3 (0.3 equiv.) was added 75 1.6 Hz, 1H, aromatic), 7.39 (dd, J = 8.3, 0.9 Hz, 1H, aromatic),
to the salicylaldehyde phenylhydrazones (3a, 3c, 3jꢀk, 3n, 1
equiv.) and ethyl 4ꢀchloroꢀ3ꢀoxobutanoate (4e, 1.2 equiv.) at
room temperature. The contents were heated to 130 °C for 8ꢀ10 h.
After completion of the reaction (TLC), the residue was purified
7.31 (td, J = 7.6, 1.1 Hz, 1H, aromatic), 2.75 (s, 3H, CH3) ppm;
13C NMR (75 MHz, CDCl3): δ 158.9, 153.13, 148.70, 144.52,
138.45, 130.42, 129.59, 129.42, 125.60, 124.44, 122.80, 117.55,
115.00, 106.49, 12.07 ppm; MS (ESI): (m/z) 277 [M+H]+; HRMS
15 by column chromatography by using silica gel (60:120, ethyl 80 (ESI): (m/z) calcd for C17H13N2O2 [M+H]+ 277.0971, Found:
acetate/hexane 5:95) and afforded chromenopyrazolones (5a, 5c,
5jꢀk, 5n). The compounds are well characterised by spectral data
and these compounds were compared with the compounds
presented in above section.
277.0966.
2,3ꢀDiphenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀone (7e). Yield:
67%, 8 h; colorless solid; mp 228ꢀ230 °C; FTꢀIR (KBr); 3453,
3063, 1734, 1590, 1554, 1493, 1466, 1387, 1331, 1269, 1228,
85 1199, 1123, 1060, 973, 746 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ
8.19 (d, J = 7.7 Hz, 1H, aromatic), 7.52ꢀ7.30 (m, 13H, aromatic)
ppm; 13C NMR (100 MHz, CDCl3): δ 157.75, 152.98, 149.18,
146.09, 139.03, 130.49, 129.91, 129.19, 128.81, 128.36, 126.94,
125.83, 124.36, 122.78, 117.39, 114.72, 106.04 ppm; MS (ESI):
20 General procedure for the preparation of ethyl 4ꢀoxoꢀ2ꢀ
phenylꢀ2,4ꢀdihydrochromeno[4,3ꢀc]pyrazoleꢀ3ꢀcarboxylates
(7aꢀk). La(OTf)3 (0.3 equiv.) was added to the 2ꢀ((2ꢀ
phenylhydrazono)methyl)phenol (3a, 1 equiv.) and diethyl butꢀ2ꢀ
ynedioate (6a, 1.2 equiv.) at room temperature. The contents
25 were heated at 130 °C for 7ꢀ8 h. After completion of the reaction 90 (m/z): 339 [M+H]+; HRMS (ESI): (m/z) calcd for C22H15N2O2
(TLC), the residue was purified by column chromatography by
using silica gel (60:120, ethyl acetate/hexane 5:95) and afforded
[M+H]+ 339.1128, Found: 339.1124.
Ethyl
7ꢀmethoxyꢀ4ꢀoxoꢀ2ꢀphenylꢀ2,4ꢀdihydrochromeno[4,3ꢀ
ethyl
4ꢀoxoꢀ2ꢀphenylꢀ2,4ꢀdihydrochromeno[4,3ꢀc]pyrazoleꢀ3ꢀ
c]pyrazoleꢀ3ꢀcarboxylate (7f). Yield: 51%, 8 h; colorless solid;
mp 188ꢀ190 °C; FTꢀIR (KBr): 3428, 2922, 2852, 1758, 1720,
carboxylate 7a as colourless solid. The substituted ethyl 4ꢀoxoꢀ2ꢀ
30 phenylꢀ2,4ꢀdihydrochromeno[4,3ꢀc]pyrazoleꢀ3ꢀcarboxylates 7bꢀk 95 1627, 1594, 1498, 1462, 1437, 1319, 1266, 1206, 1143, 1031,
1
were
prepared
by
the
reaction
of
2ꢀ((2ꢀ
982, 772 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.03 (d, J = 9.3
Hz, 1H, aromatic), 7.54 (ddd, J = 11.7, 5.1, 2.6 Hz, 5H,
aromatic), 6.91 (dd, J = 4.5, 2.3 Hz, 2H, aromatic), 4.40 (q, J =
7.1 Hz, 2H,CH2), 3.89 (s, 3H, OCH3), 1.27 (t, J = 7.1 Hz, 3H,
phenylhydrazono)methyl)phenols 3aꢀc, 3fꢀg, 3l and 3n with
activated alkynes 6aꢀe under optimized conditions. The spectral
data for 7aꢀk were depicted below.
35
Ethyl 4ꢀoxoꢀ2ꢀphenylꢀ2,4ꢀdihydrochromeno[4,3ꢀc]pyrazoleꢀ3ꢀ 100 CH3) ppm; 13C NMR (125 MHz, CDCl3): δ 161.98, 158.95,
carboxylate (7a). Yield: 64%, 7 h; colorless solid; mp 139ꢀ141
°C; FTꢀIR (KBr): 3431, 3116, 2981, 1762, 1722, 1620, 1594,
1560, 1496, 1448, 1320, 1241, 1138, 1095, 1039, 974, 759 cmꢀ1;
1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = 7.8, 1.5 Hz, 1H,
156.32, 54.46, 149.25, 139.05, 136.20, 135.21, 129.71, 129.34,
124.85, 123.85, 112.40, 106.94, 101.77, 63.06, 55.69, 13.71 ppm;
MS (ESI): (m/z) 387 [M+Na]+; HRMS (ESI): (m/z) calcd for
C20H16N2NaO2 [M+Na]+ 387.0951, Found: 387.0937.
40 aromatic), 7.61ꢀ7.51 (m, 6H, aromatic), 7.41 (d, J = 7.6 Hz, 1H, 105 Ethyl
8ꢀmethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ2,4ꢀdihydrochromeno[4,3ꢀ
aromatic), 7.36ꢀ7.31 (m, 1H, aromatic), 4.41 (q, J = 7.1 Hz, 2H,
CH2), 1.27 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100 MHz,
CDCl3): δ 158.87, 156.05, 153.03, 138.99, 136.26, 130.99,
129.81, 129.36, 124.85, 124.63, 122.94, 117.52, 114.01, 63.11,
c]pyrazoleꢀ3ꢀcarboxylate(7g).Yield: 54%, 8 h; colorless solid;
mp 160ꢀ162 °C; FTꢀIR (KBr): 3442, 2923, 2852, 1735, 1627,
1596, 1500, 1461, 1393, 1306, 1230, 1185, 1124, 1016, 913, 757
cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 7.95 (s, 1H, aromatic), 7.58ꢀ
45 13.70 ppm; MS (ESI): (m/z) 357 [M+Na]+; HRMS (ESI): (m/z) 110 7.53 (m, 5H, aromatic), 7.30 (d, J = 3.7 Hz, 2H, aromatic), 4.40
calcd for C19H14N2NaO4 [M+Na]+ 357.0846, Found: 357.0829.
Methyl 4ꢀoxoꢀ2ꢀphenylꢀ2,4ꢀdihydrochromeno[4,3ꢀc]pyrazoleꢀ
3ꢀcarboxylate (7b). Yield: 65%, 7 h; colorless solid; mp 143ꢀ145
(q, J = 7.1 Hz, 2H, CH2), 2.44 (s, 3H, CH3), 1.27 (t, J = 7.1 Hz,
3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 158.92, 156.25,
151.14, 149.12, 139.02, 134.42, 131.90, 129.77, 129.35, 124.84,
122.79, 120.41, 117.22, 113.55, 108.21, 63.10, 20.83, 13.71 ppm;
°C; FTꢀIR (KBr): 3439, 3060, 1758, 1723, 1618, 1592, 1557,
1
50 1496, 1452, 1323, 1237, 1140, 1094, 1042, 896, 761 cmꢀ1; H 115 MS (ESI): (m/z) 349 [M+H]+; HRMS (ESI): (m/z) calcd for
NMR (400 MHz, CDCl3): δ 8.16 (dd, J = 7.8, 1.5 Hz, 1H,
aromatic), 7.61ꢀ7.49 (m, 6H, aromatic), 7.41 (d, J = 7.6 Hz, 1H,
aromatic), 7.37ꢀ7.31 (m, 1H, aromatic), 3.95 (s, 3H) ppm; 13C
NMR (125 MHz, CDCl3): δ 159.46, 156.08, 138.94, 135.77,
C20H17N2O4 [M+H]+ 349.1183, Found: 349.1179.
Ethyl
8ꢀbromoꢀ4ꢀoxoꢀ2ꢀphenylꢀ2,4ꢀdihydrochromeno[4,3ꢀ
c]pyrazoleꢀ3ꢀcarboxylate (7h).Yield: 67%, 7.5 h; colorless solid;
mp 182ꢀ184 °C; FTꢀIR (KBr): 3429, 2325, 2854, 1724, 1355,
55 131.05, 129.86, 129.42, 124.72, 122.97, 117.54, 113.98, 53.61 120 1598, 1551, 1495, 1463, 1371, 1318, 1276, 1243, 1181, 1099,
ppm; MS (ESI): (m/z) 321 [M+H]+; HRMS (ESI): (m/z) calcd for
C18H13N2O4 [M+H]+ 321.087, Found: 321.0863.
2ꢀPhenylchromeno[4,3ꢀc]pyrazolꢀ4(2H)ꢀone (7c). Yield: 68%,
8 h; colorless solid; mp 207ꢀ209 °C; FTꢀIR (KBr): 3349, 3116,
1033, 984, 757 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J =
2.3 Hz, 1H, aromatic), 7.62ꢀ7.58 (m, 1H, aromatic), 7.56 (m, 5H,
aromatic), 7.29 (d, J = 8.9 Hz, 1H, aromatic), 4.43 (q, J = 7.1 Hz,
2H, CH2), 1.28 (t, J = 7.1 Hz, 3H, CH3) ppm; 13C NMR (100
60 2924, 1731, 1620, 1593, 1561, 1504, 1461, 1428, 1281, 1240, 125 MHz, CDCl3): δ 158.64, 155.42, 151.89, 147.88, 138.85, 136.47,
1188, 1104, 1041, 977, 756 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ
8.69 (s, 1H, hetero aromatic), 8.19 (dd, J = 7.8, 1.6 Hz, 1H,
aromatic), 7.87ꢀ7.82 (m, 2H, aromatic), 7.60ꢀ7.43 (m, 4H,
aromatic), 7.41 (dd, J = 8.3, 1.0 Hz, 1H, aromatic), 7.36 (td, J =
65 7.6, 1.1 Hz, 1H, aromatic) ppm; 13C NMR (125 MHz, CDCl3): δ
133.82, 129.99, 129.42, 125.66, 124.80, 120.42, 119.26, 117.48,
115.69, 63.24, 13.71 ppm; MS (ESI): (m/z) 435 [M+Na]+; HRMS
(ESI): (m/z) calcd for C19H13BrN2NaO4 [M+Na]+ 434.9951,
Found: 434.9954.
6
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DOI: 10.1039/C6RA21717F
Ethyl
8ꢀchloroꢀ4ꢀoxoꢀ2ꢀphenylꢀ2,4ꢀdihydrochromeno[4,3ꢀ
Thavonekham, M. Bo¨s and M. G. Cordingley, Bioorg. Med.
c]pyrazoleꢀ3ꢀcarboxylate (7i). Yield: 65%, 7.5 h; colorless solid; 65 Chem. Lett., 2004, 14, 739; (e) F. Uchiumi, T. Hatano, H. Ito, T.
mp 192ꢀ194 °C; FTꢀIR (KBr): 3103, 3061, 2923, 2852, 1780,
1737, 1618, 1596, 1553, 1495, 1433,1371, 1317, 1249, 1188,
Yoshida and S. Tanuma, Antiviral Res., 2003, 58, 89; (f) D. Yu,
M. Suzuki, L. Xie, S. L. MorrisꢀNatschke and K. H. Lee, Med.
Res. Rev., 2003, 23, 322; (g) A. S. Jeddy and B. L. Gleason,
Ann. Pharmacother., 2003, 37, 1502; (h) G. Pineo and R. D.
1
5
1107, 1018, 985, 758 cmꢀ1; H NMR (500 MHz, CDCl3): δ 8.14
(d, J = 2.5 Hz, 1H, aromatic), 7.56 (d, J = 1.9 Hz, 5H, aromatic),
7.46 (dt, J = 6.2, 3.1 Hz, 1H, aromatic), 7.35 (d, J = 8.9 Hz, 1H, 70 Hull, Hematol. Oncol. Clin. North Am., 2003, 17, 201; (i) J. M.
aromatic), 4.41 (q, J = 7.1 Hz, 2H, CH3), 1.27 (t, J = 7.1 Hz, 3H,
Rollinger, A. Hornick, T. Langer, H. Stuppner and H. Prast, J.
Med. Chem., 2004, 47, 6248; (j) V. Hariprasad, T. T. Talele and
V. M. Kulkarni, Pharm. Pharmacol. Commun., 1998, 4, 365.
3 V. K. Sharma, P. D. Saharo, N. Sharma, R. C. Rastogi, S. K.
CH3) ppm; 13C NMR (125 MHz, CDCl3): δ 158.65, 155.45,
10 151.38, 148.00, 138.84, 136.46, 130.96, 130.12, 129.97, 129.41,
124.79, 122.64, 118.94, 115.24, 108.08, 63.23, 13.71 ppm; MS
(ESI): (m/z) 391 [M+Na]+; HRMS (ESI): (m/z) calcd for 75 Ghoshal and D. Mohan, Spectrochim. Acta A, 2003, 59, 1161.
C19H13ClN2NaO4 [M+H]+ 391.0456, Found: 391.0472.
Ethyl 2ꢀ(4ꢀchlorophenyl)ꢀ4ꢀoxoꢀ2,4ꢀdihydrochromeno[4,3ꢀ
4 (a) Minunni, Gazzetta Chimica Italiana 1925, 55, 535; (b) B.
Chantegrel, A. Nadi and S. Gelin, Tetrahedron Lett., 1983, 24,
381; (c) V. Colotta, L. Cecchi, G. Filacchioni, F. Melani, G.
Palazzino, C. Martini, G. Giannaccini and A. Lucacchini, J.
15 c]pyrazoleꢀ3ꢀcarboxylate (7j). Yield: 74%, 7.5 h; colorless solid;
mp 170ꢀ172 °C; FTꢀIR (KBr): 3078, 2924, 1764, 1720, 1619,
1554, 1495, 1468, 1443, 1321, 1276, 1242, 1191, 1138, 1093, 80 Med. Chem., 1988, 31, 1; (d) V. Colotta, L. Cecchi, F. Melani,
1036, 979 cmꢀ1; 1H NMR (500 MHz, CDCl3): δ 8.12 (dd, J = 7.8,
1.4 Hz, 1H, aromatic), 7.55ꢀ7.50 (m, 5H, aromatic), 7.43ꢀ7.37 (m,
20 1H, aromatic), 7.36ꢀ7.31 (m, 1H, aromatic), 4.43 (q, J = 7.1 Hz,
2H, CH2), 1.33 (t, J = 7.1 Hz, 3H,CH3) ppm; 13C NMR (100
G. Filacchioni, C. Martini, S. Gelli and A. Lucacchini, J.
Pharm. Sci., 1991, 80, 276; (e) V. Snieckus and N. Carmen,
Synfacts 2015, 11, 0803; (f) H. Y. Wang, X. C. Liu, Z.
B. Huang and D. Q. Shi, J. Heterocyclic. Chem., 2015, 52, 380.
MHz, CDCl3): δ 158.73, 155.82, 153.01, 149.17, 137.42, 36.20, 85 5 (a) A. V. Burgo, A. M. O. Retana, J. M. Santos and F. Palacio,
135.86, 131.13, 129.53, 126.16, 124.67, 122.92, 117.53, 113.80,
108.38, 63.29, 13.77 ppm; MS (ESI): (m/z) 391 [M+Na]+; HRMS
25 (ESI): (m/z) calcd for C19H13ClN2NaO4 [M+Na]+ 391.0456,
Found: 391.0469.
J. Org. Chem., 2016, 81, 100; (b) N. Sachdeva, A. V.
Dolzhenko, S. J. Lim, W. L. Onga and W. K. Chuia, New J.
Chem., 2015, 39, 4796; (c) S. Tang, K. Liu, Y. Long, X. Gao,
M. Gao and A. Lei, Org. Lett., 2015, 17, 2404; (d) P. Liu, J.
90 Liu, H. Wang, Y. Pan, H. Liang and Z. F. Chen, Chem.
Commun., 2014, 50, 4795; (e) S. Benetti and R. Romagnoli,
Chem. Rev., 1995, 95, 1065.
Ethyl4ꢀoxoꢀ2ꢀ(pꢀtolyl)ꢀ2,4ꢀdihydrochromeno[4,3ꢀc]pyrazoleꢀ3ꢀ
carboxylate (7k). Yield: 77%, 7.5 h; colorless solid; mp 148ꢀ150
°C; FTꢀIR (KBr): 3124, 2386, 2320, 1740, 1726, 1618, 1562,
30 1509, 1448, 1393, 1362, 1323, 1236, 1188, 1086, 1035, 979, 772
6 (a) B. C. Raju, G. Saidachary, J. A. Kumar and B. Sridhar,
Helv. Chim. Acta, 2011, 94, 248; (b) B. C. Raju, G. Saidachary
1
cmꢀ1; H NMR (400 MHz, CDCl3): δ 8.14 (dd, J = 7.8, 1.5 Hz,
1H, aromatic), 7.71 (d, J = 8.5 Hz, 1H, aromatic), 7.52ꢀ7.48 (m, 95 and J. A. Kumar, Tetrahedron 2012, 68, 6289; (c) G.
1H, aromatic), 7.44 (s, 1H, aromatic), 7.42ꢀ7.38 (m, 1H,
Saidachary, K. Veera Prasad, D. Divya, A. Singh, U. Ramesh,
B. Sridhar and B. C. Raju. Eur. J. Med. Chem., 2014, 76, 460;
(d) B. C. Raju, K. V. Prasad, G. Saidachary and B. Sridhar, Org.
Lett., 2014, 16, 420; (e) G. Saidachary, K. V. Prasad, M. Sairam
aromatic), 7.35ꢀ7.32 (m, 3H, aromatic), 4.41 (q, J = 7.1 Hz, 2H,
35 CH2), 2.45 (s, 3H, CH3), 1.29 (t, J = 7.1 Hz, 3H, CH3) ppm; 13
C
NMR (125 MHz, CDCl3): δ 158.95, 156.02, 152.94, 148.80,
140.03, 136.50, 36.07, 130.84, 130.25, 129.84, 124.55, 122.87, 100 and B. C. Raju, Tetrahedron Lett., 2014, 55, 4753; (f) Ch.
120.20, 117.42, 114.01, 63.03, 21.21, 13.71 ppm; MS (ESI):
(m/z) 371 [M+Na]+; HRMS (ESI): (m/z) calcd for C20H16N2NaO4
40 [M+Na]+ 371.1002, Found: 371.0991.
Dayakar, D. Jyothi, P. Suman and B. C. Raju, Synth. Commun.,
2015, 45, 1642; (g) M. Sairam, G. Saidachary and B. C. Raju,
Tetrahedron Lett., 2015, 56, 1338; (h) B. C. Raju and P. Suman,
Chem. Eur. J., 2010, 16, 11840.
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Vasilye, Chem. Rev., 2016, 116, 5894; (b) R. Chinchilla and C.
Nájera, Chem. Rev., 2014, 114, 1783; (c) B. Godoi, R. F.
Schumacher and G. Zeni, Chem. Rev., 2011, 111, 2937; (d) M.
K. Saxena, M. N. Gudi and M. V. George, Tetrahedron 1973,
110 29, 101.
Acknowledgements
The authors thank Dr. S. Chandrasekhar, Director, CSIRꢀIICT for
45 constant encouragement. B. China Raju acknowledges SERBꢀ
DST, New Delhi for financial support (SB/EMEQꢀ301/2013).
8 J. A. Kumar, G. Saidachary, G. Mallesham, B. Sridhar, N. Jain,
S. V. Kalivendi, V. J. Rao and B. C. Raju, Eur. J. Med. Chem.,
2013, 65, 389.
Notes and references
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