One-pot, three-component approach to the synthesis of 3,4,5-trisubstituted pyrazoles

Article abstract of DOI:10.1021/jo502946g

An operationally simple and high yielding protocol for the synthesis of polyfunctional pyrazoles has been developed through one-pot, three-component coupling of aldehydes, 1,3-dicarbonyls, and diazo compounds as well as tosyl hydrazones. The reaction proceeds through a tandem Knoevenagel condensation, 1,3-dipolar cycloaddition, and transition metal-free oxidative aromatization reaction sequence utilizing molecular oxygen as a green oxidant. The scope of the reaction was studied by varying the aldehyde, 1,3-dicarbonyl, and diazo component individually.

Full text of DOI:10.1021/jo502946g

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Article
One-Pot, Three-Component Approach to the
Synthesis of 3,4,5-Trisubstituted Pyrazoles
Ahmed Kamal, K. N. Visweswara Sastry, D Chandrasekhar, Geeta Sai Mani, Praveen
Reddy Adiyala, Jagadeesh Babu Nanubolu, Kiran K Singarapu, and Ram Awatar Maurya
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502946g • Publication Date (Web): 07 Apr 2015
Downloaded from http://pubs.acs.org on April 8, 2015
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The Journal of Organic Chemistry
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One-Pot, Three-Component Approach to the Synthesis of 3,4,5-
Trisubstituted Pyrazoles
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Ahmed Kamal,*,†, ‡ K. N. Visweswara Sastry,†, ‡ D. Chandrasekhar,† Geeta Sai Mani,†, ‡
Praveen Reddy Adiyala,† Jagadeesh Babu Nanubolu,§ Kiran Kumar Singarapu,║ and Ram
Awatar Maurya*,†
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†
Division of Medicinal Chemistry and Pharmacology, CSIRꢀIndian Institute of Chemical Technology,
Hyderabadꢀ500007, India. Eꢀmail: ramaurya@iict.res.in (RA Maurya); ahmedkamal@iict.res.in (A Kamal)
‡
Deperatment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research,
Hyderabadꢀ500037, India
§
Centre for Xꢀray Crystallography, CSIRꢀIndian Institute of Chemical Technology, Hyderabadꢀ500007, India.
║
Centre for Nuclear Magnetic Resonance, CSIRꢀIndian Institute of Chemical Technology, Hyderabadꢀ500007,
India.
Abstract: An operationally simple and high yielding protocol for the synthesis of
polyfunctional pyrazoles has been developed through oneꢀpot, threeꢀcomponent coupling of
aldehydes, 1,3ꢀdicarbonyls, and diazoꢀcompounds as well as tosyl hydrazones. The reaction
proceeds through a tandem Knoevenagel condensation, 1,3ꢀdipolar cycloaddition, and
transition metalꢀfree oxidative aromatization reaction sequence utilizing molecular oxygen as
a green oxidant. The scope of the reaction was studied by varying the aldehyde, 1,3ꢀ
dicarbonyl and diazoꢀcomponent individually.
R1
O
N
R
O
R
Piperidinium
acetate
R
H
NH
or
N
+
R1
N
Tos
N2
R2
R2
K2CO3, Air, 12 h
32 examples
Yield 51-90%
R2 = COCH3, COOEt, COPh
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Introduction
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Pyrazole is amongst the most important privileged scaffolds found in synthetic and natural
products1 of medicinal interest. Pyrazole containing molecules possess a wide range of
biological activities such as antibacterial,2 antiviral,3 anticancer,4 antidiabetic,5 antiobesity,6
antiꢀinflammatory,7 estrogen receptor agonists,8 cannabinoid receptor antagonists,9 etc. Apart
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from their medicinal values, polysubstituted pyrazoles have been utilized for many other
10
purposes too, such as ligands for cross coupling reactions
and dyes.11 Considering the
valuable potential of pyrazoles, numerous synthetic methods were developed over the past
decades.
There are two classical methods for the synthesis of pyrazoles ꢀ 1) 1,3ꢀdipolar cycloaddition
reaction of diazoꢀcompounds with alkynes and 2) condensation reaction of 1,3ꢀdicarbonyls
with hydrazines.12 Although these methods provide pyrazoles in acceptable yields, they suffer
from their own limitations such as the use of hazardous transition metals and carcinogenic
hydrazines, limited substrate scope, and poor regioselectivity. Therefore pyrazole synthesis
was investigated extensively and several improved synthetic routes were developed.13ꢀ18 Most
of these methods rely on the reaction of diazoꢀcompounds (isolated or generated inꢀsitu from
corresponding tosyl hydrazones) with alkenes having an appropriate leaving group (Figure 1,
Eq. 1ꢀ 3). Zhang et. al. developed a synthetic route for pyrazoles through 1,3ꢀdipolar
cycloaddition reaction of inꢀsitu generated diazoꢀcompounds with vinyl azides.14 The reaction
of diazoꢀcompounds with βꢀnitrostyrenes has been reported for the synthesis of pyrazoles.15
Furthermore, βꢀnitrostyrenes have been reacted with diazoꢀcompounds containing
phosphonate and sulphonyl groups to provide pyrazoles with corresponding functionality.16
Moreover pyrazoles have been synthesized via the reaction of enol triflates17 or enaminones
(generated inꢀsitu from carbonyls and amines)18 with diazoꢀcompounds.
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Literature reports:
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R2
R
Eq. 1
-HN3
R1
H
R
+
N
N
N
Tos
N3
R2
NH
R1
R
R
Eq. 2
R2
R1
H
or
+
N
-HNO2
N2
N
Tos
NO2
R2
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R1
R2
N
R
Eq. 3
-HX
R1
NH
+
N2
X
R
X = OTf or NR2
This work:
R
R
R1
O
H
R2
or
Tos
R
R1
N
N
N
N2
+
NH
O
O
R1
R2
three-component
one-pot
R2
Not isolated
R2 = COCH3, COOEt, COPh
-AcOH
Figure 1. Various approaches for the synthesis of pyrazoles based on the reaction of alkenes with diazoꢀ
compounds.
Many of the above mentioned pyrazole synthetic routes require special substrates or reagents
(vinyl azides, nitroalkenes, enol triflates, etc.) for the success of the reaction which eventually
limit the product diversity too. Therefore a straightforward, operationally simple and high
yielding protocol for polysubstituted pyrazoles, from easily available starting materials is
highly needed. Presented in this letter are the results of oneꢀpot, threeꢀcomponent coupling of
aldehydes, 1,3ꢀdicarbonyls and diazoꢀcompounds/tosyl hydrazones to yield 3,4,5ꢀ
trisubstituted pyrazoles.
Results and Discussion
In order to study the feasibility of the cleavage of acetyl group and aerobic aromatization, we
started investigating 1,3ꢀdipolar cycloaddition reaction of 3ꢀ(4ꢀchlorobenzylidene)pentaneꢀ
2,4ꢀdione 1aa, with ethyl diazoacetate (EDA) 2a (Table 1). Firstly the reaction was attempted
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under open atmospheric condition in toluene. The reaction was very slow at room
temperature and the substrate remained unꢀreacted even after a week (Table 1, entry 1). The
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8
0
reaction was accelerated at elevated temperature and heating it at 70 C for a period of 24 h
9
lead to the complete consumption of the starting materials (Table 1, entry 2). The reaction
when performed under oxygen atmospheric condition did not significantly improve the yield
of 3aaa 68% (Table 1, entry 3). Among the several solvents screened, DMSO was found the
best in the terms of reaction time and yield (Table 1, entry 7). Since no base was needed for
the formation of 3aaa, one of the acetyl groups was presumably cleaved by the traces of
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1
water present in the reaction medium. Analyzing H NMR spectrum of the crude reaction
mixture revealed that acetic acid was a byꢀproduct of the reaction.
Table 1. Optimization of pyrazole formation from 3ꢀ(4ꢀchlorobenzylidene)pentaneꢀ2,4ꢀdione 1aa, with EDAa
O
O
O
EtO
NH
N
N2
EtO
+
Cl
O
Cl
2a
1aa
O
3aaa
Entry
Solvent
Toluene
Toluene
Toluene
CH3CN
THF
Temp. (0C)
Time (h)
168
24
Yield of 3aaa (%)b
1
2
rt
70
ND
65
68
40
55
71
84
3c
4
70
24
70
24
5
reflux
70
24
6
EtOH
24
7
DMSO
70
12
b
aReaction condition: 1aa (1 mmol), 2a (1.01 mmol), solvent (1 mL), stir in open atmosphere. Isolated
yield. cReaction was carried out under oxygen atmosphere. ND = Not determined.
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After confirming the feasibility of acetyl cleavage and aerobic oxidative aromatization, we
sought to develop a oneꢀpot, threeꢀcomponent version of the pyrazole synthesis. Therefore,
an equimolar mixture of 4ꢀClꢀbenzaldehyde 4a, acetyl acetone 5a and EDA (ratio: 1/1/1.01)
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containing 20 mol% of piperidinium acetate was heated at 70 C in DMSO under open
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atmosphere for a period of 12 h. After workꢀup and purification of the crude reaction mixture,
pyrazole 3aaa was obtained in 55% yield. Since the yield of pyrazole 3aaa was not
satisfactory, we attempted to carry out the reaction in oneꢀpot, twoꢀstep fashion. Hence an
equimolar mixture of 4ꢀClꢀbenzaldehyde and acetyl acetone (1 mmol each) was treated with
20 mol % of piperidinium acetate in solventꢀfree condition and stirred well. Formation of 1aa
was complete in about 10 minutes (TLC). Then 1 mL of DMSO and 1.01 mmol of EDA were
0
added to the reaction mixture and heated at 70 C for 12 h under open atmosphere. We were
pleased to achieve a high yield of pyrazole 3aaa (80%) using the oneꢀpot, twoꢀstep strategy.
Though the oneꢀpot, multiꢀcomponent approach gave a slightly lower yield of the pyrazole
3aaa (80%) when compared to the direct approach (84%), the added advantages of multiꢀ
component approach make up for the loss in yield.
Further we tried to explore the scope of the oneꢀpot, twoꢀstep, threeꢀcomponent approach for
the pyrazoles synthesis by varying aldehyde, 1,3ꢀdicarbonyl and diazoꢀcomponent separately.
The strategy was found to work well with both electron withdrawing and electron donating
aromatic aldehydes (Table 2). However the yields of pyrazoles were lower in case of electron
donating aromatic aldehydes (Table 2, entry 10 & 11). It was presumably due to the
incomplete conversion of the electron donating aromatic aldehydes to aldehydeꢀacetyl
acetone adducts at the very first step of the reaction. Heteroaromatic aldehydes such as
quinolineꢀ4ꢀcarboxaldehyde, Nꢀethyl carbazoleꢀ3ꢀcarboxaldehyde, and furfural gave high
yields of pyrazoles (75ꢀ82%) using the oneꢀpot, threeꢀcomponent approach (Table 2, entry
12ꢀ14).
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Table 2. Synthesis of pyrazoles 3aaa-3gaj via oneꢀpot, twoꢀstep, threeꢀcomponent reaction of aldehydes 4a-s,
1,3ꢀdicarbonyls 5a-d and diazoꢀacetates 2a-c or tosyl hydrazones 2d-j
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9
O
H
R3
O
N
Piperidinium acetate
(20 mol%), 10-30 min
R3
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N2
2a-c
or
NNHTs
2d-j
R
O
H
N
R
R2
4a-r
R
Solvent-free
R2
3aaa-3gaj
+
O
R1
O
O
R3
Not isolated
R1
R2
1
5a-d
Entry
Aldehyde (4)
1,3ꢀDicarbonyl (5)
Diazoꢀester
or
Pyrazole Yield of
(3).
pyrazole
(%)a
Tosyl hydrazone (2)
Comp.
No.
R
Comp.
R1
R2
Comp.
No.
R3
No.
1b
2b
4ꢀClꢀC6H4
4ꢀBrꢀC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
80
77
80
81
75
79
83
85
81
65
4a
5a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3aaa
3baa
3caa
3daa
3eaa
3faa
3gaa
3haa
3iaa
4b
4c
4d
4e
4f
5a
5a
5a
5a
5a
5a
5a
5a
5a
3b
4ꢀCF3ꢀC6H4
4ꢀClꢀ3ꢀFꢀC6H4
1ꢀNaphthyl
2ꢀNaphthyl
3ꢀO2NꢀC6H4
4ꢀO2NꢀC6H4
4ꢀCNꢀC6H4
4b
5 b
6b
7b
4g
4h
4i
8b
9b
10b
3ꢀ4ꢀ
Methylenedioxyꢀ
C6H3
4j
3jaa
11b
12b
13b
4ꢀMeꢀC6H4
Me
Me
Me
Me
Me
Me
COOEt
COOEt
COOEt
71
78
82
4k
4l
5a
5a
5a
2a
2a
2a
3kaa
3laa
Quinolinꢀ4ꢀyl
9ꢀEthylꢀ9Hꢀ
4m
3maa
carbazolꢀ3ꢀyl
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14b
15b
16b
17b
18b
19c
20c
21c
22c
23b
24b
25b
26b
27d
2ꢀFuryl
PhCH2
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Ph
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOtBu
COOtBu
COOBn
COOBn
75
NF
NF
51
4n
4o
4p
4q
4r
4a
4g
4i
5a
5a
5a
5a
5a
5b
5c
5c
5d
5a
5a
5a
5a
5a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2c
2d
3naa
--
(CH3)3C
--
nꢀC3H7
3qaa
3raa
3aba
3gca
3ica
3sda
3gab
3iab
3gac
3iac
3gad
10
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nꢀC5H11
57
4ꢀClꢀC6H4
3ꢀO2NꢀC6H4
4ꢀCNꢀC6H4
3ꢀFꢀC6H4
3ꢀO2NꢀC6H4
4ꢀCNꢀC6H4
3ꢀO2NꢀC6H4
4ꢀCNꢀC6H4
3ꢀO2NꢀC6H4
78
OEt
OEt
Ph
75
71
80
4s
4g
4i
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
77
78
81
4g
4i
75
3ꢀMeOꢀ
C6H4
90 (85)e
4g
28d
29d
3ꢀO2NꢀC6H4
4ꢀCNꢀC6H4
Me
Me
Me
Me
4ꢀO2NꢀC6H4
85
89
4g
4i
5a
5a
2e
3gae
3iad
3ꢀMeOꢀ
C6H4
2d
30d
4ꢀCNꢀC6H4
Me
Me
3ꢀClꢀ4ꢀO2Nꢀ
C6H3
90
4i
5a
2f
3iaf
31d
32d
33d
34d
35d
36d
37d
4ꢀCNꢀC6H4
4ꢀMeꢀC6H4
nꢀC3H7
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4ꢀO2NꢀC6H4
4ꢀO2NꢀC6H4
3ꢀO2NꢀC6H4
2ꢀFuryl
88
85
4i
5a
5a
5a
5a
5a
5a
5a
2e
2e
2g
2h
2h
2i
3iae
3kae
4qag
--
4k
4q
4q
4g
4g
4g
70
nꢀC3H7
NF
NF
NF
78
3ꢀO2NꢀC6H4
3ꢀO2NꢀC6H4
3ꢀO2NꢀC6H4
2ꢀFuryl
--
2ꢀThienyl
--
9ꢀEthylꢀ9Hꢀ
carbazolꢀ3ꢀ
yl
2j
3gaj
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38d
aIsolated yield. Reaction condition: aldehyde (1 mmol), acetyl acetone (1 mmol), piperidinium acetate (20
3ꢀO2NꢀC6H4
Me
Me
nꢀC3H7
NF
4g
5a
2k
--
b
6
7
8
9
0
c
mol%), solventꢀfree, stir, 10ꢀ30 min, then diazoꢀester (1.01 mmol), DMSO (1 mL), 70 C, 12 h. Reaction
condition: aldehyde (1 mmol), 1,3ꢀdicarbonyl (1 mmol), piperidinium acetate (20 mol%), solventꢀfree, stir, 10ꢀ
30 min, then EDA (1.01 mmol), K2CO3 (1.5 mmol), EtOH (10 mL), reflux, 24 h. dReaction condition: aldehyde
(1 mmol), acetyl acetone (1 mmol), piperidinium acetate (20 mol%), solventꢀfree, stir, 10ꢀ30 min, then tosyl
hydrazone (1.5 mmol), K2CO3 (3.0 mmol), MeOH (10 mL), reflux, 12 h. eYield in parenthesis is for gram scale
(10 mmol scale) reaction. NF = Not formed.
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The oneꢀpot, threeꢀcomponent protocol was successful with aliphatic aldehydes such as nꢀ
butanal 4q and nꢀhexanal 4r yielding the desired pyrazoles in moderate yields (Table 2, entry
17, 18). However phenyl acetaldehyde 4o and trimethylacetaldehyde 4p did not lead to the
pyrazole formation under our reaction conditions (Table 2, entry 15, 16). With phenyl
acetaldehyde the reaction mixture was too complex for purification. Purification of the
reaction mixture derived from trimethylacetaldehyde yielded an oily compound (45%) the
1
13
structure of which was assigned as 6aa by analyzing its H NMR, C NMR, IR and HRMS
spectra (Figure 2). The compound 6aa seems to be derived from the protonation EDA
followed by its coupling with acetyl acetone. However, it was surprising that compound 6aa
was not formed when a two component coupling of acetyl acetone and EDA was attempted
under the same reaction conditions.
O
O
N
H
N
O
O
6aa
Figure 2. Chemical structure of compound 6aa
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We, therefore, planned to synthesize pyrazoles by reacting the purified aliphatic aldehydeꢀ
acetyl acetone adduct 1oa and 1pa with EDA. The piperidinium acetate catalyzed reaction of
phenyl acetaldehyde 4o with acetyl acetone 5a yielded 1oa’ (Scheme 1). Since the CꢀC
double bond and carbonyls are not conjugated in 1oa’, pyrazole formation did not occur with
it. Despite many attempts, the trimethylacetaldehydeꢀacetyl acetone adduct 1pa could not be
isolated or characterized using either our piperidinium acetate catalyzed protocol or several
other acid/base catalyzed methods commonly used for Knoevenagel condensation reactions.
Therefore, the synthesis of the corresponding pyrazole could not be attempted from
trimethylacetaldehyde.
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O
O
Ph
Ph
O
O
Piperidinium acetate (20 mol%)
O
+
+
Ph
Solvent-free
10 min
O
O
4o
5a
1oa'
1oa
(Not formed)
(yield: 95%)
Scheme 1. Knoevenagel condensation reaction of phenyl acetaldehyde with acetyl acetone
Next, we started investigating the scope of the 1,3ꢀdicarbonyls in the oneꢀpot, three
component pyrazole synthesis. Acetyl acetone 5a, benzoyl acetone 5b, ethyl acetoacetate 5c,
and dibenzoyl methane 5d were taken as four different 1,3ꢀdicarbonyls for the study. The
oneꢀpot, threeꢀcomponent protocol optimized for acetyl acetone did not work for the rest of
1,3ꢀdicarbonyls 5b, 5c and 5d. In case of benzoyl acetone 5b, the acetyl group was partially
cleaved yielding a mixture of pyrazole and dihydropyrazoles which could not be separated by
column chromatography. Under our optimized conditions (Table 2, Footnote b), the acetyl
group of ethyl acetoacetate 5c was not cleaved and the reaction yielded a mixture of
inseparable diastereomers of dihydropyrazole 7gca. Similarly the benzoyl group of dibenzoyl
methane 5d was not cleaved yielding dihydropyrazoles 7ada & 7hda (Figure 3). These
results indicated that water or piperidinium acetate were incapable of removing the acetyl (or
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benzoyl) group from the products (7gca-7hda). We, therefore, used K2CO3 as a base in EtOH
for the reaction and achieved high yields (71ꢀ80%) of desired pyrazoles 3aba-sda under
standard conditions (Table 2, entry 19ꢀ22). The combination of K2CO3 and DMSO was not
suitable for the reaction as it hydrolyzed the ester, and the acid thus obtained, could not be
purified by column chromatography.
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EtOOC
EtOOC
N
NH
EtOOC
N
N
NH
O
NH
O
OEt
Ph
Ph
O
O
O
O
Cl
O2N
Ph
7ada (85%)
Ph
7hda (91%)
O2N
7gca (80%)
Figure 3. Chemical structures of dihydropyrazoles derived from threeꢀcomponent coupling of aldehyde, 1,3ꢀ
dicarbonyl and EDA under reaction conditions mentioned in footnote b of Table 2.
Next we tried to explore the scope of the reaction in terms of diazoꢀcomponent. The threeꢀ
component reaction of aldehyde, acetyl acetone and diazoꢀesters such as tertꢀbutyl
diazoacetate 2b and benzyl diazoacetate 2c proceeded successfully (Table 2, entry 23ꢀ26).
Following the optimized protocol, a number of pyrazoles 3gab-3iac were synthesized in high
yields (75ꢀ81%).
Finally the scope of the pyrazole synthesis was studied by taking tosylhydrazones as the
alternative of diazoꢀcompounds (Table 2, entry 27ꢀ38).19 The use of tosylhydrazones in the
threeꢀcomponent reaction is not only exciting from safety points of view but also it extends
the scope of the work towards a wide range of diazoꢀcompounds which are not commercially
available. After screening several conditions, we found that refluxing the reaction mixture in
MeOH using three equivalents of K2CO3 as a base gave good yields of pyrazoles. Under basic
reaction conditions (K2CO3) and heating, tosyl hydrazones were converted to corresponding
diazoꢀcompounds which reacted with aldehydeꢀacetyl acetone adducts. A series of substituted
pyrazoles 3gad-3gaj were synthesized using the oneꢀpot, threeꢀcomponent protocol in high
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yields (70ꢀ90%). In order to further demonstrate the advantage of this method, a gram scale
synthesis of 3gad was performed under standard conditions. The desired pyrazole 3gad was
obtained in 85% yield, which indicates there is potential industrial application (Table 2, entry
27). The threeꢀcomponent reaction was successful with aliphatic aldehyde (nꢀbutanal)
yielding a high yield (70%) of the desired pyrazole 4qag (Table 2, entry 33). However the
reaction was not successful with tosyl hydrazone derived from aliphatic aldehyde (Table 2,
entry 38). The reaction was also not successful with tosyl hydrazones derived from typical
heteroaromatic aldehydes such as furfural (Table 2, entry 34, 35) and 2ꢀthenaldehyde (Table
2, entry 36). It was plausibly due to the fast decomposition of furfuralꢀtosyl hydrazones into
highly reactive enynylꢀketones reported very recently.20 Furthermore, high yield (78%) of the
desired pyrazole 3gaj was obtained with tosyl hydrazone derived from 9ꢀethylꢀ9Hꢀcarbazoleꢀ
3ꢀcarbaldehyde as another heteroaromatic aldehyde.
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The high regioselectivity observed in our pyrazole synthesis is in accordance with the
previous literature reports involving 1,3ꢀdipolar cycloaddition reactions of electron deficient
olefins with diazoꢀcompounds.15ꢀ16 It can be explained by considering atomic orbital
coefficients of HOMO (diazoꢀcomponent)ꢀLUMO (alkene) favored interactions expected for
1
these type of 1,3ꢀdipolar cycloaddition reactions. In many H NMR spectra of pyrazoles
methyl hydrogen atoms of the acetyl group appeared as broad signals. And in many 13C NMR
spectra, Cꢀ3 and Cꢀ5 carbons of the pyrazole, and carbonyl carbon were not resolved from the
baseline. It is indeed due to the dynamic tautomeric forms that NHꢀpyrazole can adopt and is
well documented in literature.17, 21
The structural assignment for pyrazoles 3aaa-3gaj and dihydropyrazoles 7gca-7hda were
based on the expected direction of the 1,3ꢀdipolar cycloaddition reaction of diazoꢀcompounds
with electron deficient alkenes reported in literature. 15ꢀ16 In order to give an unambiguous
proof for the structural assignments, we attempted HMBC and 2D NOESY for several
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compounds (3kaa, 3gad, 3gae). However, due to the dynamic tautomeric structures of the
NHꢀpyrazoles (Scheme 2), these compounds did not give proper HMBC and 2D NOESY
spectra. Furthermore we attempted collecting single crystal Xꢀray analysis data for several
pyrazoles, but unfortunately the diffraction patterns were not good enough. We, therefore,
planned to eliminate the dynamic tautomerism of pyrazoles (3kaa, 3gad, 3gae) by reacting
them with ethyl αꢀbromoacetate (Scheme 2). The structural assignments for these pyrazole
derivatives (9kaaa, 9gada, 9gaea) were made through their HMBC and 2D NOESY spectra.
Finally we succeeded in getting a single crystal Xꢀray analysis of the pyrazole derivative
9gaea (Figure 4).
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O
O
H
O
N
O
N
O
O
N
NH
O
9kaaa
(81%)
N
O
N
O
O
3kaa
O
O
H
N
O
O
O
N
N
O
Br
O
N
NH
O
9gada
(83%)
N
8a (1.1 eq.)
O
K2CO3 (3.0 eq.)
CH3CN, 80 0C
3 h
O
NO2
O
3gad
NO2
NO2
O
O2N
O2N
O2N
H
O
N
N
9gaea
(85%)
N
N
N
NH
O
O
O
NO2
NO2
3gae
NO2
Scheme 2. Eliminating the possibility of dynamic tautomers by alkylating pyrazoles 3kaa, 3gad, and 3gae by
ethyl αꢀbromoacetate; Key 1Hꢀ1H (NOESY) correlations of the pyrazoles 9gada & 9gaea, and 1Hꢀ13C (HMBC)
correlations for the pyrazole 9kaaa are shown by arrows.
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Figure 4.Single crystal Xꢀray analysis of compound 9gaea (CCDC Ref. No. 1050199; for details, see
supporting information)
The structural characterizations of pyrazole derivatives (9kaaa, 9gada & 9gaea) reveal
several interesting information. Firstly, it confirms that the mode of the 1,3ꢀ dipolar
cycloaddition reaction of diazoꢀacetates (2a-c) as well as arylꢀdiazomethanes derived from
tosyl hydrazones (2d-j) towards aldehydeꢀacetyl acetone adducts is same. Secondly,
electronic tuning of the tosyl hydrazone component (3gad & 3gae) does not switch the
regiochemical outcome of the reaction.
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Formation of pyrazoles from the reaction of tosyl hydrazones with aldehydeꢀacetyl acetone
adducts might be imagined to proceed without the intermediacy of corresponding arylꢀ
diazomethanes. Such a stepꢀwise additionꢀelimination reaction might give either a different
9
regiomer or a mixture of regiomers. To get insight of such possibility, (pꢀ
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22
nitrophenyl)diazomethane
was prepared and reacted with 3ꢀnitrobenazldehydeꢀacetyl
acetone adduct. After workꢀup and purification, we got the same pyrazole 3gae (92%). This
and the regiospecificity of the reaction, therefore, indirectly prove the intermediacy of arylꢀ
diazomethanes in the pyrazole synthesis from tosyl hydrazones.
Formation of the pyrazoles can be explained by a plausible mechanism as depicted in Scheme
3. EDA (or the aryl diazomethane generated in situ from tosyl hydrazone) undergoes a 1,3ꢀ
dipolar cycloaddition reaction with alkene 1 leading to the formation of an intermediate 10
which isomerizes to 10’. Next water (or K2CO3) attacks the intermediate 10’ leading to the
formation of another intermediate 11 which loses one acetyl group to form a dihydropyrazole
12. Under aerobic conditions, the dihydropyrazole 12 aromatizes to pyrazole 3. Attempts to
isolate the dihydropyrazoles 12 by performing reactions under nitrogen atmosphere failed. It
indicated that dihydropyrazoles 12 were very much prone to aerobic oxidative aromatization
when exposed to air.
N
R1
H
R1
R1
N
R
N
N
NH
R1
N
N
O
H
NH
R
O
O
R
O
O
R
O
O
OH
O
11
1
10'
10
H2O
-AcOH
R1
R1
R1
R
N
NH
N
N
N
NH
-H2O2
NH
O
R1
O2
NH
O
R
R
H
OOH
H
R
O
O
O
O
12
3
Scheme 3. A plausible mechanism for the formation of pyrazole 3
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The proposed mechanism depicted in Scheme 3 raises several questions. Firstly it is
reasonable to argue whether the acetyl group is lost from the initially formed five member
ring (10) or from the α,βꢀunsaturated compound itself. Secondly, whether the additional
acetyl group is necessary for the success of the pyrazole synthesis? In order to address the
former query, we subjected the compound 1aa under three different reaction conditionsꢀa)
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0
Piperidinium acetate (20 mol%), DMSO, 70 C, 24 h; b) Piperidinium acetate (20 mol%),
K2CO3 (150 mol%), EtOH, reflux, 24 h; and c) Piperidinium acetate (20 mol%), K2CO3 (300
mol%), MeOH, reflux, 24 h. In all the three reaction conditions, 1aa was almost completely
recovered (≥ 90%). Next, we carried out a control reaction of furfuralꢀacetyl acetone adduct
1na with EDA in anhydrous toluene under nitrogen atmosphere as depicted in Scheme 4. The
initially formed five member adduct 7naa was isolated and its treatment with K2CO3 (150
mol%) in EtOH yielded the desired pyrazole 3naa in 95% yield. Similarly the
dyhydropyrazoles 7gca, 7ada, and 7hda were also converted to corresponding pyrazoles by
treating them with K2CO3 (150 mol%) in EtOH. These experiments clearly support that the
acetyl group is lost from the initially formed five member ring as depicted in Scheme 3.
O
O
O
O
EtO
O
NH
N
Dry toluene
4 A MS
O
EtO
O
N
NH
K2CO3 (150 mol%)
1na
EtOH, rt 12 h
Air
70 0C, 24 h
N2
+
O
O
O
O
N2
3naa
(95%)
EtO
7naa (96%)
2a
Scheme 4. Control experiment: isolation of the initially formed five member adduct 7naa and its subsequent
conversion to pyrazole 3naa
In order to address the later query regarding the necessity of the additional acetyl group, we
carried out a few control experiments. Firstly, benzaldhydeꢀacetone adduct 1te was prepared,
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and reacted with EDA as well as tosyl hydrazones (Scheme 5). Although formation of the
desired pyrazole 1tea was not observed (TLC and MS analysis) with EDA, the corresponding
reaction with tosyl hydrazone gave a high yield of the corresponding pyrazole 3teg (75%).
These results suggest that the additional acetyl group is necessary for the success of pyrazole
synthesis at least in case of diazoꢀacetates. Although we partially succeeded in synthesizing
pyrazoles from aldehydeꢀacetone adduct 1te, the overall reaction cannot be done in oneꢀpot
fashion. Therefore we conclude that an additional acetyl group is very much required in order
to achieve a general oneꢀpot, threeꢀcomponent synthesis of pyrazoles.
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O
O
N2
O
O
N
2a
(1.01 eq.)
N
H
H
K2CO3 (150 mol%)
EtOH, Reflux, 24 h, Air
O
O
O
3tea
10% NaOH (aq.)
rt, 6h, 56%
Not formed
4t
+
O
O2N
NNHTs
O2N
1te
N
2g
(1.5 eq.)
NH
5e
K2CO3 (300 mol%)
MeOH, Reflux, 12 h, Air
O
3teg
(75%)
Scheme 5. Control experiment: Preparation of benzaldehydeꢀacetone adduct 1te and its reactions with EDA 2a
and tosyl hydrazone 2g
Conclusions
In conclusion, we have developed a oneꢀpot protocol that affords excellent yields of highly
substituted pyrazoles and several dihydropyrazoles, from simple and inexpensive starting
materials, and catalysts, using the advantages of multiꢀcomponent reaction. This oneꢀpot
process does not require the purification of intermediates and eliminates the use of toxic
transition metal based catalysts or oxidants. It generates two CꢀC and one CꢀN bonds through
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a cascade of several individual reactions and is mechanistically novel in that it involves the
cleavage of an acetyl group for the pyrazole formation. A series of pyrazoles was
synthesized using electron donating/withdrawing aromatic aldehydes, heteromatic aldehydes,
1,3ꢀdicarbonyls and diazoꢀcompounds in high yield. The direct use of tosyl hydrazones
further extends the scope of the reaction and avoids handling of sensitive diazoꢀcompounds.
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Experimental Section
General: The reagents, chemicals and solvents were either purchased from commercial
suppliers or prepared and purified by standard techniques. Column chromatography was
carried out using silica gel 100ꢀ200 mesh. Infrared spectra were recorded using a FTꢀIR
1
13
spectrophotometer and values reported in cmꢀ1. H and C NMR spectra were recorded with
300 and 500 MHz NMR instruments with tertramethylsilane (TMS) as an internal standard.
Highꢀresolution mass spectra (ESIꢀHRMS) were recorded on ESIꢀQTOP mass spectrometer
.
Typical experimental procedure of the one-pot, three-component pyrazole synthesis
(3aaa-3raa): In a 10 mL round bottom flask, aldehyde (1 mmol), acetyl acetone (1 mmol)
and piperidinium acetate (0.2 mmol) were taken, and reaction mixture was shaken in a
solventꢀfree condition. The formation of aldehydeꢀacetyl acetone adduct was complete in
about 10 minutes (monitored by TLC). Next EDA (1.01 mmol) and 1 mL of DMSO was
0
added to it and the reaction mixture was heated at 70 C under open atmosphere until
pyrazole formation was complete. Next the reaction mixture was diluted with
dichloromethane (25 mL) and washed with brine (5 mL x 3). The organic layer was dried
over anhydrous sodium sulphate and evaporated under reduced pressure to yield a crude
reaction product. The crude was purified from silicaꢀgel column chromatography using ethyl
acetateꢀhexane as eluent in increasing polarity to yield the desired pyrazoles 3aaa-3raa.
Ethyl 3ꢀacetylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3aaa:
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234 mg (80%) of 3aaa was obtained as a white solid, Rf = 0.55 (ethyl acetate/
n
ꢀhexane, 3:7),
0
1
Mp. 109ꢀ110 C; IR (KBr, cmꢀ1): 3166, 2980, 1718, 1676, 1438, 1214, 1202; H NMR
7
8
(CDCl3, 500 MHz) δ: 11.42 (bs, 1H), 7.40 (d,
J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 4.27
9
(q,
J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.21 (t, J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ:
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191.8, 160.0, 134.2, 131.4, 129.2, 128.0, 125.5, 61.6, 28.2, 13.9; HRMS (ESI, Orbitrap):
calcd for C14H14ClN2O3 [M+H]+ 293.06930; found 293.06847.
Ethyl 3ꢀacetylꢀ4ꢀ(4ꢀbromophenyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3baa:
259 mg (77%) of 3baa was obtained as a white solid, Rf = 0.51 (ethyl acetate/
nꢀhexane, 3:7),
Mp. 111ꢀ112 0C; IR (KBr, cmꢀ1): 3165, 2978, 1718, 1675, 1200, 1214; 1H NMR (CDCl3, 500
MHz) δ: 11.35 (bs, 1H), 7.55 (d,
Hz, 2H), 2.39 (bs, 3H), 1.21 (t,
J
= 7.8 Hz, 2H), 7.22 (d,
J = 8.2 Hz, 2H), 4.27 (q, J = 7.2
J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 187.5, 158.5,
131.7, 131.0, 129.7, 122.5, 61.6, 28.2, 13.9; HRMS (ESI, Orbitrap): calcd for
C14H13BrN2O3Na [M+Na]+ 359.00072; found 359.00041.
Ethyl 3ꢀacetylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3caa:
261 mg (80%) of 3caa was obtained as a white solid, Rf = 0.45 (ethyl acetate/
nꢀhexane, 3:7),
Mp. 111ꢀ112 0C; IR (KBr, cmꢀ1): 3248, 2988, 1714, 1335, 1221; 1H NMR (CDCl3, 300 MHz)
δ: 11.51 (bs, 1H), 7.68 (d,
J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H),
2.41 (s, 3H), 1.19 (t,
J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ: 192.0, 159.7, 145.8,
136.0, 134.7, 130.5, 130.3 (q,
J = 32.7 Hz), 127.3 (q, J = 272.5 Hz), 125.1, 124.6 (q, J = 3.6
Hz), 61.7, 28.0, 13.7; HRMS (ESI, Orbitrap): calcd for C15H14F3N2O3 [M+H]+ 327.09565;
found 327.09596.
Ethyl 3ꢀacetylꢀ4ꢀ(4ꢀchloroꢀ3ꢀfluorophenyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3daa:
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252 mg (81%) of 3daa was obtained as a white solid, Rf = 0.35 (ethyl acetate/nꢀhexane, 3:7),
Mp. 128ꢀ130 0C; IR (KBr, cmꢀ1): 3224, 1713, 1694, 1439, 1218; 1H NMR (CDCl3, 500 MHz)
7
8
9
δ: 11.38 (bs, 1H), 7.42 (t,
1H), 4.28 (q, = 7.2 Hz, 2H), 2.44 (s, 3H), 1.22 (t,
MHz) δ: 192.0, 159.5, 158.3 (d,
J
= 7.9 Hz, 1H), 7.17 (dd,
J
J
= 1.8, 9.6 Hz, 1H), 7.07 (d, J = 8.2 Hz,
13
J
= 7.2 Hz, 3H); C NMR (CDCl3, 125
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J
= 247.9 Hz), 131.1(d, J = 7.2 Hz), 129.8, 126.8 (d, J = 2.7
Hz), 124.2, 120.9 (d,
J = 17.3 Hz), 118.7 (d, J = 21.7 Hz), 61.8, 28.0, 13.8; HRMS (ESI,
Orbitrap): calcd for C14H13ClFN2O3 [M+H]+ 311.05987; found 311.05984.
Ethyl 3ꢀacetylꢀ4ꢀ(naphthalenꢀ1ꢀyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3eaa:
231 mg (75%) of 3eaa was obtained as a white solid, Rf = 0.48 (ethyl acetate/
nꢀhexane, 3:7),
Mp. 103ꢀ104 0C; IR (KBr, cmꢀ1): 3219, 1730, 1682, 1440, 1235; 1H NMR (CDCl3, 300 MHz)
δ: 11.70 (bs, 1H), 7.93 (t,
J = 7.5 Hz, 2H), 7.57ꢀ7.40 (m, 5H), 4.05 (q, J = 7.2 Hz, 2H), 2.00
(s, 3H), 0.83 (t,
J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ: 190.4, 160.6, 133.4, 132.5,
129.0, 128.8, 128.4, 127.7, 126.4, 125.9, 125.1, 125.0, 124.6, 61.0, 27.8, 13.4; HRMS (ESI,
Orbitrap): calcd for C18H17N2O3 [M+H]+ 309.12392; found 309.12316.
Ethyl 3ꢀacetylꢀ4ꢀ(naphthalenꢀ2ꢀyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3faa:
243 mg (79%) of 3faa was obtained as a white solid, Rf = 0.51 (ethyl acetate/
nꢀhexane, 3:7),
Mp. 103ꢀ104 0C; IR (KBr, cmꢀ1): 3248, 2982, 1706, 1690, 1423, 1216; 1H NMR (CDCl3, 500
MHz) δ: 11.44 (bs, 1H), 7.94ꢀ7.87 (m, 2H), 7.84ꢀ7.80 (m, 2H), 7.53ꢀ7.48 (m, 2H), 7.45 (dd,
J
= 1.4, 8.4 Hz, 1H), 4.22 (q,
J = 7.2 Hz, 2H), 2.27 (s, 3H), 1.10 (t, J
= 7.2 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ: 191.4, 160.5, 132.9, 132.8, 129.3, 128.2, 128.0, 127.8, 127.7, 127.4,
126.8, 126.4, 126.3, 61.3, 28.3, 13.8; HRMS (ESI, Orbitrap): calcd for C18H17N2O3 [M+H]+
309.12392; found 309.12302.
Ethyl 3ꢀacetylꢀ4ꢀ(3ꢀnitrophenyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3gaa:
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252 mg (83%) of 3gaa was obtained as a white solid, Rf = 0.35 (ethyl acetate/nꢀhexane, 3:7),
Mp. 125ꢀ126 0C; IR (KBr, cmꢀ1): 3267, 2996, 1689, 1528, 1349, 1228; 1H NMR (CDCl3, 500
7
8
MHz) δ: 11.65 (bs, 1H), 8.27 (d, = 8.4 Hz, 1H), 8.24 (s, 1H), 7.70 (d,
J
J = 7.6 Hz, 1H), 7.60
9
(t, = 7.9 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 2.53 (s, 3H), 1.17 (t, J
J
= 7.2 Hz, 3H); 13C NMR
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(CDCl3, 75 MHz) δ: 192.8, 159.2, 147.6, 136.5, 132.4, 128.4, 125.8, 123.8, 122.9, 61.9, 27.8,
13.7; HRMS (ESI, Orbitrap): calcd for C14H13N3NaO5 [M+Na]+ 326.07529; found
326.07549.
Ethyl 3ꢀacetylꢀ4ꢀ(4ꢀnitrophenyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3haa:
258 mg (85%) of 3haa was obtained as a white solid, Rf = 0.34 (ethyl acetate/
n
ꢀhexane, 3:7),
1
Mp. 141ꢀ142 0C; IR (KBr, cmꢀ1): 3161, 2979, 1721, 1677, 1603, 1517, 1346, 1214; H NMR
(CDCl3, 300 MHz) δ: 11.44 (bs, 1H), 8.29 (d,
J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 4.28
(q,
J = 7.3 Hz, 2H), 2.50 (s, 3H), 1.21 (t, J
= 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ:
192.6, 159.2, 147.5, 137.9, 131.2, 124.2, 122.7, 61.9, 27.8, 13.8; HRMS (ESI, Orbitrap):
calcd for C14H14N3O5 [M+H]+ 304.09335; found 304.09291.
Ethyl 3ꢀacetylꢀ4ꢀ(4ꢀcyanophenyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3iaa:
229 mg (81%) of 3iaa was obtained as a white solid, Rf = 0.40 (ethyl acetate/
n
ꢀhexane, 3:7),
0
1
Mp. 158ꢀ160 C; IR (KBr, cmꢀ1): 3224, 2924, 2230, 1731, 1693, 1440, 1227; H NMR
(CDCl3, 500 MHz) δ: 11.84 (bs, 1H), 7.71 (d,
J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.27
(q,
J = 7.2 Hz, 2H), 2.49 (s, 3H), 1.18 (t, J
= 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ:
192.5, 159.3, 146.5, 136.0, 134.8, 131.3, 130.9, 124.5, 118.7, 111.6, 61.8, 27.8, 13.7; HRMS
(ESI, Orbitrap): calcd for C15H14N3O3 [M+H]+ 284.10352; found 284.10226.
Ethyl 3ꢀacetylꢀ4ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3jaa:
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196 mg (65%) of 3jaa was obtained as a white solid, Rf = 0.30 (ethyl acetate/
n
ꢀhexane, 3:7),
0
1
Mp. 118ꢀ119 C; IR (KBr, cmꢀ1): 3198, 2922, 1715, 1693, 1508, 1418, 1219; H NMR
7
8
(CDCl3, 500 MHz) δ: 11.48 (bs, 1H), 6.89 (d,
J
= 7.9 Hz, 1H), 6.83 (s, 1H), 6.81 (d,
J = 7.9
9
Hz, 1H), 6.04 (s, 2H), 4.30 (q,
J
= 7.2 Hz, 2H), 2.34 (s, 3H), 1.26 (t, J
= 7.2 Hz, 3H); 13C
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NMR (CDCl3, 125 MHz) δ: 191.3, 160.4, 147.6, 147.2, 126.5, 124.0, 123.7, 110.6, 107.0,
101.2, 61.3, 28.2, 13.9; HRMS (ESI, Orbitrap): calcd for C15H15N2O5 [M+H]+ 303.09810;
found 303.09823.
Ethyl 3ꢀacetylꢀ4ꢀpꢀtolylꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3kaa:
193 mg (71%) of 3kaa was obtained as a light green oil, Rf = 0.45 (ethyl acetate/nꢀhexane,
1
3:7); IR (KBr, cmꢀ1): 3274, 2926, 1718, 1440, 1215; H NMR (CDCl3, 300 MHz) δ: 11.24
(bs, 1H), 7.25ꢀ7.20 (m, 4H), 4.25 (q,
J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 1.21 (t, J =
13
7.2 Hz, 3H); C NMR (CDCl3, 75 MHz) δ: 191.2, 160.5, 143.5, 138.6, 138.0, 129.8, 128.6,
127.6, 127.1, 61.2, 28.3, 21.3, 13.9; HRMS (ESI, Orbitrap): calcd for C15H17N2O3 [M+H]+
273.12392; found 273.12422.
Ethyl 3ꢀacetylꢀ4ꢀ(quinolinꢀ4ꢀyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3laa:
241 mg (78%) of 3laa was obtained as a white solid, Rf = 0.32 (ethyl acetate/
n
ꢀhexane, 3:7),
0
1
Mp. 250ꢀ251 C; IR (KBr, cmꢀ1): 3424, 1722, 1692, 1599, 1206; H NMR (CDCl3 +
DMSOd6, 300 MHz) δ: 14.50 (bs, 1H), 8.94 (d,
J = 4.5 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H),
7.72ꢀ7.67 (m, 1H), 7.47ꢀ7.40 (m, 2H), 7.31 (d,
J = 4.5 Hz, 1H), 3.99 (q, J = 7.2 Hz, 2H), 2.44
(s, 3H), 0.73 (t,
J
= 7.2 Hz, 3H); 13C NMR (CDCl3 + DMSOd6, 125 MHz) δ: 190.4, 159.5,
148.5, 146.9, 139.2, 130.2, 129.7, 128.6, 128.3, 126.9, 125.6, 121.4, 119.9, 119.3, 60.0, 26.6,
12.4; HRMS (ESI, Orbitrap): calcd for C17H16N3O3 [M+H]+ 310.1192; found 310.1194.
Ethyl 3ꢀacetylꢀ4ꢀ(9ꢀethylꢀ9Hꢀcarbazolꢀ3ꢀyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3maa:
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308 mg (82%) of 3maa was obtained as a white solid, Rf = 0.50 (ethyl acetate/
n
ꢀhexane, 3:7),
Mp. 172ꢀ173 0C; IR (KBr, cmꢀ1): 3247, 3049, 2974, 1712, 1683, 1443, 1231, 1207; H NMR
1
7
8
9
(CDCl3, 500 MHz) δ: 8.07 (d,
7.8 Hz, 1H), 4.42 (q,
1.48 (t,
J = 8.1 Hz, 1H), 8.06 (s, 1H), 7.52ꢀ7.40 (m, 4H), 7.23 (t, J =
J
= 7.2 Hz, 2H), 4.23 (q,
J = 7.2 Hz, 2H), 2.84 (bs, 1H), 2.21 (s, 3H),
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J
= 7.2 Hz, 3H), 1.14 (t, J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ: 191.3,
160.9, 140.2, 139.7, 128.0, 127.7, 125.8, 122.7, 122.5, 122.1, 120.7, 120.5, 118.9, 108.5,
107.8, 61.1, 37.7, 28.4, 13.9, 13.8; HRMS (ESI, Orbitrap): calcd for C22H22N3O3 [M+H]+
376.16612; found 376.16634.
Ethyl 3ꢀacetylꢀ4ꢀ(furanꢀ2ꢀyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxylate 3naa:
186 mg (75%) of 3naa was obtained as a pale yellow oil, Rf = 0.43 (ethyl acetate/nꢀhexane,
3:7); IR (Neat, cmꢀ1): 3247, 2983, 1727, 1694, 1441, 1229, 1211; H NMR (CDCl3, 500
1
MHz) δ: 11.70 (bs, 1H), 7.56 (d,
J
= 1.2 Hz, 1H), 6.76 (d,
J = 3.4 Hz, 1H), 6.56ꢀ6.54 (m, 1H),
4.36 (q,
J
= 7.2 Hz, 2H), 2.44 (s, 3H), 1.32 (t, J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
δ: 191.4, 160.0, 144.9, 142.8, 142.6, 137.9, 115.5, 112.5, 111.3, 61.6, 27.9, 13.9; HRMS
(ESI, Orbitrap): calcd for C12H13N2O4 [M+H]+ 249.08753; found 249.08781.
Ethyl 5ꢀacetylꢀ4ꢀpropylꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 3qaa:
114 mg (51%) of 3qaa was obtained as a pale oil, Rf = 0.50 (ethyl acetate/nꢀhexane, 3:7); IR
(Neat, cmꢀ1): 3268, 2928, 2869, 1723, 1688, 1455, 1208; H NMR (CDCl3, 300 MHz) δ:
1
12.07 (bs, 1H), 4.42 (q,
J
= 7.2 Hz, 2H), 3.05 (t,
J = 7.4 Hz, 2H), 2.64 (s, 3H), 1.62ꢀ1.54 (m,
2H), 1.41 (t,
J
= 7.2 Hz, 3H), 0.94 (t, J
= 7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 194.7,
160.1, 148.5, 132.9, 128.4, 61.4, 27.7, 25.3, 23.8, 14.1, 13.8; HRMS (ESI, Orbitrap): calcd
for C11H17N2O3 [M+H]+ 225.1239; found 225.1257.
Ethyl 5ꢀacetylꢀ4ꢀpentylꢀ1
H
ꢀpyrazoleꢀ3ꢀcarboxylate 3raa:
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143 mg (57%) of 3raa was obtained as a pale oil, Rf = 0.35 (ethyl acetate/nꢀhexane, 3:7); IR
(Neat, cmꢀ1): 3267, 2957, 1722, 1686, 1538, 1224; 1H NMR (CDCl3, 500 MHz) δ: 10.77 (bs,
7
8
1H), 4.42 (q,
J
= 7.2 Hz, 2H), 3.04 (t,
J = 7.8 Hz, 2H), 2.60 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H),
9
1.36ꢀ1.29 (m, 6H), 0.89 (t,
J
= 7.3 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ: 194.6, 160.1,
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128.8, 61.4, 31.8, 30.3, 27.7, 23.5, 22.4, 14.2, 14.9; HRMS (ESI, Orbitrap): calcd for
C13H21N2O3 [M+H]+ 253.1552; found 253.1561.
Experimental procedure of the synthesis of compound 6aa: The typical oneꢀpot, threeꢀ
component synthetic protocol used for the pyrazoles 3aaa-3raa was also used for the
synthesis of compound 6aa. Trimethylacetaldehyde was used as the aldehyde component,
EDA as diazoꢀcomponent, and acetyl acetone as 1,3ꢀdicarbonyl component.
Ethyl 2ꢀ(2ꢀ(2,4ꢀdioxopentanꢀ3ꢀylidene)hydrazinyl)acetate 6aa:
96 mg (45%) of 6aa was obtained as a red coloured oil, Rf = 0.45 (ethyl acetate/
n
ꢀhexane,
1
3:7); IR (Neat, cmꢀ1): 3449, 2981, 2933, 1748, 1672, 1629, 1510, 1361, 1207; H NMR
(CDCl3, 500 MHz) δ: 13.23 (bs, 1H), 4.39 (d,
J = 4.7 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 2.53
(s, 3H), 2.32 (s, 3H), 1.32 (t,
J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 197.1, 196.9,
168.1, 134.2, 61.8, 54.1, 31.3, 26.2, 14.1; HRMS (ESI, Orbitrap): calcd for C9H15N2O4
[M+H]+ 215.1032; found 215.1032.
Experimental procedure of the synthesis of phenyl acetaldehyde-acetyl acetone adduct
(1oa’): In a 10 mL round bottom flask, phenyl acetaldehyde (1 mmol), acetyl acetone (1
mmol) and piperidinium acetate (0.2 mmol) were taken, and reaction mixture was shaken in a
solventꢀfree condition. After the formation of aldehydeꢀacetyl acetone adduct was complete
(TLC), the reaction mixture was directly purified from silicaꢀgel column chromatography
using ethyl acetateꢀhexane as eluent in increasing polarity to yield the 1oa’.
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192 mg (95%) of 1oa’ was obtained as a pale yellow oil, Rf = 0.55 (ethyl acetate/nꢀhexane,
1
3:7), IR (Neat, cmꢀ1): 3423, 3061, 2926, 1709, 1601, 1413, 1204; H NMR (CDCl3, 500
7
8
MHz) δ: 7.43 (dd,
J
= 1.3, 7.5 Hz, 2H), 7.35 (t,
J = 7.5 Hz, 2H), 7.27 (tt, J = 1.2, 7.3 Hz, 1H),
9
6.76 (d,
J
= 16.2 Hz, 1H), 6.43 (d, J
= 16.2 Hz, 1H), 2.22 (s, 6H); 13C NMR (CDCl3, 125
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MHz) δ: 191.1, 137.0, 134.2, 128.6, 127.6, 126.0, 122.7, 111.3, 24.2; HRMS (ESI, Orbitrap):
calcd for C13H13NaO2 [M+Na]+ 224.08132; found 224.08015.
Typical experimental procedure of the one-pot, three-component dihydropyrazole
synthesis (7gca-7hda): The protocol used for the synthesis of pyrazoles 3aaa-3raa was used
for the synthesis of dihydropyrazoles 7gca-7hda.
Diethyl 5ꢀacetylꢀ4ꢀ(3ꢀnitrophenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ3,5ꢀdicarboxylate 7gca:
302 mg (80%) of 7gca (mixture of inseparable diastereomers in 1:5 ratio) was obtained as an
yellow oil, Rf = 0.34 (ethyl acetate/
n
ꢀhexane, 3:7); IR (KBr, cmꢀ1): 3340, 2984, 1724, 1532,
= 1.9, 9.3
= 1.3 Hz, 1H), 4.22ꢀ4.10 (m,
= 7.2 Hz, 3H), 0.78 (t, J =
1
1350, 1230; H NMR (CDCl3, 500 MHz) of the major diastereomer δ: 8.16 (dd,
J
Hz, 1H), 8.06 (s, 1H), 7.54ꢀ7.44 (m, 2H), 7.19 (s, 1H), 5.37 (d,
J
4H); 3.84ꢀ3.48 (m, 1H) 3.70ꢀ3.63 (m, 1H), 2.32 (s, 3H), 1.21 (t,
J
7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ: 199.3, 196.7, 167.9, 166.4, 160.5, 148.2, 144.0,
137.7, 136.4, 134.5, 130.1, 129.6, 123.6, 122.9, 85.6, 63.7, 62.8, 61.5, 54.9, 53.5, 28.0, 25.0,
13.8, 13.3; HRMS (ESI, Orbitrap): calcd for C17H20N3O7 [M+H]+ 378.13013; found
378.13112.
Ethyl 5,5ꢀdibenzoylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 7ada:
339 mg (85%) of 7ada was obtained as a white solid, Rf = 0.50 (ethyl acetate/
nꢀhexane, 3:7),
Mp. 160ꢀ161 0C; IR (KBr, cmꢀ1): 3350, 1682, 1668, 1595, 1230; 1H NMR (CDCl3, 500 MHz)
δ: 7.84 (dd, J = 1.0, 8.4 Hz, 2H), 7.62 (dd, J = 1.0, 8.4 Hz, 2H), 7.50 (tt, J = 1.0, 7.5 Hz, 1H),
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7.41ꢀ7.36 (m, 3H), 7.30 (bs, 1H), 7.22 (t,
J
= 8.4 Hz, 2H), 7.00 (d,
J
J
= 8.5 Hz, 2H), 6.92 (d,
J
= 8.5 Hz, 2H), 5.90 (d, = 1.2 Hz, 1H), 4.22ꢀ4.10 (m, 2H), 1.21 (t,
J
= 7.2 Hz, 3H); 13C NMR
7
8
9
(CDCl3, 125 MHz) δ: 193.9, 190.3, 160.8, 146.0, 134.7, 134.2, 134.1, 133.8, 132.7, 130.8,
129.3, 129.1, 129.0, 128.4, 88.4, 61.4, 55.3, 13.9; HRMS (ESI, Orbitrap): calcd for
C26H22ClN2O4 [M+H]+ 461.12681; found 461.12763.
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Ethyl 5,5ꢀdibenzoylꢀ4ꢀ(4ꢀnitrophenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 7hda
372 mg (91%) of 7hda was obtained as a white solid, Rf = 0.40 (ethyl acetate/
nꢀhexane, 3:7),
Mp. 161ꢀ162 0C; IR (KBr, cmꢀ1): 3327, 1679, 1596, 1526, 1350, 1232; 1H NMR (CDCl3, 300
MHz) δ: 7.87 (d,
J
= 8.9 Hz, 2H), 7.83 (d,
J
7.7 Hz, 2H), 7.62 (d,
J
= 7.6 Hz, 2H), 7.53 (t,
J
=
7.4 Hz, 1H), 7.43ꢀ7.38 (m, 4H), 7.25ꢀ7.16 (m, 4H), 6.01 (s, 1H), 4.24ꢀ4.07 (m, 2H), 1.22 (t,
J
= 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 193.5, 189.8, 160.6, 147.2, 144.9, 141.7,
134.4, 134.0, 133.8, 130.4, 129.3, 129.2, 129.0, 128.6, 123.3, 88.8, 61.6, 55.3, 13.9; HRMS
(ESI, Orbitrap): calcd for C26H22N3O6 [M+H]+ 472.15086; found 472.15069.
Typical experimental procedure of the one-pot, three-component pyrazole synthesis
(3aba-3sda): In a 25 mL round bottom flask, aldehyde (1 mmol), 1,3ꢀdicarbonyl compound
(1 mmol) and piperidinium acetate (0.2 mmol) were taken, and reaction mixture was shaken
in a solventꢀfree condition. The formation of aldehydeꢀ1,3ꢀdicarbonyl adduct was complete in
about 10ꢀ30 minutes (monitored by TLC). Next EDA (1.01 mmol), K2CO3 (1.5 mmol) and 10
mL of EtOH was added to it and the reaction mixture was refluxed in open air until pyrazole
formation was complete (24 h). Next the reaction mixture was concentrated and purified
directly from silicaꢀgel column chromatography using ethyl acetateꢀhexane as eluent in
increasing polarity to yield the desired the pyrazoles 3aba-3sda.
Ethyl 5ꢀbenzoylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 3aba:
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277 mg (78%) of 3aba was obtained as a white solid, Rf = 0.40 (ethyl acetate/nꢀhexane, 1:3),
Mp. 136ꢀ138 0C; IR (KBr, cmꢀ1): 3189, 2923, 1726, 1652, 1450, 1229; 1H NMR (CDCl3, 300
7
8
MHz) δ: 11.92 (bs, 1H), 7.89 (d,
J
= 6.5 Hz, 2H), 7.51 (t,
J = 6.5 Hz, 1H), 7.40ꢀ7.17 (m, 6H),
9
4.32 (q, = 6.9 Hz, 2H), 1.23 (t,
J
J
= 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ: 187.8,
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159.7, 136.5, 133.8, 133.2, 131.7, 130.2, 128.8, 128.1, 127.7, 126.6, 61.7, 13.9; HRMS (ESI,
Orbitrap): calcd for C19H16ClN2O3 [M+H]+ 355.08495; found 355.08566.
Diethyl 4ꢀ(3ꢀnitrophenyl)ꢀ1Hꢀpyrazoleꢀ3,5ꢀdicarboxylate 3gca:
250 mg (75%) of 3gca was obtained as a white solid, Rf = 0.40 (ethyl acetate/
n
ꢀhexane, 2:3),
0
1
Mp. 174ꢀ176 C; IR (KBr, cmꢀ1): 3117, 2929, 1732, 1533, 1349; H NMR (CDCl3, 500
MHz) δ: 8.25 (d,
J
= 8.2 Hz, 1H), 8.21 (s, 1H), 7.68 (d,
= 7.2 Hz, 4H), 1.16 (t,
J
= 7.6 Hz, 1H), 7.55 (t, J = 7.8 Hz,
13
1H), 4.67 (bs, 1H), 4.24 (q,
J
J
= 7.2 Hz, 6H); C NMR (CDCl3, 75
MHz) δ: 160.4, 147.3, 137.6, 136.7, 132.6, 128.1, 125.6, 124.9, 122.6, 61.6, 13.7; HRMS
(ESI, Orbitrap): calcd for C15H16N3O6 [M+H]+ 334.10391; found 334.10410.
Diethyl 4ꢀ(4ꢀcyanophenyl)ꢀ1Hꢀpyrazoleꢀ3,5ꢀdicarboxylate 3ica:
222 mg (71%) of 3ica was obtained as a white solid, Rf = 0.33 (ethyl acetate/
n
ꢀhexane, 2:3),
0
1
Mp. 174ꢀ175 C; IR (KBr, cmꢀ1): 3440, 2925, 1732, 1606, 1538, 1440, 1281; H NMR
(CDCl3, 500 MHz) δ: 11.53 (bs, 1H), 7.68 (d,
J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 4.28
(q,
J = 7.1 Hz, 4H), 1.20 (t, J
= 7.1 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ: 159.8, 137.3,
135.8, 131.1, 131.0, 125.9, 118.7, 111.6, 61.7, 13.8; HRMS (ESI, Orbitrap): calcd for
C16H16N3O4 [M+H]+ 314.11408; found 314.11451.
Ethyl 5ꢀbenzoylꢀ4ꢀ(3ꢀfluorophenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 3sda:
270 mg (80%) of 3sda was obtained as a white solid, Rf = 0.45 (ethyl acetate/
n
ꢀhexane, 1:3),
0
1
Mp. 138ꢀ140 C; IR (KBr, cmꢀ1): 3222, 2992, 1709, 1654, 1577, 1431, 1236; H NMR
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(CDCl3, 500 MHz) δ: 12.17 (bs, 1H), 7.98ꢀ7.77 (m, 2H), 7.49 (t,
J = 7.2 Hz, 1H), 7.35 (t, J =
5
6
7
8
7.3 Hz, 2H), 7.26ꢀ7.20 (m, 1H), 7.10ꢀ7.01 (m, 2H), 6.97 (t,
J
= 7.2 Hz, 1H), 4.30 (q,
J
= 7.1
= 245.2
J = 8.2 Hz), 130.0, 129.0, 128.9 (d, J = 9.1 Hz), 126.3,
Hz, 2H), 1.22 (t,
J
= 7.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ: 187.7, 162.9 (d,
J
9
Hz), 159.8, 136.4, 133.1, 132.5 (d,
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126.2, 117.5 (d,
J = 22.7 Hz), 114.7 (d, J = 20.9 Hz), 61.7, 13.7; HRMS (ESI, Orbitrap):
calcd for C19H16FN2O3 [M+H]+ 339. 1145; found 339. 1145.
Typical experimental procedure of the one-pot, three-component pyrazole synthesis
(3gab-3iac): The protocol used for the synthesis of pyrazoles 3aaa-3raa was used for the
synthesis of compounds 3gab-3iac.
Tertꢀbutyl 5ꢀacetylꢀ4ꢀ(3ꢀnitrophenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 3gab:
255mg (77%) of 3gab was obtained as a white solid, Rf = 0.40 (ethyl acetate/nꢀhexane, 3:7),
Mp. 150ꢀ151 0C; IR (KBr, cmꢀ1): 3213, 2981, 1725, 1684, 1524, 1349, 1234, 1157; 1H NMR
(CDCl3, 500 MHz) δ: 11.80 (bs, 1H), 8.25 (d,
J = 8.2 Hz, 1H), 8.21 (s, 1H), 7.67 (d, J = 7.8
Hz, 1H), 7.57 (t,
J
= 7.9 Hz, 1H), 2.60 (bs, 3H), 1.36 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ:
193.5, 158.4, 147.5, 136.5, 132.9, 128.3, 125.5, 123.2, 122.6, 84.0, 27.8 (2C); HRMS (ESI,
Orbitrap): calcd for C16H18N3O5 [M+H]+ 332.1247; found 332.1217.
Tertꢀbutyl 5ꢀacetylꢀ4ꢀ(4ꢀcyanophenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 3iab:
243 mg (78%) of 3iab was obtained as a white solid, Rf = 0.45 (ethyl acetate/nꢀhexane, 3:7),
0
1
Mp. 184ꢀ185 C; IR (KBr, cmꢀ1): 3213, 2978, 2236, 1716, 1692, 1223, 1157; H NMR
(CDCl3, 500 MHz) δ: 11.90 (bs, 1H), 7.68 (d, = 8.2 Hz, 2H), 7.44 (d, = 8.2 Hz, 2H), 2.56
J
J
(bs, 3H), 1.36 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ: 193.2, 158.3, 136.6, 132.9, 131.2,
130.9, 127.7, 123.9, 118.8, 111.2, 83.8, 27.8 (2C); HRMS (ESI, Orbitrap): calcd for
C17H18N3O3 [M+H]+ 312.1348; found 312.1338.
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Benzyl 5ꢀacetylꢀ4ꢀ(3ꢀnitrophenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 3gac:
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296 mg (81%) of 3gac was obtained as a white solid, Rf = 0.35 (ethyl acetate/nꢀhexane, 3:7),
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9
0
1
Mp. 164ꢀ165 C; IR (KBr, cmꢀ1): 3234, 2926, 1731, 1685, 1525, 1350, 1188; H NMR
(CDCl3, 500 MHz) δ: 11.90 (bs, 1H), 8.16 (d, = 7.3Hz, 1H), 8.15 (s, 1H), 7.61 (d, = 7.6
Hz, 1H), 7.47 (t, = 7.6 Hz, 1H), 7.32ꢀ7.24 (m, 3H), 7.09 (d, = 7.0 Hz, 2H), 5.18 (s, 2H),
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J
J
J
J
2.52 (bs, 3H); 13C NMR (CDCl3, 75 MHz) δ: 192.8, 159.1, 147.4, 136.3, 133.8, 132.3, 128.7,
128.5, 128.4, 128.3, 125.3, 123.9, 122.8, 67.7, 27.8; HRMS (ESI, Orbitrap): calcd for
C19H16N3O5 [M+H]+ 366.1090; found 366.1083.
Benzyl 5ꢀacetylꢀ4ꢀ(4ꢀcyanophenyl)ꢀ1Hꢀpyrazoleꢀ3ꢀcarboxylate 3iac:
259 mg (75%) of 3iac was obtained as a white solid, Rf = 0.30 (ethyl acetate/nꢀhexane, 3:7),
Mp. 180ꢀ181 0C; IR (KBr, cmꢀ1): 3448, 3205, 2923, 2229, 1734, 1666, 1446, 1223; 1H NMR
(CDCl3, 500 MHz) δ: 11.78 (bs, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.38ꢀ7.30 (m, 6H), 7.08 (d, J =
6.8 Hz, 2H), 5.18 (s, 2H), 2.48 (bs, 3H); 13C NMR (CDCl3, 125 MHz) δ: 194.3, 159.1, 135.9,
134.0, 131.3, 130.8, 128.8, 128.5, 128.3, 126.9, 124.6, 118.6, 111.6, 67.6, 27.8; HRMS (ESI,
Orbitrap): calcd for C20H16N3O3 [M+H]+ 346.1192; found 346.1187.
Typical experimental procedure for the one-pot, three-component synthesis of pyrazole
(3gad-3gaj): In a 25 mL round bottom flask, aldehyde (1 mmol), acetyl acetone (1 mmol)
and piperidinium acetate (0.2 mmol) were taken, and reaction mixture was shaken in a
solventꢀfree condition. The formation of aldehydeꢀacetyl acetone adduct was complete in
about 10 minutes (monitored by TLC). Next tosyl hydrazone (1.5 mmol), K2CO3 (3.0 mmol)
and 10 mL of MeOH was added to it and the reaction mixture was refluxed in open
atmosphere until pyrazole formation was complete (12 h). Next the reaction mixture was
concentrated and extracted with ethyl acetate/water. Next the organic layer was dried over
anhydrous sodium sulphate, concentrated and purified directly from silicaꢀgel column
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chromatography using ethyl acetateꢀhexane as eluent in increasing polarity to yield the
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desired the pyrazoles 3gad-3gaj.
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1ꢀ(3ꢀ(3ꢀmethoxyphenyl)ꢀ4ꢀ(3ꢀnitrophenyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)ethanone 3gad:
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303 mg (90%) of 3gad was obtained as a pale yellow solid, Rf = 0.50 (ethyl acetate/
nꢀhexane,
1:1), Mp. 256ꢀ258 0C; IR (KBr, cmꢀ1): 3236, 3067, 2939, 1689, 1532, 1348, 1230, 1156; 1H
NMR (CDCl3 + DMSOd6, 300 MHz) δ: 8.20ꢀ8.13 (m, 2H), 7.62ꢀ7.49 (m, 2H), 7.20 (t, J = 8.5
Hz, 1H), 6.90ꢀ6.80 (m, 3H), 3.68 (s, 3H), 2.60 (bs, 3H); 13C NMR (CDCl3 + DMSOd6, 75
MHz) δ: 193.9, 158.6, 146.9, 136.2, 134.0, 128.9, 128.6, 128.0, 124.6, 121.0, 119.3, 116.6,
113.5, 112.4, 54.2, 26.7; HRMS (ESI, Orbitrap): calcd for C18H16N3O4 [M+H]+ 338.1141;
found 338.1129.
1ꢀ(4ꢀ(3ꢀnitrophenyl)ꢀ3ꢀ(4ꢀnitrophenyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)ethanone 3gae:
299 mg (85%) of 3gae was obtained as a white solid, Rf = 0.53 (ethyl acetate/nꢀhexane, 1:1),
Mp. 200ꢀ202 0C; IR (KBr, cmꢀ1): 3163, 2956, 1664, 1600, 1534, 1350, 1171, 1110; 1H NMR
(CDCl3 + DMSOd6, 300 MHz) δ: 14.02 (bs, 1H), 8.28ꢀ8.10 (m, 4H), 7.64ꢀ7.55 (m, 2H), 7.52
(d,
J
= 8.5 Hz, 2H), 2.63 (bs, 3H); 13C NMR (CDCl3 + DMSOd6,, 75 MHz) δ: 193.1, 146.9,
146.0, 138.8, 135.7, 133.1, 128.3, 127.4, 124.3, 122.8, 121.3, 117.7, 26.7; HRMS (ESI,
Orbitrap): calcd for C17H13N4O5 [M+H]+ 353.0886; found 353.0879.
4ꢀ(5ꢀacetylꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ1Hꢀpyrazolꢀ4ꢀyl)benzonitrile 3iad:
282 mg (89%) of 3iad was obtained as a white solid, Rf = 0.46 (ethyl acetate/nꢀhexane, 1:1),
0
Mp. 208ꢀ210 C; IR (KBr, cmꢀ1): 3264, 3061, 3008, 2922, 2229, 1682, 1607, 1433, 1391,
1263; 1H NMR (CDCl3 + DMSOd6, 300 MHz) δ: 7.77 (d,
2H), 7.25 (t, = 7.9 Hz, 1H), 6.92 (d, = 8.1 Hz, 1H), 6.80ꢀ6.76 (m, 2H), 3.66 (s, 3H), 2.53
J = 7.9 Hz, 2H), 7.40 (d, J = 7.9 Hz,
J
J
(bs, 3H); 13C NMR (CDCl3 + DMSOd6, 75 MHz) δ: 191.9, 157.3, 145.8, 139.7, 136.3, 129.7,
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