HBF4/ACN: A simple and efficient protocol for the synthesis of pyrazoles under ambient reaction conditions

Article abstract of DOI:10.1080/00397911.2019.1692869

An efficient and novel protocol for pyrazole synthesis has been developed by using fluoroboric acid as the acid catalyst. Simple and easily available 1,3-diketone and hydrazine derivatives are taken as the substrates for this purpose. The reaction entails

Full text of DOI:10.1080/00397911.2019.1692869

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
HBF4/ACN: A simple and efficient protocol for the
synthesis of pyrazoles under ambient reaction
conditions
Roktopol Hazarika, Manashjyoti Konwar, Krishnaiah Damarla, Arvind Kumar
& Diganta Sarma
To cite this article: Roktopol Hazarika, Manashjyoti Konwar, Krishnaiah Damarla,
Arvind Kumar & Diganta Sarma (2019): HBF4/ACN: A simple and efficient protocol for the
synthesis of pyrazoles under ambient reaction conditions, Synthetic Communications, DOI:
10.1080/00397911.2019.1692869
To link to this article: https://doi.org/10.1080/00397911.2019.1692869
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https://doi.org/10.1080/00397911.2019.1692869
HBF4/ACN: A simple and efficient protocol for the synthesis
of pyrazoles under ambient reaction conditions
Roktopol Hazarikaa, Manashjyoti Konwara, Krishnaiah Damarlab, Arvind Kumarb,
and Diganta Sarmaa
b
aDepartment of Chemistry, Dibrugarh University, Dibrugarh, India; AcSIR, Salt and Marine Chemicals
Division, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, India
ABSTRACT
ARTICLE HISTORY
Received 3 September 2019
An efficient and novel protocol for pyrazole synthesis has been
developed by using fluoroboric acid as the acid catalyst. Simple and
easily available 1,3-diketone and hydrazine derivatives are taken as
the substrates for this purpose. The reaction entails mild reaction
conditions and produces desired pyrazoles in good to excellent
yields. Easy accessibility, easy handling, broad substrate scope, evad-
ing metal catalyst and economic viability make this protocol advan-
tageous to most of the previously reported literature.
KEYWORDS
Pyrazole; fluoroboric acid;
hydrazine; 13-diketone;
metal free
GRAPHICAL ABSTRACT
ꢀ Metal Free protocol
ꢀ Shorter Reaction
Time(30 min. to 4 h)
ꢀ Easy Availability
ꢀ Ambient Conditions
Introduction
Along with the fast developing world, due to the revolution in lifestyles and rapid
changes in environment and climate, different diseases and disordernesses have become
the major issues of an unwealthy and unhealthy life span over the last few decades.[1]
CONTACT Diganta Sarma
dsarma22@gmail.com
Department of Chemistry, Dibrugarh University, Dibrugarh-
786004, Assam, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
R. HAZARIKA ET AL.
To overcome these difficulties, scientists are able to design varieties of drug molecules.
Despite the keen efforts to develop small molecules with enhanced therapeutic proper-
ties, the scientific community are still in a hunt for new drug molecules with improved
efficiency, selectivity and proper safety.[2] In this regards, N-heterocyclic compounds are
prominent choices for researchers as they are universally acknowledged for displaying a
broad range of biological properties.[3]
Pyrazoles, belonging to N-heterocyclic compounds are widely found as the core struc-
ture in a wide variety of organic compounds. After Knorr, who first synthesized and
exposed the biological activities of pyrazole, its pathological voyage instigates toward a
demanding future.[4–5]
Pyrazoles show some potent pharmaceutical properties against inflammation,[6a] can-
cer,[6b] obesity,[6c] gastric[6d] etc. In agricultural field, pyrazole moiety is usually consid-
ered as an important active component of some insecticidal,[7a] acaricidal,[7b]
fungicidal,[7c,d] and antiviral[7e] molecules. Along with these pharmaceutical properties,
pyrazoles can also act as ligands in different organic reactions, some pyrazoles are used
in supra-molecular[8a] and polymer chemistry,[8b] food industry,[8c] cosmetic color-
ings[8d] and UV stabilizers,[8e] while some have liquid crystal properties.[8f] Therefore,
development of efficient methodology of its construction has turned out to be an
important issue in synthetic organic chemistry. Acid catalyzed pyrazole synthesis turns
out to be a promising concept throughout this expedition.
Though there exists a numerous traditional metal free procedures for pyrazole syn-
thesis,[9–12] most of them require vigorous conditions, high loading or longer reaction
times as shown in Scheme 1. Therefore, new synthetic strategies for pyrazole are still
Scheme 1. Some literature based reports with the present work.

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SYNTHETIC COMMUNICATIONSV
3
highly desirable. Hence, we cast our interest in search of a simple acid catalyst which
behaves as an efficient catalyst in shorter reaction time compared to the previous cata-
lysts at ambient reaction conditions.
Fluoroboric acid and its salts were first studied in the earliest of 1809 and it is basic-
ally used as a precursor to synthesize some other fluoroborate salts.[13,14] This acid is a
solution of boron trifluoride in hydrogen fluoride which has super acidic property. But
the solution of HBF4 in HF is not suitable for glassware due to its corrosive nature.
Therefore, we are using aqueous fluoroboric acid in our protocol which exists and is
stable onlyꢀas a solvated ion pair [H3Oþ][BF4ꢀ]. H3Oþ acts as the cation and the tetra-
hedral BF4 acts as the anion and they bind through strong hydrogen bond which
brings extra stability to this solvated ion pair (Fig. 1).[15]
The solution of BF3 in HF is supremely acidic, with an approximate speciation of
[H2Fþ][BF4–] and having a Hammett acidity function of –16.6 at 7 mol % BF3, which
easily declares fluoroboric acid as super acid.[16] Due to its easy handling, comparable
acid strength with that of hydrochloric acid and sulfuric acid, aqueous fluoroboric acid
is a better choice to the researchers.
Results and discussion
We initiated our investigation by taking 2,4-dinitrophenyl hydrazine (1a) and acetyl
acetone (2a) as the model substrates for the desired pyrazole (3a) synthesis. Initially, we
investigated with various organic acids (Table 1, entries 1–5) and moved toward inor-
ganic acids (Table 1, entries 6–10) as no prominent results were obtained with the
organic acids in our investigation. Among the inorganic acids we have screened, fluo-
roboric acid (Table 1, entry 6) came out to be superior to the others and gave upto
95% yield in acetonitrile within 4 h. The presence of most electronegative fluorine atoms
makes fluoroboric acid supremely acidic which is confirmed by Hammet acidity func-
tion which is already discussed.[15] Therefore, it behaves as the efficient catalyst among
the screened catalysts. After optimizing the catalyst, we extended our interest to
improve the yield of the reaction by varying other parameters one at a time.
In this investigation, it was observed that the reaction gave superior results in polar
aprotic solvents such as CH3CN (Table 2, entry 7) and THF (Table 2, entry 8) as com-
pared to polar protic solvents such as CH3OH (Table 2, entry 2), C2H5OH (Table 2,
entry 3) and non-polar solvents such as toluene (Table 2, entry 10). Also we tried
some green solvents such as H2O (Table 2, entry 1), ethylene glycol (Table 2, entry 11)
Figure 1. H-bonding of fluoroboric acid in water.

4
R. HAZARIKA ET AL.
Table 1. Optimization of catalyst.a
Sl. No.
Catalyst
Cyanuric acid
Citric acid
Acetic acid
Anthranilic acid
Gallic acid
Fluoroboric acid
Boric acid
Phosphoric acid
Tungstic acid
Molybdic acid
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
6
6
6
6
6
4
6
6
6
6
50
40
30
60
40
95
40
60
60
60
10
aReaction conditions: 2,4-dinitrophenyl hydrazine (1 mmol), Acetyl acetone (1.2 mmol), catalyst (20 mol%), solvent (2 mL),
room temperature.
bIsolated yield.
Bold indicates the optimized value.
Table 2. Solvent optimization.a
Sl. No.
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
H2O
6
6
6
3
2
1
0.5
1
6
–
CH3OH
C2H5OH
CH3CN
CH3CN
CH3CN
CH3CN
THF
DMF
Toluene
Ethylene glycol
Polyethylene glycol
60
60
95
95
93
92
70
30
40
30
30
9
10
11
12
6
6
6
aReaction conditions: 2,4-dinitrophenyl hydrazine (1 mmol), Acetyl acetone(1.2 mmol), catalyst (20 mol%) in solvent
(2 mL) were stirred at room temperature.
bIsolated yield.
Bold indicates the optimized value.
and PEG (Table 2, entry 12) but the results were not convincing. The possible reason
may be, in aprotic solvent there is no scope of hydrogen bonding of the catalyst with
the solvent and therefore the hydrogen is readily available for abstraction by the car-
bonyl group which is shown in the mechanism (Scheme 2). Among all the screened sol-
vents, it was found that HBF4 in acetonitrile catalyzed the reaction very fast and it took
only 30 min for completion of the reaction and it turned out to be the best reaction
condition for our study.
To justify the optimized reaction condition and to extend the scope of the reaction,
we investigated the reaction with various hydrazines with different substituted acetyl

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5
Scheme 2. Mechanistic pathway.
acetones under the same optimized reaction condition and the results are presented in
Table 3. The expected products were obtained in reasonable reaction times with good
to excellent yields without the formation of any other side product. The yields and reac-
tion times are satisfactorial irrespective of the functional group present in both the
hydrazine and diketone derivatives.
We have further studied the tolerance of our catalytic protocol toward fused ring as
well as heteroatom bearing hydrazines and higher substituted 1,3-dicarbonyl compounds
and the reactions proceeded smoothly and gave satisfactory yields in reasonable time
periods. The results are shown in Table 4 (entries 1–5). We have also tried to extend
our protocol by using 1,3-unsymmetrical and 1,3-cyclic diketones but the production of
regio-isomers in case of unsymmetrical diketone and very negligible yield for cyclic
diketone were observed. (Table 4, entries 6–7).

6
R. HAZARIKA ET AL.
Table 3. Substrate scope for pyrazole synthesis.a
Sl. NO.:
R
R/
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
2,4-dinitro
3-NO2
3-NO2
4-Br
4-Br
3-NO2
4-CN
4-NO2
3-NO2
4-OCH3
4-Cl
4-OCH3
4-Cl
4-CH3
4-NO2
H
4-CN
4-CF3
4-CH3
H
H
CH3
H
CH3
C2H5
CH3
H
Cl
H
CH3
CH3
Cl
Cl
Cl
CH3
Cl
H
CH3
0.5
2
2
3
3
3
3
1
4
2
3
3
4
4
3
2
4
2
3
92
95
90
88
85
87
83
95
90
90
85
88
90
82
76
90
81
90
80
9
10
11
12
13
14
15
16
17
18
19
aReaction conditions: hydrazine derivatives(1 mmol), 1,3-diketones(1.2 mmol), HBF4 (20 mol%) was stirred at room temperature.
bIsolated Yield.
Table 4. Effect of fused ring, heteroatom bearing hydrazines and higher substituted 1,3-dicarbonyl
compounds on pyrazole synthesis.a
Sl. No.
1
Hydrazine derivatives
4-CF3PhNHNH2
R/, R1, R2
R/¼H, R1¼C2H5, R2¼C2H5
Time(h)
4
Yieldb(%)
90
2
3
4
R/¼Cl, R1¼CH3 ,R2¼CH3
R/¼H, R1¼C2H5, R2¼C2H5
R/¼C2H5, R1¼CH3, R2¼CH3
4
3
4
74
88
81
5
R/¼H, R1¼CH3, R2¼CH3
1
90
6
7
4-CF3PhNHNH2
R/¼H, R1¼CH3, R2¼OC2H5
4
4
70c
4-OCH3PhNHNH2
–
aReaction conditions: hydrazine derivatives(1 mmol), 1,3-diketones(1.2 mmol), HBF4 (20 mol%) was stirred at room temperature.
bIsolated Yield.
cRegio-isomers are formed.

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Proposed mechanism
Based on the literature reports, the mechanism of acid catalyzed pyrazole synthesis can
be discussed as listed in Scheme 2 which was initially proposed by Knorr himself.[17]
It starts with abstraction of the proton (from catalyst) by one of the nucleophilic car-
bonyl groups of the symmetrical diketone which is then attacked by the free nitrogen
atom of the hydrazine derivative. The same oxygen again attacks the proton on the
attached hydrazine to give intermediate 2 from where a water molecule is lost. The mol-
ecule is then cyclized (intermediate 4) and subsequent loss of water finally gives
the product.
Conclusions
In summary, a simple, efficient protocol is presented for the acid catalyzed pyrazole
synthesis which gives good to excellent yields in shorter periods of time. To the best of
our knowledge, the reaction portrayed in Scheme 1 is the first synthetic procedure of
pyrazole using Fluoroboric acid in Acetonitrile as the catalytic system. Easy handling,
easy accessibility, shorter reaction times, ambient reaction conditions are the advantages
of our protocol. We anticipate that the current method will be a more practical alterna-
tive to the other existing procedures.
Experimental
All reactions were performed under atmospheric conditions using oven dried glassware.
All reagents and solvents were purchased from common commercial sources and used
without further purification unless otherwise stated. All reported yields are isolated
yields. Thin layer chromatography (TLC) was carried out using aluminum sheets pre-
coated with silica gel 60 F254 (Merck) and was visualized under 254 nm UV light.
1
Column chromatography was performed on silica gel (120–230 mesh). H &13C NMR
spectra were recorded on 500 MHz and 125 MHz spectrometer using TMS as an internal
standard. Chemical shifts are reported in parts per million (ppm, d).
General experimental procedure for synthesis of pyrazoles using HBF4 as catalyst
room temperature
In a round bottom flask a mixture of hydrazine derivative (1 mmol) and 1,3-diketone
(1.2 mmol) was taken and Fluoroboric acid (20 mol%) was added to it and then allowed
to stir at room temperature for the given time period as mentioned in Table 3. The pro-
gress of the reaction was monitored by TLC. After completion of the reaction it was
extracted with ethyl acetate (3 ꢁ 10 mL), washed with distilled water and brine solution,
dried over anhydrous sodium sulfate and concentrated under reduced pressure. The
resulting residue was purified through silica gel column chromatography to get the
desired product.

8
R. HAZARIKA ET AL.
Spectral data for the selected compounds
1
1-(2,4-Dinitro-phenyl)-3,5-dimethyl-1H-pyrazole (Table 3, entry 1): Yield ¼ 92%; H
NMR (500 MHz, CDCl3): d ¼ 8.80 (d, J ¼ 2.5 Hz, 1 H), 8.54 (dd, J ¼ 8.7, 2.5 Hz, 1 H),
7.71 (d, J ¼ 8.7 Hz, 1 H), 6.11 (s, 1 H), 2.31–2.23 (m, 6 H).
13C NMR (126 MHz, CDCl3): d ¼ 152.36 (s), 146.24 (s), 145.64 (s), 140.92 (s), 137.94
(s), 129.36 (s), 127.35 (s), 121.00 (s), 108.89 (s), 13.47 (s), 11.61 (s).
Supporting information
1
General Information, Experimental and Analytical data, H and 13C NMR spectra and
characterization data all are found in the “Supplementary Content” section of this
article’s webpage.
Funding
D.S. is thankful to DST, New Delhi, India for a research grant [No. EMR/2016/002345]. Authors
thank the Department of Science and Technology for financial assistance under DST-FIST pro-
gram and UGC, New Delhi for Special Assistance Program (UGC-SAP) to the Department of
Chemistry, Dibrugarh University.
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