Field of Invention: In heterocyclic chemistry, 4-formylpyrazoles are one notable
examples of having important applications in the field of medicinal chemistry. They act as
important precursors or intermediates for synthesis of several heterocyclic compounds of
biological interest and drugs. This invention describes a very efficient and one-pot synthetic
process for 4-formylpyrazoles.
Background:
Pyrazoles, five-membered heterocycles, contain two adjacent nitrogen atoms and constitute
an interesting class of compounds with diverse applications particularly in the field of
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medicinal chemistry. It was Ludwig Knorr who first proposed the term "pyrazole" in 1883
and Edward Buchner who first synthesized it in 1889. Nowadays pyrazoles are attracting
researchers worldwide due to various biological activities. A small number of natural
products contain pyrazole moiety as nature has a limited number of enzymes that can form NN bond (Bioorg. Med. Chem. Lett, 2010, 4657). It has been well documented that pyrazoles
show anti-inflammatory, antiviral, antipyretic, antimicrobial, anticonvulsant, anti-depressant,
antihistaminic, insecticidal, fungicidal and anticancer properties (Chin Chem Lett. 2012, 23,
57; Eur. J. Med. Chem. 2009, 44, 3746; Bioorg. Med. Chem. 2010, 18, 4965; Eur. J. Med.
Chem. 1995, 30, 147; J. Med. Chem. 1985, 28, 256; Eur. J. Med. Chem. 2015, 90, 889;
Bioorg. Med. Chem. Lett, 2012, 22, 4773; Org. Biomol. Chem. 2013, 11, 4891; Eur. J. Med.
Chem. 2013, 62, 410). Among pyrazoles, 4-functionalized pyrazoles are of much importance
and associated with a large number of biological and other applications. The 4-
formylpyrazoles, in particular, play central role as the key intermediates or generation of
starting materials (Figure-1) for various heterocycles like Pyrazolylpyrazolines, 4-HPyrazolopyran, Pyrazolylbenzoxazole, Pyrazolothiadiazepines, Pyrazolyloxadiazolines,
Chromenopyrazolones etc. that possess excellent biological potential. A non-steroidal antiinflammatory drug, Lonazolac is synthesized via the intermediary of 4-formylpyrazole (I).
Thiazolidine-2,4-dione linked pyrazole derivatives synthesized by using 4-formylpyrazoles
(I) were found to exhibit anticancer potential (US 2008/0275094A1, 2008). 1,3-
Diarylpyrazole based carboxylic acids which were synthesized from 4-formylpyrazoles were
also found to display anti-inflammatory activity (US Patent No. 4095025, 1978). Most of
pyrazole based compounds possess biological activity such as anti-inflammatory, anti-tumor,
anti-bacterial, and anti-fungal.
Among the reported procedures the most common method for synthesizing 4-
formylpyrazoles involves the reaction of ketone with substituted hydrazine in organic
solvents like alcohols in first-step and conversion of corresponding hydrazone into 4-
formylpyrazole derivative using Vilsmeier-Haack reagent in second-step (Tetrahedron
Lett. 1969, 10, 109; Synth. Commun. 2008, 39, 316). Other methods are oxidation of
corresponding alcohols, hydrolysis of 4-arylaminomethyl-3-trimethylsilylpyrazoles
(Arkivoc 2011, 1, 196). In view of the importance of 4-formylpyrazoles in synthetic organic
chemistry and in continuation of our efforts to develop mild and efficient protocols to achieve
the compounds of importance, it was worthwhile to explore new alternates. There is still a lot
of interest in finding novel methods for preparing 4-formylpyrazole derivatives because of
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their potential application as precursors in synthesis of different organic and heterocyclic
compounds.
Figure-1: 4-Formylpyrazoles as precursors for various compounds
Detailed Description of the Invention:
As already discussed, one of the important methods for synthesizing 4-formylpyrazole derivatives is a two-step process which includes the preparation of hydrazones (Step-I) in alcohols and cyclisation followed by formylation (Step-II) using the Vilsmeier-Haack reagent (Scheme-1, Table-1). This method involves the use of different solvents and thus is responsible for generation of huge chemical wastes in addition to providing low yields.

Scheme-1: Two-Step Procedure for 4-Formylpyrazoles (used EtOH as a solvent)
Owing to huge synthetic and medicinal potential of 4-formylpyrazole derivatives and in continuation of our research work related to explore efficient and novel greener synthetic protocols for important key intermediates and bioactive heterocycles, a mild, efficient and one-pot synthetic protocol has been developed (Scheme-2). Advantageously, the present protocol involves the use of reactants and reagents in a single pot/reactor in presence of solvents. Further, it reduces the generation of huge chemical waste during work-up of the reaction in addition to giving high yield products. Initially, feasibility of the reaction to synthesize 4-formylpyrazole derivatives was studied under different reaction conditions. Then reaction conditions were optimised for better yields (Scheme-2, Table-2) via one pot method. In this method, a mixture of acetophenone (1) and phenylhydrazine (2) in N,N-dimethyl formamide (DMF) in presence of a catalytic amount of conc. sulphuric acid was stirred at 40-45? temperature for T1 time. Then reaction mixture was treated with POCl3 drop-wise at 0-5? and stirred the resulting reaction mixture for T2 time at 70-75? temperature. After workup final products were obtained in excellent percentage yields in range of 74-93 (Table-2). In order to explore the advantages of the one-pot method in terms of yields, the comparative study was also conducted by performing the reactions of various substituted acetophenones and phenylhydrazine via classical (Two-Step Procedure) in EtOH & DMF and one-pot methods. It was observed that if reactions are performed in two steps using alcohols and DMF according to reported method, the percentage yields lie in the rage 43-85. However, when DMF was taken as a solvent in both the steps the reactions led to the formation of final products in 77-87 percentage yields which are better than the reported ones.

Scheme-2: Synthesis of 4-Formypyrazoles via One-Pot Method
Table-2: Reaction times and percentage yields of the synthesized compounds under different reaction conditions (Conventional Two-Step and One-Pot Methods)
Sr. No. Compd. T1 T2 Yield (%) T3
(Step-I) T4
(Step-II) Overall
Yield (%) T3
(Step-I) T4
(Step-II) Overall
Yield (%)
One-Pot Method (in DMF) Two-Step Method (in DMF) Two-Step Method* (in EtOH)
1 4a 90 165 92 90 120 87 45 240 80
2 4b 150 180 87 120 105 85 50 220 43
3 4c 90 150 89 90 130 77 46 220 76
4 4d 105 165 95 105 150 87 40 185 82
5 4e 100 150 88 90 105 86 45 190 85
6 4f 105 165 84 NA NA - 40 130 81
7 4g 135 180 74 NA NA - 155 270 62
8 4h 180 600 80 NA NA - NA NA -
9 4i 210 900 88 NA NA - NA NA -
10 4j 150 240 83 NA NA - NA NA -
*Reported method; Reaction times T1, T2, T3 etc are given in minutes.
The synthesized compounds were characterised on the basis of their spectroscopic data. In IR spectrum, a stretching band appeared at 1670 cm-1 confirmed the presence of C=O group of aldehyde functionality. In 1H NMR spectrum, appearance of a signal near d10 due aldehydic proton further confirms the formation of 4-formylpyrazole derivatives. The chemical shift (d) near 8.5 ppm due to pyrazole-5H also supports the formation of pyrazole nucleus. In 13C NMR spectrum, chemical shift values (d) around 185 ppm indicates presence of carbonyl group in all the synthesized compounds. 13C NMR Chemical shift(d) at 154 ppm (C=N) indicates that pyrazole moiety is present in all the compounds. In case of 1H NMR spectrum of 3b a signal appears at d 2.42 ppm due to methyl protons. In case of 19F NMR spectrum 3c, a signal due to fluorine appears at d (-110) ppm which confirms the presence of fluorine in the compound.
General procedure for synthesis of 4-formypyrazole derivatives:
Acetophenone (8.3 mmol, 1eq) and phenylhydrazine (9.5 mmol, 1.1 eq) were added to DMF (7ml) in the presence of a catalytic amount of conc. sulphuric acid and reaction mixture was stirred at 40-45? for 1-2 hrs, and cooled to room temperature. Then kept the reaction mixture in an ice bath and added POCl3 (3.46 g) dropwise to the reaction mixture at 0 -10?. After that reaction mixture was stirred at 70-75? for 3-4 hrs. Reaction mixture was cooled to room temperature and poured into ice-cold water. After neutralization with sodium bicarbonate, the crude solid obtained was filtered and recrystallized from ethanol. Similarly, other derivatives were prepared.
Physical and characterization data of the synthesized compounds:
1,3-Diphenylpyrazole-4-carbaldehyde (4a): Colour: Off White, Yield: 91%, Melting point: 142-146?, NMR (CDCl3, 500 MHz)d(ppm):10.13 (s, CHO), 8.61 (s, Hpyrazole), 7.83- 7.32 (m, 10H, Haromatic), FTIR:?max (cm-1): 3121.77-3062.44 (C-H aromatic str), 1671(C=O str), 1599.48(C=N str.),1524-1449 (C=C str.),1224.95(C-N str.), 13C NMR (CDCl3,500 MHz) d(ppm): 185.22(C-1''''), 154.82 (C-3), 139.05 (C-1'), 119.78(C-4).
3-(p-Methylphenyl)1--phenylpyrazole-4-carbaldehyde (4b):Colour :Off white, Yield: 87%, Melting Point: 115?-120?, 1H NMR (CDCl3, 500 MHz)d(ppm): 10.13 (s, 1H, CHO), 8.61 (s, 1H, Hpyrazole), 7.78- 7.25 (m, 9H, Haromatic),2.42 (s,3H, CH3), FTIR:?max (cm-1): 3119.77-3030.44 (C-H aromatic str,),1670 (C=O str),1599.48 (C=N str.),1519-1452 (C=C str.), 1224.95 (C-N str.), 13C NMR (CDCl3,500 MHz) d(ppm): 185.22 (C-1''''), 154.82 (C-3), 139.05 (C-1'), 119.78 (C-4), 21.39 (C-1a).
3-(p-Flourophenyl)-1-phenylpyrazole-4-carbaldehyde (4c) :Colour: Off White, Yield: 89%, Melting point:162?-166?, 1H NMR (CDCl3, 500 MHz)d(ppm):10.02 (s, 1H, CHO), 8.51 (s, 1H, Hpyrazole), 7.88- 7.16(m, 9H, Haromatic), FTIR:?max (cm-1): ): 3123.77-3028.44 (C-H aromatic str,),1670 (C=O str), 1600.19 (C=N str.), 1451.76-1383 (C=C str.), 1224.95 (C-N str.), 13C NMR (CDCl3,500 MHz) d(ppm):185.22 (C-1''''), 164.56 (C-4''), 153.82 (C-3), 138.05 (C-1'), 115.78 (C-4), 19F NMR (CDCl3,80 MHz) d(ppm): -110
3-(p-Chlorophenylpyrazole-1-pyrazole-4-carbaldehyde(4d) :Colour: Off White, Yield: 93%, Melting point: 137?-144?, 1H NMR (CDCl3, 500 MHz)d(ppm):10.02 (s, 1H, CHO), 8.52 (s, 1H, Hpyrazole), 7.84- 7.26(m, 9H, Haromatic), FTIR:?max (cm-1): 3121.99-3065.44 (C-H aromatic str,), 1670 (C=O str), 1600.31 (C=N str.), 1520-1446 (C=C str.), 1223.95 (C-N str.), 1093 (C-Cl),13C NMR (CDCl3,500 MHz) d(ppm): 184.42(C-1''''), 153.15 (C-3), 139.91 (C-1'), 119.74 (C-4).
3(p-Methoxyphenylpyrazole)-1-phenyl-4-carbaldehyde(4e) :Colour: Off white, Yield: 88%, Melting point: 137?-142?, 1H NMR (CDCl3, 500 MHz)d(ppm):10.02 (s, 1H, CHO), 8.50 (s, 1H, Hpyrazole), 7.79- 7.01(m, 9H, Haromatic), 3.27 (s,3H, OCH3), FTIR:?max (cm-1): 3121.05-3024.17 (C-H aromatic str,), 1670.95 (C=O str), 1609.48 (C=N str.), 1520-1455 (C=C str.), 1225.98(C-N str.), 1172.82 (C-O str.), 13C NMR (CDCl3,500 MHz) d(ppm): 185.15 (C-1''''), 160.57 (C-4''), 154.82 (C-3), 139.05 (C-1'), 119.78 (C-4), 55.39 (C-1a).
3(p-Bromophenylpyrazole)-1-phenyl-4-carbaldehyde(4f) :Colour :Off White, Yield:84%, Melting Point:144?-147?, 1H NMR (CDCl3, 500 MHz)d(ppm): 10.02 (s, 1H, CHO), 8.52 (s, 1H, Hpyrazole), 7.84- 7.26(m, 9H, Haromatic), FTIR:?max (cm-1): 3120.90-3028.44 (C-H aromatic str,), 1673.20 (C=O str), 1596.48 (C=N str.), 1520.47-1452 (C=C str.),1224.95 (C-N str.), 1072.20 (C-Br str.) , 13C NMR (CDCl3,500 MHz) d(ppm): 184.40 (C-1''''), 153.15 (C-3), 138.90 (C-1’), 119.74 (C-4).
1-Phenyl-3(p-hydroxyphenylpyrazole)-4-carbaldehyde(4g):Colour: Light yellow, Yield: 74%, Melting Point: 205?-213?, 1H NMR (CDCl3, 500 MHz)d(ppm):10.02 (s, 1H, CHO), 9.96-9.25 (br,1H, OH), 8.52 (s, 1H, Hpyrazole), 7.84- 7.26 (m, 9H, Haromatic), FTIR:?max (cm-1): 3414.51 (O-H str.) 3119.77-3030.44 (C-H aromatic str,), 1670 (C=O str), 1599.48 (C=N str.), 1519-1452 (C=C str.), 1224.95 (C-N str.), 13C NMR (CDCl3,500 MHz) d(ppm): 185.22 (C-1''''), 158.38 (C-4''), 152.80 (C-3), 138.54 (C-1’), 115.23 (C-4).
3-(Naphthalen-1-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (4h):Colour: Deep Brown, Yield: 80%, Melting Point: 99?-102?, 1H NMR (CDCl3, 500 MHz)d(ppm): 10.02 (s, 1H, CHO), 8.64 (s, 1H, Hpyrazole), 7.7-7.2 (m, 14H, Haromatic), FTIR:?max (cm-1): 3121.21-3048.44 (C-H aromatic str,), 1674.10 (C=O str), 1597.92 (C=N str.), 1528.65-1463 (C=C str.), 1224.95 (C-N str.), 13C NMR (CDCl3,500 MHz) d(ppm): 185.22 (C-1''''), 154.38 (C-3), 138.54 (C-1'), 115.23 (C-4).
3-(Naphthalen-2-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (4i):Colour: Light Brown, Yield: 88%, Melting Point: 133?-140?, 1H NMR (CDCl3, 500 MHz)d(ppm):10.02 (s, 1H, CHO), 8.64 (s, 1H, Hpyrazole),8.21(s,1H, Hc), 7.7-7.2 (m, 9H, Haromatic), FTIR:?max (cm-1): 3119.10-3047.74 (C-H aromatic str,),1670(C=O str),1599.48(C=N str.),1519-1452(C=C str.),1224.95(C-N str.), 13C NMR (CDCl3,500 MHz) d(ppm): 186.13(C-1''''), 154.57(C-3), 139.04(C-1'), 118.90(C-4).
3-(2-Oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde(4j):Colour:Light yellow, Yield: 83%, Melting Point: 235?-239?, 1H NMR (CDCl3, 500 MHz)d(ppm):1H NMR (CDCl3, 500 MHz) ppm: d: 10.02 (s, 1H, CHO), 8.64 (s, 1H, Hpyrazole), 8.21 (s,1H, C9”-H), 7.7-7.2 (m, 9H, Haromatic), FTIR:?max (cm-1): 3121.77-2922.44 (C-H aromatic str,),1725.69 (C=O str. of ester),1683.87 (C=O str. of aldehyde),1599.48 (C=N str.),1518-1382.46 (C=C str.), 1214.95 (C-N str.), 13C NMR (CDCl3,500 MHz) d(ppm): 186.21 (C-1''''), 160.14 (C-2''), 154.57 (C-3), 147.83 (C-3''), 138.93 (C-1'), 116.74 (C-4).

We Claims:

1. A process for synthesis of 4-formylpyrazole derivatives (Formula-I) comprising the steps of reacting substituted acetophenones with substituted hydrazines in presence of acid catalyst in dimethylformamide followed by the treatment of resulting reaction mixture with V.H reagent in one-pot and stepwise procedures. Here, in formula I, Ar and R can be any aryl or heteroaryl group.

2. The process as claimed in claim 1, wherein the DMF solvent is used to achieve corresponding hydrazones and their conversion into final products with formula I.
3. The process as claimed in claim 1, wherein the said process provides an acid-catalysed one-pot protocol which eliminates the formation of side products.
4. The process as claimed in claim 3, wherein the yield of 74-95% can be achieved.
5. A process as recited in claim 3, wherein the temperature required is 0°C as minimum to 75°C as maximum during the whole process.