Catalyst-free domino reaction in water/ethanol: an efficient, regio- and chemoselective one-pot multi-component synthesis of pyranopyrazole derivatives

Abstract

The synthesis of pyrano[2,3-c]pyrazole derivatives has been described by regio- and chemoselective four-component reaction of a dialkyl 3-oxopentanedioate, an active carbonyl compound, hydrazine and malononitrile in water/ethanol as a green medium under catalyst-free condition.

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The pollution of nature is a major problem in the design of chemical reactions. “Green chemistry” encourages chemists to alter the chemical procedures so production and consumption of hazardous substances in chemical reactions reach a minimum value.¹

Designing simple and environmentally benign reactions for the synthesis of medicinal structures is an attractive aspect of chemical researchs. Multi-component reaction (MCR) especially in water and ethanol, eco-friendly solvents, is one of the most suitable routs which can helps chemists to conform their reaction procedures to the requirements of “green chemistry” as well as to extend libraries of medicinal scaffolds.²

Designing organic reactions in aqueous media as an abundant and environmentally secure solvent has several advantages including simple work up and purification, exhibit high reactivity and selectivity, control over exothermic reactions, salting in and salting out, increasing in rate of reactions and variation of pH.³

Pyrazoles are important constituents in many pharmaceutical scaffolds.⁴ Also pyrazoles connected to other heterocyclic rings are very attractive targets in both combinatorial chemistry and emersion biological activities.^5,6

Pyranopyrazoles are an important class of biological and pharmaceutical active compounds. They are reported to possess several of pharmacological properties including anti-inflammatory,⁷ anticancer,⁸ insecticidal,⁹ antimicrobial, and inhibitors of human Chk1 kinase.¹⁰

Some novel multi-component reactions have been introduced by employing in situ preparation of pyrazolone ring through the reaction between hydrazine and a β-dicarbonyl compound.^4,11

Herein we report a one-pot synthesis of pyranopyrazole derivatives by in situ preparation of alkyl 2-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)acetate (7) through the reaction between hydrazine and dialkyl 3-oxopentanedioate (1) and subsequent reaction to synthesize the target pyranopyrazole derivatives (Scheme 1).

Scheme 1 Synthesis of pyranopyrazole.

Two products is possible for this reaction that it is noteworthy proceeded in highly regio- and chemoselective manner and it only produced compound 5 as shown in Scheme 1.

Encouraged by gaining acceptable results in our first attempts, the synthesis of 5a was selected for optimization of the reaction conditions. As shown in Table 1, the optimal conditions for the reaction of 4-chlorobenzaldehyde, hydrazine hydrate, diethyl 3-oxopentanedioate and malononitrile were screened and H₂O/ethanol (80 : 20) was found to be the best solvent for this reaction. The uses of combination of EtOH/H₂O as solvent in multi-component reaction have already been reported.¹² We also used an acid (p-toluenesulfonic acid, Table 1, entry 5) and a base (triethylamine, Table 1, entry 4) as catalysts in this reaction, but the catalyst-free approach at 60 °C in H₂O/EtOH (80 : 20) (entry 7) gave the best result.

Table 1 Optimization of reaction conditions (5a)

Entry	Solvent	Catalyst	Temp. (°C)	Yield^a (%)
a Reaction conditions: hydrazine (1.0 mmol), diethyl-3-oxopentanedioate (1.0 mmol), malononitrile (1 mmol), 4-chlorobenzaldehyde (1 mmol), solvent (10 mL), 12 h.
1	H2O/MeOH 50/50	—	65	65
2	CH3CN	—	82	50
3	Etyl acetate	—	77	20
4	H2O/MeOH 50/50	Et3N	60	60
5	H2O/MeOH 50/50	PTSA	60	20
6	MeOH	—	65	—
7	H2O/EtOH 80/20	—	80	75
8	H2O/EtOH 80/50	—	25	65
9	H2O	—	60	40

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With the optimized reaction conditions in hand, we then probed the generality and scope of the present multi-component reaction. We were pleased to find that the reaction proceeded well with a series of different aldehydes, some isatin derivatives and acenaphthenquinone as active carbonyl compounds, malononitrile or ethyl cyanoacetate, hydrazine and dimethyl 3-oxopentanedioate or diethyl 3-oxopentanedioate to give a library of ethyl 2-(6-amino) (2,4-dihydropyrano[2,3-c]pyrazol-3-yl)acetate derivatives of type 5.

As shown in Table 2, this protocol can be applied for aromatic aldehydes with electron-withdrawing groups.

Table 2 Pyranopyrazoles synthesized from aldehydes

Product	R^1	Yield^a (%)
a Reaction conditions: hydrazine (1.0 mmol), dialkyl-3-oxopentanedioate (1.0 mmol) in water/ethanol (10 mL/8 : 2), aldehyde (1 mmol) and malononitrile (4, 1 mmol), 12 h, 60 °C.
5a	4-Cl	75
5b	3-Br	78
5c	2-NO2	60
5d	3-NO2	65
5e	4-NO2	68

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Then, we examined the possibility of the synthesis of the spiro products from isatin derivatives and acenaphthenquinone instead of aldehyde. As shown in Table 3, the spiro-products showed partly better yields than the others.

Table 3 The synthesized of spiro products

Product	R^1	R^2	X	Yield^a (%)
a Reaction conditions: hydrazine (1.0 mmol), dialkyl-3-oxopentanedioate (1.0 mmol) in water/ethanol (10 mL/8 : 2), isatin or acenaphthenquinone (1 mmol) and malononitrile (1 mmol) or etyl cyanoacetate, 12 h, 60 °C.
5f	Et	5-Br	CN	85
5g	Et	5-F	CN	82
5h	Et	H	CN	85
5i	Me	H	CN	85
5j	Et	—	CN	87
5k	Me	—	CN	76
5l	Me	—	CO2Et	68

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Finally, the structure of the compound 5f was confirmed precisely by single-crystal X-ray analysis (Fig. 1).

Fig. 1 X-ray crystal structure of 5f.

A plausible mechanism according to the same reaction¹³ is presented in Scheme 2. The mechanism involves initial condensation of β-ketoester (1) and hydrazine (2) to form pyrazolone ring (7) and subsequent attack on Knoevenagel condensation product (8) that is formed from aldehyde (3) (or 1,2-dicarbonyle compound) and malononitrile (4). In the next step, cyclization occurs to yield the final product (5).

Scheme 2 Mechanism of the reaction.

Conclusions

In summary, a facile regio- and chemoselective one-pot procedure for the synthesis of ethyl 2-(6-amino) (2,4-dihydropyrano[2,3-c]pyrazol-3-yl)acetate derivatives has been reported via a condensation reaction of a dialkyl 3-oxopentanedioate, an aldehyde (isatin derivatives or acenaphthenquinone), hydrazine and malononitrile (or ethyl cyanoacetate) in water/ethanol under catalyst-free conditions. The versatility of the functionality such as amino, ester and cyano groups makes these compounds proper candidates as precursors for further synthetic transformations in drug discovery, combinatorial chemistry and chemical biology. The simple performance, green media, good yields and easy purification are some of the advantages of this protocol.

Experimental

General procedure

A mixture of the dialkyl-3-oxopentanedioate (1, 1 mmol) and hydrazine hydrate (2, 1 mmol, 0.05 mL) in water/ethanol (10 mL/8 : 2) was magnetically stirred for 30 min at 60 °C followed by the addition of aldehyde (3, 1 mmol) and malononitrile (4, 1 mmol). The reaction mixture was stirred for 12 h at 60 °C. Then, the mixture was cooled to r.t. and 10 mL of water was added and the resulting mixture was stirred for 30 min. The precipitated product was filtered and washed with water. The products were further purified by recrystallization in ethanol.

Acknowledgements

We gratefully acknowledge financial support from the Research Council of Shahid Beheshti University. The authors are grateful to Dr Hamid Reza Khavasi and SBU X-Ray Crystallography Centre for their helpful analysis X-Ray data that helped the authors to improve the quality of this paper.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra47639a

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