Ce-catalyzed regioselective synthesis of pyrazoles from 1,2-diols via tandem oxidation and C–C/C–N bond formation

Abstract

A novel and efficient cerium-catalyzed tandem oxidation and intermolecular ring cyclization of vicinal diols with hydrazones has been achieved for the regioselective synthesis of pyrazole derivatives. The corresponding 1,3-di- and 1,3,5-trisubstituted pyrazoles were obtained in moderate to excellent yields. The reaction has the advantages of mild conditions, easily available starting materials, broad substrate scope and good functional group tolerance.

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Substituted pyrazoles are an important structural motif present in molecules having diverse applications including pharmaceuticals, agrochemicals, chemosensors, polymers, etc.¹ Interestingly, 1,3-di- and 1,3,5-trisubstituted pyrazoles constitute the core structure of many marketed drugs and crop protecting chemicals; for example, Celecoxib, a selective cox-2 inhibitor used as a non-steroidal anti-inflammatory drug.² Further examples include CDPPB, a clinical trial drug used for the treatment of schizophrenia and Difenamizole which has been used as an analgesic as well as an anti-inflammatory drug (Fig. 1).³ In addition, C3-arylated/heteroarylated N-substituted pyrazoles have also been found in the field of coordination chemistry.⁴ Recently, 1,3,5-trisubstituted pyrazoles have also been employed for C–H activation reactions (Fig. 1).⁵ The broad applications of pyrazoles stimulate organic chemists to develop efficient, general and operationally simple new synthetic methodologies.

Fig. 1 Representative examples of 1,3-di- and 1,3,5-trisubstituted pyrazoles.

The most common methods for the synthesis of pyrazoles involve the condensation of 1,3-dicarbonyl compounds with hydrazines and 1,3-dipolar cycloaddition between diazoalkanes or nitrile imines and olefins or alkynes.⁶ However, the instability of many 1,3-dicarbonyl compounds, particularly dialdehydes, the explosive nature of 1,3-dipoles and the difficulty in their synthesis and formation of regioisomeric mixtures restrict the access to substituted pyrazoles.⁷ In addition, the synthesis of unsymmetrical pyrazoles, and in particular C3-arylated N-substituted pyrazoles has remained challenging due to the lack of reactivity at the C3 position.⁸ To overcome these limitations, post-functionalization of the pyrazole core and metal-catalyzed C–C and/or C–N bond formation strategies have been employed for the regioselective synthesis of substituted pyrazoles.^8,9 With the availability of a great variety of synthetic methods, a few reports describe diols as attractive, eco-friendly, readily available and stable building blocks for the construction of regioisomerically pure pyrazoles (Scheme 1).¹⁰ For example, Panda et al. disclosed a seminal work on Fe(III)-catalyzed regioselective synthesis of pyrazoles in the presence of an excess amount of diols.^10a Later, they were able to synthesize substituted pyrazoles under neat conditions.^10c Schmitt and co-workers reported Ru-catalyzed 1,4-disubstituted pyrazoles by reacting hydrazines with 1,3-diols. Recently, diols were also employed for the synthesis of other N-heterocycles.^10d–f However, most of the methods reported to date for pyrazole synthesis by employing diols rely on the use of air-sensitive, hygroscopic catalysts as well as oxidants, stoichiometric amounts of ligands, and additives, and they have a narrow substrate scope and often require high temperature. So, the present challenge is to develop a simple and efficient catalytic system for the facile synthesis of regioisomerically pure pyrazoles under ligand-free conditions. In line with our continuing interest in metal-catalyzed C–C and C–heteroatom bond-forming reactions under ligand-free conditions,¹¹ we herein report a straightforward method for the regioselective synthesis of 1,3-di- and 1,3,5-trisubstituted pyrazoles from easily accessible hydrazones and diols by employing inexpensive ceric ammonium nitrate (CAN) as an eco-friendly catalyst under mild conditions.

Scheme 1 Synthesis of substituted pyrazoles using diols as a building block.

Although the combination of hydrogen peroxide (H₂O₂) and oxygen (O₂) is considered an economical and environmentally friendly oxidant system,¹² their applications in catalytic organic transformations are still limited.¹³ This is because of the radical nature of both hydrogen peroxide and molecular oxygen, which could trap the radical intermediate. Another issue is the generation of extremely reactive oxygen species (ROS) such as hydroxyl radicals (OH˙), peroxo-species (RO₂˙) and superoxide anion radicals (O₂˙⁻) which often result in undesired side reactions. These shortcomings may be overcome by using redox-active metal catalysts such as Cu, Fe and Ce under an oxygen atmosphere.¹⁴ Further synthesis of N-heterocycles by tandem oxidation of alcohols with the C–C/C–N bond formation strategy has not been explored by employing the Ce-catalyst. CAN which acts both as an oxidant and a Lewis acid has been utilized as a catalyst for alcohol oxidation and N-heterocycle synthesis.¹⁵ So, we envisaged the regioselective synthesis of pyrazoles by tandem oxidation/ring cyclization of 1,2-diols with hydrazones employing CAN as a redox-active metal catalyst under an oxygen atmosphere.

To demonstrate the rationality, we started our investigation by reacting diphenyl hydrazone 1a in ethylene glycol. Fortunately, the desired pyrazole 2a was isolated in 8% yield in the presence of 10 mol% CAN as the catalyst under an oxygen atmosphere (Table 1, entry 1). The formation of 1,3-diphenyl pyrazole discloses that ethylene glycol acts as a two-carbon source, which on sequential oxidation followed by ring cyclization with diphenylhydrazone 1a gave product 2a. This interesting finding inspired us to optimize the reaction conditions to provide a general methodology for the regioselective synthesis of substituted pyrazoles, in particular unsymmetrical ones, which are less accessible by traditional methods.^7b,8 Then, we investigated the optimization reaction with other cerium catalysts and unfortunately, they were found to be ineffective (Table 1, entries 2 and 3). Next, various oxidants were screened to examine their effects on the efficacy of the reaction. Oxidants such as K₂S₂O₈, oxone and I₂ resulted in poor yields of the product (Table 1, entries 4–6). Interestingly, by employing TBHP as an oxidant, the yield of 2a was dramatically improved to 55% (Table 1, entry 7). Other oxidants such as DTBP and TBPB were found to be inferior to TBHP (Table 1, entries 8 and 9). Employing H₂O₂ as an oxidant and lowering the reaction temperature to 60 °C, the yield of the product was further enhanced to 62% along with a shortened reaction time. To our delight, increasing the amount of CAN resulted in a maximum yield of product 2a (Table 1, entry 12). Further decreasing the reaction temperature as well as increasing the amount of H₂O₂ resulted in lower yields of the product (Table 1, entries 13 and 14). Additionally, the reaction was found to be sluggish with a poor yield in the absence of H₂O₂ (Table 1, entry 15). Moreover, carrying out the reaction on a gram scale afforded pyrazole 2a in 65% yield (Table 1, entry 17).

Table 1 Optimization reaction of diphenylhydrazones with ethylene glycol^a

Entry	Catalyst (mol%)	Oxidant (equiv.)	Temp. (°C)	Time (h)	Yield^b (%)
a Conditions: 1a (0.51 mmol), ethylene glycol (3.0 mL), oxidant (2.0 equiv.), H2O2 (2.0 equiv., 50%), under an O2 atm. b Isolated yields. c Oxidant (3.0 equiv.). d  1a (5.1 mmol), ethylene glycol (20.0 mL), oxidant (2.0 equiv.), H2O2 (2.0 equiv., 50%), under an O2 atm.
1	CAN (10)	—	120	6	8
2	CeO2	—	120	6	—
3	Ce(SO4)2	—	120	6	5
4	CAN (10)	K2S2O8	120	6	12
5	CAN (10)	Oxone	120	6	14
6	CAN (10)	I2	120	6	3
7	CAN (10)	TBHP	120	6	55
8	CAN (10)	DTBP	120	6	10
9	CAN (10)	TBPB	120	6	40
10	CAN (10)	H2O2	120	6	50
11	CAN (10)	H2O2	60	0.7	62
12	CAN (15)	H2O2	60	0.7	82
13	CAN (15)	H2O2	40	0.7	40
14^c	CAN (15)	H2O2	60	0.7	75
15	CAN (15)	—	60	0.7	30
16	—	H2O2	60	0.7	—
17^d	CAN (15)	H2O2	60	0.7	65

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With the optimized conditions in hand (Table 1, entry 12), we then explored the scope and limitations of the reaction (Table 2). Ethylene glycol was evaluated with differently substituted hydrazones. Diphenylhydrazones bearing both electron-donating and electron-withdrawing groups such as hydroxy, methyl, methoxy, chloro, bromo, cyano and nitro present on the phenyl ring resulted in the corresponding 1,3-disubstituted pyrazoles in moderate to excellent yields (24–85%). Interestingly, unsymmetrical 1,3-disubstituted pyrazoles were formed with complete regioselectivity (Table 2, 2b–2n, 2p–2t, and 2v–2z). Thus, the electronic nature of the substituents has little influence on product yields (Table 2, 2a–2y). Under the optimum reaction conditions, electron-deficient hydrazones resulted in moderate to good yields of 1,3-disubstituted pyrazoles (Table 2, 2f–2l, 2s, 2u, 2v and 2y) that are of interest in the pharmaceutical industry. It is interesting to note that pyrazole 2f was prepared in good yields that may be en route to the formal synthesis of the non-steroidal anti-inflammatory drug Lonazolac.¹⁶ However, thiophene-substituted hydrazones when treated with ethylene glycol resulted in a low yield of product 2m. The possible reason may be due to the formation of a complex between heteroaryl-substituted hydrazone and CAN.¹⁷ Moreover, the reaction was unsuccessful with hydrazones derived from pyridine-2-carbaldehyde and pyridine-4-carbaldehyde (Table 2, 2z and 2aa). The reason was unclear.

Table 2 Ce-catalyzed cyclization of hydrazones with ethylene glycol^a

a Unless otherwise mentioned, the reactions were performed with hydrazones 1 (0.51 mmol), H₂O₂ (1.01 mmol, 50%) and CAN (15 mol%) in ethylene glycol (3.0 mL) at 60 °C under an O₂ atm. b Temperature, 80 °C.

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After evaluating the scope of ethylene glycol with hydrazones, substituted diols such as 1,2-propanediol and glycerol were tested.

Gratifyingly, 1,3,5-trisubstituted pyrazoles 3a–3h were obtained in moderate yields when the reaction was carried out with 1,2-propanediol (Table 3). However, reactions of diarylhydrazones with glycerol resulted in the corresponding pyrazole derivatives 3i–3l in low yields. The reason for the low yield may be due to the poor solubility of the substrate under the optimized reaction conditions even at an elevated temperature.¹⁸ Competition experiments clearly indicate that reactions of diphenyl hydrazone 1a with ethylene glycol proceeded efficiently compared to those with propane-1,2-diol (Table 1, ESI†).

Table 3 Ce-catalyzed cyclization of hydrazones with alkyl-substituted 1,2-diols^a

a Unless otherwise mentioned, the reactions were performed with hydrazones 1 (0.51 mmol), H₂O₂ (1.01 mmol, 50%) and CAN (15 mol%) in ethylene glycol (3.0 mL) at 60 °C under an O₂ atm. b Temperature, 80 °C. c Temperature, 100 °C.

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Finally, the reaction was extended to the one-pot synthesis of pyrazole 2a (Scheme 2). Thus, by employing simple and commercially available starting materials such as phenylhydrazine, benzaldehyde and ethylene glycol under the optimum conditions, 2a was afforded in good yields. This modular and efficient one-pot procedure significantly enhances the usefulness and practicality of the developed method.

Scheme 2 One-pot synthesis of pyrazoles.

A series of experiments were conducted to gain some insights into the reaction pathway and regioselectivity. For example, oxidation of 4-(hydroxymethyl)cyclohexanol was carried out using the Ce catalyst. The reaction afforded 4-(hydroxymethyl)cyclohexanone in 32% yield.¹⁹ Similarly, 1-phenylethane-1,2-diols resulted in 2-hydroxy-1-phenylethanone along with some unidentified impurities. These reactions indicate that the Ce catalyst selectively oxidizes the secondary alcoholic group over the primary alcohol under the optimum conditions. Thus, the^16b reaction may proceed through a selective oxidation of 1,2-propanediol to 1-hydroxypropan-2-one and a subsequent nucleophilic attack of hydrazone on 1-hydroxypropan-2-one, followed by ring cyclization and aromatization to form the desired pyrazoles.

In conclusion, 1,3-di- and 1,3,5-trisubstituted pyrazoles can be synthesized directly using vicinal diols and hydrazones via a cerium-catalysed tandem oxidation and C–C/C–N bond formation method. A variety of regioisomerically pure pyrazoles were obtained in good to excellent yields. Considering the wide availability of a large variety of starting materials with operational simplicity (reaction conditions, work up and purification), a highly modular and practical synthesis of substituted pyrazoles has been developed. Further investigation of the detailed reaction mechanism and application of diols as dicarbonyl equivalents towards the synthesis of other heterocycles is ongoing in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from SERB (File No. YSS/2014/001017) and UGC (F-30-378/2017 (BSR)) is gratefully acknowledged. AKJ and CKP thank Prof. Niranjan Panda, NIT Rourkela for helping with the characterization. The authors are also thankful to DST-FIST, India (No. SR/FST/CS-1/2017/19) and IDP-OHEPEE (World Bank Sponsored) for funding to develop and repair the instrumentation facility at the Department of Chemistry, Maharaja Sriram Chandra Bhanja Deo University, Baripada, Odisha, India.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2ob01996e

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