Electrochemically-induced regioselective cyclization of N-methacryloyl hydrazones: efficient synthesis of phosphorylated pyrazolone derivatives

Abstract

An electrochemically driven redox strategy has been developed for the regioselective synthesis of phosphorus-containing 2-pyrazolin-5-ones via radical addition–cyclization cascades. This metal-free protocol enables the efficient incorporation of symmetrical phosphoryl radicals into N-methacryloyl hydrazones under mild conditions. The protocol demonstrates broad substrate scope. Various control experiments explored the merits and the plausible mechanism of the electrochemical phosphorylation systems. This work provides a sustainable and versatile approach to phosphorus-containing heterocycles, holding promise for applications in medicinal chemistry.

An electrochemically-induced radical addition/cyclization cascade has been developed for the regioselective synthesis of phosphorylated 2-pyrazolin-5-ones under metal-free and mild conditions.

Introduction

Pyrazolones represent an important class of N-containing heterocycles that are ubiquitously distributed in biological systems and exhibit diverse physiological and pharmacological activities, rendering them highly significant for scientific investigation.¹ In particular, 2-pyrazolin-5-ones, as an important type of pyrazolones, have potent biological activities, including neuroprotection, antitumor effects, and pancreatic lipase inhibition² (see Scheme 1A). Given their significance, the synthesis of pyrazolone derivatives has become a hotspot in organic chemistry and has drawn a lot of attention from chemists.³ Current synthetic strategies mainly focus on: (1) metal-catalyzed cyclization reactions of unsaturated hydrazones/azo compounds,⁴ (2) oxidant-promoted intramolecular cyclization strategies⁵ (3) Knorr condensation reactions of β-keto esters,⁶ (4) visible-light or electrochemically induced selective cyclization via radical addition⁷ (see Scheme 1B).

Scheme 1. Research background and our design.

Meanwhile, Phosphorus-containing nitrogen heterocycles serve as privileged scaffolds in bioactive molecules,⁸ demonstrating broad applications in medicinal chemistry,⁹ organic synthesis,¹⁰ and materials science.¹¹ Consequently, the direct incorporation of organophosphorus moieties into nitrogen heterocycles has emerged as a significant yet challenging research focus.¹² The concise and efficient formation of C–P bonds has been proven desirable and challenging in the past decades, which employs either the innate nucleophilicity of phosphorus containing reagents, or phosphonyl radicals derived from P(O)H compounds. Notably, organic electrochemistry, which offers a uniquely direct means to generate radical species, can proceed smoothly without the expense of chemical oxidants or reductants.¹³ Indeed, although traditional radical difunctionalization strategies for olefins have been widely employed to construct diverse privileged scaffolds,¹⁴ electrochemical approaches continue to exhibit considerable promise in this area. This concept has been validated by several elegant studies, in which the successful synthesis of various functionalized structures has been achieved through anodic difunctionalization.¹⁵

Herein, in continuing our research program on electro-triggered radical chemistry as well as the synthesis and application of organophosphorus chemistry,¹⁶ we have developed a green and versatile radical addition/regioselective cyclization reaction between (E)-N′-benzylidene-N-phenylmethylacrylic hydrazide¹⁷ and phosphonyl compounds. This method efficiently accesses phosphonylated 2-pyrazolin-5-one derivatives by overcoming two key challenges: (1) selective addition of phosphonyl radicals to C C double bonds; (2) regioselective intramolecular cyclization of the intermediate via C N double bonds (see Scheme 1C).

Results

At the outset of our investigations, (E)-N′-benzylidene-N-phenylmethacrylohydrazide (1a) and diphenylphosphine oxide (2a) were chosen as the model substrates to establish the optimal reaction conditions (see Table 1). The electrochemical tandem cyclization was conducted in an undivided cell. Following systematic screening, the optimal conditions were identified as follows: using a mixed solvent system of CH₃CN and dioxane in the presence of 0.5 eq. of n-Bu₄NPF₆, with DMAP serving as the base. Under a constant current of 8 mA for 4 hours, the desired phosphorylated product 3aa was obtained in 84% yield (Table 1, entry 1).

Table 1. Optimization of reaction conditions.

Entry	Variations from the standard conditions	Yieldb
1	None	84a
2	Without DMAP	47
3	DMAP (0.25 eq.) or (1.0 eq.)	69, 76
4	GF (+)/Ni (−)	22
5	GF (+)/GF (−)	n.r.
6	Pt (+)/Pt (−)	Trace
7	5 mA, 10 mA instead of 8 mA	67, 80
8	25, 60 °C instead of 80 °C	44, 54
9	CH3OH or CH3CN	57, 67
10	KI instead of n-Bu4NPF6	n.d.
11	n-Bu4NHBr instead of n-Bu4NPF6	30
12	Without electricity	n.r.

^aReaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), DMAP (0.5 mmol), n-Bu₄NPF₆ (0.25 mmol), CH₃CN/dioxane (3 mL/3 mL), GF as anode, Pt plate as cathode, constant current = 8.0 mA, 80 °C, under air, 4 h, undivided cell.

^bIsolated yield.

Control experiments revealed that DMAP is essential for this transformation (entry 2). Notably, deviations from the optimal amount led to lower yields (entries 3). Furthermore, the use of alternative electrode materials led to significantly lower product formation (entries 4–6). Variations in both current intensity and reaction temperature also failed to improve the yield (entries 7–8). In comparison, reduced yields were obtained when the model reaction was performed in other solvents, such as CH₃OH or CH₃CN (entries 9). The replacement of n-Bu₄NPF₆ with other supporting electrolytes such as KI, n-Bu₄NBr was inefficient for this reaction (entries 10 and 11). Finally, no reaction occurred when the reaction was carried out without electricity (entry 12) (see Table S2 in the SI for details).

Having identified optimal conditions for the phosphonylated pyrazolone, we turned our focus to the evaluation of the scope and functional group compatibility (see Table 2). Initially, the effects of various substituents at the phenyl ring of reactant (E)-N′-benzylidene-N-phenylmethacrylohydrazide (1a) were investigated. Gratifyingly, a broad range of N-methacryloyl hydrazones proved to be compatible with the developed protocol. Initially, a series of benzaldehyde-derived N-methacryloyl hydrazone were systematically examined: both electron-donating groups such as methoxy, methyl, ethyl, and isopropyl were well tolerated, affording the corresponding phosphorus-containing pyrazolones (3ab–3ag) in moderate to good yields. Among these, products 3ad and 3ae were obtained in slightly lower yields, which may be attributed to the unfavorable steric hindrance caused by the meta- and ortho-substituents. Subsequently, the tolerance of electron-withdrawing groups and halogen atoms was evaluated, and the desired products (3ah–3ak) were successfully obtained. In addition, the 2-naphthaldehyde-derived hydrazone was also well tolerated, delivering the target product in good yield (3al). Furthermore, the ibuprofen structural motif was successfully incorporated into the framework, affording the derivative in 41% yield under identical conditions (3am), the inadequate yield is highly probably attributed to the bulky isobutyl group (–CH₂CH(CH₃)₂) in the ibuprofen structural unit attached at the para-position of the benzylidene aryl ring, thus leading to significant spatial steric effects. Meanwhile, we systematically explored the substrate scope of phenylhydrazine derivatives. The results demonstrated that substrates bearing electron-donating groups on the N-phenyl ring generally delivered the corresponding products in excellent yields (3ba–3bg). Notably, the position of the methyl substituent on the phenyl ring exerted distinct steric effects on the reaction efficiency. When a strongly electron-withdrawing nitro group was introduced at the p-position of the N-phenyl ring, the yield of the target product dropped markedly (3bh, 34%), presumably owing to the decreased nucleophilicity of the hydrazone nitrogen and the destabilisation of key reaction intermediates. A range of N-substituents (methyl, benzyl, naphthyl, cyclohexyl, and p-toluenesulfonyl) were compatible, giving good to excellent yields (3bi–3bm). Replacing both aryl groups on the hydrazone with non-aromatic substituents also proved feasible, affording 3bn in 43% yield and broadening the scope. When the terminal methyl on the alkene was replaced with H to probe regioselectivity, no product was obtained (3bo, n.d.). This highlights the α-methyl group's critical role in stabilizing the C-centered radical intermediate and promoting cyclization, essential for this electrochemical process.

Table 2. Substrate scope of (E)-N′-arylidene-N-phenylmethacrylohydrazides^a,b.

^aReaction condition: 1a (0.5 mmol), 2a (1.0 mmol), DMAP (0.5 mmol), n-Bu₄NPF₆ (0.25 mmol), CH₃CN/dioxane (3 mL/3 mL), GF as anode, Pt plate as cathode, constant current = 8.0 mA, 80 °C, under air, 4 h, undivided cell.

^bIsolated yield.

To evaluate the substrate scope of this electrochemical C(sp³)–P bond formation, various P(O)H compounds were examined under the standard conditions (see Table 3). A range of diarylphosphine oxides bearing different substituents on the aryl rings were compatible. For example, 4-methyl and 3,5-dimethyl substituted substrates afforded products 3ca and 3cb in 89% and 90% yield, respectively. Strongly electron-donating groups, such as methoxy and 4-tert-butyl, gave the desired products in excellent yields (3cc–3ce). The ortho-methoxy analogue showed a slight steric effect, leading to a lower yield than its para counterpart. Halogen-substituted diarylphosphine oxides with –I effect nevertheless cleanly reacted to afford compounds 3cf, 3cg, and 3ch in 61%, 53%, and 42% yields, respectively. Gratifyingly, di(naphthalen-2-yl)phosphine oxide was converted to 3ci in 78% yield. Dialkylphosphine oxides were also tested to further probe the generality, furnishing 3cj and 3ck in 60% and 47% yield, respectively. Unfortunately, the unsymmetrical phosphine oxide failed to give the desired product (3cl, n.d.), we speculate that the unequal aryl groups hinder the orientation at the electrode and increase the congestion during the cyclization process. Meanwhile, the electronic imbalance raises the oxidation potential of the P–H bond and destabilizes the phosphinyl radical, which promotes its decomposition before the cyclization reaction occurs.

Table 3. Substrate scope of diarylphosphine oxides^a,b.

^aReaction condition: 1a (0.5 mmol), 2a (1.0 mmol), DMAP (0.5 mmol), n-Bu₄NPF₆ (0.25 mmol), CH₃CN/dioxane (3 mL/3 mL), GF as anode, Pt plate as cathode, constant current = 8.0 mA, 80 °C, under air, 4 h, undivided cell.

^bIsolated yield.

To further demonstrate the practical value and synthetic utility of this method, gram-scale experiments and derivatization of drug molecules were conducted. When the reaction was scaled up to 5 mmol under optimized conditions (constant current: 8 mA, 6 h), the target product 3aa was obtained in 77% yield (Scheme 2). These results confirm the robustness of both the compound and the electrochemical strategy for practical applications.

Scheme 2. Gram-scale synthesis of 3aa.

Next, to gain insight into the reaction mechanism, radical trapping experiments were conducted (see Scheme 3). When the model reaction was performed under the standard conditions in the presence of 3.0 equiv. of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), the formation of product 3aa was completely suppressed. Instead, the adduct of TEMPO with the phosphinoyl radical was detected by high-resolution mass spectrometry (HRMS) (compound 4). Similarly, the addition of 3.0 equiv. of 2,6-di-tert-butyl-4-methylphenol (BHT) resulted in only a trace amount of 3aa. Likewise, when 1,1-diphenylethylene (DPE) was employed as a radical scavenger, no desired product was observed, while the corresponding adduct 6 was successfully captured and identified by HRMS. These results suggest that a radical pathway is likely involved in this transformation (see the SI for details).

Scheme 3. Radical-trapping experiment.

The redox behavior of the substrates was investigated by cyclic voltammetry (CV, see Fig. 1). Using tetrabutylammonium hexafluorophosphate (n-Bu₄NPF₆) as the supporting electrolyte within a potential window of 0 to 3 V, the oxidation peak potential of 1a (2.36 V) was found to be higher than that of 2a (1.98 V). Furthermore, the oxidation potential of 4-dimethylaminopyridine (DMAP) is 2.07 V. The addition of DMAP significantly reduces the oxidation overpotential of 2a, and the oxidation peak shifts to 1.96 V, indicating its auxiliary oxidation effect. When DMAP was introduced into the mixture of 1a and 2a, the oxidation process similarly occurred at a reduced potential (peak at 2.03 V). These results clearly demonstrate that the presence of DMAP facilitates the electron-transfer process and markedly enhances the reaction efficiency under the electrochemical conditions.

Fig. 1. Cyclic voltammograms of substrates.^{a a}Cyclic voltammetry was recorded in the range from 0 V to 3 V. Using a glassy-carbon working electrode (diameter, 3 mm), a Pt wire auxiliary electrode, an Ag/AgCl reference electrode and a scan rate of 100 mV s⁻¹. Scan direction: positive. Blank: 0.1 M n-Bu₄NPF₆ + CH₃CN (8 mL); 1a: 4 mM; 2a: 8 mM; DMAP: 4 mM.

Based on the experimental observations above as well as previous literature reports,¹⁸ a tentative mechanism for this protocol was proposed (see Fig. 2). Initially, the key phosphinyl radical A is formed from 2a through a single electron transfer (SET) process, which selectively attacks the C C double bonds of the substrates (1a) to afford the corresponding C-centered radical B. Subsequently, this nucleophilic radical B preferentially adds to the more electron-rich C N bond of the hydrazone moiety via a 5-endo-trig cyclization, affording the N-centered radical intermediate C. Intermediate C is oxidized at the anode to undergo a SET process, generating cationic intermediate D, which subsequently undergoes oxidative dehydrogenation to afford the desired product 3aa.

Fig. 2. Plausible reaction mechanism.

Conclusions

In summary, we have developed an efficient and highly chemoselective electrochemical method for the construction of phosphorylated pyrazolin-5-ones via the electro induced phosphorylation/cyclization of (E)-N′-arylidene-N-phenylmethacrylohydrazides with diphenylphosphine oxide. The reaction proceeds under mild electrochemical conditions with high efficiency and broad substrate scope, providing the desired products in moderate to excellent yields (38 examples). Importantly, the synthetic utility of this method has been demonstrated by the late-stage modification of ibuprofen. Furthermore, the successful gram-scale synthesis highlights the potential of this catalyst-free electrochemical approach as a green and sustainable strategy for medicinal chemistry and industrial synthesis.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: detailed experimental procedures, optimization of reaction conditions, radical trapping experiments, cyclic voltammetry studies, and the characterization data (¹H NMR, ¹³C NMR, ¹⁹F NMR, ³¹P NMR, and HRMS) for all new compounds. See DOI: https://doi.org/10.1039/d6ra05060c.