Direct Cyclization/Chlorination Strategy of Hydrazines for Synthesis of 4-chloropyrazoles by TCCA

1. Introduction

Pyrazoles and its derivatives are of particular importance in organic chemistry and pharmaceutical chemistry [1]. As important heterocyclic compounds, pyrazoles exibit significant biological properties such as antimicrobial [2], anticancer [3], analgesis [4], antihyperglycemic [5] activity. In organic chemistry they could be used as intermediate to synthesis dyes, materials, medicines, etc [6]. Moreover, they also have wide applications in medical treatment [7], agricultural chemicals [8] and inhibitors [9]. A great of pyrozole’s derivatives have been uncovered with excellent bioactivities, and several classical examples are summarized in Figure 1. 4-chloro-N-((3-(4-chlorophenyl)-1-phenyl-1H- pyrazol-4-yl)methyl) aniline (Figure 1A) exhibits potent CDK2 inhibitory activities and antiproliferative activities against MCF-7 and B16-F10 cells [10]. B in Figure1 has a good antibacterial effect on Candida albicans, Cryptococcus neoformans and Staphylococcus aureus [11]. Rimonabant (Figure 1C) act as a neurokinin-3 antagonist and a selective cannabinoid CB1 receptor antagonist [12]. Lonazolac (Figure 1D) and its derivatives play an important role in anti-inflammatory [13].

Many efforts have been committed to finding effective ways to integrate the above framework owing to its unique structure. The traditional synthesis of pyrazoles based on the condensation of 1,3-dicarbonyl compounds with hydrazines and the 1,3-dipolar cycloaddition reaction of a dipole with an appropriate dipole is still applicable [14]. The cycloadditions of 1,3-dipolar and intramolecular nirogen addition to alkynes have been developed to get pyrozoles [15]. In recent years, the method of synthesizing pyrazole derivatives through metal-catalyzed C-N bond and N-N bond coupling has made great progress [16]. At the same time, progress has also been made in the synthesis of pyrazole derivatives without metal-mediated molecular oxidation and amination to form C-N bonds [17]. However, there are no reports in one step that the form of pyrazole and the fuctionazation for the synthesis of pyrazole derivatives. Herein, based on our previous works of the synthesis of notrogen-containing heterocycles [18] we report a new metal-free synthesis method for substituted pyrazoles, which uses efficient and stable TCCA as both the chlorinating agent and oxidant.

2. Results and discussion

The feasibility of the expected transformation was appraised by using 1-phenyl-2-(4-phenylbut-3-en-2-ylidene)hydrazine 1a as a model substrate and TCCA with lower toxicity as chlorine source and oxidant in solvent of TFE and results are summarized in Table 1. To our delight, the conversion of the tested substrate proceeds to the desired 4-chloropyrazole compounds 3a with 69% yield at 30 °C for 4 h (entry 1, Table 1). Encouraged by this primary result, the efficiencies of several common solvents were examined and the result showed that when TFE was used as solvent the yield of product 3a was higher than the tested others (entries 1-8, Table 1). Next, in the study of temperature effect, the yield of the target product 3a showed a trend of increasing first and then decreasing as the temperature gradually increased and when the temperature was 40 °C, the yield of the target product 3a was improved to75% (entries 9-11, Table 1). In the research of time effect, reduced yield of target product 3a was observed due to the prolongation or shortenation of time (entries 12-13, Table 1). In the end, the effect of the amounts of TCCA and TFE were conducted respectively and the results indicated to be harmful to this reaction when the two elements were altered (entries 14-15, Table 1).

In order to further improve the yield of the target compounds several additives were examinated and the results revealed that the transformation was inhibited by 4Å MS (Entry 1, Table 2). When acid CH₃COOH was used as additive a lower yield of 57% was provided (Entry 2, Table 2). Then, common organic base pyridine and inorganic base K₂CO₃ did not improve the yield of the target product 3a (entries 3-4, Table 2). Finally, the addition of metal salts did not promote the conversion of the reaction and the attempt to improve the reactivity of the substrate was unsuccessful (entries 4-7, Table 2).

With the optimal reaction conditions for the cyclization/chlorination of the standard substrte in hand, the substrate scope was then explored and the results were summarized in Table 3. Various substrates with diverse substitutions group R¹ in phenyl and R² linked to imine carbon were studied. The results shown that when the substituent R² is H, various results were produced due to different substitutions of R¹. For example, When R¹ is H, the formation of target product 3b is not observed and only the cyclized product 3b′ is obtained. On the contrary, when the substitutent R¹ is electron donating group methoxy at the para-position of the phenyl, a lower yield of 3c can be obtained. At the same time, it was also found that when R² was identified as methyl, the desired products 3d-3i could be obtained in moderate to good yields (40-92%) regardless of whether the phenyl of cinamaldehyde was substituted by para-electron-withdrawing or para-electron-donating substitutent. In addition, when 1j with double methoxy on the phenyl of cinamaldehyde was used as substrate the target product 3j can also be obtained although the yield is not quite high. Substrates with R² determined to be phenyl or p-methylphenyl were also applied to the reaction, the target product 3l-3p were obtained regardless of whether R¹ is para-substituted on the pheyl by electron withdrawing or electron donating group. However, the yields are relatively low and it may due to the large steric hindrance caused by the introduction of phenyl or p-methylphenyl and these results indicated that the steric hindrance effect of the R² group has a great effect on the transformation (3d vs 3k, 3e vs 3l, 3g vs 3m, 3h vs 3n).

Furthermore, in order to obtained more pyrozole derivates, (E)-1-((E)-2-methyl-3-phenylallylidene)-2-phenylhydrazine was employed as substrte to form the corresponding chloropyrazole, while the expected 3p wasn’t detected and only 45% yield of the cyclization product 3p’ was obtained (Scheme 1 (a)). Meanwhile, bromocyclization of 1a using 2-DBH as a replacement for TCCA afforded brominated pyrazole 3q (Scheme 1 (b)).

Following the synthesis of 4-bromopyrazole 3q, Suzuki-Miyaura cross-coupling reactions were investigated for aryl functionalization. Coupling 3q with phenylboronic acid proceeded efficiently, leveraging the bromine atom as a highly labile leaving group to afford target product 4a in 45% yield. Reactions with methylphenylboronic acid, methoxyphenylboronic acid, biphenylboronic acid, and chlorophenylboronic acid afforded products in comparable yields under varying electronic effects (electron-donating or withdrawing). Notably, coupling with 4-(trimethylsilyl)phenylboronic acid achieved an unexpectedly high yield of 86% (4d). This exceptional result may be attributed to weak coordination between the trimethylsilyl group and palladium, potentially facilitating a directing effect. Conversely, attempts to couple 3q with cyclohexylboronic acid failed to generate 4g, as cyclohexyl lacks aromatic electronic effects and conjugation capabilities. Similarly, no products 4h or 4i were observed with aliphatic or heterocyclic boronic acids.

Table 4. Arylation Scope of 4-Bromopyrazole.^a.

4a, 45%b	4b, 48%	4c, 40%
4d, 86%	4e, 37%	4f, 58%
4g, 0%	4h, 0%	4i, 0%
a Reaction conditions: 3q (0.3 mmol), R-B(OH)2 (0.36 mmol) . b Isolated determined.

Table 4. Arylation Scope of 4-Bromopyrazole.^a.

4a, 45%b	4b, 48%	4c, 40%
4d, 86%	4e, 37%	4f, 58%
4g, 0%	4h, 0%	4i, 0%
a Reaction conditions: 3q (0.3 mmol), R-B(OH)2 (0.36 mmol) . b Isolated determined.

To clarify the mechanism, sevaral controlled experiments were conducted. To the reaction mixture 3.0 equivalents even 5.0 equivalents of radical scavenger 2,2,6,6-tetramethylpiperidinooxy (TEMPO) was added, however the desired product was still obtained with isolated yield of 64% and 61%, respectively (Scheme 2 (a)). This results suggested the unpossibility of a radical pathway. Then, the chlorination of the pyrazole was examinated and the 3-methyl-1,5-diphenyl-1H-pyrazole could react in the standard conditions and provide the corresponding chlorinated product in moderate yield (Scheme 2 (b)). This reveal that the chlorination proccess could occur after the cyclization meanwhile the chlorination and cyclization could carry out at the same time. These reactions indicated the process of the reaction is compelx.

Based on experimental results and literature precedents [19], a plausible reaction mechanism is proposed (Figure 2). Initially, the chloramine moiety of oxidant TCCA reacts with hydrazone 1a, generating cationic σ-adduct intermediate A alongside a resonance-stabilized amide anion. Deprotonation of A affords chloroimine intermediate B, which undergoes oxidation by TCCA via a single-electron transfer (SET) process to form iminium cation C. Subsequent intramolecular cyclization and deprotonation yield intermediates D and pyrazole radical E, respectively. Radical E is further oxidized by TCCA, losing an electron to form F, which upon dehydrogenation gives G. Finally, G tautomerizes to the target product 3a. Throughout this process, TCCA is progressively reduced to dichloroisocyanuric acid, with its chlorine atoms being completely consumed.

5.1. General information

CDCl₃ was acted as the solvent to measure the product its ¹H and ¹³C spectra with 400/100MHz NMR or 500/125MHz NMR spectrometer at 20-25°C. Tetramethylsilane (TMS, δ = 0.00 ppm) was played the role of an internal standard to report the product its ¹H and ¹³C in parts per million. The chemical reagents involved in the experiment can be purchased directly from merchants and are all analytically pure. All weighing processes are carried out in room temperature in air and all reactions are carried out under normal pressure unless otherwise specified

5.2. General procedure for the synthesis of pyrazole derivatives(3)

The oxidant TCCA (0.5 mmol, 1.0 equiv.) was added to the stirring solution of hydrazine substrate 1 (0.5 mmol), in TFE (2 mL) then the mixture was reacted for 4 hours at 40 °C. After the reaction, it was cooled to room temperature and quenched with saturated solution of Na₂S₂O₃ (1-2 mL), diluted with EtOAc (5 mL), and extracted with ethyl acetate (3×15 mL). The separated organic solution was dried with Mg₂SO₄ and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel column by using EtOAc-petroleum ether (1:150) as eluent to obtain target products.