Halogenations of 3-aryl-1H-pyrazol-5-amines

A direct C-H halogenation of 3-aryl-1H-pyrazol-5-amines with NXS (X = Br, I, Cl) as cheap and safe halogenating reagents at room temperature has been developed. This transformation provides an effective metal-free protocol towards the synthesis of novel 4-halogenated pyrazole derivatives with moderate to excellent yields. The method represents simple and mild reaction conditions, broad substrate scope as well as gramscale synthesis. The utility of this procedure is established by further transformations of the 4-halogenated products. Mechanism studies show that DMSO plays a dual role of catalyst and solvent.

However, some problems such as the use of toxic halogen sources, poor regioselectivity, harsh reaction conditions, and narrow substrate ranges remain as challenges for these methods. Recently, the direct C-H halogenation of arene has gained considerable attention in the synthesis of organohalides. In this context, significant advances have been made in the direct halogenation catalyzed by transition metals or metal-free Conditions [18,19]. But to the best of our knowledge, the direct halogenation of pyrazol-5-amine is rare in the literature. In particular, the direct halogenation of N-arylsulfonyl-5-aminopyrazole has never been reported. In 2014, Tu group reported an oxidative dehydrogenative couplings of pyrazol-5-amines in the 3 presence of iodine and TBHP, the reaction simultaneously installs C−I and N−N bonds through iodination and oxidation (Scheme 1a) [20]. As part of our interest in the direct C-H functionalization of heterocycles [21], we herein reported a direct C-H halogenation of 3-aryl-1H-pyrazol-5-amines for the synthesis of novel 4halogenopyrazoles derivatives (Scheme 1b).
Subsequently, we examined the effects of other solvents on the reaction (entries 2-8).
The results showed that when ethanol and 1,4-dioxane were used as solvents, low yields were obtained (entries 2 and 3). In contrast, DCM, EtOAc, MeCN, and DMF are selected as solvents to provide relatively good yields (70-82%, entries 4-7). To our delight, DMSO as a solvent gave an excellent yield (95%, entry 8). Next, we adjusted the amount of NBS to 1.2 equiv, the reaction also proceeded smoothly to furnish the product 3a in nearly equivalent yield (99%, entry 9). Shortening the reaction time led to a decrease in yield (entry 10). Finally, the optimal reaction conditions emerged as 1a (0.2 mmol), 2a (1.2 equiv.), and DMSO (2 mL) at room temperature for 3 h under N2 atmosphere (entry 9). Next, With the optimized reaction conditions in hand, we then investigated the scope of N-arylsulfonyl-3-aryl-5-aminopyrazole with NBS/NIS ( Table 2). The results showed that the substituents on the aromatic ring of 3-aryl-1-tosyl-1H-pyrazol-5-amines did not hamper the reaction process. Reactions of methyl-, chloro-, or methoxy-substituted substrates with NBS proceeded efficiently to afford the desired products 3b-3f in excellent yields. The reactions were successful for both electron-donating and electron-withdrawing substituents on the aromatic rings. When 3-aryl-1-phenylsulfonyl-1H-pyrazol-5-amines were used as reactants, the brominated reaction still occurred smoothly to deliver the brominated products 3g-3j with excellent yields. The results indicated that the type and position of the substituents on the aromatic ring of the substrate had no obvious influence on the reactivity. To our delight, the structure of 3j was determined by single crystal X-ray diffraction (Figure 2, CCDC: 2090203). In addition, variation of nitrogen-tethered substituents on the pyrazole ring including naphthalen-2-ylsulfonyl and (4-(tert-butyl)phenyl)sulfonyl groups were tolerated well, leading to the desired products 3k and 3l in 78% and 60% yields, respectively.
8 Gratifyingly, the halogenation reactions were compatible with the substrate 3-phenyl-1H-pyrazol-5-amine, generating the product 3m and 4m in 70% and 80% yields, respectively (Scheme 2[a]). In addition, the ester group (1-COOMe) on the pyrazoles of the substrate were also well-tolerated, the desired products 3n and 4n in good yields (Scheme 2[b]). The structure of 4n was determined by single crystal X-ray diffraction (Figure 3, CCDC: 2090220).  To demonstrate the usefulness of the halogenation reaction, we conducted two gramscale reactions of 1a with NBS and NIS. The gram-level products 3a (1.412 g) and 4a (1.718 g) could be isolated with excellent yields (Scheme 3[a]). Furthermore, the products 3a and 4a could successfully remove the Ts group under the action of ptoluenesulfinic acid (TolSO2H), the products 3m and 4m were obtained in 80% and 86% yields, respectively (Scheme 3[b]). In the presence of 3 equivalents of Cs2CO3 To gain the reaction mechanism, we performed a series of control experiments (Scheme 4). In the presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (2,6-ditertbutyl-4-methylphenol), the halogenation of 1a with 2a was not suppressed, and the product 3a was obtained in 95% and 90% yields, respectively (Scheme 4[a]).
The result shows that a free radical pathway is not involved in the transformation process. In addition, we found that this reaction only gave a yield of 31% when ethanol was used as the solvent. However, with the addition of 20 mol% DMSO, the bromination yield can be increased to 80%. This result indicates that DMSO should play a dual role as catalyst and solvent in the halogenation process.

Scheme 4: Control experiments.
On the basis of our experimental results and previous reports, [19a] a plausible halogenation mechanism is proposed (Scheme 5). Initially, the oxygen atom of DMSO coordinated with the halogen atom of NXS to form the polarized intermediate DMSO·X + (I). [22][23][24][25] Subsequently, DMSO·X + (II) reacts with π electrons of 5-aminopyrazole to form the intermediate (III). Finally, the halogenated product is obtained with the formation of succinimide and DMSO for the next catalytic circle.

Materials and instruments
Unless otherwise noted, all synthetic steps were performed under the air atmosphere using sealed tube. The materials obtained from commercial sources were used without further purification. 1 H NMR, 13 C NMR, and 19 F NMR spectra were recorded on a Brucker Advance III HD 400 MHz spectrometer in CDCl3 solution. All chemical shifts were reported in ppm (δ) relative to the internal standard TMS (0 ppm). High-resolution mass spectra (HRMS) were acquired in electrospray ionization (APCI) mode using a TOF mass analyzer.

General procedure for gram-scale synthesis of 3a or 4a.
A mixture of 3-phenyl-1-tosyl-1H-pyrazol-5-amine (1a, 4.0 mmol), NIS or NBS (4.8 mmol), and DMSO (10 mL) was stirred at room temperature for 6 h under N2 atmosphere. Upon completion, the reaction was quenched with 25 ml of sodium thiosulfate solution and extracted with dichloromethane (25 mL × 3), saturated with NaCl solution (25 mL × 3), and concentrated in vacuo. The crude product is recrystallized in ethanol. In addition, the small amount of product 3a remaining in the ethanol filtrate could be further separated by silica gel column chromatography (DCM/EtOH). Finally, 1.412 g of the product 3a and 1.718 g of the product 4a were obtained with 90% and 98% yields, respectively.

Supporting Information
Supporting Information File 1: Characterization data and 1 H NMR, 13 C NMR spectra of the synthesized compounds.