Oxidative C–H Sulfonylation of Hydrazones Enabled by Electro-chemistry

An efficient electrochemical oxidative C(sp 2 )–H sulfonyla-tion of aldehyde hydrazones is described. A variety of sodium sufinates or sulfinic acids participate effectively in this protocol, which provides facile access to an array of alkyl and aromatic sulfonylated hydrazones with up to 96% yield. Large-scale synthesis and product derivatization show the potential utility of this methodology. Preliminary mechanistic investigations including radical-inhibition, electricity on/off experiments, and cyclic voltammetry support a radical pathway.


• green process • good functional group tolerence • simple operation • sulfinic acids and their salts as sulfonylation reagent
• broad scope A wide range of natural and unnatural compounds that have broad applications in the fields of agrochemicals, pharmaceuticals, and materials chemistry, contain organosulfones (Scheme 1). 1 These compounds are also known for their synthetic versatility as key intermediates 2 in wellknown organic transformations such as the Smiles rearrangement, 3 Ramberg-Backlund reaction, 4 van Leusen oxazole synthesis, 5 and Julia olefination. 6On the other hand, many natural and synthetic hydrazones possess multifaceted biological activities including antidepressant, 7 antimicrobial, 8 anti-inflammatory, 9 analgesic, anticonvulsant, 10 antimalarial, 11 and anticancer properties, 12 making them interesting target compounds for drug design.Conceptually, the integration of such a structural motif and sulfone group together into one molecule might open new windows of opportunity for the discovery of novel bioactive molecules.

Scheme 1 Important examples of sulfones
The chemistry of functionalized hydrazones has gained considerable momentum over the last few decades due to their important applications in organic synthesis. 13Hydrazones are versatile synthetic building blocks that participate in a plethora of synthetic transformations in which they act not only as carbonyl surrogates but also as precursors of nitrogen-containing compounds. 14Among the various hydrazone-based transformations, those that employ the C=N bonds as radical acceptors for diverse C(sp 2 )-H bond functionalizations are among the most desirable strategies (Scheme 2a). 15In recent years, electricity-initiated organic transformations have flourished as a powerful tool for the construction of chemical bonds because they

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utilize safe, traceless, renewable, and eco-friendly electrons as the sole redox reagents. 16In this context, elegant examples of direct radical functionalization of hydrazones under electrochemical conditions have been documented.In 2018, Zhang et al. 17 developed an electrochemical [3+2] cycloaddition for the synthesis of tetrazoles from azides and hydrazones.Subsequently, electrochemically enabled direct C(sp 2 )-H bond functionalization of hydrazones for the construction of C-C, C-N, C-S, and C-P bonds were independently reported by Xie, 18 Huang, 19 Liang, 20 Wang, 21 and Ruan 22 (Scheme 2b).Nevertheless, despite this important progress, the direct C(sp 2 )-H sulfonylation of hydrazones, which offers a promising complement to existing strategies, remains under-explored.Recently, the synthesis of N-acylsulfonamides through oxo-sulfonylation of hydrazones was reported by Hajra et al. 24 and Liu et al. 25 employing sulfinic acids and sodium sufinates, respectively, as the sulfonyl radical precursors under transition-metal-free and metal-catalysis approaches (Scheme 2c).In sharp contrast, we herein disclose an efficient, mild, and sustainable protocol for the preparation of a wide variety of (E)-sulfonylated hydrazones via electrochemical oxidative C(sp 2 )-H sulfonylation of aldehyde-derived hydrazones based on sulfinic acids/salts as sulfonylating reagents (Scheme 2d).
As shown in Table 1, we commenced the study with the reaction of readily accessible aldehyde hydrazone 1a with 4-methylbenzenesulfinate 2a as a sulfonyl donor.When the reaction was conducted in an undivided cell equipped with two Pt plate electrodes with n Bu 4 NBF 4 as the supporting electrolyte and MeCN/H 2 O (4:1, 3 mL) as solvent, the expected product 6a was obtained in 52% yield at 27 °C.Employing n Bu 4 NPF 6 , n Bu 4 NClO 4 , or LiClO 4 resulted in decreased reaction yields (entries 2-4).Electrode materials also had a clear influence on this reaction.Replacing the anode with graphite felt increased the yield of the sulfonylated product 6a to 61% (entry 5).When Ni foam plate, Fe sheet, or graphite rod were used as the cathodic material, the yield of 6a was reduced to 53, 52, and 47%, respectively (entries 6-8).After intensive investigation of a range of solvents, it was found that a solvent mixture of MeCN/H 2 O at a 1:1 ratio was the best chose (entries 9-13).Gratifyingly, decreasing the concentration of reagents in the solvent to 0.05 M led to further improvement of the isolated yield of 6a to 90% (entry 14).When the electrolysis was carried out in the absence of supporting electrolytes, the yield of 2a dropped to 83% (entry 15).It was observed that either decreasing or increasing the current intensity resulted in decreased reaction yield (entries 16 and 17).No desired product was obtained without the application of electricity (entry 18).
To our delight, sulfinic acid also served as a suitable sulfonyl source for our current protocol to prepare sufonylated hydrazones.Different to Hajra's work, 24 when the reaction of 1a with p-methylbenzenesulfonic acid 3a was carried out under the optimized conditions as detailed in Table 1 (entry 14), the desired product 6a could be obtained in 79% yield, and N-acylsulfonamide 6a′ was also isolated as a byproduct in 9% yield (entry 19).In this case, increasing the amount of H 2 O proved to be necessary to achieve higher yield of 6a and less byproduct.A notable 87% isolated yield of 6a was obtained when the relative proportion of acetonitrile to water was 1:2 (entry 20).Interestingly, attempts at electrochemical C-H sulfonylation using either p-toluenesulfonyl hydrazide 4 or sulfonyl chloride 5 as the sulfonylating reagents failed to give any desired product (entries 21 and 22).

d. This work: • green process • good functional group tolerence • simple operation • sulfinic acids and their salts as sulfonylation reagent
• broad scope

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With the optimized conditions in hand, we first investigated the effect of different N-substituents of hydrazones (Scheme 3).The results showed that dialkyl hydrazones 7ac were effective coupling partners, whereas diphenylhydrazone with much less electron-donating capacity proved to be essentially unreactive under identical conditions (7d).In the case of N-Bz hydrazone (7e), the reaction resulted in the consumption of the starting materials, giving rise to a complex mixture of side products.Additionally, no reaction was observed using either oxime ethers (7f) or imines (7g and 7h) as the substrates.These results suggest that the N,N-disubstituted structural motif is crucial for the desired transformation, and the alkyl group is likely an important activation unit.

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(6o)] functionalities smoothly to deliver the corresponding sulfonylated product in moderate to excellent yields (23-92%).However, the electronic properties of the substituent had a big influence, and substrates bearing strong electronwithdrawing groups provided much lower yields than those with electron-donating groups.The substrates with naphthyl, thienyl, furanyl, or pyridyl substituents were all suitable, giving the corresponding products 6p-s, albeit with lower efficiency (31-63%).Unfortunately, aliphatic aldehyde-derived hydrazone remained a challenging substrate for this transformation (6t).
To elucidate a plausible mechanism, we performed a series of control experiments.Under standard conditions, the reactions of 2a or 3a with 1a were suppressed completely after adding two equivalents of 1,1-diphenylethylene or 2,6-di-tert-butyl-4-methylphenol (BHT).The corresponding radical trapping adducts 12 and 13 could be detected by high-resolution mass spectrometry (HRMS) (Scheme 6a). 27he formation of 12 and 13 indicates that tosyl radical may be involved.A minor kinetic isotope effect (KIE) of k H /k D ≈ 1.0 was observed (Scheme 6b), suggesting a facile C−H cleavage.Additionally, we conducted electricity on/off experiments (Scheme 6c).The transformations were fully suppressed in the absence of electricity, thereby ruling out a radical-chain process.Furthermore, we carried out cyclic voltammetry to analyze the redox potential of the substrates (Figure 1).An oxidation peak of 1a was found at ca. 0.81 V, while the oxidation peaks of ArSO 2 Na and ArSO 2 H were observed at ca. 0.40 V and ca.0.62 V vs. SCE, respectively.Based on these results, it can be inferred that 2a or 3a might undergo preferential oxidation at the anode, leading to the generation of a tosyl radical.

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Based on the current results and on literature precedents, 15 we proposed a plausible reaction pathway for this electrochemical sulfonylation of hydrazones, as outlined in Scheme 7. Initially, anodic oxidation of sodium sulfinate 2a or sulfinic acid 3a generates tosyl radical A. Thereafter, tosyl radical A would be trapped by the hydrazone to generate the sulfonylated aminyl radical intermediate B, which would be oxidized at the anode to produce aminyl cationic species C. Further tautomerization and deprotonation of aminyl cation D would afford 6a.
In conclusion, we have developed a practical and efficient electrochemical procedure for the direct C(sp 2 )-H bond sulfonylation of (hetero)aromatic aldehyde hydrazones using stable and easy-to-handle sodium sulfinates or sulfinic acids as sulfonylating agent.This method is of great synthetic value due to its desirable features such as being free from external oxidants, and because of its high atomeconomy, high functional group tolerance, operational simplicity, and use of an eco-friendly energy source.Preliminary mechanistic investigations suggest the involvement of an aminyl radical/polar crossover process in the transformation.
All the reagents and solvents were obtained from commercial sources and were used without further purification unless otherwise stated.The hydrazones were prepared according to reported methods. 28The sulfinic acids and sodium sulfinates were synthesized according to reported procedures. 29The conversion of starting materials was monitored by thin-layer chromatography using silica gel plates, and components were visualized by observation under UV light (254 and 365 nm). 1 H NMR spectra were recorded at 400 MHz or 600 MHz.The 13 C NMR spectra were recorded at 100 MHz or 150 MHz. 19F NMR spectra were recorded at 376 MHz.Chemical shifts are expressed in parts per million () downfield from the internal standard tetramethylsilane (TMS), and are reported as s (singlet), d (doublet), t (triplet), dd (doublets of doublet), dt (doublets of triplet), td (triplets of doublet), and m (multiplet).The residual solvent signals were used as references and the chemical shifts are converted to the TMS scale (CDCl 3 :  H = 7.26 ppm,  C = 77.16ppm).The coupling constants J are given in Hz.High-resolution mass spectra (HRMS) were obtained in ESI mode with an Agilent Q-TOF 6540 mass spectrometer.Q.-L.Yang et al.

Gram-Scale Synthesis of 6j
The gram-scale reaction was conducted in a 150 mL straight undivided five-port electrolytic cell.The substrates 1j (1.076 g, 4.0 mmol), 2a (1.424 g, 8.0 mmol) and n Bu 4 NBF 4 (1.383 g, 6.0 mmol) were dissolved in the mixture solvent CH 3 CN/H 2 O (60:60 mL).The electrolysis was carried out at 27 °C using a constant current of 20 mA for 16 hours.After the reaction, the solvent was extracted with ethyl acetate (3 × 120 mL), dried over Na 2 SO 4 , and concentrated in vacuo.The resulting residue was purified by chromatography through silica gel (petroleum ether/EtOAc, 5:1) to afford the corresponding product 6j (1.054 g, 62%) as yellow solid.