Copper-Catalyzed Sulfonylation of Cyclobutanone Oxime Esters with Sulfonyl Hydrazides

Abstract A copper-catalyzed radical cross-coupling of cyclobutanone oxime esters with sulfonyl hydrazides has been developed. The copper-based catalytic system proved crucial for cleavage of the C−C bond of cyclobutanone oximes and for selective C–S bond-formation involving persistent sulfonyl-metal radical intermediates. This protocol is distinguished by the low-cost catalytic system, which does not require ligand, base, or toxic cyanide salt, and by the use of readily accessible starting materials, as well as broad substrate scope, providing an efficient approach to various diversely substituted cyano-containing sulfones.

Radical chemistry plays a pivotal role in the construction of complex and diverse molecules and has penetrated various fields. 1 Direct radical cross-coupling is of great significance, and represents a powerful approach for synthetic chemistry, 2 which is attributed to radicals having a strong tendency to form chemical bonds, the rapid reaction rate, and the low activation energy. 3 However, most radicals in nature are unstable and have a short survival period, while only a few persistent radicals have been reported. 4 Therefore, the regulation of radical reactions in radical chemistry has always been the most important issue. 5 There are some clues in the literature regarding the stabilization of the transient thiyl radical by metal salts. 6 It is noteworthy that Lei's group demonstrated a selective transient-radical cross-coupling reaction by tuning of the reactivity of radicals in situ. 7 Subsequently, the authors reported selective radical-radical cross-coupling between the thiyl radical and the isobutyronitrile radical on the basis of the persistent radical effect. 4b Although some progress has been made to date, direct cross-coupling of two transient radicals remains largely unexplored. 8 Alkylnitriles represent a privileged class of structural motifs that can be found in many natural products and pharmaceutical compounds. 9 More recently, remarkable advances have been made in the efficient and practical synthesis of alkylnitriles in radical chemistry. -Cyanoalkyl radical intermediates can be obtained through -scission of the iminyl radicals from cyclobutanone oxime ester derivatives (Scheme 1a). This is a very effective strategy for the introduction of -cyanoalkyl substituents to different molecular frameworks using the -cyanoalkyl radical as the receptor. 10 In 2017, Shi and co-workers developed a unique strategy to enable intermolecular Heck coupling of ketoxime esters with olefins in the presence of a copper catalyst Scheme 1 Reactions of oxime esters and reaction design  11 In 2018, Xiao and co-workers reported copper-catalyzed three-component radical cross-coupling of oxime esters, styrenes, and boronic acids (Scheme 1c). 12 Recently, Chen and co-workers found copper-catalyzed radical cross-coupling of redox-active cycloketone oxime esters with sulfinate salts to form cyanoalkylated sulfones. 13 Given the wide biological activity of aryl sulfonyl derivatives, the development of mild and efficient synthetic methods to access sulfonyl derivatives has been a long-term goal in organic synthesis. 14,15 Drawing inspiration from these works, we envisioned that iminyl radicals that derived from cyclobutanone oxime esters could combine with persistent sulfonyl radicals to generate sulfone compounds containing the alkylnitrile motifs (Scheme 1d).
Herein, we disclose a Cu(II)-catalyzed selective radical coupling reaction of cyclobutanone derivatives 1 with sulfonyl hydrazides 2. The catalyzed process could be rationalized in terms of a [Cu(OTf) 2 ] mediated reaction that generates persistent sulfonyl-metal species in situ. 4b This approach is applicable to a variety of cyclobutanone derivatives as well as various sulfonyl hydrazides, affording the corresponding remote substituted cyano-containing sulfones in good yields under mild conditions. We began our investigation using p-toluenesulfonyl hydrazide (1a) with cyclobutanone O-benzoyl oxime (2a) as model substrates for the radical cross-couplings. Optimization results from the extensive screening (Table S1-S8, including catalysts, oxidants, solvents etc.) are summarized in Table 1. The reaction was found to be facile with 2a (1.5 equiv) in the presence of the Cu(OTf) 2 catalyst (10 mol%) in dimethylacetamide (DMAC) as a polar solvent system, at 100 °C, which afforded the cross-coupling product 4-tosylbutanenitrile (3a) in 71% isolated yield (entry 1). Preliminary control experiments demonstrated that the copper salt is crucial for the success (entry 2). Polar solvent such as N,N-dimethylformamide (DMF) also provided moderate yield (entries 3) but nonpolar solvents rendered the reaction system very complex. The reaction produced one byproduct, which could not be separated when DMF was used as solvent. Intriguingly, changing the ratio of the two components 1a and 2a to 1:2 significantly impacted the process (entry 4). The results were inferior to those observed under the optimal conditions when the temperature to was changed 80 or 120 °C (entries 5 and 6). Interestingly, other copper catalysts such as CuBr 2 and CuCl made this transformation more complex (entries 7 and 8). We also tried different oxidants and solvents, but no better results were obtained (entries 10-16). In addition, the yield of the reaction decreased when 3,4,7,8-tetramethyl-1,10-phenanthroline was used as the ligand (entry 17). However, further exploration revealed that cyclobutanone O-benzoyl oxime was a superior substrate to cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime (2a′) containing electron-withdrawing groups, and the former could be converted into 3a in better yield (see the Supporting Information). With the optimal reaction conditions in hand, we examined the substrate scope and limitations of this crosscoupling reaction. As summarized in Scheme 2, the substitution patterns on the sulfonyl hydrazides were investigated. Generally, benzenesulfonyl hydrazides bearing electrondonating (e.g., Me, t-Bu, OMe) or electron-withdrawing (e.g., CN, F, Cl) substituents on the para-position of the aromatic ring worked well with 2a to give the corresponding -cyanoalkyl sulfones3a-f and 3o in moderate to good yields. Owing to the different steric bulk of the phenyl ring, the use of substituents at the para-position of the sulfonyl hydrazides provided higher yield than those with orthoand meta-substituted sulfonyl hydrazides (3f, 3h and 3j). Naphthalene-1-sulfonohydrazide (3k), naphthalene-2-sulfonohydrazide (3l), and [1,1′-biphenyl]-4-sulfonohydrazide (3n) also participated well in the reaction to give the corresponding products in good yields. However, pyridine-2-sulfonohydrazide (3m) and sulfonyl hydrazides having a bro- B. Dong et al.

Paper Synthesis
mine substituent in the para-position of the phenyl ring (3g) were not suitable for this reaction. Running the reaction on a 2.0 mmol scale of 1n afforded 3n in 49% yield and a 3.0 mmol scale reaction with 1f also provided the product 3f in 38% yield. Compound 3n was further converted into the corresponding carboxylic acid 8 in a yield of 78% under relatively simple conditions (see the Supporting Information).
The scope of the reaction with cycloketone oxime esters was then examined (Scheme 3). The reactions of cyclobutanone oxime esters bearing aryl or naphthyl groups on the 3-position with 1a proceeded smoothly to afford the desired sulfones in moderate to good yields. The 3-arylcyclobutanone oxime ester containing different substituents at the para-position were also compatible and furnished the target products 3p-s, 3u, and 3x. Notably, substituents at different positions of the aromatic ring had little effect on the reaction (3u, 3v, and 3w). Satisfactorily, the 3,3disubstituted oxime ester, containing a methyl and a phenyl group, also led to the desired product 3y, albeit with reduced yield. However, the less-strained five-membered cy-cloketone oxime ester was not applicable. The 2-benzyl cyclobutanone oxime ester was also not converted into the desired product and only delivered the corresponding elimination product 3z. The results indicate that C-C bondcleavage of the unsymmetrical cycloketone oxime ester might occur selectively at the more hindered site and gave the more stable alkyl radical from 3z, which is consistent with the previous results. 16 Scheme 3 Scope of substituted cyclobutanone oximes esters. Reagents and conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), Cu(OTf) 2 (0.02 mmol, 10 mol%) and TBHP (1.2 mmol, 6 equiv, 70% water solution) in DMAC (1.0 mL) at 100 °C under Ar for 12 h. Isolated yield.

Paper Synthesis
mediated C-C single-bond cleavage and formation of cyanoalkyl radical might be involved in the process. On the other hand, when the reaction was performed in the presence 2.0 equiv of 1,1-diphenylethylene, besides generating the desired product 3a in 30% NMR yield, vinyl sulfone 6a was identified in 2% NMR yield and 7a was detected in 13% NMR yield (Eq. 3) (see the Supporting Information). These results further verified a radical pathway for this transformation.
On the basis of the above experimental results and on previous reports, 17 a reaction mechanism was proposed as shown in Scheme 5. Initially, sulfonylhydrazides are readily transformed into sulfonyl radicals I in the presence of TBHP and Cu(I), with release of a molecule of nitrogen and Cu(II) complex via a single-electron-transfer process. 18 Subsequently, metal sulfonyl complex II is formed via sulfonyl radical coordination, which could be stabilized by Cu(I) to generate the Cu(II) intermediate II. 4b Cyclobutanone oxime is reduced by the Cu(I) catalyst to form strained iminyl radical, which is converted into isobutyronitrile radical III via homolytic C-C bond cleavage. 11,17h Based on a more reasonable Cu(I)/Cu(II) mechanism, which is in accordance with the theoretical and experimental results, 17i,j the direct sulfonyl group transfer from copper(II) sulfinates to isobutyronitrile radical III affords the sulfonylated products 3 along with the regeneration of the Cu(I) catalyst.
In summary, we have developed a simple and efficient copper-catalyzed iminyl radical-mediated C-C single-bond cleavage/radical cross-coupling reaction of oxime esters with sulfonyl hydrazides. This selective heterocoupling protocol of transient -cyanoalkyl radicals with persistent sulfonyl radicals derived from simple sulfonyl hydrazides provides an efficient strategy to rapidly forge -cyanoalkyl sulfones. These products are expected to have application in organic synthesis, and this method might be applied to the synthesis of pharmaceutical molecules and for the production of distal amino acids by breaking the C-S bond.
Unless otherwise noted, materials were purchased from commercial suppliers and used without further purification. All reactions were carried out in sealed tubes filled with argon. All reactions were monitored by thin-layer chromatography (TLC) and visualized using UV light. Products were purified by column chromatography with 200-300 mesh silica. 1 H NMR spectra were recorded with 400 or 600 MHz spectrometers. Chemical shifts () are reported in ppm from the resonance of tetramethyl silane as the internal standard (TMS: 0.00 ppm). Data are reported as chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz) and integration. 13 C NMR spectra were recorded at 100 or 151 MHz with complete proton decoupling. High-resolution mass spectra (HRMS) were measured with a Waters Q-Tof Micro MS/MS System ESI spectrometer. X-ray diffraction data were collected with an Oxford Diffraction Xcalibur CCD (X-ray single-crystal diffractometer).

Sulfonylation of Cyclobutanone Oxime Esters with Sulfonyl Hydrazides: General Procedure
A 10 mL oven-dried sealed tube equipped with a magnetic stir bar was charged with sulfonyl hydrazide 1 (0.2 mmol, 1.0 equiv) and cyclobutanone oxime ester 2 (0.3 mmol, 1.5 equiv). The tube was evacuated and backfilled with argon (three times) and then Cu(OTf) 2 (0.02 mmol), DMAC (1 mL) and TBHP (1.2 mmol, 6 equiv, 70% water solution) were injected into the tube by using a syringe. The resulting mixture was stirred for 12 h at 100 °C. Unless otherwise noted, the reaction solution was cooled to ambient temperature, and NaHCO 3 (5 mL) was added. The resulting mixture was extracted with EtOAc (3 × 10 mL), washed with NaCl, dried with MgSO 4 , and filtered. The residue was purified by flash column chromatography on silica gel (gradient eluent of petroleum ether/EtOAc, 1:3) to give the desired product 3 in yields listed in Schemes 2 and 3.

Synthesis of 4-([1,1′-Biphenyl]-4-ylsulfonyl)butanoic Acid (8): General Procedure
A 10 mL oven-dried sealed tube equipped with a magnetic stir bar was charged with sulfonyl hydrazide 3n (85.5 mg, 0.3 mmol) and NaOH (133.2 mg, 3.3 mmol). The tube was evacuated and backfilled with nitrogen (three times) and then water (0.6 mL) and EtOH (0.9 mL) were injected into the tube by using a syringe. The resulting mixture was stirred for 12 h at 100 °C. The reaction solution was cooled to ambient temperature, 1 N HCl (2.0 mL) was added and the mixture was diluted with water (10 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 × 10 mL), washed with NaCl, dried with Na 2 SO 4 and filtered. The residue was purified by flash column chromatography on silica gel to give the desired product 8.