Efficient and Sustainable Electrosynthesis of N-Sulfonyl Iminophosphoranes by the Dehydrogenative P–N Coupling Reaction

Iminophosphoranes are commonly used reagents in organic synthesis and are, therefore, of great interest. An efficient and sustainable iodide-mediated electrochemical synthesis of N-sulfonyl iminophosphoranes from readily available phosphines and sulfonamides is reported. This method features low amounts of supporting electrolytes, inexpensive electrode materials, a simple galvanostatic setup, and high conversion rates. The broad applicability could be demonstrated by synthesizing 20 examples in yields up to 90%, having diverse functional groups including chiral moieties and biologically relevant species. Furthermore, electrolysis was performed on a 20 g scale and could be run in repetitive mode by recycling the electrolyte, which illustrates the suitability for large-scale production. A reaction mechanism involving electrochemical mediation by the iodide-based supporting electrolyte is proposed, completely agreeing with all of the results.


■ INTRODUCTION
Iminophosphoranes, also referred to as phosphinimines, are nitrogen analogues of phosphonium ylides and represent powerful reagents in organic synthesis. 1−10 Furthermore, they are utilized as superbasic organocatalysts for versatile transformations, 11−14 as ligands for transition metal catalysts, 15−25 and as intermediates for amino group protection 26 and optical resolutions. 27,28Moreover, several iminophosphoranes showed biological activity and were investigated as potential anticancer agents 29−32 and acetylcholinesterase (AChE) inhibitors targeting the treatment of Alzheimer's disease (Scheme 1b). 33−46 Alternatively, Kirsanov, 47−52 Appel-type, 53−55 or Mitsunobu-type 56−62 reactions can be performed to generate an electrophilic phosphine intermediate in situ, which is then trapped by the nitrogen precursor (Scheme 2c−e).
Despite the broad applicability of these methods, they require toxic and potentially explosive reactants in stoichiometric quantities, which leads to safety risks, as well as large amounts of reagent waste and poor atom economy.
A sustainable and broadly applicable alternative to conventional synthesis approaches is electro-organic synthesis.It employs inexpensive electric current as a traceless redox agent, replacing hazardous and polluting reagents.−69 Furthermore, workup processes can be simplified, since the employed supporting electrolyte and the solvent can often be separated from the formed product by simple aqueous extraction or distillation.Due to the usually high energy demand for workup processes, this plays an essential role and makes elegant combinations of sustainable synthesis and simple workup highly desirable. 63,66−68 Iminophosphoranes can be synthesized electrochemically by reductive dehydrogenation of (alkylamino)phosphonium salts 70 or by P−N coupling reactions of a phosphine and a nitrogen compound. 71,72The latter have so far only been reported by de Oliveira and Noel et al., 71 as well as by Lehnherr and Lam et al. 72 who synthesized N-aryl iminophosphoranes from nitro arenes and N-cyano iminophosphoranes from bis(trimethylsilyl)carbodiimide, respectively (Scheme 2).These methods allow for the synthesis of numerous derivatives in good to excellent yields.However, both methods require one of the precursors to be used in large excess (3.0−3.5 equiv), resulting in additional reagent waste and poor atom economy.Furthermore, hazardous trifluoroacetic acid (TFA) and N-methyl-2-pyrrolidone (NMP) are used within the electrolyte system, leading to safety issues.Lastly, conversion rates are low due to relatively low current densities (1.45 and 4.2 mA cm −2 ), making large-scale applications less attractive.
In contrast, we herein present a sustainable, inherently safe, efficient, and easily scalable synthesis of N-sulfonyl iminophosphoranes, starting from readily available phosphines and sulfonamides by applying inexpensive electrode materials.This method features a broad and diverse scope, high conversion rates, and an excellent atom economy.

■ RESULTS AND DISCUSSION
The reaction conditions for the electrochemical formation of iminophosphoranes were optimized by using triphenylphosphine (PPh 3 , 1) and p-toluenesulfonamide (TsNH 2 , 2) as test substrates in equimolar amounts.Detailed information about the reaction optimization is provided in the Supporting Information.Initially, PPh 3 and TsNH 2 were electrolyzed under constant current conditions in an undivided cell equipped with a glassy carbon anode and a nickel cathode.The reaction was performed under air, and a mixture of NEt 4 I, tert-butanol, and acetonitrile was employed as the electrolyte.The choice of NEt 4 I as a supporting electrolyte was based on previous reports, where halide-based supporting electrolytes proved to be suitable redox mediators for various P−N coupling reactions 73−80 and for the analogue sulfilimine synthesis. 81By applying the initial conditions, iminophosphorane 3 was obtained in 33% 31 P NMR yield, while triphenylphosphine oxide (TPPO) was formed as a major product in 59% yield (Table 1, entry 1).In order to avoid TPPO formation, the reaction was repeated by applying an inert atmosphere and anhydrous acetonitrile (Table 1, entry 2).With this, the yield of product 3 could be raised to 50% and TPPO formation could be reduced to 28%, demonstrating the importance of inert conditions for an improved reaction performance.When various supporting electrolytes were screened under inert and ambient conditions, NEt 4 I turned out to be superior to the other tested supporting electrolytes and was therefore further used (see the Supporting Information).Next, various additives were investigated.The absence of additives led to a slightly lower yield for 3 (42%, Table 1, entry 3).−85 With a higher HFIP concentration of 0.15 M, product 3 yield increased to 91%, which did not significantly change at higher HFIP concentrations (Table 1, entry 5, see the Supporting Information).Therefore, HFIP at a concentration of 0.15 M was further used as the additive.When screening cathode materials, nickel could be replaced by stainless steel, being advantageous in terms of costs, availability, and safety, leading to 87% of 3 (Table 1, entry 6).Regarding the anode material, isostatic graphite provided a lower product yield compared to glassy carbon, which was therefore further used (Table 1, entry 7).Next, the interelectrode gap and the current density were investigated.With a smaller interelectrode gap of 4 mm instead of 9 mm, the cell voltage and thus the specific energy consumption of the reaction could be lowered by around 40% from 2.12 to 1.23 kJ mmol −1 while keeping the yield of 3 on a high level of 90% (Table 1, entry 8).Regarding the current Scheme 1. Possible Application Fields for Iminophosphoranes a13, 30,33 a AChE = acetylcholinesterase.density, no significant change in yield was observed within a range between 10 and 50 mA cm −2 , demonstrating the high robustness of this transformation toward fluctuations in current density (see the Supporting Information).This will be particularly important for future industrial applications in order to adapt flexibly to intermittent energy, as expected with electricity generated from renewable energy sources. 81,86To maintain a high space-time yield while increasing the energy efficiency, a current density of 30 mA cm −2 was chosen, resulting in a yield for 3 of 91% and a specific energy consumption of 0.87 kJ mmol −1 (Table 1, entry 9).The efficiency and sustainability of the reaction could further be improved by tripling the concentration of the starting material (c s.m. ), which led to the highest product yield of 95% while lowering the amounts of reagents and solvent needed relative to the amount of generated product (Table 1, entry 10).With these conditions, the HFIP concentration was finally screened.Interestingly, 3 was formed in a very good yield of 89% in the absence of HFIP, indicating no significant influence of HFIP on the reaction performance (Table 1, entry 11, see the Supporting Information).The energy demand remained at a low level of 0.92 kJ mmol −1 .Since the omission of highly fluorinated and persistent organics, such as HFIP, improves the sustainability of the reaction dramatically, these conditions were chosen to be the appropriate ones, despite a slightly lower product yield.
Subsequently, the scope of the reaction was investigated (Scheme 3).First, diverse phosphines were reacted with TsNH 2 .Test derivative 3 could be isolated in 87% yield.A similar result was obtained for 4 involving three electron-rich and sterically demanding o-tolyl substituents on the phosphorus atom.Compound 5 with three electron-deficient 4-fluorophenyl moieties could also be synthesized in a good yield of 76%.In contrast, tris(pentafluorophenyl)phosphine failed to provide the corresponding iminophosphorane when electrolyzed with TsNH 2 .Styrene substituents turned out to be tolerated in the reaction, and 4-(diphenylphosphino)styrene could be converted to the expected product 13 in 34% yield.Interestingly, hydrogenated byproduct 13′ was formed in 25% yield.Moreover, 6 bearing three 2-furyl substituents could be synthesized in 58% yield, confirming that aryl-and heteroarylsubstituted phosphines are well tolerated in this transformation.Next, alkyl-substituted phosphines were tested.Electron-rich phosphines with primary and secondary alkyl substituents, such as n-butyl and cyclohexyl groups, could be converted into corresponding iminophosphoranes 7 and 8 in a very high yield of 85%.In contrast, 9, wherein the phosphine bears three tert-butyl substituents, was not accessible by this method, likely due to the high steric hindrance caused by the substituents.Electron-withdrawing cyanoethyl groups were tolerated as well in the reaction, providing 10 in 76% yield, which is viable for further functionalization.Further, unsymmetrical iminophosphorane 12 could be isolated in a high yield of 80%, illustrating that both aryl-and alkyl-substituted phosphines are suitable for the reaction.Lastly, diiminophosphorane 11, which is an interesting ligand for organometallic complexes, 16,22 was accessible in 68% yield by reacting 1,2bis(diphenylphosphino)ethane (dppe) with 2 equiv of TsNH 2 .
Next, the sulfonamide scope was investigated.The electronrich 4-methoxybenzenesulfonamide could be converted successfully into iminophosphorane 14 in a good yield of 81%.Conversely, 15 with a p-chlorophenyl substituent was obtained in a poor yield of 20%.Sulfanilamide, which was formerly used as an antibiotic, 87 yielded 16 88 in 45% yield.−91 Moreover, redox-sensitive nitro groups were tolerated in the reaction, as is evident from 17, which was isolated in a 25% yield.Benzenesulfonamide with an unsubstituted phenyl group yielded 18 in 81%.The highest yield was obtained for iminophosphorane 19, which was formed in excellent 90%, despite bearing two sterically demanding isopropyl groups in the o-position of the phenyl group.Alkyl sulfonamides provided corresponding derivatives 20 and 21 in good yields of 76 and 87%, respectively, demonstrating that both electron-rich and electron-deficient alkyl substituents on the sulfonamide moiety are tolerated in this reaction.Furthermore, chiral iminophosphorane 22 could be prepared from enantiopure (1S)-10-camphorsulfonamide in 72% yield, showing that intermediates for chiral transformations are easily accessible by this method.Finally, 1,1bis(diphenylphosphino)methane was reacted with sulfamide, yielding heterocycle 23 88 in 20% by a 2-fold P�N bond formation.
In order to demonstrate the suitability of the established method for production on a larger scale, electrolysis of PPh 3 (1) and TsNH 2 (2) was performed on a 60 mmol scale, which corresponds to a 13-fold scale-up (Figure 1a).The electrolysis was conducted in a 200 mL glass cell, applying standard conditions (with 2.1 F) and two electrodes in the size of 4 × 12 × 0.3 cm 3 , with an active anodic surface area of 32.4 cm 2 .With this setup, 20.46 g of 3 could be generated within 3.5 h in a good yield of 79%.The workup turned out to be straightforward, since most of the formed product (14.72 g) precipitated from the electrolyte and could simply be filtered off.In addition, 88% of employed NEt 4 I could be recovered by an aqueous extraction.
These results prove that the reaction is readily scalable, since a 12-fold amount of 3 was produced in only double the time, resulting in a 6-fold higher productivity.Furthermore, it was investigated if the reaction is operable in a repetitive way by directly reusing the electrolyte and feeding it with the substrate.For this, the electrolysis of 1 and 2 was run on a small scale (4.5 mmol) under standard conditions.Then, precipitated 3 was filtered off, and the residual electrolyte was enriched with the additional starting material (4.5 mmol of 1  Triphenylphosphine (PPh 3 , 1, 1.0 equiv, 1.5 mmol for c s.m. = 0.1 M, 4.5 mmol for c s.m. = 0.3 M), p-toluenesulfonamide (TsNH 2 , 2, 1.0 equiv, 1.5 mmol for c s.m. = 0.1 M, 4.5 mmol for c s.m. = 0.3 M), NEt 4 I (0.04 M, 0.6 mmol), additive (c additive ) in acetonitrile (MeCN, 15 mL), undivided 25 mL batch-type glass cell, anode, cathode, interelectrode gap (possible settings: 4 mm/9 mm), current density j (active anodic surface: 4.8 cm 2 ), applied molar charge: 2.0 F, 30 °C, stirring speed: 400 rpm, inert (argon atmosphere, anhydrous acetonitrile) or air (air atmosphere, HPLC grade acetonitrile) conditions.Abbreviations: s.m. = starting material, TPPO = triphenylphosphine oxide, HFIP = and 2 each) and electrolyzed again applying 2 F. This procedure was repeated for three electrolysis cycles.During this experiment, 1.25 g (2.9 mmol), 1.49 g (3.5 mmol), and 1.54 g (3.6 mmol) of pure 3 were isolated by filtration after the first, second, and third electrolysis cycles, respectively.This corresponds to reaction yields of 64, 77, and 79% relative to 4.5 mmol of the starting material.Additionally, the residual electrolyte contained 1.1 mmol of 3 (determined by 31 P NMR), which resulted in an overall product yield of 82% over three electrolysis cycles.Besides this, 7% of nonconverted PPh 3 was left, and only 4% of TPPO was formed over the three cycles.These results demonstrate impressively that the electrolyte can be efficiently reused and that repetitive operation of this electrolysis is feasible by feeding the substrate while removing the precipitated product.
To obtain insights into the reaction mechanism, cyclic voltammetry (CV) measurements were performed (see the Supporting Information).Based on these results, a reaction mechanism is proposed in which the iodide-based supporting electrolyte fulfills a dual role, serving as an ionic conductor while simultaneously acting as a redox mediator (Scheme 4). 92irst, iodide is oxidized at the anode to form I 2 and I 3 − .Then, phosphine I reacts with I 2 equivalent to form intermediate II, analogously to Kirsanov reactions. 48,51,52This hypothesis is supported by a control experiment in which I 2 (1.0 equiv) instead of electric current was employed as the oxidizing agent (see the Supporting Information).Nucleophilic attack by sulfonamide III, followed by elimination of iodide and deprotonation, yields iminophosphorane IV.At the cathode, hydrogen is evolved from the liberated protons.

■ CONCLUSIONS
In summary, an efficient and sustainable electrochemical synthesis of N-sulfonyl iminophosphoranes with high atom economy has been established.The reaction protocol involves the use of a simple galvanostatic setup, inexpensive and readily available electrode materials, small amounts of NEt 4 I as inherently safe supporting electrolytes, high conversion rates, and good energy efficiency.This method was applied to synthesize 20 examples in yields up to 90%, bearing various functional groups including chiral moieties and biologically relevant species.The large-scale applicability of the reaction was demonstrated by performing the electrolysis on a 60 mmol scale (20 g) and by running it in a repetitive way reusing the electrolyte.Finally, an iodide-mediated reaction mechanism was proposed based on CV studies.

Scheme 2 .
Scheme 2. Conventional and Electrochemical Synthesis of Iminophosphoranes a

Scheme 3 .
Scheme 3. Reaction Scope Based on Diverse Phosphines and Sulfonamides f

Figure 1 .
Figure 1.(a) Scale-up of the electrolysis reaction with PPh 3 and TsNH 2 from 4.5 to 60 mmol scale (left: 25 mL glass cell; right: 200 mL glass cell, in comparison to a 1 € coin).Standard reaction conditions with 2.1 F were applied (active anodic surface: 32.4 cm 2 ).Amounts of isolated 3, reaction yields, and reaction times are compared.A 12-fold amount of 3 (20.46g vs 1.70 g) was synthesized in only double the time (3 h 30 min vs 1 h 40 min).(b) Electrolysis of PPh 3 and TsNH 2 in repetitive mode in 25 mL glass cells.Standard reaction conditions were applied.After each electrolysis (2 F), precipitated 3 was filtered off, and the residual electrolyte was enriched with the additional starting material (4.5 mmol of PPh 3 and TsNH 2 each) and electrolyzed again.A total of three electrolysis cycles was conducted reusing the electrolyte.Prior to the third electrolysis, additional acetonitrile (5 mL) was added due to losses during filtration.[a] Isolated 3 after filtration.Yield is calculated based on 4.5 mmol of the starting material.[b] The composition of the residual electrolyte after three electrolysis cycles was analyzed by 31 P NMR, using triphenyl phosphate as an internal standard.[c] Nonconverted PPh 3 .Scheme 4. Proposed Reaction Mechanism Based on CV Measurements Department of Chemistry, Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Max-Planck-Institute for Chemical Energy Conversion, 45470 Mulheim an der Ruhr, Germany Sara L. Eberwein − Department of Chemistry, Johannes Gutenberg University Mainz, 55128 Mainz, Germany Dieter Schollmeyer − Department of Chemistry, Johannes Gutenberg University Mainz, 55128 Mainz, Germany ■ ASSOCIATED CONTENT* sı Supporting InformationThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.4c00156.