Electroreductive Desulfurative Transformations with Thioethers as Alkyl Radical Precursors

: Herein, the use of aryl alkyl thioethers as precursors for C-centered alkyl radicals is demonstrated for desulfurative C-H and C-C bond formation under electroreductive conditions. The transformations occur with complete selectivity for C(sp 3 )-S bond cleavage, orthogonal to that of transition metal-catalyzed two-electron routes. Experimental and theoretical studies provide mechanistic insights that serve as a steppingstone for future use of thioethers as efficient radical precursors that can outcompete their established sulfone analogues.


Introduction:
Organosulfur compounds are prevalent among natural products, pharmaceuticals, agrochemicals, and products from the fragrance industry. 1In addition, the compound class is highly useful from a synthetic standpoint and encompasses a wide range of versatile reagents for organic transformations, including Swern oxidation and the Corey-Chaykovsky reaction.High-valent or charged organosulfur compounds, e.g.sulfones and sulfonium salts, have commonly been used as a source of alkyl and aryl groups in desulfurative syntheses in both two-and one-electron manifolds. 2,3 n contrast, the use of organosulfur reagents of lower valency, e.g.thioethers, thioesters, and thioacetals, as alkyl and aryl group precursors is primarily limited to transition metal catalyzed two-electron routes and remains underexplored in a radical setting. 4lectrochemistry has become an increasingly popular synthetic approach to break and forge bonds in organic molecules within a one-electron manifold.This contemporary interest is largely due to the strategy's inherent potential for new reactivity and selectivity, as well as for resource-efficient synthesis. 5 a reductive setting, electrosynthesis has proved a successful approach for cleavage of polarized carbon-heteroatom σ-bonds via carbon-centered alkyl radical intermediates: in particular, C-X bond cleavage for selective dehalogenation of complex organic molecules, 5c and cross-electrophile couplings of alkyl halides. 6Reductive cleavage of alkyl halides is facilitated when heavier elements in group 7 are utilized, as reflected in their respective C-X bond dissociation energies (BDEs) (Figure 1).Similarly, the BDEs for carbon-heteroatom σ-bonds in group 6 decrease with increasing atomic number and heteroatom oxidation state (Figure 1). 7This bond strength decrease is mirrored in the higher number of synthetic protocols for the formation and use of C-centered radicals via electrochemical C-S bond cleavage compared to C-O bond cleavage, 8 with sulfones being the most well-established precursor class. 9Aryl alkyl thioethers display similar BDEs to those of analogous sulfones and alkyl iodides (Figure 1).Recently, their viability as aryl donors in transition metal-catalyzed cross-couplings was demonstrated, with complete selectivity for C(sp 2 )-S bond cleavage via oxidative addition (Figure 1).4a- c In contrast, the use of thioethers as radical precursors remains highly underexplored, with only a handful of examples for cross-couplings under chemical, photochemical and electrochemical conditions. 10,11 s one of a few examples, Lei and co-workers recently disclosed an electrooxidative protocol for the formation of disulfides from aryl alkyl thioethers via radical cation intermediates (Figure 1). 12Herein, we demonstrate that aryl alkyl thioethers can be successfully used as alkyl radical precursors for desulfurative C-H and C-C bond formation under electroreductive conditions with full selectivity for C(sp 3 )-S bond cleavage.

Results and discussion:
Reaction parameters were assessed for galvanostatic electrolysis of the benchmark substrate phenyl benzyl thioether 1a in an undivided cell to afford reductive C-S cleavage (see ESI, Section S2.1).The use of a tin cathode and magnesium anode in an undivided cell with NBu4PF6 as supporting electrolyte in MeCN furnished the reduction product toluene 2a in quantitative yield along with a mixture of thiophenol and the corresponding disulfide as by-products (Table 1, entry 1).Other cathode materials such as boron-doped diamond (BDD), stainless steel, copper, and nickel (Table 1, entries 2-5) resulted in high conversions of starting material and high yields of 2a, as did the use of various sacrificial anode materials (Table 1, entries 6-7).In contrast, the use of inert anode materials resulted in unsatisfactory yields (Table 1, entries 8-9).The transformation could successfully be performed in several polar aprotic solvents, including DMF, NMP, and THF (Table 1, entries 10-12).Notably, the reaction worked well in the renewable solvent γ-valerolactone (Table 1, entry 13), with near complete selectivity for the desired 2a, albeit in lower yield.Lower yields were obtained at higher current density (Table 1, entry 15), and no starting material was converted in the absence of electricity.No electricity 0 0 *Determined by HPLC, see ESI for details With the optimized conditions at hand, a selection of phenyl alkyl thioethers were assessed to probe the generality of the transformation (Figure 2, top).Gratifyingly, primary, secondary, and tertiary benzylic, and fully aliphatic phenyl thioethers were successfully transformed into the corresponding alkanes in good to excellent yields (2a -2f).Notably, the thioether derivatives of the steroid cholestanol and amino acid cysteine were smoothly converted to their desulfurized counterparts (2g -2h), the latter demonstrating the potential of the strategy for future applications in peptide modification.Furthermore, the pinacolatoboron (BPin) substituted 2i and the indole 2j formed in good to excellent yields.By switching to CD3CN as solvent, full deuteration of the desulfurized products was gratifyingly observed (d-2c and d-2j).Such selective deuteration is of high interest from a pharmaceuticals' perspective, as an emerging strategy to modulate physiochemical and pharmacokinetic properties. 13In accordance with their known electrochemical behavior, reducible functional groups such as nitriles and nitro groups were not compatible with the reaction conditions and formed several side-products (see ESI, Section S7).
Likewise, the C(sp 2 )-Br bond was preferentially cleaved in the p-bromide analogue of 1a and did not furnish p-bromo toluene 2k under the applied conditions, whereas the corresponding halogenated toluene products 2l and 2m formed in 41% and 69% yields, respectively, after 2 F. This moderate tolerance for reducible functional groups in the original protocol prompted us to continue our screening for milder reaction conditions.Specifically, we hypothesized that judicious tuning of the electronic properties of the thioaryl sidechain could enable an anodic shift of its reduction potential, similar to that observed for sulfone derivatives.2l In turn, such a shift would enable selective C(sp 3 )-S cleavage in the functionalized substrates and thus higher functional group tolerance.Hence, the reduction potential for a selection of thioethers with extended aromatic systems or electron withdrawing groups on the thiophenol sidechain were assessed with cyclic voltammetry (CV) (Figure 2, bottom).Indeed, the anticipated shift towards more anodic onset and peak potentials compared to that of 1a was observed for thioethers 1b -1d, while the m-methoxy substituted analogue 1e displayed similar redox behavior to 1a.The greatest shift in peak potential was observed for the fluoride-containing 1b and 1c, and the 3,5-bis-trifluoromethylthiophenyl sidechain in the former was chosen for further evaluation (Figure 2, middle).Gratifyingly, the primary, secondary and tertiary benzylic compounds 2a, 2n, and 2o were formed from their corresponding 3,5-bis-trifluoromethylthiophenyl ethers in good to excellent yields, while the allylic and propargylic compounds 2p and 2q formed in moderate yields.Pyridines 2r -2s formed in good yields, as did substrates with electron-donating methoxy groups (2t -2u) and the electron-withdrawing trifluoromethyl group (2v).Notably, acetophenone 2w was formed from the corresponding α-thioether in moderate yield, despite the rich reactivity of such compounds under reductive conditions to form pinacol products etc. 14 The thiophene and furan derivatives 2x -2y formed in moderate to good yields, as did the ester functionalized 2z and m-toluidine 2aa.Finally, compound 2k with the reducible C(sp 2 )-Br bond was obtained in 38% yield and demonstrated the improved functional group tolerance that the 3,5-bis-trifluoromethylthiophenyl ethers enabled compared to its phenyl analogue.Interestingly, non-benzylic alkanes were not formed from the corresponding 3,5-bistrifluoromethylthiophenol ethers, and signs of preferential benzylic C-F bond cleavage were instead observed.Mechanistically, radical C-S bond cleavage in thioethers has been proposed to result from dissociative single-electron transfer to furnish a C-centered radical and a thiolate anion in either a concerted process or a stepwise sequence with an intermediate radical-anion (Figure 4, top), 10a, 15 similar to the reductive cleavage of other polarized σ-bonds such as C-Br.In the present system, DFT calculations indicated that the concerted or stepwise nature of the bond cleavage was substrate dependent (see ESI, Section S10).While benzylic thioethers 1a and 1b underwent spontaneous C(sp 3 )-S bond cleavage upon single-electron transfer to furnish a C-centered radical and the corresponding thiolate anion, the ethyl thioethers 1f and 1g form radical-anion intermediates that undergo C-S bond cleavage with a low energy barrier (0.9 kcal/mol).In line with the experimental observations, C(sp 3 )-S bond cleavage was found to be energetically preferred over C(sp 2 )-S in all cases.Furthermore, DFT calculations demonstrated that the thermodynamic reduction potential E 0 of thioethers were highly substrate dependent (Figure 4, bottom).The fluorinated thioethers 1b and 1g were found to be reduced at more anodic potentials compared to their phenyl analogues 1a and 1g, thereby corroborating the results from the CV study (Figure 3, bottom).In addition, the benzylic thioethers 1a and 1b were determined to have more anodic values E 0 compared to their ethyl counterparts 1f and 1g.
To furnish the corresponding alkane products, the alkyl radical intermediates that form upon C(sp 3 )-S bond cleavage may either undergo a hydrogen atom transfer (HAT) event or a radical-polar crossover event followed by protonation (Figure 4, top).Interestingly, the calculated E 0 values for all thioethers but 1b were found to be lower compared to the potentials at which the corresponding alkyl radicals undergo reduction to the corresponding carbanions (Figure 4, bottom).Hence, it is expected that there is a significant driving force for the radical intermediates formed from 1a, 1f, and 1g to undergo a second electron transfer in a radical-polar crossover event to the corresponding anions as they form at the electrode.In contrast, the potential at which 1b undergoes dissociative electron transfer to the benzyl radical was found to be similar to that required for its further reduction to the benzylic carbanion and, hence, that the driving force for a radical-polar crossover event is not as pronounced.As such, these data suggest that alkane products from benzylic phenyl thioethers and alkyl thioethers likely form via protonation of carbanions, whereas the alkane formed from 1b may form either via a HAT event or a radical-polar crossover/protonation sequence (Figure 4, top).The presence of possible carbanionic intermediates in the conversion of the thioethers to alkanes suggested that this reactive species may be possible to trap with other electrophiles than protons.Our choice fell on carbon dioxide (CO2), a well-established coupling partner for carbanions in the formation of carboxylic acids.Our DFT calculations (see ESI, Section S10) indicated that only 1b would undergo electrochemical reduction at a more anodic potential compared to CO2 itself, suggesting that substrates of this kind alone would be viable as coupling partners.Indeed, aliphatic thioethers and phenyl thioethers failed to form the electrocarboxylated products when subjected to standard conditions under a CO2 atmosphere, whereas benzylic 3,5-bis(CF3)phenylthioethers formed the corresponding electrocarboxylated products 3a -3j formed in good to excellent yields, including the formation of the β-amino acids 3f and 3g (Figure 5, top).Furthermore, the predicted ability of 1b to form a radical intermediate that may undergo reactions in a one-electron manifold intrigued us.To probe this behavior, we set out to assess benzylic 3,5-bis(CF3)phenylthioethers as radical precursors in Giese crosscouplings, a classic radical transformation for C(sp 3 )-C(sp 3 ) bond formation. 16The cross-coupling partnerelectron-deficient alkenesare known to react in hydrodimerization processes under electroreductive conditions, which would result in side-reactions and limit the yield of Giese products in the present case. 14,17 hus, experimental and theoretical assessments were carried out to identify electron-deficient alkenes with a reduction potential lower than that of thioether 1b.Benzyl acrylate 4a was determined to satisfy this condition and, indeed, the Giese product 5a was formed in 24% under standard conditions in the presence of two equivalents of acceptor 4a (Figure 4, top, and Section S4 in   ESI).By further optimization (see ESI, Section S2.2), using THF as solvent in the presence of Et3N (1 equiv.),HFIP (1 equiv.)and 10 mol% Sm(OTf)3 with continuous addition of 4a, 5a was isolated in 52% yield (Figure 5, bottom).In addition, Giese products from a small selection of thioethers with benzyl acrylate 4a as radical acceptor were formed in moderate to good yields with functional group tolerance including BPin and methoxy groups, while coupling of 1b with ethyl acrylate and phenyl vinyl sulfone resulted in moderate yields of the corresponding C(sp 3 )-C(sp 3 ) coupled products.As predicted, no Giese products were observed using aliphatic thioethers.Mechanistically, the amine additive under optimized conditions likely acts as "stripping agent" to facilitate removal of metal ions from the sacrificial anode to prevent passivation, 18 while HFIP may facilitate the solvation of intermediate anions and act as a proton source. 19Samarium salts have previously been demonstrated to improve yields in electroreductive transformations via different mechanistic routes, including Lewis acidic activation and redox mediation.An assessment of kinetic driving forces for the reduction of 1a under standard conditions (Figure 6, top left) indicated that the process is close to zero order in [1a] and has a positive rate dependence on current density, as was previously observed for other direct electrolytic protocols. 21While thioethers are underexplored as radical precursor class, the corresponding species with higher oxidation state at sulfur are well-known. 3To probe whether C-S bond cleavage occurs via in situ formed sulfoxides or sulfones, the electrochemical reduction of thioether 1a and the corresponding sulfoxide 1a' and sulfone 1a'' were assessed over time (Figure 6, top left).Notably, the latter two were converted into the product 2a in lower yields compared to the former upon full conversion of the radical precursor.Similarly, the use of the oxidized 1b analogues under Giese conditions formed product 5a in less than half of the yield produced with the thioether when all radical precursor had been consumed (Figure 6, middle).The corresponding sulfoxide or sulfone were never detected in the bulk solution when thioether 1a or 1b were employed as starting material, nor was the corresponding thioether observed when the former compounds were used as radical precursors.As such, these results demonstrate that thioethers represent a new class of radical precursors that can outcompete their well-established sulfone analogues in reductive cross-couplings.A tentative mechanism for the electroreduction of thioethers and subsequent C-H and C-C cross-couplings is found in Figure 6, bottom.As indicated by the formation of deuterated products upon the use of CD3CN as solvent (Figure 3), the proton is expected to originate from the reaction solvent.This study demonstrates the successful use of alkyl aryl thioethers as alkyl radical precursors under electroreductive conditions.By tuning the electronic nature of the thioaryl sidechain, selective hydrodesulfurization enables the formation of alkane products in good to excellent yields and good functional group tolerance with complete selectivity for C(sp 3 )-S bond cleavage.Site-selective deuteration could also be achieved by switching to d3-MeCN as solvent.Mechanistic studies indicated that the alkyl aryl thioethers form radical intermediates upon single electron reduction.Depending on the substitution, these radicals may either be trapped in C(sp 3 )-C(sp 3 ) bond forming events with electron deficient alkenes or undergo a second electron transfer to the corresponding carbanion in a radicalpolar crossover event with subsequent C(sp 3 )-C(sp 2 ) bond formation with CO2.To the best of our knowledge, this study is the first example where thioethers are used as radical precursors in the formation of C-C bonds.The use of thioethers was demonstrated to result in higher yields of both alkane and Giese products compared to the corresponding sulfoxides and sulfones.As such, this study demonstrates the significant potential of thioethers as versatile radical precursors for synthetic applications under electrochemical conditions.

Figure 4 .
Figure 4. Mechanistic information from DFT calculations.Top: Stepwise and direct routes to the conversion of thioethers to alkanes.Bottom: Thermodynamic reduction potentials for thioethers and radical intermediates.

Table 1 .
Evaluation of reaction parameters for reduction of 1a