Generation and reactions of thiirenium ions by the Cation Pool method

Thiirenium ions generated and accumulated by low-temperature electrochemical oxidation of disulfides in the presence of alkynes were successfully observed by low-temperature NMR, Raman


Introduction
Thiirenium ions 1 are important reactive intermediates in difunctionalization of alkynes.3][4][5] Some thiirenium ions having bulky substituent groups can be isolated and characterized by X-ray crystal structural analysis. 6Recently, Poleschner et al. reported the synthesis of thiirenium ions in CH 2 Cl 2 by the reaction of disulfides with alkynes having bulky substituent groups using XeF 2 as an one-electron oxidant and silylcarborate salt Me 3 Si + CHB 11 Cl 11  − as a F − acceptor. 73][4][5] Also, their generation in the presence of strong nucleophiles prevents studies on their reactivity towards various nucleophiles.Therefore, there is still room for a method for generating and accumulating thiirenium ions in normal organic solvents in the absence of strong nucleophiles.Electrochemical oxidation [9][10][11][12][13][14][15] serves as a powerful method for generating and accumulating highly reactive cationic species.3][24][25][26] This reaction presumably proceeds by generation of "ArS + " followed by its reaction with ArSSAr.Therefore, we envisaged that the anodic oxidation of ArSSAr in the presence of alkynes leads to the formation of thiirenium ions (Figure 1).The method would enable not only characterization of thiirenium ions but also a study of their reactivity towards various nucleophiles which can be added after their generation.Herein, we report the generation of thiirenium ions having no bulky substituent groups by the "cation pool" method, their spectroscopic characterization, and their reactions with subsequently added nucleophiles.

Results and Discussion
To generate and accumulate thionium ion 1a (Ar = Ph, R = Pr), electrochemical oxidation of PhSSPh (2) in the presence of 4-octyne was carried out under constant current conditions at −78 °C in an H-type divided cell equipped with an anode consisting of fine carbon fibers and a platinum plate cathode in 0.3 M Bu 4 PBF 4 /CD 2 Cl 2 (Figure S1). 27After 2.1 F of electricity was applied, the resulting anodic solution was analyzed by 1 H and 13 C NMR spectroscopies at −78 °C (Figure 2).In the 1 H and 13 C NMR spectra no signal of the disulfide 2 was observed.Only signals which can be attributed to 1a were observed.All signals were assigned as shown in Figure 2 by using HMQC and HMBC measurements (Figures S2 and S3).Correlation between H a,a' and H o,m in NOE spectrum (Figure S4) indicates the generation and accumulation of thiirenium ion 1a in the solution.The chemical shift of the alkenyl carbons (106.8 ppm) is consistent with those of a thiirenium ion having tert-butyl groups reported in the literature (114.52 6 and 113.17 7 ).Notably, two signals assigned to H a and H a' and two signals assigned to H b and H b' were observed at around 3.0 and 1.7 ppm, respectively (Figure 2a, inset), indicating that 1a has a pyramidal sulfur atom whose inversion is prohibited or slow compared to the NMR time scale.The pyramidal structure of 1a is consistent with the reported X-ray structure of the thiirenium ions bearing bulky tert-butyl groups.Thiirenium ion 1a generated in Bu 4 NB(C 6 F 5 ) 4 /CH 2 Cl 2 instead of Bu 4 PBF 4 /CD 2 Cl 2 was analyzed by coldspray-ionization mass spectroscopy (CSI-MS) 28 at 0 °C. 29The signal assigned to 1a was successfully observed (Figure S5).
Raman spectra were measured during the electrochemical oxidation at −78 °C (Figure 3a). 30,31The solution of ArSSAr (Ar = 4-FC 6 H 4 ) and 4-octyne in Bu 4 NBF 4 /CH 2 Cl 2 was electrochemically oxidized to give 1b (Ar = 4-FC 6 H 4 , R = Pr). 32Increase of the electricity applied strengthened the signal at 1874 cm −1 , which is assigned to the stretching of the C−C double bond of 1b by DFT calculations (1862 cm −1 , scaling factor: 0.9614 33 ).The vibration frequencies of the C−C triple bond of 4-octyne, the C-C double bond of 1b, and the C-C double bond of cis-4-octene show linear correlation with the C−C bond lengths obtained by DFT calculaFons (Figure 3b), which is similar to the tendency of seleniranium ions reported in the literature. 34The higher frequency and the shorter bond length of 1b than those of cis-4-octene is not because of the bond order of the C−C double bond of 1b (1.91) and cis-4-octene (1.93) but because of the higher s-character of the carbon atoms of 1b (41.1%, sp 1•43 ) than that of cis-4-octene (39.5%, sp 1•53 ).The thermal stability of thiirenium ion 1a was investigated. 35After a solution of 1a was kept at the second temperature for 30 min, the resulting solution was recooled to −78 °C.Then, Bu 4 NCl (10 equiv) was added and the mixture was stirred at −78 °C for 30 min.AIer work-up the yields of products, chloro-substituted alkene 2a and fluoro-substituted alkene 2b were determined by gas chromatography.Plots of the yield of 2a against the temperature (Figure 4) indicates that 1a is stable at temperatures lower than −40 °C.At the temperatures higher than −20 °C, the yield of 2a decreased and the yield of 2b increased with an increase in the temperature.Presumably, alkene 2b was produced by the reaction of 1a with the supporting electrolyte BF 4

− (vide infra).
Reactions of thiirenium ion 1a with various nucleophiles were investigated (Table 1).After electrochemical generation and accumulation of the thiirenium ion, a nucleophile was added to the solution.The resulting solution was stirred at −78 °C for 30 min and then at 20 °C for 30 min.Cl -reacted with 1a to give 2a in a good yield.When a nucleophile was not added intentionally, 2b was obtained in a good yield (entry 2).Presumably F − derived BF 4 − reacted with 1a.Br − , I − , ArO − (Ar = 4-O 2 N-C 6 H 4 ), AcO − , TfO − , and SCN − , reacted with 1a to give the corresponding substituted alkenes 2c-2h (entries 3-8).Stereochemistry of the alkenes was determined to be E by the NOE measurements.MeOH reacted with 1a to give ketone 4, which was probably formed via methoxy alkene (entry 9).Lithium acetylide gave a mixture of 2i and 3a (entry 10).Enyne 2i was formed by the nucleophilic attack of the acetylide on C, whereas phenylthio-substituted alkyne 3a was formed by the attack of the acetylide on S. Dimethylketene methyl trimethylsilyl acetal and Et 2 NH attacked the sulfur atom of 1a to give compounds 3b and 3c, respectively (entries 11 and 12).Recovery of the alkyne was confirmed by the reaction using 8-hexadecyne and Et 2 NH (entry 13).These results indicate that 1a acts as an ambident electrophile. 36 To obtain a deeper insight into the reactivity of the thiirenium ion we carried out DFT calculations.These calculations show that the LUMO of 1a has large coefficients on the sulfur and the two carbon atoms of the three-membered ring (Figure 5a), indicating that nucleophiles can attack both sulfur and carbon atoms.The DFT calculation also shows that the carbon atom has higher positive potential than the sulfur atom although the thiirenium ion formally has a positive charge on the sulfur atom (Figure 5b).The following mechanistic arguments may be reasonable (Figure 6).The ketene silyl acetal and Et 2 NH attack the sulfur atom, which has a formal positive charge, to give 3 and the acetylene (path a), whereas halide, acetate, triflate, and SCN anions and methanol attack the carbon atom to give 2 (path b).The lithium acetylide attacks both the carbon and sulfur atoms of 1.In the case of halide, acetate, and triflate ions as nucleophiles the reverse reaction of path a might be possible, because such nucleophiles are also good leaving groups.If such an equilibrium exists, 2 can be produced even if path a is preferable.To examine such a possibility, the experiments using an externally added acetylene having different R groups were carried out.The equilibrium would lead to the exchange of acetylenes and the formation of thiirenium ion 1 with different R groups, which eventually gives 2 with different R groups.© ARKAT USA, Inc 5-Decyne (1 equiv) was added to a solution of 1a and the mixture was reacted with Bu 4 NCl.2a was obtained as the major product (68%) in addition to 2j (14%) (Figure 7).The reaction via path a gives 3 and 4octyne, which might go out of the solvent cage.The reverse reaction of 3 with 5-decyne in the bulk solution gives 1c, which react with Cl -via path b to give 2j.This means the equilibrium discussed above does exist, although it does not play a major role.Another possibility to be considered is that an acetylene exchange reaction took place between 1a and 5-decyne to give 1c prior to the reaction with Cl -.
In a second experiment, 4-octyne (1 equiv) was added to a solution of 1c which was electrochemically generated from 5-decene and PhSSPh, and the mixture was reacted with Bu 4 NCl.2j was obtained as the major product (94%) in addition to a small amount of 2a (2%).
These experiments revealed that in the reaction of 1 with Cl -path b is faster than path a, although a small amount of 2 might be produced via 3 through path a and its reverse reaction.

Conclusions
In conclusion, we show that thiirenium ions having no bulky substituent groups can be generated and accumulated in CH 2 Cl 2 by electrochemical oxidation of disulfide in the presence of alkynes at low temperatures such as −78 °C.The thiirenium ions were successfully characterized by NMR, MS, and Raman spectroscopic analyses and exhibited two types of reactivity depending on the nature of nucleophiles.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded in CDCl 3 on Varian Mercury plus-400 ( 1 H: 400 MHz, 13 C: 100 MHz) spectrometer, or JEOL ECA-600P spectrometer ( 1 H: 600 MHz, 13 C: 150 MHz) with tetramethylsilane as an internal standard unless otherwise noted.Mass spectra were obtained on JEOL JMS-SX102A mass spectrometer (EI).GC analysis was performed on a Shimadzu GC-2014 gas chromatograph equipped with a flame ionization detector using a fused silica capillary column (column, CBP1; 0.22 mm × 25 m).Merck precoated silica gel F254 plates (thickness 0.25 mm) was used for thin-layer chromatography (TLC) analysis.Flash chromatography was carried out on silica gel (Kanto Chem.Co., Silica Gel N, spherical, neutral, 40−100 μm) unless otherwise noted.All reactions were carried out under argon atmosphere unless otherwise noted.The anodic oxidation was carried out using an H-type divided cell (4G glass filter) equipped with a carbon felt anode (Nippon Carbon GF-20-P21E, ca.160 mg for 0.25 mmol scale, dried at 300 °C/1 mmHg for 3 h before use) and a platinum plate cathode (10 mm × 10 mm) (Figure S1).Although we used a cell of our original design, similar electrochemical cells are commercially available at Adams & Chittenden Scientific Glass (http://adamschittenden.com/gallery.html?category=4) and EC Frontier.,Inc.(http://www.ec-frontier.co.jp/VB-9.html).A Kikusui PMC350-0.2Awas used as DC power supply for the electrolysis.Bu 4 NBF 4 was purchased from TCI and dried at 25 °C/1 mmHg for 12 h.Dichloromethane was washed with water, distilled from P 2 O 5 , redistilled from dried K 2 CO 3 to remove a trace amount of acid, and stored over 4Å molecular sieves.Dichloromethane-d 2 (CD 2 Cl 2 D-99.80%) was purchased and stored over molecular sieves 4A.Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification.Bis(4-fluorophenyl)disulfide was prepared according to a reported procedure. 37,38Compounds 2a, 39 2b, 40 2c, 39 2d, 39 2f, 41 2h, 39 and 3c 42 were oil, and were characterized by comparison of their 1 H NMR spectra with those reported in the literature.Reactions of thiirenium ion with nucleophiles.The electrolysis of PhSSPh (27.3 mg, 0.125 mmol) in the presence of 4-octyne (28.6 mg, 0.250 mmol) was carried out as described above.To a solution of the thiirenium ion thus generated in the anodic chamber was added a solution of nucleophile (2.50 mmol) in CH 2 Cl 2 at −78 °C and the reacFon mixture was sFrred at −78 °C for 30 min, and then at 20 °C for 30 min.The solution in the anodic chamber was collected and the solvent was removed under reduced pressure and the residue was quickly filtered through a short column (2 x 3 cm) of silica gel to remove Bu 4 NBF 4 .After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography and GPC to obtain the products.

Diethyl(phenylthio)amine (3c)
The electrolysis (2.1 F) of PhSSPh (27.6 mg, 0.126 mmol) in the presence of 8-hexadecyne (56.1 mg, 0.252 mmol), and subsequent treatment with diethylamine (185 mg, 2.53 mmol) followed by a short column of silica gel (hexane/EtOAc 1:1) and GPC gave the title compound (37.3 mg, 82%) and 8-hexadecyne (52.9 mg, 94%).In the anodic chamber were placed 5-decyne (34.6 mg, 0.25 mmol) and diphenyl disulfide (27.5 mg, 0.126 mmol).Electrochemical oxidation (2.1 F) and subsequent addition of the solution of 2.5 M Bu 4 NCl/CH 2 Cl 2 (1 mL) followed by a short column of silica gel (hexane/EtOAc 1:1) gave the crude of the title compound.After removal of the solvent under reduced pressure the crude product was analyzed by GC using tetradecane as an internal standard (99% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.27−7.19(m, 4H), 7.17−7.12(m, 1H), 2.80 (t, J 7.5 Hz, 2H), 2.37 (t, J 7.9 Hz, 2H), 1.62−1.54(m, 4H), 1.53−1.45(m, 4H), 0.91 (t, J 7.2 Hz, 3H), 0.84 (t, J 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 139.8, 135.5, 129.5, 128.9, 128.(6.0 mL) was transferred to Ar-flushed NMR tubes at −78 °C by Ar-flushed 1 mL syringe cooled with dry ice.NMR measurements were carried out using JEOL ECA-600P spectrometer ( 1 H: 600 MHz, 13 C: 150 MHz).Spectra so obtained are presented in the Supplementary File.MS analyses; typical procedure.In the anodic chamber were placed 4-octyne (118.6 mg, 1.08 mmol), PhSSPh (114.6 mg, 0.525 mmol), Bu 4 NB(C 6 F 5 ) 4 (923.9mg, 1.0 mmol), and CH 2 Cl 2 (10 mL).In the cathodic chamber were placed trifluoromethanesulfonic acid (120 μL, 1.37 mmol), Bu 4 NBF 4 (926 mg, 1.0 mmol), and CH 2 Cl 2 (10 mL).The constant current electrolysis (15.0 mA) was carried out at −78 °C with magneFc sFrring unFl 2.1 F of electricity was passed.The reaction mixture of the anodic chamber was analyzed by CSI-MS (spray temperature; 0 °C): HRMS (CSI) m/z calcd for C 14 H 19 S + (M + ): 219.1202, found: 219.1209.Raman analyses.A laser beam from a fiber-coupled output of cw laser, Toptica XTRA, 250 mW at 785 nm, was conducted through the solution in the anodic chamber of the electrochemical cell.Scattered light was collected in the direction perpendicular to the axis of the laser beam by using a combination of quartz lenses focusing the light on the surface of the entrance cross section of the bundle of forty optical fibers with a 100 μm diameter for each.The optical components were contained in a vacuum-tight glass tube sealed with rubber o-rings and partly dipped into the reactant solution.The electrochemical cell was independently purged with N 2 gas to avoid humidity in air.For the measurement, the vacuum seal of the optical component was crucial in avoiding frost, which scatters both the excitation and signal beams.The collected light was conducted through the optical fibers to a spectrometer for dispersion, Acton 320 PI (1200 G/mm blazed at 500 nm or 600 G/mm blazed at 1000 nm), and detected by using a liquid-nitrogen cooled CCD array detector, PyLoN:256-OE 1024 x 256 pixels of 26 x 26 μm 2 .To minimize stray light, a sharpedge long-pass filter, Semrock RazorEdge 785R (o.d.<10 −6 at 785 nm), was placed in front of the entrance slit of the spectrometer, where the image of the exit cross section of the fiber bundle with vertically aligned forty optical fibers was focused.Spectra were accumulated for 6 min 40 sec (a 4-sec exposure time by 100 times accumulation) for each and redundantly stored one by one for 4 hours (400 sec by 60 spectra) during the electrolysis.Spectral resolution was ~0.2 nm, which corresponds to ~3 cm −1 at 815 nm where a Raman band of 470 cm −1 was observed.DFT calculations.DFT calculations were conducted with the Gaussian 09 program. 43All geometry optimizations were carried out at the B3LYP level of density functional theory with the 6-31G(d) basis set.The bond order and s-character were obtained by the natural bond orbital (NBO) analysis.See Supplementary file.

Figure 6 .
Figure 6.Plausible explanation for the product selectivity.

Figure 7 .
Figure 7. Reactions of 1 with Cl -in the presence of alkynes.

Figure 8 .
Figure 8.An H-type divided cell for electrolysis.
Thermal stability.After generating thionium ion from PhSSPh (27.3 mg, 0.125 mmol) and 4-octyne (28.6 mg, 0.25 mmol) at −78 °C as described above, the solution was stirred at T °C (T = −78, −60, −40, −20, and 0) for 30 min.The solution was recooled to −78 °C, added Bu 4 NCl (2.5 mmol) in CH 2 Cl 2 and stirred at −78 °C for 30 min and then at 20 °C for 30 min.The solvent was removed under reduced pressure and the residue was quickly filtered through a short column (2 x 3 cm) of silica gel to remove Bu 4 NBF 4 .The silica gel was washed with hexane/EtOAc 1:1.After removal of the solvent under reduced pressure, the crude product was analyzed by gas chromatography.Reference reaction.In the anodic chamber were placed 4-octyne or 5-decyne (0.25 mmol), and PhSSPh (0.125 mmol), Bu 4 NBF 4 (3.0 mmol), and CH 2 Cl 2 (10 mL).In the cathodic chamber were placed trifluoromethanesulfonic acid (60 μL), Bu 4 NBF 4 (3.0 mmol) and CH 2 Cl 2 (10 mL).The constant current electrolysis (8.0 mA) was carried out at −78 °C with magneFc sFrring unFl 2.1 F of electricity was passed.To the anodic chamber was added another alkyne (0.25 mmol).The solution was stirred for 10 min at −78 °C.To the anodic chamber was added 2.5 M Bu 4 NCl/CH 2 Cl 2 (1 mL), and to the cathodic chamber CH 2 Cl 2 (1 mL) was added at −78 °C.The soluFon was sFrred for 30 min at −78 °C, and then 30 min at 20 °C.The solution in the anodic chambers was collected and the solvent was removed under reduced pressure.The residue was filtered through a short column (2 x 4 cm) of silica gel to remove Bu 4 NBF 4 by using hexane/EtOAc (1:1 v/v) as an eluent.After removal of the solvent under reduced pressure the crude product was analyzed by GC using tetradecane as an internal standard.(E)-5-Chloro-6-phenylthio-5-hexene(2j) 6,7

Table 1 .
Reactions of thiirenium ion 1a with nucleophiles a