One-Pot Synthesis of N-Iodo Sulfoximines from Sulfides

This is the first report on the synthesis and characterization of N-iodo sulfoximines. The synthesis was designed as a room temperature one-pot cascade reaction from readily available sulfides as starting compounds, converted into sulfoximines by reaction with ammonium carbonate and (diacetoxyiodo)benzene, followed by iodination with N-iodosuccinimide or iodine in situ, in up to 90% isolated yields, also at a multigram scale. Iodination of aryls with N-iodo sulfoximines, oxidation, and conversion to N-SCF3 congeners have been demonstrated.

T he increasing interest in sulfoximines 1−9 in drug discovery, 10−14 medicine, 15−18 and agrochemistry 19,20 has led to a rapidly growing number of publications 21−34 in these and other research areas. 35 These compounds are of great importance as ligands, auxiliaries, and catalysts, e.g., in asymmetric synthesis and catalysis. 36,37 Recently, a large number of reports on their synthesis and transformations have appeared in the literature, 38 (Figure 1g), 51 for example.
Surprisingly, unlike the halogen and chalcogenide derivatives, the N-iodo sulfoximines remain elusive. These compounds have been proposed as reactive intermediates in the iodine-mediated Hofmann−Lofer−Freytag reaction of sulfoximines, leading to dihydroisothiazole oxides ( Figure  1f). 50 Five decades ago, two N-iodo sulfoximines were mentioned in the patent literature, but without any characterization data. 52 All subsequent attempts to prepare these compounds were unsuccessful. 43,51 Our experience with halogenations of organic compounds and green chemistry 53−57 prompted us to develop a reliable method for the synthesis of N-iodo sulfoximines. With simplicity and sustainability in mind, we developed a one-pot cascade protocol using sulfides as starting materials. Selected transformations were also demonstrated.
In initial screening experiments, PhSONHMe was reacted with I 2 /K 2 CO 3 , giving supposedly 2a with 95% conversion in MeCN and DCM. High conversion stimulated us to develop the one-pot protocol from sulfides. Thioanisole (1a, 1 mmol) was allowed to react with (NH 4 ) 2 CO 3 (1.5 equiv) and (diacetoxyiodo)benzene (DIB, 2.3 equiv) in MeOH (10 mL) to give PhSONHMe. Then the reaction solvent was replaced by DCM (10 mL), followed by the addition of Niodosuccinimide (NIS, 1.2 equiv) for iodination. Although complete conversion to a product tentatively identified as 2a by 1 H NMR (see below) was observed after 16 h of stirring at room temperature, attempts to isolate the product failed. Repeating both steps in MeOH (10 mL) as the sole reaction solvent also resulted in complete conversion to the same product, but with the same failure to isolate as described above (Table 1, entry 1). Shortening the reaction time for the iodination step proved to be beneficial. After 2 h, the precipitate formed in the reaction mixture was collected by filtration, and NMR analysis showed the desired product 2a in 57% yield, accompanied by unreacted NIS and succinimide (Table 1, entry 2).
Further reduction of the reaction time to 0.33 h yielded 67% of impure 2a (Table 1, entry 3). Finally, halving the volume of MeOH from 10 to 5 mL at this point allowed the isolation of pure 2a in good 74% yield (Table 1, entry 4). Further reduction in the volume of reaction solvent did not prove beneficial (Table 1, entries 5−8). It is noteworthy that the success of crystallization of 2a from the reaction mixture depends strongly on the surface area of the reaction vessel, as can be concluded from several successive repeating of the above experiments. The best yields of the isolated product were obtained when the reaction was carried out in a worn (scratched) glass round-bottom flask, in a polyethylene vessel, or in the presence of a glass frit that aided the nucleation process (vide infra).
Product 2a showed a characteristic singlet resonance (δ = 3.33 ppm) for the S-CH 3 group in 1 H NMR spectra (CDCl 3 ), which was deshielded as compared to both thioanisole (1a, δ = 2.44 ppm) and PhSONHMe (δ = 3.12 ppm). HRMS analysis in positive ESI+ mode confirmed the ion formula of C 7  Having identified the optimal reaction conditions, we focused on screening the substrate scope (Scheme 1). Mixed phenyl alkyl sulfides 1b−1d gave the corresponding N-iodo sulfoximines 2b−2d regardless of alkyl chain length or branching. Electron-rich and electron-poor aryl alkyl sulfides gave the desired products 2e−2o in good to high yields. Phenyl alkyl and pentafluorophenyl alkyl sulfides 1p−1s reacted smoothly and gave the expected products 2p−2s in up to 90% yields. The C 6 F 5 motif in product 2r is notable for its intrinsic properties that allow molecular recognition and improved structural ordering. 58,59 Relatively challenging substrates, diphenyl sulfide 1t and dibenzothiophene 1u, afforded the corresponding products 2t and 2u in reasonable yields. Benzyl methyl-, symmetric and unsymmetric dialkyl sulfides 1v−1y afforded products 2v−2y in moderate yields. The method was also suitable for heteroaromatic sulfides, as shown by the formation of the product 2z formation in 66% yield. In some cases, those of 2d, 2e, 2g, 2j−2s, 2v, 2x, and 2y, the product did not precipitate from the reaction mixture as described above for 2a. Since attempts to precipitate pure products by addition of a co-solvent (EtOAc, Et 2 O, DCM, AcOH, PE, or hexanes) failed, MeOH was evaporated and the residue was subjected to rapid flash chromatography through a short silica gel plug with DCM as eluent. Prolonged contact The Journal of Organic Chemistry pubs.acs.org/joc Note with SiO 2 , Al 2 O 3 (neutral or basic), activated carbon, or extractive workup was detrimental to the N-iodo sulfoximines. The scalability of the protocol was tested using sulfide 1a as a model substrate. A mixture of 1a (10 mmol), (NH 4 ) 2 CO 3 (15 mmol), and DIB (23 mmol) in MeOH (50 mL) was stirred in a used polyethylene flask for 1 h at room temperature. After addition of NIS (11 mmol) and further stirring of the reaction mixture for 1 h, the precipitate was collected by filtration to afford pure 2a in 78% yield. Repeating the above procedure in a new round-bottom glass flask gave 2a in only a modest 44% yield, consistently indicating the importance of the surface area of the reaction vessel for nucleation.
In addition to NIS, I 2 was tested as an iodinating agent. Under the same reaction conditions as in Scheme 1, sulfide 1a was reacted in situ to give PhSONHMe and then treated with I 2 to give 2a. The iodination proceeded smoothly without the need for a catalyst or promoter. The optimization process of the reaction conditions is summarized in Table 2.
Reaction of the sulfoximines generated in situ from 1a with I 2 (1.1 equiv) in MeOH (5 mL) gave 2a in moderate yield ( Table 2, entries 1 and 2). Reducing the amount of reaction solvent to 1 mL gave impure 2a ( Table 2, entry 3). Optimal results were obtained with 2 mL of MeOH and 1.1−1.25 equiv of I 2 (Table 2, entries 5 and 6). On a larger scale, experiments using I 2 as the iodinating agent were performed with 10 and 25 mmol amounts of 1a to give pure 2a in consistent 74% (2.09 g) and 75% (5.31 g) yields, respectively (Table 2, entries 7 and 8).
Having in hand the one-pot protocol for the N-iodination of sulfoximines formed in situ, we decided to briefly extend it to the preparation of N-bromo sulfoximine 3 and N-chloro sulfoximine 4 (Scheme 2). The reactions were carried out with 1a (1 mmol) in MeOH (5 mL) at room temperature with variable amounts of N-bromosuccinimide (NBS) and Nchlorosuccinimide (NCS). The yields of products 3 and 4 depended strongly on the amount of halogenating agent.
Finally, to demonstrate the applicability of the N-iodo sulfoximines, we decided to test their potential in the electrophilic aromatic substitution reaction with activated benzene derivatives ( Table 3). Treatment of 5 with 2a in AcOH for 1.5 h at 22°C resulted in full conversion to 4iodoanisole (6, entry 1). At elevated temperature (60°C), product 6 formed in 1.5 h and was isolated in 86% yield (entry 2). No reaction was observed in DCM, MeOH, or MeCN as reaction solvent, with unconsumed 5 being regenerated (entries 3−5). This is in sharp contrast to NIS, which proved to work best in MeCN 60 and TFA, 61 suggesting potential orthogonality of these two reagents in iodinations. Phenol (7) was triiodinated with 2a at room temperature to give 8 (entry 6), while 1-methoxynaphthalene (9) gave the 4-iodo derivative 10 (entry 7). Iodination also proceeded with less activated 4nitrophenol (11) to give the diiodinated derivative 12 in excellent yield (entry 8). Thiophenol (13), on the other hand, gave diphenyl disulfide quantitatively (14, entry 9). After completion of the reactions from Table 3, the resulting PhSONHMe was simply removed by extractive workup (HCl aq /DCM), yielding a pure product that required no further purification.
We also tested the reactivity of N-iodo sulfoximines toward silver(I) trifluoromethanethiolate (AgSCF 3 ). The desired N-SCF 3 -substituted sulfoximines 15 were obtained in good to excellent yields (Table 4). This is complementary to the   The Journal of Organic Chemistry pubs.acs.org/joc Note procedure of Bohnen and Bolm, 43 who developed the synthesis of N-trifluoromethylthiolated sulfoximines from sulfoximines via the corresponding N−Br derivatives, and will add to the chemistry of this specific type of compounds. 43 In summary, we have developed a one-pot telescoped synthesis of N-iodo sulfoximines from sulfides using NIS or I 2 .
The reaction proceeds via sulfoximines as reaction intermediates. The protocol is simple and suitable for obtaining a series of structurally diverse (hetero)aryl-, alkyl-, and benzylsubstituted products that can be easily isolated as stable compounds in pure form and in high yields. A multigram scale synthesis was also demonstrated. The reactivity of N-iodo sulfoximines was preliminarily investigated, revealing interesting properties as iodinating and oxidizing agents. For example, unlike NIS, which performs best in MeCN, no iodination of activated anisole occurs with 2a. In contrast, iodination in acetic acid is readily possible, even with 4-nitrophenol as an example of a deactivated substrate. N-Iodo sulfoximines were also found to be valuable intermediates in the synthesis of N-SCF 3 -substituted sulfoximines. An in-depth study of the chemistry of N-iodo sulfoximines is underway.

■ EXPERIMENTAL SECTION
General Considerations. Chemicals and solvents were obtained from commercial sources. TLC was performed on Merck-60-F 254 plates using mixtures of petroleum ether (PE), hexane, dichloromethane (DCM), diethyl ether, ethyl acetate, and methanol. For flash chromatography, silica gel (63−200 μm, 70−230 mesh ASTM; Fluka) was used. The glass frit MPLC Buchi was utilized for induction of nucleation of the products. Products were characterized by 1 H, 13 C, and 19 F NMR spectroscopy, IR spectroscopy, HRMS, and melting points of solids. All NMR spectra were recorded in CDCl 3 using Me 4 Si as an internal standard. Chemical shifts are reported in δ (ppm) values relative to δ = 0.00 ppm (Me 4 Si) for 1 H NMR, and to the central line of CDCl 3 (δ = 77.16 ppm) for 13 C NMR. 19 F spectra were referenced to CFCl 3 as an external standard at δ = 0.00 ppm. 1 H, 13 C, and 19 F NMR spectra were recorded with a Bruker Avance III 500 instrument at 500, 126, and 471 MHz, respectively. IR spectra were recorded with a Bruker FTIR Alpha Platinum spectrophotometer. LC-HRMS analyses were performed on a Shimadzu LCMS-IT-TOF system (Kyoto, Japan), composed of a liquid chromatograph Nexera XR hyphenated to a mass spectrometer with an ion trap and time-of-flight tube equipped with an electrospray ionization (ESI) source. The melting points were determined with an OptiMelt MPA100. By heating, all N-iodo sulfoximines first changed color from orange or yellow to brown and then melted into brown oily liquids. A change of color could imply partial degradation. Elemental combustion analyses were performed with a PerkinElmer analyzer 2400 CHN.
Then, 1.1 equiv of NIS (1.1 mmol, 248 mg) was added, and the stirring was continued for another hour.
The method of isolation was chosen depending on whether the product 2 precipitated or not.
The precipitate was collected by vacuum filtration using a Buchner funnel, washed with a small amount of MeOH, and dried under reduced pressure (vacuum pump) to obtain pure product 2.
The reaction solvent was removed under reduced pressure; the residue was redissolved in small amounts of DCM and subjected to flash chromatography under pressure (nitrogen gas) through a short plug of SiO 2 as a stationary phase and DCM as eluant. The elution was performed in less than 3 min to avoid decomposition of the product. The progress of separation was monitored visually and, if necessary, by TLC analysis. Pink-colored fractions that eluted first contained I 2 and PhI and were disposed of. Orange-colored fractions containing product 2 were collected into 50−100 mL flasks, and the solvent was removed under reduced pressure to obtain a brownorange semisolid. It was redissolved in small amounts of DCM, triturated with large amounts of PE (or hexane) to induce solidification (for solid products), and evaporated to dryness under reduced pressure. The process was repeated 2−3 times to remove any residual I 2 or PhI, resulting in pure product 2.
Synthesis of 2w. A mixture of DMSO (78 mg, 1 mmol), 2 mL of MeOH, 1.5 equiv of (NH 4 ) 2 CO 3 (1.5 mmol, 144 mg), and 1.3 equiv of DIB (1.3 mmol, 419 mg) were charged into a 10 mL round-bottom flask equipped with a magnetic stirrer. The flask was closed with a glass stopper, and the reaction mixture was let to stir vigorously for 1 h. Then, 1.1 equiv of I 2 (1.1 mmol, 279 mg) was added, and stirring was continued for another hour. The reaction mixture was cooled to −5°C (using an ice/NaCl cooling bath); the precipitate was collected by vacuum filtration using a Buchner funnel and washed with small amounts of cold (−5°C) MeOH, followed by large amounts of hexane. The product was dried under reduced pressure (vacuum pump) to obtain an orange-brown solid of 2w (68 mg, 0.31 mmol, 31%).
Synthesis of 2a Using NIS (10 mmol Scale). A mixture of methyl phenyl sulfide (1a, 10 mmol, 1242 mg), 50 mL of MeOH, 1.5 equiv of (NH 4 ) 2 CO 3 (15 mmol, 1440 mg), and 2.3 equiv of DIB (23 mmol, 7410 mg) was charged into a 250 mL polyethylene container equipped with a large magnetic stirrer. The container was closed with a plastic screw top, and the reaction mixture was let to stir vigorously for 1 h. Then, 1.1 equiv of NIS (11 mmol, 2480 mg) was added, and the stirring was continued for another hour. The precipitate was collected by vacuum filtration using a Buchner funnel, was washed with small amounts of MeOH, and dried under reduced pressure (vacuum pump) to obtain a pale yellow solid of 2a (2182 mg, 7.8 mmol, 78%).
Repeating the synthesis under the same reaction conditions in a flawless 250 mL round-bottom flask, equipped with a magnetic stirrer, afforded 2a in 44% yield (1244 mg, 4.4 mmol).
Synthesis of 2a Using I 2 (10 mmol Scale). A mixture of methyl phenyl sulfide (1a, 10 mmol, 1242 mg), 20 mL of MeOH, 1.5 equiv of (NH 4 ) 2 CO 3 (15 mmol, 1440 mg), and 2.3 equiv of DIB (23 mmol, 7410 mg) was charged into a 250 mL polyethylene container equipped with a large magnetic stirrer. The container was sealed with a plastic screw top, and the reaction mixture was let to stir vigorously for 1 h. Then, 1.1 equiv of I 2 (11 mmol, 2794 mg) was added, and the stirring was continued for another hour. The precipitate was collected by vacuum filtration using a Buchner funnel, was washed with small amounts of MeOH and large amounts of hexane, and dried under The Journal of Organic Chemistry pubs.acs.org/joc Note reduced pressure (vacuum pump) to obtain 2a (2090 mg, 7.4 mmol, 74%) as an orange solid. Synthesis of 2a Using I 2 (25 mmol Scale). A mixture of methyl phenyl sulfide (1a, 25 mmol, 3105 mg), 50 mL of MeOH, 1.5 equiv of (NH 4 ) 2 CO 3 (37.5 mmol, 3603 mg), and 2.3 equiv of DIB (57.5 mmol, 18521 mg) was charged into a 250 mL polyethylene container equipped with a large magnetic stirrer. The container was sealed with a plastic screw top, and the reaction mixture was let to stir vigorously for 1 h. Then, 1.1 equiv of I 2 (27.5 mmol, 6980 mg) was added, and the stirring was continued for another hour. The precipitate was collected by vacuum filtration using a Buchner funnel, was washed with small amounts of MeOH and large amounts of hexane, and dried under reduced pressure (vacuum pump) to obtain 2a (5305 mg, 18.75 mmol, 75%) as an orange solid.
N-Iodo-S-methyl-S-phenyl Sulfoximine (2a). 1a (1 mmol, 124 mg), 1.5 equiv of (NH 4 ) 2    Preparation of Other Sulfides. Synthesis of 1p. A mixture of thiophenol (2.200 g, 20 mmol) and styrene (2.184 g, 21 mmol) was charged into a 100 mL round-bottom flask. The flask was sealed with a glass stopper, equipped with a magnetic stirrer, and let to stir overnight at 60°C. After completion of the reaction as determined by TLC analysis, the crude product was purified by vacuum distillation, furnishing 1p as a yellow oil in 90% yield.
Synthesis of 1q. A mixture of thiophenol (1.533 g, 13.9 mmol) and pentafluorostyrene (2.980 g, 15.35 mmol) was charged into a 100 mL round-bottom flask. The flask was sealed with a glass stopper, equipped with a magnetic stirrer, and let to stir overnight at 60°C. After completion of the reaction as determined by TLC analysis, the crude product was purified by vacuum distillation, furnishing 1q as a yellow oil in 85% yield.
Synthesis of 1r. A mixture of pentafluorothiophenol (4.000 g, 20 mmol) and styrene (2.080 g, 20 mmol) was charged into a 100 mL round-bottom flask. The flask was sealed with a glass stopper, equipped with a magnetic stirrer, and let to stir overnight at 60°C. After completion of the reaction as determined by TLC analysis, the crude product was purified by vacuum distillation, furnishing 1r as a yellow oil in 92% yield.
Synthesis of 1s. To a solution of thiophenol (2.200 g, 20 mmol) in 80 mL of MeCN, K 2 CO 3 (3.312 g, 24 mmol) and 1-bromo-3phenylpropane (4.179 g, 21 mmol) were consecutively added, and the mixture was let to stir overnight at room temperature. After completion, as determined by TLC analysis, the reaction solvent was evaporated, and the residue was partitioned three times between DCM and water. The combined organic phase was dried over anhydrous MgSO 4 , and solvent was removed. The oily residue was purified by vacuum distillation, furnishing 1s as a yellow oil in 94% yield.
Synthesis of 1y. A mixture of 1-octanethiol (2.926 g, 20 mmol) and 1-octene (2.244 g, 20 mmol) was charged into a 100 mL roundbottom flask equipped with a magnetic stirrer. The flask was sealed with a glass stopper, and the reaction mixture was let to stir overnight at 60°C. After completion, as determined by TLC analysis, the crude product was purified by vacuum distillation, furnishing 1y as a yellow oil in 92% yield.
Experimental procedures and analytic data for the compounds described and copies of NMR spectra (PDF)