Selective Synthesis of N-Cyano Sulfilimines by Dearomatizing Stable Thionium Ions.

For the selective synthesis of N-cyano sulfilimines, we have developed a new method based on the soft-soft interaction between thionium ion electrophiles and cyanonitrene nucleophiles. The stable thionium ion was successfully obtained by oxidative dearomatization using phenyliodine (III) diacetate (PIDA) in N,N-dimethylformamide (DMF). The sulfur imination reactions were tolerant to a wide range of functional groups and exhibited high selectivities and excellent yields. The existence of thionium ion intermediates was confirmed by ultraviolet/visible (UV/vis) spectroscopy and 1H NMR experiments.

Introduction

Sulfilimines―mono-aza analogues of sulfoxides―were first reported in 1921.[1] The S–N bond in sulfilimines is more reactive and polarized than the S–O bond in sulfoxides (Figure a).[2] Due to the interesting features of this moiety, sulfilimines have played important roles in a broad range of fields, including synthetic chemistry,[3] catalysis,[4] crop protection,[5] and medicinal chemistry.[6] For example, in sulfilimine-applied organic reactions, there are aza-Mislow–Evans reactions,[3a] Diels–Alder reactions with furan and acyclic dienes,[3b] dichloroketene-induced cyclization reactions,[3c] the syntheses of γ-butyrolactams[3d] and α-hydroxy-β-amino acid derivatives,[3e] oxidative Mannich reactions,[3f] the direct thioamination of arynes,[3g] and the synthesis of new palladacycles.[4] In crop protection, the discovery of sulfoxaflor by Dow AgroSciences (Figure b) stimulated a large number of subsequent investigations.[7] With regards to drug discovery, AstraZeneca and Bayer employed sulfoximine-containing substances in selective kinase inhibitors, which are clinical candidates AZD6738[8a] and BAY1000394.[8b] Researchers at AstraZeneca and Bayer demonstrated that one-atom replacement at the sulfur core—from oxygen to nitrogen—led to a compound with highly enhanced absorption, distribution, metabolism, and excretion (ADME) properties.[8] For recent applications of these moieties inside living systems, the sulfilimine bond—a bond between methionine sulfur and hydroxylysine nitrogen—was first identified in native biomolecules.[9] In addition, new bioorthogonal reactions using the sulfilimine chemistry have been reported for the development of an alternative approach to well-known click chemistry.[10] In short, there has been an increasing awareness of the versatility of sulfilimine-based compounds as important reagents in organic synthesis and as highly potent molecules in drug development and agrochemical research (Figure b).

Figure 1

(a) Selected sulfur(IV) functional groups. (b) Biologically active N-cyano sulfilimines and sulfoximines.[12]

In general, the nitrogen end of the sulfilimine linkage is stabilized by strong electron-withdrawing groups (Figure a).[2] Among the possible diversity of the imine nitrogen, we are particularly interested in the cyano substituent, which exhibits high metabolic stability, a powerful electron-withdrawing nature, and improved ADME-toxicology profiles.[11]

Few studies have demonstrated the formation of N-cyano sulfilimines from sulfides.[13,14] As shown in Figure a, strategies include using sulfonium salt intermediates, adding halogenating reagents (e.g., N-halosuccinimides and t-BuOCl) to sulfides, and undergoing nucleophilic sulfur imination.[13] Swern reported that cyanonitrene is formed by the reaction of t-butyl hypochlorite and sodium cyanamide.[13a,13b] However, N-sodio-N-chlorocyanamide was generated at a very low temperature using flammable t-butyl hypochlorite, which did not seem to be attractive from a practical synthesis perspective. For other oxidative imination approaches, Bolm reported that the combination of sulfides with N–bromosuccinimide (NBS), cyanamide, and sodium t-butoxide produces the desired cyano sulfilimines (Figure a).[13c] Although a well-behaved procedure, this procedure was limited using a strong base and the production of the undesirable sulfoxide. Consequently, practical procedures of synthesizing biologically active N-cyano sulfilimine (Figure b) are strongly required.

Figure 2

(a) Previously reported oxidative imination approach.[13] (b) Our thionium ion approach.[13b,14a,15,16]

For the selective synthesis of the desired N-cyano sulfilimine, the in situ formation of the thionium ion and subsequent nucleophilic substitution with a cyanogen amine was envisaged. In the reported approaches (Figure a), a sulfonium salt was generally used as an unstable electrophile, which produced a significant amount of undesirable sulfoxide. To achieve the proper electrophile–nucleophile interaction, we designed a new reaction that proceeded via the intramolecular formation of thionium ions, which may act as stable softer electrophiles (Figure b). In principle, ortho- and para-substituted aromatic thionium ions could be formed by the oxidative dearomatization of anilides.[17] Among the possible oxidants, hypervalent iodine (III) reagents have been widely used because of their moderate reactivity and broad applicability.[18] For the softer nucleophile, a cyanamide/phenyliodine (III) diacetate (PIDA) system, which generated a nitrene or nitrene-like intermediate,[13b,14a,16] was applied in this study.

Results and Discussion

Initially, the reaction of the iodine (III) reagents with anilide 1 and H2NCN was investigated in various solvents, such as CH2Cl2,[14a] CH3CN,[14d] and N,N-dimethylformamide (DMF).[14e] The combination of sulfide 1 with PIDA (1 equiv) and H2NCN (1 equiv) in CH2Cl2 and CH3CN for 5.5 h at room temperature produced a low yield of the desired sulfilimine 2a (each 27%, Table , entries 1 and 2). In the case of using DMF as a solvent, however, N-cyano sulfilimine 2a was obtained with a 57% yield (entry 3). Thus, this reaction was substantially influenced by the choice of the solvent. These preliminary results support the hypothesis that DMF would promote the formation of thionium ions.[19] Changing the amount of PIDA (from 0.1 to 1.0 equiv) helped to increase the yield (Table , entries 3 to 6), whereas excess PIDA led to negative effects (entry 7).[20] Then, we screened the amount of cyanamide (entries 3, 8, and 9), and the best result was obtained when 3 equiv of cyanamide were added. For the 1H NMR study of the mixture of PIDA and H2NCN in deuterated DMF, we found that the proton peak corresponding to cyanamide rapidly disappeared. Thus, a sufficient amount of cyanamide is required to produce the desired N-cyano sulfilimine 2a. A combination of 1 equiv of sulfide 1, 1 equiv of PIDA, and 3 equiv of H2NCN in DMF prove to be the most effective (entry 9). As shown in Table (entry 10), the attempt to use phenyliodine (III) bis(trifluoroacetate) (PIFA)[18f,21] was unsuccessful.[22]

Table 1

Imination Reaction of Sulfide 1 Using Iodine (III) Reagents and Cyanamide

	reaction conditionsb
entry	iodine (III) (equiv)a	H2NCN (equiv)	solvent	yield (%)c
1	PIDA (1.0)	1.0	CH3CN	27
2	PIDA (1.0)	1.0	CH2Cl2	27
3	PIDA (1.0)	1.0	DMF	57
4	PIDA (0.1)	1.0	DMF	8
5	PIDA (0.5)	1.0	DMF	24
6	PIDA (2.0)	1.0	DMF	53
7	PIDA (3.0)	1.0	DMF	d
8	PIDA (1.0)	2.0	DMF	74
9	PIDA (1.0)	3.0	DMF	80
10	PIFA (1.0)	1.0	DMF	d

PIDA: phenyliodine(III) diacetate, PIFA: phenyliodine(III) bis(trifluoroacetate).

For highlighting the addition order of reagents, to a solution of sulfide 1 and iodine (III) reagent in DMF was added H2NCN in DMF at room temperature (RT).

After column chromatography.

No desired reaction.

Next, the scope of the reaction was examined using the optimized reaction conditions (Scheme ). 2- or 4-Thiomethyl phenyl compounds proved to be generally excellent substrates for this transformation. Excellent yields of anilides, acetate, and benzoyl, for example, were all obtained (2–9, 11–14). The X-ray crystal structures of N-cyano sulfilimine 2a are illustrated.[23] For sulfilimine 10, a moderate yield was observed when using N-(2-(methylthio)phenyl)pyridin-2-amine as a substrate. Interestingly, the yields of the 4-substituted sulfides (3, 5, 7, 9) were better than those of the 2-substituted ones (2a, 4, 6, 8). In the case of compounds 11–14, high yields were also obtained.

Scheme 1

Reaction Scope with Various Sulfides

To seek insight into the mechanism and find evidence of the thionium ion species, we performed control experiments (Table ). For the previously reported sulfonium salt-mediated approach (entry 1, method i),[13c] the unwanted sulfur oxidation reaction predominated over sulfilimine formation. Interestingly, in the absence of cyanonitrene, the Pummerer rearrangement products 2d, 2e,[24] and sulfoxide 2c were obtained in low yields (entry 2, method ii). In contrast to the sulfonium salt electrophile, the thionium ion only generated a small quantity of sulfoxide 2c after the H2O workup (entry 1 vs 2). These results clearly demonstrated the existence of a stable thionium ion. When trifluoroacetamide was applied in this transformation as an imination source, the desired sulfilimine 2f was observed in only trace amounts (entry 3, method iii) We assume that the nitrene or nitrene-like intermediate could not be generated in the PIDA/H2NCOCF3 system.[25] For 3-(S-methylsulfilimidoyl)phenyl compound 2g, no desired reaction occurred (entry 4). Importantly, this result indirectly demonstrates the formation of thionium ions, because 2- and 4-substituted compounds, which have conjugation systems, exhibited an excellent transformation.

Table 2

Control Experiments

R’ = C(O)Ph.

Method i: NBS (1.5 equiv), t-BuOK (1.2 equiv), H2NCN (1.3 equiv), MeOH, RT, 4 h; method ii: PIDA (1 equiv), DMF, RT, 5.5 h; method iii: PIDA (1 equiv), H2NC(O)CF3 (1 equiv), DMF, RT, 5.5 h; method iv: PIDA (1 equiv), H2NCN (1 equiv), DMF, RT, 5.5 h.

After column chromatography.

To determine the mechanism of our thionium ion approach, we carried out an extensive UV and 1H NMR investigation to monitor the reaction of sulfide 1 with PIDA.

The ultraviolet/visible (UV/vis) spectrum of 1 with combined PIDA was illustrated in Figure a. A solution of N-phenylbenzamide (without sulfide) and PIDA in DMF was also measured and used as a control experiment. The spectrum of each solvent showed different spectroscopic characteristics at 346 nm (acetonitrile, ACN), 350 nm (dichloromethane, DCM), and 358 nm (N,N-dimethylformamide, DMF). In the case of the mixture of N-phenylbenzamide in DMF, the characteristic band at 343 nm was observed. If larger conjugation systems are present, the absorption peak wavelengths tend to appear in regions where the wavelength is large, and the absorption peaks tend to be larger.[26] Consequently, the UV/vis study suggested that DMF is the best solvent for this transformation.

Figure 3

(a) UV absorption spectra of a solution of sulfide 1 with PIDA in various solvents. (b) 1H NMR studies of a solution of sulfide 1 with PIDA in deuterated DMF.

Figure b shows the 1H NMR study results, which demonstrate the formation of the thionium ion. 1H NMR spectra of the reaction mixture of sulfide 1 and PIDA in deuterated DMF was obtained with respect to the reaction time. The remaining percent of each peak was calculated (Figure B, equation). Interestingly, Ha (NH of 1, black color) and He (protons of PIDA, green color) displayed a similar decreased pattern until 2 h, while the peak corresponding to PIDA rapidly disappeared after that time. In the case of Hb (S-methyl of 1, red color) and Hc (aromatic proton of 1, blue color), the same trend was observed. Note that the 4-position proton (Hd, pink color) was almost unchanged for 6 h.[27]

Hence, the UV/vis spectroscopy and 1H NMR studies lead us to conclude that the thionium ion is formed by oxidative dearomatization.

Conclusions

In summary, we have developed a thionium ion-mediated reaction and demonstrated that the soft–soft interaction between thionium ions and cyanonitrene would be a better method to access the N-cyano sulfilimine functionality. The mechanism involving the formation of stable softer thionium ion electrophiles was undoubtedly proven by (i) the sulfur imidation of the reactive functional group-substituted thioanisoles at the 2- and 4-position and (ii) UV/vis spectroscopy and 1H NMR studies of the solution of sulfide 1 and PIDA. Further investigations that aim to expand the scope of this transformation using harder nucleophiles are in progress in our laboratory.

Experimental Section

General Information

Analytical thin-layer chromatography (TLC) was performed on Kieselgel 60 F254 glass plates precoated with a 0.2 mm thickness of silica gel. The TLC plates were visualized by UV (254 nm), potassium permanganate, or ceric ammonium molybdate stain. Flash chromatography was carried out with Kieselgel 60 (230–400 mesh) silica gel. Melting points: Barnstead/Electrothermal 9300, measurements were performed in open glass capillaries. IR spectra: Bruker α-P. NMR spectra: Bruker AV 300 MHz (1H NMR: 300 MHz, 13C NMR: 75 MHz), AV 400 MHz (1H NMR: 400 MHz, 13C NMR: 100 MHz), AV 500 MHz (1H NMR: 500 MHz, 13C NMR: 125 MHz), and AV2 500 MHz (19F NMR: 470 MHz), the spectra were recorded in CDCl3, MeOD, and DMSO-d6 using tetramethylsilane (TMS) as the internal standard and are reported in ppm. 1H NMR data are reported as follows: (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, m = multiplet; coupling constant(s) J are given in Hz; integration, proton assignment). High-resolution mass spectra (HRMS): JEOL JMS-700. X-ray crystallography: Bruker SMART APEX II X-ray diffractometer. UV–VIS spectra: SCINCO S-4100 diffuse reflectance-ultraviolet/visible (DR-UV/VIS) spectrophotometer. All solvents were purified using a column filter solvent purification system before use unless otherwise indicated. Reagents were purchased and used without further purification.

General Imination Method

To a solution of sulfide 1 (0.2 mmol) and PhI(OAc)2 (0.2 mmol) in DMF (1 mL) was added H2NCN (0.6 mmol) in DMF (1 mL) at RT. The reaction mixture was stirred at RT for 5.5 h and quenched with water. The reaction mixture was extracted with CH2Cl2 (30 mL). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired product.

(E)-N-(2-(N-Cyano-S-methylsulfinimidoyl)phenyl)benzamide (2a)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 2a as a white solid (44 mg, 79% yield). mp 173–174 °C; IR (KBr): ν 2135 (CN), 1314, 1254, 1165, 960, 760 cm–1; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 7.9 Hz, 2H), 7.74 (t, J = 7.7 Hz, 1H), 7.62–7.69 (m, 2H), 7.58 (t, J = 7.5 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H), 3.19 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 160.1 (CO), 135.9, 134.1, 133.6, 132.8, 132.6, 128.7, 128.2, 128.0, 126.5, 126.3, 120.8 (CN), 35.5 (CH3); HRMS (EI) calcd for C15H13N3OS 283.0779, found 283.0763.

(E)-N-(2-(N-Cyano-S-methylsulfinimidoyl)–5-(trifluoromethyl)phenyl)benzamide (2b)

To a solution of sulfide 1 (155 mg, 0.5 mmol) and PhI(OAc)2 (161 mg, 0.5 mmol) in DMF (1 mL) was added H2NCN (63 mg, 1.5 mmol) in DMF (1 mL) at RT. The reaction mixture was stirred at RT for 5.5 h and quenched with water. The reaction mixture was extracted with CH2Cl2 (30 mL). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 2b as a white solid (104 mg, 59% yield). mp 146–147 °C; IR (KBr): ν 2154 (CN), 1662, 1534, 1475, 1338, 1283, 980, 704 cm–1; 1H NMR (500 MHz, CDCl3) δ 10.63 (s, 1H), 8.26 (d, J = 7.6 Hz, 2H), 7.96 (dd, J = 4.7 Hz, J = 8.7 Hz, 2H), 7.60 (dd, J = 7.3 Hz, J = 7.6 Hz, 1H), 7.49–7.62 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1 (CO), 137.8, 135.5 (q, J = 33.4 Hz, CF3), 133.6, 133.0, 131.8, 128.9, 128.0, 127.6, 124.1, 123.5, 122.7, 121.4(CN), 37.1(CH3) 19F NMR (471 MHz, CDCl3) δ −63.2 (s, CF3); HRMS (EI) calcd for C16H12F3N3OS 351.0653, found 351.0656.

N-(2-(Methylsulfinyl)phenyl)benzamide (2c)

To a solution of sulfide 1 (97 mg, 0.4 mmol) and NBS (110 mg, 0.6 mmol) in MeOH (1 mL) were added t-BuOK (54 mg, 0.48 mmol) and H2NCN (21 mg, 0.52 mmol) in MeOH (1.5 mL) at RT. The reaction mixture was stirred at 0 °C for 4 h and quenched with water. The reaction mixture was extracted with CH2Cl2 (30 mL). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the sulfoxide 2c as a white solid (81 mg, 78% yield). 1H NMR (300 MHz, CDCl3) δ 11.48 (s, 1H), 8.67 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 7.5 Hz, 2H), 7.64 (dd, J = 2.3 Hz, J = 8.9 Hz, 1H), 7.46–7.60 (m, 3H), 7.42 (d, J = 2.3 Hz, 1H), 2.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3 (CO), 140.8, 133.8, 132.7, 132.1, 128.9, 127.5, 127.3, 125.8, 123.5, 123.0, 40.8 (CH3).

((2-Benzamidophenyl)thio)methyl Acetate (2d) and N-(2-((Hydroxymethyl)thio)phenyl)benzamide (2e)

Sulfide 1 (121 mg, 0.5 mmol) and PhI(OAc)2 (161 mg, 0.5 mmol) were dissolved in DMF (1 mL), and the reaction mixture was stirred at RT for 5.5 h and quenched with water. The reaction mixture was extracted with CH2Cl2 (30 mL). The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (n-Hex/ EtOAc = 10:1) to give the sulfoxide 2c (27 mg, 26% yield), the compound 2d as a colorless liquid (8 mg, 5% yield), and the compound 2e as a white solid (5.1 mg, 4% yield). 2d: IR (neat): ν 3253, 1739, 1648, 1519, 1471, 1306, 1226, 1072, 1025, 757, 710 cm–1; 1H NMR (500 MHz, CDCl3) δ 9.34 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 7.7 Hz, 1H), 7.59 (dd, J = 7.2 Hz, J = 7.4 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.47 (dd, J = 7.8 Hz, J = 7.9 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 5.24 (s, 2H), 1.81 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.0 (CO), 165.0 (CO), 140.3, 136.1, 134.7, 132.1, 131.2, 128.9, 127.1, 124.5, 121.4 (CN), 120.4, 69.9 (CH2), 20.5 (CH3); HRMS (EI) calcd for C16H15NO3S 301.0773, found 301.0773. 2e: mp 97-98 °C; IR (KBr): ν 1986, 1645, 1509, 1465, 1068, 1024, 911, 742 cm–1; 1H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 7.7 Hz, 1H), 7.48–7.60 (m, 5H), 7.17 (t, J = 7.6 Hz, 1H), 4.82 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 165.2 (CO), 140.6, 136.4, 134.7, 132.1, 128.9, 127.2, 124.6, 120.8, 120.4, 52.5 (CH2).

(E)-N-(4-(N-Cyano-S-methylsulfinimidoyl)phenyl)benzamide (3)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 3 as a white solid (48 mg, 85% yield). mp 173–174 °C; IR (KBr): ν 2141 (CN), 1322, 1250, 1143, 959, 841, 768 cm–1; 1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 7.7 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 7.3 Hz, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 3.15 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 166.2 (CO), 143.3, 134.4, 132.1, 130.0, 128.6, 127.9, 127.8, 120.9, 120.5 (CN), 34.7 (CH3); HRMS (FAB) calcd for C15H14N3OS 284.0858, found 284.0860.

tert-Butyl (E)-(2-(N-cyano-S-methylsulfinimidoyl)phenyl)carbamate (4)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 4 as a white solid (31 mg, 55% yield). mp 132–133 °C; IR (KBr): ν 2141 (CN), 1286, 1235, 1156, 990, 762 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.71–7.80 (m, 2H), 7.55 (dd, J = 7.3, J = 8.5, 1H) 7.29 (t, J =7.7, 1H), 3.10 (s, 3H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.5 (CO), 138.2, 134.2, 127.7, 125.5, 123.9, 120.8 (CN), 82.0, 35.7 (CH3), 29.7 (C), 28.2 (3 x C, CH3); HRMS (EI) calcd for C13H17N3O2S 279.1041, found 279.1057.

tert-Butyl (E)-(4-(N-cyano-S-methylsulfinimidoyl)phenyl)carbamate (5)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 5 as a white solid (60 mg, quantitative yield). mp. 123–124 °C; IR (KBr): ν 2141(CN), 1314, 1229, 1147, 961, 830, 762 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.22 (s, 1H), 2.99 (s, 3H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 152.2 (CO), 143.6, 128.2, 127.5, 120.6 (CN), 119.2, 81.6, 36.1 (CH3), 29.7 (C), 28.2 (3 × C, CH3); HRMS (FAB) calcd for C13H18N3O2S 280.1120, found 280.1118.

(E)-N-(2-(N-Cyano-S-methylsulfinimidoyl)phenyl)acetamide (6)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 6 as a colorless liquid (28 mg, 63% yield). IR (neat): ν 2138 (CN), 1684, 1476, 1253, 1187, 983, 767 cm–1; 1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 3.17 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, MeOD) δ 173.2 (CO), 137.1, 135.1, 134.4, 129.5, 127.6, 126.4, 123.1 (CN), 36.8 (CH3), 22.7 (CH3); HRMS (EI) calcd for C10H11N3OS 221.0623, found 221.0610.

(E)-N-(4-(N-Cyano-S-methylsulfinimidoyl)phenyl)acetamide (7)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 7 as a white solid (29 mg, 66% yield). mp 175–176 °C; IR (KBr): ν 2145 (CN), 1685, 1444, 1380, 1161, 973, 838, 758 cm–1; 1H NMR (500 MHz, MeOD) δ 7.88 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 3.10 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, MeOD) δ 172.2 (CO), 145.0, 130.9, 128.9, 122.7 (CN), 121.7, 36.4 (CH3), 24.2 (CH3); HRMS (FAB) calcd for C10H12N3OS 222.0701, found 222.0711.

(E)–2-(N-Cyano-S-methylsulfinimidoyl)phenyl Acetate (8)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 8 as a colorless liquid (25 mg, 60% yield). IR (neat): ν 2151 (CN), 1725, 1456, 1371, 1182, 963, 865, 755 cm–1; 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.53 (dd, J = 7.6 Hz, J = 7.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 3.01 (s, 3H), 2.39 (s, 3H); 13C NMR; 168.4 (CO), 147.2, 134.2, 129.2, 128.0, 126.4, 123.4, 120.2 (CN), 36.2 (CH3), 20.7 (CH3).

(E)-4-(N-Cyano-S-methylsulfinimidoyl)phenyl Acetate (9)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 9 as a white solid (32 mg, 74% yield). mp 99–100 °C; IR (KBr): ν 2137 (CN), 1747, 1496, 1356, 1190, 952, 844, 759 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 3.02 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.6 (CO), 154.3, 133.1, 127.6, 123.8, 120.1 (CN), 36.7 (CH3), 21.1 (CH3); HRMS (EI) calcd for C10H11N3OS 221.0463, found 222.0478.

(E)-N-(Methyl(2-(pyridin-2-ylamino)phenyl)-λ4-sulfanylidene)cyanamide (10)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 10 as an orange solid (18 mg, 35% yield). mp 153–154 °C; IR (KBr): ν 2135 (CN), 1467, 1186, 967, 765 cm–1; 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 8.16 (d, J = 5.1 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 7.9 Hz, J = 8.6 Hz, 1H), 7.53 (dd, J = 7.8 Hz, J = 7.9 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.85 (dd, J = 5.8 Hz, J = 6.7 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 3.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.6, 147.5, 141.3, 138.3, 134.3, 128.1, 123.9, 123.6, 123.0, 121.0 (CN), 116.9, 111.4, 35.0 (CH3); HRMS (EI) calcd for C13H12N4S 256.0783, found 256.0793.

(E)-N-(2-(N-Cyano-S-methylsulfinimidoyl)phenyl)furan-2-carboxamide (11)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 11 as a white solid (43 mg, 80% yield). mp 82–83 °C; IR (KBr): ν 2146 (CN), 1310, 1167, 973, 759 cm–1; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.58–7.65 (m, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.57–6.61 (m, 1H), 3.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.2 (CO), 146.5, 145.7, 136.8, 134.3, 127.7, 127.2, 126.9, 125.1, 120.8 (CN), 116.6, 112.6, 36.2 (CH3); HRMS (EI) calcd for C13H11N3O2S 273.0572, found 273.0569.

(E)-N-(2-(N-Cyano-S-methylsulfinimidoyl)phenyl)quinoline-2-carboxamide (12)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 12 as a white solid (62 mg, 91% yield). mp 125–126 °C; IR (KBr): ν 2148 (CN), 1313, 1185, 1132, 982, 839, 764 cm–1; 1H NMR (500 MHz, CDCl3) δ 11.24 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.01 (dd, J = 8.8 Hz, J = 9 Hz, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.84 (dd, J = 7.5 Hz, J = 7.8 Hz, 1H), 7.68 (t, J = 7.9 Hz, 2H), 7.47 (t, J =7.7 Hz, 1H), 3.21 (s. 3H); 13C NMR (125 MHz, CDCl3) δ 163.9 (CO), 148.0, 146.4, 138.1, 136.5, 134.2, 130.7, 130.1, 129.6, 128.8, 127.7, 127.6, 127.0, 124.8, 120.9 (CN), 118.6, 36.2 (CH3); HRMS (EI) calcd for C18H14N4OS 334.0888, found 334.0899.

(E)-1-(2-(N-Cyano-S-methylsulfinimidoyl)phenyl)-3-phenylurea (13)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 13 as a white solid (43 mg, 72% yield). mp 184–185 °C; IR (KBr): ν 2149 (CN), 1312, 1230, 1165, 963, 762 cm–1; 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.03 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.5 Hz, J = 7.9 Hz, 1H), 7.42–7.53 (m, 4H), 7.30 (dd, J = 7.7 Hz, J = 7.8 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 3.18 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 154.0 (CO), 139.1, 137.0, 133.4, 132.0, 128.8, 126.6, 126.3, 124.4, 122.5, 120.9 (CN), 118.8, 35.1 (CH3); HRMS (EI) calcd for C15H14N4OS 298.0904, found 298.0896.

(E)–2-(N-Cyano-S-methylsulfinimidoyl)phenylbenzoate (14)

This follows the general imination method. The residue was purified by column chromatography on a silica gel (EtOAc only) to give the desired sulfilimine 14 as a colorless liquid (68 mg, quantitative yield). IR (neat): ν 2151 (CN), 1252, 1202, 1052, 969, 761, 707 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.16–8.22 (m, 3H), 7.72 (dd, J = 7.9 Hz, J = 8.4 Hz, 2H), 7.58 (dd, J = 7.7 Hz, J = 8.0 Hz, 3H), 7.41 (d, J = 8.2 Hz, 1H), 3.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.4 (CO), 147.6, 134.8, 134.3, 130.4, 129.8, 129.1, 128.1, 127.5, 126.5, 123.5, 120.2 (CN), 36.4 (CH3); HRMS (EI) calcd for C15H12N2O2S 284.0619, found 284.0629.

For Figure a, Measurement Procedure of UV Absorption Spectra

To a solution of sulfide 1 (50 mg, 0.2 mmol) in the solvent (1 mL) was added PhI(OAc)2 (66 mg, 0.2 mmol) at RT. On shaking, a clear solution was obtained immediately. After maintaining the resulting solution at RT for 10 min, the measurement of UV absorption spectra was performed.