Construction of N–S and C–N Bonds from Reactions of Benzofuroxans with DMSO or THF

Abstract

Novel ring-opening reactions are achieved employing benzofuroxan as a new type of iminating or aminating reagent. These diverse transformations give access to three types of molecular scaffolds, N-aryl dimethylsulfoximines, methanesulfonamides, and hemiaminal ethers, which are important structural motifs in organic and medicinal chemistry. The procedures feature solvent-involved reactions, easily available starting materials, operational simplicity, high atom economy, and the potential further transformation of nitro group.

Introduction

Solvent-involved reactions have drawn considerable interest owing to the rather low cost, relative stability, and low toxicity of solvents. In the past decades, numerous procedures using dimethyl sulfoxide (DMSO)¹ or tetrahydrofuran (THF) as versatile reagents have been developed.² Sulfoximines have attracted a great deal of attention owing to their remarkable biological activities³ and successful use as ligands and auxiliaries in asymmetrical synthesis, structural units in pseudopeptides, and directing groups for catalytic C–H functionalizations.⁴ Two regular routes for the preparation of sulfoximines involve an oxidative imination of a sulfoxide and a nucleophilic substitution of the corresponding sulfonimidoyl halide or sulfonimidate.⁵ Transition-metal-catalyzed cross-coupling reactions between aryl halides or pseudohalides and N-unsubstituted sulfoximines have been established for the formation of N-aryl sulfoximines in recent years.⁶ On the other hand, hemiaminal ethers are the commonly found structural motifs in many biologically active natural products and pharmaceutical agents.⁷ Although some traditional methods have been developed for the construction of these skeletal structures, current interest focused on the direct amination of C(sp³³)–H bonds adjacent to an oxygen atom under transition-metal catalysis or metal-free conditions.⁸ This strategy circumvented the preinstallation of functional groups with high atom and step economy. Despite the significant advancement, the development of powerful and complementary transformations for sulfoximine and hemiaminal ether synthesis is still desirable.

Benzofuroxan (benzo[1,2-c]1,2,5-oxadiazole N-oxide, BFX) derivatives exhibit a broad biological activity, including antifungal, antileukemic, antibacterial, acaricidal, and immunodepressive properties.⁹ The traditional approaches used for the preparation of BFX included oxidation of o-nitroanilines and the tandem nucleophilic substitution/intramolecular cyclization of o-chloronitrobenzene with sodium azide in good yields.¹⁰ Hence, the BFX derivatives have been utilized as synthetic intermediates to react with rich electron species to produce heterocycle derivatives, through the Beirut reaction.¹¹ Herein, we disclosed a direct imination of DMSO to N-(2-nitro)phenyl dimethylsulfoximines using benzofuroxans as aryliminating reagents (Scheme 1a).¹² In the meantime, it was also demonstrated that methanesulfonamides could be synthesized in DMSO/H₂O mixed solvent (Scheme 1b).¹³ It is important to note that although DMSO has been employed as a multipurpose precursor for carbon, sulfur, and oxygen sources for incorporation into target molecules, only few examples act as −SO₂Me source.¹⁴ Furthermore, we reported a novel protocol for α-C–H amination with THF to hemiaminal ethers under ruthenium catalyst with benzofuroxans as the nitro and nitrogen sources (Scheme 1c).

Scheme 1. Diverse Transformations of Benzofuroxan with Different Solvents.

Results and Discussion

Initially, we employed benzofuroxan 1a in DMSO as a model reaction to screen the reaction conditions. As shown in Table 1, the reaction temperature is vital to the transformation, but below 100 °C, the reaction failed to produce the desired product (entry 1). When the reaction was carried out at higher temperature, it showed that 135 °C was suitable for this system (entries 2–4). We noted that the starting material was not consumed completely for 8 h, then the reaction time was examined, and good isolated yield was obtained for 16 h (entries 5–7). To our surprise, both sulfoximine 3a and methanesulfonamide 4a could be formed in similar yields when the reaction was proceeded in DMSO/H₂O (3:1). Considering the importance of methanesulfonamide in the fields of pharmaceuticals, pesticides, and materials, the optimal conditions were also investigated. It indicated that too much or too little water was detrimental to the formation of 4a, and equivalent amounts of DMSO and water afforded the best results (entries 8–11). After a few attempts, the suitable condition to sulfoximine is DMSO solvent and that to methanesulfonamide is DMSO/H₂O (1:1) mixed solvent at 135 °C for 16 h.

Table 1. Optimization of Reaction Conditions^a.

				yieldb (%)
entry	solvent	temp/°C	time/h	3a	4a
1	DMSO	100	8	n.p.	n.p.
2	DMSO	120	8	13	n.p.
3	DMSO	135	8	70	n.p.
4	DMSO	145	8	71	n.p.
5	DMSO	135	12	76	n.p.
6	DMSO	135	16	87	n.p.
7	DMSO	135	20	87	n.p.
8c	DMSO/H2O	135	16	35	33
9d	DMSO/H2O	135	16	0	76
10e	DMSO/H2O	135	16	0	65
11f	DMSO/H2O	135	16	0	20

^aReaction conditions: benzofuroxan (0.2 mmol) and solvent (1.2 mL).

^bIsolated yield.

^cThe volume ratio of DMSO and H₂O is 3:1.

^dDMSO/H₂O (1:1).

^eDMSO/H₂O (1:3).

^fDMSO/H₂O (1:11). n.p. = no product.

With optimized reaction conditions available, we proceeded to evaluate the scope of the reaction. As illustrated in Scheme 2, a wide range of benzofuroxans underwent smoothly to furnish the corresponding products under the standard conditions. Benzofuroxans with electron-rich and electron-poor substituents were all compatible with this method (3b–3l). The substrates bearing a bulky tert-butyl group delivered the product in good yield (3d). To our delight, bromide- and iodide-substituted substrates can be smoothly converted into the corresponding iminating products, which provided opportunities for further coupling reactions under transition-metal-catalyzed conditions (3i and 3j). In addition, the substrates containing two substituents with the same or opposite electron nature were also tolerated and showed little effect on the efficiency (3c, 3h, 3k, and 3l). It should be noted that there was an interconversion of 1-oxide/3-oxide tautomers of benzofuroxan derivatives through the transient formation of an o-dinitroso intermediate; therefore, N-aryl sulfoximine isomers were obtained from asymmetrical substrate.¹⁵ Interestingly, the C5 products were the major products in most cases, irrespective of the C5- or C6-substituted benzofuroxan (3b, 3d–3g, and 3i). The ratios of C4 and C5 products were determined by ¹H NMR spectroscopy. However, other sulfoxide derivatives such as diethylsulfoxide, dipropyl sulfoxide, and phenylmethyl sulfoxide were found to be unsuitable for this reaction, and no corresponding products were detected. Moreover, this imination reaction in a gram scale performed well and gave 3a in satisfactory yield (3a). The structure of 3a was further confirmed by X-ray crystal diffraction measurements (Figure 1).¹⁶ Following the above results, three examples for methanesulfonamide synthesis were demonstrated under DMSO/H₂O solvent. Both electron-donating and electron-withdrawing benzofuroxans could be successfully transformed to the corresponding methanesulfonamides in good yields (4a–4c).

Scheme 2. Synthesis of Sulfoximine or Methanesulfonamide Derivatives from Benzofuroxans^,,,,,,,

Unless otherwise noted, reaction conditions: benzofuroxan (0.2 mmol) and DMSO (1.2 mL) at 135 °C for 16 h; yields of isolated products are given.

10 mmol scale of the reaction.

Raw material is C6-substituted benzofuroxan.

Raw material is C5-substituted benzofuroxan.

Only the major isomer is shown.

5-Chloro-6-methylbenzofuroxan was used as raw material.

5-Chloro-6-fluorobenzofuroxan was used as raw material.

Reaction conditions: benzofuroxan (0.2 mmol), DMSO (0.6 mL), and H₂O (0.6 mL) at 135 °C for 16 h.

Figure 1.

X-ray crystal structures of 3a and 5f.

The reaction of benzofuroxan 1a and THF was explored to search for suitable conditions (Table 2). Various commonly used transition-metal catalysts were used to conduct this reaction. To our delight, we found that RuCl₃ could render the corresponding product in 10% yield (entries 1–8). The reaction did not proceed without ruthenium salt (entry 9). Encouraged by these results, a number of other ruthenium catalysts were tested. The results showed that [RuCl₂(p-cymene)]₂ displayed the highest catalytic activity for this reaction, and 5a was isolated in 72% yield (entries 10–13). The effect of reaction time was further examined, and the model reaction took place for 12 h, leading to the best yield of 5a (entries 13–15). Lower temperature was disadvantageous to this transformation (entry 16). Therefore, both ruthenium catalyst and reaction temperature are crucial for this transformation.

Table 2. Optimization of Reaction Conditions^a.

entry	catalyst	solvent	temp/°C	time/h	yieldb (%)
1	Pd(OAc)2	THF	80	12	n.p.
2	Pd(COD)Cl2	THF	80	12	n.p.
3	RhCl3	THF	80	12	n.p.
4	[Rh(COD)Cl]2	THF	80	12	n.p.
5	Ni(COD)2	THF	80	12	n.p.
6	Co(OAc)2	THF	80	12	n.p.
7	Pt(COD)Cl	THF	80	12	n.p.
8	RuCl3	THF	80	12	10
9		THF	80	12	n.p.
10	Ru(acac)3	THF	80	12	trace
11	Ru(PPh3)3Cl2	THF	80	12	trace
12	Ru(phen)3Cl2	THF	80	12	trace
13	[RuCl2(p-cymene)]2	THF	80	12	72
14	[RuCl2(p-cymene)]2	THF	80	9	65
15	[RuCl2(p-cymene)]2	THF	80	15	72
16	[RuCl2(p-cymene)]2	THF	60	12	55

^aReaction conditions: benzofuroxan (0.2 mmol), THF (1 mL), and catalyst (2 mol %).

^bIsolated yield.

Subsequently, the scope of benzofuroxans was investigated for the present transformation using THF as a standard substrate (Scheme 3). A set of substituted benzofuroxans underwent ring-opening amination reaction smoothly (5b–5f). The symmetrical bisubstituted benzofuroxans yielded the products in optimized conditions. It can be inferred that the electron-donating groups are beneficial to the transformation compared to the electron-deficient groups (5b and 5c). In addition, unsymmetric monosubstituted benzofuroxans were applicable with excellent regioselectivity. Notably, these halide-substituted substrates were compatible under standard conditions, providing the possibility for further functionalization (5d–5f). Other cyclic ethers such as isochroman showed good reactivity to render the corresponding product in medium yield (5g). However, tetrahydropyran did not generate the desired product. Moreover, the exact structure of 5f was also confirmed by X-ray crystal diffraction measurements (Figure 1).¹⁷

Scheme 3. Ru-Catalyzed C–N Coupling of Benzofuroxans with Tetrahydrofuran or Isochroman^,

Reaction conditions: benzofuroxan (0.2 mmol), THF or isochroman (1 mL), and [RuCl₂(p-cymene)]₂ (2 mol %) at 80 °C (oil bath temperature) for 12 h; yields of isolated products are given.

Raw material is C6-substituted benzofuroxan; only the major isomer of the product is shown.

To illustrate the synthetic utility of the sulfoximine, further transformation is investigated in Scheme 4. Starting from N-(2-nitro)phenyl dimethylsulfoximine 3a, the desired benzene-bridged aminosulfoximines 7 were prepared by a two-step reaction sequence. First, the nitro group of 3a was reduced to afford aniline 6a; subsequent aniline reacted readily with aromatic aldehydes to generate the target molecules 7 via reductive amination. It is noteworthy that chiral benzene-bridged benzylaminosulfoximines have been proved to be effective ligands for copper-catalyzed asymmetric Mukaiyama aldol reactions.¹⁸

Scheme 4. Preparation of Benzene-Bridged Benzylaminosulfoximines.

To probe the mechanism, some controlled experiments were carried out (Scheme 5). The deuterium-labeling experiments with DMSO-d₆ demonstrated that dimethyl sulfoxide and methylsulfonyl moieties came from DMSO (Scheme 5a,b). Subsequently, the model reaction was performed under an argon atmosphere, and 4a was isolated in 86% yield (Scheme 5c). Additionally, the isotopic labeling experiment using H₂¹⁸O was conducted and ¹⁸O-labeled 4a was obtained in 70% yield (Scheme 5d). These results proved that the additional oxygen atom in 4a originated from H₂O. No product was detected when 3a was subjected to H₂O or DMSO/H₂O; it suggested that 3a was not the intermediate for the formation of 4a (Scheme 5e). Radical trapping experiments were performed in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy or butylated hydroxytoluene. The yields just decreased slightly, which suggested that this should not be a radical pathway (Scheme 5f,g). Moreover, the reaction proceeded smoothly under argon atmosphere (Scheme 5h).

Scheme 5. Controlled Experiments.

On the basis of controlled experiments and earlier related literature, plausible mechanisms are proposed in Scheme 6. Initially, the nitrene intermediate A was formed through the retrocleavage of the furoxan ring at the N–O bond (Scheme 6, eq 1). Dimethyl sulfoxide reacted with the nitrene intermediate to yield the product 3a (Scheme 6, eq 2).¹⁹ Moreover, the Ru catalyst activated the C(sp³)–H bonds adjacent to the oxygen atom of THF and 5a was formed via the nitrene insertion and protodemetalation process (Scheme 6, eq 3).²⁰ The possible mechanism for the formation of product 4a was unclear at the present stage.

Scheme 6. Possible Mechanism.

Conclusions

In summary, we have developed diverse transformations based on the reactions of benzofuroxans with DMSO or THF. The approach allowed facile access to three types of molecular scaffolds: N-aryl dimethylsulfoximines, methanesulfonamides, and hemiaminal ethers. The practical potential of the methodology was highlighted by transformation of the sulfoximines into aminosulfoximines. Further investigations on the synthetic applications and detailed mechanism are currently underway in our laboratory.

Experimental Section

General Information

¹H and ¹³C NMR spectra were obtained on 400 and 100 MHz NMR spectrometers. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm, respectively. Chloroform is the solvent with tetramethylsilane as the internal standard unless otherwise noted. Mass spectra were recorded on a GC-MS spectrometer at an ionization voltage of 70 eV equipped with a DB-WAX capillary column (internal diameter: 0.25 mm, length: 30 m). Elemental analyses were performed with a Vario EL elemental analyzer. High-resolution mass spectra (HRMS) (ion trap) were measured by electrospray ionization (ESI) mass spectrometry. Silica gel (300–400 mesh) was used for flash column chromatography, eluting (unless otherwise stated) with ethyl acetate (EA)/petroleum ether (PE) (60–90 °C) mixture.

General Procedure for the Preparation of Sulfoximines

A mixture of benzofuroxan (0.2 mmol) and DMSO (1.2 mL) was taken in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 135 °C for 16 h under open atmosphere. After the reaction was complete, water (5 mL) was added and the solution was extracted with ethyl acetate (3 × 5 mL); the combined extract was dried with anhydrous MgSO₄. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.

General Procedure for the Synthesis of Methanesulfonamides

A mixture of benzofuroxan (0.2 mmol), DMSO (0.6 mL), and water (0.6 mL) was taken in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 135 °C for 16 h under open atmosphere. After the reaction was complete, water (5 mL) was added and the solution was extracted with ethyl acetate (3 × 5 mL); the combined extract was dried with anhydrous MgSO₄. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.

General Procedure for the Synthesis of Hemiaminal Ethers

A mixture of benzofuroxan (0.2 mmol), [RuCl₂(p-cymene)]₂ (2 mol %), and THF (1.0 mL) was taken in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 80 °C for 12 h under open atmosphere. After the reaction was complete, water (5 mL) was added and the solution was extracted with ethyl acetate (3 × 5 mL); the combined extract was dried with anhydrous MgSO₄. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.

N-[2-(Nitro)phenyl]-S-dimethylsulfoximine (3a)

The reaction was performed by following the general procedure. White solid, 37 mg, yield: 87% (purified by silica gel chromatography using PE/EA 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (d, J = 7.6 Hz, 1H), 7.37–7.33 (m, 2H), 7.05–7.00 (m, 1H), 3.16 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.8, 138.6, 132.4, 125.4, 124.2, 122.0, 42.4. MS (EI) m/z: 214, 136, 121, 104, 78, 63, 51. HRMS (ESI): calcd for C₈H₁₁N₂O₃S [M + H]⁺ 215.0485, found: 215.0476.

Mixture of N-[4 or 5-(Methyl)-2-(nitro)phenyl]-S-dimethylsulfoximine (3b)

The reaction was performed by following the general procedure. Yellow oil, 41 mg, yield: 90%, C4/C5 = 1:1.6 (purified by silica gel chromatography using PE/EA 5:1). C4–CH₃ product: ¹H NMR (400 MHz, CDCl₃): δ = 7.44 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.4, 1.6 Hz, 1H), 3.14 (s, 6H), 2.31 (s, 3H); C5–CH₃ product: ¹H NMR (400 MHz, CDCl₃): δ = 7.58 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 0.8 Hz, 1H), 6.82 (dd, J = 8.4, 0.8 Hz, 1H), 3.17 (s, 6H), 2.32 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.6, 143.7, 143.4, 138.7, 135.8, 133.3, 132.3, 126.1, 125.6, 124.5, 124.4, 122.9, 42.5, 42.3, 21.3, 20.3. HRMS (ESI): calcd for C₉H₁₃N₂O₃S [M + H]⁺ 229.0641, found: 229.0638.

N-[4,5-(Dimethyl)-2-(nitro)phenyl]-S-dimethylsulfoximine (3c)

The reaction was performed by following the general procedure. Yellow solid, 35 mg, yield: 72% (purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.50 (s, 1H), 7.14 (s, 1H), 3.16 (s, 6H), 2.24 (s, 3H), 2.22 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.3, 142.6, 136.2, 131.2, 127.1, 125.2, 42.4, 19.8, 18.9. HRMS (ESI): calcd for C₁₀H₁₅N₂O₃S [M + H]⁺ 243.0798, found: 243.0793.

Mixture of N-[4 or 5-(tert-Butyl)-2-(nitro)phenyl]-S-dimethylsulfoximine (3d)

The reaction was performed by following the general procedure. Yellow solid, 38 mg, yield: 70%, C4/C5 = 1:1.3 (purified by silica gel chromatography using PE/EA 6:1). C4–C₄H₉ product: ¹H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 3.15 (s, 6H), 1.28 (s, 9H); C5–C₄H₉ product: ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 8.4, 2.0 Hz, 1H), 3.16 (s, 6H), 1.29 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.8, 145.7, 145.4, 143.2, 138.5, 135.8, 129.7, 125.3, 124.2, 123.0, 120.9, 119.5, 42.4, 42.4, 34.9, 34.3, 31.0, 30.9. MS (EI) m/z: 270, 255, 192, 177, 148, 117, 91, 79, 63, 41. Anal. calcd for C₁₂H₁₈N₂O₃S: C, 53.31; H, 6.71; N, 10.36. Found: C, 53.04; H, 6.82; N, 10.44.

N-[5-(Methoxy)-2-(nitro)phenyl]-S-dimethylsulfoximine (3e)

The reaction was performed by following the general procedure. Yellow solid, 36 mg, yield: 73%, 1:8 (only the major isomer was shown, purified by silica gel chromatography using PE/EA 3:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.77 (d, J = 9.2 Hz, 1H), 6.83 (d, J = 2.8 Hz, 1H), 6.55 (dd, J = 9.2, 2.8 Hz, 1H), 3.82 (s, 3H), 3.19 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 162.9, 141.4, 138.8, 126.9, 109.9, 108.6, 55.7, 42.6. Anal. calcd for C₉H₁₂N₂O₄S: C, 44.25; H, 4.95; N, 11.47. Found: C, 44.03; H, 4.89; N, 11.56.

N-[5-(Fluoro)-2-(nitro)phenyl]-S-dimethylsulfoximine (3f)

The reaction was performed by following the general procedure. White solid, 41 mg, yield: 88%, 1:8 or 40 mg, yield: 86%, 1:20 (only the major isomer was shown, purified by silica gel chromatography using PE/EA 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.72–7.68 (m, 1H), 7.11–7.08 (m, 1H), 6.73–6.68 (m, 1H), 3.20 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.2 (d, J = 253 Hz), 141.9, 141.4 (d, J = 11 Hz), 126.5 (d, J = 11 Hz), 111.8 (d, J = 24 Hz), 109.1 (d, J = 24 Hz), 42.7. HRMS (ESI): calcd for C₈H₁₀FN₂O₃S [M + H]⁺ 233.0391, found: 233.0395.

Mixture of N-[4 or 5-(Chloro)-2-(nitro)phenyl]-S-dimethylsulfoximine (3g)

The reaction was performed by following the general procedure. White solid, 42 mg, yield: 85%, 1:2.5 or 40 mg, yield: 81%, 1:2.8 (purified by silica gel chromatography using PE/EA 4:1). C4–Cl product: ¹H NMR (400 MHz, CDCl₃): δ = 7.61 (s, 1H), 7.31 (d, J = 1.2 Hz, 2H), 3.16 (s, 6H); C5–Cl product: ¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.8, 2.0 Hz, 1H), 3.19 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.6, 143.8, 140.1, 138.2, 137.4, 132.4, 126.7, 126.3, 125.4, 124.7, 124.1, 121.8, 42.6, 42.5. MS (EI) m/z: 248, 218, 170, 140, 112, 79, 63, 47. HRMS (ESI): calcd for C₈H₁₀ClN₂O₃S [M + H]⁺ 249.0095, found: 249.0109.

N-[4,5-(Dichloro)-2-(nitro)phenyl]-S-dimethylsulfoximine (3h)

The reaction was performed by following the general procedure. Yellow solid, 45 mg, yield: 80% (purified by silica gel chromatography using PE/EA 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.77 (s, 1H), 7.52 (s, 1H), 3.20 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 138.4, 136.8, 126.3, 125.7, 125.3, 42.8. HRMS (ESI): calcd for C₈H₉Cl₂N₂O₃S [M + H]⁺ 282.9705, found: 282.9696.

Mixture of N-[4 or 5-(Bromo)-2-(nitro)phenyl]-S-dimethylsulfoximine (3i)

The reaction was performed by following the general procedure. White solid, 46 mg, yield: 78%, C4/C5 = 1:2 (purified by silica gel chromatography using PE/EA 4:1). C4–Br product: ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (m, 1H), 7.47–7.44 (m, 1H), 7.28–7.26 (m, 1H), 3.17 (s, 6H); C5–Br product: ¹H NMR (400 MHz, CDCl₃): δ = 7.55–7.54 (m, 1H), 7.53–7.50 (m, 1H), 7.16–7.13 (m, 1H), 3.20 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 146.0, 144.4, 140.1, 137.9, 135.3, 127.9, 127.0, 126.7, 126.6, 125.5, 124.9, 113.7, 42.7, 42.6. HRMS (ESI): calcd for C₈H₁₀BrN₂O₃S [M + H]⁺ 292.9590, found: 292.9595.

Mixture of N-[4 or 5-(Iodo)-2-(nitro)phenyl]-S-dimethylsulfoximine (3j)

The reaction was performed by following the general procedure. Yellow solid, 50 mg, yield: 73%, C4/C5 = 3:1 (purified by silica gel chromatography using PE/EA 4:1). C4–I product: ¹H NMR (400 MHz, CDCl₃): δ = 7.90 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 3.17 (s, 6H); C5–I product: ¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 1.6 Hz, 1H), 7.38–7.33 (m, 2H), 3.19 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 146.2, 145.1, 141.1, 139.8, 138.6, 133.9, 132.6, 130.9, 126.9, 125.3, 99.0, 82.8, 42.7, 42.6. HRMS (ESI): calcd for C₈H₁₀IN₂O₃S [M + H]⁺ 340.9451, found: 340.9449.

N-[5-(Chloro)-4-(methyl)-2-(nitro)phenyl]-S-dimethylsulfoximine (3k)

The reaction was performed by following the general procedure. Yellow solid, 43 mg, yield: 83%, 20:1 (only the major isomer was shown, purified by silica gel chromatography using PE/EA 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.56 (s, 1H), 7.40 (s, 1H), 3.18 (s, 6H), 2.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 138.5, 137.4, 130.3, 126.0, 125.7, 426, 19.2. HRMS (ESI): calcd for C₉H₁₂ClN₂O₃S [M + H]⁺ 263.0252, found: 263.0249.

N-[4-(Chloro)-5-(fluoro)-2-(nitro)phenyl]-S-dimethylsulfoximine (3l)

The reaction was performed by following the general procedure. Yellow solid, 42 mg, yield: 79%, 5:1 (only the major isomer was shown, purified by silica gel chromatography using PE/EA 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.77 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 6.8 Hz, 1H), 3.20 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.5 (d, J = 255 Hz), 139.9 (d, J = 11 Hz), 126.9, 126.6 (d, J = 12 Hz), 113.9 (d, J = 20 Hz), 112.5 (d, J = 23 Hz), 42.8. MS (EI) m/z: 266, 236, 188, 158, 142, 130, 79, 63, 47. HRMS (ESI): calcd for C₈H₉ClFN₂O₃S [M + H]⁺ 267.0001, found: 266.9998.

N-(2-Nitrophenyl)methanesulfonamide (4a)¹³

The reaction was performed by following the general procedure. Yellow solid, 33 mg, yield: 76% (purified by silica gel chromatography using PE/EA 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.76 (s, 1H), 8.27 (dd, J = 8.8, 1.6 Hz, 1H), 7.89 (dd, J = 8.4, 1.2 Hz, 1H), 7.70–7.66 (m, 1H), 7.26–7.21 (m, 1H), 3.15 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 136.2, 134.3, 126.6, 123.6, 119.6, 119.5, 40.7. MS (EI) m/z: 216, 138, 108, 91, 79, 52.

N-(4,5-Dimethyl-2-nitrophenyl)methanesulfonamide (4b)¹³

The reaction was performed by following the general procedure. Yellow solid, 34 mg, yield: 70% (purified by silica gel chromatography using PE/EA 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.62 (s, 1H), 8.01 (s, 1H), 7.63 (s, 1H), 3.10 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.3, 134.5, 133.1, 131.9, 126.6, 120.7, 40.4, 20.5, 19.0. MS (EI) m/z: 244, 165, 149, 135, 118, 107, 91, 79, 65, 39.

N-(4,5-Dichloro-2-nitrophenyl)methanesulfonamide (4c)

The reaction was performed by following the general procedure. Yellow solid, 32 mg, yield: 56% (purified by silica gel chromatography using PE/EA 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.72 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 3.19 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 141.5, 134.5, 133.4, 127.7, 127.7, 120.7, 41.1. MS (EI) m/z: 284, 206, 176, 147, 112, 97, 79, 52. HRMS (ESI): calcd for C₇H₇Cl₂N₂O₄S [M + H]⁺ 284.9498, found: 284.9495.

N-(2-Nitrophenyl)tetrahydrofuran-2-amine (5a)

The reaction was performed by following the general procedure. Yellow liquid, 30 mg, yield: 72% (purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.19 (s, 1H), 8.16 (dd, J = 8.4, 1.2 Hz, 1H), 7.49–7.45 (m, 1H), 8.23 (d, J = 0.8 Hz, 1H), 6.77–6.73 (m, 1H), 5.52–5.48 (m, 1H), 3.95–3.92 (m, 2H), 2.42–2.34 (m, 1H) 2.18–2.08 (m, 1H), 2.05–1.90 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 136.0, 132.9, 126.4, 117.0, 1157, 83.7, 67.0, 32.8, 24.8. MS (EI) m/z: 208, 138, 122, 92, 71, 43. HRMS (ESI): calcd for C₁₀H₁₂N₂NaO₃ [M + Na]⁺ 231.0740, found: 231.0779.

N-(4,5-Dimethyl-2-nitrophenyl)tetrahydrofuran-2-amine (5b)

The reaction was performed by following the general procedure. Yellow solid, 32 mg, yield: 67% (purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.12 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.00 (s, 1H), 5.51–5.47 (m, 1H), 3.92 (t, J = 6.8 Hz, 2H), 2.38–2.32 (m, 1H), 2.27 (s, 3H), 2.17 (s, 3H), 2.13–2.08 (m, 1H), 2.03–1.86 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.1, 142.2, 130.8, 126.1, 126.1, 116.0, 83.7, 66.9, 32.8, 24.8, 20.6, 18.5. MS (EI) m/z: 236, 166, 136, 120, 91, 71, 43. HRMS (ESI): calcd for C₁₂H₁₆N₂NaO₃ [M + Na]⁺ 259.1053, found: 259.1057.

N-(4,5-Dichloro-2-nitrophenyl)tetrahydrofuran-2-amine (5c)

The reaction was performed by following the general procedure. Yellow solid, 26 mg, yield: 47% (purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.26 (s, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.40 (s, 1H), 5.43–5.39 (m, 1H), 3.95–3.91 (m, 2H), 2.42–2.35 (m, 1H), 2.16–2.11 (m, 1H), 2.05–1.89 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 142.7, 140.9, 131.4, 127.3, 120.6, 117.2, 83.7, 67.2, 32.8, 24.6. MS (EI) m/z: 276, 206, 109, 97, 71, 43. HRMS (ESI): calcd for C₁₀H₁₀Cl₂N₂NaO₃ [M + Na]⁺ 298.9961, found: 298.9968.

N-(5-Fluoro-2-nitrophenyl)tetrahydrofuran-2-amine (5d)

The reaction was performed by following the general procedure. Yellow liquid, 25 mg, yield: 56%, 11:1 (only the major isomer was shown, purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.31 (s, 1H), 8.22–8.18 (m, 1H), 6.93–6.90 (m, 1H), 6.49–6.44 (m, 1H), 5.43–5.39 (m, 1H), 3.93 (t, J = 6.4 Hz, 2H), 2.41–2.34 (m, 1H), 2.16–2.10 (m, 1H), 2.04–1.93 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.2 (d, J = 255 Hz), 146.2 (d, J = 14 Hz), 130.8, 129.5 (d, J = 12 Hz), 105.5 (d, J = 24 Hz), 101.8 (d, J = 27 Hz), 83.8, 67.1, 32.8, 24.7. MS (EI) m/z: 226, 150, 110, 83, 71, 43. HRMS (ESI): calcd for C₁₀H₁₂FN₂O₃ [M + H]⁺ 227.0826, found: 227.0823.

N-(5-Chloro-2-nitrophenyl)tetrahydrofuran-2-amine (5e)

The reaction was performed by following the general procedure. Yellow solid, 33 mg, yield: 68%, >20:1 (only the major isomer was shown, purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.22 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 9.2, 2.4 Hz, 1H), 5.45–5.41 (m, 1H), 3.93 (t, J = 7.2 Hz, 2H), 2.40–2.33 (m, 1H), 2.15–2.09 (m, 1H), 2.03–1.92 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.4, 142.6, 131.4, 127.7, 117.5, 115.3, 83.6, 67.1, 32.8, 24.7. MS (EI) m/z: 242, 172, 105, 71, 43. HRMS (ESI): calcd for C₁₀H₁₂ClN₂O₃ [M + H]⁺ 243.0531, found: 243.0538.

N-(5-Iodo-2-nitrophenyl)tetrahydrofuran-2-amine (5f)

The reaction was performed by following the general procedure. Yellow solid, 40 mg, yield: 60%, >20:1 (only the major isomer was shown, purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.15 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.8, 1.6 Hz, 1H), 5.46–5.42 (m, 1H), 3.95–3.91 (m, 2H), 2.40–2.33 (m, 1H), 2.15–2.09 (m, 1H), 2.04–1.90 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.0, 132.4, 127.2, 126.3, 124.7, 104.7, 83.6, 67.2, 32.9, 24.7. MS (EI) m/z: 334, 264, 218, 130, 91, 71, 43. HRMS (ESI): calcd for C₁₀H₁₂IN₂O₃ [M + H]⁺ 334.9887, found: 334.9888.

N-(2-Nitrophenyl)isochroman-1-amine (5g)

The reaction was performed by following the general procedure. Yellow solid, 31 mg, yield: 57% (purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 6.0 Hz, 1H), 8.21 (dd, J = 8.8, 1.6 Hz, 1H), 7.56–7.52 (m, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.33–7.28 (m, 1H), 7.26 (d, J = 3.6 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 6.85–6.81 (m, 1H), 6.16 (d, J = 6.4 Hz, 1H), 4.16–4.09 (m, 1H), 3.97–3.92 (m, 1H), 3.08–3.00 (m, 1H), 2.81–2.75 (m, 1H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.4, 136.1, 134.6, 133.8, 133.2, 129.0, 128.4, 126.8, 126.6, 126.4, 117.4, 115.9, 79.0, 58.7, 28.0. MS (EI) m/z: 270, 220, 133, 115, 105, 79, 55. HRMS (ESI): calcd for C₁₅H₁₅N₂O₃ [M + H]⁺ 271.1077, found: 271.1081.

N-(2-Benzylaminophenyl)-S-dimethylsulfoximine (7a)

Purple liquid, 47 mg, yield: 87% (purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.32 (m, 4H), 7.27 (ddd, J = 7.0, 3.9, 1.5 Hz, 1H), 7.11 (dd, J = 7.6, 1.4 Hz, 1H), 6.90 (td, J = 7.7, 1.5 Hz, 1H), 6.64–6.57 (m, 2H), 4.37 (s, 2H), 3.13 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 142.7, 139.8, 130.8, 128.4, 127.2, 126.8, 123.3, 121.6, 116.7, 110.3, 48.0, 41.8. MS (EI) m/z: 274, 195, 119, 105, 91, 65, 51. Anal. calcd for C₁₅H₁₈N₂OS: C, 65.66; H, 6.61; N, 10.21; found: C, 65.38; H, 6.70; N, 10.29.

N-[2-(4-Methoxybenzylamino)phenyl]-S-dimethylsulfoximine (7b)

Purple liquid, 49 mg, yield: 80% (purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.30–7.27 (m, 2H), 7.09 (dd, J = 8.0, 1.5 Hz, 1H), 6.92–6.88 (m, 1H), 6.88–6.85 (m, 2H), 6.62–6.58 (m, 2H), 4.28 (s, 2H), 3.79 (s, 3H), 3.14 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 158.6, 142.8, 131.9, 130.7, 128.5, 123.4, 121.8, 116.8, 113.9, 110.3, 55.2, 47.5, 42.0. MS (EI) m/z: 304, 224, 209, 181, 112, 77, 63, 39. Anal. calcd for C₁₆H₂₀N₂O₂S: C, 63.13; H, 6.62; N, 9.20; found: C, 62.87; H, 6.73; N, 9.32.

N-[2-(3-Fluorobenzylamino)phenyl]-S-dimethylsulfoximine (7c)

Purple liquid, 48 mg, yield: 83% (purified by silica gel chromatography using PE/EA 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.25 (m, 1H), 7.15–7.05 (m, 3H), 6.93 (td, J = 8.3, 2.2 Hz, 1H), 6.87 (td, J = 7.8, 1.5 Hz, 1H), 6.61 (td, J = 7.6, 1.4 Hz, 1H), 6.51 (dd, J = 8.0, 1.3 Hz, 1H), 4.36 (s, 2H), 3.16 (s, 6H). ¹³C NMR (100 MHz, CDCl₃): δ = 163.0 (d, J = 244 Hz), 142.8 (d, J = 6 Hz), 142.4, 130.9, 129.9 (d, J = 8 Hz), 123.3, 122.5 (d, J = 2 Hz), 121.7, 117.1, 113.8 (d, J = 22 Hz), 113.6 (d, J = 21 Hz), 110.3, 47.5 (d, J = 1 Hz), 42.0. MS (EI) m/z: 292, 213, 119, 105, 78, 51. Anal. calcd for C₁₅H₁₇FN₂OS: found: C, 61.62; H, 5.86; N, 9.58; found: C, 61.40; H, 5.97; N, 9.65.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b03353.

• Copies of NMR spectra for all compounds (PDF)

• Crystallographic datas (CIF) (CIF)

Author Contributions

^§ B.L. and P.L. contributed equally to this work.

The authors declare no competing financial interest.