Accessing Perfluoroaryl Sulfonimidamides and Sulfoximines via Photogenerated Perfluoroaryl Nitrenes: Synthesis and Application as a Chiral Auxiliary

Abstract

Sulfonimidamides (SIAs) and sulfoximines (SOIs) have attracted attention due to their potential in agriculture and in medicinal chemistry as bioisosteres of biologically active compounds, and new synthetic methods are needed to access and explore these compounds. Herein, we present a light-promoted generation of perfluorinated aromatic nitrenes, from perfluorinated azides, that subsequently are allowed to react with sulfinamides and sulfoxides, generating achiral and chiral SIAs and SOIs. One of the enantiopure SIAs was evaluated as a novel chiral auxiliary in Grignard additions to the imines yielding the product in up to 96:4 diastereomeric ratio.

Introduction

During the last decades, the utility of sulfonimidamides (SIAs)¹⁻⁵ and sulfoximines (SOIs)⁶⁻¹² has been demonstrated in synthesis, agrochemical applications, and as bioisosteres in medicinal chemistry due to their notable properties, such as basicity, nucleophilicity, and solubility in polar solvents. The classical synthetic routes¹³ to access SIAs usually rely on the formation of sulfonimidoyl chloride as a precursor, followed by an amidation reaction (Figure 1).

Figure 1.

(1) Routes to SIAs: (a) oxidative imidation, (b) oxidative chlorination, (c) deoxychlorination, (d) Grignard addition and chlorination, (e) sulfur–fluorine exchange via sulfinimidoyl fluoride; (2) routes to SOIs: (f) imidation, (g) oxidation, (h) desymmetrization of SOIs, and (i) S-alkylation; and (3) this work: SIAs and SOIs via photogenerated nitrenes.

Sulfonimidoyl chloride can be generated in several different ways, such as oxidative imidation (Figure 1a),¹⁴ oxidative chlorination (Figure 1b),¹⁵ deoxychlorination¹⁶ (Figure 1c), and via Grignard addition to a sulfinylamine, followed by chlorination (Figure 1d).¹⁷ Similarly, sulfur–fluorine exchange reactions (Figure 1e) with sulfonimidoyl fluoride as the key intermediate have been used to yield SIAs.^18,19 Other approaches to form SIAs involve copper-catalyzed transamidation of sulfinamides (SAs) or copper-catalyzed oxidation of methyl SOIs.^20,21 Furthermore, several metal-free approaches using N–H transfer to SAs have been disclosed.²²

One of the most convenient ways to synthesize chiral SOIs²³ involves the formation of a sulfur–nitrogen bond between chiral SOs and nitrenes, either using metal-catalyzed procedures (Fe, Rh, and Ag)²⁴⁻²⁸ or hypervalent iodine or bromine reagents (Figure 1f).²⁹⁻³² Other approaches involve stereospecific oxidation of enantioenriched sulfinimines (Figure 1g), desymmetrization of homochiral SOIs^33,34 (Figure 1h), and stereospecific S—alkylation of chiral SOIs (Figure 1i).³⁵

The introduction of fluoro-substituents into drug-like molecules and agrochemicals can tremendously affect their properties by, for example, decreasing their basicity and improving their bioavailability,³⁶⁻³⁸ and in this context, several different methods to synthesize fluorinated SOIs were developed.³⁹⁻⁴⁶ In addition, SOIs containing N–C_aryl–F bonds can be accessed either via copper-catalyzed direct sulfoximination or via S_NAr.^47,48 An alternative approach is to incorporate aromatic fluorinated moieties via perfluorinated aromatic azides (PFAAs). Phenyl azides can generate, either via photo- or thermolysis, highly reactive nitrenes that rapidly rearrange via ring-expansion to form ketenimines. These ketenimines will ultimately lead to polymeric tar unless intercepted with a good nucleophile.⁴⁹ On the contrary, PFAAs are regarded as superior phenylnitrene precursors, enabling higher yields of the C–H and N–H insertion products.^50,51 The improved selectivity is attributed to the “ortho-difluoro effect” where fluorine atoms in the ortho-position to the azide effectively retard the ring-expansion pathway and instead promote a long-lived singlet nitrene that is responsible for the productive bimolecular reaction.⁵² The reaction between dimethyl sulfoxide (DMSO) and perfluorinated phenylnitrene, generated via the thermolysis of 4-azido-2,3,5,6-tetrafluoropyridine, was first observed by Banks and Sparkes,⁵⁰ but no attempts to expand the nitrene-promoted coupling between PFAAs and SOs or related derivatives were undertaken. In this work, we investigated a light-promoted approach to ortho-fluoro nitrenes from PFAAs, leading to the stereospecific addition to SAs and SOs. In addition, one of the chiral SIAs was evaluated as a chiral auxiliary in the stereoselective addition of Grignard reagents to SIA-derived imines, yielding the addition products in high stereoselectivity (up to 96:4).

Results and Discussion

Upon the irradiation of PFAA (1a) in DMSO with a 390 nm light-emitting diode (LED) light, we noticed the formation of an SOI adduct between the in situ generated perfluoroaryl nitrene and DMSO. In our group, we have previously developed procedures for the catalytic formation of sulfinimines from chiral SAs and aldehydes,^53,54 and therefore, we became interested in investigating the reactivity between perfluoroaryl nitrenes and optically active SAs or SO. Our initial screening started with 1a and (S)-tert-butylsulfinamide in different solvents and with an irradiation of 390 nm light for 1.5 h at room temperature. In most of the solvents (Table 1, entries 1–9), SIA (S)-1 is formed together with varying amounts of the perfluorinated aniline.

Table 1. Optimization of Reaction Conditions for the Synthesis of (S)-1^a.

entry	solvent	yield (S)-1 (%)b	aniline (%)b
1	THF	23	77
2	EtOH	21	59
3	toluene	52	21
4	acetone	51	9
5	CH2Cl2	47	4
6	CHCl3	57	6
7	MeCN	47	6
8	EtOAc	65	5
9	PhCF3	66	4
10	DMF	–b	–
11	H2O	0b	1

^aReaction conditions: azide (0.075 mmol, 0.05 M), (S)-tert-butylsulfinamide (0.15 mmol, 1.5 equiv), degassed solvent (1.5 mL), and 390 nm Kessil LED light, 1.5 h.

^bDetermined by ¹H NMR with an internal standard.

In tetrahydrofuran (THF) and ethanol, perfluorinated aniline was the major product (Table 1, entries 1–2), while reactions in toluene, acetone, dichloromethane, chloroform, and acetonitrile led to increased yields of (S)-1 and with less formation of the aniline derivative (Table 1, entries 3–7). The highest yields, together with the lowest formation of side products, were obtained in ethyl acetate and α,α,α-trifluorotoluene (PhCF₃) (Table 1, entries 8 and 9), while DMF gave a complex mixture of fluorinated products and the reaction in water led to the formation of the perfluorinated azo-compound mainly (Table 1, entries 10–11). The reaction also proceeded using blue light (440 nm), but the reaction times increased significantly (about 10 times).

Next, we explored the substrate scope of the photopromoted coupling between enantiopure tert-butylsulfinamides and different PFAAs using PhCF₃ as the solvent (Table 2). Methyl 4-azidotetrafluorobenzoate reacted with both (S)- and (R)-tert-butylsulfinamides to form SIAs (S)-1 and (R)-1 in good yields (66 and 65%, respectively) and without the loss of enantiopurity, as determined by chiral high-performance liquid chromatography (HPLC). The cyano-substituted PFAA derivative showed increased reactivity than the ester-containing substrate and yielded product (S)-2 in 62% yield upon irradiation at 390 nm for merely 2 h in the presence of (S)-tert-butylsulfinamide. The pyridine-based PFAA gave similar yields toward the formation of products (S)-3 and (R)-3 (64 and 65%, respectively) but required a considerably longer irradiation time (16 h). Next, the reaction was extended to other PFAA derivatives, such as pentafluoroazidobenzene and 4-azido-tetrafluorobenzoic acid. However, this afforded lower yields of the target products (S)-4 and (S)-5 (32 and 34%, respectively) compared to the other derivatives (1–3). This highlights the importance of the substituent in para-position in influencing the reactivity of the photogenerated nitrene.

Table 2. Synthesis of SIAs from PFAA and SAs^a.

^aReaction conditions: PFAA (0.3–0.9 mmol, 0.05 M), SA (0.45–1.35 mmol, 1.5 equiv), degassed PhCF₃, 390 nm Kessil LED light, 2–16 h, r.t.

^bAverage yield of two syntheses.

^cFrom the racemic starting material.

The photopromoted reaction of PFAAs with p-toluenesulfinamide was less satisfying, and (S)-6 was only obtained in trace amounts together with other side products. Better results were obtained for the more reactive cyano-substituted PFAA yielding the product (S)-7 in 42% yield. The poorer reactivity was ascribed to the scarce solubility of p-tolylsulfinamide compared to that of tert-butylsulfinamide. A secondary SA, racemic 1-(phenylsulfinyl)piperidine, was made to react with methyl 4-azidotetrafluorobenzoate to yield the target product rac-8 in 42% yield.

In addition to the synthesis of perfluorinated SIAs, the generality of the nitrene addition was expanded through reactions with SOs to yield perfluorinated SOIs (Table 3).

Table 3. Synthesis of SOIs from PFAA and SOs^a.

^aReaction conditions: PFAA (0.3 mmol, 0.05 M), SO (0.45 mmol, 1.5 equiv), degassed PhCF₃, 390 nm Kessil LED light, 1–4 h, r.t.

^bEtOAc as the solvent.

The photopromoted PFAA-nitrenes readily reacted with SOs to form SOIs and did not react further under prolonged light irradiation. This differs from the reactivity in the work by Bolm and coworkers where they observed the light-promoted formation of nitrenes from SOIs.⁵⁵ For example, DMSO reacted with the photogenerated nitrene to yield SOI 9 in high yield (78%) after only 2 h. A fast reaction was also observed for racemic methyl phenyl SO, yielding product 10 in good yield (61%). Racemic phenylvinyl SO led to the formation of product 11 (56%) without affecting the double bond. The lower yield was accompanied by an increased formation of the corresponding aniline derivative (methyl 4-amino-2,3,5,6-tetrafluorobenzoate), which was also observed in the reaction with racemic methyl 2-phenylsulfinylacetate, affording rac-12 in 47% yield. An enantiomerically pure SO was also converted to (R)-13 in a stereospecific addition of the PFAA-nitrene in 66% yield. Furthermore, the reaction was feasible with the racemic SO derived from the pesticide chlorbensid, but due to poor solubility in PhCF₃, ethyl acetate was used as the solvent, yielding product rac-14 in moderate yield (53%) after 2 h. Finally, the reaction was tested with methionine SO, derived from the oxidized form of the amino acid l-methionine, which is associated with aging when present in increased levels in tissues.^56,57 The Boc-protected SO yielded the target product 15 after merely 1 h and was obtained in 49% yield again with an increased formation of the aniline derivative as the side product.

The use of enantiopure tert-butylsulfinamide is an established strategy to access valuable chiral amines. In the standard approach, the chiral auxiliary group is introduced via condensation with aldehydes or ketones, followed by stereoselective nucleophilic addition and chiral auxiliary removal to yield the enantioenriched amine.^58,59 We hypothesized that the free NH₂ group in enantiomerically pure SIAs could act as a chiral auxiliary via the reaction with carbonyl compounds to yield imines, which could subsequently be used in stereoselective addition reactions. Previously, SIAs were used in asymmetric reactions as ligands,^60,61 organocatalysts,⁶² or nitrene-transfer agents,⁶³⁻⁷¹ but there are no reports of SIAs as chiral auxiliaries.

Indeed, the chiral pyridine-based (R)-3 formed stable imines from pivaldehyde and aromatic benzaldehydes using reaction conditions reported by Cid and coworkers.⁷² The reactions proceeded to completion after 20–44 h at reflux in CH₂Cl₂, yielding the target imines in high to excellent yields (78–90%, Scheme 1).

Scheme 1. Synthesis of Imines from SIA and Aldehydes.

Reaction conditions: (R)-3 (0.8 mmol, 0.1 M), aldehyde (2 equiv), pyrrolidine (0.1 equiv), CH₂Cl₂ (8 mL, dry), molecular sieves (4 Å), reflux, N₂ atmosphere.

Unfortunately, enolizable aldehydes, such as butyraldehyde, led to a complex reaction mixture with side products. The obtained imine derivatives 16a–c were used to investigate the ability of SIAs to function as chiral auxiliaries in stereoselective carbonyl addition reactions with Grignard reagents.

Initially, the addition of phenylmagnesium bromide to imine (R)-16a was investigated in several different solvents (Scheme 2). After 6 h of the reaction at −78 °C, the results revealed that both CH₂Cl₂ and THF failed to give full conversion, while toluene provided full conversion and high stereoselectivity according to ¹H NMR. Conducting the reaction in diethylether and hexane also gave full conversion of the starting material but with slightly lower diastereoselectivity.

Scheme 2. Solvent Screening for Grignard Addition to SIA Imines.

Reaction conditions: phenylmagnesium bromide (0.14 mmol, 2.5 equiv), imine (0.057 mmol, 1 equiv), solvent (0.5 mL, dry), N₂ atmosphere, −78 °C.

With the optimal reaction conditions in hand, we investigated the scope of the Grignard addition to imines derived from SIA (R)-3. The imines were made to react with Grignard reagents at −78 °C for 6 h, and the reaction mixtures were allowed to reach room temperature overnight. The reaction was quenched and extracted, and the product yield was determined using ¹H NMR with tert-butylmethyl ether as the internal standard.

Addition of aromatic Grignard regents (Table 4, entries 1–3) to the imine derived from pivaldehyde gave the addition product in high yields (86–98%) and with high diastereomeric ratios (up to 96:4) which are comparable to Grignard additions to tert-butyl sulfinyl imines.⁷³ Methyl magnesium bromide yielded the product (86%) but with much lower selectivity compared to tert-butyl sulfinimines,⁷³ while aliphatic isopropylmagnesium chloride gave only small amounts of the addition product together with the reduced product derived from a hydride transfer (Table 4, entries 4–5). The addition of aromatic Grignard reagents to the SIA imine derived from aromatic benzaldehyde provided products in high yields and diastereomeric ratios (Table 4, entries 6–10) that are comparable with the selectivities obtained with the tert-butyl sulfinyl imines.^74,75 Methyl magnesium bromide gave low selectivity in toluene, while an improved selectivity (dr 84:16) was observed in CH₂Cl₂ (Table 4, entry 8).

Table 4. Scope of the Addition of Grignard Reagents to Imines Derived from SIAs^a.

entry	R1	R2	X	yieldb	drc
1	tBu	Ph	Br	86	95:5
2	tBu	3-methoxy-C6H4	Br	90	96:4
3	tBu	4-chloro-C6H4	Br	98	93:7
4	tBu	Me	Br	86	67:33
5	tBu	iPr	Cl
6	Ph	3-methoxy-C6H4	Br	85	92:8
7	Ph	4-chloro-C6H4	Br	85	92:8
8	Ph	Me	Br	80	84:16d
9	4-chloro-C6H4	Ph	Br	86	84:16
10	4-chloro-C6H4	3-methoxy-C6H4	Br	90	94:6

^aReaction conditions: imine (0.05 mmol, 1 equiv), Grignard reagent (2.5 equiv), toluene (0.5 mL), −78 to r.t.

^bThe yield was determined by ¹H NMR spectroscopy using tert-butyl methyl ether as the internal standard.

^cDetermined by ¹H NMR spectroscopy or chiral HPLC.

^dReaction performed in CH₂Cl₂.

Finally, we performed the synthesis between imine 16a and 3-methoxyphenylmagnesium bromide in a 0.3 mmol scale which gave product 17 in 95% yield and 95:5 diastereomeric ratio (Scheme 3).

Scheme 3. Larger Scale Synthesis and Removal of Chiral Auxiliary.

Reaction conditions: 3-methoxyphenylmagnesium bromide (0.75 mmol, 2.5 equiv), imine (0.3 mmol, 1.0 equiv), toluene (2.5 mL, dry), N₂-atmosphere −78 °C to r.t. Compound 17 (0.09 mmol, 1 equiv), anisole (20 equiv), TfOH (9 equiv), CH₂Cl₂, 0 °C to r.t.

The classical approach used to cleave the SA auxiliary involves acidic condition in protic solvents, typically HCl or trifluoroacetic acid in methanol.^76,77 Unfortunately, those conditions did not work and a complex reaction mixture was obtained. Finally, the SIA chiral auxiliary was removed by treatment with triflic acid and anisole in CH₂Cl₂⁷⁸ and the amine was obtained in 90% yield and 95:5 dr (Scheme 3).

Conclusions

We have developed a photopromoted reaction between perfluorinated aromatic azides and SAs or SOs to obtain SIAs and SOIs, respectively. The fluoro substituents on the aromatic ring of the azides were critical for accessing synthetically useful nitrenes. The reaction proceeded via in situ generated perfluorinated nitrenes and stereospecific addition, enabling the formation of optically pure compounds. One of the chiral SIAs, derived from the perfluorinated pyridine azide, was condensed with aliphatic and aromatic aldehydes to yield enantiopure imine-derivatives in good to excellent yields. The use of the synthesized SIA was evaluated as a potential chiral auxiliary for the addition of Grignard reagents to the chiral SIA-derived imines at −78 °C in toluene. The investigation demonstrated that Grignard reagents were successfully added to the imines in high to excellent yields (up to 98%) and good to excellent diastereoselectivity (up to 96:4 dr). The use of SIA as a chiral auxiliary is to the best of our knowledge unprecedented, and we believe that these new types of SIAs find applications as novel scaffolds in asymmetric synthesis.

Experimental Section

All reagents were obtained from commercial sources and used without further purification. The perfluorinated aromatic azides were synthesized according to the literature.⁷⁹ All solvents were purified and dried according to standard methods prior to use, unless stated otherwise. Degassed solvents were obtained by bubbling the solvent with inert gas through a needle. Anhydrous dichloromethane was obtained by distillation over calcium hydride, and anhydrous diethyl ether, THF, and toluene were obtained from a Glass Contour solvent dispensing system. Heating of reaction mixtures was performed in oil baths, and experiments at lower temperatures (−78 °C) were carried out with dry ice/acetone baths. Thin-layer chromatography (TLC) was performed using 60 mesh silica gel plates visualized with short-wavelength UV light (254 nm). Silica gel 60 (200–300 mesh) was used for column chromatography. HPLC analyses were conducted using a UV detector (Shimadzu SPD-20A) and a chiral column (Kromasil 5-CelluCoat RP, 0.46 × 25 cm) using a flow of 1.0 mL/min of the eluent system hexane/iso-propanol. A Bruker Ascend 400 spectrometer (400 MHz) or Bruker Avance DMX 500 (500 MHz) spectrometer was used for the recording of ¹H NMR spectra, ¹³C{1H} NMR spectra, and ¹⁹F NMR spectra. Proton chemical shifts are reported as δ values (ppm) relative to tetramethylsilane with residual undeuterated CHCl₃ (δ 7.26), DMSO-d₆ (δ 2.50), and methanol-d₄ (δ 3.31) as internal standards. ¹³C{1H} chemical shifts are reported as δ values (ppm) relative to tetramethylsilane with CDCl₃ (δ 77.16 ppm), DMSO-d₆ (δ 39.52 ppm), or methanol-d₄ (δ 49.0 ppm) as internal standards. Data for ¹H NMR are reported as follows: chemical shift (δ, ppm) and multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br = broad singlet, and J = coupling constants in Hz, integration). High-resolution mass spectrometry (HRMS) measurements were performed on methanolic solutions of the compounds using a Bruker maXis impact II micrOTOF spectrometer [direct injection and electrospray ionization (ESI)]. The light-promoted reactions were run using a 390 nm light source (40 W, Kessil PR160, set to maximum intensity) at a distance of 3.0 cm from the reaction vessel. Experimental details, such as spectroscopic characterizations (¹H, ¹³C{1H}, and ¹⁹F NMR), HPLC chromatograms, and HRMS, are given in the Supporting Information.

General Procedure A for the Synthesis of SIAs

To an 8 mL vial equipped with a magnetic stir bar, the perfluorinated aromatic azido (PFAA) compound (1 equiv, 0.3 mmol, 0.05 M), SA (1.5 equiv, 0.45 mmol), and degassed α,α,α-trifluorotoluene (PhCF₃) (6 mL) were added. At this point, the vial was evacuated and back filled with N₂, and the vial was capped with a rubber septum. The reaction mixture was irradiated at 390 nm (40 W, Kessil PR160, set to maximum intensity, 3.0 cm from the reaction vessel) while stirring. After the completion of the reaction, the crude obtained upon solvent removal under reduced pressure was purified by flash column chromatography using either petroleum ether and ethyl acetate (PE/EtOAc) or petroleum ether, dichloromethane, and ethyl acetate (PE/DCM/EtOAc) as the eluent system to afford the pure product. All compounds were characterized via HRMS and ¹H NMR, ¹³C{1H} NMR, and ¹⁹F NMR spectroscopies.

Methyl (S)-4-((Amino(tert-butyl)(oxo)-λ⁶-sulfaneylidene)amino)-2,3,5,6-tetrafluorobenzoate (S)-1

The compound was obtained according to general procedure A using azide 1a (75 mg, 0.3 mmol, 1 equiv) and (S)-tert-butylsulfinamide (64 mg, 0.5 mmol, 1.7 equiv). The reaction was completed after 6 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 6:1:1 → 3:1:1) (rf: 0.25, eluent: 4:1:1) as a pale-yellow precipitate (72 mg, 70%). HPLC (Kromasil 5-CelluCoat RP, 0.46 cm × 25 cm, n-hexane/isopropanol = 90/10, flow rate = 1.0 mL/min, λ = 220 nm) t_R = 22.8 min (major), 41.4 min (minor). mp: 154–155 °C. ¹H NMR (CDCl₃, 400 MHz): δ 4.31 (br, 2H, NH₂), 3.94 (s, 3H, OCH₃), and 1.60 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 161.1, 146.0 (dm, J = 256 Hz), 142.9 (dm, J = 243 Hz), 127.4, 105.1, 62.1, 53.0, and 24.3; ¹⁹F NMR (CDCl₃, 376 MHz): δ −141.1 (m, 2F) and −149.2 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₂H₁₄F₄N₂O₃SNa, 365.0554; found, 365.0554. [α]_D²⁰ + 32 (c 0.5, CHCl₃).

Methyl (R)-4-((Amino(tert-butyl)(oxo)-λ⁶-sulfaneylidene)amino)-2,3,5,6-tetrafluorobenzoate (R)-1

The compound was obtained according to general procedure A using azide 1a (77 mg, 0.3 mmol, 1 equiv) and (R)-tert-butylsulfinamide (55 mg, 0.5 mmol, 1.4 equiv). The reaction was completed after 6 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 6:1:1 → 3:1:1) (rf: 0.25, eluent: 4:1:1) as a pale-yellow precipitate (68 mg, 65%). HPLC (Kromasil 5-CelluCoat RP, 0.46 cm × 25 cm, n-hexane/isopropanol = 90/10, flow rate = 1.0 mL/min, λ = 220 nm) t_R = 23.4 min (minor), 41.7 min (major). mp: 150–153 °C. ¹H NMR (CDCl₃, 400 MHz): δ 4.49 (br, 2H, NH₂), 3.93 (s, 3H, OCH₃), and 1.58 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 161.1, 145.9 (dm, J = 256 Hz), 142.9 (dm, J = 244 Hz), 127.6, 104.9, 62.1, 53.0, and 24.3; ¹⁹F NMR (CDCl₃, 376 MHz): δ −141.3 (m, 2F), −149.2 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₂H₁₄F₄N₂O₃SNa, 365.0554; found, 365.0555. [α]D20 – 32 (c 0.5, CHCl₃).

(S)-N′-(4-Cyano-2,3,5,6-tetrafluorophenyl)-2-methylpropane-2-sulfonimidamide (S)-2

The compound was obtained according to general procedure A using azide 1b (68 mg, 0.3 mmol, 1 equiv) and (S)-tert-butylsulfinamide (54 mg, 0.5 mmol, 1.5 equiv). The reaction was completed after 2 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 10:1:1 → 6:1:1) (rf: 0.15, eluent: 6:1:1) as an off-white precipitate (60 mg, 62%). mp: 126–127 °C. ¹H NMR (CDCl₃, 400 MHz): δ 4.46 (br, 2H, NH₂), and 1.59 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 147.8 (dm, J = 259 Hz), 142.5 (dm, J = 246 Hz), 130.9, 108.6, 85.95, 62.6, and 24.2; ¹⁹F NMR (CDCl₃, 376 MHz): δ −135.4 (m, 2F), −146.9 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₁H₁₁F₄N₃OSNa, 332.0452; found, 332.0451. [α]D27 + 68 (c 0.4, CHCl₃).

(S)-2-Methyl-N′-(perfluoropyridin-4-yl)propane-2-sulfonimidamide (S)-3

The compound was obtained according to general procedure A using azide 1c (62 mg, 0.3 mmol, 1 equiv) and (S)-tert-butylsulfinamide (56 mg, 0.5 mmol, 1.5 equiv). The reaction was completed after 16 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 8:1:1 → 4:1:1) as an off-white precipitate (58 mg, 64%). mp: 123–125 °C. ¹H NMR (CDCl₃, 400 MHz): δ 4.44 (br, 2H, NH₂) and 1.60 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 144.1 (dm, J = 241 Hz), 137.6 (dm, J = 253 Hz), 136.1, 62.4, and 24.0; ¹⁹F NMR (CDCl₃, 376 MHz): δ −93.2 (m, 2F) and −151.5 (m, 2F). HRMS (ESI-TOF) m/z: calcd for C₉H₁₁F₄N₃OS [M + Na]⁺, 308.0451; found, 308.0449. [α]_D³⁰ + 280 (c 0.3, acetonitrile).

(R)-2-Methyl-N′-(perfluoropyridin-4-yl)propane-2-sulfonimidamide (R)-3

The compound was obtained according to general procedure A using azide 1c (58 mg, 0.3 mmol, 1 equiv) and (R)-tert-butylsulfinamide (51 mg, 0.5 mmol, 1.5 equiv). The reaction was completed after 16 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 6:1:1 → 3:1:1) (rf: 0.3, eluent: 4:1:1) as an off-white precipitate (56 mg, 65%). mp: 122–123 °C. ¹H NMR (CDCl₃, 400 MHz): δ 4.37 (br, 2H, NH₂) and 1.60 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ 144.2 (dm, J = 241 Hz), 137.5 (dm, J = 251 Hz), 62.6 and 24.2; ¹⁹F NMR (CDCl₃, 376 MHz): δ −93.1 (m, 2F) and −151.5 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₉H₁₁F₄N₃OSNa, 308.0451; found, 308.0451. [α]_D³⁰ – 290 (c 0.4, acetonitrile).

(S)-2-Methyl-N′-(perfluorophenyl)propane-2-sulfonimidamide (S)-4

The compound was obtained according to general procedure A using azide 1d (65 mg, 0.3 mmol, 1 equiv) and (S)-tert-butylsulfinamide (54 mg, 0.5 mmol, 1.5 equiv). The reaction was completed after 19 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 10:1:1 → 6:1:1) (rf: 0.28, eluent: 6:1:1) as an off-white precipitate (30 mg, 32%). mp: 101–103 °C. ¹H NMR (CDCl₃, 400 MHz): δ 4.27 (br, 2H, NH₂) and 1.59 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 143.4 (dm, J = 243 Hz), 138.0 (dm, J = 257 Hz), 137.8 (dm, J = 246 Hz), 118.6, 61.5, and 24.2; ¹⁹F NMR (CDCl₃, 376 MHz): δ −150.1 (m, 2F), −164.2 (m, 1F), and −164.5 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₀H₁₁F₅N₂OSNa, 325.0405; found, 325.0404. [α]_D²⁷ + 28 (c 0.3, CHCl₃).

(S)-4-((Amino(tert-butyl)(oxo)-λ⁶-sulfaneylidene)amino)-2,3,5,6-tetrafluorobenzoic Acid (S)-5

The compound was obtained according to general procedure A using azide 1e (68 mg, 0.3 mmol, 1 equiv) and (S)-tert-butylsulfinamide (57 mg, 0.5 mmol, 1.5 equiv). The reaction was completed after 10 h of the reaction. The pure product was obtained after flash column chromatography (eluent: 5% MeOH in CH₂Cl₂ + 0.5% formic acid) (rf: 0.19, eluent: 5% MeOH in CH₂Cl₂ + 0.5% formic acid) as a white precipitate (31 mg, 34%). mp: 74 °C. ¹H NMR (DMSO-d₆, 400 MHz): δ 6.88 (br, 2H, NH₂) and 1.43 (s, 9H, t-Bu); ¹³C{¹H} NMR (DMSO-d₆, 125 MHz): δ 161.0, 144.9 (dm, J = 249 Hz), 141.6 (dm, J = 243 Hz), 129.1, 103.8, 60.6, and 23.8; ¹⁹F NMR (DMSO-d₆, 376 MHz): δ −143.5 (m, 2F) and −148.8 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₁H₁₂F₄N₂O₃SNa, 351.0397; found, 351.0399. [α]_D³¹ – 4 (c 0.4, methanol).

(S)-N′-(4-Cyano-2,3,5,6-tetrafluorophenyl)-4-methylbenzenesulfonimidamide (S)-7

The compound was obtained according to general procedure A using azide 1b (62 mg, 0.3 mmol, 1 equiv) and (S)-p-toluenesulfinamide (55 mg, 0.4 mmol, 1.3 equiv). The reaction was completed after 5 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 8:1:1 → 6:1:1) (rf: 0.12, eluent: 6:1:1) as an off-white precipitate (41 mg, 42%). mp: 175–177 °C. ¹H NMR (DMSO-d₆, 500 MHz): δ 7.85 (d, J = 8.3 Hz, 1H), 7.78 (br, 2H, NH₂), 7.43 (d, J = 8.1 Hz, 1H), and 2.39 (s, 3H, CH₃); ¹³C{¹H} NMR (DMSO-d₆, 125 MHz): δ 147.3 (dm J = 258 Hz), 143.0, 141.0 (dm J = 244 Hz), 140.4, 132.0, 129.6, 126.3, 109.0, 83.2, and 21.0; ¹⁹F NMR (DMSO-d₆, 376 MHz): δ −134.9 (m, 2F) and −146.4 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₄H₉F₄N₃OSNa, 366.0295; found, 366.0296. [α]_D³¹ – 49 (c 0.3, acetonitrile).

Methyl 2,3,5,6-Tetrafluoro-4-((oxo(phenyl)(piperidin-1-yl)-λ⁶-sulfaneylidene)amino)-benzoate rac-8

The compound was obtained according to general procedure A using azide 1a (75 mg, 0.3 mmol, 1 equiv) and 1-(phenylsulfinyl)piperidine (94 mg, 0.45 mmol, 1.5 equiv). The reaction was completed after 6 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 20:1:1 → 10:1:1) as a white precipitate (51 mg, 42%). mp: 85–86 °C. ¹H NMR (CDCl₃, 400 MHz): δ 7.94 (m, 2H), 7.62 (m, 1H), 7.56 (m, 2H), 3.93 (s, 3H), 3.05 (m, 4H), 1.54 (m, 4H), and 1.40 (m, 2H); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 161.1, 145.9 (dm, J = 255 Hz), 142.5 (dm, J = 245 Hz), 136.3, 133.1, 129.3, 128.1, 127.4, 104.5, 52.9, 47.6, 25.5, and 23.6; ¹⁹F NMR (CDCl₃, 376 MHz): δ −141.2 (m, 2F) and −147.8 (m, 2F). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₉F₄N₂O₃S, 431,1047; found, 431.1049.

General Procedure B for the Synthesis of SOIs

To an 8 mL vial equipped with a magnetic stir bar, PFAA compound (1 equiv, 0.3 mmol, 0.05 M), SO (1.5 equiv, 0.45 mmol), and degassed α,α,α-trifluorotoluene (PhCF₃) (6 mL) were added. At this point, the vial was evacuated and back filled with N₂, and the vial was capped with a rubber septum. The reaction mixture was irradiated at 390 nm (40 W, Kessil PR160, set to maximum intensity, 3.0 cm from the reaction vessel) while stirring. After the completion of the reaction, the crude obtained upon solvent removal under reduced pressure was purified by flash column chromatography using either petroleum ether and ethyl acetate (PE/EtOAc) or petroleum ether, dichloromethane, and ethyl acetate (PE/DCM/EtOAc) as the eluent system to afford the pure product. All compounds were characterized via HRMS and ¹H NMR, ¹³C{1H} NMR, and ¹⁹F NMR spectroscopies.

Methyl 4-((Dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-2,3,5,6-tetrafluorobenzoate 9

The compound was obtained according to general procedure B using azide 1a (75 mg, 0.3 mmol, 1 equiv) and DMSO (32 μL, 0.45 mmol, 1.5 equiv). The reaction was completed after 2 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/EtOAc, 2:1 → 1:1) (rf: 0.3, eluent PE/EtOAc 1:1) as a white precipitate (70 mg, 78%). mp: 129–130 °C ¹H NMR (CDCl₃, 400 MHz): δ 3.94 (s, 3H, OCH₃), and 3.29 (s, 6H, CH₃); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 160.9, 146–0 (dm, J = 256 Hz), 142.1 (dm, J = 243 Hz), 127.6, 104.7, 53.0, and 44.8; ¹⁹F NMR (CDCl₃, 376 MHz): δ −140.8 (m, 2F) and −149.5 (m, 2F). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₀H₁₀F₄NO₃S, 300.0312; found, 300.0312.

Methyl 2,3,5,6-Tetrafluoro-4-((methyl(oxo)(phenyl)-λ⁶-sulfaneylidene)amino)benzoate rac-10

The compound was obtained according to general procedure B using azide 1a (64 mg, 0.26 mmol, 1 equiv) and phenyl vinyl SO (51 mg, 0.36 mmol, 1.4 equiv). The reaction was completed after 4 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 10:1:1 → 6:1:1) (rf: 0.36, eluent: 6:1:1) as a white precipitate (57 mg, 61%). mp: 140–142 °C. ¹H NMR (CDCl₃, 400 MHz): δ 8.03–7.93 (m, 2H), 7.72–7.64 (m, 1H), 7.63–7.54 (m, 2H), 3.90 (s, 3H), and 3.36 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 161.0, 145.7 (dm, J = 255.4 Hz), 141.7 (dm, J = 244.6 Hz), 139.6, 134.1, 129.9, 128.0, 127.7, 104.2, 52.9, and 47.3; ¹⁹F NMR (CDCl₃, 376 MHz): δ −141.0 (m, 2F) and −148.6 (m, 2F). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₂F₄NO₃S, 362.0468; found, 362.0466.

Methyl 2,3,5,6-Tetrafluoro-4-((methyl(oxo)(vinyl)-λ⁶-sulfaneylidene)amino)benzoate rac-11

The compound was obtained according to general procedure B using azide 1a (75 mg, 0.3 mmol, 1 equiv) and phenyl vinyl SO (rac) (46 μL, 0.42 mmol, 1.4 equiv). The reaction was completed after 4 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 10:1:1 → 6:1:1) (rf: 0.4, eluent: 6:1:1) as an off-white precipitate (63 mg, 56%). mp: 106–107 °C. ¹H NMR (CDCl₃, 400 MHz): δ 8.06–7.91 (m, 2H), 7.72–7.63 (m, 1H), 7.60–7.53 (m, 2H), 6.74 (dd, J = 16.2, 9.4 Hz, 1H), 6.56 (d, J = 16.5 Hz, 1H), 6.14 (d, J = 9.3 Hz, 1H), and 3.91 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 161.0, 145.7 (dm, J = 255.5 Hz), 142.0 (dm, J = 244.8 Hz), 138.6, 138.3, 134.1, 129.8, 129.4, 128.4, 127.8, 104.6, and 52.9; ¹⁹F NMR (CDCl₃, 376 MHz): δ −141.0 (m, 2F) and −148.1 (m, 2F). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₂F₄NO₃S, 374.0468; found, 374.0467.

Methyl 2,3,5,6-Tetrafluoro-4-(((2-methoxy-2-oxoethyl)(oxo)(phenyl)-λ⁶-sulfaneylidene)-amino)benzoate rac-12

The compound was obtained according to general procedure B using azide 1a (74 mg, 0.3 mmol, 1 equiv) and methyl-phenylsulfinylacetate (rac) (91 mg, 0.45 mmol, 1.5 equiv). The reaction was completed after 2 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 10:1:1 → 6:1:1) (rf: 0.14, eluent: 6:1:1) as an off-white precipitate (58 mg, 47%). mp: 97–98 °C. ¹H NMR (CDCl₃, 500 MHz): δ 8.05–7.96 (m, 2H), 7.83–7.67 (m, 1H), 7.66–7.58 (m, 2H), 4.38 (s, 2H), 3.92 (s, 3H), and 3.70 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 162.4, 160.9, 145.9 (dm, J = 255.8 Hz), 141.8 (dm, J = 244.9 Hz), 137.9, 134.7, 129.8, 128.8, 127.2, 104.8, 62.8, 53.3, and 53.0; ¹⁹F NMR (CDCl₃, 376 MHz): δ −140.8 (m, 2F) and −148.3 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₇H₁₃F₄NO₅SNa, 442.0344; found, 442.0341.

Methyl (R)-2,3,5,6-Tetrafluoro-4-((methyl(oxo)(p-tolyl)-λ⁶-sulfaneylidene)amino)benzoate (R)-13

The compound was obtained according to general procedure B using azide 1a (74 mg, 0.3 mmol, 1 equiv) and (R)-methyl p-tolyl SO (64 mg, 0.4 mmol, 1.4 equiv). The reaction was completed after 2 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM/EtOAc, 6:1:1) (rf: 0.44, eluent: 4:1:1) as a white precipitate (74 mg, 66%). mp: 86–87 °C. ¹H NMR (CDCl₃, 400 MHz): δ 7.83 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.34 (s, 3H), and 2.44 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 161.0, 145.9 (dm, J = 255.3 Hz), 145.2, 141.9 (dm, J = 244.7 Hz), 136.4, 130.6, 128.3, 127.7, 104.1, 52.9, 47.4, and 21.7; ¹⁹F NMR (CDCl₃, 376 MHz): δ −141.1 (m, 2F) and −148.1 (m, 2F). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₄F₄NO₃S, 376.0625; found, 376.0626. [α]_D²⁷ – 113 (c 0.4, CHCl₃).

Methyl 4-(((4-Chlorobenzyl)(4-chlorophenyl)(oxo)-λ⁶-sulfaneylidene)amino)-2,3,5,6-tetrafluorobenzoate rac-14

The compound was obtained according to general procedure B using azide 1a (56 mg, 0.2 mmol, 1 equiv) and chlorbensid SO (85 mg, 0.3 mmol, 1.3 equiv). The reaction was run in ethyl acetate (deg) and was completed after 2 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/DCM, 1:1 → 1:2) (rf: 0.15, eluent: PE/DCM, 1:1) as a colorless solid (60 mg, 53%). mp: 109–110 °C. ¹H NMR (CDCl₃, 500 MHz): δ 7.61–7.49 (m, 2H), 7.48–7.41 (m, 2H), 7.33–7.22 (m, 2H), 7.16–7.05 (m, 2H), 4.79–4.34 (m, 2H), and 3.90 (s, 3H); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 160.9, 145.9 (dm, J = 255.7 Hz), 141.7 (dm, J = 244.6 Hz), 141.18, 136.0, 135.4, 132.8, 130.2, 129.9, 129.1, 127.7, 125.8, 104.3, 64.6, and 52.9; ¹⁹F NMR (CDCl₃, 376 MHz): δ −140.8 (m, 2F) and −148.4 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₁H₁₃Cl₂F₄NO₃SNa, 527.9822; found, 527.9823.

(2S)-2-((tert-Butoxycarbonyl)amino)-4-(S-methyl-N-(2,3,5,6-tetrafluoro-4-(methoxycarbonyl)-phenyl)sulfonimidoyl)butanoic Acid 15

The compound was obtained according to general procedure B using azide 1a (75 mg, 0.3 mmol, 1 equiv) and l-methionine SO N-Boc protected (120 mg, 0.45 mmol, 1.5 equiv). The reaction was completed after 1 h of the reaction. The pure product was obtained after flash column chromatography (eluent: 2.5% MeOH in DCM + 0.25% formic acid → 5.0% MeOH in DCM + 0.25% formic acid) (rf: 0.25, eluent: 5.0% MeOH in DCM + 0.5% formic acid) as a pale-yellow precipitate (72 mg, 49%). mp: 111–112 °C. ¹H NMR (CDCl₃, 500 MHz): δ 9.97 (br, 1H, CO₂H), 7.05–5.52 (br, 1H, NH), 4.45–4.40 (s, 1H, CH), 3.92 (s, 3H, OCH₃), 3.57–3.66 (m, 2H, CH₂), 3.21 (s, 3H, S-CH₃), 2.56–2.33 (m, 2H, CH₂), and 1.50–1.42 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 174.1, 161.0, 156.9, 155.9, 145.9 (dm, J = 256 Hz), 142.0 (dm, J = 240 Hz), 127.5, 104.6, 83.21, 81.1, 53.3, 53.0, 52.0, 42.5, 28.3, and 25.9; ¹⁹F NMR (CDCl₃, 376 MHz): δ −140.7 (m, 2F) and −149.2 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₈H₂₂F₄N₂O₇SNa, 509.0976; found, 509.0973.

General Procedure C for the Condensation Reaction

To a dry round-bottom flask equipped with a magnetic stir bar, a reflux condenser and 4 Å molecular sieves (MSs), SIA (1 equiv, 0.8 mmol, 0.1 M), aldehyde (2 equiv), pyrrolidine (0.08 mmol, 0.1 equiv), and anhydrous CH₂Cl₂ (8 mL) were added. The reaction was refluxed under an inert atmosphere (N₂). After the completion of the reaction, the crude obtained upon solvent removal under reduced pressure was purified by flash column chromatography using petroleum ether, dichloromethane, and ethyl acetate (PE/EtOAc) as the eluent system to afford the pure product. All compounds were characterized via HRMS and ¹H NMR, ¹³C{1H} NMR, and ¹⁹F NMR spectroscopies.

(S,E)-N-(2,2-Dimethylpropylidene)-2-methyl-N′-(perfluoropyridin-4-yl)propane-2-sulfonimidamide (R)-16a

The compound was obtained according to general procedure C using compound (R)-3 (1 equiv) and pivaldehyde (2.0 equiv). The reaction was completed after 40 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/EtOAc 20:1) as a white precipitate (125 mg, 90%). mp: 88 °C. ¹H NMR (CDCl₃, 500 MHz): δ 8.50 (s, 1H, imine), 1.54 (s, 9H, t-Bu), and 1.42 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 189.4, 144.3 (dm, J = 240 Hz), 137.1 (dm, J = 252 Hz), 136.7, 62.0, 38.9, 26.1, and 23.8; ¹⁹F NMR (CDCl₃, 376 MHz): δ −93.8 (m, 2F) and −152.0 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₄H₁₉F₄N₃OSNa, 376.1077; found, 376.1078. [α]_D³¹ – 64 (c 0.2, CHCl₃).

(S,E)-N-Benzylidene-2-methyl-N′-(perfluoropyridin-4-yl)propane-2-sulfonimidamide (R)-16b

The compound was obtained according to general procedure C using compound (R)-3 (1 equiv) and benzaldehyde (2.0 equiv). The reaction was completed after 40 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/EtOAc 20:1) as a white crystal (60 mg, 78%). mp: 68–70 °C. ¹H NMR (CDCl₃, 500 MHz): δ 9.06 (s, 1H, imine), 7.99 (m, 2H), 7.69 (m, 1H), 7.55 (m, 2H), and 1.61 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 174.6, 144.20 (dm, J = 240 Hz), 137.1 (dm, J = 252 Hz), 136.7, 135.7, 132.2, 131.6, 129.5, 62.5, and 23.9; ¹⁹F NMR (CDCl₃, 376 MHz): δ −93.9 (m, 2F) and −152.0 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₆H₁₅F₄N₃OSNa, 396.0764; found, 396.0768. [α]_D³¹ – 404 (c 0.3, CHCl₃).

(S,E)-N-(4-Chlorobenzylidene)-2-methyl-N′-(perfluoropyridin-4-yl)propane-2-sulfonimidamide (R)-16c

The compound was obtained according to general procedure C using compound (R)-3 (1 equiv) and 4-chloro benzaldehyde (2.0 equiv). The reaction was completed after 40 h of the reaction. The pure product was obtained after flash column chromatography (eluent: PE/EtOAc 20:1) as white crystals (254 mg, 78%). mp: 99–100 °C. ¹H NMR (CDCl₃, 500 MHz): δ 9.02 (s, 1H, imine), 7.93 (d, J = 8.5, 2H), 7.54 (d, J = 8.5, 2H), and 1.60 (s, 9H, t-Bu); ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 173.1, 144.1 (dm, J = 241 Hz), 142.4, 137.1 (dm, J = 252 Hz), 136.5, 132.7, 130.7, 130.1, 62.6, and 24.0; ¹⁹F NMR (CDCl₃, 376 MHz): δ −93.77 (m, 2F) and −151.89 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₁₆H₁₄ClF₄N₃OSNa, 430.0375; found, 430.0376. [α]_D³¹ – 194 (c 0.2, CHCl₃).

General Procedure D for the Solvent Screening of Grignard Addition Reactions

To a dry Biotage microwave vial equipped with a magnetic stir bar, a 0.5 mL solution of SIA-imine (1 equiv, 0.05 mmol, 0.1 M) was added. The solution was allowed to reach −78 °C in an acetone/dry ice bath, and 47 μL of a solution (3.0 M in Et₂O) of phenyl magnesium bromine was added drop-wise. The reaction mixture was stirred for 6 h. The crude reaction mixture was sampled, quenched with sat. aq. sol. of NH₄Cl, and analyzed via ¹H NMR to determine the conversion and the dr.

General Procedure E for Grignard Addition Reactions

To a dry Biotage microwave vial equipped with a magnetic stir bar, a 0.5 mL solution of SIA-imine (1 equiv, 0.05 mmol, 0.1 M) was added. The solution was allowed to reach −78 °C in an acetone/dry ice bath and the Grignard reagent (0.125 mmol, 2.5 equiv) was added dropwise to the solution. The reaction mixture was stirred at −78 °C for 6 h and then let reach r.t. overnight. The crude reaction mixture was quenched with sat. aq. sol. of NH₄Cl (2 mL) and extracted with EtOAc (4 × 1 mL). The organic phases were combined, dried over Na₂SO₄, and filtered, and the solvent was removed via rotary evaporation in vacuo. The yield of the reaction was obtained via ¹H NMR using tert-butyl methyl ether as the internal standard. The dr was obtained via ¹H NMR analysis.

(S)-N-(1-(3-Methoxyphenyl)-2,2-dimethylpropyl)-2-methyl-N′-(perfluoropyridin-4-yl)propane-2-sulfonimidamide 17

The compound was obtained according to general procedure E using imine (R)-16a (1 equiv, 0.3 mmol, 100 mg) and a 1.0 M solution of 3-methoxyphenylmagnesium bromide in THF (2.5 equiv). The crude reaction mixture was quenched with sat. aq. sol. of NH₄Cl (10 mL) and extracted with EtOAc (4 × 8 mL). The organic phases were combined, washed with H₂O, dried over Na₂SO₄, and filtered, and the solvent was removed via rotary evaporation in vacuo. The pure product was obtained without further purification as colorless powder (124 mg, 95% yield, 95:5 dr). HPLC (Kromasil 5-CelluCoat RP, 0.46 cm × 25 cm, n-hexane/isopropanol = 98/2, flow rate = 1.0 mL/min, λ = 220 nm) t_R = 14.5 min (major), 22.1 min (minor). mp: 152–153 °C. ¹H NMR (500 MHz, CDCl₃): δ 7.06 (t, J = 7.9 Hz, 1H), 6.66 (m, 1H), 6.59 (m, 1H), 6.49 (m, 1H), 4.21 (d, J = 9.9 Hz, 1H, NH), 4.13 (d, J = 9.8 Hz, 1H, CH), 3.73 (s, 3Hm OCH₃), 1.52 (s, 9H, t-Bu), and 0.94 (s, 9H, t-Bu); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 159.1, 143.8 (dm, J = 243 Hz), 142.6, 137.9 (dm, J = 253 Hz), 136.1, 128.8, 120.2, 114.4, 111.5, 67.6, 64.1, 55.1, 35.8, 27.5, and 24.6. ¹⁹F NMR (CDCl₃, 376 MHz): δ −93.6 (m, 2F) and −151.2 (m, 2F). HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₁H₂₇F₄N₃O₂SNa, 484.1653; found, 484.1654. [α]_D³¹ – 20 (c 0.2, CHCl₃).

1-(3-Methoxyphenyl)-2,2-dimethylpropan-1-amine 18

Compound 17 (1 equiv, 0.09 mmol, 40 mg) and anisole (20 equiv) were introduced into a round-bottom flask, equipped with a magnetic stirrer, containing 8 mL of dichloromethane. The reaction mixture was cooled down to 0–5 °C (ice bath), and a 4 mL solution of triflic acid in dichloromethane (0.2 M) was added dropwise. After the addition, the reaction was let reach room temperature. After the completion of the reaction (2 h), the crude mixture was quenched with aqueous NaOH (2 M, 10 mL) and extracted with dichloromethane (3 × 10 mL). The reunited organic phase was dried over Na₂SO₄ and filtered, and the solvent was removed via rotary evaporation in vacuo. The pure product was obtained via preparative-TLC (eluent: 5% MeOH in DCM) (rf: 0.2, eluent: 5% MeOH in DCM) as a colorless liquid (15 mg, 90%, 95:5 dr). HPLC (ReproSil Chiral-NR, 0.46 cm × 25 cm, n-hexane/isopropanol = 70/30, flow rate = 1.0 mL/min, λ = 220 nm) t_R = 6.5 min (minor), 8.4 min (major). mp: 152–153 °C. ¹H NMR (500 MHz, CDCl₃): δ 7.20 (m, 1H), 6.85 (m, 2H), 6.78 (m, 1H), 3.80 (s, 3H, OCH₃), 2.94 (br, 2H, NH₂), and 0.92 (s, 9H, t-Bu); ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 159.2, 144.8, 128.6, 121.0, 114.3, 112.2, 65.4, 55.3, 35.1, and 26.7. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₂H₂₀NO, 194.1539; found, 194.1541. [α]_D³⁰ – 2.4 (c 0.5, methanol).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c02241.

• Supporting Information includes spectroscopic characterizations (¹H, ¹³C, and ¹⁹F NMR), HRMS, and HPLC chromatograms (PDF)

The authors declare no competing financial interest.