Diarylamine Synthesis via Desulfinylative Smiles Rearrangement

Diarylamines are obtained directly from sulfinamides through a novel rearrangement sequence. The transformation is transition metal-free and proceeds under mild conditions, providing facile access to highly sterically hindered diarylamines that are otherwise inaccessible by traditional SNAr chemistry. The reaction highlights the distinct reactivity of the sulfinamide group in Smiles rearrangements versus that of the more common sulfonamides.


General Remarks
All solvents and reagents were purchased from Sigma Aldrich, Thermo Fisher Scientific, Apollo Scientific or Fluorochem and were used as received without further purification. Flash column chromatography was performed using either Biotage Snap Ultra cartridges or Biotage Sfar Silica cartridges on a Biotage Isolera automated column. 1 H, 13 C and 19 F NMR spectroscopy were recorded on either 400 MHz or 500 MHz Bruker Avance NMR spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) and multiplicities are reported as either singlets (s), doublets (d), triplets (t), quartets (q) or multiplets (m). Coupling constants (J) are reported in Hertz (Hz). All 1 H NMR and 13 C NMR shifts were referenced to the residual solvent peak of CDCl3 ( 1 H referenced to 7.26 ppm and 13 C referenced to 77.16 ppm), DMSO-d6 ( 1 H referenced to 2.50 ppm and 13 C referenced to 39.52 ppm) and acetone-d6 ( 1 H referenced to 2.06 ppm and 13 C referenced to 29.84 ppm). All 19 F chemical shifts were unadjusted from raw data. 2D heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond correlation (HMBC) and homonuclear correlation spectroscopy (COSY) NMR spectroscopy was used to assist the assignment of signals. High resolution mass spectrometry (HRMS) was recorded on a Waters QTOF, using either ESI or APCI as ionisation methods. Thin layer chromatography (TLC) was carried out using commercially available coated TLC plates and spots were illuminated either by UV light (254 nm) or by staining the plate with a KMnO4 solution. Compound names are those generated by ChemBioDraw TM (CambridgeSoft) following International Union of Pure and Applied Chemistry (IUPAC) nomenclature. Novel compounds are labelled in italics. Melting points (MPs) were recorded on a Griffin melting point apparatus to the nearest degree. Reactions which proceeded under microwave irradiation were performed in a Biotage Initiator Microwave Synthesizer.

2-methoxy-4-nitro-N-phenylbenzenesulfinamide (3s)
Synthesised by adaptation of a literature procedure. 11 A 100 mL round-bottomed flask was charged with 2-methoxy-4-nitrobenzenesulfonyl chloride (1 g, 4 mmol), evacuated under vacuum and filled with nitrogen. Anhydrous DCM ( 10 mL) was added, alongside NEt3 (8 mmol, 1.12 mL) and the solution was stirred at 0°C . A separate 100 mL round-bottomed flask was charged with PPh3 (1.052 g, 4 mmol), evacuated under vacuum and filled with nitrogen. Anhydrous DCM (10 mL) and aniline (365 µL, 4 mmol) was added and the solution was stirred at 0°C. The contents of the second flask were added dropwise to the first flask over ice, and the reaction mixture was left stirring for 16 hours. The reaction mixture was extracted with DCM (20 mL), washed with H2O (3 x 20 mL), dried with anhydrous MgSO4. The organic layers were then filtered, concentrated in vacuo and purified by flash column chromatography (0-40% EtOAc in hexane). The pure product was afforded as a yellow solid (247 mg, 21% yield).

Compounds Synthesised for Mechanistic investigations 4-nitro-N-phenylbenzenesulfonamide (1a)
Prepared according to a literature procedure. 12 A 50 mL round-bottomed flask was charged with 4nitrobenzenesulfonyl chloride (244 mg, 1.1 mmol), which was evacuated under vacuum and filled with nitrogen. Pyridine (5 mL) was added, alongside aniline (91 µL, 1 mmol), and the reaction mixture was stirred at room temperature for 3 hours. Toluene (10 mL) was added to the reaction mixture and the solvent was evaporated in vacuo. The reaction mixture was then dissolved in DCM (20 mL), extracted from H2O (2 x 20 mL), dried with anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by flash column chromatography (10-30% EtOAc in hexane) affording the pure product as a white solid (126 mg, 45%).

2-((4-nitrophenyl)thio)aniline (11)
A 100 mL round-bottomed flask was charged with 4-fluoronitrobenzene (282 mg, 2 mmol) and K2CO3 (553 mg, 4 mmol), which was evacuated under vacuum and filled with nitrogen. Anhydrous DMF (10 mL) was added to the mixture which was stirred in a pre-warmed oil bath at 70 °C. 2aminobenzenethiol (0.207 mL, 2 mmol) was added dropwise and the mixture was left to stir at 70 °C for 1 h. The reaction mixture was dissolved in EtOAc (20 mL) and washed with 10% (w/v) aqueous LiCl (3 x 20 mL). The aqueous layer was then extracted with EtOAc (3 x 20 mL) and the combined organic layers were dried with anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by flash column chromatography (0-40% EtOAc in hexane), affording the pure product as a brown solid (456 mg, 93% yield).

2-((4-nitrophenyl)sulfinyl)aniline (10)
A 100 mL round-bottomed flask was charged with 2-((4-nitrophenyl)thio)aniline 11 (440 mg, 1.78 mmol), evacuated under vacuum and filled with nitrogen. DCM (10 mL) was added and the mixture was stirred at 0 °C. A second 100 mL round-bottomed flask was charged with Metachloroperoxybenzoic acid, 70% (m-CBPA) (230 mg, 1.9 mmol), evacuated under vacuum and filled with nitrogen. DCM (10 mL) was added and the contents of this flask were added slowly to the first flask. The reaction mixture was stirred at 0 °C for 1 h, at which point the ice bath was removed and the mixture was allowed to warm to room temperature. On consumption of starting material (monitored by TLC) the reaction was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were then dried with anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by flash column chromatography (20-60% EtOAc in hexane), affording the pure product as a yellow solid (163 mg, 35% yield).