Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce–Smiles Rearrangement

Abstract A new benzyne transformation is described that affords versatile biaryl structures without recourse to transition‐metal catalysis or stoichiometric amounts of organometallic building blocks. Aryl sulfonamides add to benzyne upon fluoride activation, and then undergo an aryl Truce–Smiles rearrangement to afford biaryls with sulfur dioxide extrusion. The reaction proceeds under simple reaction conditions and has excellent scope for the synthesis of sterically hindered atropisomeric biaryl amines.


General Information:
Nuclear Magnetic Resonance (NMR) spectra were recorded on 500 or 400 MHz Bruker NMR spectrometers in CDCl 3 at 298 K (unless stated otherwise). All chemical shift values are reported in parts per million (ppm) with coupling constant (J) values reported in Hz. All spectra were referenced to CDCl 3 the residual solvent peak CHCl 3 (δ = 7.26 ppm) for 1H NMR and the CDCl 3 solvent peak (δ = 77.16 ppm) for 13 C{ 1 H} NMR. The notation of signals is: Proton: δ chemical shift in ppm (number of protons, multiplicity, J value(s), proton assignment). Carbon: δ chemical shift in ppm (carbon assignment). Fluorine: δ chemical shift in ppm (Fluorine assignment). Splitting patterns are assigned s = singlet, b = broad, d = doublet, td = triplet of doublet, dt = doublet of triplet, t = triplet, q = quartet.
Low resolution mass spectrometry was performed on an Agilent 6100 mass spectrometer (ES ionisation) and Hewlett Packard 5971 MSD (GC/MS with EI). High resolution mass spectrometry was performed on a Waters QTOF with ESI/APCI ionisation and a Thermo Finnigan MAT95XP (EI). Chiral stationary phase HPLC was performed using an Aglient 1200 Series HPLC with a Chirapak IB 4.6 × 250 mm column and eluted with 1% isopropyl alcohol and 99% hexane at a rate of 1mL/min with absorbance reported at 254 nm.
Melting points were determined using a Kofler hot-stage apparatus or Stuart Scientific SMP10 apparatus and are uncorrected. Thin layer chromatography (TLC) was performed using pre-coated Merck 60F254 silica plates. Visualization was performed using UV light (285 nm) and treatment with acidic potassium permanganate. Flash chromatography was performed using silica gel (Sigma Aldrich, 40-63 μ, 60 Å) and a Biotage ® Isoleara TM equipped with 10 g or 25 g Biotage ® SNAP Ultra cartridges.
Tetrahydrofuran (THF) was distilled over sodium wire and benzophenone. CH 2 Cl 2 and toluene and distilled over calcium hydride. Diethyl ether was dried using a solvent purification system. All other solvents and reagents were purchased from commercial sources and used as supplied. S5

Synthesis of Sulfonamide Starting Materials
General procedure A for synthesis of N-aryl sulfonamides N-Aryl sulfonamides were synthesised according to the following modified literature procedure. [1] The sulfonyl chloride (1 eq.) was dissolved in ethanol (0.5 M) and the respective aniline (2 eq.) was added. The reaction mixture was stirred and monitored by TLC analysis (1:3 v/v EtOAc:hexane). Upon completion the reaction mixture was acidified with HCl (1 M) and stirred at 0 °C for 5 minutes and then was then diluted with EtOAc and water. The aqueous phase was washed twice with EtOAc, and the combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude reaction mixture was then purified by column chromatography.

General procedure B for synthesis of N-aryl sulfonamides
N-Aryl sulfonamides were prepared by following the literature procedure. [2] A solution of sulfonyl chloride (1.0 mmol) in dry CH 2 Cl 2 (15 mL) was added over 15 min to a solution of amine (1.1 mmol) and pyridine (1.1 mmol) in dry CH 2 Cl 2 (15 mL). The reaction was stirred at ambient temperature for 2 -3 hours and the progress of the reaction was monitored by TLC (1:3 v/v EtOAc:hexane). Upon completion the reaction mixture was acidified with HCl (1 M, pH 2), the aqueous phase was separated and extracted with CH 2 Cl 2 (2 × 10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and evaporated to dryness to give sulfonamide as a crystalline solid. The crude material was purified by column chromatography.
General procedure C for the synthesis of N-alkyl sulfonamides N-Alkyl sulfonamides were synthesised according to modified literature procedures. [3] The sulfonyl chloride (1 mmol, 1 eq.) was dissolved in THF (0.2 M) and appropriate amine (3 eq.) was added to the reaction mixture. The reaction was stirred for 30 minutes at ambient temperature until completion was indicated by TLC (1:3 v/v EtOAc:hexane). The reaction mixture as acidified with 1 M HCl (pH 2) at 0 °C, then diluted with EtOAc and water. The aqueous phase was washed twice with EtOAc and the combined organics were washed with saturated brine and dried over magnesium sulfate, filtered and concentrated under vacuum.

Compound 1d
Conc. HCI (4 mL) was added to a solution of 2-chloro-4-nitroaniline (2.10 g, 12.1 mmol) in TFA (40 mL). The mixture was cooled to 0 °C and then a solution of sodium nitrite (1.06 g, 15.4 mmol) in water (3 mL) was added over a 20 minute period maintaining the temperature at 0°C. After 20 minutes the reaction mixture was poured into a solution of CuCl (80 mg), CuCl 2 (0.826 g, 6.2 mmol) and H 2 SO 3 (40 ml) in acetic acid (40 mL) and kept at 0°C. After the initial effervescence subsided, the reaction mixture was allowed to sit at room temperature. After 30 minutes, the reaction mixture was diluted with 200 mL of water and extracted with hexane (2 × 100 mL). The combined organics were evaporated under vacuum to give the crude sulfonyl chloride as an amber oil (1.75 g). The sulfonyl chloride was used directly in the next step without further purification.

Compound 1u
N-Phenylbenzo[d]thiazole-2-sulfonamide 1u was synthesised according to modified literature procedure. [12] A stirred suspension of 2-mercaptobenzothiazole (2.0 g, 12 mmol, 1 eq.) in HCl (1M, 30 mL) and CH 2 Cl 2 (0.2 M, 60 mL) was cooled in a salt ice bath and sodium hypochlorite (~10%, 36 mL, 0.36 mmol, 0.03 eq.) was slowly added. The solution continued to be stirred for 1 hour. The reaction mixture was then separated in a pre-cooled separating funnel, and the aqueous layer was extracted with cold CH 2 Cl 2 (10 mL). The organic layers were quickly washed with cold NaHCO 3 and saturated brine, and dried over MgSO 4 for 30 minutes at -78 °C under a nitrogen atmosphere, then filtered and concentrated under vacuum.

General Procedures for Synthesis of Biaryls General Procedure D
The sulfonamide (1 eq.), potassium fluoride (3 eq.) and 18-crown-6 (3 eq.) were measured into a microwave vial and then THF (0.1M) and the aryne precursor (1 eq.) were added. The vial was sealed with a cap and the solution was then stirred at reflux for 24 hours. The reaction was then cooled, and then diluted with ethyl acetate and water. The aqueous phase was separated and extracted twice with ethyl acetate. The combined organic were washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated under vacuum. The crude product was then purified using column chromatography (SiO 2 gel, 0:1 to 1:9 v/v EtOAc:hexanes) to afford the title compound.