Selective C–H Iodination of (Hetero)arenes

Iodoarenes are versatile intermediates and common synthetic targets in organic synthesis. Here, we present a strategy for selective C–H iodination of (hetero)arenes with a broad functional group tolerance. We demonstrate the utility and differentiation to other iodination methods of supposed sulfonyl hypoiodites for a set of carboarenes and heteroarenes.


MATERIALS AND METHODS
All reactions were carried out under an ambient atmosphere unless otherwise stated and monitored by thinlayer chromatography (TLC). Concentration under reduced pressure was performed by rotary evaporation at 25-40 °C at an appropriate pressure. Purified compounds were further dried under high vacuum (0.008-0.5 Torr). Yields refer to purified and spectroscopically pure compounds.

Solvents
Dichloromethane was purchased from Sigma-Aldrich and used as received. Acetonitrile was purchased from fisher scientific and used as received. All deuterated solvents were purchased from Euriso-Top.

Chromatography
Thin layer chromatography (TLC) was performed using EMD TLC plates pre-coated with 250 m thickness silica gel 60 F254 plates and visualized by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (40-63 m particle size) purchased from Geduran®. Preparatory high-performance liquid chromatographic separation was executed on a Shimadzu Prominence Preparative HPLC system.

Spectroscopy and Instruments
NMR spectra were recorded on a Bruker Ascend TM 500 spectrometer operating at 500 MHz, 125 MHz, and

Starting materials
All substrates were used as received from commercial suppliers, unless otherwise stated.

General procedure for C-H iodination of (hetero)arenes
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with arene (0.200 mmol, 1.00 equiv), molecular iodine (50.8 mg, 0.200 mmol, 1.00 equiv), Ag (I) salt (0.200 mmol, 1.00 equiv), and MeCN (1.0 mL, c = 0.20 M). Subsequently, the vial was capped, and the reaction mixture was stirred at 23 °C for 24 h. The reaction mixture was diluted with EtOAc (5 mL), and the resulting mixture was filtered through a short pad of silica gel using EtOAc (5 mL) as eluent. The filtrate was collected and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel to afford iodinated product.
The filtrate was collected and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel eluting with a solvent mixture of ethyl acetate:pentane (5:95 (v:v)) to afford 42 mg of 2 as a colorless solid (80% yield).

4-Iodoanisole (4)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with

4-Iodoacetanilide (6)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with

4-Iodofluorobenzene (7)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with

4-Iodonitrobenzene (8)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with SUPPORTING INFORMATION S10 molecular iodine (51.0 mg, 0.200 mmol, 1.00 equiv), AgOTf (51.0 mg, 0.200 mmol, 1.00 equiv), nitrobenzene (S8) (20.5 µL, 24.7 mg, 0.200 mmol, 1.00 equiv), and DCM (1.0 mL, c = 0.20 M). The vial was capped, and the reaction mixture was stirred at 23 °C for 24 h. The reaction mixture was diluted with EtOAc (5 mL), and the resulting mixture was filtered through a short pad of silica gel using EtOAc (5 mL) as eluent. The filtrate was collected and concentrated by rotary evaporation. No evidence of product was observed in 1 H NMR.

4-Iodoaniline (9)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with

3-Iodoazaindazole (12)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with
The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over

Iodinated-coumarin1 (19)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with

Gram-scale synthesis: Iodinated-coumarin1 (19)
Under an ambient atmosphere, a 50 mL round-bottom flask with a magnetic stir bar was charged with molecular iodine (1.09 g, 4.32 mmol, 1.00 equiv), AgOMs (0.880 g, 4.32 mmol, 1.00 equiv), coumarin1 (S19) (1.00 g, 4.32 SUPPORTING INFORMATION S18 mmol, 1.00 equiv), and K2CO3 (0.600 g, 4.32 mmol, 1.00 equiv), and MeCN (21.6 mL, c = 0.200 M). The round bottom flask was capped with a rubber septum, and the reaction mixture was stirred at 23° C for 24 h. The reaction mixture was diluted with EtOAc (20 mL), and the resulting mixture was filtered through a short pad of silica gel using EtOAc (20 mL) as eluent. The filtrate was transferred to a separatory funnel and 1N HCl (20 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure to afford 1.4 g of 19 as a pale brown solid (90% yield).

Iodinated-procymidone (20)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with molecular iodine (61.0 mg, 0.240 mmol, 1.20 equiv), AgOTf (62.0 mg, 0.240 mmol, 1.20 equiv), procymidone (S20) (57.80 mg, 0.200 mmol, 1.00 equiv), and DCM (1.0 mL, c = 0.20 M). The vial was capped, and the reaction mixture was stirred at 23 °C for 24 h. The reaction mixture was diluted with EtOAc (5 mL), and the resulting mixture was filtered through a short pad of silica gel using EtOAc (5 mL) as eluent. H2O (10 mL) was added and the resulting mixture was transferred to a separation funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent mixture of ethyl acetate:pentane (10:90 (v:v)) to afford 51 mg of 20 as a colorless liquid (82% yield).

S20
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with molecular iodine (66.0 mg, 0.260 mmol, 1.00 equiv), AgOTs (67.0 mg, 0.260 mmol, 1.00 equiv), diclofenac (S22) (59.0 mg, 0.200 mmol, 1.00 equiv), and CH3CN (1.0 mL, c = 0.20 M). The vial was capped, and the reaction mixture was stirred at 23 °C for 24 h. The reaction mixture was diluted with EtOAc (10 mL), and the resulting mixture was filtered through a short pad of silica gel using EtOAc (10 mL) as eluent. The residue was purified by column chromatography on silica gel eluting with a solvent mixture of ethyl acetate:pentane (30:70 (v:v)) to afford 101 mg of 22 as a pale yellow solid (96% yield).
Rf (ethyl acetate:pentane, 40:60 (v:v)) = 0.56. was diluted with EtOAc (5 mL), and the resulting mixture was filtered through a short pad of silica gel using EtOAc (5 mL) as eluent. The filtrate was transferred to a separatory funnel and 1N HCl (5 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure to afford 79 mg of 23 as a colorless solid (99% yield).

Iodinated-fenobirinacid (24)
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with molecular iodine (51.0 mg, 0.200 mmol, 1.00 equiv), AgOTf (51.0 mg, 0.200 mmol, 1.00 equiv), fenobirinacid (24) (63.7 mg, 0.200 mmol, 1.00 equiv), and DCM (1.0 mL, c = 0.20 M). The vial was capped, and the reaction mixture was stirred at 23 °C for 24 h. The reaction mixture was diluted with EtOAc (5 mL), and the resulting mixture was filtered through a short pad of silica gel using EtOAc (5 mL) as eluent. H2O (10 mL) was added and the resulting mixture was transferred to a separation funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent mixture of ethyl acetate:pentane (30:70 (v:v)) to afford 61 mg of 24 as a colorless solid (98% yield).

Formation of acetyl hypoiodite
Under an ambient atmosphere, a 4 mL borosilicate vial equipped with magnetic stir bar was charged with molecular iodine (25.0 mg, 0.100 mmol, 1.00 equiv), AgOAc (16.7 mg, 0.100 mmol, 1.00 equiv), and CD3CN (0.5 mL, c = 0.20 M). The vial was capped, and the reaction mixture was stirred at 23 °C for 10 minutes. The reaction mixture was then filtered through a short pad of silica gel using CD3CN (0.5 mL) as eluent. The filtrate was collected directly in the NMR tube.

Comparison to NIS method
In comparison to modern C-H iodination methods, that use NIS as an iodinating reagent; our method is applicable to a broader electronic scope of aromatic (hetero) arenes and avoids double iodination (Table S1)

Electrochemical data Cyclic Voltammograms
Cyclic voltammograms were recorded using an Autolab PGSTAT204 potentiostat and a Pt working electrode, a Ag/AgCl reference electrode and a Pt sheet auxiliary electrode. The voltammograms were recorded at a Ag/AgCl reference electrode and a Pt sheet auxiliary electrode. The voltammograms were recorded at room temperature in 0.1 M tetrabutylammonium hexafluorophosphate in MeCN (3 mL) containing Ag(I) salts and molecular iodine (I2). AgI was filtered off before measuring the redox potentional of the corresponding hypoiodites. The scan rate was 100 mV s-1. Figure S2. Cyclic voltammetry of hypoiodites in MeCN.

S25
Note: CV of AgOTf and I2 was measured in DCM.