Arylation with Unsymmetrical Diaryliodonium Salts: A Chemoselectivity Study

Phenols, anilines, and malonates have been arylated under metal-free conditions with twelve aryl(phenyl)iodonium salts in a systematic chemoselectivity study. A new “anti-ortho effect” has been identified in the arylation of malonates. Several “dummy groups” have been found that give complete chemoselectivity in the transfer of the phenyl moiety, irrespective of the nucleophile. An aryl exchange in the diaryliodonium salts has been observed under certain arylation conditions. DFT calculations have been performed to investigate the reaction mechanism and to elucidate the origins of the observed selectivities. These results are expected to facilitate the design of chiral diaryliodonium salts and the development of catalytic arylation reactions that are based on these sustainable and metal-free reagents.

Precautions to exclude air or moisture were not taken, except when mentioned. Commercial mCPBA was dried under vacuum at rt for 1 hour and subsequently the percentage of active oxidising reagent was determined by iodometric titration. [1] All other commercially available chemicals were used as supplied. For TLC analyses precoated silica gel 60 F 254 plates were used; and for column chromatography 40-60 µm, 60A silica gel was used. Melting points were measured using a STUART SMP3 and are reported uncorrected. NMR spectra were recorded using a 400 MHz Bruker AVANCE II with a BBO probe at 298 K, unless otherwise mentioned, using CDCl 3 and DMSO-d 6 as solvents. Chemical shifts are given in ppm relative to the (residual) solvent peak ( 1 H NMR: CHCl 3 δ 7.27, DMSO-d 5 δ 2.50; 13 C NMR: CDCl 3 δ 77.23, DMSO-d 6 δ 39.52) with multiplicity (br=broad, s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, app=apparent), coupling constants (in Hz) and integration. High resolution mass analyses were obtained using a Bruker microTOF ESI with a time-of-flightdetector. Combined isolated yield refers to calculated yield based on the isolated mass of the two products and their NMR integrals.

Aryl exchange study by HRMS
The aryl exchange studies were performed by setting up reactions according to the experimental protocols for arylation of 4, 5 and 6 (see the paper or Sections 5-7). A sample was taken via syringe and immediately dissolved in a mixture of MeOH and H 2 O (10 mL 1:1). This mixture was then further diluted (by a factor of 10) before analysis. The samples were taken after 5 min, 30 min and then once every hour up to ten hours unless otherwise noted.

Radical trap experiments
The radical trap experiments were performed by setting up reactions according to the experimental procedure in Sections 5-7 with the addition of a radical trap, which was added as the last reagent into the reactions. The results are given in Table S1. We have previously reported radical trap experiments with phenols and DPE. [2]  [a] Chemoselectivities were not altered.

One-pot methods
Many diaryliodonium salts are now commercially available. For convenience, we have synthesized most of the salts used in this investigation according to the one-pot methods previously developed in our group (Scheme S1). Scheme S1. Our one-pot syntheses of diaryliodonium salts. (1 equiv) Table S2. Synthesis of diaryliodonium salts 1a-1f, 1h-j and 2a.
[a] Method in Scheme S1. [b] Reference to analytical data. [c] This salt was synthesized in order to selectively prepare the minor arylation product, to confirm the product ratio analysis.

Stepwise methods
General procedure for anion exchange to triflate The diaryliodonium salt (5 mmol) was dissolved in dichloromethane (30 mL) and washed with an aqueous NaOTf solution (3 x 50 mmol). The organic layer was concentrated without drying. Et 2 O (20 mL) was added and the mixture was stirred at room temperature for 30 min to precipitate a solid. The solid was filtrated and washed with Et 2 O and dried under vacuum to give the triflate salt. The anion exchange was confirmed by NMR analysis.

Arylation of Phenol 3 to Products 4, 5
Experimental procedure: [8] To a suspension of t BuOK (1.1 equiv, 43 mg, 0.37 mmol) in THF (1.5 mL) was added phenol 3 (1.0 equiv, 0.34 mmol) at 0 °C and the reaction was left to stir at this temperature for 15 min. Diaryliodonium salt 1 or 2 (1.2 equiv, 0.40 mmol) was added in one portion and the reaction was stirred in an oil bath preheated to 40 °C until TLC indicated complete consumption of 1 or 2. The reaction was then quenched with H 2 O at 0 °C, the organic phase was separated and the water phase was extracted with CH 2 Cl 2 (3 × 10 mL). The combined organic phases were dried (Na 2 SO 4 ) and concentrated in vacuo. The crude material was purified by flash chromatography to give the diaryl ethers 4 and 5. The product ratio was determined by isolating 4 and 5 respectively. The analytical data of 4 [8] , 5a [9] and 5b-f [4] were in agreement with previous reports. Experimental procedure: [10] Diaryliodonium salt 1 or 2 (1 equiv, 0.25 mmol) was dissolved in dry DMF (2 mL). m-Anisidine (1 equiv, 0.028 mL, 0.25 mmol) was added under stirring at rt. The reaction mixture was submitted to a 130 °C oilbath and stirred for 24 h. The reaction was treated with Na 2 CO 3 (1 M, 2 mL), extracted with EtOAc (3 × 5 mL) and washed with H 2 O (1 × 10 mL) and brine (2 × 10 mL). The combined organic phases were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified with flash chromatography to give the diarylamines 7 and 8 as an inseparable mixture. The product ratio was determined by NMR from the crude mixture.

N-(3-methoxyphenyl)-aniline (7):
Synthesized according to the general protocol with salt 2e to give 7 in 70% yield as a colorless oil. Analytical data were in accordance with previously reported data. [11]

Arylations to obtain reference products
The following compounds were synthesized separately to obtain NMR data of the pure minor products, in order to confirm the NMR analysis of the crude mixtures.

Arylation with unsymmetric diaryliodonium salts 1, 2
Experimental procedure: [19] NaH (60% dispersed in mineral oil, 1.3 equiv, 0.33 mmol, 10 mg) was suspended in DMF (0.5 mL) and diethylmethylmalonate 9 (0.25 mmol, 44 mg) was added dropwise at 0 °C. The reaction was allowed to stir at rt for 10 min. A solution of diaryliodonium salt 1 or 2 (1.3 equiv, 0.33 mmol) in DMF (0.5 mL) was added via cannulation to the reaction mixure at 0 °C. The reaction mixture was stirred at rt until TLC indicated complete consumption of 9. The reaction was quenched with H 2 O at 0 °C, extracted with EtOAc (3 × 5 mL) and washed with H 2 O (1 × 10 mL) and brine (2 × 10 mL). The combined organic phases were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified with flash chromatography to give products 10 and 11 as an inseparable mixture. The product ratio was determined by NMR from the crude mixture.

Diethyl 2-methyl-2-phenylmalonate (10):
Synthesized according to the general procedure using salt 1f, giving 10 as a colorless oil in 55% yield. Analytical data was in agreement with the reported analytical data. [20] Diethyl 2-(2-methylphenyl)-2-methylmalonate (11b): Synthesized according to the general procedure using salt 1b, and isolated as a mixture of 10 and 11b. The presence of 11b was confirmed by comparing with the reported analytical data. [21] 6.2 Arylations to obtain reference products The following compounds were synthesized separately to obtain NMR data of the pure minor products, in order to confirm the NMR analysis of the crude mixtures.

Computational details
All calculations reported in the present study were carried out using density functional theory with the B3LYP functional, 25 as implemented in the Gaussian09 program package. 26 For geometry optimizations, the 6-31G(d,p) basis set was used for the C, N, O, F, Cl, H elements, and the LANL2DZ 27 pseudopotential with the corresponding basis set, augmented with d polarization and p diffuse functions, 28 for I. Based on these optimized geometries, singlepoint calculations were carried out with the same basis set for I and the 6-311+G(2d,2p) basis set for all other elements. The stationary points were confirmed as minima (no imaginary frequencies) or transition states (only one imaginary frequency) by analytical frequency calculations at the same theory level as the geometry optimizations. The reported energies are Gibbs free energies, which include zero-point vibrational corrections, thermal corrections at 298 K (or 403 K for reaction with anilines), and solvation free energies. The latter are calculated as single-point corrections on the optimized structures using the conductor-like polarizable continuum model (CPCM) 29 method with the UFF radii and with the parameters for THF or DMF, according to experiments. All energies are also corrected for dispersion effects using the B3LYP-D3 method of Grimme, 30