IrIII‐Catalyzed Selective ortho‐Monoiodination of Benzoic Acids with Unbiased C−H Bonds

Abstract An iridium‐catalyzed selective ortho‐monoiodination of benzoic acids with two equivalent C−H bonds is presented. A wide range of electron‐rich and electron‐poor substrates undergo the reaction under mild conditions, with >20:1 mono/di selectivity. Importantly, the C−H iodination occurs selectively ortho to the carboxylic acid moiety in substrates bearing competing coordinating directing groups. The reaction is performed at room temperature and no inert atmosphere or exclusion of moisture is required. Mechanistic investigations revealed a substrate‐dependent reversible C−H activation/protodemetalation step, a substrate‐dependent turnover‐limiting step, and the crucial role of the AgI additive in the deactivation of the iodination product towards further reaction.


Optimization Studies Initial Screening
General conditions 1: Potassium benzoate (1aK-salt, 40.1 mg, 0.25 mmol) was dissolved in 1,1,1,3,3,3hexafluoro-2-propanol (HFIP, 2.5 mL, 0.1 M). In a separate screw capped vial [Cp*Ir(H₂O)₃]SO₄ (3.5 mg, 7.5 µmol, 3 mol%), AgOAc, I2 and additive were added. The substrate (1aK-salt) solution was added to this mixture with a pasteur pipette, the vial closed and covered with aluminum foil, and the mixture stirred vigorously at room temperature (23 °C) under air atmosphere. After the given reaction time, 0.5 mL of the reaction mixture was added to a mixture of saturated aqueous Na2S2O3 solution (0.5 mL), aqueous HCl (1.5 mL, 1 M) and CH₂Cl₂ (2 mL). The organic phase was separated, and the aqueous phase extracted with CH₂Cl₂ (2 x 1.5 mL). The combined organic phases were concentrated, and the residue dissolved in CD3OD (0.5 mL). Screening details and entries shown in Table S1. , AgOAc and I2 were added. The solution/suspension of the benzoate salt was added to this mixture, the vial closed and covered with aluminum foil, and the mixture stirred vigorously at room temperature (23 °C) under air atmosphere. After the given reaction time, 0.5 mL of the reaction mixture was added to a mixture of saturated aqueous Na2S2O3 solution (0.5 mL), aqueous HCl (1.5 mL, 1 M) and CH₂Cl₂ (2 mL). The organic phase was separated, and the aqueous phase extracted with CH₂Cl₂ (2 x 1.5 mL). The organic phase was separated, and the aqueous phase extracted with CH₂Cl₂ (2x1 mL). The combined organic phases were concentrated, and the residue dissolved in CD3OD (0.5 mL). The product distribution and conversion were determined by 1 H NMR. Screening details and entries shown in Table S2.

Solvent Screening
Screening conducted according to General conditions 1, alternative solvents used. Screening details and entries shown in Table S3.

Silver source screening
Screening conducted according to General conditions 1, alternative silver sources used. Screening details and entries shown in Table S4.  Figure S1). Figure S1. Dependence of conversion to 2a and 2a' on AgOAc loading. An overall increase in conversion was observed with AgOAc loading from 0.56 to 1.46 equiv, albeit with decreasing selectivity for 2a. Selectivity was restored with 1.66 equiv AgOAc, albeit with lower conversion. Further increasing AgOAc loading led to improved conversion and high selectivity for 2a.  solution was added to this mixture, the vial covered with aluminum foil, and the mixture stirred vigorously at room temperature (23 °C) under air atmosphere. After the given reaction time, 0.5 mL of the reaction mixture was added to a mixture of saturated aqueous Na2S2O3 solution (0.5 mL), aqueous HCl (1.5 mL, 1 M) and CH₂Cl₂ (2 mL). The organic phase was separated, and the aqueous phase extracted with CH₂Cl₂ (2 x 1.5 mL). The combined organic phases were concentrated, and the residue dissolved in CD3OD (0.5 mL). The product distribution and conversion were determined by 1 H NMR. Screening details and entries shown in Table S6. General procedure for the ortho monoiodination of benzoic acids (1) Note: I2 was ground to a fine powder prior to use.

para-Substituent effect
Conditions identical to ortho-Substituent effect study. Deuterium incorporation determined by 1 H NMR (Table S8). Percentage of mono-and dideuteration established by ion count from direct injection HRMS (adjusted to 13 C content, Table S8).

Deuterium incorporation: site selectivity
The site selectivity for the ortho-deuteration was confirmed for selected substrates by comparing 1 H and 2 H NMR spectra. In all representative cases complete selectivity for ortho-deuteration was observed, with no deuterium incorporation to other sp 2 and sp 3 C-H bonds. The samples investigated were from the deuterium incorporation study presented above. In Figure S2, Entry 1a (Table S7), 2b (Table S8)    and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (4 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in DCM and applied on a silica plug (2.0 g). The plug was washed with heptane/EtOAc (1:1, 2% AcOH, 30 mL). The organic phase was concentrated under reduced pressure. The residue was dissolved in CD3OD (3 mL). Deuterium incorporation to the ortho position was established by 1 H NMR (Table S9).
Significant increase in deuterium incorporation was observed with KOAc as the acetate source compared to AgOAc. We propose the formation of an Ag I complex of 2a, which supresses further C-H activation and thus protodemetalation and deuterium incorporation.

Iridacycle Ic-3 as precatalyst
The iridacycle Ic-3 was prepared according to published procedure. 2 Benzoic acid (1a, 61.1 mg, 0.5 mmol) was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, 5.0 mL, 0.1 M), followed by addition of Et₃N (69.7 µL, 0.5 mmol). In a separate vial Ic-3 (8.1 mg, 3 mol%) and AgOAc (309 mg, 1.85 mmol) were added. The benzoic acid (1a) solution was added, followed by addition of I2 (279 mg, 1.1 mmol), and the reaction vessel covered with aluminum foil and the mixture was stirred vigorously at room temperature (23 °C) for 18 hours. After this Na2SO3 (600 mg) and water (5 mL) were added and the mixture shaked. The mixture was then partitioned between aqueous HCl (1.0 M, 50 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (4 x 40 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in CH₂Cl₂ and applied on a silica plug (10 g). The plug was washed with heptane/EtOAc (1:1, 2% AcOH, 100 mL). The organic phase was concentrated under reduced pressure. The residue was redisolved in CD3OD (3 mL) and 1,1,2,2-tetrachloroethane (52.8 µL, 0.5 mmol) was added as internal standard. NMR yield 76%. 2-toluic acid generated from Ic-3 observed by NMR.   Figure S4. Iodination of 1a-D5, initial rate kinetic profile The measured kH/kD = 2.19. Based on the kH/kD value, together with the observation of deuterium incorporation for this substrate from previous experiments (Table S8) C-H bond cleavage to take part in the turnover-limiting step together with the subsequent oxidative addition step for this substrate.  Table S10, plotted in Figure S7. For the 4-substituted substrates the results are shown in Table S11, plotted in Figure S8.  In an HMBC NMR experiment the disappearance of the carboxylate carbon cross-peak was observed in experiment 2 (Table S12, Entry 3, visualised in Figure S10). The cross-peak was detected when HMBC was recorded at 50 °C (Entry 4, visualised in Figure S10). Furthermore, the NMR shift differed from both standards (Entries 1 and 2), indicating an interaction of the benzoate. Results shown in Table S12, spectral overlaps in Figure S9.  Figure S10. HMBC experiment of the reaction mixture e2. Up: Entry 3 -no cross-peak. Entry 4 -crosspeak observed at elevated temperature.
In a competition experiment with equimolar 2-iodobenzoic acid 2a only the disappearance of the benzoic acid 1a carboxylate cross-peak was observed ( Figure S11). Figure S11. Resting state competition experiment. 2a cross-peak remains visible, while 1a cross-peak is missing, suggesting incorporation in the resting state In combination, these point to a resting state with benzoic acid bound complex such as 3a, where L is possibly an oxygen from a μ2 bound acetate as reported by Ison. [[14]] Figure S12. Ortho substituent effect on iodination rate From the obtained results an ortho-substituent steric effect was apparent, reaction rates decreasing as substituent size was increased ( Figure S12). A ratio kH/kMe = 4.00 was measured.