Transition-Metal-Free Decarboxylative Iodination: New Routes for Decarboxylative Oxidative Cross-Couplings

Constructing products of high synthetic value from inexpensive and abundant starting materials is of great importance. Aryl iodides are essential building blocks for the synthesis of functional molecules, and efficient methods for their synthesis from chemical feedstocks are highly sought after. Here we report a low-cost decarboxylative iodination that occurs simply from readily available benzoic acids and I2. The reaction is scalable and the scope and robustness of the reaction is thoroughly examined. Mechanistic studies suggest that this reaction does not proceed via a radical mechanism, which is in contrast to classical Hunsdiecker-type decarboxylative halogenations. In addition, DFT studies allow comparisons to be made between our procedure and current transition-metal-catalyzed decarboxylations. The utility of this procedure is demonstrated in its application to oxidative cross-couplings of aromatics via decarboxylative/C–H or double decarboxylative activations that use I2 as the terminal oxidant. This strategy allows the preparation of biaryls previously inaccessible via decarboxylative methods and holds other advantages over existing decarboxylative oxidative couplings, as stoichiometric transition metals are avoided.


Preparation of 4-(2-(dimethylamino)-2-oxoethoxy)benzoic acid (1q)
Adapted from the reported procedure. 5 Alkylation: Benzyl 4hydroxybenzoate (1.14 g, 5.0 mmol, 1.0 equiv), N,N-dimethyl-2chloroacetamide (0.6 mL, 5.5 mmol, 1.1 equiv) and potassium carbonate (1.00 g, 7.5 mmol, 1.5 equiv) were mixed in dry DMF (5 mL) and stirred at room S7 temperature for 16 h to afford. The reaction mixture was quenched with water and extracted with EtOAc (3 x 15 mL), the organic extracts were combined, washed with brine and dried over magnesium sulphate, the solvents were then removed in vacuo to yield benzyl 4-(2-(dimethylamino)-2-oxoethoxy)benzoate as an oily liquid. The crude product was used without further purification. Hydrogenolysis of benzyl 4-(2-(dimethylamino)-2-oxoethoxy)benzoate: A 250 mL oven dried flask was charged with the 4-(2-(dimethylamino)-2-oxoethoxy)benzoate (720.7 mg, 2.3 mmol 1.0 equiv), to it Pd/C 10%w (23 mg, 0.23 mmol, 10 mol%) and dry EtOAc (100mL) was added. The reaction mixture was flushed and stirred under of hydrogen (1 atm) for 16 h. The reaction mixture was filtered through Celite with further washings of EtOAc. The filtrate was then basified by Na2CO3 sat. and the organic layers removed. The aqueous layer was then acidified to ~pH 2 with HCl (2 M) and the product was extracted with EtOAc (3 x 15 mL) which after removal of the solvents afforded pure 4-(2-(dimethylamino)-2oxoethoxy)benzoic acid (950 mg; 85%). 1  Carboxylation: In the glove box, a vial was charged with NaH (60% dispersion in mineral oil, 240.0 mg, 6.0 mmol, 4.0 equiv) estrone (405.6 mg, 1.50 mmol, 1.0 equiv) and 2,4,6trimethylphenol (204.3 mg, 1.50 mmol, 1.0 equiv). Then anhydrous THF (6 mL) was added and the mixture stirred for 5 min at room temperature. The THF was carefully removed under vacuum and the remaining solid mixture was ground to a fine powder using a spatula before sealing and removing the vial from the glove box. The mixture was purged with CO2 and reacted under a balloon filled with CO2 at 185 °C for 16 h. After this time, the reaction mixture was cooled to room temperature, and quenched with H2O (60 mL). To the mixture was added sat. Na2CO3 (aq, 20 mL) and the aqueous phase washed with EtOAc (3  30 mL). The aqueous phase was then acidified to pH 2 with 2 M aq HCl and extracted with EtOAc (3  30 mL), dried over MgSO4, filtered and concentrated under vacuum. Methylation: To the crude mixture was added DMF (20 mL), MeI (1.87 mL, 30.0 mmol, 20.0 equiv) and Na2CO3 (1.59 g, 15.0 mmol, 10.0 equiv). The mixture was heated at 100 o C for 48 h. After this time, the reaction was cooled to room temperature and H2O (60 mL) was added and the mixture extracted with EtOAc (3  30 mL). The organic phases were combined then washed with brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum. Hydrolyisis of ester: The crude mixture was dissolved in ethanol (6.0 mL), and aqueous NaOH (2 M, 2.0 mL) was added. The mixture was stirred at room temperature for 16 h. After this time, sat. Na2CO3 (aq, 20 mL) was added and the aqueous phase washed with EtOAc (3  30 mL). The aqueous phase was then acidified to pH 2 with 2 M aq HCl and extracted with EtOAc (3  30 mL), dried over MgSO4, filtered and concentrated under vacuum to provide the desired product as a white solid (226.6 mg, 46%).

Preparation of 1-tosyl-1H-indole-3-carboxylic acid (1al)
Following the reported procedure, 6 to a cooled solution (-78 o C) of 1H-indole-3-carboxylic acid (1.50 g, 9.30 mmol, 1.0 equiv) in THF (60.0 mL) was added dropwise n-BuLi (1.5 M in hexane, 14.0 mL, 22.0 mmol, 2.3 equiv.). The reaction mixture was stirred at -78 o C for 3 h then a solution of tosyl chloride (4.20 g, 22.00 mmol, 2.3 equiv) in THF (40.0 mL) was added dropwise. The reaction was allowed to warm to room temperature over 12 h. The reaction was quenched with 5% aqueous NaHSO4 (100.0 mL) and extracted with EtOAc. Concentration of the combined organic phases gave a deep purple solid. The solid was filtered and washed with cold EtOAc to provide the desired product as a white solid (1.47 g, 50%).
Spectroscopic data matched those previously reported.

Optimisation of the Decarboxylative Iodination
The general procedure A was applied with I2 (152.3 mg, 0.60 mmol, 3.0 equiv), 2methoxybenzoic acid (30.4 mg, 0.20 mmol, 1.0 equiv) and the appropriate base (equivalents given in Table S1) at 100 o C for 4 h. On completion of the reaction, the mixture was cooled to room temperature then 15% Na2S2O8 (aq, 2.0 mL), 2 M aq HCl (0.5 mL), CDCl3 (1.0 mL) and CH2Br2 (2.8 µL, 0.04 mmol, 0.2 equiv) were added. An aliquot of the organic layer was filtered through a short plug of MgSO4 directly into an NMR tube for analysis.

4-iodoanisole (2b)
The general procedure A was applied with 4-methoxybenzoic acid (76.1 mg, 0.50 mmol, 1.0 equiv) at 100 o C for 2 h. The general work-up procedure was applied then the mixture was dissolved in pentane/EtOAc (5.0 mL, 98:2) and filtered through a short plug of silica with further washings of pentane/EtOAc (4 × 10 mL, 98:2). Removal of the solvent in vacuo gave the desired product as a white solid (108.8 mg, 93%).
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported. 11 S12
Spectroscopic data matched those previously reported. 12
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.

Pentafluoroiodobenzene (2ac)
The general procedure A was applied with pentafluorobenzoic acid (106.0 mg, 0.50 mmol, 1.0 equiv) at 100 o C for 16 h. Then 15% aq. Na2S2O8 (2.0 mL), CDCl3 (1.0 mL) and fluorobenzene (46.9 µL, 0.50 mmol, 1.0 equiv) were added. An aliquot (200 µL) of the organic layer was passed through a plug of MgSO4 directly into an NMR tube and diluted with CDCl3 (400 µL) for quantitative 19 F NMR analysis to yield the crude product (>99%). Due to the volatility of pentafluoroiodobenzene 2ac, this product could not be isolated with a yield comparable to the 19 F NMR yield.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported. 31 1
Spectroscopic data matched those previously reported.

3-iodo-2-methoxypyridine (2ax)
The general procedure A was applied with 2-methoxynicotinic acid (76.5 mg, 0.50 mmol, 1.0 equiv) at 100 o C for 9 h. The general work-up procedure was followed then the mixture was dissolved in pentane/EtOAc (5.0 mL, 98:2) and filtered through a short plug of silica with further washings of pentane/EtOAc (4 x 10.0 mL, 98:2). Removal of the solvent in vacuo gave the desired product as a colourless oil (72.8. mg, 62%).
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.
Spectroscopic data matched those previously reported.

Entries 2, 25, 27 and 30
In these cases, the additive was not transferred quantitatively using the standard work-up procedure, therefore, this experiment was run in duplicate. The first experiment followed the standard work-up procedure in order to determine the yield of product and recovery of starting material. The second experiment used an alternative work-up procedure in order to determine the recovery of the additive: On completion of the reaction, the mixture was cooled to room temperature and H2O (0.5 mL), EtOAc (4.0 mL) and mesitylene (28 µL, 0.20 mmol, 1.0 equiv) were added. An aliquot of the organic layer (0.4 mL) was diluted with EtOAc (2.0 mL) and transferred to a GCMS vial for analysis.
Reactions carried out at a 0.2 mmol scale of 1a. Yields and recoveries determined by crude GC-FID analysis. a Alternative work-up procedure followed. b 1,3-dinitrobenzene used as standard.

Procedure for Multi-Gram Scale Synthesis of 2-Iodo-1,3-dimethoxybenzene (2f)
In a glove box, a flame-dried 1 L pear-shaped flask was charged with 2,6-dimethoxybenzoic acid (10.0 g, 55.0 mmol, 1.0 equiv), anhydrous K3PO4 (11.7 g, 55.0 mmol, 1.0 equiv) and anhydrous MeCN (275 mL, 0.2 M). Outside the glove box, a 100 mL flame-dried roundbottomed flask was charged with I2 (55.8 g, 220.0 mmol, 4.0 equiv) and transferred to the glove box. The I2 was then added to the mixture in the pear-shaped flask ( Figure S1). The mixture was stoppered, transferred out of the glove box and stirred at 23 o C for 2 h under a nitrogen balloon ( Figure S2). After this time H2O (800 mL) was added and the reaction triturated with Na2S2O8 (60.0 g). The mixture was transferred to a 2 L separating funnel and sat. Na2CO3 (aq, 200 mL) and pentane (500 mL) were added. The organic layer was collected and the aqueous layer was further washed with pentane (3 x 200 mL). The organic fractions were dried with MgSO4 (60.0 g) and concentrated in vacuo to yield the desired product as a white solid (14.1 g, 97%, Figure S3).

Computational Methods
All the calculations were performed at the DFT level with Gaussian 09, revision B.01. 41 All optimisations and single point calculations were performed using the B97D3 functional 42 with the LanL2DZ 43 basis set and ECPs for I atom and 6-31G(d) for all other atoms (C, H, and O). 44 Stationary points were characterized as minima or saddle points by frequencies analysis using an acetonitrile solvent correction. Representative transition states were confirmed to correspond to the desired step by optimization through the intrinsic reaction coordinate (IRC) to starting materials and products. 45 Dispersion corrections where calculated from single point calculations at the optimized geometries using an acetonitrile solvent correction. Gibbs free energies were evaluated at 298 K and 1 atm.    IV(B)). The results showed that 2-methoxybenzoic acid has a lower barrier to decarboxylation, consistent with a higher reactivity of this substrate under our standard conditions. The ortho-substituted hypoiodite I(A) is higher in energy than the non-orthosubstituted analogue I(B) by 4.5 kcal mol -1 and the ortho-substituted transition state is higher in energy than the non-ortho-substituted one by 3.6 kcal mol -1 . It is likely that the difference in energy between the ortho-and non-ortho-substituted species is due to steric destabilization.
This shows that if an ortho-effect, similar to that observed in transition metal-catalysed decarboxylations, is present in our system, it is of much less significance.
Scheme S4. Energies measured in kcal mol -1 for DFT modelling using an acetonitrile solvent correction.