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. 2017 Aug 23;139(33):11527-11536.
doi: 10.1021/jacs.7b05155. Epub 2017 Aug 8.

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

Gregory J P Perry  1 , Jacob M Quibell  1 , Adyasha Panigrahi  1 , Igor Larrosa  1
Affiliations

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

Gregory J P Perry et al. J Am Chem Soc. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Comparison of Traditional Cross-Couplings, Decarboxylative Oxidative Couplings, and This Report
Scheme 2
Scheme 2. Current Status of the Aromatic Hunsdiecker Reaction
Scheme 3
Scheme 3. Scope of the Decarboxylative Iodination of Benzoic Acids
Reactions carried out at a 0.5 mmol scale of 1. Ratios in brackets indicate mono-:diiodinated material by crude GC-FID analysis. Asterisk indicates position of diiodination. I2 (3.0 equiv). NMR yield for reactions employing I2 (1.0–2.0 equiv), 170 °C and 1,4-dioxane or o-DCB as solvent. I2 (6.0 equiv), 140 °C. I2 (2.0 equiv). MeCN (5.0 mL). I2 (3.0 equiv), 1,4-dioxane (1.0 M), 170 °C. Yields determined by quantitative 19F NMR. I2 (2.5 equiv).
Scheme 4
Scheme 4. Scope of the Decarboxylative Iodination of Heterobenzoic Acids
Reactions carried out at a 0.5 mmol scale of 1. Ratios in brackets indicate mono-:diiodinated material by crude GC-FID analysis. Asterisk indicates position of diiodination. I2 (2.0 equiv). NMR yield for reactions employing I2 (1.0–2.0 equiv), 170 °C and 1,4-dioxane or o-DCB as solvent. MeCN (5.0 mL). I2 (6.0 equiv).
Scheme 5
Scheme 5. Multi-Gram-Scale Synthesis of 1-Iodo-2,6-dimethoxybenzene 2f
Scheme 6
Scheme 6. Possible Pathways for the Decarboxylative Iodination of Aromatic Acids
Pathway A: radical decarboxylation–radical recombination pathway. Pathway B: concerted decarboxylation–iodination pathway. Structures and energies calculated by DFT (B97D3/LanL2DZ for I, 6-31G(d) for other atoms); Gibbs free energies (G) are in kcal mol–1. Total energy for 2a + CO2.
Scheme 7
Scheme 7. Radical Clock Experiment with Benzoic Acid 1A
Scheme 8
Scheme 8. Comparing the Ortho Effect of Transition-Metal-Mediated Decarboxylations and Transition-Metal-Free Decarboxylative Iodination
(i) Investigating the ortho effect in the transition-metal-free decarboxylative iodination. Energies measured in kcal mol–1 for DFT modeling using an acetonitrile solvent correction. Structures and energies calculated by DFT (LanL2DZ for I, 6-31G(d) for other atoms); Gibbs free energies (G) are in kcal mol–1. (ii) The ortho effect in palladium-catalyzed decarboxylations as reported by Su et al. (iii) The ortho effect in silver-catalyzed decarboxylations as reported by Su et al.
Figure 1
Figure 1
Hammett plot of the decarboxylative iodination. Equation of fit: y = −4.59x + 0.09. R2= 0.92. Position (meta/para) of substituent is with respect to the carboxyl group.
Scheme 9
Scheme 9. Scope of the Decarboxylative Oxidative Cross-Coupling between Benzoic Acids and Arenes
Reactions carried out at a 0.5 mmol scale of 4. All three steps are conducted between 150 and 190 °C. K3PO4 (6.5–8.0 equiv) total across three steps. Ratios in brackets indicate ratio of regioisomeric products by crude GC-FID analysis. Asterisk indicates position of minor regioisomer.
Scheme 10
Scheme 10. Scope of the Double Decarboxylative Oxidative Cross-Coupling between Two Benzoic Acids
Reactions carried out at a 0.5 mmol scale of 6. K3PO4 (5.5–6.5 equiv) total across three steps. The potassium salt of 7 was used in this case. Yield determined by quantitative 19F NMR. Step 3: no CuI/Phen added, PdCl2/BINAP (9 mol%), Ag2CO3 (3.20 equiv). The potassium salt of 6 was used in this case.
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