Carboxylic acid as a traceless directing group for palladium-catalyzed proaromatic C(alkenyl) – H arylation

A Pd-catalyzed tandem decarboxylative C – H arylation/rearomatization of proaromatic acids with aryl iodides is reported. This method using carboxylic acid as a traceless directing group for proaromatic C(alkenyl) – H arylation followed by a decarboxylative rearomatization in the presence of Pd/Ag bimetallic system, allowing preparation of 2-alkylated biaryls. Additionally, experimental results suggest that the carboxylic acid functional group is crucial for the reaction outcome


Introduction
Carbon-hydrogen bond is the most abundant and chemically inert covalent bond which is ubiquitous in all organic compounds.5][6] In general, site-selective C−H activation can be realized by conducting with an exogenous directing group which can guide the metal to the selected position allowing formation of an energetically favored metallocycle intermediate.Using directing group strategy, these reactions can deliver site-selective C−H functionalization products in a predictable fashion.Many directing groups have been used for direct C−H functionalization with remarkable results. 7However, certain directing groups needed several steps in prefabrication and remove it after functionalization.
][10][11][12] In addition, carboxylic acid groups can also serve as traceless directing groups. 13In 2007, Daugulis disclosed the first case of using carboxylic acid as a traceless directing group for C−H functionalizations. 14Later on, Gooßen's group further demonstrated this traceless directing group strategy by two step reaction sequences of palladium-catalysed ortho C−H bond arylation of benzoic acids followed by copper-catalysed protodecarboxylation for preparation of biaryls (Scheme 1a). 15A protocol for the one-pot C−H arylation/decarboxylation of benzoic acids was reported by Larrosa and coworkers in which ortho-substituted benzoic acids reacted with aryl iodides in the presence of a Pd/Ag bimetallic catalytic system in acetic acid solvent (Scheme 1b). 16Previously, we have reported a carboxylatedirected Pd-catalyzed C(alkenyl)−H olefination of proaromatic acids with alkenes followed by tandem decarboxylative rearomatization, resulting in generation of ortho-alkylated vinylarenes (Scheme 1c). 9 We envisioned that the aformentioned approach could be extented to arylation.Herein, we report a method using carboxylic acid as a traceless directing group for proaromatic C(alkenyl)-H arylation with aryl iodides followed by a decarboxylative rearomatization in the presence of Pd/Ag bimetallic system, allowing the synthesis of 2alkylated biaryls.(Scheme 1d).

Scheme 3. Control experiment.
Scheme 4. Proposed mechanism for the Pd-catalyzed proaromatic C(alkenyl)-H arylation using carboxylic acid as a traceless directing group.
On the basis of our experiment results, a plausible mechanism for this Pd-catalyzed proaromatic C(alkenyl)-H arylation using carboxylic acid as a traceless directing group was proposed and is illustrated in Scheme 4. First, proaromatic acid 1 is deprotonated with silver acetate to generate Ag−carboxylate species A followed by a C(alkenyl)-H bond activation with Pd(II), leading to formation of a five-membered palladacycle B. Subsequently, palladacycle B undergoes oxidative addition with aryl iodide 2 affords a Pd(IV) species C, which is followed by a reductive elimination to give the arylated Ag−carboxylate D and regenerating the Pd(II)−species to complete the catalytic cycle.Meanwhile, arylated Ag−carboxylate D readily undergoes decarboxylative rearomatization in the presence of a Pd catalyst, therefore eventually delivering the desired 2alkylated biaryls.

Conclusions
In conclusion, we have developed a Pd-catalyzed tandem decarboxylative C-H arylation/rearomatization of proaromatic acids with aryl iodides.This method using carboxylic acid as a traceless directing group for proaromatic C(alkenyl)-H arylation followed by a decarboxylative rearomatization in the presence of Pd/Ag bimetallic system, allowing the synthesis of 2-alkylated biaryls.The reaction mechanism most likely proceeds through a Pd(II)/Pd(IV) catalytic cycle.In addition, the control experiment suggests that the carboxylic acid functional group is essential for controlling the reaction outcome.

Experimental Section
General.Proton nuclear magnetic resonance ( 1 H NMR) spectra and carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Varian-Mercury-300 (300 MHz) spectrometer.Chemical shifts for protons are reported in parts per million (ppm) downfield from TMS and are referenced to residual proton in the solvent (CDCl3 δ = 7.26).Chemical shifts for carbon are reported in ppm and are referenced to the carbon signal (CDCl3 δ = 77.0ppm).NMR data are represented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constants in Hertz (Hz).TLC was examined by using Merck silica gel 60 F-254 plates, and detection of compounds with UV light or dipping into a solution of KMnO4 followed by heating.Flash column chromatography was performed by using Merck silica gel 60 (40-63 μm).Melting point were performed by using Fargo MP-2D.In relative rate experiments the ratio of the products were determined through NMR by using 1,3,5-trimethoxybenzene as internal standard.The single crystal X-ray diffraction data were obtained using a Bruker APEX DUO.The electron impact (EI) mass spectral data were obtained using a SHIMADZU QP2020 and JEOL AccuTOF GCx-plus.Proaromatic acids 1a-1h were prepared in accord to the earlier reported method. 9,10,17 Gral procedure for Pd(II)-catalyzed tandem decarboxylative C-H arylation/rearomatization. To a screw cap Schlenk tube, AgOAc (0.4 mmol), aryl iodide (0.2 mmol), Pd(OAc)2 (20 mol %, 0.04 mmol), HFIP (1 mL), and 1,4-alkylated cyclohexa-2,5-dienyl carboxylic acid were added.The resulting mixture was stirred under Argon atmosphere at 75 °C for 24 h.The crude mixture was extracted with ethyl acetate (75 mL), and the organic phases were then dried over MgSO4 for 10 min.The crude mixture was purified by flash column chromatography (SiO2) to afford desired product of 3a-3t.