Suzuki-Miyaura cross-coupling towards 4-amino biphenyl intermediates
The preparation of biphenyl derivatives bearing amino groups via direct cross-coupling reaction is being widely explored due to its importance for many branches of the chemical industry. One of the necessary components for such a transformation are halogenated arenes. In order to make the process more economical, we focus on inexpensive and easily available aryl chlorides which usually are not considered reagents of choice for catalytic couplings. In the following short communication, we report the results of the coupling of relatively unreactive chloroaniline with a fluorinated phenylboronic acid leading to the corresponding aminobiphenyl.
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<p>The synthesis of biaryl units (mainly amino biphenyls) has attracted a lot of attention and efforts from many research groups, both in academy and industry, due to their importance as key intermediates in the synthesis of pharmaceuticals, agrochemicals, natural products, etc.</p><p>The Suzuki-Miyuara cross-coupling reaction is an extremely useful approach for the construction of biaryl units as the reaction is much less sensitive to moisture and oxygen in comparison to other cross-coupling reactions and it allows very low metal catalyst loadings, which has a significant impact on price reduction on industrial scale.</p><p>While the Suzuki-Miyaura cross-coupling usually works well with aryl iodides, bromides, and triflates when reacting with boronic acids, the reaction is usually less efficient with aryl chlorides. An even larger challenge is reacting electron-rich aryl chlorides such as chloroanilines, 1,2 which are the desired starting materials towards aminobiphenyl species, as they are much cheaper than the respective aryl bromides. For this reason, few examples in the literature show successful reactions with chloroanilines and these usually with unsubstituted boronic acids. 3 An additional challenge is to perform these reactions with phenylboronic acids substituted by more than two halogens. Barder et al. have presented an example of Suzuki-Miyaura cross coupling of 4-chloroaniline with 2,4-difluorophenylboronic acid with a high yield of 96% in the presence of 1 mol% of  These authors contributed equally. * Corresponding author, e-mail: rafal.lisiak@selvita.com Pd(OAc)2 catalyst and 2 mol% of a bulky phosphine ligand (SPhos). However, when attempting the same reaction with 2,4,6-trifluorophenylboronic acid, it did not proceed efficiently. 4 Here we report an attempt to perform a Suzuki-Miyaura cross coupling reaction of 4-chloroaniline with 3,4,5-trifluoroboronic acid in a similar catalytic system.</p><p>In this case, we were able to reach a somewhat low conversion (19%) under these conditions. We managed to slightly improve the conversion to 42% by altering the reaction conditions, but still obtained relatively low yields, which is in line with the significant challenge and unpredictability of reacting chloroanilines with multisubstituted phenylboronic acids in the presence of SPhos and similar ligands.</p><!><p>26 mg of Pd(OAc)2 (0.12 mmol, 0.01 eq.) and 97 mg of SPhos (0.24 mmol, 0.02 eq.) were dissolved in 15 ml of toluene and 1.5 ml of H2O under nitrogen in a pressure tube, and stirred for 15 min at RT to form a catalyst solution. Then, 4.99 g of K3PO4 (0.0235 mol, 2 eq), 3.1 g of 3,4,5-trifluorophenylboronic acid (0.0176 mol, 1.5 eq) and 1.5 g of 4-chloroaniline (0.01176 mol, 1 eq) were added to the catalyst solution. The reaction mixture was heated to 100° C for 15 h. The reaction mixture was cooled to 25 °C, and the layers were separated. The organic phase was analyzed by GC area %: 19.9 % calculated conversion towards the desired product (3,4,5-trifluoro-4'-aminobiphenyl).</p><!><p>6 mg of palladium chloride (0.03 mmol, 0.1 mol%) and 28 mg of SPhos (0.06 mmol, 0.2 mol%) were dissolved in 20 ml of DMAc -water solution (1:1) at 25°C, under nitrogen, and stirred for 15 min to form a catalyst solution. Then, 7 g of potassium carbonate (0.050 mol, 1.5eq), 6 g of 3,4,5trifluorophenylboronic acid (0.034 mol, 1 eq) and 4.35 g of 4-chloroaniline (0.034 mol, 1 eq) were added to the catalyst solution. 25 ml of additional water -DMAc solution (1:1) were used to transfer the starting materials completely. The reactor was heated to 10 0°C inner temperature for 5 h. The reactor was cooled to 25 °C and the layers were separated. The organic phase was analyzed by GC area %: 42 % calculated conversion towards the desired product (3,4,5-trifluoro-4'-aminobiphenyl).</p>