Aminomethylations via Cross-Coupling of Potassium Organotrifluoroborates with Aryl Bromides

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070543e.html

From Prof. Gary A. Molander's group at University of Pennsylvania, Philadelphia, PA

The paper recently appeared in Org Lett ASAP presented a novel Suzuki-Miyaura cross-coupling reaction using potassium organotrifluoroborate salt as an aminomethyl transfering reagent in cross-coupling with aryl halide.

Prior to this work, only one example of aminomethyl transfer is known using organotin reagent as shown below. The use of tin reagent is naturally objectionable as tin is toxic and purification is usually not simple. Plus, the tin reagent sometimes requires a tedious synthesis of its own.

The use of potassium organotrifluoroborate salt as a coupling partner in Suzuki-Miyaura reaction is attractive because this reagent is nontoxic, and air- and moisture-stable. The studies were first conducted using potassium N-(trifluoroboratomethyl)piperidine, which could be conveniently prepared based on a known procedure. The reaction was screen with different aryl bromides. The results are summarized in the table below. Note: XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

As seen in the table, the reaction tolerated well with various aryl bromide derivatives, whether it was electron-rich, or electron-deficient. Steric hindrance in proximity of the coupling site was also well-tolerated. Some of the reactions were found to give higher yields when they were conducted in cyclopentyl methyl ether (CPME)/water mixture (10:1), possibly because reactions could be heated at higher temperature than THF/water.

The reaction of the same borate salt was expanded to react with a variety of heteroaromatic systems. (Table 2).Again, the reactions proceeded well with all heteroaromatic coupling partners examined. In these cases, the reactions were found to work better (higher yields) with the original THF/water system.

Next, different aminomethyl reagents were examined. Various aminomethyltrifluoroborate salts were prepared from potassium trifluoroboratomethyl bromide with stoichiometric amines and the results are summarized below.

As can be seen, in all cases tertiary amine borate salts could be prepared in good yields with great structural diversities. These salts were subjected to the standard coupling conditions in THF/water with 4-bromoanisole to afford coupling products in good to excellent yields (Table 4), with only exceptions of 5e and 5f where there was no reaction both in CPME/water and THF/water systems.