Pd-Catalyzed Kumada-Corriu Cross-Coupling Reactions at Low Temperatures Allow the Use of Knochel-type Grignard Reagents

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/asap/abs/ja070830d.html

From Prof. Stephen L. Buchwald's group at MIT

A new method from the Buchwald group at MIT, exploring the use of Knochel-type Grignard reagents in Pd-catalyzed cross-coupling with aryl halides. The method presented a new way to do cross-coupling with reactive Grignard reagents at lower temperature (-20 to -65 °C) while tolerating a wide range of functionaly groups in both partners.

In the first step, screening for the optimal reaction conditions, including the search for the right ligand. As shown in Table 1, ligand L3 was found to give the best result with aryl trfilate. However, it was later discovered that the reaction could perform much better when the coupling partner was switched to aryl iodide.

Next, the scope of the coupling reaction was explored using aryl iodide and various functionalized Grignard reagents prepared by the method of Knochel's (Mg/I exchange method). The coupling results and the conditions for each coupling are summarized in Table 2.

As shown, their version of the Pd-catalyzed Kumada-Corriu cross-coupling reaction manifests a broad substrate scope:

- Ortho-, meta- and para-substituted biaryls could all be efficiently prepared.

- In addition, a variety of functional groups were tolerated, including nitriles (entries 1 and 2), amines (entries 3 and 10), esters (entries 5 and 7), heterocycles (entries 6 and 7), and a benzylic acetal (entry 6).

- This process could also be employed for challenging cross-coupling reactions at -50 °C (entries 2 and 9) or at -65 °C (entry 3), as well as for the construction of a triortho-substituted biaryl (entry 4). To the best of their knowledge, no other Pd-catalyzed biaryl-forming reactions have been accomplished at such temperatures.

- Moreover, the process showed excellent chemoselectivity toward aryl halide substituents, as chlorides (entries 2, 3, and 8), fluorides (entry 10), and even bromides (entry 8) were tolerated, making them available, in many instances, for further functionalization via conventional cross-coupling techniques.

Table 3 demonstrates the utility of this method in cross-coupling of a variety of heteroaryl Grignard reagents. In these cases, catalyst L2 was found to perform better than L3 while other reaction conditions are essentially identical.

In electron-deficient arylboronic acid such as ortho-fluoro derivatives are often poor substrate due to their low reactivity in the transmetalation process and higher tendency to homocouple. It was expected that the higher reactivity of Grignard reagents would overcome the difficulty of the transmetalation step, even though these organometallic species are unstable at ambient temperatures, decomposing via benzyne and other pathways.

However, as shown in Table 4, the fears were not warranted as highly electron-deficient aryl Grignard reagents cross-coupled smoothly with aryl iodides providing various 2-fluoro and, especially, 2,6-difluoro biaryls, which have been quite difficult to make, in good to excellent yields. In addition, a variety of functional groups were well-tolerated in these reactions.