Palladium-Catalyzed Cross Coupling

Pd-catalyzed cross coupling reactions consist of an electrophile (typically an organohalide), a nucleophile (typically an organometallic compound or an alkene), and a palladium catalyst. Regardless of the electrophile or nucleophile used, all Pd-catalyzed cross couplings rely on the Pd-catalyst to activate and combine both partners. Generally speaking, a Pd(0) species reacts with the organohalide via an oxidative addition to form an organopalladium species (RPdX). This organopalladium species then reacts with the nucleophilic partner to generate a new organopalladium species and ultimately construct a new carbon-carbon bond. Depending of the nucleophilic partner, the Pd-catalyzed cross coupling is given a specific name (see Table 1 below).

Table 1: List of Pd-catalyzed cross coupling reaction names and their nucleophilic partners.

There are two general mechanisms associated with these Pd-catalyst cross couplings. One for the Heck reaction, and one for the other cross coupling reactions. Overall, the Heck reaction couples an alkene with an organohalide to generate a now more substituted olefin (Figure 1). The first step of a Heck reaction is the same as all other Pd-catalyzed cross couplings. To begin, oxidative addition occurs between the Pd(0)-catalyst and the organohalide to generate an organopalladium(II) species. Next, the olefin coordinates to this newly formed organopalladium(II) species. After olefin coordination, carbopalladation occurs to generate a new carbon-carbon and carbon-palladium bond. Next, beta-hydride elimination occurs to generate a Pd(II)-hydride species and the olefin product. Finally, reductive elimination of HX regenerates the Pd(0)-catalyst, which can continue coupling to another molecule of organohalide and olefin.

Figure 1: The Heck reaction couples an alkene with an organohalide to generate a now more substituted olefin.

For the remaining cross coupling reactions, the mechanism is as follows (Figure 2). Oxidative addition between the organohalide and Pd(0) catalyst results in the formation of an organopalladium(II) species. This organopalladium(II) species reacts with the nucleophilic organometallic compound in a step called transmetalation to generate an organopalladium(II) species with two carbon-palladium bonds. Finally, reductive elimination occurs to create a new carbon-carbon bond and regenerate the Pd(0) catalyst.

Figure 2: Mechanism for the remaining cross coupling reactions.

The product should be a solid with the follow ¹H NMR spectrum: ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 2.60 (s, 3H), 6.67 (d, J = 16.0 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H). 7.83 (d, J = 8.4 Hz, 2H). 7.97 (d, J = 8.4 Hz, 2H).

These Pd-catalyzed cross coupling reactions have changed the way molecules are synthesized in academic and industrial settings. The impact of this technology can be seen in how chemists construct complex structures for pharmaceuticals, agriculture chemicals, and materials. Beyond Pd-catalyzed cross couplings, transition metal catalysis has changed (and is continuing to change) the way synthetic chemists prepare molecules that can have an impact on society through their potential therapeutic use.

Many molecules of interest for treating diseases have linkages connecting aromatic or heteroaromatic rings. Palladium cross coupling reactions, like the Suzuki reaction, have found widespread use in the pharmaceutical industry for making these types of structures. For example, Crizotinib (Xalkori), an anti-cancer drug for the treatment of non-small cell lung carcinoma, is synthesized on a several kilo-scale using a Suzuki coupling.

Figure 3: Crizotinib (Xalkori), an anti-cancer drug.

Palladium cross couplings have also been applied towards the synthesis of Taxol (an anticancer drug), Varenicline (an anti-smoking drug), and precursors for high performance electronic resins.

Figure 4: Taxol (an anticancer drug), Varenicline (an anti-smoking drug), and precursors for high performance electronic resins.