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Alternatives to expensive palladium catalysts are gaining acceptance for commercial API synthesis.
Cross-coupling reactions enable the synthesis of complex building blocks and intermediates with structural motifs common in many classes of APIs. Numerous cross-coupling methodologies that allow the reaction of unsaturated substrates (acetylenes, alkenes, aryls) with a wide range of functionalized organohalides have thus been employed in the commercial manufacture of APIs. These reactions, however, are typically mediated by expensive and often toxic palladium catalysts with specially designed ligands. Consequently, there is significant interest in developing alternative catalyst systems that avoid these issues.
Advances in cross-coupling chemistry have had a significant impact on API synthesis at commercial scale, according to Chris Senanayake, vice-president of chemical development in the United States at Boehringer Ingelheim Pharmaceuticals. “The expanded substrate scope, the availability of a variety of novel ligands, and the in-depth mechanistic understanding of cross-coupling reactions have led to shorter development times and enhanced process robustness,” he notes.
The most commonly used cross-coupling reactions, most of which are catalyzed by palladium-based, transition-metal complexes, include Suzuki and Sonogashira coupling, according to Jeff Song, director of development, also with Boehringer Ingelheim Pharmaceuticals.
When first developed, the Suzuki reaction involved the cross coupling of aryl organoboronic acids with halides. Today, the substrate scope is much broader and includes alkyl, alkenyl, and alkynyl compounds. In addition, potassium trifluoroborates and organoboranes/boronate esters can be used instead of boronic acids, while in some cases triflates or other pseudohalides can be used instead of actual organohalides.
The Sonogashira reaction involves the coupling of terminal alkynes with aryl or vinyl halides. In addition to the palladium catalyst, a copper(I) cocatalyst and an amine base are required. When first introduced, maintaining anhydrous and oxygen-free conditions was essential for this coupling method, but newer versions do not require such strict control of the reaction environment.
Suzuki reactions at Boehringer Ingelheim
In the past few years, scientists at Boehringer Ingelheim have employed Suzuki coupling chemistry for the preparation of FLAP (1), HCV Polymerase (2), and 11-β-HSD 1 inhibitors (3). In the first case, a Suzuki reaction was used to form the key biaryl bond between an aryl bromide and aminopyrimidine boronic acid. In the second example, a one-pot sequential borylation−Suzuki coupling process was devised to efficiently couple 2-iodo-5-bromopyrimidine and a 2-bromoindole substrate. The third reaction involved a Suzuki coupling using a pyridone boronic acid on scale.
“Non-precious-metal catalysis is a new horizon for the field of cross coupling,” observes Senanayake. “Iron, copper, cobalt, and nickel catalysts for cross-coupling reactions have begun to be applied on large scales,” he adds.
In fact, Boehringer Ingelheim, Pfizer, and AbbVie have formed a cross-company consortium with the aim of jointly driving research in this area. The goal of the Non-Precious-Metal Catalysis Alliance is to advance the development of abundant-metal catalysts and replace precious-metal catalysts in the synthesis of APIs.
“The use of non-precious-metal catalysis on large scales will greatly improve the economics and sustainability of chemical processes,” asserts Song. He points to a recent example from Boehringer Ingelheim that involves an iron-catalyzed Kumada coupling reaction under flow conditions (4). In the reaction, 2-chloropyrazine can be coupled with various aryl Grignard reagents with catalyst loadings as low as 0.5 mole percent. Switching from batch to continuous processing avoided large exotherms, providing a longer catalyst lifetime and higher yields. The scale-dependent issues often observed with Kumada coupling reactions were also eliminated, making scale up easier.
A key area for additional development in coupling chemistry, according to Song, is their use in the synthesis of chiral compounds. “In the next few years, we expect to see further advancement in methodology development for asymmetric cross couplings, including for biaryl and sp3 coupling reactions. In fact, significant progress has recently been made, as exemplified by the asymmetric Suzuki reactions using ligands developed at Boehringer Ingelheim,” he notes.
For instance, novel monophosphorous ligands that are chiral at the phosphorus atom were employed for the palladium-catalyzed asymmetric Suzuki-Miyaura coupling of aryl boronic acids with aryl halides in the presence of tripotassium phosphate to afford functionalized chiral biaryls compounds under mild conditions and up to 96% enantiomeric excess (5). These reactions were applied to the asymmetric synthesis of an atropisomeric HIV integrase inhibitor on large scales (6). Similar asymmetric coupling reactions were used to achieve the first total syntheses of biaryl natural products korupensamine A and B (7).
Silicon-based cross-coupling reactions have recently been shown to have potential advantages over existing cross-coupling chemistry, particularly with respect to alkyl-aryl and alkyl-alkenyl (sp3-sp2) cross-couplings, according to Gerald L. Larson, a senior research fellow at Gelest.
Because the energy barrier for these couplings is high, reactions with transition-metal catalysts must be run under extreme conditions or using highly reactive substrates, which prevents the incorporation of many functional groups.
The newer silicon-based reactions involve both photoredox and cross-coupling catalysts to facilitate cross-coupling reactions of a variety of substrates, such as trifluoroborates and carboxylic acids. Unlike traditional cross-coupling reactions mediated by palladium, these dual-catalyst reactions proceed via radical mechanisms. As a result, they are not plagued by the high-energy barriers that exist for conventional cross-coupling reactions.
Gary A. Molander and his research group at the University of Pennsylvania have been very active in this area (8). Organosilicates such as alkylbis(catecholato)silicates serve as excellent radical precursors for nickel/photoredox dual catalysis. The organosilicates undergo single-electron oxidative fragmentation upon exposure to visible light in the presence of a ruthenium catalyst. The generated radicals then participate in single-electron transmetallation mediated by more environmentally friendly and less expensive nickel complexes.
One benefit of this approach, according to Larson, is the greater stability of the nucleophilic partners used in the cross-coupling reactions. In addition, the organosilicates are easily prepared from readily available precursors. “The ability to cross couple alkyl and, particularly primary alkyl groups in sp3-sp2 cross-coupling protocols, as well as the ability to cross couple nucleophilic substrates containing unprotected amino groups are key advantages,” he adds. The use of nickel rather than palladium also reduces the overall cost and eliminates the need to remove the metal from the final reaction mixture, according to Larson. “As importantly,” he observes, “there is no need to synthesize boronic acids, silanols, trifluoroborates, or zinc reagents, and both preparation of the silicate reagents and the cross-coupling reactions are fully scalable.”
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3. Y. Zhang et al. J. Org. Chem. 81 (6) 2665-2669 (2016).
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5. W. Tang et al., Org. Lett. 14 (9) 2258 (2010).
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7. G. Xu et al., J. Am. Chem. Soc. 136 (2) 570-573 (2014).
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