Novel synthetic route points the way to innovative materials.
Organometallic intermediates are highly useful for the synthesis of many drugs, pigments and plastics, and are often essential due to their unique properties and chemical reactivities. Heterocyclic compounds such as pyridines and quinolines serve as precursors for the formation of such commodities, and therefore represent feedstocks for many important chemical syntheses. The development of novel chemicals and therapeutics would be greatly facilitated, if a simple access for specific addition of functional groups to pyridines and related compounds can be found. A team of chemists at LMU, led by Professor Paul Knochel, has now discovered an efficient way to generate a wide variety of functionalized pyridines. The key to the new method is the use of so-called frustrated Lewis pairs, single or mixed compounds that contain both a strong Lewis acid and a strong Lewis base. These reagents are highly reactive and facilitate the rapid metalation of polyfunctional heterocycles. The new synthetic route could form the basis for a new field of chemical research, since frustrated Lewis pairs are likely to find broad application as innovative reagents for metalation reactions. (Angewandte Chemie International Edition, online, July 2010)
Organometallic compounds are of great importance in many areas of synthetic chemistry, because they can accommodate a great variety of functional groups and thus offer a unique access to a wide range of functional materials and biologically active compounds. In particular, organometallic intermediates play an important role in the synthesis of polyfunctional heterocylces such as pyridine and quinoline derivatives (in which a nitrogen atom replaces one of the carbons in their ring-shaped skeletons). Due to the high occurrence in natural products and their specific properties, pyridines and quinolines are important building blocks especially in the synthesis of medicinal compounds as well as dyes and plastics. “Conventional methods for the introduction of metals, such as magnesium, zinc or aluminium, into pyridines bearing sensitive functional groups are rather unsatisfactory“, says LMU chemist Professor Paul Knochel. “Metalation reactions on these substrates are generally very slow and quite inefficient.“ This situation now looks set to change, as Knochel and his team have just discovered a new group of metalation reagents that significantly accelerate the rates of reactions and considerably improve the yields of the desired products.
So-called frustrated Lewis pairs are characterized by their outstandingly high reactivity. Classical Lewis pairs consist of a Lewis acid and a Lewis base forming an unreactive salt. In frustrated Lewis pairs, the formation of a stable acid-base adduct is inhibited, because the attractive sites of both components are shielded by bulky groups maintaining the ability of reversible association. In particular, these unstable, reactive adducts dissociate upon interaction with substrates. In their new study, Knochel and his coworkers used a mixture of boron trifluoride (BF3) as their Lewis acid, and a metal amide containing magnesium, zinc or aluminium as the base. They found that these acid-base combinations remarkably accelerated the rate of metallation of pyridine and quinoline derivatives, as evidenced by the fact that reaction occurred within 10 minutes at a temperature of –40 °C. “This tells us that the new Lewis pair possesses remarkable reactivity”, says Benjamin Haag, a member of Knochel’s group and co-author of the new study. “This was quite a surprise, because one would intuitively expect that this mixture would not be reactive at all.“
On the basis of theoretical calculations and nuclear magnetic resonance measurements, the team was able to characterize the new organometallic intermediates in detail. “The results revealed the mechanistic mode of action of these reagents“ says Haag. “And we were also able to prove that we had indeed discovered a completely new class of organometallic compounds and a direct way of generating these species.“ The new Lewis pairs offer an easy and rapid access for the functionalization of pyridines and related heterocyclic molecules. In addition, the new reaction allows the researchers to introduce the metal at defined positions in the target molecule. “The new method is of particular interest for applications that require precise control of synthetic steps, in the production of fine chemicals and new types of drugs, or in material science“, says Haag. It could also form the basis for an entirely new field of chemical research devoted to the synthesis and characterization of organometallic compounds using the new combinations of frustrated Lewis pairs. (CA/suwe)
"Highly Selective Metalations of Pyridines and Related Heterocycles Using New Frustrated Lewis Pairs or Zn- and Mg-TMP-Bases with BF3•OEt2";
Milica Jaric, Benjamin A. Haag, Andreas Unsinn, Konstantin Karaghiosoff, Paul Knochel;
Angewandte Chemie, International Edition, online, July 2010