Ruthenium catalysis in organic synthesis*

Ruthenium, rhodium, iridium, and rhenium hydride complexes are highly useful redox Lewis acid and base catalysts. Various substrates bearing hetero atoms are activated by these catalysts and undergo reactions with either nucleophiles or electrophiles under neutral conditions. These types of catalytic reactions are described together with their application to the preparation of various biologically active compounds. Ruthenium has various valencies (0 to 8 valene) and is not so expensive transition metal; therefore, various useful catalytic reactions for organic synthesis have been explored [1]. It is noteworthy that the medical property of ruthenium is now being recognized, and ruthenium anticancer agents have recently entered the clinic, showing promising activity on resistant tumors. We have developed various ruthenium-catalyzed reactions. Among them, I would like to focus on our findings that low-valent ruthenium hydride complexes can be used as alternatives to the conventional Lewis acids and bases. Furthermore, using iridium, rhodium, and rhenium hydride complexes, various novel and unique catalytic reactions can be explored. Reactions promoted by Lewis acids and bases are fundamental in organic synthesis; however, most such reactions are merely stoichiometric. Therefore, the development of catalytic reactions that use transition-metal complex catalysts under neutral and mild reaction conditions is particularly important; society needs forward-looking technology, which is based on environmental acceptability. The criteria include atom efficiency, formation of little inorganic waste, and selective synthesis of desired products. We should use instead environmentally friendly catalytic processes that will not produce such waste. If one could design Lewis acid and base catalysts with low redox potentials, their reactions would occur catalytically under neutral conditions. We have, therefore, been searching for transitionmetal complex catalysts, which we call redox Lewis acid and base catalysts [2]. We found that divalent ruthenium hydride complexes act as redox Lewis acid catalysts and also as redox base catalysts. Generation of carbon nucleophiles from pronucleophiles by activation of the α-C–H bond adjacent to hetero atoms followed by reaction with various electrophiles affords catalytic carbon–carbon bond forming reactions under neutral and mild reaction conditions. In principle, conventional acids and bases cannot be used at the same time because of neutralization; therefore, we developed Lewis acid base ambiphilic catalysts which can be utilized as either Lewis acid or bases in one-pot reaction. Low-valent ruthenium, iridium, rhodium, and rhenium hydride catalysts can be used as catalysts to replace both Lewis acids and strong bases, and they can be used in combinatorial chemistry. *Lecture presented at the 11th IUPAC International Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS-11), Taipei, Taiwan, 22–26 July 2001. Other presentations are presented in this issue, pp. 1–186. ‡Corresponding author REDOX LEWIS ACID CATALYSTS Reactions with transition-metal complexes used as redox Lewis acid catalysts will open up new possibilities, because they proceed catalytically with high selectivity under neutral conditions. To explore the possibilities, we focused on low-valent ruthenium dihydride phosphine complexes, because they have low redox potentials, strong coordination ability to heteroatoms, and hydride ligands that are small and labile. The basic concept of redox Lewis acid catalysts has been shown for the activation of nitriles [3]. Nitriles are activated upon coordination to ruthenium complexes. Capture of the ruthenium-coordinated nitriles with various nucleophiles, such as water, alcohols, and amines, provides a new type of catalytic transformation of nitriles that proceeds under neutral conditions. The concept of transition-metalbased Lewis acid catalysts has been shown by Bosnich et al. [4]. The underlying principle is used in the design of new kinds of catalytic reactions [5]. However, the above reactions of nitriles with nucleophiles such as amines do not occur with these catalysts. This difficulty may arise if redox processes are important in the reaction. We found ruthenium hydride complex RuH2(PPh3)4 (1) catalyzed hydration of nitriles with only 1–2 molar amounts of water under neutral conditions to give the corresponding amides in excellent yields (eq. 1) [6]. The usefulness of the present reaction is illustrated by the synthesis of (–)-pumiliotoxin C, which is an interesting skin alkaloid produced by a Central American frog [7]. Using the same principle, novel methods for synthesis of esters and amides from nitriles under neutral conditions were discovered. When alcohols are used as nucleophiles, the ruthenium-catalyzed reaction of nitriles with alcohols in the presence of 1–2 molar amounts of water proceeds to give the corresponding esters with evolution of ammonia (eq. 2) [8]. Similar treatment of nitriles with amines gives the corresponding amides along with ammonia (eq. 3) [9]. The efficiency of these reactions is highlighted by the synthesis of industrially important polyamides as shown in Scheme 1. In the presence of 2 molar amounts of water and catalyst 1, the reaction of adiponitrile (2) with 1,6-hexamethylenediamine (3) proceeds to give nylon-6,6 in 98% yield along with ammonia. This process is attractive in comparison with the conventional methods, because (i) the dinitrile 2 can be readily prepared by nickel-catalyzed hydrocyanation of butadiene, (ii) diamine 3 can be readily prepared by nickel-catalyzed hydrogenation of dinitriles, and (iii) polyamides are S.-I. MURAHASHI © 2002 IUPAC, Pure and Applied Chemistry 74, 19–24 20