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Directed C-H functionalization (carbon-hydrogen bond to carbon-heteroatom bond) is becoming a valuable tool in organic synthesis. Applications of this methodology, however, are currently limited by the carbon-heteroatom bond that can be formed. C-H functionalization with metal boryl complexes provides regioselective formation of carbon-boron bonds (selective for aryl and terminal alkyl C-H bonds) from carbon-hydrogen bonds. Because the C-B bond can be converted into C-C, C-O, C-N, and other C-X bonds, this method provides a very general way to convert simple substrates into synthetically valuable products if a single reactive site is present in the substrate (for example, one terminal –CH₃ group).

            This report describes our progress in the synthesis and evaluation of the reactivity of boron-substituted analogues of metal–ligand bifunctional catalysts (1, Scheme 1). Initial results in this area focused on optimizing the synthesis of ruthenium boryl complexes and the exploration of the resulting reactivity of these complexes in hydroboration and C–H functionalization reactions. Replacement of the ligand-based O–H group with an O–B group (2) has led to a complex that is reactive in the hydroboration of aldehydes, ketones, and imines (published in Organometallics, 2009 and discussed in the previous progress report). Replacement of the metal-based Ru–H with a Ru–B substituent (3) results in a complex that functionalizes C-H bonds alpha- to oxygen of an ether substrate selectively over alternative terminal C-H bonds. The resulting boronate esters are prone to decomposition and could not be isolated. The novel synthesis and properties of complex 3 were recently reported (published in Organometallics, 2010).

Scheme 1. Boron-Substituted Analogues of the Shvo Hydrogenation Catalyst

Synthesis of ruthenium boryl complexes related to complex 3 (Scheme 1) was achieved by the activation of bis(catecholato)diboron in the presence and absence of a phenol. The addition of bis(catecholato)diboron to ruthenium dimer 4 provided RuBcatOBcat complex 6 in 70% NMR yield (Scheme 2). The O–B bond of complex 6 was highly labile, precluding the isolation of the pure complex. Addition of 4-methoxyphenol to complex 6 resulted in selective cleavage of the O–B bond to generate RuBcatOH complex 7. Under these conditions complex 7 was isolated in 51% yield. Alternatively, conducting the reaction between dimer 4 and bis(catecholato)diboron in the presence of 4-methoxyphenol provided complex 7 in 74% NMR yield. Isolation of complex 7 from this reaction provided a 30% yield. The isolation of 7 was hindered by the formation of a ruthenium hydride impurity. The removal of this impurity resulted in decreased yields. An X-ray crystal structure of complex 7 confirmed the anticipated structure and regiochemistry. Please see additional details in the publication (Organometallics, 2010).

Scheme 2. Synthesis of Ruthenium Boryl Complexes

            The synthesis of additional ruthenium boryl complexes has been explored. The activation of B₂cat₂ shown in Scheme 2 provides low yields for the activation of B₂pin₂. The application of pinacolato-substituted boronate esters to metal-ligand bifunctional borylation reactions is desired because these complexes typically provide products that are less prone to decomposition. Toward this end, we have begun to explore the synthesis of boron-substituted analogues of Noyori's transfer hydrogenation (8) and hydrogenation (9) catalysts (Scheme 3). Initially, hydroboration using these complexes was explored to help us determine the reactivity of these complexes toward reactive boron sources. The hydroboration of ketones using these asymmetric complexes was also desired because the sterically congested boronate ester was expected to increase the enantioselectivity in hydroboration reactions. To test this hypothesis, the hydroboration of acetophenone was examined using a catalytic amount of each Noyori catalyst. In both cases, the resulting hydroboration product was racemic (determined by hydrolysis of O–B bond and analysis using chiral GC).

            Scheme 3. Ruthenium-Catalyzed Hydroboration of Acetophenone

            Control reactions were used to determine why the hydroboration reaction was completely unselective. The hydroboration of acetophenone was examined in the absence of a transition metal catalyst. The hydroboration was found to be catalyzed by NaOt-Bu rather than by Noyori's catalysts (eq 1), which accounts for the lack of asymmetric induction. Spectroscopic studies were used to study the active hydroboration complex. Using this information, with the observed reactivity, a catalytic cycle was proposed (Scheme 4). These results, along with the scope of the hydroboration reaction are the topic of a manuscript that is currently being prepared for submission.

Scheme 4. Proposed Catalytic Cycle for Alkoxide-Mediated Hydroboration of Ketones

            Due to the challenges faced with the Shvo and Noyori complexes in developing highly reactive borylation catalysts, we shifted our attention to metal–ligand bifunctional borylation catalysts that can easily access coordinatively unsaturated electronic states. Rh, Ir, and Ru complexes with diamine ligands were initially chosen based on the known role of these complexes in metal-catalyzed borylation reactions. We have preliminary results that support this concept using iridium-catalyzed arene C–H borylation. After screening a range of diamine ligands, picolylamine was found to be a reactive ligand in the ortho borylation of the arene C–H bond of N, N-dimethylbenzylamine (Scheme 5). At 70 °C, 72% conversion (with respect to B₂pin₂) to the ortho borylation product was observed. Running a similar reaction under known non-directing conditions (using 4,4'-di-tert-butylbypyridine) led to <10% conversion, with an unselective mixture of isomers. The reaction is believed to proceed via a hydrogen bond between the N–H bond of the ligand and the basic amine of the substrate, leading to an optimal transition state for ortho C–H borylation (TS-A).

Scheme 5. Ligand-Directed C–H Borylation

In summary, the synthesis of boron-substituted analogues of metal–ligand bifunctional catalyst have provided complexes that are active as either hydroboration catalysts or C–H borylation complexes.