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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 the Shvo hydrogenation catalyst (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). 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. Current efforts are focused on finding conditions that lead to isolation of these valuable products.

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

The initial focus of our research was on the synthesis and reactivity of RuHOBR₂ (2, Scheme 1). Synthesis of this complex was achieved by addition of pinacolborane to ruthenium dimer 4 (Scheme 2). The resulting complex (RuHOBpin 5) was found to be catalytically active in the hydroboration of aldehydes, ketones, and imines. Preliminary mechanistic studies suggest that the reaction proceeds by a similar pathway to the unusual outer-sphere ligand–metal bifunctional Shvo catalyst (1, Scheme 1). See publication for details.

Scheme 2. Synthesis of RuHOBpin 5

Synthesis of ruthenium boryl complexes (such as 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 3). 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 39% 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. An X-ray crystal structure of complex 7 confirmed the anticipated structure and regiochemistry.

Scheme 3. Synthesis of Ruthenium Boryl Complexes

With a method to synthesize ruthenium boryl complex 7, we investigated the ability of this complex to mediate ligand-directed C–H borylation reactions. The hydroxy group on the Cp′ ligand was expected to interact with the heteroatom of a substrate through a hydrogen bond, resulting in directed functionalization of the C-H bond via an optimized transition-state structure. Initial development of directed C-H borylation reactions was examined with simple ether substrates. Ruthenium boryl complex 7 was photolyzed in the presence of diethyl ether-d₁₀, providing several undesired products. The poor selectivity of diethyl ether-d₁₀ likely reflects a non-optimal chain length for C-H functionalization. Butyl methyl ether was chosen as the next substrate due to the presence of multiple potentially reactive C-H bonds (eq 1). Under similar photolytic conditions, butyl methyl ether provided an 80% NMR yield of 8 (> 95% selectivity by ¹H and ¹¹B NMR spectroscopy), resulting from functionalization of the methoxy C–H bond. This result is consistent with an optimal transition-state structure for directed C-H functionalization.

            a-Alkoxy boronate esters are known to be prone to decomposition. Isolation of these substrates by the exclusion of air and moisture is typically possible. In our experience, boronate ester 8 is difficult to separate from the ruthenium hydride (1') by-product without decomposition. Attempts to filter out 1' or distill off 8 have been unsuccessful, typically resulting in multiple decomposition products. We are currently attempting to overcome this isolation issue by derivatizing 8 into an air- and moisture-stable product (Scheme 4). Examples of a-alkoxy trifluoroborate salts, for example, were reported by Molander to be stable products. Synthesis of trifluoroborate salt 9 was achieved by a procedure reported by Molander for related substrates. We are currently developing conditions for the conversion of 8 to 9.

Scheme 4. Conversion of Boronate Ester 8 to Trifluoroborate Salt 9

            In addition to the results described above, the synthesis of additional ruthenium boryl complexes is being explored. The activation of B₂cat₂ shown in Scheme 3 provides low yields for the activation of B₂pin₂. The application of pinacolato-substituted boronate esters to ligand-directed C–H borylation reactions is desired because these complexes typically provide higher yields in the C–H functionalization reaction and also 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 hydrogenation catalyst (Scheme 5). Treatment of ruthenium chloride 10 with bis(pinacolato)diboron and NaOt-Bu in benzene-d₆ resulted in a product with spectroscopic properties that are consistent with the anticipated ruthenium boryl complex 11. Attempts to grow X-ray quality crystals have not been successful up to this point.

Scheme 5. Synthesis of Alternative Ruthenium Boryl Complex 11

            In summary, the synthesis of boron-substituted analogues of the Shvo hydrogenation catalyst have provided complexes that are active as either hydroboration catalysts or C–H borylation complexes. Current efforts are focused on developing a method to isolate C–H borylation product 8 and on the synthesis of alternative ruthenium boryl complexes.