Michael Joseph Krische

Stoichiometric organometallic reagents are used in countless C–C bond-forming processes but are often hazardous, display poor functional group compatibility, and require multistep preparation from the parent platform chemicals. Zerovalent metals are also used to mediate reductive C–C bond formation, but their use at scale poses similar safety and engineering concerns. The formation of C-nucleophiles as transient catalytic intermediates via hydrogen transfer from abundant low-molecular-weight reductants (H2, Me2CHOH, HCO2H) offers a more ideal alternative to preformed carbanions or zerovalent metals in reductive C–C bond formation. Related hydrogen autotransfer processes where reactants serve as redox pairs en route to products of C–C coupling also are desirable, as they avoid both sacrificial reductants and premetalated reagents. In this Review, hydrogen-mediated variants of classical reactions that exploit carbanions or zerovalent metals are described.

Using a ruthenium catalyst derived from RuHCl(CO)(PPh ₃ ) ₃ and Cy‐BIPHEP, 2‐propanol‐mediated reductive coupling of phenyl acrylate with aromatic or aliphatic nitriles occurs to form α,β‐unsaturated β‐amino esters. Although the reaction products, which incorporate acyclic tetrasubstituted alkenes, are challenging substrates for asymmetric hydrogenation, trifluoroethanol (TFE) enabled rhodium‐Walphos‐catalyzed hydrogenation occurs with high levels of enantioselectivity. Thus, through successive transfer hydrogenative coupling‐asymmetric hydrogenation events, abundant nitrile and acrylate feedstocks are converted to enantioenriched β‐amino esters. This method represents a new catalytic transformation of nitriles and the first reductive C─C coupling of nitriles beyond the use of stoichiometric metals or metalloids.

Using a ruthenium catalyst derived from RuHCl(CO)(PPh ₃ ) ₃ and Cy‐BIPHEP, 2‐propanol‐mediated reductive coupling of phenyl acrylate with aromatic or aliphatic nitriles occurs to form α,β‐unsaturated β‐amino esters. Although the reaction products, which incorporate acyclic tetrasubstituted alkenes, are challenging substrates for asymmetric hydrogenation, trifluoroethanol (TFE) enabled rhodium‐Walphos‐catalyzed hydrogenation occurs with high levels of enantioselectivity. Thus, through successive transfer hydrogenative coupling‐asymmetric hydrogenation events, abundant nitrile and acrylate feedstocks are converted to enantioenriched β‐amino esters. This method represents a new catalytic transformation of nitriles and the first reductive C─C coupling of nitriles beyond the use of stoichiometric metals or metalloids.

Using the inexpensive, air-stable ruthenium catalyst derived from RuHCl(CO)(PPh3)3 and the achiral ligands Cy-BIPHEP or dCypb, acetylenic bicyclooctyl, azabicycloheptyl, adamantyl, bicyclopentyl and azabicyclooctyl bioisosteres 2a–2f are conjugated to diverse azines and azoles 1a–1t via Csp2–Csp3 bond formation. Using chiral ruthenium catalysts modified by (S)-Cy-SEGPHOS or (R)-Cy-BINAP, high levels of enantioselectivity are obtained in reactions of azines. Late-stage C–H functionalization of the B(Epin) derivative of bortezomib (Velcade) and studies corroborating the reaction mechanism are described.

Halide-dependent regio- and enantioselectivity is observed in methoxyallene-aldehyde reductive couplings mediated by 2-propanol that are catalyzed by the pseudo-diastereomeric-at-metal complexes RuX[η3-(α-MeO)allyl](CO)[(S)-SEGPHOS], where X = Cl vs I. In reactions of the chloride-bound catalyst, for which the CO and chloride ligands adopt a trans-diapical arrangement, equimolar quantities of linear and branched adducts are formed with low levels of enantiomeric enrichment. In reactions of the iodide-bound catalyst, the CO and halide ligands reside in adjacent coordination sites, and complete branched regioselectivity is accompanied by high levels of anti-diastereo- and enantioselectivity. In prior work on isoprene-mediated carbonyl prenylation, the stereochemistries of the chloride- and iodide-bound ruthenium-SEGPHOS catalysts were established by X-ray diffraction and 31P nuclear magnetic resonance spectroscopic analyses of the parent π-allylruthenium complexes, RuX(η3-C3H5)(CO)[(S)-SEGPHOS], where X = Cl vs I. In the present carbonyl (α-methoxy)allylations, calculations of the 24 possible diastereomeric complexes reveal that 4 isomers constitute 93.1% of the resting state, but the kinetic contribution to carbonyl addition is dominated by just the two most stable transition states. These computational data align with experimentally observed diastereo- and enantioselectivities and demonstrate that diastereomeric-at-metal catalysts embody distinct regio- and stereoselectivities, a fact that has broad implications for the field of enantioselective metal catalysis.

Metal-catalyzed N-heteroaryl C-H functionalizations to form quaternary heterobenzylic carbon centers are described. Exposure of 1,1-disubstituted allenes to the ruthenium catalyst derived from RuHCl(CO)(PPh₃)₃ and Cy-BIPHEP results in generation of allylruthenium nucleophiles that engage in azine or azole C═N addition to deliver transient dearomatized homoallylic amidoruthenium complexes, which upon β-hydride elimination release products bearing quaternary N-heterobenzylic carbon centers with regeneration of the starting ruthenium hydride. The dearomative addition-β-hydride elimination pathway is corroborated by deuterium-labeling experiments and interception of the dearomatized amidoruthenium intermediate through its protonolytic cleavage by 2-propanol and conversion to the methanesulfonamide. Comparison of RuCl(η³-C₃H₅)(CO)(Cy-BIPHEP) vs RuCl(η³-C₃H₅)(CO)(BIPHEP), including single crystal X-ray diffraction and IR data, provides insight into the superior performance of the Cy-BIPHEP-modified catalyst.

ZUSAMMENFASSUNG: Ein Iodid‐gebundener Rutheniumkatalysator auf Basis von RuHCl(CO)(PPh ₃ ) ₃ und ( S , S )‐Ph‐BPE katalysiert die hochenantioselektive Alkinylierung von Fluoral Hydrat 2a und verwandten α,α‐Difluoroaldehyden 4a – 4f durch terminal Alkine 1a – 1y . Der Ruthenium‐(Ph‐BPE)‐Komplex ist tolerant gegenüber Luft und Wasser, operiert in Abwesenheit externer Basen und ist chemoselektiv für die Alkinylierung fluorierter Aldehyde in der Gegenwart aromatischer Aldehyde. DFT‐Rechnungen zeigen, dass von den 12 möglichen von Fluoral gebundenen Ruthenium‐(Ph‐BPE)‐Acetylidkomplexen mit metallzentrierter Chiralität nur 2 dieser oktaedrischen Komplexe über 99.9 % der Boltzmannpopulation ausmachen. Carbonyladdition erfolgt jedoch kinetisch kontrolliert in einem Curtin‐Hammet Szenario aus dem weniger stabilen dieser 2 Diastereomere. FBO Analyse der Formyl‐Wasserstoffbrückenbindungen zu Iodid vs. Chlorid in den Übergangszuständen der Carbonyladdition zeigt, dass die C–H···I Bindung stärker ist, mutmaßlich aufgrund der Größe und Polarisiertbarkeit des Iodids, welche zu einer erhöhten Enantioselektivität des Iodid‐gebundenen Katalysators beiträgt.

An iodide‐bound ruthenium catalyst derived from RuHCl(CO)(PPh ₃ ) ₃ and ( S,S )‐Ph‐BPE catalyzes highly enantioselective alkynylations of terminal alkynes 1a – 1y with fluoral hydrate 2a and related α,α‐difluoro‐aldehydes 4a – 4f . The ruthenium‐(Ph‐BPE)‐catalyst is air‐ and water‐tolerant, operates in the absence of exogenous base, and is chemoselective for alkynylation of fluorinated aldehydes in the presence of aromatic aldehydes. Calculations of the 12 possible stereogenic‐at‐metal ruthenium‐(Ph‐BPE) acetylide complexes bound by fluoral reveal that 2 of the 12 octahedral complexes comprise 99.9% of the Boltzmann population, yet, in a Curtin‐Hammett‐type scenario, the less stable of these two diastereomers dominates the kinetics of carbonyl addition. Fuzzy bond order (FBO) analysis of formyl‐hydrogen bonds to iodide versus chloride in the transition states for fluoral addition reveals that the C–H···I hydrogen bonds are stronger due to iodide's greater size and polarizability, which, in part, accounts for the enhanced enantioselectivities of the iodide‐bound catalyst.

Biaryl motifs figure prominently in commercial pharmaceutical and agrochemical ingredients and are used widely in organic optoelectronic materials. Traditional palladium-catalyzed cross-coupling reactions, such as Suzuki, Negishi and Stille couplings, are powerful methods for aryl–aryl bond formation, but their reliance on premetalated reagents poses practical limitations. As most arylmetal reagents derive from the corresponding aryl halides, considerable effort has been devoted to the development of direct catalytic aryl halide reductive couplings. However, most methods require metallic reductants. In this monograph, metal-catalyzed aryl halide reductive homocouplings (Ullmann reactions) and cross-couplings mediated by nonmetallic reductants are surveyed.

From the first report of 1,3-butadiene-mediated carbonyl crotylation in 2008 to the recent development of a simple ruthenium-JOSIPHOS catalyst derived from inexpensive, air-stable RuHCl(CO)(PPh₃)₃, the discovery and evolution of 1,3-butadiene-mediated carbonyl crotylation is reviewed. The key role of iodide counterions in guiding metal-centered stereogenicity and, therefrom, regio-, stereo- and site-selectivity is highlighted, as are applications in polyketide total synthesis. These methods are unique in their ability to affect crotylation of primary alcohol proelectrophiles in the presence of free secondary hydroxyl groups and offer an atom-efficient alternative to classical protocols for aldehyde crotylations that rely on premetalated reagents.