Computational Study of the Ir-Catalyzed Formation of Allyl Carbamates from CO2.

We have employed computational methods to investigate the iridium-catalyzed allylic substitution leading to the formation of enantioenriched allyl carbamates from carbon dioxide (CO2). The reaction occurs in several steps, with initial formation of an iridium-allyl, followed by nucleophilic attack by the carbamate formed in situ from CO2 and an amine. A detailed isomeric analysis shows that the rate-determining step differs for the (R)- and (S)-pathways. These insights are essential for understanding reactions involving enantioselective formation of allyl carbamates from CO2.

Nickel Catalyzed Carbonylative Cross Coupling for Direct Access to Isotopically Labeled Alkyl Aryl Ketones.

Here we present an effective nickel-catalyzed carbonylative cross-coupling for direct access to alkyl aryl ketones from readily accessible redox-activated tetrachlorophthalimide esters and aryl boronic acids. The methodology, which is run employing only 2.5 equivalents of CO and simple Ni(II) salts as the metal source, exhibits a broad substrate scope under mild condition. Furthermore, this carbonylation chemistry provides an easy switch between isotopologues for stable (13CO) and radioactive (14CO) isotope labeling, allowing its adaptation to the late-stage isotope labeling of pharmaceutically relevant compounds. Based on DFT calculations as well as experimental evidence, a catalytic cycle is proposed involving a carbon-centered radical formed via nickel(I)-induced outer-sphere decarboxylative fragmentation of the redox-active ester.

Revisiting the Mechanism of Asymmetric Ni-Catalyzed Reductive Carbo-Carboxylation with CO2: The Additives Affect the Product Selectivity.

The mechanistic details of the asymmetric Ni-catalyzed reductive cyclization/carboxylation of alkenes with CO2 have been revisited using DFT methods. Emphasis was put on the enantioselectivity and the mechanistic role of Lewis acid additives and in situ formed salts. Our results show that oxidative addition of the substrate is rate-limiting, with the formed Ni(II)-aryl intermediate preferring a triplet spin state. After reduction to Ni(I), enantioselective cyclization of the substrate occurs, followed by inner sphere carboxylation. Our proposed mechanism reproduces the experimentally observed enantiomeric excess and identifies critical C-H/O and C-H/N interactions that affect the selectivity. Further, our results highlight the beneficial effect of Lewis acids on CO2 insertion and suggest that in situ formed salts influence if the 5-exo or 6-endo product will be formed.

Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling.

Carbon isotope labelling of bioactive molecules is essential for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs ubiquitous in pharmaceutically active molecules and are ideal targets for the installation of a radioactive tag employing isotopically labelled CO2. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO2, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalysts. Herein, we report the development of a practical and affordable Pd-catalysed electrocarboxylation setup. This approach enables the use of near-stoichiometric 14CO2 generated from the primary carbon-14 source Ba14CO3, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.

Kinetically-Controlled Ni-Catalyzed Direct Carboxylation of Unactivated Secondary Alkyl Bromides without Chain Walking.

Herein, we report the direct carboxylation of unactivated secondary alkyl bromides enabled by the merger of photoredox and nickel catalysis, a previously inaccessible endeavor in the carboxylation arena. Site-selectivity is dictated by a kinetically controlled insertion of CO2 at the initial C(sp3)-Br site by the rapid formation of Ni(I)-alkyl species, thus avoiding undesired ß-hydride elimination and chain-walking processes. Preliminary mechanistic experiments reveal the subtleties of stereoelectronic effects for guiding the reactivity and site-selectivity.

Comparative study of CO2 insertion into pincer supported palladium alkyl and aryl complexes.

The insertion of CO2 into metal alkyl bonds is a crucial elementary step in transition metal-catalyzed processes for CO2 utilization. Here, we synthesize pincer-supported palladium complexes of the type (tBuPBP)Pd(alkyl) (tBuPBP = B(NCH2PtBu2)2C6H4-; alkyl = CH2CH3, CH2CH2CH3, CH2C6H5, and CH2-4-OMe-C6H4) and (tBuPBP)Pd(C6H5) and compare the rates of CO2 insertion into the palladium alkyl bonds to form metal carboxylate complexes. Although, the rate constant for CO2 insertion into (tBuPBP)Pd(CH2CH3) is more than double the rate constant we previously measured for insertion into the palladium methyl complex (tBuPBP)Pd(CH3), insertion into (tBuPBP)Pd(CH2CH2CH3) occurs approximately one order of magnitude slower than (tBuPBP)Pd(CH3). CO2 insertion into the benzyl complexes (tBuPBP)Pd(CH2C6H5) and (tBuPBP)Pd(CH2-4-OMe-C6H4) is significantly slower than any of the n-alkyl complexes, and CO2 does not insert into the palladium phenyl bond of (tBuPBP)Pd(C6H5). While (tBuPBP)Pd(CH2CH3) and (tBuPBP)Pd(CH2CH2CH3) are resistant to ß-hydride elimination, we were unable to synthesize complexes with n-butyl, iso-propyl, and tert-butyl ligands due to ß-hydride elimination and an unusual reductive coupling, which involves the formation of new C-B bonds. This reductive process also occurred for (tBuPBP)Pd(CH2C6H5) at elevated temperature and a related process involving the formation of a new H-B bond prevented the isolation of (tBuPBP)PdH. DFT calculations provide insight into the relative rates of CO2 insertion and indicate that steric factors are critical. Overall, this work is one of the first comparative studies of the rates of CO2 insertion into different metal alkyl bonds and provides fundamental information that may be important for the development of new catalysts for CO2 utilization.

Conformational tuning improves the stability of spirocyclic nitroxides with long paramagnetic relaxation times.

Nitroxides are widely used as probes and polarization transfer agents in spectroscopy and imaging. These applications require high stability towards reducing biological environments, as well as beneficial relaxation properties. While the latter is provided by spirocyclic groups on the nitroxide scaffold, such systems are not in themselves robust under reducing conditions. In this work, we introduce a strategy for stability enhancement through conformational tuning, where incorporating additional substituents on the nitroxide ring effects a shift towards highly stable closed spirocyclic conformations, as indicated by X-ray crystallography and density functional theory (DFT) calculations. Closed spirocyclohexyl nitroxides exhibit dramatically improved stability towards reduction by ascorbate, while maintaining long relaxation times in electron paramagnetic resonance (EPR) spectroscopy. These findings have important implications for the future design of new nitroxide-based spin labels and imaging agents.

Lignocellulose Conversion via Catalytic Transformations Yields Methoxyterephthalic Acid Directly from Sawdust.

Poly(ethylene terephthalate) polyester represents the most common class of thermoplastic polymers widely used in the textile, bottling, and packaging industries. Terephthalic acid and ethylene glycol, both of petrochemical origin, are polymerized to yield the polyester. However, an earlier report suggests that polymerization of methoxyterephthalic acid with ethylene glycol provides a methoxy-polyester with similar properties. Currently, there are no established biobased synthetic routes toward the methoxyterephthalic acid monomer. Here, we show a viable route to the dicarboxylic acid from various tree species involving three catalytic steps. We demonstrate that sawdust can be converted to valuable aryl nitrile intermediates through hydrogenolysis, followed by an efficient fluorosulfation-catalytic cyanation sequence (>90%) and then converted to methoxyterephthalic acid by hydrolysis and oxidation. A preliminary polymerization result indicates a methoxy-polyester with acceptable thermal properties.

Mechanistic Investigations of the Asymmetric Hydrogenation of Enamides with Neutral Bis(phosphine) Cobalt Precatalysts.

The mechanism of the asymmetric hydrogenation of prochiral enamides by well-defined, neutral bis(phosphine) cobalt(0) and cobalt(II) precatalysts has been explored using(R,R)-iPrDuPhos ((R,R)-iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene) as a representative chiral bis(phosphine) ligand. A series of (R,R)-(iPrDuPhos)Co(enamide) (enamide = methyl-2-acetamidoacrylate (MAA), methyl(Z)-α-acetamidocinnamate (MAC), and methyl(Z)-acetamido(4-fluorophenyl)acrylate (4FMAC)) complexes (1-MAA, 1-MAC, and 1-4FMAC), as well as a dinuclear cobalt tetrahydride, [(R,R)-(iPrDuPhos)Co]2(µ2-H)3(H) (2), were independently synthesized, characterized, and evaluated in both stoichiometric and catalytic hydrogenation reactions. Characterization of (R,R)-(iPrDuPhos)Co(enamide) complexes by X-ray diffraction established the formation of the pro-(R) diastereomers in contrast to the (S)-alkane products obtained from the catalytic reaction. In situ monitoring of the cobalt-catalyzed hydrogenation reactions by UV-visible and freeze-quench electron paramagnetic resonance spectroscopies revealed (R,R)-(iPrDuPhos)Co(enamide) complexes as the catalyst resting state for all the three enamides studied. Variable time normalization analysis kinetic studies of the cobalt-catalyzed hydrogenation reactions in methanol established a rate law that is first order in (R,R)-(iPrDuPhos)Co(enamide) and H2 but independent of the enamide concentration. Deuterium-labeling studies, including measurement of an H2/D2 kinetic isotope effect and catalytic hydrogenations with HD, established an irreversible H2 addition step to the bound enamide. Density functional theory calculations support that this step is both rate and selectivity determining. Calculations, as well as HD-labeling studies, provide evidence for two-electron redox cycling involving cobalt(0) and cobalt(II) intermediates during the catalytic cycle. Taken together, these experiments support an unsaturated pathway for the [(R,R)-(iPrDuPhos)Co]-catalyzed hydrogenation of prochiral enamides.

Cobalt-Catalyzed Asymmetric Hydrogenation of Enamides: Insights into Mechanisms and Solvent Effects.

The mechanistic details of the (PhBPE)Co-catalyzed asymmetric hydrogenation of enamides are investigated using computational and experimental approaches. Four mechanistic possibilities are compared: a direct Co(0)/Co(II) redox path, a metathesis pathway, a nonredox Co(II) mechanism featuring an aza-metallacycle, and a possible enamide-imine tautomerization pathway. The results indicate that the operative mechanism may depend on the type of enamide. Explicit solvent is found to be crucial for the stabilization of transition states and for a proper estimation of the enantiomeric excess. The combined results highlight the complexity of base-metal-catalyzed hydrogenations but do also provide guiding principles for a mechanistic understanding of these systems, where protic substrates can be expected to open up nonredox hydrogenation pathways.

Room-Temperature-Stable Magnesium Electride via Ni(II) Reduction.

Herein, we report the synthesis of highly reduced bipyridyl magnesium complexes and the first example of a stable organic magnesium electride supported by quantum mechanical computations and X-ray diffraction. These complexes serve as unconventional homogeneous reductants due to their high solubility, modular redox potentials, and formation of insoluble, non-coordinating byproducts. The applicability of these reductants is showcased by accessing low-valent (bipy)2Ni(0) species that are challenging to access otherwise.

Ligand and solvent effects on CO2 insertion into group 10 metal alkyl bonds.

The insertion of carbon dioxide into metal element σ-bonds is an important elementary step in many catalytic reactions for carbon dioxide valorization. Here, the insertion of carbon dioxide into a family of group 10 alkyl complexes of the type (RPBP)M(CH3) (RPBP = B(NCH2PR2)2C6H4 -; R = Cy or t Bu; M = Ni or Pd) to generate κ1-acetate complexes of the form (RPBP)M{OC(O)CH3} is investigated. This involved the preparation and characterization of a number of new complexes supported by the unusual RPBP ligand, which features a central boryl donor that exerts a strong trans-influence, and the identification of a new decomposition pathway that results in C-B bond formation. In contrast to other group 10 methyl complexes supported by pincer ligands, carbon dioxide insertion into (RPBP)M(CH3) is facile and occurs at room temperature because of the high trans-influence of the boryl donor. Given the mild conditions for carbon dioxide insertion, we perform a rare kinetic study on carbon dioxide insertion into a late-transition metal alkyl species using ( t BuPBP)Pd(CH3). These studies demonstrate that the Dimroth-Reichardt parameter for a solvent correlates with the rate of carbon dioxide insertion and that Lewis acids do not promote insertion. DFT calculations indicate that insertion into ( t BuPBP)M(CH3) (M = Ni or Pd) proceeds via an SE2 mechanism and we compare the reaction pathway for carbon dioxide insertion into group 10 methyl complexes with insertion into group 10 hydrides. Overall, this work provides fundamental insight that will be valuable for the development of improved and new catalysts for carbon dioxide utilization.

Titanium isopropoxide-mediated cis-selective synthesis of 3,4-substituted butyrolactones from CO2.

We report a Ti(OiPr)4-mediated multicomponent reaction, which produces 3,4-substituted cis-δ-lactones from alkyl magnesium chloride, benzaldehyde and CO2. The key intermediate, titanacyclopropane, is formed in situ from Ti(OiPr)4 and a Grignard reagent, which enables 1,2-dinucleophilic reactivity that is used to insert carbon dioxide and an aldehyde. An alternative reaction route is also described where a primary alkene is used to create the titanacyclopropane. A computational analysis of the elementary steps shows that the carbon dioxide and the aldehyde insertion proceeds through an inner-sphere mechanism. A variety of cis-butyrolactones can be synthesized with up to 7 : 1 diastereoselectivity and 77% yield.

Ni(I)-Alkyl Complexes Bearing Phenanthroline Ligands: Experimental Evidence for CO2 Insertion at Ni(I) Centers.

Although the catalytic carboxylation of unactivated alkyl electrophiles has reached remarkable levels of sophistication, the intermediacy of (phenanthroline)Ni(I)-alkyl species-complexes proposed in numerous Ni-catalyzed reductive cross-coupling reactions-has been subject to speculation. Herein we report the synthesis of such elusive (phenanthroline)Ni(I) species and their reactivity with CO2, allowing us to address a long-standing question related to Ni-catalyzed carboxylation reactions.

Formal C-H Carboxylation of Unactivated Arenes.

A formal C-H carboxylation of unactivated arenes using CO2 in green solvents is described. The present strategy combines a sterically controlled Ir-catalyzed C-H borylation followed by a Cu-catalyzed carboxylation of the in situ generated organoboronates. The reaction is highly regioselective for the C-H carboxylation of 1,3-disubstituted and 1,2,3-trisubstituted benzenes, 1,2- or 1,4-symmetrically substituted benzenes, fluorinated benzenes and different heterocycles. The developed methodology was applied to the late-stage C-H carboxylation of commercial drugs and ligands.

Exploration of New Biomass-Derived Solvents: Application to Carboxylation Reactions.

A range of hitherto unexplored biomass-derived chemicals have been evaluated as new sustainable solvents for a large variety of CO2 -based carboxylation reactions. Known biomass-derived solvents (biosolvents) are also included in the study and the results are compared with commonly used solvents for the reactions. Biosolvents can be efficiently applied in a variety of carboxylation reactions, such as Cu-catalyzed carboxylation of organoboranes and organoboronates, metal-catalyzed hydrocarboxylation, borocarboxylation, and other related reactions. For many of these reactions, the use of biosolvents provides comparable or better yields than the commonly used solvents. The best biosolvents identified are the so far unexplored candidates isosorbide dimethyl ether, acetaldehyde diethyl acetal, rose oxide, and eucalyptol, alongside the known biosolvent 2-methyltetrahydrofuran. This strategy was used for the synthesis of the commercial drugs Fenoprofen and Flurbiprofen.

Caesium fluoride-mediated hydrocarboxylation of alkenes and allenes: scope and mechanistic insights.

A caesium fluoride-mediated hydrocarboxylation of olefins is disclosed that does not rely on precious transition metal catalysts and ligands. The reaction occurs at atmospheric pressures of CO2 in the presence of 9-BBN as a stoichiometric reductant. Stilbenes, ß-substituted styrenes and allenes could be carboxylated in good yields. The developed methodology can be used for preparation of commercial drugs as well as for gram scale hydrocarboxylation. Computational studies indicate that the reaction occurs via formation of an organocaesium intermediate.

Iron-Catalyzed Carbenoid-Transfer Reactions of Vinyl Sulfoxonium Ylides: An Experimental and Computational Study.

A method for the generation of unprecedented vinyl carbenoids from sulfoxonium ylides has been developed and applied in the synthesis of a diverse array of heterocycles such as indolizines, pyrroles, 3-pyrrolin-2-ones, and furans. The reactions proceed by FeBr2 catalysis under mild reaction conditions with a broad substrate scope. A reaction pathway involving iron carbenoids is proposed based on a series of control experiments and DFT calculations.

Cobalt-catalysed alkene hydrogenation: a metallacycle can explain the hydroxyl activating effect and the diastereoselectivity.

Bis(phosphine)cobalt dialkyl complexes have been reported to be highly active in the hydrogenation of tri-substituted alkenes bearing hydroxyl substituents. Alkene substrates containing ether, ester, or ketone substituents show minimal reactivity, indicating an activating effect of the hydroxyl group. The mechanistic details of bis(phosphine)cobalt-catalysed hydrogenation were recently evaluated computationally (X. Ma, M. Lei, J. Org. Chem. 2017, 82, 2703-2712) and a Co(0)-Co(ii) redox mechanism was proposed. However, the activating effect of the hydroxyl substituent and the accompanying high diastereoselectivity were not studied. Here we report a computational study rationalizing the role of the hydroxyl group through a key metallacycle species. The metallacycle is part of a non-redox catalytic pathway proceeding through Co(ii) intermediates throughout. The preference for alcohol over ether substrates and the high diastereoselectivity of terpinen-4-ol hydrogenation are correctly predicted in computations adopting the new pathway, whereas the alternative redox mechanism predicts ethers rather than alcohols to be more reactive substrates. Additional experimental evidence supports the role of the hydroxyl group in the metallacycle mechanism. Our work highlights the importance of employing known substrate preferences and stereoselectivities to test the validity of computationally proposed reaction pathways.

Rhodium-Catalyzed Synthesis of Sulfur Ylides via in Situ Generated Iodonium Ylides.

A convenient strategy for the synthesis of sulfur ylides via rhodium-catalyzed coupling of in situ generated iodonium ylides with sulfides or sulfoxides has been developed. A wide range of sulfur ylides were obtained in moderate to good yields from inexpensive sulfur compounds and active methylene compounds with a short reaction time (MW, 5-10 min) or 12-16 h at rt. Furthermore, these sulfoxonium ylides were used as novel acceptor/acceptor carbenes for N-H insertion reactions.