Direct Heterocycle C-H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation.

One of the major challenges in developing catalytic methods for C-C bond formation is the identification of generally applicable reaction conditions, particularly if multiple substrate structural classes are involved. Pd-catalyzed direct arylation reactions are powerful transformations that enable direct functionalization of C-H bonds; however, the corresponding direct alkenylation reactions, using vinyl (pseudo) halide electrophiles, are less well developed. Inspired by process development efforts toward GSK3368715, an investigational active pharmaceutical ingredient, we report that a Pd(II) palladacycle derived from tri-tert-butylphosphine and Pd(OAc)2 is an effective single-component precatalyst for a variety of direct alkenylation reactions. High-throughput experimentation identified optimal solvent/base combinations for a variety of HetAr-H substrate classes undergoing C-H activation without the need for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative catalytic mechanism, where in situ-generated Pd(0) supports a canonical Pd(0)/(II) cross-coupling cycle and the palladacycle effects C-H activation via CMD in a redox-neutral cycle. In all, 192 substrate combinations were tested with a hit rate of approximately 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale.

High-Throughput Discovery and Evaluation of a General Catalytic Method for N-Arylation of Weakly Nucleophilic Sulfonamides.

Through targeted high-throughput experimentation (HTE), we have identified the Pd/AdBippyPhos catalyst system as an effective and general method to construct densely functionalized N,N-diaryl sulfonamide motifs relevant to medicinal chemistry. AdBippyPhos is particularly effective for the installation of heteroaromatic groups. Computational steric parametrization of the investigated ligands reveals the potential importance of remote steric demand, where a large cone angle combined with an accessible Pd center is correlated to successful catalysts for C-N coupling reactions.

N-Hydroxyphthalimide-Mediated Electrochemical Iodination of Methylarenes and Comparison to Electron-Transfer-Initiated C-H Functionalization.

An electrochemical method has been developed for selective benzylic iodination of methylarenes. The reactions feature the first use of N-hydroxyphthalimide as an electrochemical mediator for C-H oxidation to nonoxygenated products. The method provides the basis for direct (in situ) or sequential benzylation of diverse nucleophiles using methylarenes as the alkylating agent. The hydrogen-atom transfer mechanism for C-H iodination allows C-H oxidation to proceed with minimal dependence on the substrate electronic properties and at electrode potentials 0.5-1.2 V lower than that of direct electrochemical C-H oxidation.

Co/NHPI-mediated aerobic oxygenation of benzylic C-H bonds in pharmaceutically relevant molecules.

A simple cobalt(ii)/N-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C-H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C-H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90-100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate (AMG 579) under process-relevant reaction conditions.

Dinuclear Pd(I) complexes with bridging allyl and related ligands.

There are many important synthetic methods that utilize palladium catalysts. In most of these reactions, the palladium species are proposed to exist exclusively in either the Pd(0) or Pd(II) oxidation states. However, in the last decade, dinuclear Pd(I) complexes have repeatedly been isolated from reaction mixtures previously suggested to involve only species in the Pd(0) and Pd(II) oxidation states. As a consequence, in order to design improved catalysts there is considerable interest in understanding the chemistry of dinuclear Pd(I) complexes. A significant proportion of the known dinuclear Pd(I) complexes are supported by bridging allyl or related ligands such as cyclopentadienyl or indenyl ligands. This review provides a detailed account of the synthesis, electronic structure and stoichiometric reactivity of dinuclear Pd(I) complexes with bridging allyl and related ligands. Additionally, it describes recent work where dinuclear Pd(I) complexes with bridging allyl ligands have been detected in catalytic reactions, such as cross-coupling, and discusses the potential implications for catalysis.

Insight into the efficiency of cinnamyl-supported precatalysts for the Suzuki-Miyaura reaction: observation of Pd(I) dimers with bridging allyl ligands during catalysis.

Despite widespread use of complexes of the type Pd(L)(η(3)-allyl)Cl as precatalysts for cross-coupling, the chemistry of related Pd(I) dimers of the form (µ-allyl)(µ-Cl)Pd2(L)2 has been underexplored. Here, the relationship between the monomeric and the dimeric compounds is investigated using both experiment and theory. We report an efficient synthesis of the Pd(I) dimers (µ-allyl)(µ-Cl)Pd2(IPr)2 (allyl = allyl, crotyl, cinnamyl; IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) through activation of Pd(IPr)(η(3)-allyl)Cl type monomers under mildly basic reaction conditions. The catalytic performance of the Pd(II) monomers and their Pd(I) µ-allyl dimer congeners for the Suzuki-Miyaura reaction is compared. We propose that the (µ-allyl)(µ-Cl)Pd2(IPr)2-type dimers are activated for catalysis through disproportionation to Pd(IPr)(η(3)-allyl)Cl and monoligated IPr-Pd(0). The microscopic reverse comproportionation reaction of monomers of the type Pd(IPr)(η(3)-allyl)Cl with IPr-Pd(0) to form Pd(I) dimers is also studied. It is demonstrated that this is a facile process, and Pd(I) dimers are directly observed during catalysis in reactions using Pd(II) precatalysts. In these catalytic reactions, Pd(I) µ-allyl dimer formation is a deleterious process which removes the IPr-Pd(0) active species from the reaction mixture. However, increased sterics at the 1-position of the allyl ligand in the Pd(IPr)(η(3)-crotyl)Cl and Pd(IPr)(η(3)-cinnamyl)Cl precatalysts results in a larger kinetic barrier to comproportionation, which allows more of the active IPr-Pd(0) catalyst to enter the catalytic cycle when these substituted precatalysts are used. Furthermore, we have developed reaction conditions for the Suzuki-Miyaura reaction using Pd(IPr)(η(3)-cinnamyl)Cl which are compatible with mild bases.

Naturally occurring eccentric cleavage products of provitamin A ß-carotene function as antagonists of retinoic acid receptors.

ß-Carotene is the major dietary source of provitamin A. Central cleavage of ß-carotene catalyzed by ß-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs). Eccentric cleavage of ß-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are ß-apocarotenals and ß-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the ß-apocarotenoids significantly activated RARs. Importantly, however, ß-apo-14'-carotenal, ß-apo-14'-carotenoic acid, and ß-apo-13-carotenone antagonized ATRA-induced transactivation of RARs. Competitive radioligand binding assays demonstrated that these putative RAR antagonists compete directly with retinoic acid for high affinity binding to purified receptors. Molecular modeling studies confirmed that ß-apo-13-carotenone can interact directly with the ligand binding site of the retinoid receptors. ß-Apo-13-carotenone and the ß-apo-14'-carotenoids inhibited ATRA-induced expression of retinoid responsive genes in Hep G2 cells. Finally, we developed an LC/MS method and found 3-5 nm ß-apo-13-carotenone was present in human plasma. These findings suggest that ß-apocarotenoids function as naturally occurring retinoid antagonists. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary ß-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer.

Palladium(I)-bridging allyl dimers for the catalytic functionalization of CO2.

In general, the chemistry of both η(1)-allyl and η(3)-allyl Pd complexes is extremely well understood; η(1)-allyls are nucleophilic and react with electrophiles, whereas η(3)-allyls are electrophilic and react with nucleophiles. In contrast, relatively little is known about the chemistry of metal complexes with bridging allyl ligands. In this work, we describe a more efficient synthetic methodology for the preparation of Pd(I)-bridging allyl dimers and report the first studies of their stoichiometric reactivity. Furthermore, we show that these compounds can activate CO(2) and that an N-heterocyclic carbene-supported dimer is one of the most active and stable catalysts reported to date for the carboxylation of allylstannanes and allylboranes with CO(2).

Efficient, Low-Cost Synthesis of Retinal (Vitamin A Aldehyde).

Inexpensive retinyl acetate has been subjected to transesterification followed by allylic oxidation to give retinal in 98% yield as a 92:8 mixture of all-trans/13-cis isomers after chromatographic separation. More convenient methods of isolating the all-trans isomer have also been employed.

The eccentric cleavage product of ß-carotene, ß-apo-13-carotenone, functions as an antagonist of RXRα.

In this study, we investigated the effects of eccentric cleavage products of ß-carotene, i.e. ß-apocarotenoids (BACs), on retinoid X receptor alpha (RXRα) signaling. Transactivation assays were performed to test whether BACs activate or antagonize RXRα. Reporter gene constructs (RXRE-Luc, pRL-tk) and RXRα were transfected into Cos-1 cells and used to perform these assays. None of the BACs tested activated RXRα. Among the compounds tested, ß-apo-13-carotenone was found to antagonize the activation of RXRα by 9-cis-retinoic acid and was effective at concentrations as low as 1 nM. Molecular modeling studies revealed that ß-apo-13-carotenone makes molecular interactions like an antagonist of RXRα. The results suggest a possible function of BACs on RXRα signaling.

Identification and quantification of apo-lycopenals in fruits, vegetables, and human plasma.

Research has suggested that lycopene may be metabolized by eccentric cleavage, catalyzed by beta-carotene oxygenase 2, resulting in the generation of apo-lycopenals. Apo-6'-lycopenal and apo-8'-lycopenal have been reported previously in raw tomato. We now show that several other apo-lycopenals are also present in raw and processed foods, as well as in human plasma. Apo-lycopenal standards were prepared by in vitro oxidation of lycopene, and a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method using atmospheric pressure chemical ionization in negative mode was developed to separate and detect the apo-6'-, apo-8'-, apo-10'-, apo-12'-, apo-14'-, and apo-15'-lycopenal products formed in the reaction. Hexane/acetone extracts of raw tomato, red grapefruit, watermelon, and processed tomato products were analyzed, as well as plasma of individuals who had consumed tomato juice for 8 weeks. Apo-6'-, apo-8'-, apo-10'-, apo-12'-, and apo-14'-lycopenals were detected and quantified in all food products tested, as well as plasma. The sum of apo-lycopenals was 6.5 microg/100 g Roma tomato, 73.4 microg/100 g tomato paste, and 1.9 nmol/L plasma. We conclude that several apo-lycopenals, in addition to apo-6'- and -8'-lycopenal, are present in lycopene-containing foods. In addition, the presence of apo-lycopenals in plasma may derive from the absorption of apo-lycopenals directly from food and/or human metabolism.

The Reaction of Carbon Dioxide with Palladium Allyl Bonds.

A family of palladium allyl complexes of the type bis(2-methylallyl)Pd(L) (L = PMe(3) (1), PEt(3) (2), PPh(3) (3) or NHC (4); NHC = 1,3-Bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene) have been prepared through the reaction of bis(2-methylallyl)Pd with the appropriate free ligand. Compounds 1-4 contain one η(1) and one η(3)-2-methylallyl ligand and 3 was characterized by X-ray crystallography. These complexes react rapidly with CO(2) at low temperature to form well defined unidentate palladium carboxylates of the type (η(3)-2-methylallyl)Pd(OC(O)C(4)H(7))(L) (L = PMe(3) (6), PEt(3) (7), PPh(3) (8) or NHC (9). The structure of 9 was elucidated using X-ray crystallography. The mechanism of the reaction of 1-4 with CO(2) was probed using a combination of experimental and theoretical (density functional theory) studies. The coordination mode of the allyl ligand is crucial and whereas nucleophilic η(1)-allyls react rapidly with CO(2), η(3)-allyls do not react. We propose that the reaction of η(1)-palladium allyls with CO(2) does not proceed via direct insertion of CO(2) into the Pd-C bond but through nucleophilic attack of the terminal olefin on electrophilic CO(2), followed by an associative substitution at palladium.