Carbonylative Cyclization Research Articles

Manganese- and Iron-Catalyzed Carbonylation Reactions: A Personal Account

AbstractTransition-metal-catalyzed carbonylative transformations have been widely employed to convert CO gas into valuable carbonyl-containing molecules, mainly using noble metals (Pd, Rh, Ir, Ru) and more recently nickel and other catalysts. Although noble-metal catalysts have the advantage of reaction efficiency, their high-cost has led scientists to explore alternative procedures. Also under these backgrounds, we carried out some studies on nonexpensive metal-catalyzed carbonylative transformations. In this Account, we summarize the carbonylation reactions developed in our research group by using manganese and iron catalysis. These carbonylation reactions proceeded either via SET (single-electron transfer) or TET (two-electron transfer) mechanism.1 Introduction2 Manganese-Catalyzed Carbonylation of Alkyl Chlorides3 Manganese-Catalyzed Carbonylation of Alkyl Iodides4 Iron/Copper-Catalyzed Carbonylation of Alkyl Bromides5 Iron-Catalyzed Carbonylation of Alkyl Bromides6 Iron-Catalyzed Carbonylation of Alkyl-Boronic Pinacol7 Iron-Catalyzed Aminoalkylative Carbonylative Cyclization of Alkenes8 Conclusion and Outlook

Carbonylative Cyclization of 2-Iodofluorobenzenes and 2-Aminophenols with Recyclable Palladium-Complexed Dendrimers on SBA-15: One-Pot Synthesis of Dibenzoxazepinones.

A novel, efficient, and practical route to dibenzoxazepinones has been developed through a one-pot heterogeneous palladium-catalyzed aminocarbonylation/aromatic nucleophilic substitution (SNAr) sequence starting from readily available 2-iodofluorobenzenes and 2-aminophenols. The carbonylative cyclization reaction proceeds smoothly in dimethyl sulfoxide (DMSO) at 120 °C with 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as the base by using a polyamidoamine (PAMAM)-dendronized SBA-15-supported bidentate phosphine-palladium complex [G(1)-2P-Pd(OAc)2-SBA-15] as the catalyst under 10 bar of CO, yielding a wide variety of dibenzo[b,e][1,4]oxazepin-11(5H)-one derivatives in good to excellent yields. Moreover, this new heterogenized dendritic palladium catalyst has competitive advantages in that it can be facilely recovered by simple filtration in air and recycled more than eight times without any significant loss of activity. The broad substrate scope, high functional group tolerance, and excellent palladium catalyst recyclability of the reaction make this approach a general, efficient, and economical method for the construction of valuable dibenzoxazepinone derivatives.

Cobalt-Catalyzed Carbonylative Cyclization of Homoallylic Alcohols and Amines

Cobalt-Catalyzed Carbonylative Cyclization of Homoallylic Alcohols and Amines

Palladium-catalyzed difluorocarbene transfer enables access to enantioenriched chiral spirooxindoles

AbstractWe disclose herein an unprecedented Pd-catalyzed difluorocarbene transfer reaction, which assembles a series of structurally interesting chiral spiro ketones with generally over 90% ee. Commercially available BrCF2CO2K serves as the difluorocarbene precursor, which is harnessed as a user-friendly and safe carbonyl source in this transformation. Preliminary mechanistic studies exclude the formation of free CO in the reaction process, and importantly, we also find that BrCF2CO2K outcompete gaseous CO and several common CO surrogates in this asymmetric process. The reaction mechanism, including the in-situ progressive release of the difluorocarbene, the rapid migratory insertion of ArPd(II) = CF2 species, and subsequent defluorination hydrolysis by water to introduce the carbonyl group, accounts for the overall high efficiency and uniqueness. This work clearly showcases the advantage and potential of the difluorocarbene in synthesis and supplies a mechanistically distinct route for asymmetric carbonylative cyclization reactions.

Palladium-Catalyzed Carbonylative Cyclization of 1-Alkynyl-2-iodo-d-glucal.

Cascade reactions are important synthetic tools for the synthesis of heterocyclic molecules, particularly those catalyzed by palladium. Herein, we report a palladium-catalyzed aminocarbonylative cyclization of new 1-alkynyl-2-iodo-d-glucals, which undergo a tandem carbonylative cyclization in the presence of various amine nucleophiles. A broad range of aromatic and aliphatic amines were applied as coupling partners, resulting in the selective and high-yield synthesis of glycosides fused to pyridinones. A plausible mechanism is proposed, proceeding via a tandem palladium aminocarbonylation followed by a palladium-catalyzed endo-dig cyclization.

Construction of Six-Membered Lactam and Lactone Structures via Ligand-Free Pd-Catalyzed C-H Activation/[5 + 1] Cyclization Carbonylation.

An approach for the ligand-free Pd-catalyzed C-H activation/[5 + 1] cyclization carbonylation by employing readily available ClCF2COONa as a carbonyl source via difluorocarbene transfer and hydrolysis has been developed. The current protocol enables us to obtain a series of carbonylation cyclization product benzopyranone and phenanthridinone derivatives in up to 91% yield with excellent functional group compatibility. This protocol has the advantages of mild reaction conditions, wide applicable substrates, and simple and safe operation and provides a new method for the synthesis of complex lactam and lactone compounds.

Palladium-catalyzed intramolecular Heck-type carbonylative cyclization cascade reaction and its application in total synthesis of complex natural products

Palladium-catalyzed intramolecular Heck-type carbonylative cyclization cascade reaction and its application in total synthesis of complex natural products

Silver-Catalyzed Carbamoylation and Carbonylative Cyclization of Alkenes with Oxamic Acids.

Transition metal-catalyzed carbonylation functionalization reaction of alkenes is an attractive research area in modern organic chemistry. However, there have been very few reports on silver-catalyzed reactions in carbonylation reactions. Herein we developed a silver-catalyzed carbamoylation and carbonylative cyclization of alkenes with oxamic acids to obtain 2-acetylamino-1-tetralone derivatives. Various desired cyclized products were formed in moderate to good yields through radical intermediates.

Rh-Catalyzed Carbonylative Cyclization of Propargylic Alcohols with Aryl Boronic Acids.

2(3H)-Furanones are tremendously important not only because of their wide occurrence in bioactive compounds but also due to their versatility in organic synthesis. Here, a straightforward approach to 2(3H)-furanones from readily available tertiary propargylic alcohols with arylboronic acids in the presence of CO using rhodium as a catalyst has been established. The method exhibits a broad substrate scope tolerating useful functional groups with a moderate to high stereoselectivity.

Site-Selective Carbonylative Cyclization with Two Allylic C-H Bonds Enabled by Radical Differentiation.

Controlling the site-selectivity of C-H functionalization is of significant importance and a formidable undertaking in synthetic organic chemistry, motivating the continuing development of efficient and sustainable technologies for activating C-H bonds. However, methods that control the site-selectivity for double C-H functionalization are rare. We herein report a conceptually new method to achieve highly site-selective C-H functionalization by implementing a radical single-out strategy. Leveraging the steric hindrance-sensitive CO-insertion as the radical differentiation process, a site-selective and stereoselective carbonylative formal [2 + 2] cycloaddition of imines and alkenes by sequential double allylic C-H bond activation was established without special and complicated HAT-reagents. This reaction was compatible with a wide range of alkenes and imines with diverse skeletons to deliver allylic β-lactams that are of synthetic and medicinal interest.

Palladium-Catalyzed Three-Component Cascade Carbonylation Reaction to Construct Benzofuran Derivatives.

A novel three-component cyclization carbonylation reaction of iodoarene-tethered propargyl ethers with amine and CO is reported. This palladium-catalyzed cascade reaction undergoes a sequence of oxidative addition, unsaturated bond migration, carbonyl insertion, and nucleophilic attack to deliver the benzofuran skeleton. Both aromatic amines and aliphatic amines could proceed smoothly in this transformation under one atm of CO.

Iron-Catalyzed Aminoalkylative Carbonylative Cyclization of Alkenes toward α-Tetralones.

Carbonylative multifunctionalization of alkenes is an efficient approach to introduce multiple functional groups into one molecule from easily available materials. Herein, we developed an iron-catalyzed radical relay carbonylative cyclization of alkenes with acetamides. Various α-tetralones can be constructed in moderate yields from readily available substrates with an earth-abundant iron salt as the catalyst.

Photochemical properties and toxicity of fluoroquinolone antibiotics impacted by complexation with metal ions in different pH solutions

Acid-base dissociable antibiotic-metal complexes are known to be emerging contaminants in the aquatic environments. However, little information is available on the photochemical properties and toxicity of these complex forms. This study investigated the spectral properties of three fluoroquinolones (FQs) with and without metal ions Fe(III), Cu(II), and Al(III) in solutions under different pH conditions, as well as evaluated the changes in toxicity due to the complex with these metal ions using luminescent bacteria (vibrio fischeri). FQs showed a higher tendency to coordinate metal ions under alkaline conditions compared to neutral and acidic conditions, and the formation of complexes weakened the ultraviolet-absorbing ability of FQs. At pH = 7.0, Cu(II) quenched the fluorescence intensity of FQs. Moreover, their Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy were explored, revealing that the coordination sites of Cu(II) in three FQs were situated in a bidentate manner through the oxygen atom of the deprotonated carboxyl group and cyclic carbonyl oxygen atom. This conclusion was further verified by the theory of molecular surface electrostatic potential. In addition, except for complexes of ciprofloxacin-metals, enhanced toxicity of FQs upon coordination with Fe(III) was observed, while reduced toxicity was found for coordination with Cu(II) and Al(III). These results are important for accurately evaluating the photochemical behavior and risk of these antibiotics in aquatic environments contaminated with metal ions.

Enhanced Selectivity in 4-Quinolone Formation: A Dual-Base System for Palladium-Catalyzed Carbonylative Cyclization with Fe(CO)5.

The use of gaseous CO in Pd-catalyzed carbonylative quinolone synthesis presents challenges related to safety and precise pressure control. In response, a streamlined non-gaseous synthesis of 4-quinolone compounds has been developed. This study introduces a tunable CO-releasing system utilizing Fe(CO)5 activated by a dual-base system of piperazine and triethylamine. This alternative liquid CO resource facilitates the palladium-catalyzed carbonylative C-C coupling and subsequent intramolecular cyclization. By tuning the tandem kinetics of carbonylation and cyclization, this non-gaseous method achieves the successful synthesis of 22 distinct 4-quinolones with excellent yields. This is achieved through the three-component condensation of sub-stoichiometric amounts of Fe(CO)5 with 2-iodoaniline and terminal alkynes. Operando mechanistic studies have revealed a novel CO transfer mechanism that facilitates homogeneous carbonylative cyclization, distinguishing this method from traditional techniques. In addition to addressing safety concerns, this approach also provides precise control over selectivity, with significant implications for pharmaceutical research and the efficient synthesis of pharmaceutical and bioactive compounds.

Tropospheric Photochemistry of 2-Butenedial: Role of the Triplet States, CO and Acrolein Formation, and the Experimentally Unidentified Carbonyl Compound—Theoretical Study

Solar irradiation of 2-butenedial in the lower troposphere mainly produces isomeric ketene-enol (a key intermediate product), furanones, and maleic anhydride, the formation pathways of which were investigated in a previous study. The other main products were carbon monoxide and an experimentally unidentified carbonyl compound. This was the subject of the present study. The oxidative reaction mechanisms were studied using DFT calculations. Water intervention is found essential. Its addition and subsequent water-assisted isomerizations (an ene-gem-diol/enol and a carboxylic acid/enol form), followed by cyclization, lead to an interesting cyclic carbonyl compound, but this pathway appears to be rather energy demanding. An alternative implies water cooperation in a ketene-enol + carboxylic acid/enol addition that gives the relevant anhydride. The anhydride is proposed as a candidate for the experimentally unidentified carbonyl product. Regarding CO and acrolein formation, the role of the triplet states, as defined by the probability of intersystem crossing from the excited singlet state S1 to T2 and T1, is discussed. The T1 photolysis pathway connecting butenedial to propenal + CO was then defined.

Carbonylative cyclization of biaryl enones with aldehydes and oxamic acids.

An oxidative radical-promoted carbonylative cyclization strategy for the synthesis of phenanthren-9-(10H)-one frameworks from biaryl enones using aldehydes as the carbonyl radical sources is disclosed. The reaction proceeds through a sequential addition of a carbonyl radical to the olefin followed by cyclization with an aryl ring. The method is further extended to carbamoyl radicals generated from oxamic acids to access the corresponding phenanthrenones with amide functionalities.

Rational design of a cyclohexanone dehydrogenase for enhanced α,β-desaturation and substrate specificity.

The selective α,β-desaturation of cyclic carbonyl compounds, which are found in the core of many steroid and bioactive molecules, using green chemistry is highly desirable. To achieve this task, we have for the first time described and solved the de novo structure of a member of the cyclohexanone dehydrogenase class of enzymes. The breadth of substrate specificity was investigated by assaying the cyclohexanone dehydrogenase, from Alicycliphilus denitrificans, against several cyclic ketones, lactones and lactams. To investigate substrate binding, a catalytic variant, Y195F, was generated and used to obtain a crystallographic complex with the natural substrate, cyclohexanone. This revealed substrate-active site interactions, as well as the proximity of the cofactor, flavin adenine dinucleotide, and enabled us to propose a mechanistic function to key amino acids. We then used molecular dynamic simulations to guide design to add functionality to the cyclohexanone dehydrogenase enzyme. The resulting W113A variant had overall improved enzyme activity and substrate scope, i.e., accepting the bulkier carbonyl compound, dihydrocoumarin. Structural analysis of the W113A variant revealed a broader, more open active site, which helped explain the modified substrate specificity. This work paves the way for future bespoke regioselective α,β-desaturation in the synthesis of important bioactive molecules via rational enzyme engineering.

Green Synthesis of 3‐Alkylidenefuran‐2‐ones by Palladium‐Catalyzed Cyclocarbonylation of Aryl Iodides with Benzyl Acetylenes in 2‐MeTHF

AbstractA novel, highly efficient heterogeneous palladium‐catalyzed carbonylative cyclization of aryl iodides and benzyl acetylenes has been developed under an atmospheric pressure of CO. The reaction proceeds smoothly in a bioderived solvent 2‐methyltetrahydrofuran (2‐MeTHF) at 50 °C using an MCM‐41‐anchored bidentate phosphine palladium complex [Pd(OAc)2‐MCM‐41‐P,P] as catalyst with DiPEA as base, delivering a wide variety of 3‐alkylidenefuran‐2‐ones in good to excellent yields. The Pd(OAc)2‐MCM‐41‐P,P complex can be easily recovered by a simple centrifugation and recycled more than ten times without any remarkable loss of catalytic activity. The present method not only avoids the use of toxic solvents such as benzene, toluene and THF, but also addresses the key problem of expensive palladium catalyst recovery and recycle, thus preventing palladium contamination in the final product.

Rh(I)-Catalyzed Cascade Carbonylative Cyclization of Propargyl α-Diazoindolacetates for Construction of Carbazoles.

A Rh(I)-catalyzed carbene migration/carbonylation/cyclization (MCC) strategy has been established for the construction of diverse functionalized carbazoles from propargyl α-diazoindolacetates. Rh(I)-stabilized carbene with different electrophilic properties displays specific reactivity toward alkyne and CO during the transformation, ensuring the smooth progress of the tandem cyclization. Other heteroaryl scaffolds were achieved simultaneously through this cascade protocol, thus offering a straightforward pathway toward functionalized polycyclic aromatic molecule synthesis.

An efficient synthesis of the last step key intermediate for telmisartan via Pd-catalyzed carbonylative cyclization

The Pd-catalyzed carbonylative cyclization method is adopted for the synthesis of the penultimate intermediate of telmisartan. This highly atom-efficient reaction proceeded smoothly to provide target intermediate 1 with 87% yield under CO pressure (1 MPa) in toluene at 100 °C. Furthermore, the utilization of HNO3/H2SO4 in making benzimidazole 5 and polyphosphoric acid (PPA) in making bis-benzimidazole 7 in the existing processes are avoided.