Pd-catalyzed Carbonylation Research Articles

Challenges with Literature-Derived Data in Machine Learning for Yield Prediction: A Case Study on Pd-Catalyzed Carbonylation Reactions.

The application of machine learning (ML) to predict reaction yields has shown remarkable accuracy when based on high-throughput computational and experimental data. However, the accuracy significantly diminishes when leveraging literature-derived data, highlighting a gap in the predictive capability of the current ML models. This study, focusing on Pd-catalyzed carbonylation reactions, reveals that even with a data set of 2512 reactions, the best-performing model reaches only an R2 of 0.51. Further investigations show that the models' effectiveness is predominantly confined to predictions within narrow subsets of data, closely related and from the same literature sources, rather than across the broader, heterogeneous data sets available in the literature. The reliance on data similarity, coupled with small sample sizes from the same sources, makes the model highly sensitive to inherent fluctuations typical of small data sets, adversely impacting stability, accuracy, and generalizability. The findings underscore the inherent limitations of current ML techniques in leveraging literature-derived data for predicting chemical reaction yields, highlighting the need for more sophisticated approaches to handle the complexity and diversity of chemical data.

Synthesis of 6- or 8-Carboxamido Derivatives of Imidazo[1,2-a]pyridines via a Heterogeneous Catalytic Aminocarbonylation Reaction.

Imidazo[1,2-a]pyridines and especially their amide derivatives exhibit a wide range of favourable pharmacological properties. In this work, Pd-catalysed carbonylation was used for the first time for the introduction of the carboxamide moiety into positions 6 or 8. A recyclable Pd catalyst, with palladium immobilised on a supported ionic liquid phase decorated with pyridinium ions, was used efficiently for the conversion of 6- or 8-iodo derivatives to the products. In the case of 6-iodo derivatives, a competing mono- and double carbonylation could be observed in the reactions of aliphatic amines as nucleophiles, but under the proper choice of reaction conditions, good-to-excellent selectivities could be achieved towards either the corresponding amides or α-ketomides. The heterogeneous catalyst showed excellent recyclability and low Pd-leaching.

Co2(CO)8 as a CO-source for Pd-catalyzed Carbonylations: An Update

Abstract: Palladium-catalyzed carbonylative cross-coupling reactions with various carbon monoxide (CO) sources cultivate competent routes for the synthesis of bulk and value-added chemicals. However, the practical use of this odorless, inflammable, lethal gas has always raised a concern for chemists. The attention and advancement of various CO-surrogates is surely wel-comed as a green alternative to CO-gas. However, the main concern lies in the suitability and scalability of these CO-surrogate-driven reactions. Literature showed the progress of various ways to make in-situ CO from these CO surrogates. One of the most convenient sources is using metal carbonyls which are already known to lose CO easily. Among all the kinds, Mo(CO)6 gained much popularity but its toxic nature and demand for high temperatures restricted its use. However, Co2(CO)8 is popular as a catalyst but as an in-situ CO-source reports are scarce. This low-melting CO-releaser was found effective in flourishing aminocarbonylation, alkoxycar-bonylation, and reductive carbonylation under mild conditions. This mini-review portrays the recent developments of palladium-catalyzed carbonylation reactions using Co2(CO)8 as a CO source.

Mechanistic Insights into the Palladium-Catalyzed Perfluoroalkylative Carbonylation of Unactivated Alkenes to β-Perfluoroalkyl Esters: A DFT Study.

Transition metal-catalyzed multicomponent carbonylation is an efficient synthetic strategy to access multifunctional esters in high yields with broad functional group tolerance and good chemoselectivity. Considering the development of highly efficient synthetic methods for esters, it remains significant to grasp the mechanism of constructing multifunctional esters. Herein, density functional theoretical calculations were carried out to acquire mechanistic insight into the synthesis of β-perfluoroalkyl esters from a specific palladium-catalyzed perfluoroalkylative carbonylation of unactivated alkenes using carbon monoxide. A detailed mechanistic understanding of this reaction route includes (1) multistep radical reaction process, (2) C-C coupling and CO insertion, (3) ligand exchange, and (4) Pd-based intermediate oxidation and reductive elimination. The multistep radical process was fundamentally rationalized, including Rf· formation and radicals A and E from unactivated alkene and CO oxidation, respectively. The potential energy calculation indicated that the CO insertion into the perfluorinated alkyl radicals preceded Pd-catalyzed oxidation in the competitively multistep free radical reaction process. In addition, the I-/PhO- exchange step was predicted to be spontaneous to products. The IGMH analysis further attested to the reductive elimination process involved in the rate-determining step. Thus, a simple and valid density functional theory (DFT) approach was developed to reveal the multistep radical mechanism for the Pd-catalyzed perfluoroalkylative carbonylation of unactivated alkenes to access functional β-perfluoroalkyl esters.

Stereoselective Synthesis of 3,4-Dihydrobenzofuro[3,2-b]pyridin-2(1H)-ones Enabled by Pd/Chiral Isothiourea Relay Catalysis

AbstractA highly enantioselective [4+2] cyclization of azadienes with ketene in situ generated from Pd-catalyzed carbonylation of benzyl bromides, is established through Pd/chiral isothiourea relay catalysis. The key in this transformation is the formation of a C1-ammonium enolate from the in situ generated ketene and a chiral isothiourea catalyst, which subsequently undergoes a formal [4+2] reaction, leading to 3,4-dihydrobenzofuro[3,2-b]pyridine derivatives in high yields and excellent levels of stereoselectivity.

Pd-catalyzed CO-free double carbonylation for the synthesis of 1,4-ketoesters with Mo(CO)6 as the carbonyl source.

An unprecedented Pd-catalyzed CO-free double carbonylation using Mo(CO)6 as a safe carbonyl source for the efficient synthesis of 1,4-ketoesters in an atom- and step-economic manner has been developed. The current method features operational safety, a wide substrate range, good functional group compatibility and easy scale-up. The application of carbonylation using a safe carbonyl source for the synthesis of biologically and synthetically useful carbonyl-containing molecules is underway in our lab.

The synthesis of alk-2-ynl Weinreb amides via Pd/Cu-catalysed oxidative carbonylation of terminal alkynes.

Synthesis of alk-2-ynl-Weinreb amides via Pd-catalyzed oxidative carbonylation of terminal alkynes and N,O-dimethylhydroxylamine hydrochloride at room temperature under low CO/O2 pressure is reported for the first time. This protocol offers tolerance of various functional groups under mild reaction conditions. The protocol incorporates aromatic- and aliphatic-substituted alkynes through a one-step oxidative carbonylative route toward desired alkynyl Weinreb amides, which are of considerable importance as valuable synthetic building blocks.

Supported Pd-catalyzed decarboxylative carbonylation reaction of 2-alkynoic acids and aryl iodides

A tandem polystyrene-supported Pd catalyzed decarboxylative carbonylation reaction between 2-alkynoic acids and aryl iodides using oxalic acid as a CO source under milder reaction conditions with vast substrate scope has been developed.

"One pot" synthesis of quinazolinone-[2,3]-fused polycyclic scaffolds in a three-step reaction sequence.

Diverse quinazolinone-[2,3]-fused polycyclic skeletons occupy a prominent position in drug discovery. Even with currently available methods there still remain unmet needs for flexible access to such structures. Herein, we have explored a mild "one pot" procedure for the construction of various quinazolinone-[2,3]-fused polycycles. The procedure involves Pd-catalyzed carbonylation of N-(2-iodophenyl)acetamides, release of the masked terminal amine, and two sequential and spontaneous cyclizations. This generally applicable approach features easy assembly of precursors from readily available starting materials, mild reaction conditions, non-cumbersome operation, and polycyclic diversity.

Robust Phosphine-based Covalent-Organic Framework Palladium Catalysts for the Highly Efficient Carbonylation Coupling Reaction

The first vinyl-linked PPh3-based covalent-organic frameworks (Pd@TMBen-PPh3 and Pd@TMBen-4F-PPh3) were facilely constructed via direct three-component Knoevenagel condensation, which could serve as outstanding heterogeneous catalysts for the Pd-catalyzed carbonylation coupling reaction...

Pd-Catalyzed Carbonylation of Propargylic Acetates to Access Non-Symmetrical Diamides and Amido Esters

Pd-Catalyzed Carbonylation of Propargylic Acetates to Access Non-Symmetrical Diamides and Amido Esters

Application of Pd-catalyzed carbonylation followed by spontaneous oxa-Michael addition/diastereoselective reduction of ynone: Synthesis of (+)-goniofufurone

Synthesis of (+)-goniofufurone isolated from Goniothalamus giganteus was achieved. The key steps involve Pd-catalyzed carbonylation followed by spontaneous oxa-Michael reaction for lactone ring formation and diastereoselective reduction of ynone for preparing the chiral building block toward the synthesis of the titled compound.

Palladium-Catalyzed C-N Coupling in the Synthesis of 1,4-Benzodiazepines Fused with 5-Membered Carbo- and Heterocycles

Abstract: In this review, we have focused our attention on Pd-catalyzed amination and arylation reactions for the construction of various benzodiazepine scaffolds. It includes numerous types of synthetic strategies like C-H arylation, Pd-catalyzed carbonylation, and Buchwald Hartwig coupling. To synthesize different functionalized benzodiazepines, the domino processes as intra- or intermolecular reactions are developed as an eco-friendly and effective tool. Benzodiazepines exhibit several biological activities and play a valuable role in medicinal and pharmaceutical chemistry. This review article mainly focuses on synthesizing a 1,4- benzodiazepine nucleus fused with 5-membered carbo- and heterocycles in the presence of palladium catalysts.

Pd-catalyzed oxidative carbonylation of sulfurated substrates: Theoretical mechanistic outcomes

In the present study, a detailed computational investigation has been carried out on the recently reported PdI2/KI-catalyzed conversion of 1-(methylthio)-3-yn-2-ols to thiophene-3-carboxylate esters, using 2-methyl-1-(methylthio)oct-3-yn-2-ol as the model substrate. On the basis of a number of mechanistic hypotheses that were taken into account, outcomes on the energetic feasibility of the generally-accepted reaction scheme for this process have been provided. The current investigation indeed dissects the role of each species coming into play during the reaction, in each step of the mechanism. In detail, the contribution of co-catalytic KI for the demethylation of the S-containing nucleophilic agent, concertedly to the 5-endo-dig mechanism, from the early stage of the reaction has been highlighted, as well as the role of transient dimethyl ether cation for the dehydration step and that of the solvent methanol molecules for the formation/energy stabilization of the product. The calculated barriers are in good agreement with available experimental data.

In-situ formed aryl acid-triggered intramolecular dehydrative cyclization whilst supported Pd-catalyzed carbonylative synthesis of 2-aryl benzimidazoles

Herein, polystyrene supported palladium (Pd@PS) nanoparticles (NPs) catalyzed carbonylative synthesis of 2-aryl benzimidazoles from aryl iodides and aromatic diamines has been introduced. In-situ formed aryl carboxylic acid was revealed as a catalyst for dehydrative cyclization of secondary (2°) and tertiary (3°) amides formed via aminocarbonylation between aryl iodides and aromatic diamines. Herein, oxalic acid acts as carbon monoxide (CO) and carbon dioxide (CO2) gases source plausibly leading to aminocarbonylation via CO gas as major pathway and carboxylation of aryl iodides via CO2 as minor pathway. The Pd@PS catalyst was found to be easily separable, air/moisture stable and recyclable under the targeted reaction conditions. In addition, the present protocol requires only catalytic amount of inorganic base (K2CO3) to achieve the highest yields of desired products.

Direct Access to α,β-Alkynylamides via Pd-Catalyzed Carbonylation of Terminal Alkynes with Amines Using Chloroform as the CO Surrogate.

We describe the first-time use of a palladium-di(1-adamantyl)-n-butylphosphine catalytic system for the synthesis of alk-2-ynamides from terminal alkynes via aminocarbonylation reaction. This method avoids the direct use of toxic CO gas by utilizing chloroform as an in situ CO source. The aminocarbonylation of both aromatic and aliphatic electron-rich alkyne nucleophiles is reported for the first time. The mild condition provides alk-2-ynamides within 50 min under microwave irradiation at 80 °C.

3-Cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione

The synthesis of a novel uracil derivative, 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4), is reported via a four-component reaction involving an α-chloroketone (1), an aliphatic isocyanate (2), a primary aromatic amine (3) and carbon monoxide. The proposed reaction mechanism involves a Pd-catalyzed carbonylation of 2-chloro-1-phenylethan-1-one (1), leading to a β-ketoacylpalladium key intermediate, and, at the same time, in situ formation of non-symmetrical urea deriving from cyclohexyl isocyanate (2) and p-toluidine (3). After a chemo-selective acylation of the non-symmetrical urea and the subsequent cyclization of the acylated intermediate, 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4) is formed. Uracil derivative 4 was isolated in good yield (73%) and fully characterized by 1H, 13C, 2D 1H-13C HSQC and 2D 1H-13C HMBC NMR, FT-IR spectroscopy and GC-MS spectrometry.

Asymmetric construction of phosphono dihydropyranones from α-ketophosphonates enabled by Pd/chiral isothiourea relay catalysis.

A highly enantio- and diastereoselective approach has been developed for the synthesis of chiral phosphono dihydropyranones. This approach is enabled by Pd/chiral isothiourea relay catalysis under mild reaction conditions, starting from readily available benzyl bromides, CO, and α-ketophosphonates. The cascade reaction involves the generation of a ketene intermediate from Pd-catalyzed carbonylation of benzyl bromide and subsequent chiral Lewis base catalyzed formal [4 + 2] reaction. Phosphono lactone products can also be transformed to chiral 1,5-diester products in good yield and high stereoselectivity.

Carbonylative Co- and Terpolymerizations of 10-Undecen-1-ol: A Route to Polyketoesters with Tunable Compositions

A strategy to synthesize branched polyketoesters from the carbonylative polymerization of bifunctional α,ω-alkenols such as 10-undecen-1-ol is presented. This strategy hinges on the competitive application of two related catalytic manifolds, alternating alkene/CO copolymerization, and alkene hydroesterification, which share a common metal acyl intermediate. Small molecule model studies of cationic Pd-catalyzed alkene carbonylation in the presence of alcohols demonstrate that the relative rates of ketone formation (through alternating alkene/CO insertion) and ester formation (through metal acyl alcoholysis) can be tuned across a wide range through judicious bis(phosphine) ligand design. Carbonylative polymerization of 10-undecen-1-ol with a (dppp(3,5-CF3)4)Pd(OTs)2 catalyst (dppp(3,5-CF3)4 = 1,3-bis[bis[3,5-bis(trifluoromethyl)phenyl]-phosphino]propane) led to the formation of high molecular weight polyketoesters with intermediate dispersity (Mn > 20,000 g/mol, D̵ = 2.6) and a ketone/ester microstructure ratio of approximately 1:2. In these polymerization reactions, deploying electron-deficient bis(phosphines) to suppress deleterious alkene isomerization was the key to accessing the high molecular weight polymer. Further, terpolymerization reactions of 1-hexene/10-undecen-1-ol/CO or 1-fluoro-10-undecene/10-undecen-1-ol/CO by (dppp(3,5-CF3)4)Pd(OTs)2 were also successful. This proof of concept polymerization unlocks access to tunable polymer microstructures without extensive postpolymerization treatment.

Light-Activated CO Donor as a Universal CO Surrogate for Pd-Catalyzed and Light-Mediated Carbonylation.

A low-molecular-weight, solid CO surrogate that only requires a low-power LED for activation to release 2 equiv of CO is reported. The surrogate can be universally implemented in various palladium-catalyzed carbonylative transformations. It is also compatible with protocols that employ blue-light to activate conventionally inaccessible substrates such as nonactivated alkyl halides. Furthermore, we demonstrate that the photolabile CO-releasing scaffold can be installed into polymeric materials, thereby creating new materials with CO-releasing capabilities.