Palladium-catalyzed Carbonylation Research Articles

Palladium-catalyzed difluoroalkylative carbonylation of unactivated alkenes toward γ-Lactams

Palladium-catalyzed difluoroalkylative carbonylation of unactivated alkenes toward γ-Lactams

Ten-Step Total Synthesis of (±)-Phaeocaulisin A Enabled by Cyclopropanol Ring-Opening Carbonylation.

We report an efficient total synthesis of (±)-phaeocaulisin A, a guaianolide sesquiterpene natural product possessing a complex tetracyclic skeleton embedded with an oxaspirolactone and a fused bicyclic lactone, four oxygen-containing stereocenters, and an 8-oxabicyclo[3.2.1]octane core. Our synthesis features a novel palladium-catalyzed cyclopropanol ring-opening carbonylation to access a key γ-ketoester, a chemo- and stereoselective aldol cyclization to form the seven-membered carbocycle, and a cascade ketalization-lactonization to construct the desired tetracyclic skeleton. With these strategically important C-C and C-O bond formation transformations, a 10-step total synthesis of (±)-phaeocaulisin A was achieved. We further developed the cyclopropanol ring-opening carbonylation chemistry to provide an alternative approach to prepare γ-ketoesters. Biologically, the penultimate intermediate with an α-methylene γ-butyrolactone moiety was identified as a promising lead compound with anticancer proliferation activity against a panel of triple-negative or HER2+ breast cancer cell lines.

Synthesis of Lactic Acid via Palladium-Catalyzed Carbonylation of Vinyl Acetate

The methoxycarbonylation of vinyl acetate monomer (VAM) was studied with Pd-catalysts at 5.4 MPa CO partial pressure and 373 K. The effects of several acidic and basic ligands in the presence and absence of a promoter were investigated. Using pyridine as ligand in the [PdCl2(PPh3)2]-TsOH catalyst system resulted in 90.01% conversion of VAM and 76.12% selectivity for carbonylation products (methyl-2-acetoxypropionate and methyl lactate). The VAM methoxycarbonylation could be facilitated in a non-polar solvent media and produces methyl-2-acetoxypropionate and methyl lactate, which can be easily converted to lactic acid via hydrolysis.

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.

Palladium-Catalyzed Asymmetric Desymmetrization for the Simultaneous Construction of Chiral Phosphorus and Quaternary Carbon Stereocenters.

A palladium-catalyzed asymmetric tandem Heck and carbonylation of bisallyl-phosphine oxides has been developed. This desymmetrization process provided an efficient route to the simultaneous synthesis of a chiral P-stereogenic center and a chiral quaternary carbon stereocenter in good yields with good diastereo- and enantioselectivities.

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.

Palladium-Catalyzed Cascade Carbonylation Reaction: Synthesis of Fused Isoindolinones.

A palladium-catalyzed cascade carbonylation reaction of 2-bromo-N-(2-iodophenyl)benzamides with benzylidenecyclopropanes for the synthesis of fused isoindolinone derivatives has been developed. A broad range of 6/5/6/6 tetracyclic isoindolinone products were efficiently prepared in moderate to good yields with diverse substitution. Two carbonyl groups were incorporated into the substrates in a single step with the formation of four carbon-carbon bonds and two carbon-heteroatom bonds.

Synthesis of Multisubstituted 2,3-Allenamides via Palladium-Catalyzed Carbonylation of Propargylic Esters.

2,3-Allenamides are an important class of unsaturated group-substituted carbonyl compounds. A palladium-catalyzed aminocarbonylation of propargyl acetates with amines for the synthesized tri-/tetrasubstituted 2,3-allenamides has been developed. A broad range of tri-/tetrasubstituted 2,3-allenamides have been prepared from propargyl acetates in good to excellent yields. The reaction featured mild reaction conditions and good functional group tolerance. The applicability of this methodology was further highlighted by the late-stage modification of several natural products and pharmaceuticals.

Palladium-Catalyzed Multicomponent Carbonylation of Halides to Acylhydrazones.

The current methods for synthesizing acylhydrazones are limited by their multistep processes, narrow substrate scope, low selectivities, and poor yields. Herein, a fundamentally novel approach to bioactive acylhydrazones was developed based on the palladium-catalyzed multicomponent tandem condensation carbonylation of halides with aldehydes and hydrazines. This method provides a useful and efficient strategy for generating grams of various acylhydrazones in a one-pot manner. Mechanistic studies provided evidence of facile carbonylation of halides with the weak nucleophile hydrazones facilitated by a base.

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.

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.

A general palladium-catalyzed carbonylative synthesis of α-CF3-substituted ketones and carboxylic acid derivatives

α-CF3-substituted carboxylic acid derivatives have drawn wide attention owing to their importance for both pharmaceutical and synthetic communities. However, methodologies for their construction are still very limited. Herein, we developed a general palladium-catalyzed carbonylative procedure for the synthesis of α-CF3-substituted ketones and carboxylic acid derivatives. With amines, phenols, alcohols, arylboronic acids, and even less-nucleophilic sulfonamides and amides as the reaction partners, the corresponding amides, esters, ketones and imides were obtained in good yields with excellent functional group tolerance. Furthermore, this protocol has also been applied to the late-stage modification of 25 densely functionalized pharmaceutical agents and natural products.

Palladium-Catalyzed Esterification of Aryl Fluorosulfates with Aryl Formates.

An efficient palladium-catalyzed carbonylation of aryl fluorosulfates with aryl formates for the facile synthesis of esters was developed. The cross-coupling reactions proceeded effectively in the presence of a palladium catalyst, phosphine ligand, and triethylamine in DMF to produce the corresponding esters in moderate to good yields. Of note, functionalities or substituents, such as nitro, cyano, methoxycarbonyl, trifluoromethyl, methylsulfonyl, trifluoromethoxy, fluoro, chloro, bromo, methyl, methoxy, N,N-dimethyl, and [1,3]dioxolyl, were well-tolerated in the reactions, which could be kept for late-stage modification. The reactions employing readily available and relatively robust aryl fluorosulfates as coupling electrophiles could potentially serve as an attractive alternative to traditional cross-couplings with the use of aryl halides and pseudohalides as substrates.

Palladium-Catalyzed Iodine Assisted Carbonylation of Indoles with ClCF2CO2Na and Alcohols.

A palladium-catalyzed iodine-assisted carbonylation reaction of indoles with readily available ClCF2CO2Na and alcohols has been developed. This protocol provides a practical and efficient approach to highly regioselective indole-3-carboxylates via a preiodination strategy of indoles. Different from classic carbonylation using toxic and difficult-to-handle carbon monoxide, this operationally simple and scalable reaction employed difluorocarbene as the carbonyl surrogate.

Competing Mechanisms in Palladium-Catalyzed Alkoxycarbonylation of Styrene.

Palladium-catalyzed carbonylation is a versatile method for the synthesis of various aldehydes, esters, lactones, or lactams. Alkoxycarbonylation of alkenes with carbon monoxide and alcohol produces either saturated or unsaturated esters as a result of two distinct catalytic cycles. The existing literature presents an inconsistent account of the procedures favoring oxidative carbonylation products. In this study, we have monitored the intermediates featured in both catalytic cycles of the methoxycarbonylation of styrene PhCH=CH2 as a model substrate, including all short-lived intermediates, using mass spectrometry. Comparing the reaction kinetics of the intermediates in both cycles in the same reaction mixture shows that the reaction proceeding via alkoxy intermediate [PdII]-OR, which gives rise to the unsaturated product PhCH=CHCO2Me, is faster. However, with an advancing reaction time, the gradually changing reaction conditions begin to favor the catalytic cycle dominated by palladium hydride [PdII]-H and alkyl intermediates, affording the saturated products PhCH2CH2CO2Me and PhCH(CO2Me)CH3 preferentially. The role of the oxidant proved to be crucial: using p-benzoquinone results in a gradual decrease of the pH during the reaction, swaying the system from oxidative conditions toward the palladium hydride cycle. By contrast, copper(II) acetate as an oxidant guards the pH within the 5-7 range and facilitates the formation of the alkoxy palladium complex [PdII]-OR, which favors the oxidative reaction producing PhCH=CHCO2Me with high selectivity. Hence, it is the oxidant, rather than the catalyst, that controls the reaction outcome by a mechanistic switch. Unraveling these principles broadens the scope for developing alkoxycarbonylation reactions and their application in organic synthesis.

Palladium-Catalyzed Carbonylation Reaction of Indole/Pyrrole Involving HCFO-1233zd (E).

3-Indole-3-one is a key intermediate in the synthesis of many drugs and plays an important role in synthetic chemistry and biochemistry. A new method for synthesizing trifluoromethylated 3-indoleketones by Pd(0)-catalyzed carbonylation was introduced. In the absence of additives, 1-chloro-3,3,3-trifluoropropyl (an inexpensive and environmentally friendly synthetic block of trifluoromethyl) reacts with indole and carbon monoxide to generate trifluoromethylindole ketones with good yields, regioselectivity, and chemical selectivity; furthermore, the products exhibit strong resistance to basic functional groups, such as alkynes, aldehydes, and esters. In addition to the conversion of indole compounds into corresponding products, pyrrole and heteroindole may be suitable for corresponding chemical transformations. This study provides a synthetic method for the further construction of trifluoromethylated 3-indole ketones.

Identification of a potent palladium-aryldiphosphine catalytic system for high-performance carbonylation of alkenes

The development of stable and efficient ligands is of vital significance to enhance the catalytic performance of carbonylation reactions of alkenes. Herein, an aryldiphosphine ligand (L11) bearing the [Ph2P(ortho-C6H4)]2CH2 skeleton is reported for palladium-catalyzed regioselective carbonylation of alkenes. Compared with the industrially successful Pd/1,2-bis(di-tert-butylphosphinomethyl)benzene catalyst, catalytic efficiency catalyzed by Pd/L11 on methoxycarbonylation of ethylene is obtained, exhibiting better catalytic performance (TON: >2,390,000; TOF: 100,000 h−1; selectivity: >99%) and stronger oxygen-resistance stability. Moreover, a substrate compatibility (122 examples) including chiral and bioactive alkenes or alcohols is achieved with up to 99% yield and 99% regioselectivity. Experimental and computational investigations show that the appropriate bite angle of aryldiphosphine ligand and the favorable interaction of 1,4-dioxane with Pd/L11 synergistically contribute to high activity and selectivity while the electron deficient phosphines originated from electron delocalization endow L11 with excellent oxygen-resistance stability.

Palladium-catalyzed directly carbonylative synthesis of fluoro-substituted malonates from (fluoro)bromoacetates

Traditional procedures toward 2-fluoromalonates tend to meet overfluorination. Herein, we describe a mild and efficient palladium-catalyzed carbonylative strategy for the synthesis of dialkyl 2-fluoromalonate derivatives avoided the mentioned challenges. By this new procedure, a range of malonates and difluoromalonate derivatives were prepared with good functional-group tolerance and excellent chemoselectivity. This procedure can also be applied in the late-stage carbonylation of various bioactive molecules. Furthermore, a low-pressure experiment and two scale-up reactions were performed smoothly in good to excellent yield.

Palladium-Catalyzed Carbonylative Multicomponent Fluoroalkylation of 1,3-Enynes: Concise Construction of Diverse Cyclic Compounds.

Multicomponent reactions, particularly those entailing four or more reagents, have presented a longstanding challenge due to the inherent complexities associated with balancing reactivity, selectivity, and compatibility. In this study, we describe a palladium-catalyzed multi-component fluoroalkylative carbonylation of 1,3-enynes. A series of products featuring three active functional groups-allene, fluoroalkyl, and carboxyl, were efficiently and selectively integrated in a single chemical operation. Furthermore, more intricate fluoroalkyl-substituted pyrimidinones can be constructed by simply altering the 1,3-bisnucleophilic reagent. This approach also provides a valuable strategy for the late-stage modification of naturally occurring molecules and concise construction of diverse cyclic compounds.

Palladium-catalyzed desulfonylative carbonylation reaction of benylsulfonyl chlorides with anthranils for the synthesis of 3-arylquinoin-2(1H)-ones

A direct and efficient palladium-catalyzed desulfonylative carbonylation reaction for the synthesis of 3-arylquinoin-2(1H)-ones has been disclosed. The reaction proceeds with a rapid elimination of SO2 process by employing benzylsulfonyl chlorides as effective C(sp3) electrophiles, with anthranils as the N-source, a variety of 3-arylquinoin-2(1H)-ones were obtained in moderate to high yields. This protocol provides a good supplement for applying benzylsulfonyl chlorides as C(sp3) electrophiles in carbonylation reactions.