Palladium-catalyzed Carbonylation Research Articles

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 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.

Palladium-catalyzed carbonylation of activated alkyl halides via radical intermediates

In this review, we summarize and discuss recent achievements in palladium-catalyzed carbonylative reactions of activated alkyl halides. Aliphatic carboxylic acid derivates were prepared effectively with various nucleophiles.

Palladium-catalyzed allylation and carbonylation: access to allylhydrazones and allyl acylhydrazones.

A palladium-catalyzed allylation of hydrazines with allyl alcohols and aldehydes was developed, enabling the syntheses of a series of allylhydrazones in good to excellent yields with high regioselectivity. Furthermore, the four-component tandem allylation carbonylation of hydrazines with allyl alcohols and aldehydes was established using the catalytic system, producing various allyl acylhydrazones. Additionally, the functionalized allyl acylhydrazones could be smoothly constructed with the catalytic system employing allylhydrazones as a partner. The catalytic system exhibited good functional tolerance with excellent regioselectivities and scaled-up capability, overcoming the limitations of chemoselectivity of the multicomponent transformation and poor conversion of the weak nucleophile.

Palladium-Catalyzed Tandem Cyclization of Bromoalkynes, Anilines and CO: Access to 1,3-Substituted Maleimides.

A novel palladium-catalyzed three-component carbonylation reaction for the assembly of various 1,3-substituted maleimide derivatives from haloalkynes and simple anilines. The nucleophilic addition reaction of haloalkynes, anilines and CO, and insertion of carbonyl have been achieved sequentially in this reaction. The high chemo- and regioselectivities, as well as no need of expensive ligands or additives further illustrate the synthetic value of this approach.

Palladium-catalyzed tandem carbonylative synthesis of indeno[1,2-b]indol-10(5H)-one scaffolds from 2-alkynylanilines

A novel palladium-catalyzed tandem cyclization and carbonylation of 2-alkynylanilines has been developed for the construction of indeno[1,2-b]indol-10(5H)-one scaffolds. By using formic acid as the CO source, this reaction proceeded smoothly to afford various indeno[1,2-b]indol-10(5H)-one derivatives in high yields. Notably, this protocol can be used in modifications of several bioactive molecules.

Extension of Highly Efficient Alcohol-promoted Rearrangement into One-pot Domino Palladium-catalyzed Carbonylation for Sterically Crowded Aromatic Six-membered Imides

Extension of Highly Efficient Alcohol-promoted Rearrangement into One-pot Domino Palladium-catalyzed Carbonylation for Sterically Crowded Aromatic Six-membered Imides

A straightforward trifluoromethylation at the C6 position of morphinane alkaloids, their modification and evaluation of inhibition of the SARS-CoV-2 main protease

A catalytic trifluoromethylation of stereoisomeric 6-ketomorphinans using Ruppert–Prakash reagent and tetrabutylammonium fluoride (TBAF) was studied. 14β-Hydroxycodeinone, 4-O-methylsinomenine and 1-iodo-4-O-methylsinomenine provided good to excellent yields of the corresponding 6-trifluoromethylated compounds. The new morphinan derivative (6-deoxo-1-iodo-6α-(trifluoromethyl)-4-O-methylsinomenin-6β-ol) was involved in some catalytic transformations for introduction of additional substituent on C-1 position of the morphinan core. The palladium-catalyzed carbonylation–cross coupling reaction of 1-iodo-derivative with phenylacetylene in the presence of PdCl2-(1-Ad)2PBn catalytic system and Mo(CO)6 as a source of carbon monoxide in MeCN proceeds with high selectivity with the formation of alkynyl ketone as the main product. The cyclocondensation with acetamidine hydrochloride afforded the arylpyrimidine – 6α-(trifluoromethyl)-4-O-methylsinomenin-6β-ol hybrid compound. The action of the dehydration system (SOCl2-Py-DMAP) on 6-deoxo-6α-(trifluoromethyl)-4-O-methylsinomenin-6β-ol have led to the formation оf 8β‑chloro-6,7-didehydro-6-(trifluoromethyl)morphinan which showed inhibition the main viral protease (3CLpro) of SARS-CoV-2 at IC50 value of 25 μM.

Palladium-Catalyzed Carbonylative Homocoupling of 2-Iodophenols for the Synthesis of Symmetrical Xanthones

AbstractHerein, we report the palladium-catalyzed carbonylative synthesis of symmetrical xanthones from functionalized 2-iodophenols in a one-pot manner. The protocol involves homocoupling of 2-iodophenols using Pd catalyst, Cs2CO3 as base, with gaseous CO as C1 building block. The simple, ligand- and additive-free strategy provides moderate to good yields of symmetrical xanthones. The reaction was also examined with the combination of 2-hydroxyphenyl boronic acid as another coupling partner. Additionally, this protocol was extended for the synthesis of aryl and alkyl salicylate derivatives by varying the reaction conditions.

Palladium-Catalyzed Carbonylative Difunctionalization of Unactivated Alkenes Initiated by Unstabilized Enolates.

This report describes the first example of palladium-catalyzed carbonylative difunctionalization of unactivated alkenes initiated by enolate nucleophiles. The approach involves initiation by an unstabilized enolate nucleophile under an atmospheric pressure of CO and termination with a carbon electrophile. This process is compatible with a diverse range of electrophiles, including aryl, heteroaryl, and vinyl iodides to yield synthetically useful 1,5-diketone products, which were demonstrated to be precursors for multi-substituted pyridines. A PdI -dimer complex with two bridging CO units was observed although its role in catalysis is not yet understood.