Pd-catalyzed Alkoxycarbonylation Research Articles

Pinwheel-like tridentate phosphines for controlling divergent regioselectivity in Pd-catalyzed alkoxycarbonylation of alkenes

The elaborate control of regioselectivity regulated by the involved ligands with specific structural skeleton and compositions is always demanded in alkoxycarbonylation of alkenes. Herein, a series of pinwheel-like tridentate phosphine ligands with rotatable flexibility (L3) or hard rigidity (L5–L7) were synthesized and characterized for the first time, in which the incorporated three PPh2-fragments are located at meta-positions of phenyl groups. It was proved that the tridentate phosphine of L3 with the flexible configuration favorably corresponded to the linear regioselectivity with l/b ratio of 98/2, whereas L7 with the rigid configuration absolutely did favor to the branched regioselectivity with l/b ratio of 1/99. The presence of the three PPh2-frgaments in L3 did contribute to the remarkable performance of L3-Pd(TFA)2 system in terms of activity, linear regioselectivity and stability, subjected to 10-run recycling uses in anti-Markovnikov’s methoxycarbonylation of styrene without activity loss and Pd-black precipitation. In comparison, although the optimal L7-Pd(MeCN)2Cl2 system could catalyze Markovnikov’s alkoxycarbonylation of alkenes to afford the branched esters with excellent regioselectivity in the fresh use, its stability was too poor to support the recycling experiments. L3-Pd(TFA)2 and L7-Pd(MeCN)2Cl2 catalytic systems were both applicable to a wide range of substrates in alkoxycarbonylation of alkenes to afford the target esters in the isolated yields of 41–91 %, with the well maintained divergent regioselectivity.

Rationally designed acidic deep eutectic solvent induced catalysis and spontaneous catalyst recycling of Pd-catalyzed ethylene alkoxycarbonylation

Rationally designed DES-induced homogeneous catalysis and heterogeneous separation of alkoxycarbonylation enabled remarkably prolonged catalyst lifespan over homogeneous systems.

Gas-free alkoxycarbonylation of aryl iodides in a phosphonium-based deep eutectic solvent with Mo(CO)6 as a solid CO source.

Pd-catalyzed alkoxycarbonylation of aryl iodides has been explored, for the first time, in phosphonium-based deep eutectic solvents under gas-free conditions, by using Mo(CO)6 as the CO source. The method allows the preparation of ethylene glycol and glycerol esters in high yields (up to 99%), short reaction times and under mild reaction conditions with a very low catalyst loading (0.5 mol%).

Multiple-Functional Diphosphines: Synthesis, Characterization, and Application to Pd-Catalyzed Alkoxycarbonylation of Alkynes

Multiple-Functional Diphosphines: Synthesis, Characterization, and Application to Pd-Catalyzed Alkoxycarbonylation of Alkynes

Catalytic Transformations of Sulfonium Salts via C-S Bond Activation.

After the 20-year dormant period since Liebeskind's seminal report, triorganosulfonium salts have now proved to be reliably useful surrogates of or complement to organic halides in a variety of transition-metal-catalyzed transformations. By necessity, my group developed Suzuki-Miyaura ring-opening arylation of sulfonium salts of dibenzothiophenes with tetraarylborates and Pd-catalyzed intramolecular C-H/C-S coupling. Following this starting point and experiencing the decent reactivity of sulfonium salts, in order to maximize the synthetic utility of organosulfur compounds, we successfully applied readily available sulfonium salts to Ni-catalyzed coupling with arylzinc reagents, Pd- or photoredox-catalyzed Mizoroki-Heck reaction, Pd-catalyzed alkoxycarbonylation, Pd-catalyzed Miyaura borylation, Ni-catalyzed reductive carboxylation, and Ni-catalyzed zincation. I sincerely hope this Personal Account will facilitate further development of reactions of triorganosulfonium salts which are difficult to achieve using conventional organic (pseudo)halides.

State-of-the-art palladium-catalyzed alkoxycarbonylations

State-of-the-art Pd-catalyzed alkoxycarbonylation: catalyst development and applications.

Mechanism and Origin of Ligand-Controlled Chemo- and Regioselectivities in Palladium-Catalyzed Methoxycarbonylation of Alkynes.

Pd-catalyzed alkoxycarbonylation of alkynes provided a redox-neutral method to selectively access branched/linear α,β-unsaturated monoesters and 1,4-dicarboxylic acid diesters. Herein, a systematic computational study was performed to elucidate the mechanism and origin of ligand-controlled chemo- and regioselectivities. It is found that the catalytic cycle, including hydrometallation, carbon monoxide insertion, and methanolysis, is more likely than that involving palladium alkoxycarbonyl intermediates. Both hydrometallation and methanolysis stages are important to determine the chemo- and regioselectivities. Hydrometallation proceeds via anti-Markovnikov-selective migratory insertion or Markovnikov-selective ligand-participated electrophilic addition. A flexible bidentate phosphine ligand slows down migratory insertion due to the stronger trans effect of the CO ligand but accelerates the ligand-participated electrophilic addition by adopting better orbital orientations. On the other hand, a ligand-participated mechanism and an unrevealed mechanism involving ketene intermediates can promote methanolysis, whereas ligands with large bite angles or bulky substituents are detrimental to methanolysis. On the basis of these mechanistic foundations, the influence of the flexibility, basicity, bite angle, and steric hindrance of ligands on chemo- and regioselectivities was clarified. The present study provided more universal and deeper mechanistic insights into Pd-catalyzed alkoxycarbonylation reactions and shed light on the superior regulation performance of the bifunctional pyridyl-containing phosphine ligands.

Stereoselective Synthesis of Highly Substituted Conjugated Dienes via Pd-Catalyzed Carbonylation of 1,3-Diynes.

The stereoselective synthesis of conjugated dienes was realized for the first time via Pd-catalyzed alkoxycarbonylation of easily available 1,3-diynes. Key to success is the utilization of the specific ligand 1,1'-ferrocenediyl-bis(tert-butyl(pyridin-2-yl)phosphine) (L1), which allows this novel transformation to proceed at room temperature. A range of 1,2,3,4-tetrasubstituted conjugated dienes are obtained in this straightforward access in high yields and selectivities. The synthetic utility of the protocol is showcased in the concise synthesis of several important intermediates for construction of natural products rac-cagayanin, rac-galbulin, rac-agastinol, and cannabisin G.

Novel multi-dentate phosphines for Pd-catalyzed alkoxycarbonylation of alkynes promoted by H2O additive

A series of novel multi (bi-/tri-/tetra-)-dentate phosphines with good robustness against water and oxygen were synthesized and fully characterized. It was found that the developed ionic tri-dentate phosphine (L2′) enabled Pd-catalyzed alkoxycarbonylation of alkynes most efficiently while H2O was used as an additive instead of acid. As for L2′, its unique steric configuration with two types of potential P-P chelation modes (P⋯P distance of 4.31 Å and 4.36 Å respectively) to Pd-centre rendered the corresponding Pd-catalyst high activity and good stability for alkoxycarbonylation of alkynes. The in situ FT-IR analysis also verified that the formation and stability of Pd–H active species were greatly facilitated with the presence of L2′ as well as H2O additive. In addition, as an ionic phosphine, L2′ based PdCl2(MeCN)2 system immobilized in RTIL of [Bmim]NTf2 could be recycled for 7 runs without obvious activity loss or metal leaching.

Pd-catalyzed alkoxycarbonylation of alkenes promoted by H2O free of auxiliary acid additive

The Pd-catalyzed alkoxycarbonylation of alkenes using water as a promoter has been scarcely reported before. Herein, water instead of Brønsted/Lewis acid was found to effectively improve the catalytic performance of Pd(MeCN)2Cl2-Xantphos system for alkoxycarbonylation of alkenes. Under the optimal conditions, the best yield of 97% was obtained for the target products (methyl 3-phenylpropanoate and methyl 2-phenylpropanoate) with L/B of 4.3 and TON of 192. With the involvement of water, Pd(MeCN)2Cl2-Xantphos system also exhibited the moderate to good generality to alkoxycarbonylation of different kinds of alkenes with alcohols. The in situ high pressure FT-IR analysis verified that water played an important role in promoting formation and stability of PdH active species which was responsible for the efficient alkoxycarbonylation of alkenes. In addition, the ligand effect of Xantphos on this reaction was discussed.

Bifunctional ligands for Pd-catalyzed selective alkoxycarbonylation of alkynes

Catalytic carbonylations of alkynes represent straightforward and atom-economic synthesis of α,β-unsaturated carbonyl compounds. One of the issues associated with the currently known catalytic systems is insufficient efficiency. In this context, Pd/ligand-catalyzed regioselective and efficient alkoxycarbonylation of terminal alkynes is desirable for the synthesis of α,β-unsaturated esters. Herein, we present the use of a newly designed bifunctional ligand for efficient Pd-catalyzed alkoxycarbonylation of alkynes. Both aliphatic and aromatic alkynes were smoothly transformed to the branched desired products with high selectivity (28 examples, 45–96% yields, 95.0–99.9% selectivity).

Synthesis of phthalic acid derivatives via Pd-catalyzed alkoxycarbonylation of aromatic C–H bonds with alkyl chloroformates

A Pd(ii)-catalyzed alkoxycarbonylation of aromatic C-H bonds with alkyl chloroformates has been developed. A broad range of benzamides and alkyl chloroformates are compatible with this protocol. The reaction is operationally simple and scalable. The direct group could be readily removed to access substituted phthalic acid esters (PAEs), 1,2-dibenzyl alcohols and phthalamides. Besides alkoxycarbonylation of benzamide β-C-H bonds, γ-alkoxycarbonylation of 2-phenylacetamide is also feasible.

Utilizing Glycerol as an Ex Situ CO-Source in Pd-Catalyzed Alkoxycarbonylation of Styrenes

We report on an efficient Ir-catalyzed decarbonylation of glycerol, which could be coupled to an ensuing Pd-catalyzed alkoxycarbonylation of styrenes. The formation of hydrogen could be avoided by employing 1,4-benzoquinone (BQ) as an external oxidant. A wide variety of styrenes underwent the esterification in good yields and high regioselectivity. Applying catalytic amounts of hexafluoroisopropanol provided access to alcohols other than methanol, which this transformation is often limited to. Finally, we demonstrate the suitability of this methodology for the preparation of three well-known nonsteroidal anti-inflammatory drugs (NSAIDs).

Synthesis of pregnane 3-carboxylic acids via Pd-catalyzed alkoxycarbonylation and their effect on NMDA receptor activity

We have prepared 20-oxo-5α- and 20-oxo-5β-pregnane-3-carboxylic acids by palladium catalyzed alkoxycarbonylation using triflate and nonaflate as the leaving groups in this substitution reaction. The activity of the synthesized compounds was studied in cultured rat hippocampal neurons under voltage-clamp conditions. The 5β-carboxylic acid derivatives were found to diminish NMDA-induced responses, whereas the 5α-derivative potentiated the response.

A Scaleable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate

A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1b), starting from 5-bromo-2-methoxypyridine (8) and 4-fluorobenzaldehyde (9), is described. Key steps in the process include lithium–bromine exchange of 8, addition of the resulting lithiate to aldehyde 9, regioselective nitration of pyridone 12, and Pd-catalyzed alkoxycarbonylation of bromopyridine 15b. Overall yield of the five-stage synthesis was 23%; intermediates 10, 12, 13, 15b, and final product 1b·HCl were isolated as filterable solids. Compounds 1a,b are important intermediates in the synthesis of 7-benzylnaphthyridinones (e.g., 2) and related HIV-1 integrase inhibitors.