Palladium-Catalyzed Oxyarylation Research Articles

New 5-carba-pterocarpans: Synthesis and preliminary antiproliferative activity on a panel of human cancer cells

Natural pterocarpans and synthetic 5-carba-pterocarpans are isosteres in which the oxygen atom at position 5 in the pyran-ring of pterocarpans is replaced by a methylene group. These 5-carba-analogues were obtained in good yields through the palladium-catalyzed oxyarylation of alcoxy-1,2-dihydronaphthalens with o-iodophenols in PEG-400. They were evaluated on human cancer cell lineages derived respectively from prostate tumor (PC3, IC50 = 11.84 μmol L−1, SI > 12)) and acute myeloid leukemia (HL-60, IC50 = 8.81 μmol L−1, SI > 16), highly incident cancer types presenting resistance against traditional chemotherapeutics. Compound 6c (LQB-492) was the most potent (IC50 = 3.85 μmol L−1, SI > 37) in SF-295 cell lineage (glioblastoma). Such findings suggest that 5-carba-pterocarpan can potentially be new hit compounds for further development of novel antiproliferative agents.

Synthesis of pterocarpans through palladium-catalyzed oxyarylation of alkoxy-2H-chromenes with o-iodophenols

Abstract The oxyarylation of alkoxy-2H-chromenes (1a-e) with o-iodophenols substituted by electron-withdrawing (CHO) and electron-donating (OMe) groups is studied under two experimental conditions: a) Pd(OAc)2, Ag2CO3 in PEG-400 at 140 °C, 10 min and b) oxime-based palladacycle, DIPEA, in PEG-400 at 150 °C, 3–4 h. Pterocarpans are obtained in moderate to good chemical yields.

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

BackgroundDespite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones.MethodsThe second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells.ResultsIn this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production.ConclusionsThe data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.

Ligand-Free Palladium-Catalyzed Oxyarylation of Dihydronaphthal­enes and Chromenequinone with o-Iodophenols and 3-Iodolawsone in PEG-400: An Efficient Synthesis of 5-Carbapterocarpans and Pterocarpanquinones

Dihydronaphthalenes were oxyarylated with o-iodophenols, in PEG-400 at 140 or 170 °C, leading regio- and stereoselectively to 5-carbapterocarpans. By using Pd(OAc)2 (5–10 mol%) as precatalyst and Ag2CO3 (1.1 equiv) as base (conditions A), products were obtained in good to excellent chemical yields, in 5–30 minutes, irrespective of the pattern of substitution the starting materials. Alternatively, when p-hydroxyacetophenone oxime derived palladacycle (1 mol%) was used as precatalyst, and dicyclohexylamine (2 equiv) was used as base (silver-free, conditions B), the corresponding adducts were obtained in moderate to good yields, in 0.5 to 4 hours. Finally, the oxyarylation of dihydronaphthalenes­ and chromenquinone with o-iodophenols and 3-iodolawsone in PEG-400 under conditions A led regio- and stereoselectively to the formation of carbapterocarpanquinones and pterocarpanquinones in moderate yield.

Palladium-Catalyzed Oxyarylation, Azaarylation and α-Arylation Reactions in the Synthesis of Bioactive Isoflavonoid Analogues

Isoflavonoids constitute an important class of natural products, comprising great structural diversity. Known as phytoalexins and phytoestrogens, these compounds exhibit interesting biological activities. The corresponding carba-analogues, in which the oxygen atom at the B-ring is replaced by a methylene, are emerging as an attractive alternative for the preparation of new bioactive compounds. In this review, we report our results on the synthesis of isoflavonoid analogues (5-carba-pterocarpans, 1-carba-isoflavanones, 5-carba-11-aza-pterocarpan and pterocarpanquinones) with anti-cancer, antiparasitic and anti-viral properties. Palladium-catalyzed oxyarylation and azaarylation of dihydronaphthalenes and α-arylation of α- tetralones were the key steps in the developed synthetic approaches. A historical background, as well as a brief mechanistic discussion of these reactions, will be presented. Keywords: Isoflavonoids, Carba-isoflavonoids, Oxyarylation, Azaarylation, α-Arylation, Palladium-catalyzed.

Palladium-Catalyzed Oxyarylation of Hydroxyalkenes

Palladium-Catalyzed Oxyarylation of Hydroxyalkenes

ChemInform Abstract: Microwave‐Promoted Palladium‐Catalyzed Oxyarylation of Dihydronaphthalene and Chromenes by o‐Iodophenols and Its Acetates.

AbstractThe best yields are obtained for reactions of electron‐rich olefins (I) and (IV) with iodophenols substituted by electron‐withdrawing groups.

Alternative pathways for Heck intermediates: palladium-catalyzed oxyarylation of homoallylic alcohols.

Alternative pathways for Heck intermediates: palladium-catalyzed oxyarylation of homoallylic alcohols.

Functionalized 2,3-dihydrofurans via palladium-catalyzed oxyarylation of α-allyl-β-ketoesters

The palladium-catalyzed reaction of (hetero)aryl bromides, chlorides, and nonaflates with α-allyl-β-ketoesters provides ready efficient access to functionalized 2,3-dihydrofurans. The reaction tolerates several useful substituents including chloro, fluoro, ether, ketone, ester, cyano, and nitro groups.

Trans-Dihydrobenzofurans via Diazotization-Palladium-Catalyzed Oxyarylation

Reported is the stereoselective synthesis of trans-2-aryl-3-methyldihydrobenzofurans 3 from ortho-aminophenols 1 and arylal­kenes 2 via diazotization and palladium-catalyzed oxyarylation in a one-pot reaction. The sequence is based on the diastereoselective Heck oxyarylation reaction of anethole with 2-hydroxybenzenediazonium salts 4 in the presence of Pd2(dba)3 and CaCO3 as base (K. Kikukawa, K. Nagira, F. Wada, T. Matsuda Tetrahedron 1981, 37, 31). However, due to the unavailability and difficult preparation of the diazonium salt, an in situ generation followed by palladium-catalyzed oxyarylation in one-pot was developed for the synthesis of 3. After screening of bases, catalysts, ligands (NHC), solvents, and diazotization reagents, the optimum conditions of NOPF6 as diazotization ­reagent and Pd2(dba)3/ZnCO3 as catalyst/base for the Heck oxyarylation were established. The scope of the ­diazotization-oxyarylation was examined with 2-aminophenols bearing EDGs and EWGs in reactions with a variety of alkenes. However, alkenes with ortho-substituents on the aromatic ring as well as heteroatoms on the propenyl moiety afforded decreased product yields.

Palladium-catalyzed oxyarylation of olefins using silver carbonate as the base. Probing the mechanism by electrospray ionization mass spectrometry

The Pd(OAc) 2-catalyzed oxyarylation of electron-rich ( 8 and 12) and electron-poor ( 10) olefins by ortho-iodophenols ( 3a– d) was studied using Ag 2CO 3 as the base, in acetone, and in the presence and absence of PPh 3. The corresponding adducts of oxyarylation were obtained in moderate yields. The reaction mechanism was examined by electrospray ionization mass spectrometry (ESI-MS). Cationic arylpalladium intermediate ( 14), formed by the oxidative insertion of Pd(0) into 3a, and the cationic palladacycles ( 15), obtained by reaction of 14 with olefins 8 and 12, were intercepted by ESI-MS and characterized by ESI-MS/MS.