Efficient Synthesis of Highly Substituted Diaryl Ethers on Solid Supports Using the Ullmann Reaction

Abstract

Diaryl ethers are important structures found in both nature and biologically active compounds. Some diaryl ethers exert considerable pharmacological activity, such as perrottetines, riccardin B, and marchantin quinone, all of which influence blood coagulation; 1 the antiviral cyclic peptide K-13; 2 and the glycopeptide antibiotics Vancomycin, Teicoplanin, and Complestatin. 2-5 Until recently, the synthesis of diaryl ethers having sensitive groups remained a challenge. 6-8 Therefore, diaryl ethers are a promising class of potentially useful pharmacologically active compounds, and their synthesis in liquid phase, particularly by nucleophilic aromatic substitution and Ullmann-type reactions, has found widespread application in organic chemistry. 9 The solid-phase synthesis of diaryl ethers mainly focuses on nucleophilic displacement of fluoronitroarenes in an intermolecular or intramolecular sense, furnishing 7-, 10 13-, 11 14-, 11-13 15-, 16-, 11,12,14 and 17-membered rings, 11 as demonstrated in the total synthesis of OF 4949. 14 Analogously, cyclic alkylaryl ethers 15 and thioethers 16 were synthesized using this strategy. Results and DiscussionWe were intrigued by the possibility of generating diaryl ethers on solid supports using the Ullmann reaction variant reported by Nicolaou et al., 5 since this reaction is particularly suitable for the synthesis of triazenyl-substituted diaryl ether and has been used in the total synthesis of the glycopeptide antibiotic Vancomycin. 5,17 The reaction temperature required is in contrast to classical Ullmann conditions compatible with solid-phase chemistry. Triazenes are masked diazonium ions and are convertible to a broad range of heterocycles. 18 In this manuscript, we disclose the first solid-phase UllmannNicolaou reaction.The required ortho-halo triazene resins 1{1-6} were synthesized via optimized procedures from anilines and arylmethylaminomethyl polystyrenes, which are available from chloromethylated polystyrene (1-2% cross-linked) in one synthetic step in large quantities (Scheme 1). 19,20 Five different anilines 21 were immobilized on benzylaminesubstituted Merrifield resin under standard conditions using this route. 22 The loadings were determined by elemental analysis.The Nicolaou variant of the Ullmann reaction was performed on the resins 3{1-4} (500-mg scale) at 75-85°C in acetonitrile/pyridine or dimethylformamide/pyridine for 36-48 h with 1.1-5.0 equiv of eight different phenols 4{1-8} 21 in the presence of the soluble copper complex CuBr‚SMe 2 (1 equiv) (Scheme 2). During the reaction, a color change of the resin from a slightly reddish color into a deep red color was observed. Heteroatoms such as nitrogen or oxygen atoms and simple functional groups (double bonds, amides, amines) at the phenolic moiety were tolerated; however, it was puzzling to note that extension to mono and

New Cu‐Based Catalysts Supported on TiO2 Films for Ullmann SNAr‐Type CO Coupling Reactions

“…Examples of Ullmann ether synthesis, Ullmann-Goldberg amination, and Goldberg amidation reactions. [22,26] A considerable amount of product (60 %) was already present in the reaction mixture after 5 min reaction time at 140 8C. However, the maximum yield was similar to that recently observed over CuZn NPs.…”

“…Investigations of the Ullmann syntheses of diazodiarylethers on structured supports have been reported by Knepper et al, who used triazene-functionalized polyA C H T U N G T R E N N U N G (styrene) resins to couple various substituted phenols with yields of up to 95 %. [22] Deposition of the active metals onto inorganic supports with a relatively low specific surface area requires low metal loadings to minimize particle sintering. Additionally loss of the active metal due to leaching may occur during operation of the catalytic reactor.…”

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

“…These aryl triazenes can be modified on the polymer support in a number of different reactions, for example, the Ullmann–Nicolaou reaction (Scheme ). The cleavage of the resulting aryl triazenes 17 to azides 18 is then carried out in good yields in the presence of trimethylsilyl azide 44. 45…”

Organische Azide – explodierende Vielfalt bei einer einzigartigen Substanzklasse

“…B. durch die Ullmann‐Nicolaou‐Reaktion (Schema ). Die so erhaltenen Aryltriazene 17 können in Gegenwart von Trimethylsilylazid in guten Ausbeuten in die Azide 18 umgesetzt werden 44. 45…”