Transition‐Metal‐Free Intramolecular Ullmann‐Type O‐Arylation: Synthesis of Chromone Derivatives

Abstract

Aromatic C O bond-forming reactions are important in organic synthesis because these bonds occur in numerous natural products, biological compounds, pharmaceuticals, fragrances, cosmetics, and polymers. Traditionally, aryl ethers have been prepared by copper-mediated Ullmann coupling reactions of aryl bromides/iodides and phenols, but the drawbacks include harsh reaction conditions, such as: the need for a strong base, long reaction times in high polar solvents, and a stoichiometric amount of copper. Subsequently, some significant achievements in the palladiumcatalyzed O-arylation have been made under mild reaction conditions (Scheme 1a). Recently, copper-catalyzed Ullmann-type O-arylations have been developed under milder reaction conditions (Scheme 1a) using inexpensive copper salts and readily accessible ligands, such as phenanthrolines, N,N-dimethyl glycine, pyridine derivatives, bdiketones, 1,1,1-tris(hydroxymethyl)ethane, and pyrrolidine-2-phosphonic acid phenyl monoester. Palladiumor copper-catalyzed intramolecular O-arylations have attracted much attention, and some oxygen heterocycles were constructed with the Ullmann-type O-arylation strategy, for example copper-catalyzed synthesis of substituted 4H-1benzopyrans (Scheme 1b), 2,3-dihydro-1,4-benzoxazines (Scheme 1c), benzoxazoles (Scheme 1d), and copper[6g,h] and palladium-catalyzed synthesis of five and sixmembered oxygen heterocycles (Scheme 1e). The results above show that transition-metal catalysts (palladium and copper) seem to be necessary in O-arylations. Chromone derivatives are ubiquitous to green-plant cells and are highly diverse; more than 2000 different flavonoids have been identified, and their number is growing rapidly. These derivatives show various biological and pharmaceutical activity, so they are interesting as structural scaffolds and have been assigned as privileged structures in drug development. Although some approaches to the chromone derivatives have been developed, the methods often suffer from harsh reaction conditions, limited substrate scope, poor substituent tolerance, and low yields. Several efficient palladium-catalyzed routes have been developed for the synthesis of chromone derivatives. The excellent results from the copperand palladium-catalyzed O-arylations above prompted us to make chromone derivatives by using a transition-metal-catalyzed strategy. Thus, considering the ready availability and low toxicity of copper catalysts, we first screened copper-catalyzed reaction conditions by using the intramolecular O-arylation of 1-(2-bromophenyl)-3-ptolylpropane-1,3-dione (1a) as the model reaction (Table 1). Surprisingly, a more highly efficient O-arylation was observed in the absence of a copper salt (entry 7, Table 1). Herein, we report the unexpected transition-metal-free intramolecular Ullmann-type O-arylation leading to chromone derivatives (Scheme 1 f). 1-(2-Bromophenyl)-3-p-tolylpropane-1,3-dione (1a) was first used as the model substrate to screen the reaction conditions for the optimization of the catalyst, base, solvent, temperature, and reaction time under air. As shown in Table 1, six copper catalysts were tested at 110 8C in the presence of one equivalent of Cs2CO3 (relative to the amount Scheme 1. a–e) Copperand palladium-catalyzed Ullmann-type O-arylations (previous research). f) Transition-metal-free intramolecular Ullmann-type O-arylation leading to chromones (this work). DMF=N,N’dimethylformamide.