Coupling–Isomerization Synthesis of Chalcones

Abstract

The Sonogashira coupling of electron-deficient (hetero)aryl halides 1 and (hetero)aryl or alkenyl 1-propargyl alcohols 2 does not terminate at the stage of the expected internal propargyl alcohols, but rather gives rise to the formation of alpha,beta-unsaturated ketones 3 with a variety of acceptor substituents. This new domino reaction, a coupling-isomerization reaction (CIR), can be rationalized as a sequence of rapid Pd/Cu-catalyzed alkynylation followed by a slow amine-base-catalyzed propargyl alcohol-enone isomerization. Performing the CIR in deuterated protic solvents or with a selectively deuterated propargyl alcohol revealed that the base-catalyzed isomerization step proceeds through a formal 1,3-H shift with minimal H/D exchange with the surrounding solvent. Additionally, 19F NMR kinetic measurements on the isomerization step with the fluorinated propargyl alcohol 4 r support the mechanistic rationale.

Synthesis, Structure and Emission Properties of Spirocyclic Benzofuranones and Dihydroindolones: A Domino Insertion–Coupling–Isomerization– Diels–Alder Approach to Rigid Fluorophores

“…Domino synthesis of spirobenzofuranones and spirodihydroindolones: In recent years we have developed consecutive multicomponent syntheses of pharmaceutically relevant heterocycles [10,11] initiated by a coupling-isomerization reaction [10,12] (CIR) (Scheme 1).…”

Microwave‐Accelerated Coupling‐Isomerization Reaction (MACIR) – A General Coupling‐Isomerization Synthesis of 1,3‐Diarylprop‐2‐en‐1‐ones

“…Kinetics of the model reaction under conventional heating revealed that, for the rate-limiting isomerization step, dipolar aprotic solvents such as acetonitrile and DMF give rise to fastest conversions and almost quantitative yields. [5] However, under dielectric heat-ing the yields in acetonitrile never exceeded 67 % (entries 1-8). Increasing the effective temperature inside the reaction vessel from 120 to 150 8C led to decreased yields of 4a (entries 3 and 4), whereas, a shorter reaction time at higher temperature gave comparable yields (entry 5).…”

“…Kinetic studies of the isomerization step show that the reaction proceeds fastest at a more than five-fold excess of amine base and in a dipolar aprotic medium. [5] Although the CIR is a mild and versatile synthesis of chalcones it has some inherent scope limitations and shortcomings under the conditions of conductive heating. Besides a limited choice of the reaction media, a relatively large excess of base, and long reaction times (16-24 h), most strikingly, the demand for an activating electron-deficient (hetero)aryl halide as a coupling partner is less advantageous.…”

“…A suitable model reaction to optimize the MACIR is the reaction of p-bromobenzonitrile (1a) and 1-phenylpropyn-1-ol (2a) that has been thoroughly studied under conductive heating (Scheme 2). [5] After Sonogashira alkynylation, the intermediate propargyl alcohol 3a is isomerized by triethylamine to furnish the chalcone 4a. Therefore, parameters such as solvent, effective temperature in the reaction vessel, irradiation time, triphenylphosphane, triethylamine and substrates concentrations were varied and optimized ( Table 1).…”

A Facile and Efficient Synthesis of Dihydroisobenzofuran Derivatives via Tandem Palladium‐Catalyzed Coupling, Propargyl‐Allenyl Rearrangement, [4+2] Cycloaddition and Aromatization Reaction

“…[7,8] Indeed, compared with the traditional intramolecular Diels-Alder reaction, the presence of an allene motif enhances the diversity of reaction possibilities, thus serving as a potentially diversifiable approach to fused rings systems [Eqs. (1) to (4), Figure 1].…”