Ph3P-I2–mediated amide bond activation and functionalization

Abstract

The amide bond is an important functional group in organic chemistry. Not only it is present in a wide range of biologically important molecules, such as proteins, peptides, and nucleic acids, but also important in the synthesis of many pharmaceuticals and other organic compounds. Thus, the ability to selectively activate and structurally modify amide bonds makes it possible to synthesize complex molecules with specific functional groups and properties. In this study, the amide bond activation and functionalization have been investigated under the combination of Ph3P and I2. The use of these inexpensive and readily available reagents is particularly attractive since it can reduce the cost and increase the accessibility of the synthetic route. Additionally, their ease of handling can make the synthesis process more convenient. The developed protocols have led to convenient syntheses of a range of valuable products including amidoximes, benzimidazoles, indoloquinazoline derivatives and C-12 spiro-γ -lactone.

In the first study, N-substituted amidoximes were synthesized from secondary amides or intermediate amides. The use of a Ph3P-I2-mediated dehydrative condensation allows for the quick and mild conversion of these amides into N-aryl and N-alkyl amidoximes with a variety of substituents, such as aryl, alkyl, or benzyl. The one-pot approach is particularly advantageous, as it reduces the need for multiple steps and intermediate purification. The short reaction times and mild conditions are also desirable, as they minimize unwanted side reactions and the need for harsh reagents. In the next study, benzimidazolones were prepared via the Ph3P-I2 mediated reaction of hydroxamic acids. The reaction involves a Lossen-type rearrangement of the O-activated hydroxamic acids. Upon amide bond activation, the in situ generated isocyanates undergo an intramolecular attack by ortho N-nucleophiles producing the cyclized benzimidazolones in good yields under mild conditions. The method is advantageous as it allows for the direct preparation of a single regioisomer of N-monosubstituted derivatives using readily accessible starting materials and low-cost reagents. The broad substrate scope of the reaction also offers the potential for the synthesis of a variety of benzimidazolone derivatives with different substituents. Finally, through an amide bond activation using PPh3-I2 combination, diverse indoloquinazoline structures were readily synthesized. The method utilizes a phosphonium-mediated reaction of isatins in the presence of alcohol, which results in the formation of C-12 modified tryptanthrin derivatives. The reaction is versatile and allows for the construction of various C-12 functionalized indoloquinazolines using simple precursors and under mild, metal-free conditions. The use of excess phenols also enables the production of C-12 aryloxy ester products in moderate to good yields. The method also enables the synthesis of novel C-12 spiro-γ-lactone derivatives from fused bicyclic hydroxyaryl derivatives.