Aminophthalimide as a Protected Nitrogen Source for N-Insertion to Indenones

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Nitrogen scanning is crucial in medicinal chemistry for developing new drug candidates.
• Synthesizing N-positional variants and N-H analogues of nitrogen-containing compounds often requires complex de novo synthesis routes.

Purpose of the Study:

• To develop an efficient and versatile method for synthesizing N-H isoquinolinones.
• To overcome the limitations of traditional de novo synthesis for N-positional variants.

Main Methods:

• A two-step, one-pot reaction utilizing a nitrene-based formal N-H insertion into indenones.
• Activation of N-aminophthalimide with PIDA to form an aziridinating intermediate.
• Acid-promoted rearrangement of the N-NPhth intermediate followed by deprotection.

Main Results:

• Successful synthesis of isoquinolinones via a novel nitrene-based approach.
• The method demonstrates broad substrate scope, including challenging 2-alkyl and electron-poor enones.
• Easy deprotection allows access to N-H isoquinolinones, valuable in medicinal chemistry.

Conclusions:

• The reported method provides a streamlined and efficient route to N-H isoquinolinones.
• This strategy simplifies the synthesis of N-positional variants, expanding medicinal chemistry toolkits.
• The reaction's tolerance for diverse substrates enhances its applicability in drug discovery.