Strategies to the synthesis under continuous flow of new nitrogen heterocycles and spiroimides

Author(s)

Milene Macedo Hornink

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2023-05-18

Examining board members

Leandro Helgueira Andrade; Paulo Sergio de Carvalho; Alvaro Takeo Omori; Bruno Matos Paz

• Advisor: Leandro Helgueira Andrade

Abstract

Nitrogen heterocycles are ubiquitous in nature and the pharmaceutically active ingredients in many drugs. The growing need for the sustainable design of organic compounds marked the last decades. In this context, this work aims to approach via two catalytic ways the preparation of new nitrogen heterocycles. The N-phenylallylic e N-phenylacrylic derivatives, when possible, were prepared from renewable building blocks, and its rectivity explored in addition/cyclization reactions. In the first approach the photo Fenton process was applied, which enabled the generation of carbamoyl radicals to the construction of the target nucleous (di-hydroquinolin-2- ones and indolin-2-ones). The reaction happened within 10 minutes, with efficiency, in contiuos flow, then its functionalization to spiroimides was carried out with high yields (20-90%). Next, several indolines were prepared from the acrylic derivatives, the methyl 2-((Nphenylpivalamido)methyl)acrylates. The indolines were obtained in a fast way, within 1 minute in excellent yields (57-99%). A one-pot protocol under continuous flow to the synthesis of new N-fused indoles under ultrasonic irradiation was envisioned. The approach enabled the preparation of new N-fused indoles in high yields (22-85%). Expanding, the studies of the reactivity of the N-phenylallylic compouns, it was noticed that the latters containing non-activated double bonds were also carbamoyl radicals acceptors in addition/cyclization reactions. Thus, the indoine synthesis from the carbamoyl radical generated by the TBADT fotocatalyst was possible with yields up to 73 %. The second approach involved the application of the enzyme Vanadium haloperoxidase under continuous flow conditions to the catalyzis of addition/cyclization reactions, promoted through the enzyme generation of an electrophilic halogen specie. To the achievement of this approach the previous biopropecting of the enzyme in marina algae from the brazilian coast was proposed. A study of the extraction and purification of the VBrPO enzyme was carried out. The enzyme was obtained partially purified and immobilized in Purolite® generating the VBrPPur catalyst which was applied to the in batch halogenation of phenol red and tymol and showed the desired catalytic activity. (AU)

• FAPESP's process: 18/07152-4 - Application of vanadium-dependent haloperoxidase in a continuous flow system aiming selective reactions
• Grantee: Milene Macedo Hornink
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)