Studies aiming at the preparation of alkylated prochiral α-carbonyl sulfoxonium ylides and their applications in the synthesis of isoquinoline derivatives

Author(s)

Matheus Pereira de Jesus

• Document type: Doctoral Thesis
• Press: São Carlos.
• Institution: Universidade de São Paulo (USP). Instituto de Química de São Carlos (IQSC/BT)
• Defense date: 2025-05-16

Examining board members

Antonio Carlos Bender Burtoloso; Giuliano Cesar Clososki; Caio Costa Oliveira; Bruno Matos Paz

• Advisor: Antonio Carlos Bender Burtoloso

Abstract

Sulfur ylides constitute an important synthetic tool for organic chemists, as they are employed as building blocks in total synthesis, materials chemistry, and drug production, among other applications. However, alkylation of these compounds, particularly stabilized ones, remains a significant challenge. As a result, the synthesis of prochiral sulfur ylides without the use of diazo compounds is still a synthetic challenge, given that no methodologies for the direct α-alkylation of these compounds have been reported in the literature. In this context, aiming to obtain prochiral molecules, the first chapter of this work focused on developing a methodology for the α-alkylation of α-carbonyl sulfoxonium ylides. A study involving a series of electrophiles was conducted, with success achieved only when Michael acceptors were evaluated. A total of 25 novel α-alkylated sulfoxonium ylides were obtained in yields ranging from 12% to 67%. To demonstrate possible applications of these α-functionalized sulfoxonium ylides, heterocyclic scaffolds such as 2-mercaptobenzothiazoles, 1,4- benzothiazin-3-ones, and coumarin derivatives were synthesized. The second chapter, in turn, focused on studies aimed at obtaining α-alkenylated sulfur ylides. However, an intriguing transformation was observed when dimethyl acetylenedicarboxylate (DMAD) was used as an electrophile. The major products obtained were a trisubstituted 1,3-diene and a vinyl sulfoxide, both formed in a stereoselective manner. After optimizing the reaction, nine novel examples of 1,3- dienes and four new examples of sulfoxides were synthesized, with yields of up to 70% and 83%, respectively. Two selected dienes were subsequently used in the synthesis of novel nitrogen-containing heterocycles. When di-tert-butyl acetylenedicarboxylate (DtBAD) or alkyl propiolates were tested, the isolated product arose from a classical Michael addition, yielding 15 new examples of vinyl sulfoxonium ylides with up to 89% yield. Finally, the third chapter aimed to evaluate the synthetic potential of acetylenic sulfur ylides in gold-catalyzed intramolecular cyclization reactions to obtain isoquinoline derivatives. Various gold(I/III) catalysts were tested for the activation of the alkyne triple bond in a model reaction with sulfoxonium ylides. However, promising results were obtained only in the intramolecular version of the reaction, using a γ-alkynyl ylide and JohnPhosAu(MeCN)SbF6 as the catalyst. Using different nucleophiles, three product classes were obtained: a naphthoquinone, an amide, and an amino naphthol, with yields close to 10%. (AU)

• FAPESP's process: 20/07143-5 - Studies aiming the preparation of pro-chiral ²-ceto sulfoxônios -ketosulfoxonium ylides and their applications in the synthesis of isoquinoline derivatives
• Grantee: Matheus Pereira de Jesus
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)