Heck reaction of substituted acrylates with arenediazonium salts in organic solvents and ionic liquids. Application to the synthesis of paroxetine, nocaine, indaline and sertraline

Author(s)

Júlio Cezar Pastre

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2009-07-08

Examining board members

Carlos Roque Duarte Correia; Yves Genisson; Luiz Fernando da Silva Junior; Paulo Cesar Muniz de Lacerda Miranda; Lucia Helena Brito Baptistella

• Advisor: Carlos Roque Duarte Correia

Abstract

In this work, we present a study of the Heck reaction of substituted acrilates with arenediazonium salts. A stereoselective protocol for the preparation of b,b-disubstituted acrylates in good yields by means of a Heck-Matsuda reaction was accomplished. The method employs a base- and ligand-free Heck reaction of methyl cinnamate using arenediazonium salts as electrophiles. The Heck reaction displays a remarkable electronic dependence regarding the diastereoselectivity of the arylation process, which correlates with the electronic nature of the arenediazonium salts employed. The overall methodology provides a convenient route to 3-arylindanones and 4-aryltetralones allowing the concise formal total syntheses of the therapeutically important psychoactive compounds (±)-indatraline (4 steps, 54 % global yield) and (±)-sertraline (7 steps, 49 % global yield). The methodology was also successfully extended to more substituted acrylates and the Heck adducts were obtained in good to excellent yields, regardless of the substitution pattern of the arenediazonium salt employed. This methodology was applied to the total synthesis of (±)-paroxetine (8 steps, 15 % global yield) and (±)nocaine (6 steps, 20 % global yield). We also verified that the Heck reaction using arenediazonium salts occurs in an efficient way in alternative reaction media, like PEG and ionic liquids. A series of new chiral ionic liquids was prepared and evaluated in the Heck reaction. In spite the overall performance of the Heck reaction, in all the cases studied no asymmetric induction was detected. Our results demonstrate the enormous synthetic potential of the Heck reaction using arenediazonium salts, constituting a versatile methodology in Organic Synthesis. (AU)