Copper (II) catalysed aminal synthesis under mild conditions and their applications Juliana Pereira, Lídia A.S. Cavaca, João P.M. António, Rafael F.A. Gomes, Carlos A.M. Afonso University of Lisbon, Portugal Aminals are the condensation product of aldehydes and secondary amines. Structurally similar to acetals, these compounds have been used as intermediates, chiral auxiliaries and protection groups in reactions and in the biology field. 1 The most common methodology for the formation of aminals involves the condensation of aldehydes with amines in ethanol or toluene under high temperatures using dehydrating agents to remove the water in the reaction, shifting the equilibrium to the product. 2 However, performing the reaction in aqueous media instead of organic solvents is an environmentally competitive process for the preparation of aminals. This work reports on the formation of aminals, from aromatic aldehydes and furfural derivatives with different secondary amines in water under mild conditions (Figure 1a) as well as the formation of several thioaminals with yields up to 97% (Figure 1b) . 3 This is followed by the stability studies of different aminals and their use as protection group for aldehydes. Applying this approach together with the advantages of a continuous flow system allowed us to develop a new, simple and rapid methodology for selective removal of genotoxic aldehydes from APIs (Active Pharmaceutical Ingredient). Our method uses the diamine scavenging resin in a continuous flow system, generating the aminal within the microreactor efficiently (Figure 2) . 4 The described aminal compounds were prepared with a more sustainable methodology allowing the use of these interesting molecules as protection group and presenting a noteworthy role on the removal of genotoxic impurities (a). (b).
Figure 1. (a) Preparation of aminals from aromatic aldehydes and furfural derivatives with different secondary amines and (b) preparation of thioaminals from aromatic aldehydes with alkyl and aryl thiols, and morpholine in water under mild conditions.
Figure 2. A new strategy for selective removal of genotoxic aldehydes from APIs. Acknowledgments: The authors acknowledge Fundação para a Ciência e Tecnologia (FCT)(UIDB/04138/2020, UIDP/04138/2020, PD/BD/143162/2019)for financial support. The project leading to this application has received funding from the EuropeanUnion’sHorizon 2020 research and innovation programme under grant agreement No 951996. References 1. Alexakis A.; Lensen N.; Mangeney P. Tetrahedron Letters, 1991 , 109 , 1171. 2. Ramirez M. A.; Ortiz G.; Levin G.; McCormack; Blanco W. M. M.; Perillo I. A.; Salerno A.; Tetrahedron Letters, 2014, 55, 477 3. Cavaca L.A. S; Gomes R. F. A.; Afonso C. A. M Molecules, 2022 , 27, 1673. 4. Pereira J. G.; António J. P. M.; Mendonça R.; Gomes R. F. A.; Afonso C. A. M. Green Chemistry, 2020 , 22, 7484.
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