TELESCOPIC SYNTHESIS OF FUNCTIONALIZED CHIRAL AMINES AND DEVELOPMENT OF A NEW CHEMODIVERGENT TRANSFORMATION

Abstract The present thesis covers three different topics: the development of a novel chemodivergent transformation involving nitroalkanes (Figure 1a); the stereoselective, metal-free, catalytic synthesis of differently functionalized chiral 1,2-diamines in a two-step, continuous-flow process (Figure 1b); [1] and the telescopic continuous flow enantioselective synthesis of a fluorinated active pharmaceutical ingredient (API) precursor A[2] (Figure 1c). Figure 1 More in detail, a General introduction containing literature background regarding the use of trichlorosilane will be provided, since this versatile reagent was used for different purposes in all the three projects presented here. Subsequently, in Chapter 1 we will focus on transformations of nitroalkanes, and we will present an unprecedented chemodivergent transformation, allowing to selectively obtain amines or nitriles starting from aliphatic nitro derivatives. Furthermore, we will report the application of this new synthetic methodology to chiral, optically active nitroalkanes, demonstrating the utility of the protocol that provides access to classes of compounds that are otherwise not easily accessed by classical methods in organic synthesis. The following chapter will deal with synthetic applications of continuous flow processes for the telescopic synthesis of chiral amines. In particular, in Chapter 2.1 a stereoselective, metal-free synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan A (Figure 1) has been studied in batch and under continuous flow conditions, affording the target molecule in good yields and high diastereoselectivity. Crucial step is the catalytic stereoselective reduction of a fluorinated enamine with trichlorosilane as reducing agent in the presence of a chiral Lewis base. Finally, in Chapter 2.2, we will focus on the development of a two-step, continuous-flow process for the stereoselective, metal-free, catalytic synthesis of chiral differently functionalized chiral 1,2-diamines. At first, the enantioselective organocatalytic reduction of aryl-substituted nitroenamines under continuous-flow conditions will be discussed. The chapter will include preliminary screening with a 10 µl microreactor, to establish the best reaction conditions, followed by a scaled-up in a 0.5 ml mesoreactor. Subsequently, the in-flow nitro reduction will be studied, either by Raney-Ni catalyzed hydrogenation, and by a metal-free methodology based on the use of trichlorosilane. Preliminary attempts to obtain a continuous flow telescopic synthesis, avoiding the isolation of intermediates will be also discussed. The Appendix included at the end of the present work, is related to the pharmaceutical industry, to briefly summarize the work performed during a two months traineeship spent in Flamma Innovation.