The combination of multicomponent approaches with light-driven processes opens up new scenarios in the area of synthetic organic chemistry, where the need for sustainable, atom- and energy-efficient reactions is increasingly urgent. Photoinduced multicomponent reactions are still in their infancy, but significant developments in this area are expected in the near future.
Scheme 1. General multicomponent approach to captodative olefins 1. FG = functional group.Scheme 2. Comparison between a) the previously reported method [7] and b) the new Passerini-like multicomponent reactions with arylketenes as carbonyl surrogates.
The crucial structural motive in viral protease inhibitors such as atazanavir and darunavir is a chiral aminoalcohol structure. The structure is generally introduced during the synthesis of the protease inhibitor via an α-chloroketone intermediate. The α-chloroketone can be synthesized in a multistep sequence from naturally occurring L-phenylalanine. Herein, we report a onepot synthesis of an α-chloroketone starting from N-Boc-L-phenylalanine in a novel type of "tube-in-flask" semi-batch diazomethane generator. Activation of the amino acid to the mixed anhydride was carried out in the flask, while diazomethane was generated from in situ formed N-nitroso-N-methylurea within a gas-permeable tubing contained inside the flask. The diazomethane diffused through the gas-selective membrane into the flask, and reacted with the anhydride to the diazoketone (Arndt-Eistert reaction). The addition of aqueous hydrogen chloride provided the α-chloroketone and destroyed any excess of diazomethane. The desired product was isolated by extraction in excellent purity and yield (90%-96%).
The photoinduced, multicomponent reaction of α-diazoketones, silanols, and isocyanides affords α-silyloxy acrylamides, formally derived from α-keto amides. The presence of a secondary amido group makes classic preparative methods for silyl enol ethers unfeasible in this case, while the mild conditions required by this photochemical approach allow their synthesis in good yields; moreover, the general structure can be easily modified by varying each component of the multicomponent reaction. Fine-tuning of the reaction conditions (i.e., solvents, radiation, additives) can be exploited to obtain complete Z selectivity. The reactivity of this overlooked class of silyl enol ethers has been investigated, and features that could pave the way to new applications have been found.
We report a straightforward approach to synthesize 2-acyloxyacrylamides, which are useful synthons in organic synthesis. This involves a photoactivated multicomponent reaction, performed both in batch and under continuous flow conditions. This process affords the desired compounds in a stereoselective fashion from readily available starting materials in one step, without the aid of metal catalysis. This paper illustrates the preliminary work, the extensive experiments carried out to understand the limitations of the approach, and the optimization of the conditions for the synthesis of these particular captodative olefins.
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