A proper copper catalyst with a chiral pyridine‐2,6‐bisoxazoline (pybox) ligand was used to convert a variety of propargylic acetates with aromatic side chains (R=Ar) into their amine counterparts in high yield and with good selectivity (up to 88 % ee). The resulting chiral propargylic amines can be elaborated further into P,N ligands (see scheme; DIPEA=diisopropylethylamine).

The Vilsmeier–Haack formylation of aromatic compounds is a well-established process in organic synthesis, largely driven by the fact that the resulting aldehydes are generally useful intermediates for the synthesis of fine chemicals and pharmaceutical products. Industrial-scale production, however, is often hampered by laborious procedures requiring the use of hazardous chemicals to produce the highly reactive intermediates. In order to circumvent these issues, a flow chemistry approach was developed. This article describes the design and semiautomated optimization of the Vilsmeier–Haack formylation in continuous flow and subsequent scale-up to preparative volumes in an intrinsically safe manner.

a b s t r a c tThe intrinsically small volumes and highly controlled reaction conditions render continuous flow microreactors ideal systems for the synthesis of potentially explosive compounds such as organic azides. In this article, we report the formation of benzyl azide from benzylamine using imidazole-1-sulfonyl azide hydrochloride as diazotransfer reagent. In a small scale (semi-automated) continuous flow setup the diazotransfer reaction was optimized using minimal amounts of reagents; less than 400 mg of benzylamine was required to perform 60 optimization reactions. The optimal reaction conditions were indentified to be room temperature, 600 s of residence time and an imidazole-1-sulfonyl hydrochloride to benzylamine stoichiometric ratio of 3 to 4. Furthermore, we successfully scaled up the reaction with a factor of 200 to gram scale using one single continuous flow reactor.

SummaryEthyl diazoacetate is a versatile compound in organic chemistry and frequently used on lab scale. Its highly explosive nature, however, severely limits its use in industrial processes. The in-line coupling of microreactor synthesis and separation technology enables the synthesis of this compound in an inherently safe manner, thereby making it available on demand in sufficient quantities. Ethyl diazoacetate was prepared in a biphasic mixture comprising an aqueous solution of glycine ethyl ester, sodium nitrite and dichloromethane. Optimization of the reaction was focused on decreasing the residence time with the smallest amount of sodium nitrite possible. With these boundary conditions, a production yield of 20 g EDA day−1 was achieved using a microreactor with an internal volume of 100 μL. Straightforward scale-up or scale-out of microreactor technology renders this method viable for industrial application.

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