A scalable synthesis of trifluoromethylated imidazo-fused N-heterocyles from heterocyclic benzylamines using TFAA as trifluoromethylating reagent is presented. The reaction proceeds via intermediate benzylic N-trifluoroacetamides followed by dehydrative cyclization to the products. To further broaden the scope and practicality, a new method for the preparation of benzylic N-trifluoroacetamides via alkylation of trifluoroacetamide with benzyl (pseudo)halides was developed. Both methods proceed under mild conditions, and their symbiosis provides access to a wide range of novel CF-heterocycles.

To avoid the use and handling of Lawesson's reagent or other thiation agents in the in-house kilolab, a new scalable route to ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (1) was developed. The key to success was the use of a commercially available amino-thiadiazole building block, which was converted into the desired product via a sequence of Sandmeyer bromination and Suzuki−Miyaura coupling. The different parameters of the Pd-catalyzed coupling have been studied in detail and allowed the reaction to be performed under mild conditions at room temperature and with low catalyst loading. The inconsistencies of the initial scale-up runs with regard to the sluggish conversion of the Suzuki−Miyaura coupling due to Cu contamination were addressed, and the findings were directly implemented in the subsequent batches, which finally led to an improved overall understanding and robustness of the process.

A robust and scalable route toward key heterocyclic building block 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride from cyclopropanated starting material 1-amino-1-cyclopropanecarbonitrile hydrochloride was successfully developed.The key to success was the construction of a pyrimidine ring via cyclization from an amidine intermediate and a bench-stable 2chloro vinamidinium hexafluorophosphate salt. The cyclization was performed under mild conditions, and the resulting 4cloropyrimidine derivative was isolated in high yield and purity. The final hydrogenation was intensively optimized: A combination of Pd(OH) 2 /C as a catalyst and NaOMe as a base at 1 bar H 2 pressure in MeOH simultaneously cleaved the Cbz group and dechlorinated the pyrimidine ring while at the same time suppressing the over-reduction of the pyrimidine ring to below 1.0%. After acidification with HCl, followed by removal of the catalyst and NaCl by filtration, the final product was isolated in high yield and purity as a bench-stable off-white solid. The overall yield of the five-step sequence was 57%.

A novel reductive amination procedure for electron-poor heterocyclic amines with aromatic and aliphatic aldehydes has been developed. The key to success was the use of triethylsilane (Et3SiH) as reducing agent, in combination with trifluoroacetic acid (TFA) in refluxing CH2Cl2. The reductive aminations are fast, clean and allow for the isolation of the alkylated amines in high yields and purity after crystallization or chromatographic purification. The robustness and scalability of the process has been demonstrated for one substrate combination on 750 g scale, leading to the isolation of the corresponding product in 93% yield.