A Trimethylsilylamine-Acyl Fluoride Amide Bond Forming Protocol for Weakly Nucleophilic Amines that is Amenable to the Parallel Synthesis of Di(hetero)arylamides

Abstract

The reaction of a 2-pyridinone-based acid fluoride with the N-TMS derivatives of different weakly nucleophilic heteroaryl/arylamines in acetonitrile containing catalytic fluoride ion provides a clean, efficient and simple means to access a diverse range of polar di(hetero)arylamide structures. This amide bond forming protocol is readily amenable to the parallel synthesis of compound libraries.Key words amide coupling, di(hetero)arylamide, acid fluoride, heteroarylamine, N-TMS activation, parallel synthesisThe screening of compound libraries has repeatedly demonstrated its effectiveness as a research tool in drug discovery. In particular, when mechanistic and/or structural details for the therapeutic target are lacking, compound library screening is one of very few options possible to identify new and/or groundbreaking avenues for drug development. In our laboratory, parallel synthesis is used to connect and functionalize novel scaffolds into libraries of bioactive molecules containing different architectures. In particular, amide bond formation was used to generate molecules that possess a di(hetero)arylamide (DHA) substructure. The screening of a 256-membered library containing 119 DHA compounds identified four novel and related molecules 1-4 (Figure 1) that block HIV-1 replication by a mechanism involving perturbation of the alternative splicing events leading to production of key HIV regulatory proteins. 1a,b For the construction of the amide bond, a wide range of peptide (amide) bond forming reagents and conditions are available. 2 However, in our library project, where electrondeficient (weakly nucleophilic) heterocyclic amines were engaged, 3 the yield of the DHA product in reactions using the acid chloride method and different peptide coupling reagents rarely exceeded 10-30%. In fact, the formation of complex mixtures of polar compounds was generally observed, complicating workup and isolation/purification of the desired product. To advance the anti-HIV project, and other applications for the DHA library, it became important to develop a new amide synthesis protocol.

Strecker Reactions of Formaldehyde with TMSCN, Catalyzed by TBAF and Formic Acid: N‐Monocyanomethylation of Primary Amines

“…Based on the aforementioned experimental results and related literature, [7b,c,d] a plausible reaction mechanism for this selective coupling reaction was proposed as shown in Scheme 3. Firstly, aniline 2 a was silylated by 1 equivalent of TMSCN to generate N ‐trimethylsilylated aniline, which carries out a nucleophilic attack on the formic acid activated formaldehyde followed by dehydration giving rise to a N ‐trimethylsilylated imine (or iminium ion) intermediate I .…”

Synthetic Advantages of Defluorinative C−F Bond Functionalization

“…The released fluoride anion in defluorinative acylation can be used to activate silylated derivatives of weakly nucleophilic coupling partners. This is illustrated for a reaction developed by the Grierson Group with heteroaryl amines in Scheme 12a (bottom), where attempts at coupling acyl chlorides with non‐silylated amines led to low yields and mass balance [62] . A separate advantage of fluoride byproducts discovered by Rovis and co‐workers is illustrated in Scheme 12b for the reductive acylation of chiral lactones [63] .…”