Late‐Stage Amination of Drug‐Like Benzoic Acids: Access to Anilines and Drug Conjugates through Directed Iridium‐Catalyzed C−H Activation

Abstract

The functionalization of C−H bonds, ubiquitous in drugs and drug‐like molecules, represents an important synthetic strategy with the potential to streamline the drug‐discovery process. Late‐stage aromatic C−N bond–forming reactions are highly desirable, but despite their significance, accessing aminated analogues through direct and selective amination of C−H bonds remains a challenging goal. The method presented herein enables the amination of a wide array of benzoic acids with high selectivity. The robustness of the system is manifested by the large number of functional groups tolerated, which allowed the amination of a diverse array of marketed drugs and drug‐like molecules. Furthermore, the introduction of a synthetic handle enabled expeditious access to targeted drug‐delivery conjugates, PROTACs, and probes for chemical biology. This rapid access to valuable analogues, combined with operational simplicity and applicability to high‐throughput experimentation has the potential to aid and considerably accelerate drug discovery.

Merging Directed C−H Activations with High-Throughput Experimentation: Development of Predictable Iridium-Catalyzed C−H Aminations Applicable to Late-Stage Functionalization

“…In terms of reaction conditions, we identified several desirable features of "ideal" C−H activation methodologies applicable to HTE. [34][35][36] These include: 1) Use of soluble reagents and liquid dispensing.…”

“…The following set of conditions was identified based on these criteria after Step 1, initial optimizations (see SI), and used for the directing group informer library. [Cp*Ir(H2O)3SO4] was chosen as catalyst, 34,37 allowing the reaction to be performed in absence of silver salts and insoluble additives, thus facilitating the use of liquid handling systems. Commercially available MozN3 (Moz = pmethoxybenzyloxycarbonyl) was selected as the nitrogen source, allowing for deprotection of the obtained carbamate under a number of conditions.…”

“…The additives were chosen as a means of representing functional groups commonly present in druglike molecules. 30,33,34 In terms of solvent effect, only minimal differences in performance between NMP (top bars) and DCE (bottom bars) were observed. To our delight, out of 47 modified conditions, 35 had no effect on the reaction outcome.…”

“…This observation is in accordance to similar studies. 33,34 2) The majority of polar functional groups commonly present in drug-like molecules were well tolerated. This includes the ether, alcohol, phenol, aldehyde, ketone, carboxylic acid, ester, primary and secondary amides, urea, Weinreb amide and sulfonamides.…”

“…In the informer library approach, the compatibility of a methodology with a large number of complex substrates bearing structural features relevant to pharmaceuticals is evaluated. While the former has been previously used for reported C−H activation methodologies, 33,34 the latter has so far only been applied to more well established crosscoupling reactions. 7,32 Herein we report the development of an iridium-catalyzed directed ortho-C−H amination applicable to a large number of directing groups (DGs) with outstanding functional group tolerance and regioselectivity.…”