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1. Non-Classical Amide Bond Formation: Transamidation and Amidation of Activated Amides and Esters by Selective N–C/O–C Cleavage

   https://doi.org/10.1055/s-0040-1707101  

   Li, Guangchen; Szostak, Michal (January 2020, Synthesis)

   In the past several years, tremendous advances have been made in non-classical routes for amide bond formation that involve transamidation and amidation reactions of activated amides and esters. These new methods enable the formation of extremely valuable amide bonds via transition-metal- catalyzed, transition-metal-free or metal-free pathways by exploiting chemoselective acyl C–X (X = N, O) cleavage under mild conditions. In a broadest sense, these reactions overcome the formidable challenge of activating C–N/C–O bonds of amides or esters by rationally tackling nN→π*C=O delocalization in amides and nO→π*C=O donation in esters. In this account, we summarize the recent remarkable advances in the development of new methods for the synthesis of amides with a focus on (1) transition-metal/NHC- catalyzed C–N/C–O bond activation, (2) transition-metal-free highly selective cleavage of C–N/C–O bonds, (3) the development of new acyl-transfer reagents, and (4) other emerging methods. 

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2. Synthesis of Amides by Transamidation and Amidation of Activated Amides and Esters

   Li, Guangchen; Szostak, Michal (January 2020, Science of synthesis)

   This chapter provides a summary of the recent advances in direct transamidation and amidation reactions of activated amides and esters via transition- metal-catalyzed and transition-metal-free C(acyl)–N and C(acyl)–O bond cleavage as a new disconnection for the synthesis of amide bonds. 

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3. Highly selective transition-metal-free transamidation of amides and amidation of esters at room temperature

   https://doi.org/10.1038/s41467-018-06623-1  

   Li, Guangchen; Szostak, Michal (October 2018, Nature Communications)

   Abstract Amide chemistry has an essential role in the synthesis of high value molecules, such as pharmaceuticals, natural products, and fine chemicals. Over the past years, several examples of transamidation reactions have been reported. In general, transition-metal-based catalysts or harsh conditions are employed for these transformations due to unfavorable kinetics and thermodynamics of the process. Herein, we report a significant advance in this area and present the general method for transition-metal-free transamidation of amides and amidation of esters by highly selective acyl cleavage with non-nucleophilic amines at room temperature. In contrast to metal-catalyzed protocols, the method is operationally-simple, environmentally-friendly, and operates under exceedingly mild conditions. The practical value is highlighted by the synthesis of valuable amides in high yields. Considering the key role of amides in various branches of chemical science, we envision that this broadly applicable method will be of great interest in organic synthesis, drug discovery, and biochemistry. 

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4. Highly Chemoselective Transamidation of Unactivated Tertiary Amides by Electrophilic N−C(O) Activation by Amide‐to‐Acyl Iodide Re‐routing

   https://doi.org/10.1002/anie.202202794  

   Zuo, Dongxu; Wang, Qun; Liu, Long; Huang, Tianzeng; Szostak, Michal; Chen, Tieqiao (April 2022, Angewandte Chemie International Edition)

   Abstract The challenging transamidation of unactivated tertiary amides has been accomplished via cooperative acid/iodide catalysis. Most crucially, the method provides a novel manifold to re‐route the reactivity of unactivated N,N‐dialkyl amides through reactive acyl iodide intermediates, thus reverting the classical order of reactivity of carboxylic acid derivatives. This method provides a direct route to amide‐to‐amide bond interconversion with excellent chemoselectivity using equivalent amounts of amines. The combination of acid and iodide has been identified as the essential factor to activate the amide C−N bond through electrophilic catalytic activation, enabling the production of new desired transamidated products with wide substrate scope of both unactivated amides and amines, including late‐stage functionalization of complex APIs (>80 examples). We anticipate that this powerful activation mode of unactivated amide bonds will find broad‐ranging applications in chemical synthesis. 

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5. Transamidation of thioamides with nucleophilic amines: thioamide N–C(S) activation by ground-state-destabilization

   https://doi.org/10.1039/D2OB00412G  

   Zhang, Jin; Zhao, Hui; Li, Guangchen; Zhu, Xinhao; Shang, Linqin; He, Yang; Liu, Xin; Ma, Yangmin; Szostak, Michal (January 2022, Organic & Biomolecular Chemistry)

   Thioamides are ‘single-atom’ isosteres of amide bonds that have found broad applications in organic synthesis, biochemistry and drug discovery. In this New Talent themed issue, we present a general strategy for activation of N–C(S) thioamide bonds by ground-state-destabilization. This concept is outlined in the context of a full study on transamidation of thioamides with nucleophilic amines, and relies on (1) site-selective N -activation of the thioamide bond to decrease resonance and (2) highly chemoselective nucleophilic acyl addition to the thioamide CS bond. The follow-up collapse of the tetrahedral intermediate is favored by the electronic properties of the amine leaving group. The ground-state-destabilization concept of thioamides enables weakening of the N–C(S) bond and rationally modifies the properties of valuable thioamide isosteres for the development of new methods in organic synthesis. We fully expect that in analogy to the burgeoning field of destabilized amides introduced by our group in 2015, the thio amide bond ground-state-destabilization activation concept will find broad applications in various facets of chemical science, including metal-free, metal-catalyzed and metal-promoted reaction pathways. 

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