Ynamides are versatile building blocks used to develop various attractive organic molecules. Because of the importance of ynamides, many synthetic methods have been developed (Scheme 1; a-c). These previous synthetic methods are general and practical to afford multiple types of ynamides. However, they cannot be employed for synthesizing complex molecule-derived ynamides because of the harsh reaction conditions and limited substrate availability.
In our research on developing hypervalent iodine compounds, we recently developed a synthetic method of ynamides by the copper-catalyzed N-alkynylation of sulfonamide with alkynyl benziodoxolone. However, this method has a limited substrate scope because of the limited availability of alkynyl benziodoxolone. In the backdrop of these studies, we hypothesized that the combination of the synthesis of a terminal diynamide by the copper-catalyzed electrophilic diynylation of sulfonamides with diynyl benziodoxolones (diyne-BX) with silyl-protective groups and late-stage copper-catalyzed azide-alkyne cycloaddition (CuAAC) could enable the synthesis of a complex molecule-derived ynamides. We present a novel diversity-oriented synthetic method for ynamides with complex molecule substituents using the copper-catalyzed N-diynylation of sulfonamide with triisopropylsilyl-diyne-BX, deprotection, and late-stage CuAAC sequence (Scheme 1; d).
First, we devised a method for synthesizing TIPS-diyne-BX (Scheme 2; 3). Importantly, 3 can be handled at room temperature under air and stored in the refrigerator for at least a month. Next, we examined the reaction conditions for the electrophilic diynylation using N-tosylaniline (2a) and TIPS-diyne-BX (3). By examining the solvent, catalyst, ligand, and base, the optimized reaction conditions were determined. The features of this reaction were as follows: (1) EtOH afforded a better yield than other solvents; (2) CuI afforded a better yield than other metal catalysts (Ni, Co, Fe and Au); (3) the electron-rich bipyridine ligand (L1) afforded a better yield than other ligands, such as phenanthroline, terpyridine, diketone, and amino acid; and (4) finely powdered potassium carbonate afforded a higher yield than other bases, including granular potassium carbonate. With the knowledge of the optimized reaction conditions, we investigated the scope and limitations (Scheme 2).
Next, we examined the deprotection conditions. We obtained the terminal diynamide (Scheme 3; 5) in high yield with tetrabutylammonium fluoride in the presence of AcOH as a proton source. Subsequently, we examined the reaction conditions for late-stage CuAAC with terminal diynamide 5 and benzyl azide (6a). To our knowledge, CuAAC with terminal diynamide has not been reported before. Probably because of the sensitivity of the ynamide moiety to hydrolysis, an aqueous solvent afforded poor results. However, high yield of desired ynamide 7a was obtained under anhydrous condition with dichloromethane as the solvent (Scheme 3). Under the optimized condition, various complex molecules-derived ynamides were synthesized using various azides with pyrene, amino acids, nucleoside, and N-acetylglucosamines in good to high yields; such ynamides are difficult to obtain by other synthetic methods (Scheme 3).
In conclusion, we developed a novel synthetic method for ynamides with a late-stage diversification strategy through the copper-catalyzed electrophilic diynylation of sulfonamide with TIPS-diyne-BX, deprotection, and CuAAC sequence. The versatility of this diversity-oriented synthetic method was demonstrated by synthesizing the complex molecule-derived ynamides with pyrene, amino acids, nucleoside, and N-acetylglucosamines as substituents.
This work was supported by JSPS KAKENHI Grant Nos. 19K06977 and 22K06530 and Grants for Research from OGAWA Science and Technology Foundation and SIS (The Society of Iodine Science).
Literature name : Chemical Communications
Article title : Late-stage diversification strategy for synthesizing ynamides through copper-catalyzed diynylation and azide-alkyne cycloaddition
Author list : Ryohei Kawakami, Suguru Usui, Norihiro Tada*, Akichika Itoh*
Volume and number : Vol. 59, No. 4
Page : 450-453
Laboratory of Pharmaceutical Synthetic Chemistry