Iodine‐Mediated Condensation–Cyclization of α‐Azido Ketones with p‐Toluenesulfonyl Hydrazide for Synthesis of 4‐Aryl‐NH‐1,2,3‐Triazoles

Abstract

A molecular iodine mediated condensation-cyclization reaction for the synthesis of 4-aryl-NH-1,2,3-triazoles has been developed from readily available α-azido acetophenones NH-1,2,3-triazoles are an important class of nitrogen-containing heterocyclic compounds, and their derivatives exhibit widespread potent biological and pharmaceutical activities, such as inhibition of IDO, hMetAP2, HER2, and VIM-2, and anticancer activity ( Figure 1). [1] [a] azido ketone was not tolerated in this annulation reaction, and we could not gain the corresponding product 3t. Encouraged by the results described above, the scope of αazido ketones was further examined (Scheme 3). To our delight, when α-substituent was an electron-donating methyl or phenyl group, the corresponding products 3u-3w were obtained in moderate-to-good yields (58-82 %). Unfortunately, the substrate with an electron-withdrawing ester at α position was not tolerated in this cyclization reaction, and we could not obtain the corresponding product 3x.Scheme 3. Scope of α-azido ketones.In order to gain insight into the reaction mechanism, we performed a series of control experiments, as shown in Scheme 4. Initially, α-azido phenylethanone (1a) reacted with p-toluenesulfonyl hydrazide (2) in CH 3 CN at room temperature for 48 h leading to α-azido N-tosylhydrazone 1a′ with 68 % yield. If this reaction was carried out in the presence of iodine, the yield increased to 85 %, and the reaction time was shortened to 6 hours. Later, compound 1a′ could be transformed into the target product 3a in 89 % yield in the presence of TBHP in DMSO at 100°C for 3 h. These results indicated that iodine promoted the first condensation process, and 1a′ is a possible intermediate for this reaction. Scheme 4. Control experiments.Based on the abovementioned experimental results, a possible reaction mechanism for this reaction is proposed, as shown in Scheme 5 (using 3a as the example). Initially, α-azido phenyl-

Direct Synthesis of 4-Aryl-1,2,3-triazoles via I2-Promoted Cyclization under Metal- and Azide-Free Conditions

“…Subsequently, great progress has been made in cycloadditions of electron-withdrawing alkenes or in situ -generated olefins with azides to construct NH -1,2,3-triazoles by transition-metal catalysis . Importantly, organocatalytic approaches as alternatives to metal-catalyzed reactions for the generation of 4-aryl- NH -1,2,3-triazoles have been reported by Guan, Shu, and Dehaen et al (Scheme a) . However, despite the above advances all these reactions inevitably require the use of azides, which are not friendly substrates.…”

Iodine and DMSO as Surrogate of Hazardous Metal and Non‐Metal Reagents in Organic Synthesis

“…To overcome this, Ren et al employed organic azides such as derivatives of αazido ketones with p-toluenesulfonyl hydrazide using 0.5 equivalent of molecular iodine in DMSO at 100 °C, resulting in 65 % yield of the desired product (Scheme (g)). [365] The addition of THBP as an additive increased the yield up to 87 %. The absence of iodine or DMSO resulted in no product formation.…”

I2/DMSO-mediated oxidative C–C and C–heteroatom bond formation: a sustainable approach to chemical synthesis

“…[88][89][90][91] Hence, by employing readily available a-azido acetophenones 90 and ptoluene sulfonyl hydrazide 91 in the presence of DMSO solvent, Wen-Ming Shu et al successfully devised a condensation/ cyclization methodology mediated by molecular iodine for the production of 4-aryl-NH-1,2,3-triazoles 92 (Scheme 52). 92 Under ideal circumstances, this reaction presents a method that does not require the use of metals to sequentially develop C-N and N-N bonds. The compounds that correspond to a-azido ketones and possess either an electron-donating or withdrawing group can be synthesized in high yields.…”