Metal-free Three-Component Synthesis of 1,2,3-Triazoline-4-sulfonamides

Abstract

A new type of diazo compounds, namely, CH-diazomethane sulfonamides (generated in situ from readily available α-acetyl-α-diazomethane sulfonamides), was employed in a 1,3-dipolar cycloaddition reaction with imines (also formed in situ from primary amines and aldehydes). The reaction gave hitherto undescribed 1,5-disubstituted 1,2,3-triazoline-4-sulfonamides, which were obtained in good to excellent yields with complete trans diastereoselectivity. These new sulfonamides based on the nonaromatic 1,2,3-triazoline core are rather attractive from a medicinal chemistry standpoint in light of the strong emphasis recently put on the nonflat, more saturated (higher Fsp3) scaffolds for lead-generation libraries. The oxidative aromatization of 1,2,3-triazoline-4-sulfonamides by manganese­(IV) oxide gave nearly quantitative yields of 1,2,3-triazole-4-sulfonamides, of which only two examples have been reported in the literature.

Novel Bis-Triazole Scaffold Accessed via Two Tandem [3+2] Cycloaddition Events Including an Uncatalyzed, Room-Temperature Azide-Alkyne Click Reaction

“…Recently, we reported a novel, metal-free synthesis of 1,5-disubstituted 1,2,3-triazoles via a three-component reaction of α-acetyl-α-diazomethane sulfonamide 1 with aldehydes and amines [4]. The reaction proceeded, presumably, through the formation of the initial 1,2,3-triazoline adduct 2 [5] which underwent aromatization with the loss of sulfur dioxide and N-Boc aniline.…”

Metal-Free Synthesis of 1,5-Disubstituted 1,2,3-Triazoles

“…Recently, we have reported a three-component synthesis of 1,2,3-triazoline-4-sulfonamides 1 via a three-component reactionof α-acetyl-α-diazomethane sulfonamides 2 with amines and aldehydes that proceeds through in situ deacetylation to give C-H α-diazomethane sulfonamides 3 and the Schiff base, followed by [3+2] dipolar cycloaddition of the latter two intermediates. 1,2,3-Triazolines 1 were eventually oxidized using manganese dioxide in toluene at elevated temperature to give the respective 1,2,3-triazole-4-sulfonamides 4 (Scheme a) . When searching for suitable conditions for the latter aromatization, methanol and ethanol were tried as the solvents.…”

“…The two-step synthesis of triazoles 5a – k included the recently published metal-free, three-component synthesis of 1,2,3-triazoline-4-sulfonamides 1a – k using a single α-acetyl-α-diazomethane sulfonamide 2a reacting with the imines formed in situ from various aromatic aldehydes and aliphatic amines. Triazolines 1a – k were isolated chromatographically in good to excellent yields and subjected to thermal aromatization in ethanol.…”

“…1,2,3-Triazolines 1 were eventually oxidized using manganese dioxide in toluene at elevated temperature to give the respective 1,2,3-triazole-4sulfonamides 4 (Scheme 1a). 12 When searching for suitable conditions for the latter aromatization, methanol and ethanol were tried as the solvents. At elevated temperature, in both solvents, an unexpected side-reaction was observed which led, in the case of 1,2,3-triazoline 1a, to the formation of 1,2,3triazole 5a lacking the sulfonamide moiety.…”

“…The spectral characteristics matched the previously reported data. 12 1,2,3-Triazole 5g was prepared from 1,2,3-triazoline 1g according to GP 2. Yield 109 mg (92%).…”