A Reliable Multi-Kilogram Preparation of 4-Phenylurazole

Triazolinediones as Highly Enabling Synthetic Tools

“…While Thiele was the first to report on the synthesis of 4-substituted urazoles, this procedure mostly gives poor isolated yields because of competitive formation of diphenylurea ( 6 ) and the difficult separation of products from unreacted or excess starting materials. ,,− Multiple variations of this original Thiele procedure have been reported in order to optimize the yield of 4-substituted urazoles. The overall efficiency is improved by using an excess of biurea, , by performing the reaction in a high-boiling solvent such as sulfolane or N -methylpyrrolidone, , or by physical removal of ammonia (Scheme a) using a slight vacuum. − , Use of the hydrochloride salt rather than the neutral amine starting material, to allow acid-catalyzed cyclization, is absolutely required in the case of anilines, since the presence of free aniline rapidly results in the formation of unreactive diarylurea. , This factor seems less crucial for the synthesis of 4-alkylurazoles, where these side products are not isolated .…”

“…However, in most cases this alternative two-step synthesis is not a solution. Efficient examples of this approach are mostly limited to the synthesis of 4-aminourazoles, ,− 4-methylurazoles, , and a few arylurazoles. − , Furdik et al have reported a general synthesis of 4-alkylurazoles in moderate to high yields (52–94%) from 1,6-dialkylbiureas, but the reported yields have been found to be hard to reproduce in later studies. , Relying on similar reactivity, amines have also been directly condensated with 1,2,4-triazolidine-3,5-dione ( 3 ) at elevated temperatures, thus giving the corresponding 4-substituted urazoles (Scheme c). For most substrates, the isolated yield of 4-alkylurazoles in this transimidation approach is lower than in the corresponding amine–biurea condensation–cyclization .…”

“…However, Yamada and Shimizu did report a synthesis of (3-chloropropyl)­semicarbazide 11 (Figure ), , in which the alkyl chloride can be used as a functional handle to introduce various nucleophilic groups, while Read and Richardson reported on the synthesis of a semicarbazide bearing a carboxybenzyl-protected amine ( 12 ), whichafter deprotectioncan be derivatized by various electrophilic groups . On the matter of (industrial) scalability, Chandrasekhar et al prepared nearly 4 kg of 4-phenylurazole in one batch with an overall yield exceeding 90% …”

“…Since the decreased reactivity of diethyl carbonate required harsher (alkaline) reaction conditions, the product is also immediately cyclized to the urazole under these conditions (vide infra). However, overall, this strategy is usually less practical with regard to isolation of compounds, generally being lower-yielding and, in the case where ethyl choloformate is used, more costly than the Cookson method. , …”

Triazolinediones (TADs)

“…2 Urazoles and their oxidation products (TADs) are commercially available. 3 Recently, several heterogeneous systems have been reported for the oxidation of urazoles to their corresponding triazolinediones. 4 (C) PTAD oxidizes alcohols to aldehydes or ketones at room temperature in a few hours with high yields.…”