Fluorous parallel synthesis of a hydantoin/thiohydantoin library

Abstract

Fluorous tagging strategy is applied to solution-phase parallel synthesis of a library containing hydantoin and thiohydantoin analogs. Two perfluoroalkyl (Rf)-tagged α-amino esters each react with 6 aromatic aldehydes under reductive amination conditions. Twelve amino esters then each react with 10 isocyanates and isothiocyanates in parallel. The resulting 120 ureas and thioureas undergo spontaneous cyclization to form the corresponding hydantoins and thiohydantoins. The intermediate and final product purifications are performed with solid-phase extraction (SPE) over FluoroFlash™ cartridges, no chromatography is required. Using standard instruments and straightforward SPE technique, one chemist accomplished the 120-member library synthesis in less than 5 working days, including starting material synthesis and product analysis.

Fluorous Synthesis of Hydantoin‐, Piperazinedione‐, and Benzodiazepinedione‐Fused Tricyclic and Tetracyclic Ring Systems

“…Preparations of fluorous amino esters 5 and one‐pot, three‐component 1,3‐dipolar cycloaddition reactions were conducted by following established procedures 6a,6b. Thus a mixture of a fluorous amino ester (1.0 equiv.…”

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

“…This procedure could be performed on solid phase, 236−238 as well as with fluorous tagged reactants, that allowed easy purification via F-SPE (fluorous solid-phase extraction). 239,240 Similar methods were described, preparing the N-substituted amino acid or nitrile from amination of α-bromocarboxylic acids 241,242 or Strecker reaction, 243 respectively. N-substituted glycine derivatives were also prepared via a PEG-supported solution-phase method performed under microwave irradiation.…”

“…The obtained N- substituted amino acids then react with substituted isocyanates in the presence of a base to afford the corresponding 1,3,5-trisubstituted hydantoins (Scheme ). This procedure could be performed on solid phase, − as well as with fluorous tagged reactants, that allowed easy purification via F-SPE (fluorous solid-phase extraction). , …”

An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries

“…Nevertheless, examples of hydantoin libraries synthesis were described in the literature previously. Many of them relied on the use of isocyanates (Figure , pathway B and other transformations); − some allowed for the preparation of the libraries with specific substitution patterns − or were multistep. ,− But isocyanates are toxic, have limited shelf stability and commercial availability (as compared to other common building blocks), which hampers wide application of the synthetic procedures cited above in the parallel conditions.…”