Synthesis of a Dithiocarbazate Linker on Solid Support

The heterocyclic-oriented thioureas have scarcely been reported in the research field of drug-like library construction by solid-phase synthesis, compared to their ureas and simple aromatic thiourea analogues. We have previously described the dithiocarbazate linker 42 and its application to drug-like heterocycle formation. The key intermediate, the 

In the first step, Fmoc (9-fluorenylmethoxycarbonyl)-protected dithiocarbazate resin 43 was prepared by a three-component reaction of Merrifield resin 1 and carbon disulfide with Fmoc-protected hydrazine in the presence of sodium hydride in DMF at room temperature. Deprotection of the Fmoc group of resin 43 with 5% piperidine produced the corresponding free dithiocarbazate resin 42. In this step, the use of 5% piperidine was essential because a higher concentration caused loss of the desired substrate from resin 43. In addition, we have developed a more convenient synthetic route to the resin 42, compared to the previous report using hydrazine monohydrate and carbon disulfide with potassium hydroxide in ethanol solvent. Under these reaction conditions, we obtained the polymer-bound dithiocarbazate 42 without the Fmoc protection step of the hydrazine. 

2 Solid-Phase Synthesis of Pyrazoles via a Dithiocarbazate Linker 

The desired 5-amino-l-(substituted-thiocarbamoyl)pyrazoles 7 were finally liberated firom resin 44 using various amines (see Table 10.6) by thermal cleavage reaction in toluene at 60 °C. Various types of amine (R R N diversity elements) afforded the 5-amino-1-(substituted-thiocarbamoyl)pyrazole derivatives 7 in good four-step overall yields (22 examples, 33-17% yields, 99-67% purities. Table 10.6) from Merrifield resin 1 with high purities, except for sterically hindered secondary amines, such as diisopropylamine and diisobutylamine. 

T A B L E 10.6. 5-Amino-1 -(substituted-thiocarbamoyl)pyrazole 7 and Their Yields  

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