A FACILE SYNTHESIS OF THIOSEMICARBAZIDESAND THIOSEMICARBAZONES BY THETRANSAMINATION OF 4-METHYL-4-PHENYL-3-THIOSEMICARBAZIDE

Abstract

Thiosemicarbazones of α-(N)-heterocyclic ketones and aldehydes possess a broad spectrum of potentially useful chemotherapeutic activities. Thus, the antimalarial, antibacterial, and antiviral properties of this class have been explored by Klayman, et al.¹ The antileishmanial activity of a series of acetyl β-carboline thiosemicarbazones was recently described by Dodd and coworkers ^.2 The α-(N)-heterocyclic thiosemicarbazones act as tridentate ligands for transition metals³; this property has been implicated in their biological mechanism of action.⁴ The synthesis thiosemicarbazone-transition metal complexes and the spectroscopic investigation of structure and bonding in these complexes is being actively pursued ⁵ In order to facilitate these investigations, an improved method of synthesizing thiosemicarbones is desirable. Such a synthesis should be efficient (high yield), general (afford thiosemicarbazones of N⁴-monosubstitution or N⁴,N⁴-disubstitution patterns), safe (avoids toxic or unpleasant reagents and byproducts) and direct (a single step reaction which does not require the isolation of any intermediates). Klayman and Lin described the preparation of a variety of N⁴-mono and N⁴,N⁴-disubstituted thiosemicarbazones by the displacement of the dimethylamino function of the corresponding thiosemicarbazones by a primary or secondary amine.⁶ Thus, refluxing a solution of benzaldehyde 4,4-dimethyl-3-thiosemicarbazone (A) in acetonitrile (bp 82°C) for 6 h with two equivalents of aniline gave a 63% yield of benzaldehyde 4-phenyl-3-thiosemicarbazide (B). When the thiosemicarbazone substrate bore a hydrogen atom as an N⁴-substitutient, low yields (ca. 20%) of thiosemicarbazones could only be obtained under forcing conditions (24 h at 109°C in toluene). This clearly established the requirement for a secondary amine as a leaving group for facile transamination at the thiocarbonyl carbon atom. With this observation in mind, the reaction might be improved further by the substitution of a phenylmethylamino group for a dimethylamino group. Substitution of the electron withdrawing pheny group for one of the methyl groups should enhance the electrophilicity of the thiocarbonyl group. Furthermore, the aromatic amine, being a weaker base, ought to serve as a better leaving group. In this communication, I describe the facile preparation of thiosemicarbazides (1) by transamination of 4-methyl-4-phenyl-3-thiosemicarbazide (la), and thiosemicarbazones (2), by trans-amination of l a in the presence of the requisite aldehyde or ketone.

Key Words:

• Thiosemicarbazones
• Thiosemicarbazides
• 4-Methyl-4-phenyl-thiosemicarbazide
• activated transamination reactions.