Exclusive Solvent-Controlled Regioselective Catalytic Synthesis of Potentially Bioactive Imidazolidineiminodithiones: NMR Analysis, Computational Studies and X-ray Crystal Structures

Abstract

Herein, we describe the first consistent regiospecific reaction of isothiocyanates with a variety of substituted N-arylcyanothioformamides in a 1:1 molar ratio to generate a series of imidazolidineiminodithiones decorated with a multitude of functional groups on both aromatic rings. The reaction is carried out at room temperature using a 20 mol% catalytic amount of triethylamine with DMF as the solvent to selectively form the mentioned products with exclusive regioselectivity. The methodology features wide substrate scope, no requirement for chromatography, and good to high reaction yields. The products were isolated by simple ether/brine extraction and the structures were verified by multinuclear NMR spectroscopy and high accuracy mass measurements. The first conclusive molecular structure elucidation of the observed regioisomer was established by single-crystal X-ray diffraction analysis. Likewise, the tautomer of the N-arylcyanothioformamide reactant was proven by X-ray diffraction analysis. Density functional theory computations at the B3LYP-D4/def2-TZVP level in implicit DMF solvent were conducted to support the noted regiochemical outcome and proposed mechanism.

Keywords: N-arylcyanothioformamides; density functional theory; imidazolidineiminodithiones; isothiocyanates; thiazolidinethiones.

Scheme 1

Previous preparation and some selected reactions of imidazolidineiminothiones 3.

Scheme 2

Ketcham’s ring-closing reactions of N-phenylcyanothioformamide (1a) and N-methyl-(1a′) with aryl (16a) and alkyl (16a′) under various conditions.

Scheme 3

(a) Preparation of variously substituted N-arylcyanothioformamides 1a–g and (b) commercial isothiocyanates 16a–i coupling partners and preparation of isothiocyanate 16j.

Scheme 4

Synthetic approach to prepare different derivatives of variously substituted regioisomerically pure imidazolidineiminodithiones 18a–z, 18a′–z′, and 18a″–18e″.

Scheme 5

Proposed mechanism for the formation of substituted imidazolidineiminodithiones 18 from isothiocyanates 16 and N-arylcyanothioformamides 1. The reaction “path b” is dominant.

Figure 1

Expanded and truncated ¹HNMR spectra showing the N-H protons as representative signals to demonstrate product distribution of the imidazolidineiminodithione 18a vs. the thiazolidinethione product 17a using various solvents.

Figure 2

Preparation of variously substituted imidazolidineiminodithiones derivatives 18a–z, 18a′–z′, and 18a″–18f″. All products shown were isolated from the reaction mixture by ether/aqueous workup.

Figure 3

Assigned ¹H- and ¹³C-NMR chemical shifts of imidazolidineiminodithione 18g′.

Figure 4

Thermal ellipsoid plots of 5-imino-1-(4-nitrophenyl)-3-(p-tolyl)imidazolidine-2,4-dithione (18g′) (Deposition Number 2246320) with ellipsoids drawn at the 50% probability level. For the bond distances (Å) and angles (deg), see the Supporting Information Section.