An expedient synthesis of N-tosyl macrocycles containing two thiourea moieties from trisulfonamide and bis-dithiocarbamate salts at room temperature in aqueous media

The nucleophilic reaction of diamines and carbon disulfide in aqueous NaOH afforded a series of bis-dithiocarbamate salts. Activation of these with aqueous ClCH2COOK and subsequent nucleophilic substitution reaction with trisulfonamide aqueous KOH at room temperature provided N-tosyl-macrocycles containing two thiourea units. This strategy has the advantages of simple operation, mild reaction condition, easy product-isolation and environmental friendliness.


Introduction
Macrocyclic anion receptors 1 based on directed hydrogen-bonding interactions including macrocyclic thiourea are well known.The continued interest in novel macrocyclic thiourea ligands stems from their applications in many areas of chemistry and biochemistry, including ion-selective electrodes and optodes, 2 their easy complexation of anions 3 and N-protected glutamate dianion, 4 and antimicrobial studies. 5Our ongoing studies are concerned with the simple, convenient preparation of these macrocycles.We have noted that the traditional methods 6 of this kind involve volatile and toxic organic solvent, hyper-toxic thiophosgene or unstable (sulfonyl) isothiocyanate, and cumbersome product-isolation procedures.
We have recently reported the synthesis of calix [4]crown-5-sulfonyl imidazolidinethione from calix [4]crown-5-monosulfonyldiamine and carbon disulfide by intramolecular cyclization at room temperature in water. 7In our study of these N-sulfonyl macrocycles, we now report the synthesis of methylene-bridged cyclophane-thiones from trisulfonamide and activated bisdithiocarbamate salts by intermolecular cyclization at room temperature in water (Scheme 1).
The structures of 1a-e were characterized by melting point, IR, 1 H NMR, 13 C NMR, thinlayer chromatography (TLC), and elemental analyses.The infrared spectra of the thiourea macrocycles 1a-e revealed a C=S stretching vibration at 1280-1295 cm −1 and 1380-1395 cm −1 , two bands for the symmetrical and asymmetrical vibrations of the SO2 group at 1145-1158 cm −1 and 1345-1355 cm −1 as well as a Ts-H out-of-plane C-H bending vibration with two adjacent hydrogens at 852-856 cm −1 and C-O stretching with broad and strong absorption at 1090 cm −1 in compound 1b, ortho-xylylene out-of-plane C-H bending with four adjacent hydrogen at 755 cm −1 in case of compound 1c, meta-xylylene C-H bending with three adjacent hydrogen and one isolated hydrogen at 770 cm −1 in case of compound 1d, and para-xylylene C-H bending with two adjacent hydrogen at 830 cm −1 in case of compound 1e.The N-H bands appeared at 3332-3347 cm −1 .The 1 H NMR data showed a broad singlet in the region δ 7.65-7.83ppm for NH, multiplets at δ 3.47-3.61ppm and δ 3.61-3.64ppm for the NCH2 and OCH2 of 1a and 1b, respectively.Multiplets at δ 7.65-7.83ppm for four hydrogens of the ortho-xylylene ring in compound 1c as well as a singlet at 6.87 ppm for the isolated hydrogen of the meta-xylylene ring moiety in 1d, and a doublet for four protons at 6.95 ppm for the para-xylylene ring in compound 1e.Further evidence about the structure of the foregoing compounds 1a-e has been derived from their 13 C NMR spectra which revealed the expected number of signals for the mentioned compounds as well as C= S signals at δ 207.1-208.3ppm for thiourea macrocycles, respectively.In addition, elemental analysis supported the suggested structures.

Conclusions
We have demonstrated that our strategy for the green synthesis of large-ring compounds can be applied to the preparation of various N-tosyl macrocycles with two thiourea moieties using lowtoxic, inexpensive, and easily available reagents in water.Our example show trisulfonamide 2 and bis-dithiocarbamate salts 3a-e can be used as a very versatile synthon, prepared in facile steps in aqueous media, in order to synthesize derivatives of cyclam family including cyclophane-based cyclic thioureas.Five novel sulfonylthiourea macrocycles were synthesized and characterized using the method.These compounds offer the opportunity for selective desulfonylation 12 and then oxidation 13 allowing the possibility of the preparation of a range of macrocyclic (thio)ureas.

Experimental Section
General.The reagents used were of reagent grade and used as purchased.Melting points were measured by using a XT-4 Electrothermal micro-melting-point apparatus and are uncorrected.NMR spectra were recorded at 400 ( 1 H) and 100 ( 13 C) MHz, respectively, on a Bruker Avance III Plus 400 spectrometer in DMSO-d6 using TMS as internal reference.Chemical shifts (δ) are given in ppm.Infrared spectra were obtained on a Bio-Rad spectrophotometer using thin films on NaCl windows or in KBr pellets and are reported as cm -1 .Elemental analysis was determined on a Yanaco CHN Corder elemental analyzer.