The aqueous-phase synthesis of sulfonylthioureas and a study of their properties as anion receptors

A series of mono-or bis-sulfonylthioureas has been synthesized via nucleophilic substitution of potassium sulfonamides and sodium dithiocarbamate in water under mild conditions, and their properties as anion receptors in the absence and presence of K + have been investigated by 1 H NMR spectroscopy. It was found that calix[4]crown-5 derivative 10 shows much higher selective complexation capability with H 2 PO 4 - in the presence of K + than in the absence of K + , which indicates the physical dimension of K + and H 2 PO 4 - , respectively, matched the corresponding cavity of the host compound.


Introduction
Thioureas are useful reagents for f. ex.anion complexation 1 and sensing 2 , asymmetric catalysts 3 and solar cell construction 4 .The derived sulfonylthioureas display a broad spectrum of biological and pharmacological properties with action as antidiabetics 5 , enhancers of parasympathetic system function 6 , anticonvulsants 7 , antiarrhythmics 8 or herbicides 9 .Furthermore, they are often used as synthetic intermediates 10 for a variety of guanidine drugs and also as building blocks 11 in the synthesis of heterocycles.Direct condensation of sulfonylisothiocyanate with amine in dry CHCl3 or CH2Cl2 is the general procedure for the synthesis of sulfonylthioureas. 12Another synthetic route 13 is nucleophilic addition of sulfonamide and isothiocyanate in the presence of inorganic bases in anhydrous acetone, DMF or DMSO.The two methods are frequently limited by harsh reaction conditions, lower yields, longer reaction times, and use of toxic solvents.To the best of our knowledge, the voluminous literature about applications of sulfonylthioureas does not mention the use of sulfonylthioureas as anion receptors probably due to their inaccessibility by traditional synthetic methods.We now report the aqueous-phase synthesis of sulfonylthioureas and a study of their properties as anion receptors.

Aqueous-phase synthesis of sulfonylthioureas
The aqueous-phase synthetic method we offered holds many advantages such as mild reaction conditions, free organic solvent, high isolated product yields and very short reaction time.Thus it provided a better and more practical alternative to existing procedures.The synthetic route is outlined in Scheme 1. C=S of 12 has been activated by ClCH2COONa.The reaction time is shorter for the preparation of 7 and 10.It is because that benzo-18-crown-6 and calix [4] Sulfonylthioureas 1-10 has been synthesized via nucleophilic substitution of potassium sulfonamides 11 and dithiocarbamate 12 at rt to 50-60 °C within 1.0 h in water.Aqua 11 were prepared from ArSO2NH2 and equivalent KOH in water.Corresponding ArSO2NH2 for the synthesis of compound 10 was obtained based on the modified procedures.14a,15 Aqua 12 were afforded from sodium dithiocarbamate and ClCH2COONa in water following the method.14b All new compounds were characterized by IR, 1 H NMR, 13 C NMR, mass spectra and elemental analysis.
In conclusion, we have designed and developed a convenient, efficient, economically and environmentally benign procedure for the synthesis of sulfonylthioureas which will be studied below for their properties as anion receptors.
Sulfonylthiourea-based properties as anion receptors.2 and 7-10 were selected as test objects.Their properties as anion receptors were investigated by standard 1 H NMR titration using a ligands concentration (0.1-2.0 mM) and an increasing concentration of appropriate anion to obtain different host : guest ratios (0.1-20 : 1).To ensure the solubility of both organic ligands and inorganic anions, a mixed solvent system (CDCl3-CD3CN 4:1, v/v) was used.All anions were added as their tetrabutylammonium salts to minimize possible interactions of sulfonylthioureas with counter cations.The addition of anions led to the down-field shifts of -SO2NHsignals.Another experiment was carried out repeatedly in the presence of 2 eq. of KBPh4 by the same procedure as described above.
Results are summarized in Table 1 and 2 where diphenylthiourea is taken as a reference.The binding constants of 8 and 10 towards some anions are too large to be determined accurately by 1 H NMR spectroscopy and the values given are rough estimations.Table 1 shows that the association constants follow the trend H2PO4 -＞ HSO4 -＞ Cl -＞ Br -＞ I -for 2 and 7-10 as well as Ph-TU.The observed binding selectivity can be roughly explained by the anion basicity order. 2 and 7-10 lead to much higher complexation constants if compared with the reference.This can be understood by considering the electron-withdrawing effect of SO 2 groups.The influence of the naphthyl group of 9 is less beneficial for complexation likely because of a decrease in electron delocalization energy.10 showed higher selective affinity for H2PO4 -due to the enhanced hydrogen bonding ability of the sulfonylthiourea -NH protons.Most important of all, the cavity of 10 matched the size and shape of given H2PO4 -.
Table 2 indicates that 7 and 10 work as a novel bifunctional receptor for simultaneous complexation of K + and anions, where the ability of 7 and 10 to bind anions is significantly enhanced when K + is bound to the crown moiety.This is supported by their 1 H NMR spectroscopy, in which downfield shifts for sulfonylthiourea protons were observed upon complexation of K + at the crown moiety.But, no complexes of crown moiety can be detected when K + is replaced by the other metal ion such as Na + , Rb + , and Cs + .By contrast, Ph-TU, 2, 8, and 9, which lack crown ether moiety for K + binding, shows a small decrease for anions.10 can act as a better bifunctional receptor.Selective complexation model of 10 with H2PO4 -in the presence of K + is depicted in Scheme 2.

Conclusions
In this study, a series of mono-or bis-sulfonylthioureas as potential hydrogen bond donors to bind some anions, has been synthesized via nucleophilic substitution of potassium sulfonamides and sodium dithiocarbamate in water under mild conditions, and the anion complexation in the absence and presence of K + has been examined by 1 H NMR spectroscopy.The presence of electron withdrawing sulfonyl group results in very high binding affinity towards anions compared with reference Ph-TU.7 and 10 bearing crown ether moiety are found to work as a novel bifunctional receptor for simultaneously selective complexation of K + and H2PO4 -, where the ability of 7 and 10 to bind H2PO4 -is significantly enhanced when K + is bound to the crown moiety, whereas receptor 10 shows a much higher complexation degree with H2PO4 -due to the cavities of crown moiety and calixarene matching the physical dimensions of K + and H2PO4 -, respectively.

Experimental Section
General.The reagents used were of reagent grade and used as purchased.Melting points were measured by using a XT-4A 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.Infrared spectra were obtained on a Bio-Rad spectrophotometer using KBr pellets.Mass spectra were measured using Agilent 6100B and Agilent 6220 Time-of-Flight LC/MS.Elemental analysis was determined on a Vario EL III elemental analyzer.

Typical procedure to synthesize sulfonylthioureas (1-10).
To the aqueous solution of ArSO2NHK 11 (1 eq.) was dropwise added an aqueous solution of sodium dithiocarbamates 12 (1eq.).After the addition was completed, the reaction mixture was stirred for about 30 min at room temperature and was subsequently heated to 50-60 o C for another 30 min or so.Finally, the mixture was cooled to room temperature.The resulting precipitate was collected by suction filtration and washed successively with H2O, then dried under vacuum over P4O10 to afford sulfonylthioureas 1-10 in high purity and yields.Sulfonylthiourea 1.Yield, 85%, white crystalline powder, mp 146-148 o C (lit.

Measurement of sulfonylthiourea-based properties as anion receptors
The measurements were performed by 1 H NMR titration experiments in CDCl3-CD3CN (v/v=4 : 1) at 298 K using a constant host concentration of 2.0 mM and a varying guest concentration of 0.1-20 mM.For each Kass value determination, 5-10 different guest concentrations were taken As a probe, the chemical shift of the SO2NH signal was used.
In the presence of K + , anion complexation was measured analogously to the above procedure.The K ass values were calculated by the equation below as described in literature 18 .