Synthesis of novel 18-crown-6 type ligands containing a phenothiazine 5,5-dioxide unit

Novel crown ethers containing a phenothiazine 5,5-dioxide unit have been synthesized. Macrocyclization reactions rendering N -tosyl protected crown ethers were performed in the absence of metal ion templates. These new crown ethers are useful precursors of sensor and selector molecules with wide applications

In this paper we report the synthesis of a new class of macrocycles containing a phenothiazine unit (1 and 2, Fig. 1.) in which the NH group of the phenothiazine is part of the macroring.These macrocycles can be very useful intermediates in the synthesis of sensor and selector molecules with diverse applications.

Results and Discussion
Crown ethers 1 and 2 were prepared starting from ditosylamides 3 and 4 in two steps (Scheme 1).Ditosylamides 3 and 4 were reacted with tetraethyleneglycol ditosylate 5 41  Tert-butyl substituted crown ether 6 was first prepared by a usual method using potassium carbonate as a base and acetonitrile as a solvent.The same conditions were applied for the synthesis of crown ether 7, but the desired product could not be isolated.The formation of crown ether 7 was not observed when using other bases containing alkaline metal cations as templates (cesium carbonate or potassium tert-butoxide), but when Hünig's base was used in different solvents, formation of crown ether 7 did occur.Using dimethoxyethane and diglyme as solvents gave poor results, and the yield worsened in larger scales.Acetonitrile proved to be the best solvent for the reaction with reproducible yields even in larger scales.Since crown ether 7 could be prepared in the presence of Hünig's base, we examined whether the latter base could also be used in the synthesis of tert-butyl substituted crown ether 6.Similar results were found as in the case of crown ether 7, crown ether 6 could be isolated in a poor yield using dimethoxyethane and in a good yield using acetonitrile.
The tosyl protecting groups of crown ethers 6 and 7 were removed by amalgamated sodium in methanol to give crown ethers 1 and 2 in good yields (Scheme 1) using similar conditions as described for the removal of tosyl groups from a triaza-crown ether containing a pyridine unit. 42itosylamide 3 was prepared from diamine 8 43 with tosyl chloride in pyridine in a good yield (Scheme 2).The synthesis of ditosylamide 4 was carried out as outlined in Scheme 3.

Scheme 3. Synthesis of ditosylamide 4.
The tert-butyl protecting groups of the reported diacetamide 9 43 were removed by aluminium chloride in the presence of phenol in toluene to give diacetamide 10.Hydrolysis of diacetamide 10 with aqueous hydrochloric acid gave the hydrochloride salt 11.As aminophenothiazines are

Experimental Section
General.Reagents were purchased from Sigma-Aldrich Corporation unless otherwise noted.Silica gel 60 F254 (Merck) plates were used for TLC.Silica gel 60 (70-230 mesh, Merck) was used for column chromatography.Ratios of solvents for the eluents are given in volumes (mL/mL).Solvents were dried and purified according to well-established methods. 44vaporations were carried out under reduced pressure unless otherwise noted.Infrared spectra were recorded on a Bruker Alpha-T FT-IR spectrometer. 1 H (500 MHz) and 13 C (125 MHz) NMR spectra were obtained on a Bruker DRX-500 Avance spectrometer. 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were obtained on a Bruker 300 Avance spectrometer.Elemental analyses were performed in the Microanalytical Laboratory of the Department of Organic Chemistry, Institute for Chemistry, L. Eötvös University, Budapest, Hungary.Melting points were taken on a Boetius micro-melting point apparatus and were uncorrected.Mass spectra were recorded on an Agilent 6410 TQMS instrument using ESI method.
General procedure for the synthesis of crown ethers 1 and 2. To a mixture of crown ether 6 or 7 and disodium hydrogenphosphate (5 equiv.) in MeOH was added finely powdered sodium amalgam (4 w/w% Na, 15 equiv.)under Ar at rt.After addition of the sodium amalgam, the mixture was stirred for 3 h at reflux temperature.After the reaction was completed, the cooled reaction mixture was diluted with CH2Cl2, and then it was removed from the mercury by decantation.The solvent was evaporated, and the crude product was suspended in water, the pH was adjusted to 7 using acetic acid, the solid material was filtered, washed with water and triturated with hot MeOH to give 1 or 2 as offwhite crystals.17,23-Di-tert-butyl-5,8,11-trioxa-20 6 -thia-2,14,26-triazatetracyclo[13.9.3.0 19,27 .0 21,25 General procedure for the synthesis of ditosylamides 3, 4 and 12 by reaction of diamines 8, 11 and 14 with tosyl chloride.To a solution of diamines 8 43 , 11 or 14 in pyridine was added tosyl chloride (2.2 equiv.)under Ar at 0 °C and the mixture was stirred at 0 °C for 1 h.The reaction mixture was poured into water-ice mixture and the pH was adujsted to 3 with hydrochloric acid.The solid material was filtered, washed with water, and the crude product was triturated with MeOH to give ditosylamides 3, 4 or 12 as offwhite crystals.

Synthesis of tosylamide 4 starting from tosylamide 12.
A. Using hydrogen peroxide.To a solution of ditosylamide 12 (0.1 g, 0.186 mmol) in acetic acid (2 mL) was added 30% aqueous hydrogen peroxide (0.19 mL, 1.86 mmol).The reaction mixture was stirred at rt for 1 day, then the crystals were filtered.The crude product was triturated with hot MeOH to give ditosylamide 4 (20 mg, 18%) as offwhite crystals.Ditosylamide 4 had the same physical properties and spectral data as the one prepared above from diamine 14.B. Using meta-chloroperbenzoic acid.To a suspension of ditosylamide 12 (3.8g, 7.07 mmol) in dichloromethane (80 mL) was added meta-chloroperbenzoic acid (70 w/w%, wet with water, 8.71 g, 35.3 mmol) at 0 °C .The reaction mixture was stirred at 0 °C for 15 min and then at rt for 7 days.The solid material was filtered.This crude product was suspended in water, the pH was adjusted to 7 with NaHCO3, the solid material was filtered and then triturated with MeOH to give ditosylamide 4 (3.67 g, 90%) as offwhite crystals.Ditosylamide 4 had the same physical properties and spectral data as the one prepared above from diamine 14.
General procedure for the synthesis of crown ethers 6 and 7. (Table 2 A mixture of ditosylamide 3 or 4, tetraethyleneglycol ditosylate 5 41 (1.1 equiv.)and a base (10 equiv.) was heated in a solvent under Ar with stirring for 1 week (see Table 2. for other reaction conditions).After the reaction was completed, the solvent was removed, and the residue was taken up in a mixture of CH2Cl2 and water.The phases were shaken well, separated, and the aqueous phase was extracted 3 times with CH2Cl2.The combined organic phase was dried over MgSO4, filtered, and the solvent was removed.The crude product was purified by column chromatography on silica gel using acetone-CH2Cl2 (1:50) mixture as eluent to give 6 as white crystals or 7 as pale yellow crystals.8 mmol) at 0 °C .The reaction mixture was stirred at 0 °C for 10 min, at rt for 7 days, then the solid material was filtered.This crude product was suspended in water, the pH was adjusted to 7 using NaHCO3, the solid material was filtered and then triturated with MeOH to give diacetamide 13 (3.87 g, 88%) as offwhite crystals.Diacetamide 13 had the same physical properties and spectral data as the one prepared above using hydrogen peroxide.1,9-Diamino-5,10-dihydro-5 6 -phenothiazine-5,5-dione (14).A suspension of diacetamide 13 (1.84 g, 5.34 mmol) in 20% aqueous HCl (100 mL) was stirred under Ar at reflux temperature for 4 h.After the reaction was completed, the mixture was cooled to rt, and the solid material was filtered and washed with water.The crystals were suspended in water, and the pH was adjusted to 7 using NaHCO3, the solid material was filtered and washed with water to give

Table 1 .
Yields of the macrocyclization reactions in the presence of different bases in different solvents

Table 2 .
.) Conditions and yields of the macrocyclization reactions