Chemistry of Catechol Sulfates. Regioselective Ring Opening and Stabilization of Reaction Product by Hydrogen Bonding.

 

Zoltan G. Hajos a

 

Formerly at Princeton University, Department of Chemistry, Princeton NJ

 

 

Abstract

The chemistry of catechol sulfonanilides 2 and 4 has been reinvestigated. It was found that the cyclic sulfate ring of the sulfonanilide 2 and the C-1 sulfonanilide group would regioselectively hydrolyze in refluxing aqueous acetone with aniline to the catechol O-sulfonic acid 3 stabilized by intramolecular H-bonding. On the other hand, the cyclic sulfate of the N-methyl sulfonanilide 4 remains unchanged in refluxing aqueous acetone with N-methyl aniline. It undergoes, however, hydrolysis to intermediate 4A, the N-methyl analog of compound 3 by refluxing it in aqueous acetone in the presence of aniline. Intermediate 4A is not stabilized by intramolecular H-bonding; it undergoes therefore hydrolysis to the catechol derivative 5.

 

Keywords: benzenesulfonanilides, catechol sulfate derivatives, regioselective hydrolysis, intramolecular H-bonding, inhibition of hydrolysis in aqueous media.

 

 

Introduction

 

A paper by Pollak and Gebauer-Fülnegg concerning the chemistry of cyclic catechol sulfate derivatives appeared in 1926. Twentyseven years later, because of the interest in catechol and homo pyrocatechol derivatives at the Technical University, Budapest, Hungary the Pollak, Gebauer-Fülnegg data have been reinvestigated 1. Still later, at Princeton University the synthetic scheme of oxygen containing 5-ring heterocyclic vicinal diones and diols  involved intermediate SO2 addition products 2. Therefore, our interest in the chemistry of aromatic vicinal diols and their SO2 derivatives has been renewed. More recently, a publication renewed the biological interest in the area due to a publication entitled “Effect of oral absorption of benzenesufonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation” 3. The results obtained at the Technical University have been later expanded to include data of proton NMR spectroscopy once the spectroscopic equipment became commercially available.

 

 

Results and Discussion

 

The authors of the 1926 paper reacted compound 1, the disulfonyl chloride of catechol cyclic sulfate with an excess of aniline in refluxing acetone. They filtered the reaction mixture and crystallized the precipitate by refluxing it in aqueous acetone. Upon cooling they claimed to have obtained compound 2, mp at about 304o C with decomposition. They characterized the reaction product by nitrogen determination only (N, 5.67-6.0) 1. By repeating the original procedure, we found the correct structure to be the water insoluble compound 3. Its melting point was identical to that reported earlier 1 (mp 304o C, dec.). Compound 2 and compound 3 have rather similar N-values. Nitrogen determination alone is therefore insufficient to characterize these compounds.

 

The cyclic catechol sulfate group of compound 2 hydrolyzed by regioselective ring opening due to the anchimeric assistance of the ortho standing sulfonanilide group. This was responsible for the stereoselectivity of the hydrolytic attack of the aniline/ aniline-hydrochloride system in the refluxing aqueous acetone medium. The resulting catechol O-sulfonic acid 3 was stabilized by intramolecular H-bonding. Also, since the compound was practically insoluble in water its precipitation protected it from further hydrolysis. O-sulfonic acid derivatives of catechol have been described in the scientific literature.4a,b              The reaction therefore constitutes an example of inhibition from hydrolysis in the presence of water due to insolubility of the substrate in water and its stabilization by intramolecular hydrogen bonding. The results are shown in Scheme 1.

In modern organocatalysis water insoluble proline derivatives have been successfully used to catalyze intermolecular aldol reactions in water.5

The facile opening of the five-membered ring catechol cyclic sulfate has been well documented in the scientific literature.6  A paper entitled: “Intramolecular Nucleophilic Catalysis by the Neighboring Hydroxyl Group in Acid-Catalyzed Benzenesulfonamide Hydrolysis”7  describes the regioselective hydrolysis of a sulfoanilide group assisted by a vicinal hydroxyl group.

 

Using the theoretically necessary four equivalents of aniline, and by executing the reaction at RT in dry acetone we obtained the cyclic catechol sulfate 2. It analyzed correctly for C, H, N and S, and had mp of 125°C. Its 1H NMR spectrum was in good agreement with structure 2. The compound was thus clearly different from the one described earlier1.

 

Pollak and Gebauer-Fülnegg also described treatment of 1 with N-methylaniline to give the cyclic catechol sulfate ester 4, the N-methyl analog of 2. Compound 4 had mp 146°C, and was again characterized by nitrogen determination only 1. Using our procedure (4 equivalents of N-methylaniline in acetone at RT), we too obtained compound 4, mp 145-146°C, and confirmed its structure by C, H, N and S analysis and 1H NMR. While nitrogen determination can practically not differentiate between compounds 2 and 3, the C, H and S values of these two compounds are clearly different.

 

The cyclic sulfate of the N-methyl sulfonanilide 4 remains unchanged in refluxing aqueous acetone with N-methyl aniline 1, but undergoes hydrolysis to the intermediate 4A, the N-methyl analog of 3  in the presence of aniline under identical reaction conditions. Since 4A is not being stabilized by H-bonding it undergoes hydrolysis to the catechol 5, mp 86°C. It analyzed correctly for C, H, N and S. Its 1H NMR spectrum was in good agreement with structure 5. Compound 5 is new. The conversion of the cyclic catechol sulfate 4 to the catechol 5 most likely proceeds via the 4A-type sulfonic acid derivative, the N-methyl analogue of compound 3. However, unlike compound 3 intermediate 4A is not being stabilized by intramolecular H-bonding, and is therefore readily converted to compound 5. It is interesting to note that the cyclic catechol sulfate ring does not open with N-methyl aniline, but opens readily with aniline a primary amine. The results are shown in Scheme 2.

 

Experimental Section

 

General Procedures.

 

Melting point determinations were done on a Thomas Hoover capillary melting point apparatus and are uncorrected. Nuclear-magnetic-resonance (1H NMR) spectra were recorded on a Varian HR 100 spectrometer. Chemical shifts (d) are reported in parts per million downfield relative to tetramethylsilane as a standard. All new compounds gave consistent 1H NMR spectra.

 

 

1,3,2-benzodioxathiole-2,2-dioxide-4,6-disulfonyl dichloride (1). Compound 1 has been prepared by the literature procedure1 in 47.7% yield. Mp 141-143 oC (lit. 1 mp 143 oC).

1H NMR (100 MHz, DMSO-d6) d 7.6 (1H, d), 8.0 (1H, d). Anal. Calcd. for C6H2Cl2O8S3: C,19.52; H, 0.55; S, 26.06. Found: C, 19.30; H, 0.62; S, 25.91.

 

1,3,2,benzodioxathiole-2,2-dioxide-4,6-disulfonic acid bis-phenylamide (2). To compound 1 (1.8 g, 4.9 mmol) dissolved in acetone (5 mL) was added dropwise aniline (1.8 g, 19.6 mmol) dissolved in acetone (5 mL). It was allowed to stand at RT for 16 h., filtered, and the solvent was evaporated in vacuo. The residue was dissolved in chloroform, and washed with water to remove aniline hydrochloride. It was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to give an oily solid (2.4 g, 4.9 mmol). Recrystallization from ether-hexane gave compound 2 (1.8 g, 76%) needles, mp 123-125 oC; 1H NMR (100 MHz, CDCl3) d 4.0 (2NH, s), 6.5 (4H, d), 6.6 (2H, d), 7.0 (4H, d), 7.2 (1H, d), 8.0 (1H, d). Anal. Calcd. for C18H14N2O8S3: C,44.81; H, 2.92; N, 5.81; S, 19.94. Found: C, 44.75; H, 3.00; N, 5.80; S, 19.86.

 

Sulfuric acid mono-(2-hydroxy-4,6-bis-phenylsulfamoyl-phenyl) ester (3).

To compound 1 (3.0 g, 8.1 mmol) in acetone (5 mL) was added dropwise aniline (4.5 g, 48.4 mmol) dissolved in acetone (10 mL). The reaction turned slightly warm, and a thick precipitate formed. It was then filtered, and washed with a small amount of acetone to remove the excess aniline. The solid was dispersed in aqueous acetone (20 mL), and it was boiled for 30 min. It was cooled to RT, and filtered. The water insoluble solid has been compound 3 (3.0 g, 75%), mp 304o C, dec. 1H NMR (100 MHz, DMSO-d6)  d 2.0 (1H, s), 4.0 (2H, s), 5.0 (1H, s), 6.46 (4H, m), 6.6 (2H, d), 7.0 (4H, d), 7.2 (1H, d), 8.0 (1H, d). Anal. Calcd. for C18H16N2O9S3: C,43.19; H, 3.22; N, 5.60; O, 28,77; S, 19.22. Found: C, 43.20; H, 3.20; N, 5.66; S, 19.20.

 

1,3,2-Benzodioxathiole-2,2-dioxide-4,6-disulfonic acid bis-(methyl-phenyl-amide) (4). To compound 1 (1.8 g, 4.9 mmol) dissolved in acetone (5 mL) was added dropwise N-methylaniline (2.1 g, 19.6 mmol) dissolved in acetone (5 mL). It was allowed to stand at RT for 16 h. Work up similar to that of compound 2 gave compound 4 (2.1 g, 85%) needles, mp 145-146 oC (lit1 mp 146 oC); 1H NMR (100 MHz, CDCl3) d 2.8 (2NCH3, d), 6.4 (4H, d), 6.6 (2H, d), 7.0 (4H, d), 7.2 (1H, d), 8.0 (1H, d). Anal. Calcd. for C20H18N2O8S3: C, 47.05; H, 3.55; N, 5.49, S, 18.84.  Found: C, 47.00; H, 3.50; N, 5.50 (lit2 N, 5.63), S, 18.80.

 

4,5-Dihydroxy-benzene-1,3-disulfonic acid bis-(methyl-phenyl-amide), 5. To compound 4 (1.0 g, 1.96 mmol) dissolved in acetone (5.0 mL) was added aniline (3.6 g, 3.9 mmol) dissolved in acetone (5.0 mL). To the resulting solution was added water (5.0 mL), and it was refluxed for 1h. The solvent was evaporated in vacuo. The residue was dissolved in ether, and washed with water to remove the aniline sulfate byproduct. It was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a solid (0.8 g, 1.8 mmol). Recrystallization from ether-hexane gave compound 5 (0.7 g, 79%) needles, mp 86oC; 1H NMR (100 MHz, CDCl3 ) d 2.8 (2NCH3, d), 5.0 (2OH, s), 6.4 (4H, d), 6.6 (2H, d), 7.0 (4H, d), 7.2 (1H, d), 8.0 (1H, d). Anal. Calcd. for C20H20N2O6S2: C, 53.56; H, 4.49; N, 6.25, S, 14.30.  Found: C, 53.40; H, 4.50; N, 6.20; S, 14.25.

 

References

 

a.       Private communication by Zoltan G, Hajos, 802-A Pompton Road, Monroe Township, NJ 08831-7261, USA. E-mail:  zghajos@t-online.hu

1.      Pollak, J.; Gebauer-Fülnegg, E., Monatshefte, 1926, 47, 109

2.      Kendall, E.C.; Hajos, Z.G., J.Am.Chem.Soc., 1960, 82, 3219.

3.      Zheng, X.; Oda; H.; Harada, S.; Sugimoto, Y.; Tai, A.; Sasaki, K.; Kakuta, H., J. Pharm. Sci., 2008, 97, 5446-5452.

4.      a. Cerfontain, H.; Coenjaarts, N.J.; Koeberg-Telder, A., Recl. Trav. Chim.  Pays-Bas, 1988, 107, 325; b. Miyazaki, M.;  Fishman, J., J. Org. Chem., 1968, 33 (2), 662.

5.      Qingquan Zhao, Yu-hong Lam, Mahboubeh Kheirabadi, Chongsong Xu, K.N. Houk and Christian E. Schafmeister, Hydrophobic Substituent Effects on Proline Catalysis of Aldol Reactions in Water, J. Org. Chem., 2012, 77 (10), pp 4784–4792 DOI: 10.1021/jo300569c

6.      Emil Thomas Kaiser, Acccounts Chem.Res., 1970, 3, 145.

7.      Wagenaar, Anno; Kirby, Anthony J.; Engberts, Jan B.F.N. J.Org.Chem., 1984, 49, 3445.

                                                                                      

 

 

 

 

 

Graphical Abstract

 

Chemistry of Catechol Sulfate Derivatives

 

Zoltan G. Hajos

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

To see the Scientific Activities of Zoltan G. Hajos click on:
http://www.dobroka.hu/zghajos/index.htm .