TEMPLATE DESIGN © 2007

Studies on the Fries Rearrangement of Sulfonanilides to SulfonesSheladia, H.*; McKee, J.R.; and Zanger M.

Department of Chemistry & Biochemistry. University of the Sciences in Philadelphia, Philadelphia, Pennsylvania,19104

Abstract

Introduction

Methods

The acid catalyzed Fries rearrangement of sulfonanilides to sulfones has been thought to proceed via an intramolecular migration of the sulfone group from nitrogen to the ortho-carbon. In some cases, however, we have observed a migration of the sulfone to the para-carbon. This would suggest that at least some of the reactions proceed through an intramolecular process. It is the aim of this current study to trap the proposed intermediate and isolate and characterize it. If successful, this will suggest that at least part of the rearrangement is intramolecular in nature.

Proposed Mechanism of the Reaction

Spectra

Results

References

Synthesis of pure 2’-methylamino-5’methyl-2-nitrophenylsulfoneIn a 500 mL round bottom flask, add 12.12 g (.1 mol) of n-methyl-p-toluidine, 22.1 g (.13 mol) ortho-nitrobenzenesulfonyl chloride and 20 mL of pyridine. Mix the yellow oil-like solution for 3 days at room temperature. Next add 150 mL of water to the dark red solution and mix at room temperature for 2 hours. Decant the red liquid and vacuum filter to receive a red powder. The solid is dissolved using acetone and put into a evaporating dish to let the acetone evaporate. The product is dark red square crystals. The crystals will be recrystallized and the product will be analyzed by GC/MS, NMR, and IR.

Dimethylsulfate

Base

NO2

SO2

NH2 O

O

S

NO2

Cl Cl

NH

NH

NO2

O

O

S

NH2

Cl

Cl

NO2

O

O

S

N

Cl

Cl

NO2

O

O

S

N

Cl

Cl

Zanger.M, Diarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus. U.S Patent. 6063790. May 16,2000Kahn,T.,Kinetics and Mechanism of the Acid-Catalyzed Rearrangement of N-Alkyl Aryl Sulfonamides Ph.D. Thesis, University of the Sciences in Philadelphia (1975). Patel.B.Unpublished Communication.2007.Warren, L. Rearrangement of O-aminosulfones. J.C.S London. 1932.2774-2887

Both the starting material and the methylated material, 2,6-dichloro-2’-nitrobenzenesulfonanilide and N-methyl-2,6-dichloro-2’-nitrobenzenesulfonanilide, were very pure and had a high yields. The yields of the rearranged and trapped materials were very low. A more efficient procedure is needed to obtain a larger yield. Also in order to compare the crude trapped compound a pure trapped material was synthesized and characterized by GC/MS. The crude trapped material did not match that of the pure trapped material.

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A former graduate student of Dr. Murray Zanger, Taquir Kahn, did an experiment in which 2’methylamino-5’methyl-2-nitrophenylsulfone was created when 2,6 dichloro-2’-nitrobenzenesulfonanilide reacts with N-methyl-p-toluidine in the presence of sulfuric acid. This reaction is the product of the rearrangement of the sulfonyl group from one amine to the other. It is strongly suggested by this reaction that at some stage the amine had to be separated from the sulfonium ion. Earlier authors thought that the reaction was intramolecular with the sulfonyl group remaining bound to the starting amine.

H+

Kahn’s work proposed that ,at some stage, the sulfonium ion is not closely corresponded with the starting amine.

H+

The goal of this project is to repeat the work of Dr. Kahn and attempt to isolate and characterize some of the rearranged material. The experiment with be carried out in different stages: 1) Preparation of 2,6-dichloro-2’-nitrobenzenesulfonanilide 2) Methylation of the 2,6-dichloro-2’-nitrobenzenesulfonanilide 3) Reaction of N-methyl-2,6-dichloro-2’-nitrobenzenesulfonanilide with N-methyl-p-toluidine. The reaction product to stage 3 will be isolated using column chromatography.

Preparation of 2,6 Dichloro-2’-NitrobenzenesulfonanilideIn a 500-mL round-bottomed flask equipped with a magnetic stirrer, add 64.8rams (0.4 mol ) of 2,6-dichloroaniline and 40 mL (.5 mol) of pyridine drop wise. Once the 2,6-dichloroaniline has dissolved add 44.2 grams (0.2 mol) of ortho-nitrobenzenesulfonyl chloride to the solution. The yellow, oil-like solution is stirred at room temperature for 5 days. After 5 days, 300 mL of 4% sodium hydroxide is added to the round bottom flask creating a pink solution. This solution is then mixed for 1 ½ hours. The solution changes from a pink color to a dark orange color with a yellow solid at the bottom of the flask. A pH test is taken to see if the solution is alkaline. The liquid is then decanted into a 1 L beaker leaving behind the yellow sludge-like solid. The dark orange liquid is then acidified to a pH of 4 or 5 using concentrated acetic acid. The acetic acid causes a yellowish white precipitate to form. The acidified mixture should be put into an ice bath for ½ hour. The yellowish white material is suction filtered and left out to dry overnight. The yield was 28.22 grams (80%). Melting point taken was 184-186 °C compared to the literature value of 177-178 °C. The IR spectrum was taken of the product that was obtained FTIR (on NaCl plates): 3313.31 cm-1 (s, NH-), 1534.34 cm-1 (s, sulfone). The NMR spectrum was taken on a 1H NMR (DMSO) δ 8.0 (m, 6.57H, aromatic).

+

NO2

Cl

O OS

NO2

O

O

SN

Cl

Cl

Cl Cl

NH2

The recrystallization yielded 11. 84 grams ( 66%) of pure white N-Methyl-2,6 Dichloro-2’-Nitrobenzenesulfonanilide crystals. The melting point was 166 to 168 C compared to the literature value of 169.50-170 C. The IR spectrum was taken of the product that was obtained FTIR (on NaCl plates): 1540.85 cm-1 (s, sulfone). The NMR spectrum was taken on a 1H NMR (CDCl3) δ 2.0 (q, 3.00H, -CH3).

O OS

N

H

O OS

N

NO2O

O

SN

Cl

Cl

O OS

Cl Cl

NH

3,5-dichloro-4-methylamino-2-nitrodiphenylsulfone NMR

N-methyl-2,6-Dichloro-2’-Nitrobenzenesulfonanilide NMR

Pure Trapped 2’-methylamino-5’methyl-2-nitrophenylsulfone GC/MS

O OS

Cl Cl

NH

Synthesis of N-Methyl-2,6 Dichloro-2’-NitrobenzenesulfonanilideIn a 800-mL beaker equipped with a magnetic stirrer suspend 20.96 grams (0.06 mole) of 2,6 Dichloro-2’- Nitrobenzenesulfonanilide in 350 mL of water. Next add concentrated sodium hydroxide dropwise until most of the 2,6 Dichloro-2’- Nitrobenzenesulfonanilide is dissolved. .Then this mixture is stirred for 30 minutes. The clear yellow solution is then gravity filtered into a clean 800-mL beaker to remove suspended yellow solids. Next .06 moles of dimethyl sulfate (~ 7 mL) was added slowly to the 800-mL beaker containing the filtrate. This solution is stirred overnight at room temperature. The mixture is then suction filtered to yield 17.86 (85%) grams of N-Methyl-2, 6-dichloro-2’ nitrobenzenesulfonanilide, a white solid. The 17.86 grams of N-Methyl-2,6 Dichloro-2’-Nitrobenzenesulfonanilide was recrystallized using 95% ethanol. The crystals are then suction filtered and dried overnight.

NO2

O

O

S

N

Cl

ClNH

NH2 O

O

S

NO2

Trapping of 2’-methylamino-5’methyl-2-nitrophenylsulfone Experiment 2In a 500 mL round bottom flask, add 1.87 g (.006 mol) of N-Methyl-2,6 Dichloro-2’-Nitrobenzenesulfonanilide, 100 mL of sulfuric acid and 2.00 g (.0165 mol) of n-methyl-p-toluidine. The yellow solution was fitted with a glass stopper and heated for 3 days at 105 degrees. The dark purple solution was then quenched with ice water and vacuum filtered. The purple crystals were washed with 200 mL of sodium bicarbonate to remove any excess sulfuric acid. The purple powder was then left out to dry over night. The filter was then put into a 25 mL soxlet and extracted with ethanol for 4 days. The dark purple filtrate was then left out to evaporate the ethanol. A purple crystal was obtained. The reaction yielded .43 grams. (22% yield). The product will be analyzed by GC/MS, NMR, and IR.

+ Sulfuric acid/Δ

Future Work

Currently, the problem centers on obtaining a high yield of the rearranged and trapped sulfones. Once the enough material is produced the products will be characterized by GC/MS, NMR and IR. Also the GC/MS spectra obtained of the crude material compared to the pure trapped material are inconsistent. The next step in this process would be the mass reaction of N-methyl-2,6-dichloro-2’-nitrobenzenesulfonanilide with N-methyl-p-toluidine in a crossover experiment using sulfuric acid as the catalyst .The product of this reaction will then be identified using GC/MS to verify its components. These components will then be separated using recrystallization (if product is major components) or chromatography (if the product is the minor component). Once the material is isolated, it will be characterized by GC/MS, NMR, IR, and elemental analysis. It will also be compared to a pure trapped compound that will be synthesized.