One-pot synthesis of novel thioxanthone crown ethers

The reaction of thiosalicylic acid (TSA) and benzocrown ethers in concentrated sulfuric acid affords a general and efficient way to prepare thioxanthone crown ethers. This chemistry presumably proceeds by intermolecular sulfur electrophilic reaction and subsequently intramolecular electrophilic cyclization. Most of the reactions show high regioselectivity in good yields.


Introduction
Thioxanthones are an important class of molecules and are a common heterocyclic scaffold in biologically active and medicinally significant compounds.The thioxanthone ring is the core structure of a wide variety of naturally occurring and synthetic compounds that exhibit extraordinary anti-tumor [1][2][3]6,9 anti-parasitic 4,5 and anti-cancer activity 6,7,10 . Tioxanthone derivatives are potential anti-cancer drugs and some thioxanthones containing plant extract are directly used in traditional medicines.[5][6][7] Crown ethers have enjoyed widespread use in various areas of science and technology 11 ever since the first preparation of the ligands by Pederson. 12

Results and Discussion
7][8] Other methods for the synthesis of thioxanthones are used of concentrated sulfuric acid at room or high temperature. 13,14Also we have recently reported preparation of hydroxythioxanthone derivatives and some of their applications. 15,16,17 KAT USA, Inc.
We now wish to report a novel and efficient one-pot method for synthesis of thioxanthone crown ether under concentrated sulfuric acid at room temperature (Scheme 1).

Scheme 1
To develop an efficient reagent for the synthesis of thioxanthone crown ethers, we initially examined the reaction of thiosalicylic acid (TSA) with benzo-15-crown-5 (2c) in the presence of various reagents.The reaction monitored via TLC (n-hexane/CH 2 Cl 2 ) and 1 H NMR spectroscopy (Table 1).As is shown in Table 1 the best results were obtained using concentrated sulfuric acid at room temperature for 2 hours.The ratio TSA/crown ether is 1:7 (Table 1: Entry 13).No increase in the yields was observed with improving the temperature.To establish the generality and applicability of this method, various crown ethers were subjected to the same reaction conditions to furnish the corresponding thioxanthone crown ethers in good yields (Scheme 2) (Table 2).No attempt has been made to probe the mechanism of the reaction.We assume that the mercapto group 1 (TSA) is oxidized to sulfenic acid which immediately decomposes to a sulfenium ion 4 14a (Scheme 3).Electrophilic substitution of sulfenium ion with the benzo-15crown-5 (2c) would then give intermediate thioether and the cyclization of thioether gives the thioxanthone-15-crown-5 ether (3c) (Scheme 4).Thioxanthone crown ether yields depended directly upon the sulfuric acid concentration because sulfonation of 2c competes with the generation of sulfenium ion (4) and subsequent electrophilic substitution 14 .
The experimental procedure for the preparation of thioxanthone crown ethers are remarkably simple and does not require the use of any solvent or inert atmosphere and does not require the purification of products by column chromatography.Experimental Section General Procedure.Thiosalicylic acids, benzocrown ethers and sulfuric acid (98%), were purchased from Fluka and Merck in high purity.The preparation of the benzo-9-crown-3 used as precursors has been described and it was purified by chromatography on silica-gel, eluted with 1:1 CH 2 C1 2 : diethyl ether (See reference 18).NMR spectra were recorded in CDCl 3 or DMSOd 6 on a Bruker Advanced Dpx-250 ( 1 H NMR 250 MHz and 13 C NMR 62.9 MHz) spectrophotometer using TMS as internal standard.Infrared spectra were recorded on a Perkin Elmer IR-157G spectrometer, UV spectra were recorded on a Pharmacia Biotech (Ultrospec 3000) UV/Visible spectrometer and melting points were taken on a Büchi melting apparatus.
The TLC was performed on plates coated with silica gel (silica gel 60 GF 254 , Merck).

Table 1 .
The a Isolated yield, b ratio 1:7 of TSA/Crown ether were used

Table 2 .
The results of reaction of 1 (1 mmol) and 2a-d (7 mmol) in the presence a Isolated yield