Synthesis of Five Membered Heterocycles Using Microwaves Technique

ABSTRACT A series of N-(5-substituted 1,3,4–thiadiazol-2-yl maleimides (14-18) were prepared by cyclization of corresponding maleamic acids (7-12).These acids were prepared by the reaction of 2-amino-5-aryloxymethyl–1,3,4–thiadiazoles (1-6) with maleic anhydride. The starting amines (1-6) were prepared from different aryloxyacetic acids and thiosemicarbazide . The structure of the prepared compounds was suggested in the light of IR and UV Spectroscopy.


INTRODUCTION
Several procedures were reported for the synthesis of 2-amino-1,3,4-thiadiazoles, in many of these methods a thiosemicarbazide was the starting material which first acylated to 1acylthiosemicarbazide (Saied, 1983) which cyclized with a suitable dehydrating agents such as phosphorus pentachloride (Rabjohn et al., 1973 andKulchitskaya et al., 1956), phosphorous oxychloride and thionyl chloride (Rabjohn et al., 1973 andKretov et al., 1956).Acylation and cyclization could be achieved in a one step reaction by heating an acyl halide, or even a carboxylic acid with a thiosemicarbazide in the presence of phosphorous acid or concentrated sulfuric acid (Saied, 1983).
The pyrolysis accompanied by a number of undesirable products (Saied, 1983) in addition to long reaction times and complications of materials handling were the causes of low yield of these thiadiazoles (Al-Gwady;2007) .
Because microwave heating had emerged as a powerful technique to promote a variety of chemical reactions, recent applications were used this technology in hetero ring cyclization and in many important reactions (Katritzky and Singh, 2003;Tierney and Westman, 2001 ;Tanaka and Toda, 2000).
As part of continuous program directed toward the synthesis of important heterocyclic compounds, oxygenous and nitrogenous five and six membered rings (Shandala et al., 1998); (Shandala et al., 2001) (Shandala et al., 2002) and (Ayoub et al., 2001), it was become of interest to investigate preparative routs to synthesize N-substituted 1,3,4-thiadiazolyl maleimides due to their immunosuppressive properties which were studied by measuring their ability to inhibit nitrogen-induced leukemia-cell by reaction with more cellular thiols (Freed et al., 1999).

Method (b) (microwave irradiation):
In a three-necked flask provided with a paddle type stirrer, a reflux condenser and a dropping funnel, (9.8 gm, 0.1 mole) of maleic anhydride and 100 ml of ethanol was placed.When the entire compound was dissolved by stirring, a solution of (0.1mole) of appropriate amine (1)(2)(3)(4)(5)(6) in 20 ml of dimethyl formamide was run dropwise through the dropping funnel.The resulting thick suspension was stirred at room temperature for one hour and was then cooled to 15-20 o C in an ice bath.The product was obtained by suction filtration, and treated with 5 % solution of sodium carbonate, filtered and acidified with dilute hydrochloric acid.
The precipitate was filtered, washed with cold water, and dried in oven at (100 o C ), then recrysytallized from ethanol.Melting points, yields and IR spectral data of compounds (7-12) were listed in Table (2).
Appropriate maleamic acid (0.05 mole) was dissolved in 2 ml dimethyl formamide.To this solution (0.1mole ) phosphorous pentoxide was added.The mixture was heated at 70-80 o C for two hours.
After cooling to room temperature and evaporating of the solvent, the solid material was crushed well and washed with 5% sodium carbonate solution to dissolve the un-reacted maleamic acid.The precipitate was filtered off, washed well with water and dried in oven at (100 o C) to give the crude maleimide, which was purified by recrystallization from DMF .Purity of compounds was established by a single spot in TLC.Melting points, yields and IR spectral data of compounds (13-18) were listed in Table (3).(El-Emam and Lehmann, 1994) and (Rabjohn, 1973).

Method (d) (microwave irradiation):
Appropriate maleamic acid (0.05 mole) was irradiated for 12 minutes in 210W microwave oven.The resulting liquid, which solidified when cooled, was worked up as in method (c).

RESULTS AND DISCUSSION
Scheme (1) summarized the synthetic route for the preparation of the designed compounds.While in method (b), the microwave irradiation for 3 minutes in present of small amounts of spectra was good indication of conversion of -yl) maleamic acids (7-12) were prepared 2-Amino-5-aryloxymethyl-1,3,4-thiadiazoles (1)(2)(3)(4)(5)(6) were prepared via a one step acylation and cyclization of carboxylic acid with a thiosemicarbazide in the presence of phosphorous oxychloride as shown in Scheme (2) (Al-Gawady , 2009) and ( Zheng Li et al., 2005).Two different procedures were used, in method (a), a conventional procedure in which large amounts of phosphorous oxychloride are used to give (30 -50%) yield in one hour ( dehydrating agent (only one gram of Ca SO 4 ) was used to give the highest yield (80-90%) (El-Emam andLehmann, 1994) and(Rabjohn, 1973).Here the microwave radiation accelerated solvent-free cyclization (Zheng Li et al., 2005).The disappearance of C=O stretching in IR acid to heteroring, in addition to the following frequencies: 3100-3300 cm -1 and 1560-1590 cm - 1 due to NH stretching and bending respectively, 1595-1600 cm -1 for C=N stretching, and 1520 cm -1 for C=C ring stretching, Table (1).The UV spectra showed absorption peaks at λmax 240-270 nm for (n→π*) electronic transitions.
Imides (13-18) showed characteristic absorption bands in the 1690-1710 cm -1 region of their IR spectra, Table (3), these two bands come from a mechanical coupling carbonyl groups in acid anhydrides (Matsuo, 1964).The increase in the values λmax in the spectra of these compounds about (64-66 nm) due to the * transition due to ring system.