Synthesis of xanthine derivatives by microwave-assisted ring closure reaction

Ring closure of the imidazole ring is a key step in the synthesis of xanthine and other purine derivatives. A microwave-assisted procedure involving triethyl orthoformate is presented. High yields are achieved even on a gram scale, while reaction times are considerably shortened compared to conventional heating conditions


Introduction
The plant alkaloid caffeine, 1,3,7-trimethylxanthine, is the most frequently used psychostimulant drug world-wide.It exerts its effects by the blockade of adenosine receptors in the brain. 1 Theophylline, 1,3-dimethylxanthine, which is also naturally occurring, is therapeutically applied as an anti-asthmatic drug.A large number of derivatives and analogs of caffeine and theophylline have been synthesized and pharmacologically investigated. 2,3][6] The latter is clinically used for the treatment of peripheral vascular disease. 6Other xanthine derivatives, such as lisofylline, are experimental anti-inflammatory drugs. 7Further xanthine derivatives are currently in pre-clinical or clinical development as novel drugs for various indications and many xanthine derivatives have become important pharmacological tools. 8It is thus justified to claim that the xanthine scaffold belongs to the so-called "privileged structures" 9 in medicinal chemistry and drug development.
A key step in the classical synthetic route towards xanthines is the ring closure of the imidazole ring, which leads to the purine ring system.The classical Traube synthesis of 8unsubstituted xanthine derivatives comprises the reaction of a 5,6-diaminouracil derivative with formic acid in a two step procedure, involving tedious workup of the intermediate formamide. 10,11cheme 1. Examples of xanthine drugs.
As an alternative, a very efficient ring-closure reaction was first described by Grundmann and Kreutzberger. 12The reaction of 1,3-dimethyl-4,5-diaminouracil with 1,3,5-triazine led to very pure theophylline in quantitative yield after a reaction time of less than one minute.Although this finding appeared to be very encouraging, its applicability is limited since 1,3,5triazine is not a readily accessible reagent.
Another ring closure procedure is the reaction of 5,6-diaminouracils with triethyl orthoformate, which is easily accessible and requires no special precautions in handling, as it is relatively stable towards hydrolysis.A disadvantage of this method are long reaction times of up to several hours. 13,14Poor solubility of the precursors in triethyl orthoformate appears to be one of the problems.The present study was aimed at developing a fast, easy and general method for imidazole ring formation.

Results and Discussion
We were especially interested in a facile synthesis of 1,3-diethylxanthine 1, which was required as a reaction intermediate in our investigations on the structure-activity relationship of adenosine receptor antagonists, and 1,3-dibutylxanthine 2 as a precursor to denbufylline.As starting materials the 1,3-dialkyl-5,6-diaminouracils 3 and 4 were prepared as previously described. 10In order to obtain highly pure compounds separation methods for these air-and temperature-sensitive materials had to be developed (see Experimental), since no detailed procedures are given in the literature.Although the subsequent reactions work well with impure starting materials (containing small quantities of water, inorganic salts or other by-products of the synthesis), highly pure 5,6-diaminouracils were required for the precise determination of the yields.
To test the scope of our microwave-assisted method, we also investigated the reaction of the poorly soluble derivatives 1-butyl-5,6-diaminouracil 5 and 5,6-diamino-1-propargyluracil 6 in triethyl orthoformate.Reaction times of 5 h for the preparation of 7 and 1.5 h for 8 have been reported for conventional reaction conditions. 13After 5 min of microwave irradiation no residual starting material could be detected.The corresponding 8-unsubstituted xanthine derivatives 7 and 8 were isolated in excellent yields of up to 90% depending on the purity of the employed 5,6diaminouracils.To test whether this acceleration was only due to the higher temperature applied, a sample of 5,6-diamino-1-propargyluracil 6 was mixed with triethyl orthoformate and conventionally heated at 160°C in a glass pressure tube for 10 minutes.After workup, most of the starting material could be recovered, while only traces of xanthine 8 were detected by TLC.c Taken from the literature 13 .
Notably, the reactions proceeded smoothly, although the employed quantity of triethyl orthoformate was far too little to dissolve either the starting materials or the products.This greatly facilitated purification and workup, especially when working on a gram scale.We were thus able to drastically shorten the reaction times in the synthesis of xanthines using triethyl orthoformate by applying microwave energy.This reaction seems to have a broad scope concerning substitution patterns at the 1-and 3-position and is thus an easy and convenient procedure to synthesize 8-unsubstituted xanthine derivatives.

Table 1
a Heating with triethyl orthoformate under reflux.b Heating with triethyl orthoformate at 160°C with microwave irradiation.