Microwave-Assisted Synthesis of Phenothiazine and Quinoline Derivatives

Application of a dynamic microwave power system in the chemical synthesis of some phenothiazine and quinoline derivatives is described. Heterocyclic ring formation, aromatic nucleophilic substitution and heterocyclic aldehydes/ketones condensation reactions were performed on solid support, or under solvent free reaction conditions. The microwave-assisted Duff formylation of phenothiazine was achieved. Comparison of microwave-assisted synthesis with the conventional synthetic methods demonstrates advantages related to shorter reaction times and in some cases better reaction yields.


Introduction
Microwave assisted organic synthesis became an increasingly popular technique in academic and industrial research laboratories, due to certain advantages, particularly shorter reaction times and rapid optimization of chemical reactions.
The experimental technique applied for the organic syntheses described below, is based on microwave power processing of materials using a dynamic control of the microwave power magnetron [1][2][3]. The aim of this work was to test the efficiency of this new dynamic microwave power system in the organic synthesis by optimizing the chemical synthesis of some interesting phenothiazine and quinoline derivatives.
Syntheses of symmetrically 4,6-bis-substituted amino-, oxo-and thio-pyrido[3,2-g]quinoline derivatives were previously reported [4,5] and their MDR reversal activity [6] was demonstrated. Unsymmetrical substituted derivatives were also synthesized with the aim to investigate their biological activity [7,8]. The cyclization reaction of substituted diphenylamines for phenothiazine ring formation was achieved by microwave-assisted synthesis, even in the presence of bulky substituents [9], which dramatically reduced the reaction yields when classical methods were employed. Arylsubstituted phenothiazinyl-enones and higher homologues (e.g. bis-chalcones) [10] are compounds, which could develop unconventional physical properties due to their structure combining the electron donor effects of the phenothiazine nucleus with those of an extended π conjugated system.

Results and Discussion
The microwave assisted syntheses of quinoline and phenothiazine derivatives were performed in the resonance cavity of a dynamic microwave power system using microwave irradiation at variables duty cycles and power levels. The microwave input in material is controlled in every second from 0 % to 100% of the time by a dynamic control of the microwave power magnetron. The reactions took place at normal pressure (in an open vessel). The processing techniques employed were: i) "dry media" procedure, ii) solvent heating and iii) simultaneous cooling method in the presence of a solvent. Several solid supports such as silica gel, alumina and clay (bentonite), were tested in dry media procedures.
The microwave assisted syntheses of quinoline derivatives are described by the chemical equations presented in scheme 1. Table 1 presents a comparison between the results obtained by microwave assisted synthesis, versus conventional heating method [7,8]. The Skraup synthesis of 7-amino-8methylquinoline 1 [11,12] was performed starting with a mixture of 2,6-diaminotoluene, glycerol, sulfuric acid and arsenic pentoxide. Even though the reaction yield was not improved, an important decrease of the reaction time was achieved (table 1). The condensation reaction of 1 with the ethyl-(etoxymethylene)-cyanoacetate on silica gel solid support gave a dramatic decrease of the reaction time simultaneous to an increase of the reaction yield.
The microwave assisted syntheses of phenothiazine derivatives are described by the chemical equations presented in scheme 2. Table 2 presents a comparison between the results obtained by microwave assisted synthesis, versus conventional heating method [9].  The heterocyclic chalcones 9a-f were obtained by the condensation of 3-formyl-10methylphenothiazine with substituted acetophenones. Good reaction yields were obtained under microwave irradiation, using both dry media procedure and simultaneous cooling method. For the preparation of heterocyclic bis-chalcones 10 and 11 the simultaneous cooling method is recommended by higher reaction yields, even though dry media procedure give also satisfactory results.
Duff formylation reaction was applied for the first time to a phenothiazine substrate. The microwave-assisted Duff formylation of phenothiazine with urotropine in acetic acid gave unexpectedly good yields of 10(H)-3-formyl-phenothiazine 12, in significantly shorter reaction time as compared to classical reaction protocol.
Conclusions: The dynamic microwave power system employed offered an efficient heating of the materials; thus, reduced chemical reactions times and increased reaction yields were observed in most of the experiments performed.

Experimental Section
The reactions were performed in the resonance cavity of a dynamic microwave power system, designed at INCDTIM Cluj-Napoca, Romania. Reagents from Merck and Aldrich Chemical Co. were used. Anhydrous Silica gel 60 (0.063-0.2 mm) was used as solid support after dehydration under microwave irradiation for 4 minutes. TLC was used to monitor the reaction progress (Merck silica gel F 254 plates). The structures of the reaction products were assigned according to NMR spectra recorded using a 400 MHz Brucker NMR spectrometer.

General procedures i) Dry media procedure
The reagents were solved in a low boiling point solvent at room temperature; anhydrous microwave transparent inorganic solid support (silica gel, alumina or clay) was added and the solvent was removed under vacuum. The adsorbed reaction mixture was introduced in an open quartz tube, which was then subjected to microwave irradiation in the resonance cavity of the microwave power system. Initial and final sample temperatures were measured. The sample was cooled in an ice bath, and the irradiation was repeated several times. TLC was used to monitor the reaction progress. The reaction product was extracted with solvent; the extract was filtered, dried over anhydrous sodium sulfate and then the solvent was removed. The products were purified by recrystallization or column chromatography.

ii) Solvent heating
The reaction mixture solved in the properly choose solvent was introduced in an open quartz tube, which was then subjected to microwave irradiation. Initial and final sample temperature was measured. The sample was cooled in an ice bath, and the irradiation was repeated several times. TLC was used to monitor the reaction progress. The solvent was removed under vacuum and the product was purified by recrystallization or column chromatography.

iii ) Simultaneous Cooling Method
The reaction mixture solved in the properly choose solvent was subjected to microwave irradiation in a reaction vessel provided with a cooling mantle. During irradiation, the circulation of the cooling agent ensures the control of the reaction temperature and avoids the super heating of the solvent. Work-up of the reaction product was similar to the methods indicated above.