Selective Oxidaton Methods for Preparation of N-Alkylphenothiazine Sulfoxides and Sulfones

Abstract

Efficient and selective oxidation methods for preparation of jV-alkylphenothiazine sulfoxides 2a-h and sulfones 3a-h starting from jV-alkylphenothiazines la-h are described.In the metabolism of the phenothiazine-based drugs often occuring metabolites are the corresponding sulfoxides, 7-hydroxylated derivatives or even sulfones (1-4).Phenothiazines have been oxidized by various oxidizing agents. Most frequently H2O2 in various solvents has been used for S-oxidation (1). In ethanol (5) or in ethanol-acetone mixture (6), H2O2 produced phenothiazine-5-oxides. Sulfones were usually formed by H2O2/ACOH (7) which generates in situ peracetic acid. Similarly, oxidation with organic peracids, such as m-chloroperoxybenzoic acid (8), provided sulfones.Sulfone formation was also achieved with sodium perborate (9) or NaOCl (10). Sulfoxide formation by peracid systems was only reported for ammonium persulfate (11) or H202/oxalic acid (12). Transformation of phenothiazine derivatives into sulfoxides was achieved by several inorganic nitrogen oxides. Phenothiazines substituted with electron withdrawing groups were converted to sulfoxides by nitric acid (1). Sulfoxides were obtained by using nitrous acid generated in situ from NaN02 by acids like AcOH (13) or aqueous HCl (14).Phenothiazines were converted into sulfoxides by nitrogen dioxide/02 (15) or N0 ( " ) BF 4 (+) /02(16). Heavy metalbased systems were also used for ^-oxidation of phenothiazines. KMnO^O (17), Et 3 PhN (+> Mn04 ( " ) in organic

Raman, Infrared, and Surface-Enhanced Raman Spectroscopy in Combination with ab Initio and Density Functional Theory Calculations on 10-Isopropyl-10H-phenothiazine-5-oxide

“…Phenothiazine and its derivatives have been extensively investigated because of their interesting pharmacological activity. − Phenothiazine and related compounds have significant physiological activity and can be used as tranquilizers , and the schematic structure of 10-isopropyl-10 H -phenothiazine-5-oxide compound is illustrated in Figure .

1 Schematic structure of 10-isopropyl-10 H -phenothiazine-5-oxide compound.

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“…[1][2][3] Phenothiazine and related compounds have significant physiological activity and can be used as tranquilizers. 4 A new series of phenothiazine derivatives, which are important intermediates in the metabolism of phenothiazine drugs, have been prepared, 5,6 and the schematic structure of 10-isopropyl-10H-phenothiazine-5-oxide compound is illustrated in Figure 1.…”

Recent advances in the development of phenothiazine and its fluorescent derivatives for optoelectronic applications

“…The S atom in phenothiazine was converted to form sulfoxide and sulfone derivatives by reacting it with 3-chloroperbenzoic acid ( m -CPBA) in dichloromethane at low temperature (Scheme 12). 100…”

Synthesis and pharmacological investigation of new N-hydroxyalkyl-2-aminophenothiazines exhibiting marked MDR inhibitory effect

“…Also, selective procedures to sulfoxides and sulfones have been described. 22 In order to prepare a series of amine-containing sulfoxides (e.g. 4f) the chloro compound 5 was first oxidized by m-CPBA to the 2-chlorosulfoxide 10 22 (Scheme 3) and, then this compound was subjected to Buchwald-Hartwig cross-coupling reaction with three selected secondary amines to give 4h,i.…”