2H-1,4-Benzothiazine hydrosaniic acids of type V (see Table I) are readily prepared b y reducing suitably substituted (0-nitropheny1thio)acetates (11, R" = Me or E t ) by means of sodium borohydride and palladium-charcoal. The ester precursors can be prepared by the interaction of o-nitrothiophenols and or-bromoesters, but such a method is limited in scope. Diethyl bromomalonate, for example, reacts atypically with o-nitrothiophenol. T h e ester precursors are better prepared by Fischer-Speier esterification of the corresponding acids (11, R" = H ) which, in turn, are the products of nucleophilic attack by or-mercaptoacids on suitable o-chloro-(or bromo-) nitrobenzenes. This general preparative method failed in two instances. When o-chloronitrobenzelle or 4-chloro-3-nitrotoluene was reacted with a-mercaptoisobutyric acid, the only acidic product obtained was a,al-dithiodiisobutyric acid.Reduction of methyl 2-(0-nitropheny1thio)benzoate (VI) with sodium borohydride and palladium-charcoal gave a n azoxy compound, namely 2,2'-bis((o-methoxycarbonyl)phenylthio)azoxybenzene (VI I).When suitably substituted aromatic o-nitroesters are reduced with sodium borohydride and palladium-charcoal, the nitro group is converted into a hydroxylamino group which then cyclizes with the ester group, and cyclic hydroxamic acids are the result. Using this method of reduction, we have prepared a variety of such compounds (1, 2) including 3,4-dihydro-4-hydroxy-3-oxo-2H-1,4-benzothiazine (Ia), the related sulfone (Ib) and the corresponding benzoxazine (16). AiIany cyclic hydroxamic acids possess antibacterial properties (2, 3 , 4 ) ; Dimboa (3,4-dihydro-2,4-dihydroxy-7-methoxy-3-oxo-2H-l,4-benzoxazine) exhibits antimetabolic activity ( 5 ) and benzothiazines related t o I have been shown to possess anthelmintic properties (6, 7). For these reasons, i t was of interest t o prepare simple derivatives of Ia and test them initially for antibacterial activity and for their (a) X = S (b) X = SO* (6) X = 0 action on selected enzymes. This investigation also offered a n opportunity to study further the reducing properties of sodium borohydride in the presence of palladium-charcoal.For the preparation of the precursors (11) required for reduction t o 2-substituted 3,4-dihydro-4-hydroxy-3-oxo-2H-l,4-benzothiazines, the initial method chosen was t o condense the appropriate sodium a-nitrothiophenolate with suitable a-bromoesters (Scheme I). This reaction, however, proved t o be unsatisfactory. In the first place, the yields of pure o-nitrothiophenol obtained by mild reduction of bis(o-nitrophenyl) disulfide (IIIa) according to the methods of Claass (8,9) and Mills and Whitworth (10) were poor, as were the yields of products; in addition, the scope of the reaction was limited by the
Reduction of three α-(o-nitrophenylthio)ketones with sodium borohydride and palladium–charcoal gave mainly α-(o-nitrophenylthio)alcohols and, as minor products, α-(o-aminophenylthio)alcohols. Only two benzothiazines were formed. Bis[2-(3-phenyl-2H-1,4-benzothiazine)] was a minor product of the catalyzed reduction of ω-(o-nitrophenylthio)acetophenone whereas 1-(3,4-dihydro-4-hydroxy-3-oxo-2H-1,4-benzothiazin-2-yl)benzyl alcohol was the main product of the catalyzed reduction of α-benzoyl-α-(o-nitrophenylthio)acetate.
Bei der Reduktion des Ketons (I) mit Na‐B‐hydrid entstehen in Abwesenheit eines Katalysators der Nitroalkohol (IIa) und in Gegenwart von Pd‐Kohle neben (IIa) geringe Mengen des Aminoalkohols (IIb).
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