Preparation of certain 2-N-alkylamino-and 2-N,N-dialkylamino-10-methylphenothiazines via phenothiazyne

The treatment of 2-chloro-10-methylphenothiazine, 1 , with lithium alkylamide/alkylamine or lithium dialkylamide/dialkylamine yields the corresponding 2-N-alkylamino-or 2-N,N-dialkylaminophenothiazines in good yields via phenothiazyne. No significant reduction of 1 to 10-methylphenothiazine is observed. Yields of amines obtained by this method are considerably higher than those obtained by reacting 1 with sodamide in refluxing amine solvent. Attempts to introduce the -CH₂CN moiety onto the phenothiazine nucleus by treating 1 with sodamide and acetonitrile in liquid ammonia produced only 2-amino-10-methylphenothiazine.     

Furopyridines. XVII . Cyanation,chlorination and nitration of furo[3,2-b]pyridine N-oxide

The N-oxide 2 of furo[3,2-b]pyridine ( 1 ) was cyanated by the Reissert-Henze reaction with potassium cyanide and benzoyl chloride to give 5-cyano derivative 3 , which was converted to the carboxamide 4 , carboxylic acid 5 , ethyl ester 6 and ethyl imidate 8 . Chlorination of 2 with phosphorus oxychloride yielded 2-9a , 3- 9b , 5- 9c and 7-chloro derivative 9d . Reaction of 9d with sodium methoxide, pyrrolidine, N,N-dimethylformamide and ethyl cyanoacetate afforded 7-methoxy- 10 , 7-(1-pyrrolidyl)- 11 and 7-dimethylaminofuro[3,2-b]pyridine ( 14 ) and 7-(1-cyano-1-ethoxy-carbonyl)methylene-4,7-dihydrofuro[3,2-b]pyridine ( 12 ). Nitration of 2 with a mixture of fuming nitric acid and sulfuric acid gave 2-nitrofuro[3,2-b]pyridine N-oxide ( 15 ).     

A reinvestigation of the bamberger-ham phenazine. Synthesis: A limitation

The Bamberger-Ham condensation of 4-substituted nitrosobenzenes in concentrated sulfuric acid reported as a method of synthesis for phenazine N-oxides has been found to be limited to electron donating substituents. Methyl 4-nitrosobenzoale has been found to react under these conditions to give dimethyl 2-nitrodiphenylamine-4, 5-diearboxylate ( 2 ). Compounds of unknown structure previously reported to arise from acid treatment of 4-bromo- and 4-chloronilrosobenzene have been shown to be 4, 5-dibromo-2-nitrosophenylamine ( 10 ) and the analogous dichloro compound. Treatment under stronger acidic conditions (oleum) converted 10 but not 2 into the corresponding phenazine N-oxide. Mechanistic implications are discussed.     

Studies in the heterocyclic series. XXI. A novel tetraaza-analog of phenothiazine

As a continuation of our search for new pharmaco-active phenothiazine compounds, the synthesis of 1,4,6,8-tetraazabenzo[b]phenothiazine ring system is described. Derivatives of this new heterocycle were prepared by converting 4,5-diamino-6-hydroxypyrimidine to 4,5-diaminopyrimidine-6-(1H)thione followed by the action of 2,3-dichloroquinoxaline in refluxing DMF or DMAC. The reaction of mixed nitric and sulfuric acids with 9-amino-12-chloro-1,4,6,8-tetraazabenzo[b]phenothiazine gave 9-amino-12-chloro-13-nitro-1,4,6,8-tetraazabenzo[b]phenothiazine 5-oxide in satisfactory yields. Diazotization of 9-amino-1,4,6,8-tetraazabenzo-[b]phenothiazine led to 1,4,6,8-tetraazatriazolo[4,5,1-kl]benzo[b]phenothiazine which is a new heterocyclic compound and the parent compound of this ring system. The mechanistic pathways to these compounds are also proposed.     

Chemistry of thienopyridines. XXXIII. Synthetic routes to 5- and 7-substituted thieno[3,2-b]pyridines from the N-oxide

Thieno[3,2-b]pyridine ( 1 ) is oxidized to N-oxide 1a by means of m-chloroperoxybenzoic acid (83%). Compound 1a forms adducts with hydrogen chloride and picric acid and gives ring substitution alpha or gamma to the heteronitrogen atom. Thus, 1a plus nitric and sulfuric acids produces the 7-nitro-N-oxide 1m (63%), or plus phosphorus oxychloride gives a mixture of 5-chloro and 7-chloro ( 1j ) derivatives of 1 . Compound 1m is convertible into a variety of other derivatives of 1 , viz. 7-chloro-N-oxide, 1j , 7-bromo-N-oxide, 7-nitro and 7-amino. 5-Cyano- 1 , formed from 1a , is, in turn, transformed into a methyl imidate (93%), cyclic amidines, and a 5-tetrazolyl- 1 (91%). These results confirm the prediction that 1a , thieno[2,3-b]pyridine-4-oxide and quinoline 1-oxide should exhibit closely similar (i.e. analogous) chemical reactions.     

Chemistry of sulfonyl isocyanates and sulfonyl isothiocyanates. X. Possible routes to substituted imidazolidinethiones and hexahydropyrimidinethiones

4-Toluenesulfonyl isocyanate (I) reacted with 2-aminoethanol and 3-amino-l-propanol to give 2:1 isocyanate/amino alcohol addition products. 1-Amino-2-propanol and I gave 1:1 and 2:1 adducts while 2-amino-2-methyl-l-propanol afforded only a 1:1 adduct. 4-Toluenesulfonyl isothio-cyanate (III) gave 1:1 adducts with 2-aminoethanol, l-amino-2-propanol and 3-amino-l-propanol, the first two of which were cyclized by concentrated sulfuric acid to 1-(4-toluenesulfonyl)-imidazoline-2-thiones and the third to 1-(4-toluenesulfonyl)hexahydropyrimidine-2-thione. A 1:2 adduct was obtained from III and 2-amino-2-methyl-l-propanol. Amino acids reacted with I and with 4-chlorobenzenesulfonyl isocyanate (II) to give N-(arylsulfonyl)-N¹-(carboxylic acid)-ureas. N-(4-Toluenesulfonyl)-N¹-(acetic acid)-urea (XVI) was converted to the methyl ester (XIX) by concentrated sulfuric acid and methanol and to water-soluble unrecoverable products by sulfuric acid alone. Glycine and III gave N-(4-toluenesulfonyl)-N¹-(acetic acid)-thiourea (XX) which was converted to the methyl ester (XXII) by concentrated sulfuric acid/methanol and to the cyclic 1-(4-toluenesulfonyl)imidazolin-5-one-2-thione (XXI) by sulfuric acid alone.     

Chemistry of thienopyridines. XXIII. Mass spectra of some N-oxides,sulfoxides, and sulfones

The mass spectral fragmentation patterns of a series of thienopyridine N-oxides, S-oxides, and S,S-dioxides were elaborated as a means of structural determination. Observation of a significant (M-16) peak is diagnostic for the presence of either an N-oxide or an S-oxide function (indistinguishable from one another by this method) but does not occur for an S,S-dioxide function. For a substituted thieno[2,3-b]pyridine 7-oxide, structural rearrangement to a pyridone (followed by emission of carbon monoxide or formyl radical) or side-chain fission may be competitive with de-N-oxygenation. For two tricyclic parent S-oxides, rearrangement and de-S-oxygenation are competing initial processes. For parent S,S-dioxides structural rearrangement precedes fragmentation, wherein the oxygen is ejected in such forms as sulfur monoxide, carbon monoxide, formyl or cyanate radicals, and ketene.     

2,3,5,6-tetramethylmorpholine. VI. Cyclization of N-substituted 3,3′-iminobis-2-butanols

The cyclization of N-substituted 3,3′-iminobis-2-butanols to N-substituted 2,3,5,6-tetramethylmorpholines in sulfuric acid is studied. The ring closure seems to be exclusively a normal S_N2-type substitution with partial inversion of configuration before the cyclization. The steric influence of the N-substituents on the S_N2-reaction and on the inversion is discussed.     

Synthesis of homologous monomers and polymers of carbazole,phenothiazine and dibenzazepine

Monomers and polymers of 3-vinyl-N-ethylcarbazole, 3-vinyl-N-methylphenothiazine, 3,7-divinyl-N-methylphenothiazine, N-acrylylcarbazole, N-acrylylphenothiazine, and N-acrylyl- and N-methacrylyldibenzazepine have been synthesized. The synthetic procedures for preparing the monomers and polymers are described.     

Alcoholysis of 2,2-Dichloropropyl Derivatives of Carbazole, Phenothiazine, and Phenoxazine

Reactions of 9-(2,2-dichlorocyclopropyl)carbazole, 10-(2,2-dichlorocyclopropyl)phenothiazine, and 10-(2,2-dichlorocyclopropyl)phenoxazine with alcohols in the system t-BuOK-DMSO yield the corresponding N-(1-alkoxy-2-propynyl) derivatives. Hydrolysis of 9-(1-methoxy-2-propynyl)carbazole and 10-(1-methoxy-2-propynyl)phenothiazine in 60% aqueous dioxane in the presence of sulfuric acid gives the corresponding heterocyclic amine and 2-propynal.     

Chemistry of thienopyridines. VIII. Substitution products derived from thieno[2,3-b] pyridine 7-oxide

Thieno[2,3-b]pyridine (I) was concerted to the N-oxide (II, 53%) by means of hydrogen peroxide and acetic acid. Nitration of II in sulfuric acid gave 4-nitrothieno[2,3-b]pyridine 7-oxide (III, 50%), while nitration in acetic acid formed the isomeric 5-nitrothieno[2,3-b]pyridine 7-oxide (IV, 54%). Compounds III and IV were reduced to the corresponding 4- and 5-aminothieno[2,3-b]pyridines, respectively. Treatment of III with acetyl chloride gave 4-chlorothieno-[2,3-b]pyridine 7-oxide (XI, 81%), convertible in two steps to 4-(N-substituted amino)thieno-[2,3-b]pyridines (especially of the 4-dialkylaminoalkylamino type) for screening as potential antimalarial drugs. 4-Aminothieno[2,3-b]pyridine reacted with aromatic aldehydes to give Schiff's bases and other products. Mechanisms for some of the reactions are suggested. NMR spectral data are reported for various 4-substituted thieno[2,3-b]pyridine compounds.     

Synthesis of possible metabolites of menazon

A product of the peracetic acid oxidation of 2,4-diamino-6-methylthiomethyl-1,3,5-triazine is identical with a major urinary metabolite of the aphicide, menazon, in the rat. This product has been shown to be the S-oxide 2,4-diamino-6-methylsulphinyl-methyl-1, 3, 5-triazine and not the N-oxide.     

A mechanistic study on the disproportionation and oxidative degradation of phenothiazine derivatives by manganese(III) complexes in phosphate acidic media

The oxidative degradation of phenothiazine derivatives (PTZ) by manganese(III) was studied in the presence of a large excess of manganese(III)-pyrophosphate (P₂O₇ ²⁻), phosphate (PO₄ ³⁻), and H⁺ ions using UV–vis. spectroscopy. The first irreversible step is a fast reaction between phenothiazine and manganese pyrophosphate leading to the complete conversion to a stable phenothiazine radical. In the second step, the cation radical is oxidized by manganese to a dication, which subsequently hydrolyzes to phenothiazine 5-oxide. The reaction rate is controlled by the coordination and stability of manganese(III) ion influenced by the reduction potential of these ions and their strong ability to oxidize many reducing agents. The cation radical might also be transformed to the final product in another competing reaction. The final product, phenothiazine 5-oxide, is also formed via a disproportionation reaction. The kinetics of the second step of the oxidative degradation could be studied in acidic phosphate media due to the large difference in the rates of the first and further processes. Linear dependences of the pseudo-first-order rate constants (k _obs) on [Mn^III] with a significant non-zero intercept were established for the degradation of phenothiazine radicals. The rate is dependent on [H⁺] and independent of [PTZ] within the excess concentration range of the manganese(III) complexes used in the isolation method. The kinetics of the disproportionation of the phenothiazine radical have been studied independently from the further oxidative degradation process in acidic sulphate media. The rate is inversely dependent on [PTZ^+.], dependent on [H⁺], and increases slightly with decreasing H⁺ concentration. Mechanistic consequences of all these results are discussed.     

Preparation of 4-substituted 1,3-oxathiolan-5-ones via the sulphenium ion intermediate generated by the pummerer rearrangement

4-Substituted 1,3-oxathiolan-5-ones have been synthesized via the Pummerer rearrangement from the S-oxide of the parent molecule. The 4,5-dione is obtained in the presence of pyridine N-oxide.     

Inhibition of acrylic acid polymerization by phenothiazine and p-methoxyphenol. II. Catalytic inhibition by phenothiazine

Inhibition of acrylic acid by p-methoxyphenol fits a conventional stoichiometric mechanism but phenothiazine inhibits acrylic acid via a completely different, catalytic cycle which does not depend on the presence of oxygen. We propose that this mechanism may involve a pair of single electron transfer reactions between free radicals, phenothiazine N-radicalcation, and phenothiazine itself, the latter being cyclically regenerated. Arrhenius equations were derived for the rates of disappearance of inhibitor and oxygen in acrylic acid stabilized with phenothiazine and with p-methoxyphenol and also with phenothiazine in the absence of oxygen. The practical implication of high oxygen to p-methoxyphenol consumption ratios is quite important: if commercial acrylic acid (usually stabilized with p-methoxyphenol) is inadvertently heated during storage, the limiting substance determining the onset of polymerization will be the dissolved oxygen and not p-methoxyphenol unless oxygen (air) is being supplied to and dissolved in the liquid at a rate sufficient to overcome the rate of its consumption.     

Fused 1,2-dithioles. IV. Synthesis and reactions of 1,2-dithiole s-oxides

1,2-Dithiolopyrrolones and their heterologues of type 1 are resonance stabilized systems displaying a high dipole moment. Upon oxidation with organic peracids compounds 2 , 5 , 15a, 16a, 20a and 25a gave the corresponding S(2)-oxides and, depending on substituents, in some cases the S(2)- and S(1)-dioxides. The S(2)-monoxides showed a proclivity to disproportionation and were easily reduced to dithioles with symme trical dimethylhydrazine. From S(2)-oxides and several primary amines bicyclic isothiazole-S-oxides were obtained (S/N-exchange reaction). From the N-unsubstituted isothiazole S-oxide 10e the N-hydroxyisothiazole 9d was synthesized by an aza-Pummerer-type rearrangement. The assumption is made that S(2)-oxides may be biologically important as active metabolites of pyrrothines and analogues of type 1 in their action as antibacterials and antimycobacterials.     

Synthesis of Some Selectively N-Protected (1S,2S)-p-Nitrophenylserinol–Based Diamino-1,3-dioxanes and Tripodands

The unconventional methodology for the non-epimerizable cycloacetalization of optically active (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (p-nitrophenylserinol) (condensed H₂SO₄ 96% as solvent and catalyst, i.e., sulfuric transacetalization) producing (2R,4S,5S) diamino-1,3-dioxanes was enlarged by the use of N-protected forms of 2,2-dimethoxyethylamine (DMEA, aminoacetaldehyde dimethylacetal). Conversely, N-protected derivatives of p-nitrophenylserinol were successfully cyclocondensed with DMEA in the same sulfuric conditions. N-Functionalization of DMEA upon treatment with trimesic acid trichloride and cyanuric chloride yielded the corresponding triple amide and melamine, respectively. Their adapted sulfuric transacetalization in triplicate in reaction with arylserinols (aryl: phenyl, p-nitrophenyl) afforded a new series of optically active tripodands.     

Chemistry of thienopyridines. XII. Selective formation of N-oxides,sulfoxides, and sulfones in some tricyclic systems

Direct conversion of [1]benzothieno[3,2-b]pyridine (IVa), thieno[3,2-b:4,5-b']dipyridine (Va), and thieno[2,3-b:4,5-b']dipyridine (VIa) into their sulfoxides was effected by means of an equimolar quantity of iodobenzene dichloride in aqueous acetonitrile. Treatment of IVa-VIa with excess chlorine gas in carbon tetrachloride and then with water gave the corresponding sulfones, IVc-VIc. Hydrogen peroxide in glacial acetic acid converted Va and VIa into di-N-oxides, thieno[3,2-b]pyridine into its N-oxide, and sulfone VIc into an N-oxide sulfone (X). Spectral and chemical means of distinguishing amongst the oxide functions are noted, and rationalizations for selectivity in the oxidations are discussed.     

Chemistry of thienopyridines. XIX. Further studies on chlorination and S-oxidation in the thieno[2,3-b] pyridine system

Treatment of thieno [2,3-b] pyridine (1a) with chlorine gas in chloroform (plus water) gave a mixture of two 2,3-dichloro-2,3-dihydrothieno[2,3-b] pyridine 1-oxides [trans-syn (IIa), and cis-anti (IIb)) [and 2,3,3-trichloro-2,3-dihydrothieno[2,3-b]pyridine syn-1-oxide (IVa), as well as a non-isolated fourth product (prohably the anti isomer of IVa) and sometimes a small amount of thieno[2,3-b]pyridine 1,1-dioxide (III). Treatment of Ia in a solvent (water, chloroform-water, or THF-water) with sulfuric acid and sodium hypochlorite gave a mixture of IIb and III. Effects of variations of reaction conditions on the composition of the product mixture were ascertained through chemical isolation and/or pmr analysis. Products formed were rationalized in terms of the chlorine-water-hypochlorous acid equilibrium, plus attack of chlorine variously at positions 1 (S-atom), 2, and 3 of 1a, but of hypochlorous acid only at position 1. Thermal and chromatographic limitations on isolation procedures for some of the products were established. Stereochemistries of IIa, IIb, and IVa were assigned by means of pmr spectrometry with the aid of the shift reagent Eu(fod)₃. Spin-spin couplings between the proton at position 2 and those at positions 4 and 6 were observed at high resolution. In exploratory runs, 5-ethyl-la was converted into isolable 2,3-dichloro-5-ethyl-2,3-dihydrothieno[2,3-b]pyridine 1-oxide, and 5-acetyl-Ia yielded 3-chloro-5-acetylthieno] 2,3-b]pyridine. Mass spectral fragmentation patterns for the various products are presented.     

Studies in the heterocyclic series. XX. 1,4-Diazaphenoxazine and related compounds

As part of our program on the synthesis of new psychotropic agents, the parent rings of two diazaphenox-azines are described. The reaction of 2-aminophenol and 2,3-dichloropyrazine in alkaline media gave good yields of 1,4-diazaphenoxazine. Replacement of 2,3-dichloropyrazine with 2,3-dichloroquinoxaline gave on the other hand the heterocycle, 1,4-diazabenzo[b]phenoxazine. Nitration and S-oxide formation were achieved by reaction with mixed nitric and sulfuric acids. Mechanistic pathways to these compounds were also discussed.