Studies on phenothiazines. Part 11. Synthesis and spectral studies of substituted 1-chloro/methyl/nitrophenothiazines

Synthesis of the title compounds by the Smiles rearrangement has been reported. 1-Nitrophenothiazines have been prepared by the reaction of 2-amino-3-chloro/methyl/methoxythiophenol with substituted o-halonitrobenzenes in ethanolic sodium hydroxide, in which Smiles rearrangement occurs in situ. 1-chloro/methyl-7-substituted phenothiazines have been prepared by Smiles rearrangement of 3-chloro/methyl-2-formamido-2′-nitro-4′-substituted diphenyl sulphides. The latter were prepared by the formylation of the diphenyl sulphides obtained by the condensation of 2-amino-3-chloro/methylthiophenols with substituted o-halogenonitrobenzenes in ethanolic sodium acetate. Spectral studies are also included.     

Synthesis of 7-ethoxy- and 7-fluoro-phenothiazines

Synthesis of 7-ethoxy- and 7-fluoro-phenothiazines is reported by Smiles rearrangement of 5-ethoxy- and 5-fluoro-2-formamido-2′-nitrodiphenylsulfides. The later were obtained by the formylation of 2-amino-5-ethoxy/5-fluoro-2′-nitrodiphenylsulfides which were prepared by the condensation of 2-amino-5-ethoxy/5-fluoro-benzenethiols with o-halonitrobenzenes.     

Reactions of thioquinanthrene with sodium alkanethiolates. The smiles rearrangement of diquinolinyl sulfides

Reactions of thioquinanthrene 1 with sodium alkanethiolates or S-alkylisothiouronium salts (in the presence of sodium hydroxide) at 70° in DMSO or DMF yielded 4,4′-dialkylthio-3,3′-diquinolinyl sulfides 3 , which were results of the S-S type of the Smiles rearrangement of primary reaction products - sodium 3-quinoline-thiolates 6. When the reactions were carried out at 20° the products were 3′,4-dialkylthio-3,4′-diquinolinyl sulfides 2.     

Analogues of antipsychotic phenothiazines. 10-(β-dialkylamino) ethylaminophenothiazines

A series of 10-(β-dialkylaniino) ethylarninophenothiazines III was obtained by lithium alumi-um hydride reduction of 10-dialkylaminoacetylaminophenothiazines II. Compounds II were synthesized by intramolecular cyclization, via a Smiles rearrangement, of 2-nitro-2′-(β-dialkyl-aminoacetyl) hydrazinodiphenyl sulfides I and XI, which in turn were best prepared by condensation of the appropriate dialkylaminoacetic acid hydrochloride with the corresponding 2-nitro-2′-hydrazinodiphenyl sulfide in the presence of dicyclohexyl carbodiimide. Other attempted methods for the synthesis of compounds 1 are also described.     

The synthesis of novel dipyridazinothiazine ring systems

The synthesis of several dipyridazinothiazines have been accomplished by: (a) cyclization in concentrated hydrochloric acid solution of the appropriate intermediates; and (b) via the Smiles rearrangement in either basic or glacial acetic acid solution of the appropriate intermediates. The following ring systems have been prepared and characterized: 10H-dipyridazino-[4,3-b:4′,5′-e]-1,4-thiazine, 5H-dipyridazino[3,4-b:4′,5′-e]-1,4-thiazine, 10H-dipyridazino[4,5-b:-4′,5′-e]-1,4-thiazine, 5Hdipyridazino[5,4-b:4′,3′-e]-1,4-thiazine, and 10H-dipyridazino[3,4-b:-3′,4′-e]-1,4-thiazine.     

Synthesis of the 3-methyl and 4-methyl derivatives of 3-amino-3,4-dihydro-1-hydroxycarbostyril and related compounds

The 3-methyl and 4-methyl derivatives of 3-amino-3,4-dihydro-1-hydroxycarbostyril were synthesized by the reductive cyclization of α-methyl-β-(o-nitrophenyl)alanine and α-amino-β-(o-nitrophenyl)butyric acid hydrohalides, respectively, under conditions of catalytic hydrogenation in acidic solution. The free bases of the latter two o-nitroaromatic amino acids were also catalytically hydrogenated under neutral conditions to yield the respective α-methyl-β-(o-aminophenyl)alanine and α-amino-β-(o-aminophenyl)butyric acid which were converted to the corresponding lactams, 3-methyl- and 4-methyl-3-amino-3,4-dihydrocarbostyrils. α-Methyl-β-(o-nitrophenyl)alanine was obtained by acid hydrolysis of 5-methy)-5-(o-nitrobenzyl)hydantoin which was prepared by treatment of o-nitrophenylacetone with potassium cyanide and ammonium carbonate. α-Amino-β-(o-nitrophenyl)butyric acid was synthesized by condensation of α-bromo-o-nitroethylbenzene with diethyl acetamidomalonate, followed by acid hydrolysis of the condensation product. The 4-methylated compounds were obtained as synthetic mixtures of two diasteromeric racemates in nearly the same amounts as shown by nmr spectral analysis. Unlike the demethylated parent compound, 3-amino-3,4-dihydro-1-hydroxycarbostyril, neither the 3-methyl nor 4-methyl analog was found to possess any antibacterial activity.     

Umlagerungsreaktionen von (2′-Propinyl)cyclohexadienolen und -semibenzolen

Rearrangements of (2′-Propinyl)cyclohexadienols and -semibenzenes The acid-catalyzed dienol-benzene rearrangement of 3- and 5-methyl-substituted (2′-propinyl)cyclohexadienols has been investigated. Treatment of the dienols with CF₃COOH in CCl₄ yields allenyl- and (2′-propinyl)benzenes via [3,4]- and [1,2]-sigmatropic rearrangements, respectively. The reaction with H₂SO₄ in Et₂O leeds to a mixture of allenyl-, 2′-propinyl-, 3′-butinyl- and (2′,3′-butadienyl)benzenes (Scheme 3). The latter are products of a thermal semibenzene-benzene rearrangement (cf. Scheme 9). The corresponding semibenzenes have been prepared by dehydration of the cyclohexadienols with H₂SO₄ or POCl₃ (Schemes 6 and 7). Under acidic conditions, the p-(2′-propinyl)semibenzenes 33–35 (Scheme 8) undergo [3,4]- and [1,2]-sigmatropic rearrangements to give again allenyl- and (2′-propinyl)benzenes, whereas the thermal rearrangements to the 3′-butinyl- and (2′,3′-butadienyl)benzenes (Scheme 9) involves a radical mechanism. In contrast, the o-(2′-propinyl)semibenzene b (Scheme 7) leads to (2′,3′-butadienyl)benzene 32 via a thermal [3,3]-sigmatropic rearrangement.     

Synthesis of 10-aminophenothiazines and derivatives

In this paper it is shown that 2-nitro-2′-(β-acetyl) hydrazinodiphenyl sulfides cyclize, via a Smiles rearrangement, to 10-acetylaminophenothiazines, which are inert to alkalis and suffer a strong decomposition by acids. 10-Aminophenothiazine has been obtained by ring closure of 2-bromo-2′-hydrazinodiphenyl sulfide via an assumed benzyne intermediate.     

Zur Synthese sulfonierter Derivate von 2,3-Dimethylanilin und 3,4-Dimethylanilin

On the Synthesis of Sulfonated Derivatives of 2,3-Dimethylaniline and 3,4-Dimethylaniline Baking the hydrogensulfate salt of 2,3-dimethylaniline ( 1 ) or of 3,4-dimethylaniline ( 2 ) led to 4-amino-2,3-dimethylbenzenesulfonic acid ( 4 ) and 2-amino-4,5-dimethylbenzenesulfonic acid ( 5 ), respectively (Scheme 1). The sulfonic acid 5 was also obtained by treatment of 2 with sulfuric acid or by reaction of 2 with amidosulfuric acid. 3-Amino-4,5-dimethylbenzenesulfonic acid ( 3 ) and 5-Amino-2,3-dimethylbenzenesulfonic acid ( 6 ) were prepared by sulfonation of 1,2-dimethyl-3-nitrobenzene ( 9 ) to 3,4-dimethyl-5-nitrobenzenesulfonic acid ( 11 ) and of 1,2-dimethyl-4-nitrobenzene ( 10 ) to 2,3-dimethyl-5-nitrobenzenesulfonic acid ( 12 ), respectively, with subsequent Béchamp reduction (Scheme 1). Preparations of 2-amino-3,4-dimethylbenzenesulfonic acid ( 7 ) and of 6-amino-2,3-dimethylbenzenesulfonic acid ( 8 ) were achieved by the sulfur dioxide treatment of the diazonium chlorides derived from 3,4-dimethyl-2-nitroaniline ( 24 ) and from 2,3-dimethyl-6-nitroaniline ( 31 ) to 3,4-dimethyl-2-nitrobenzenesulfonyl chloride ( 29 ) and 2,3-dimethyl-6-nitrobenzenesulfonyl chloride ( 32 ), respectively, followed by hydrolysis to 3,4-dimethyl-2-nitrobenzenesulfonic acid ( 30 ) and 2,3-dimethyl-6-nitrobenzenesulfonic acid ( 33 ), and final reduction (Scheme 3). Compound 7 was also synthesized by reaction of 4-chloro-2,3-dimethylaniline ( 23 ) with amidosulfuric acid to 2-amino-5-chloro-3,4-dimethylbenzenesulfonic acid ( 20 ) and subsequent hydrogenolysis (Scheme 2). 4′-Bromo-2′, 3′-dimethyl-acetanilide ( 13 ) and 4′-chloro-2′, 3′-dimethyl-acetanilide ( 14 ) on treatment with oleum yielded 5-acetylamino-2-bromo-3,4-dimethylbenzenesulfonic acid ( 17 ) and 5-acetylamino-2-chloro-3,4-dimethylbenzenesulfonic acid ( 18 ), respectively. Their structures were proven by hydrolysis to 5-amino-2-bromo-3,4-dimethylbenzenesulfonic acid ( 21 ) and 5-amino-2-chloro-3,4-dimethylbenzenesulfonic acid ( 22 ), followed by reductive dehalogenation to 3 .     

Studies on phenothiazines. Part 7. Synthesis of 3-substituted 2-aminobenzenethiols and their conversion into phenothiazines

Synthesis of substituted 1-nitrophenothiazines is reported by the Smiles rearrangement in situ, which involves condensation of 3-chloro or methyl-2-aminobenzenethiol with o-halonitrobenzenes (2,4,6-trinitochloro-benzene, 1,4-dichloro-2,6-dinitrobenzene, 2,4,6-tribromo-1,3-dinitrobenzene) in the presence of ethanolic sodium hydroxide. Ir and mass spectral studies are included.     

Sensitive and Visual Detection of Phosgene by a TICT-Based BODIPY Dye with 8-(o-Hydroxy)aniline as the Active Site

Phosgene and its substitutes (diphosgene and triphosgene) are widely utilized as chemical industrial materials and chemical warfare agents and pose a threat to public health and environmental safety due to their extreme toxicity. Research efforts have been directed to develop selective and sensitive detection methods for phosgene and its substitutes. In this paper, we have prepared two BODIPY-based fluorescent probes, o-Pah and o-Pha, which are two isomers with different active sites, ortho-aminohydroxy (3′,4′ or 4′,3′) phenyls at meso position of BODIPY, and compared their sensing performance toward triphosgene. The probe with o-(4′-amino-3′-hydroxyl), o-Pha, exhibits better sensing performance over the o-(3′-amino-4′-hydroxyl), o-Pah, for instance, a lower limit of detection (LOD) (0.34 nm vs. 1.2 nm ), and more rapid response (10 s vs. 200 s). Furthermore, based on the above comparative studies, a red-fluorescence probe o-Phae has been constructed through extending 3,5-conjugation of o-Pha. The probe o-Phae displays rapid response (60 s), high sensitivity to triphosgene (LOD=0.88 nm ), and high selectivity for triphosgene over relevant analytes including nitric oxide. Finally, a facile test strip for phosgene was fabricated by immobilizing o-Phae in a polyethylene oxide membrane for sensitive (<2 ppm) and selective detection of phosgene in the gas phase.     

Studies in spiroheterocycles. Part XVII. synthesis of novel fluorine containing spiro[indole-pyranobenzopyran] and spiro[indenopyran-indole] derivatives

An elegant one-step synthesis of two novel spiro ring systems viz: spiro[3H-indole-3,4′-(2′-amino-3′-carbonitrile-[4′H]-pyrano[3,2-c]benzopyran)]-2,5′(1H)-dione8 and spiro[(2-amino-3-carbonitrile-indeno[1,2-b]pyran)-4(5H)>3′-[3H]indole]-2′,5(1′H)-diones in 80–85% yields is described. The spiro heterocycles were prepared by the reactions of fluorine containing 3-dicyanomethylene-2H-indol-2-ones with 4-hydroxy-2H-1-benzopyran-2-one and 1H-indene-1,3(2H)-dione respectively. The synthesized compounds have been characterized on the basis of elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral data.     

Novel one pot synthesis of 2-amino-4-chloroquinolines via Smiles rearrangement

We have developed a novel one pot synthesis of 4-chloroquinolin-2-ylamines via Smiles rearrangement under milder condition. The key transformation involves O-alkylation of 4-chloro-1H-quinolin-2-ones with chloroacetamide followed by Smiles rearrangement. The scope of this methodology is further extended to the synthesis of 4-chloroquinolin-2-ylmethylamines and 2-(4-chloroquinolin-2-ylamino)ethanols. This methodology has furnished good yields of 2-amino-4-chloroquinolines.     

Synthesis of 3-amino-3,4-dihydro-2(1H)-quinazolinones as potential anticonvulsants

Thirteen 3-amino-3,4-dihydro-2(1H)-quinazolinones have been synthesized from ethyl chloroformate and o-aminobenzylhydrazines. The latter compounds were obtained from the metal hydride reduction of either o-aminobenzhydrazides or o-acylaniline hydrazones. All compounds were evaluated in mice in the maximal electroshock (MES) seizure and pentylenetetrazole (sc Met) seizure threshold tests for anticonvulsant activity and in the rotorod test to determine neurotoxicity. Five of the compounds showed activity in one or both tests at a dose of 300 mg/kg or lower. The most active compound is 3-dimethylamino-3,4-dihydro-2(1H)-quinazolinone.     

Nucleotide Coupling in Reverse Micelles

Nucleotide coupling was investigated in reverse micelles formed by (cetyl)trimethylammonium bromide (CTAB), in hexane/pentan-1-o1. In particular, the coupling of 2′ -deoxy-5′-O-methylcytidine 3′ O-phosphate, prepared by phosphoramidite chemistry, with 5′-amino-5-deoxythymidine was studied in the presence of a H₂O-soluble carbodiimide at (w_o) = 11 and 22 (w_o=[H₂O]/[CTAB]). The effect of w_o on the reaction rate was investigated. A solid-phase strategy was developed for the synthesis of 2′-deoxy-5′O-methyl-cytidyl-(3′-5′)-5′-amino-5′deoxythymidine. The nucleotide coupling yieldig the expected product occurred readily in reverse micelles. Nucleotide coupling is thus possible in reverse micelles, and this is discussed in connection with the micellar self-replication program.     

Synthesis and micropatterning properties of a novel base‐soluble,positive‐working,photosensitive polyimide having an o‐nitrobenzyl ether group

A novel positive‐working, photosensitive polyimide, poly[1,4‐phenyleneoxy‐1,4‐phenylene‐2,2′‐di(2‐nitrobenzyloxy)benzophenone‐3,3′,4,4′‐tetracarboxdiimide] (OPI‐Nb), developable with an aqueous base was prepared by the o‐nitrobenzylation of a polyimide, poly(1,4‐phenyleneoxy‐1,4‐phenylene‐2,2′‐dihydroxybenzophenone‐3,3′,4,4′‐tetracarboxdiimide) (OPI), derived from 2,2′‐dihydroxy‐3,3′,4,4′‐benzophenonetetracarboxylic dianhydride (DHBA) and 4,4′‐oxydianiline, and it micropatterning properties were investigated. The o‐nitrobenzylation of OPI to OPI‐Nb was conducted with o‐nitrobenzyl bromide in N‐methyl‐2‐pyrrolidinone containing Et₃N. The DHBA monomer was synthesized by exhaustive KMnO₄ oxidation of bis(2‐dimethoxy‐3,4‐dimethylphenyl)methane obtained by etherification of bis(2‐hydroxy‐3,4‐dimethylphenyl)methane with iodomethane, followed by deprotection of the methoxy groups and cyclodehydration of the obtained 2,2′‐dihydroxy‐3,3′4,4′‐benzophenonetetracarboxylic acid. The intermediate bis(2‐hydroxy‐3,4‐dimethylphenyl)methane was prepared by the condensation of 2,3‐dimethylphenol with paraformaldehyde. The degree of o‐nitrobenzylation was determined to be over 94 mol % from ¹H NMR absorption of benzylic CH₂ protons. The aromatic OPI was perfectly soluble in a dilute aqueous NaOH solution and tetramethylammonium hydroxide (TMAH), whereas OPI‐Nb was not even swellable in them. In the micropatterning process, OPI‐Nb showed a line‐width resolution of 0.4‐μm and a sensitivity of 5.4 J/cm² when its thin films were irradiated with 365‐nm light and developed with a 2.38% aqueous TMAH solution at room temperature for 90 s. The thickness loss of OPI‐Nb films measured after postbaking at 350 °C was in the 8–9% range. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 776–788, 2007     

Synthesis of new spirobenzazolines including a furo[3,4-b]pyran ring system

A series of 4,5-dihydrofuro[3,4-b]pyran-6-spiro-2′-benzazolines 3 were prepared by reaction of 4,4-dimethyl-2,6-dioxo-4,5-dihydrofuro[3,4-b]pyran 1 with o-phenylenediamine, o-aminophenol, o-aminothiophenol or their derivatives. Most of these compounds exhibited a significant analgesic activity.     

1,3,4-Benzotriazepinones. Formation and rearrangement

Anthranilic hydrazide reacts with orthoesters to produce mixtures of 3 products: 3,4-dihyro-5H-1,3,4-benzotriazepin-5-ones ( 1 ), 3-amino-3,4-dihydro-4-quinazolinones ( 2 ) and 2-(2-aminophenyl)-1,3,4-oxadiazoles ( 4 ). The origin of these materials has been investigated. Product distributions depend on the nature of substituents, solvent and time. In ethanol benzotriazepinones are kinetically favored, but formed reversibly they subsequently rearrange to 2 and 4 . Aminoquinazolinone formation is suppressed in aprotic solvents at moderate temperatures. Earlier failures to obtain 1 are due to its tendency to isomerize. Acid, base and thermal rearrangements have been observed. Mechanisms are proposed for the formation of 1, 2 and 4 , and for the rearrangements of the benzotriazepinones. Pyrazolo- and imidazotriazepinones have been prepared from the corresponding o-aminoazole hydrazides.     

Alkene Carboarylation through Catalyst-Free,Visible Light-Mediated Smiles Rearrangement

A light-mediated Truce–Smiles arylative rearrangement is described that proceeds in the absence of any photocatalyst. The protocol creates two C−C bonds from simple starting materials, with the installation of an aryl ring and a difluoroacetate moiety across unactivated alkenes. The reaction proceeds via a radical mechanism, utilizing a light-mediated reduction of ethyl bromodifluoroacetate by N,N,N′,N′-tetramethylethylenediamine (TMEDA) to set up intermolecular addition to an unactivated alkene, followed by Truce–Smiles rearrangement.     

Synthesis of 7‐chloro‐9‐trifluoromethyl‐/7‐fluorophenothiazines

Synthesis of 7‐chloro‐9‐trifluoromethyl‐/7‐fluorophenothiazines is reported by Smiles rearrangement of 5‐chloro‐3‐trifluoromethyl‐/5‐fluoro‐2‐formamido‐2′‐nitrodiphenyl sulfides. The later were obtained by the formylation of 2‐amino‐5‐chloro‐7‐trifluoromethyl‐/5‐fluoro‐2′‐nitrodiphenyl sulfides, which were prepared by the condensation of 2‐amino‐5‐fluoro‐/5‐chloro‐3‐trifluoromethyl benzenethiols with o‐halonitrobenzenes. 1‐Nitrophenothiazines have also been synthesized by the condensation of 2‐aminobenzenethiols with o‐halonitrobenzenes, involving Smiles rearrangement in situ. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:81–86, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20235