Tetracyclic phenothiazines. III. . Intermolecular hydride transfer in acid induced disproportionation of 1,2-dihydro-3-hydroxy-3H-pyrido[3,2,1-kl] phenothiazines

1,2-Dihydro-3-hydroxy-3H-pyrido[3,2,1-kl]phenothiazines and 1H-pyrido[3,2,1-kl]phenothiazines undergo acid catalyzed disproportionation with intermolecular hydride transfer to form pyrido[3,2,1-kl]phenothiazinium salts and 1,2-dihydro-3H-pyrido[3,2,1-kl]phenothiazines. Sodium borohydride reduction of 3-alkyl- or 3-arylpyrido[3,2,1-kl]phenothiazinium salts gives 3-alkyl- or 3-aryl-1H-pyrido[3,2,1-kl]phenothiazines. In the presence of a proton source, borohydride reduction of pyrido[3,2,1-kl]phenothiazinium fluoroborate or 3-chloropyrido-[3,2,1-kl]phenothiazinium perchlorate gives 1,2-dihydro-3H-pyrido[3,2,1-kl]phenothiazine, while 1H-pyrido[3,2,1-kl]phenothiazine is formed in aprotic solvents with pyridine present.     

On the synthesis of 3-amino-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine 5,5-dioxide and of 3-amino-1,2-dihydro-3H-dibenzo[c,jk]pyrido[2,1-c]-1,4-thiazepine 7,7-Dioxide

3-Amino-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine 5,5-dioxide and 3-amino-1,2-dihydro-3H-dibenzo-[c,jk]pyrido[2,1-c]-1,4-thiazepine 7,7-dioxide were synthesized from the corresponding 3-oxime acetates by reduction with the borane-tetrahydrofuran complex. Reduction was not successful in the case of 2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine-3-oxime acetate.     

Preparation of pyrrolo[3,2,1-jk]carbazole by nickel(0) mediated ring contraction of pyrrolo[3,2,1-kl]phenothiazine. Proton NMR and mass spectral studies

Pyrrolo[3,2,1-jk]carbazole 1a , the previously unreported 16π-electron parent compound, has been synthesized by treatment of pyrrolo[3,2,1-kl]phenothiazine 2a with a 1:1 mixture of bis(1,5-cyclooctadiene) nickel(0) and 2,2′-bipyridyl. An unequivocal assignment of the ¹H nmr spectrum of 1a was made by decoupling experiments and by comparison with the ¹H nmr spectrum of 1,9-dideuteriopyrrolo[3,2,1-jk]carbazole 1b . Metastable ion studies, exact mass measurements and the dideuterioderivative 1b were utilized to investigate the electron impact induced fragmentation of 1a .     

Tetracyclic phenothiazines IV . Synthesis of 1,2,3,4-Tetrahydro-azepino [3,2,1-kl] phenothiazin -4-one

The synthesis of 1,2,3,4-tetrahydroazepine[3,2,1-kl]phenothiazin-4-one was accomplished by cyclization of phenothiazine-10-butanoic acid using phosphorus pentoxide and absolute ethanol. The title compound represents the first reported example of the azepino[3,2,1-kl]phenothiazine ring system. A vastly improved malonic ester-type synthesis of the precursor acid has also been developed.     

Total assignment of the 1H NMR spectra of 5H-indolo[1,7-ab] [1]benzazepine,6,7-dihydro-5H-indolo[1,7-ab][1]benzazepine and pyrrolo[3,2,1-kl ] phenothiazine

The total assignment of the ¹H nmr spectrum of the three tetracyclic compounds: 5H -indolo[1,7-ab][1]benzazepine,6,7-dihydro-5H -indolo[1,7-ab ][1]benzazepine and pyrrolo[3,2,1-kl ]phenothiazine is described. Assignments were based on decoupling experiments and the spectrum of 1,10-dideuteriopyrrolo[3,2,1-kl]phenothiazine and the spectral parameters were verified by spin-simulation techniques. A temperature study of 6,7-dihydro-5H -indolo[1,7-ab][1]benzazepine was also performed.     

Synthesis of a non-flexible analog of chlorpromazine

9-Chloro-2-dimethylaminomethyl-1,2-dihydropyrrolo[3,2,1-kl]phenothiazine (3b), a conformationally restricted analog of chlorpromazine, has been synthesised and has been found to be devoid of neuroleptic activity.     

Synthesen von Heterocyclen, 31. Mitt.: Über kondensierte N-Heterocyclen

Zusammenfassung Es wird über Synthesen des 4,6-Dioxo-5,6-dihydro-4 Hpyrido[3,2,1-de]-carbazols I und 1,3-Dioxo-2,3-dihydro-1 Hpyrido[3,2,1-kl]-phenothiazins berichtet.Schweizer Priorität vom 9. 6. 1959.     

A synthesis of pyrrolo[ 3,2,1-kl] phenothiazine and derivatives

A synthesis of pyrrolo[3,2,1-kl]phenothiazine ( 1 ) is described. Electrophilic substitution of 1 leads to functionalization at the 2 position.     

Tetracyclic phenothiazines. VII. Electron impact promoted mass spectral fragmentation of some pyrido[3,2,1-kl]phenothiazines

The mass spectral fragmentation pattern of a series of pyrido[3,2,1-kl]phenothiazines is reported. The major fragments are derived from the breakdown of the pyrido ring and substituents thereon. The 1,2-/2,3-unsaturated, unsubstituted and most of the 3-substituted compounds show the molecular ion as the base peak indicative of their relative stability toward electron impact. The genesis of the base peaks from the molecular ions of the 2,2-dithiophenyl substituted compounds probably involves a concerted expulsion of a neutral diphenyldisulfide molecule and hydrogen atom transfer from the 1-position to the 2-position in the pyrido ring. On the other hand, 2-thiophenyl substituted molecular ions lead to base peaks involving simultaneous ring opening of the pyrido ring, cleavage of phenylthiomethylene moiety as a radical and contractive ring closure to the pyrrole system. These two mechanisms appear to be diagnostic for distinguishing 2,3- versus 2,2-positional isomers. The McLafferty rearrangement takes place in the 2-thiophenyl and 2,2-dithiophenyl substituted compounds. The retro-Diels-Alder fragmentation of the pyrido ring occurs in varying degrees depending on the nature of the 2- and 3- substituents and also the presence or absence of unsaturation in the pyrido ring. In the 2-thiophenyl-3-keto compounds, thiophenyl group participation with 3-carbonyl carbon and oxygen atoms is observed in the genesis of some interesting ion fragments. The detection of metastable ions in the spectra of 1,2-dihydro-2-thiophenyl-, 1,2-dihydro-2,2-dithiophenyl-3-hydroxy-, and 1,2-dihydro-2,2-dithiophenyl-3-keto-3H-pyrido[3,2,1-kl]phenothiazines; and spectra of 1,2-dihydro-3-methyl-, 1,2-dihydro-2-carbethoxy-3-keto- and 1,2-dihydro-2-thiophenyl-3-keto-3H-pyrido[3,2,1-kl]pheno-thiazines at low voltage support major fragmentation pathways.     

A simple synthesis of 1-phenothiazineethanolamines: Potential antimalarials

Two routes for the synthesis of the 1-phenothiazineethanolamine (4) starting from 1,2-dioxo-1,2-dihydropyrrolo[3,2,1-kl]phenothiazine are described.     

New tetracyclic ring systems. Synthesis of 1H-oxazolo[5,4,3-kl]phenothiazines and [1,4]oxazino[2,3,4-kl]phenothiazines

1-Hydroxyphenothiazine was converted to 1H-oxazolo[5,4,3-kl]phenothiazin-1-one, 1H-oxazolo[5,4,3-kl]-phenothiazine-1-thione,[1,4]oxazino[2,3,4-kl]phenothiazin-1(2H)one and [1,4]oxazino[2,3,4-kl]phenothiazine-1,2-dione. Also prepared from 1-hydroxyphenothiazine were the N-chloroacetyl derivative, the O-chloroacetyl derivative, the N,O-di(chloroacetyl) derivative and the sulfoxide.     

Synthesis of new heterocyclic ring systems. Reaction of indolines and hexahydrocarbazole with α,β-unsaturated acids

Reactions of indoline (I), 2-methylindoline (II) and hexahydrocarbazole (III) with α,β-unsaturated acids in the presence of polyphosphoric acid have been investigated. Reaction of 1 with acrylic acid afforded two compounds which were identified as 1,2,4,5-tetrahydro-6H-pyrrolo-[3,2,1-ij] quinolin-6-one (IV) and 2,3,5,6,9,10-hcxahydro-1H-cyclopenta[f lpyrrolo [3,2,1-ij|-quinoline-1,8-dione (VII). The reaction oi 1 with crotonic acid gave compounds V and VIII, analogous-to IV and VII. The reaction of II with acrylic acid yielded two compounds VI and IX, whereas with crotonic acid, only X was isolated. With 111, acrylic acid afforded 5,6,8,9,10. 11,8a,11a-octahydro-4H-pyrido[3,2,1-jk]carbazol-4-one (XI) and a compound with a heretofore unknown ring system, viz., 2,3,5,6,7,8,11,12,5a,8a-decahydro-1H-cyclopenta[h] pyrido [3,2,1-jk |earbazole-1,10-dione. The structures of these compounds were deduced on the basis of their spectral and analytical data.     

A novel synthesis of the isoxazolo[5,4,3-kl]acridine ring system

The Schmidt reaction of 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one ( 1 ) is described. In addition to the expected isomeric lactams, 3-phenyl-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-4-one ( 3 ) and 7,8-dihydro-3-phenyl-4H-isoxazolo[4,5-b]azepin-5(6H)-one ( 4 ), 4-amino-3-phenyl 1,2-benzisoxazole (5) was isolated, along with 4,5-dihydro-3H-isoxazolo[5,4,3-kl]acridine ( 6 ). Possible mechanisms for the formation of these products are discussed and some chemistry of the little-known ring system represented by 6 is also described.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XIV. Total assignment of the 13C-Nmr spectrum of pyrrolo[3,2,1-kl]phenothiazine

Total assignment of the ¹³C-nmr spectrum of the novel tetracyclic phenothiazine, pyrrolo[3,2,1-kl]phenothiazine is described. Assignments were determined from model systems, ¹H-¹³C spin-coupling behavior in conjunction with selective excitation techniques and spin-lattice (T₁) relaxation measurements. The anisotropic reorientation of this ring system via a principal axis passing through the center of the molecule, which provides a qualitative basis for signal discrimination, is also discussed.     

Quinolizines and indolizines. Part 16 . Synthesis of pyrrolo[3,2,1-ij]quinolin-4-ones with potential fungicidal activity

The synthesis of some derivatives of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (pyroquilon) having potential fungicidal activity has been accomplished starting with readily available 6-hydroxy-1,2-dihydro-4-pyrrolo[3,2,1-ij]quinolin-4-ones 3, 7. Functionalization in 6- or 5-position gave rise to the corresponding 6-and 5-substituted derivatives 8-12, 17 and 13-16, 20, 21 respectively. The formation of pyrrolo[3,2,1-ij]-pyrano[3,2-c]quinolines ( 5, 22, 23 ) and their degradation to acyl-substituted derivatives of 7 was studied.     

Cyclization of 1-acylaminoacridones into 7H-pyrido[2,3,4-kl]acridin-2(3H)-ones

1-Acylamino-10-methylacridones in a polar aprotic solvent underwent base-catalyzed cyclization into the corresponding 7-methyl-7H-pyrido[2,3,4-kl]acridin-2(3H)-ones. Heating of 1-butylaminoacridone in acetic anhydride in the presence of p-toluenesulfonic acid and potassium acetate afforded 3-butyl-7H-pyrido[2,3,4-kl]acridin-2(3H)-one, while heating of 1-aminoacridone under the same conditions gave 9-acetoxy-1-acetylimino-1,10-dihydroxy-acridine. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1433–1437, August, 2006.     

Heterocyclization of N-propenyl-substituted phenothiazines and phenoxazines using electrophiles in an anhydrous medium

10-Propenylphenothiazine reacts with a catalytic amount of BF₃·Et₂O in dry ethyl acetate via intramolecular heterocyclization of an intermediate dimeric cation to give mainly 1-ethyl-2-methyl-3-(phenothiazin-10-yl)-2,3-dihydro-1H-pyrido[3,2,1-k,l]phenothiazine and a minor product through fission of phenothiazine which is 1-ethyl-2-methyl-1H-pyrido[3,2,1-k,l]phenothiazine. Under similar conditions 10-propenylphenoxazine gave an oligomer (degree of polymerization 4.4) and the minor product 1-ethyl-2-methyl-1H-pyrido[3,2,1-k,l]phenoxazine likely formed similarly to the phenothiazine analog from the corresponding product of intramolecular heterocyclization (the latter not being observed in the reaction mixture). Dedicated to Academician of the Russian Academy of Sciences B. A. Trofimov on his jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1855–1860, December, 2008.     

Tetracyclic phenothiazines. VI. Attempted pummerer cyclization of 10-(2-Keto-3-methylsulfinylpropyl)phenothiazine

The title compound ( 3 ), a β-ketosulfoxide prepared by a Claisen-type condensation of ethyl 2-(10-phenothiazino)acetate ( 4 ) with dimsyl carbanion, was subjected to a variety of catalysts in attempts to achieve a Pummerer cyclization to 1,2-dihydro-3-methylthio-2-oxo-3H-pyrido[3,2,1-kl]phenothiazine ( 2 ). Although the Pummerer rearrangement product, 10-(2-oxo-3-hydroxy-3-methylthiopropyl)phenothiazine ( 5 ), could be obtained in excellent yield under mild conditions, neither it nor the β-ketosulfoxide could be successfully cyclized under any of the conditions attempted. Instead, phenothiazine, 2-hyroxy-3-(10-phenothiazinyl)-2-propen-1-al ( 7 ), 3-(10-phenothiazinyl)-1,1-di(methylthio)propan-2-one ( 8 ), 3-(10-phenothiazinyl)-1-methylthiopropan-2-one ( 9 ) and 10-phenothiazinylformamide ( 10 ) were variously obtained.     

First straightforward synthesis of 2,4-disubstituted benz[g]isoquinoline-3,5,10(2H)-triones, 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones

Structural modifications to the benz[g]isoquinoline skeleton of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were envisaged in order to make future SAR studies possible for this type of bioactive compounds. Several N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were converted to novel 2,4-substituted benz[g]isoquinoline-3,5,10(2H)-triones, new tetracyclic 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones. All the synthesized target compounds represent new heterocyclic systems, which were previously undescribed in the literature.     

Azaindolo[3,2,1-jk]carbazoles: New Building Blocks for Functional Organic Materials

The preparation and characterization of 12 azaindolo[3,2,1-jk]carbazoles is presented. Ring-closing C−H activation allowed for the convenient preparation of six singly and six doubly nitrogen-substituted indolo[3,2,1-jk]carbazole derivatives in which ten of the materials have not been described in the literature before. The detailed photophysical and electrochemical characterization of the developed materials revealed a significant impact of the incorporation of pyridine-like nitrogen into the fully planar indolo[3,2,1-jk]carbazole backbone. Furthermore, the nitrogen position decisively impacted intermolecular hydrogen bonding and thus the solid-state alignment. Ultimately, the versatility of the azaindolo[3,2,1-jk]carbazoles scaffold makes this class of materials an attractive new building block for the design of functional organic materials.