The Synthesis of Linearly Annelated Polycyclic Ketones by Friedel-Crafts Rearrangements of Their Angular Isomers

Derivatives of 5H-dibenzo[a, d]cycloheptene carrying an alkylamine side chain at position 5 serve as useful drugs in the chemotherapy of mental diseases.^1–2 During a study of the effect of annelation on the activity of these psychopharmacological agents of the amitryptyline type, it was deemed necessary to synthesize the linear 13,14-dihydro-6H-cyclohepta-[1,2-b:4,5-b']dinaphthalen-6-one (I). The method of approach was the general synthesis of the polycyclic skeleton of amitryptyline, in which the seven-membered ring is constructed by a Friedel-Crafts (F - C) intramolecular acylation.^3–4 Ketone I, however, contains two 2,3-disubstituted naphthalene moieties condensed to the central seven-membered ring.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Über die Synthese von 1-Aryl-und 1-Alkyl-2, 3-dimethyl-chinoxalinium-perchloraten. 2. Mitteilung. Synthese und 1H-NMR.-Spektren von 2,3-Dimethyl-1-phenyl-6-X-chinoxalinium-perchloraten

On the Synthesis of 1-Aryl- and-1-Alkyl-2, 3-dimethyl-quinoxalinium Perchlorates. 2nd Communication

1 1. Mitt.: [1].

. Synthesis and ¹ H-NMR. Spectra of 2, 3-Dimethyl-1-phenyl-6-X-quinoxlinium Perchlorates The synthesis of the title compounds ( 5 ) which have been useful as precursors for a lot of conventional and new-type dyes [2-8] has yet been limited to examples with X?H [2] [3] [11] [15] and with electron-donating [4] [12] or at best slightly electron-accepting [1] [6] substituents X and R. We now describe a method suitable even for compounds 5 with strongly electron-accepting substituents: N-monosubstituted o-phenylendiamines 4 , were condensed with 2, 3-butanedione and perchloric acid in mixed solvents containing an excess of diethyl ether. The products - mostly substituted at position 6 of the quinoxalinium ring - are chracterized by ¹H-NMR. spectra, elemental analyses and in most cases by isolation of the corresponding bases 6 . Correlations of chemical shifts with Hammett's σ_p [18] are given by equations (1)-(5).     

Investigation of the reactions of fluorine containing 3-hydrazino-5H-1, 2, 4-triazino[5, 6-b]indoles with ethyl acetoacetate. Synthesis of some novel tetracyclic ring systems

Novel tetracyclic ring systems viz. 3-methyl-1-oxo-12H-1, 2, 4-triazepino[3′,4′:3, 4][1, 2, 4]triazino[5, 6-b]indole ( 4a ) and 3-methyl-5-oxo-12H-1, 2, 4-triazepino[4′,3′:2, 3][1, 2, 4]triazino[5, 6-b]indole ( 5a ), having angular and linear structures respectively, were synthesized by the cyclization of 3-oxobutanoic acid [5H-1, 2, 4-triazino-[5, 6-b]indole-3-yl]hydrazone ( 3a ). However, cyclization of 3b (R = CH_a, R¹ = R² = H) afforded the angular product 4b exclusively. Moreover, cyclization of 3c (R = R³ = H, R¹ = F) yielded 7-fluoro-1-0xo-10H-1, 3-imidazo[2′,3′:3, 4][1, 2, 4]triazino[5, 6-b]indole ( 6c ) and 7-fluoro-3-oxo-10H-1, 3-imidazo[3′,2′:2, 3][1, 2, 4]triazino-[5, 6-b]indole ( 7c ) instead of the expected triazepinone derivatives. Compound 3d (R = R¹ = H, R² = CF₃) also gave an imidazole derivative but only one angular product was obtained. In all these reactions, formation of the angular product involving cyclization at N-4 is favoured. Characterization of these products have been done by elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral studies.     

Reaction of ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates with N-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10 % KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58 % yield. Under these conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar²-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar²-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (37-51 %). In the absence of KOH, only the substituted pyridine-2(1 H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.     

Synthesis and 13C-NMR study of novel pyrazolo[5′,1′:3, 4][1, 2, 4]triazino[5, 6-d]pyrimidines

The pyrazolo[5′, 1′:3, 4][1, 2, 4]triazino[5, 6-d]pyrimidines 5a-c, 6 were synthesized from the pyrazolo[5, 1-c]-[1, 2, 4]triazines 1a, c and the ring carbon signals of 5a-c, 6 were assigned by the aid of coupling constant [J( 13 C-¹H)] data.     

Synthesis of 6-Amino-5-R2-7-(6-R1-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

It has been found that malonodinitrile and 2-(6-R¹-oxo-3,4-dihydro-2-quinazolyl)acetonitrile in the presence of triethylamine undergo hetarylation by 5,6-dichloro-2,3-pyrazinedicarbonitrile at the active methylene group to give the triethylammonium salt of 2-(3-chloro-5,6-dicyano-2-pyrazinyl)malononitrile or 5-chloro-6-cyano(6-R¹-4-oxo-1,2,3,4-tetrahydro-2-quinazolylidene)methyl-2,3-pyrazinedicarbonitriles. Reaction of these with primary amines leads to annelation of the pyrrole ring at the pyrazine [b] edge to give 6-amino-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3,7-tricarbonitriles and 6-amino-5-R²-7-(6-R¹-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles respectively.     

Isolation and identification of three urinary metabolites of retinoic acid in the rat.

After the intraperitoneal administration of high doses of ¹⁴C- and ³H-labelled retinoic acid ( 1 ) to rats three major urinary metabolites have been isolated in microgram amounts by use of column, thin-layer and high-pressure liquid chromatography. Their structures were elucidated by mass spectroscopy and Fourier transform ¹H-NMR. spectroscopy as 2 (5-methyl-5-[2-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)vinyl]-2-tetrahydrofuranone), 3 (5-[2-(6-hydroxymethyl-2,6-dimethyl-3-oxo-1-cyclohexen-1-yl)vinyl]-5-methyl-2-tetrahydrofuranone) and 4 (6-(6-hydroxymethyl-2,6-dimethyl-3-oxo-1-cyclohexen-1-yl)-4-methyl-4-hexenoic acid). In these metabolites the tetraene side chain of 1 is shortened and the cyclohexene ring oxidized. The radioactivity of 2 and 3 accounted for about 10% (0.9% of the dose) each, metabolite 4 for about 6% (0.5% of the dose) of the total urinary radioactivity.     

Synthesis of ethyl 4,5-disubstituted 2-azido-3-thiophenecarboxylates and use in the synthesis of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones

New heterocyclic azides, ethyl 2-azido-4-R¹-5-R²-3-thiophenecarboxylates, were synthesized by diazotization of 2-aminothiophenes and subsequent treatment with sodium azide. The reactions of these heterocyclic azides with β-ketoesters and activated acetonitriles were studied. The derivatives of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine, a new ring system, were prepared in high yields via an anionic hetero-domino reaction.     

The addition of benzocyclobutenylidene to benzene : The facile rearrangement of spiro[benzocyclobutene-1,7'-cyclohepta-1',3',5'-triene] to 9a,10-dihydrobenz[α]azulene

Thermal decomposition of the sodium salts of benzocyclobutenone tosylhydrazone and 2-methylbenzocyclobutenone tosylhydrazone in benzene affords 9a,10-dihydrobenz[α]azulene 4 and trans-10-methyl-9a, 10-dihydrobenz[α]azulene 3, respectively. A mechanism involving initially the addition of the carbene benzocyclobutenylidene, or its 2-Me derivative, to the benzene ring is postulated. A proposed intermediate in the reaction, spiro [benzocyclobutene 1,7' cyclohepta-1',3',5'-triene] 12 has been synthesised, and shown to give rise to 4 under the reaction conditions. The rate of rearrangement of 12 → 4 has been measured, and the activation energy determined: E_a = 125.9 ± O.8 KJmol^?1 and A = 1.38 × lO¹⁴sec^?1. The mechanism for the rearrangement must involve ring opening of the benzocyclobutene moiety of 12 to give an o- xylylene intermediate which is postulated to possess considerable diradical character. At 71.8 °, this ring opening is 2.7 × 10⁶ times faster than the ring opening of the parent benzocyclobutene molecule. The decomposition of the sodium salt of 2-(7' -cyclohepta-1',3',5' trienyl)benzaldehyde tosylhydrazone has also been investigated and is shown to yield 4a,10-dihydrobenz[α]azulene, 9,10-dihydrobenz[α]azulene and 8,9-benzotricyclo [5.3.0.0^2.10]deca-3,5,8-triene. A mechanism involving intramolecular 1,3-dipolar addition of a diazo grouping to a cycloheptatriene Π-bond, followed by decomposition of the resulting pyrazoline intermediate, is proposed.     

Catalytic hydrogenation of methyl 3,4-diazatricyclo-[5.2.1.0<Superscript>2,6</Superscript>]dec-4-ene-5-carboxylate

The hydrogenation at Raney nickel of the pyrazoline ring in methyl exo-3,4-diazatricyclo-[5.2.1.0^2,6]dec-4-ene-5-carboxylate takes place quantitatively with the preferential formation of the trans isomer of 5-amino-exo-3-azatricyclo[5.2.1.0^2,6]decan-4-one. The 3-methoxycarbonylmethyl-, 3-acetyl-, and 3-nitroso-substituted esters are not hydrogenated under these conditions.     

Nucleophilic and Electrophilic Properties of Carbenes,II. 4-Biphenylyl-4-pyridylcarbene

Flash pyrolysis of 4-biphenylyl-4-pyridyldiazomethane ( 4 gave 7-phenyl-2-azafluorene) 5 , which was also synthesized from 3-mesitoylpyridine in four steps. 4-Biphenylyl-4-pyridyl-[¹³C]-diazomethane ( 9 ) was prepared from isonicotinic [¹³C]-acid chloride in three steps. Flash pyrolysis of 9 established that 4a- and 4b-[¹³C]-7-phenyl-2-azafluorenes are formed in a carbene-carbene rearrangement in which ring expansion of the biphenyl part dominates over that of the pyridine ring. These results support the postulate that carbene-carbene rearrangements are favoured by a nucleophilic interaction between the filled singlet carbene sp² (σ) orbital and the lowest unoccupied molecular orbital (LUMO) of the aromatic ring.     

Oxidative and hydrolytic cleavage of cyclopropane and spirocyclobutane derivatives of 6,8-dioxabicyclo[3.2.1]octane,the products of transformation of levoglucosenone

A new method for the synthesis of (1R,4S,5S)-4-hydroxymethyl-3-oxabicyclo[3.1.0]hexan2-one, the cyclopropane analog of (S)-5-hydroxypent-2-en-4-olide, has been suggested based on oxidation of (1S,2S,4R,6R)-7,9-dioxatricyclo[4.2.1.0^2,4]nonan-5-one. Oxidation of cyclobutanones, spirojoined with the fragments of 6,8-dioxabicyclo[3.2.1]oct-2-ene, 6,8-dioxabicyclo[3.2.1]octane (at position 4), or 7,9-dioxatricyclo[4.2.1.0^2,4]nonane (at position 5), upon the action of m-chloroperoxybenzoic acid or the KMnO₄-H₂SO₄-H₂O system leads to the corresponding spirojoined butanolides in 73–85% yields. The same cyclobutanones easily undergo the four-membered ring opening upon the action of dilute H₂SO₄ at 50–90 °C to form 6,8-dioxabicyclo[3.2.1]octane-4- or 7,9-dioxatricyclo[4.2.1.0^2,4]nonane-5-propionic acid.     

Mononuclear and binuclear tricarbonylchromium complexes of aryl-substituted [2.2]paracyclophanes

The complexation reactions of monoaryl- and diaryl-substituted [2.2]paracyclophanes with (NH₃)₃Cr(CO)₃ have been studied. The aromatic rings of [2.2]paracyclophane are more favorable for coordination than aryl substituents. This leads to the regioselective formation of the corresponding mono- or binuclear tricarbonylchromium complexes. In some cases, the tricarbonylchromium group is coordinated to the aryl ring of the substituent to form (in low yields) the corresponding mononuclear complex or binuclear complexes with both the aromatic ring of paracyclophane and the aryl ring of the substituent involved in coordination. The structure of such complex, namely, [4-(η⁶-2,4,6-trimethylpheny)-11-16-η⁶-[2,2]paracyclophane]bis[tricarbonylchromium(0)] was confirmed by X-ray diffraction study. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 142–150, January, 1998.     

The octant rule. XIV. synthesis and circular dichroism of α-exo and endo-deuteriobicyclo[3.2.1]octan-3-one and 6,6-dimethybicyclo[3.1.1]heptan-3-one

(1R,5S)-2S-Deuteriobicyclo[3.2.1]octan-3-one ($\text{1}$) and (1R,5S)-2R-Deuteriobicyclo[3.2.1]octan-3-one ($\text{2}$), prepared by diazomethane ring enlargement of (1S,4R)-2(exo)-deuteriobicyclo-[2.2.1] heptan-2-one and (1S,4R)-2(endo)-deuteriobicyclo[2.2.1]heptan-2-one respectively, both gave (?) n-π^* circular dichroism (CD) Cotton effects, Δε^max₂₉₄ = ?0.05 and Δε^max₂₉₄=?0.1, respectively, in hydrocarbon solvent. (1S,5R)-2S-Deuterio-6,6-diaethylbicyclo[3.1.1] heptan-3-one ($\text{3}$) and (1S,5R)-2R-deuterio-6,6-dimethylbicyclo[3.1.1] heptan-3-one ($\text{4}$), prepared from (-) myrtenal, both exhibited extraordinary vibrational fine structure for the n-π^* CD transitions observed in hydrocarbon solvent and oppositely?signed CEs, Δε^max₂₈₂=?0.01 and Δε^max₂₇₉=+0.01 respectively in CF₃CH₂OH solvent.     

Mononitration of derivatives of benzisatins

The mononitration of benz[e]-, benz[f]-, and benz[g]isatins and their tetrahydro derivatives was realized. It was established on the basis of an analysis of the ¹H NMR and mass spectra that substitution takes place at position 5 in the derivatives of the [g] series and at the position adjacent to the NH group in derivatives of the [f] series and in the case of 6,7,8,9-tetrahydrobenz [e]isatin. This reaction path corresponds to the maximum electron density in the HOMO, calculated by the CNDO method. In benz[e]isatin, contrary to the general relationship and to the quantum-chemical prediction, the nitro group initially enters the ring annellated with the indole ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 60–65, January, 1989.     

Inherently chiral biscalixarene cone–cone conformers consisting of calix[4]arene and calix[5]arene subunits

Inherently chiral biscalixarenes with hetero-cavities were synthesized by a covalent assembly of p-tert-butylcalix[5]arene with a 1,3-substituted calix[4]arene via 1,3-alkylation reaction and subsequent desymmetrization. The racemates were resolved by chiral HPLC method. ¹H NMR spectra, VT-NMR spectra, and theoretical calculations support that the calix[5]arene subunit of the inherently chiral calix[4][5]arene ester adopts a cone-in conformation, with the aromatic ring bearing the CH₂CO₂Et group tilting inward the calix[5]arene cavity. By contrast, such a cone-in structural feature of the calix[5]arene subunit disappears for the corresponding inherently chiral calix[4][5]arene carboxylic acid, due to the intramolecular hydrogen bonding between the carboxyl group and an ethereal oxygen of the glycolic chain.     

Saturated heterocycles. 254 . synthesis and stereochemistry of saturated or partially saturated pyridazino-[6,1-b]- and phthalazino[1,2-b]quinazolinones

By the reaction of anthranilic hydrazide 1 with cis-2-(p-methylbenzoyl)-1-cyclohexanecarboxylic acid 2a or diendo-3-(p-methylbenzoyl)bicyclo[2.2.1]heptane-2-carboxylic acid 2b , fused tetra- and pentacyclic ring systems 3a, b were prepared, trans-2-Amino-1-cyclohexanecar-bohydrazide 4b was reacted with 3-(p-chlorobenzoyl)propionic acid 5 to yield the pyridazino[6,1-b]quinazolinone 6 . From the reaction of cis-2-amino-1-cyclohexanecarbohydrazide 4a with 2a , three isomeric partially saturated 8H-phthalazino[1,2-b]quinazolin-8-ones 7a-c were formed. The reaction of diexo-2-aminobicyclo[2.2.1]heptane-3-carbohydrazide 4c and 2a furnished the pentacyclic derivatives 8 and 9 containing a 3-aryl-4,5-dihydropyridazine or 3-arylhexahydropyridazine ring C with cis annelated C/D rings. The formation of 8 and 9 involving different ring systems can be rationalized by two reaction pathways: (i) in the bislactam 9 the carboxyl group acylates the hydrazide, while (ii) in 8 it forms a pyridazine ring with the cyclic amino group by cyclocondensation. The structures of the products were elucidated by ¹H and ¹³C nmr methods, including DEPT, DNOE and 2D-HSC measurements.     

Alpha selective epoxide opening with F: synthesis of 4-(3-[F]fluoro-2-hydroxypropoxy)benzaldehyde ([F]FPB) for peptide labeling

Strained tricyclic ring systems such as epoxides are rarely used as precursors for the introduction of anionic fluorine-18 into organic compounds intended for positron emission tomography (PET). Here we report the alpha selective ring opening of epoxides for the introduction of fluorine-18 into small as well as larger biomolecules via 1- and 2-step protocols. [¹⁸F]fluoromisonidazole ([¹⁸F]MISO), a tracer for hypoxia imaging, and the tumor targeting peptide Tyr³-octreotate (TATE) were radiolabeled using epoxide opening reactions. In the latter case, the new prosthetic labeling synthon 4-(3-[¹⁸F]fluoro-2-hydroxypropoxy)benzaldehyde ([¹⁸F]FPB) has been used for ¹⁸F-introduction.     

Synthesis of a series of diaminobenzo[f]- and diaminobenzo[h]pyrimido[4,5-b]quinolines as 5-deaza tetracyclic nonclassical antifolates

A series of diaminobenzo[f]- and diaminobenzo[h]pyrimido[4,5-b]quinolines 1–11 were designed as 5-deaza tetracyclic nonclassical, lipophilic antifolates. The compounds were designed as conformationally semi-rigid and rigid analogs of 2,4-diamino-6-phenyl- 12 and 2,4-diamino-7-phenylpyrido[2,3-d]pyrimidines 13 and 14 . The target compounds were synthesized by cyclocondensation of chlorovinyl aldehydes obtained from appropriately substituted 1- or 2-tetralone, with 2,4,6-friaminopyrimidine. Compounds 1–11 were evaluated as inhibitors of P. carinii and T. gondii dihydrofolate reductases. These pathogens cause fatal opportunistic infections in AIDS patients. In addition, the selectivity of these agents was evaluated using rat liver dihydrofolate reductase as the mammalian source. In general the benzo[f]pyrimido[4,5-b]quinolines 1–5 were more potent than the corresponding benzo[h]pyrimido[4,5-b]quinoline analogues 6–11 against P. carinii and rat liver dihydrofolate reductase and were equipotent against T. gondii dihydrofolate reductase. Compounds 6–11 were moderately selective towards T. gondii dihydrofolate reductase with IC₅₀S in the 10⁻⁷ M range. In contrast analogues 1–5 lacked selectivity against P. carinii or T. gondii dihydrofolate reductase and were, in general, potent inhibitors of rat liver dihydrofolate reductase with IC₅₀S in the 10⁻⁸ M range. Analogues 1 and 4 were evaluated against a series of tumor cell lines in vitro and were found to have moderate antitumor activity (IC50 10⁻⁶ M). The structure activity/selectivity relationships suggest that benzo[f]pyrimido analogues 1–5 with the phenyl ring substitution in the “upper” portion of the tetracyclic ring are better accommodated within the rat liver (mammalian) dihydrofolate reductase and P. carinii dihydrofolate reductase active sites compared to the benzo[h]pyrimido analogues 6–11 which have the phenyl ring substitution in the “lower” portion of the tetracyclic ring. In contrast T. gondii dihydrofolate reductase does not discriminate between the isomers and binds to both series of compounds with similar affinities.