Conformational analysis of benzoannulated nine-membered rings. Part 3. 1,4,5,7-Tetrahydro-3H-2,6-benzodiselenine and its 4-spiro derivatives

The ¹H and ¹³C nmr spectra of 1,4,5,7-tetrahydro-3H-2,6-benzodiselenine (1) and three 4-spiro derivatives 2–4 as well as the ⁷⁷Se nmr spectra of 2 have been recorded at different temperatures in order to investigate their conformational behavior. It was found that in analogy to corresponding dithionins the molecules adopt a chiral ground state conformation (Figure 2), and coalescence effects are due to racemization.     

4-Substituted-3-alkyl-3,4-dihydro-2H-1,3-benzoxazin-2-ones. IV (2-4). Keto-Enol tautomerism of β-keto ester derivatives. Reaction of β-dicarbonyl compounds with diamines

A series of α-[3-alkyl-3,4-dihydro-2-oxo-2H-1,3-benzoxazin-4-yl]-β-keto ester derivatives 1 (Table I) were synthesized by the condensation of 3-alkyl-3,4-dihydro-4-hydroxy-2H-1,3-benzoxazine-2-ones 3 (2) with β-keto esters 4 in the presence of traces of mineral acids under azeotropic conditions. Condensation of 1 with hydrazines 5 gave pyrazolone derivatives 2 (Table II). Condensation of β-diketone derivatives 6 with hydrazines 5 and with 1,2-benzenediamine ( 8 ) resulted in the formation of pyrazoles ( 7a-c ) and diazepine derivatives 12 (Table III) and 13 , respectively.     

On triazoles. VIII The reaction of 5-amino-1,2,4-triazoles with ethyl 2-cyano-3-ethoxyacrylate and 2-cyano-3-ethoxyacrylonitrile

The reaction of different 5-amino-3-Q-1H-1,2,4-triazoles 1 with ethyl 2-cyano-3-ethoxyacrylate ( 5a ) and 2-cyano-3-ethoxyacrylonitrile ( 5b ) to yield either the a type 5-amino-, or the b type 7-amino-1,2,4-triazolo[1,5-a]-pyrimidine derivatives 6–10 was studied. The structure of compounds 6 and 9 was proved by their degradation to the corresponding derivatives 17a and 18a , respectively, through intermediates 11a, 12a, 13a, 14a, 15a and 16a , respectively. The structure of derivatives 7, 8 and 10 was proved on the basis of the analogy of their uv spectra with those of 6a and 9a , respectively. The isolation of the intermediates 19 and 20 helped to prove the mechanism of the reactions leading to the formation of 6a and 9a , respectively. In the reaction of the N-substituted 5-amino-1,2,4-triazoles with 5a the expected condensed ring products were not formed. Instead the aminoacrylates 22 and 24 were obtained. The “Z”-“E” isomeric structure of derivatives 19, 20, 22 and 24 was proved with the help of their pmr spectra. The “Z” isomeric structure of the thermodynamically stabile 22 was corroborated with the help of its proton coupled cmr spectra, too.     

Azetidinyl ketones. Synthesis of 1-Alkyl-2,4-diphenyl-3-benzoylazetidines

α-(α'-Bromobenzyl)chalcone ( 3 ) reacts with primary amines (t-butyl, isopropyl,cyclohexyl) to give α-(α'-alkylaminobenzyl)chalcones ( 4, 5 and 6 ). When these allylic amines are treated with hydrogen bromide followed by reaction with base, they produce l-alkyl-2,4-diphenyl-3-benzoyl-azetidines ( 7,8 and 9 ). These azetidines were readily converted to their 3-deuterio derivatives ( 10 , 11 and 12 ) by treatment with sodium methoxide in deuteriomethanol. The configurations were assigned primarily by pmr spectra and mass spectra in reference to analogous compounds.     

On triazoles. I. The reaction of N-cyanocarbonimidodithioic acid diesters with hydrazines

The reaction of N-cyanocarbonimidodithioic acid di(alkyl and aralkyl)esters with different alkyl-, aralkyl- and arylhydrazines to yield 1-substituted-3-R-thio-5-amino-1H-1,2,4-triazoles ( 3 ) and 2-substituted-3-R-thio-5-amino-2H-1,2,4-triazoles ( 4 ) was studied. Isolation of the different types of isomeric pairs of 3 and 4 helped to prove the structure of products obtained which made possible correction of some confusion in the literature. The 3 (R = H) tautomeric structure of the non-substituted derivatives was supported by comparison of their uv and cmr spectra with those of the alkylated and aralkylated derivatives 3 and 4 , respectively, again correcting confusion in the literature. An hplc determination of the ratio of products 3 and 4 formed in the above reactions with different hydrazines made it possible to prove the mechanism of the reaction.     

Nucleophilic Substitutions of N-Acyl-4-Chloro-3-Thiazolidines with the Organometallic Selenolates LiSeMcp(CO)3, M = Mo,W. Crystal Structure of (RS)-3-Acetyl-4-[(η5-cyclopentadienyl)(tricarbonyl)selenolato-tungsten(II)]-2,2,5,5-tetramethyl-3-thiazolidine

Selenolato complexes of molybdenum(II) and tungsten(II) with biologically important thiazolidine N/S-heterocycles have been prepared via nucleophilic attack of LiSeMocp(CO)₃ or LiSeWcp(CO)₃ on N-acyl-4-chloro-thiazolidines, easily accessible by reaction of acyl chlorides with 3-thiazolines. The resulting complexes represent the first examples of organometallic derivatives of this class of heterocycles. They are stable under nitrogen in the solid state, but decompose in solution when exposed to air. An X-ray structure analysis of (RS)-3-acetyl-4-[(η⁵-cyclopentadienyl)(tricarbonyl)(selenolato)tungsten(II)]-2,2,5,5-tetramethyl-3-thiazolidine ( 2 a ) has been performed (C₁₇H₂₁NO₄SSeW, orthorhombic, Pbca, a = 1579.5(3) pm, b = 1138.7(2) pm, c = 2209.4(3) pm, Z = 8). It revealed a monomeric structure with a non-planar heterocyclic substituent in an envelope conformation and a W–Se bond length of 264.96(10) pm. ⁷⁷Se-NMR spectra displayed chemical shifts in the range –280 to –350 ppm. These values are consistent with earlier results on related complexes.     

Reactions of Polyhalopyridines. 17. Synthesis of 2-, 3-, and 4-Perfluoroalkylthiopolychloropyridines

2-, 3-, and 4-Perfluoroalkylthiopolychloropyridines have been synthesized using perfluoroalkylated thiol and disulfide derivatives of polychloropyridines via the thermal decomposition of Xe(II) bisperfluoroalkylcarboxylates. It was shown that their formation takes place from the starting thiols only through the formation of the disulfides. It was found that 3,4,5,6-tetrachloro-2-trifluoromethylthiopyridine reacts with potassium p-tolylthiolate with retention of the fluorine containing fragment and substitution of the chlorine atom in position 4 of the pyridine ring by the tolythio group.     

The reaction of 2-acetoacetamidopyridines with phosgene. A route to novel 3-Acetyl-2-chloro-4H-pyrido[ 1,2-a] pyrimidin-4-ones

2-(Acetoacetamido)pyridine, 1 , and its 5-methyl derivative, 2 , with phosgene, gave 3-acetyl-2-chloro-4H-pyrido[1,2-a]pyrimidin- 4 -one, 5 , and 3-acetyl-2-chloro-7-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one, 6 , respectively. The structures of these compounds followed from their elemental analyses, and interpretations of their uv, ir, pmr, and X-ray spectra. An alternative route to 5 and 6 , which sought first to react 1 and 2 with methyl - and benzyl chloroformates, was unsuccessful, and led, instead, to elimination of the acetoacetyl group with concomitant formation of the carbamate derivatives, 10 and 11 .     

Synthesis of 1-Isonicotinoyl-3-Methyl-4-(Substituted AZO) Pyrazol-5-Ones

Isonicotinic acid hydrazide (INH) and their derivatives are generally used as antitubercular agent. We synthesised 1-isonicotinoyl-3-methyl-4-(substituted azo) pyrazol-5-one and their derivatives. Their Rf values, chemical analyses and IR spectra were recorded, The compounds had shown significant central nervous system stimulant activity.     

Synthesis of 3-(1-hydroxyalkyl)-4,5,6,7-tetrahydroindazole derivatives. Structure determination of N-alkyl isomers

A novel series of 3-(1-hydroxyalkyl)-4,5,6,7-tetrahydroindazoles and their 1 and 2-alkyl-3-(1-hydroxyalkyl)-or-3-(1-acetoxyalkyl) derivatives were synthesized via condensation between 3-oxo-2,3,4,5,6,7-hexahydrobenzo[b]furans or 2-(2-acetoxyacyl)cyclohexanones and hydrazines. Structure assignment are based on ¹H and ¹³C nmr spectra.     

Reaction of ethyl γ-bromo-β-methoxycrotonate with carbonyl compounds. Synthesis of 4-methoxy-6-substituted-5,6-dihydro-2H-pyran-2-ones and 3-substituted 3-pyrazolin-5-ones

Ethyl β-methoxycrotonate I reacts with substituted carbonyl compounds II in benzene to give 4-methoxy-6-substituted-5,6-dihydro-2H-pyran-2-ones III. The reaction of IIIa and j with hydrazine hydrate in ethanol leads to 3-[(1′-thienyl-1-hydroxy)methyl]-5-hydroxy-1H-pyrazole (IVa) and 3-[1′-styryl-1′-hydroxy)methyl]-5-hydroxy-1H-pyrazole (IVj) in good yields. The structure of the products were assigned and confirmed on the basis of their elemental analysis and the electronic absorption, infrared and nmr spectra.     

The Difference in the Behaviour of Hydrazine and p-Substituted Phenylhydrazines on Various 4-(3-Aryl-3-Oxopropenyl) Antipyrines

A series of novel 4-(3-aryl-4,5-dihydro-lH-pyrazol-5-yl)-l, 5-dimethyl-2-phenyl-lH-pyrazol-3(2H)-oncs (III) were synthesized. Thus, the key intermediates, 4-(3-aryl-3-oxopropenyl-1,5- dimethyl-2-phenyl-1H-pyrazol-3(2H)-ones (II) were cyclized with hydrazine hydrate containing a few drops of ethanol gave the desired pyrazoline derivatives (III), which can be acetylated to afford the target N-acetyl derivatives (IV). On the other hand, the same reaction condition using p-substituted phenylhydrazines, the starting key intermediates (II) were recovered unchanged. The use of glacial acetic acid instead of ethanol, lead to a new series of 1,3-diarylpyrazoles (VI) by a different pathway. The structure of the newly synthesized compounds was elucidated by elemental analyses, IR, ¹H-NMR and mass spectra.     

Furopyridines. XI. 13C NMR Spectra of 2- or 3-Substituted Furo[2,3-b]-, Furo[3,2-b]-, Furo[2,3-c]- and Furo[3,2-c]pyridine

The ¹³C nmr spectra of 2- or 3-monosubstituted furo[2,3-b]- 1a-1j , furo[3,2-b]- 2a-2j , furo[2,3-c]- 3a-3j and furo[3,2-c]pyridine derivatives 4a-4j are reported. Effects by change in annelation and substituent effects on ¹³C chemical shifts and carbon-proton coupling constants are discussed. The spectra of benzo[b]furan derivatives 5a-5j having the corresponding substituent are also reported for comparison.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XX. Synthesis of 2H-pyrano[2,3-f]quinazoline derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-6-aminomethylene-7,8-dihydro-(2-methyl)(2-phenyl)quinazolin-5(6H)-ones III , prepared in good yields from 7,8-dihydro-(2-methyl)-(2-phenyl)quinazolin-5(6H)-ones via their 6-hydroxymethylene derivatives I and II , gave in satisfactory to excellent yields N-N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-(8-methyl)(8-phenyl)-2H-pyrano- [2,3,-f]quinazolin-2-ones IV , which are derivatives of the new heterocyclic system pyrano[2,3-f]quinazoline. This cycloaddition occurred both in the case of aliphatic and aromatic N-substitution only with 2-phenyl-enaminones III , whereas with 2-methyl derivatives III the reaction took place only in the case of aromatic N-monosubstitution. Dehydrochlorination of IV with DBN afforded, generally in excellent yields, N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-y]quinazolin-2-ones, which were dehydrogenated with DDQ to give N,N-disubstituted 4-amino-3-chloro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-f]quinazolin-2-ones in excellent yields.     

α-Pyrones. II . Synthesis of tetrahydroquinoline derivatives of 4-aminobutanoic and 2-amino-2-pentenedioic acids

Ethyl 3-benzoylamino-2-oxo-6-triphenylphosphoranylidenemethyl-2H-pyran-5-carboxylate ( 1 ) reacts with 2- nitrobenzaldehydes ( 2 ) to give 6-(2-nitrostyryl)-2H-pyran-2-ones ( 3 ), as the E stereoisomers, in good yields. The reduction of compounds 3 , performed with hydrogen over Pd/C at room temperature and 1 atmosphere, leads to a mixture of 2-amino-4-tetrahydroquinolinylidene-2-pentenedioic acid derivatives 5a-d as the main products, the corresponding 3-butenoic acid derivatives 6 and a minor amount of pyrano[2,3-c]benzazocines 9a-c. At 40 atmospheres and 90°, the reduction gives 4-amino-2-tetrahydroquinolinylbutanoic acid derivatives 8a-d as the main products and their precursors 7a,b,d as the minor ones. Amines 4c,d are isolated by stopping the reduction after the uptake of 3 equivalents of hydrogen.     

N.m.r. spectra of cyclic amines. II—Factors influencing the chemical shifts of α-protons in aziridines

Proton magnetic resonance spectra of trans and cis-2,3-diphenylaziridine (1 and 2) and their N-ethyl derivatives 3 and 4 were measured in carbon tetrachloride, chloroform, and benzene-d₆ at low temperatures (1 and 3) and in dry conditions (1 and 2). On the basis of these results it was concluded that an N-ethyl group exerts a shielding influence on a cis ring proton and a deshielding influence on a trans ring proton. From results obtained by measuring the ¹H n.m.r. spectra of 1–4 in deuterochlorofom-trifluoroacetic acid it was derived that the lone pair of the aziridine nitrogen exerts a shielding influence on cis related ring hydrogens. In most N-alkylaziridines the effect of the N-alkyl group predominates.     

New Cell Growth-Inhibitory Cyclohexadienone Derivatives from Hypericum calycinum L.

The crude petroleum-ether extract of the aerial parts of Hypericum calycinum L. (Guttiferae) exhibited in vitro growth-inhibitory activity against the Co-115 human colon carcinoma cell line. Bioassay-guided fractionation of this extract allowed the isolation of the cyclohexadienone derivatives 1–5 , four of which are previously undescribed compounds. The structures of the known chinesin II (1) and of 2 (hypercalin A) were established by ¹H- and ¹³C-NMR spectroscopy and were confirmed by X-ray analysis of their crystalline mixture which revealed the complete relative configuration of both compounds. The structure of 3 (hypercalin B) was elucidated by means of extensive 1D- and 2D-NMR experiments, including DQ-COSY, HETCOR and LR-HETCOR. The structure of compound 4 (hypercalin C) was established by ¹H- and ¹³C-NMR spectroscopy and confirmed by X-ray analysis to be the 3,5-dihydroxy-4-{[(1R*,2S*, 5S*)-2-hydroxy-2-methyl-5-(1-methylethenyl)cyclopentyl]methyl}-6,6-bis-(3-methylbut-2-enyl)-2-(2-methylpropanoyl)cyclohexa-2,4-dien-1-one. The structures of the higher isomeric homologues 5a/5b were deduced by comparison of their UV, ¹H-, and ¹³C-NMR spectra with those of 4 . The isolated compounds appeared to be related to chinesin I and II previously isolated from Hypericum chinense L. and were responsible for the growth-inhibitory activity of the extract against the Co-115 human carcinoma cell line. Moreover, 1/2 and 3 showed molluscicidal activity against the schistosomiasis-transmitting snail Biomphalaria glabrata.     

On triazoles. XVII . The reaction of 5-amino-1,2,4-triazoles with N-heterocyclic β-oxo-esters

Pyrrolo[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidinone ( 3d ), pyrido[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidinone ( 3e ) and pyrido[4,3-e]-1,2,4-triazolo[1,5-a]pyrimidinone ( 4e ) derivatives representing three new ring systems were synthesised. Their structure was proved by comparing their uv and cmr spectra with those of the known benzo- and thieno-1,2,4-triazolo[1,5-a]pyrimidinones used as model compounds.     

Novel polycyclic heterocycles. XII. Reactions of 1,2-dihydro-11-(trifluoromethyl)-3H-7H-quino[8, 1-cd] [1,5]-benzoxazepin-3-one with aromatic aldehydes

The Claisen-Schmidt condensation between 1,2-dihydro-11-(trifluoromethyl)-3H,7H-quino-[8,1 -cd][1,5]benzoxazepin-3-one, 1 , and aromatic aldehydes has been investigated. The acid catalyzed reactions yielded the trans-2-benzylidene derivatives, 4 ; the structures and configurations of the group of compounds represented by 4 have been confirmed by pmr in conjunction with the Eu(fod)₃ shift reagent. In contrast, catalysis with sodium hydroxide gave the isomeric 2-benzyl-endocyclic α,β-unsaturated ketones, 3. Finally, the 4 could be isomerized to the corresponding 3 by means of sodium hydroxide. The ir, uv, and pmr spectra of these compounds are discussed.     

On triazoles. V. Synthesis of 1- and 2-R1-3-R2,R3-amino-5-amino-1,2,4-triazoles

The correct isomeric and tautomeric structure of different 1- and 2-R¹-3-R²,R³-amino-5-amino-1,2,4-triazole derivatives prepared from the corresponding N-cyano-N'-R²,R³-S-methyl-isothioureas and the corresponding hydrazines was proved with the help of their ir, uv, ¹H-nmr and ¹³C-nmr spectra as well as the uv spectra of the Schiff bases of an isomeric pair.