Pál Sohár

Synthesis, Structure, and in vitro Antitumor Activity of Some Glycoside Derivatives of Ferrocenyl-Chalcones and Ferrocenyl-Pyrazolines†

Some new glycosides of 3‐ferrocenyl‐1‐(4′‐hydroxyphenyl)‐prop‐2‐en‐1‐one were prepared and transformed into the corresponding pyrazoline and pyrazole derivatives. Using methyl‐hydrazine, formation of regioisomers was observed. DDQ was found to be a mild and efficient reagent for the pyrazoline‐pyrazole dehydroaromatization process. The structure of the new compounds was proved by IR and NMR spectroscopy. The in vitro antitumor activity of the substances was investigated against human leukemia (HL‐60) cells by the MTT method. Among these new compounds some chalcone derivatives (3 a, 3 b, 5 a, and 5 b) showed attractive in vitro antitumor effects on human leukemia cells. These molecules contained ferrocenyl moieties and a p‐hydroxy‐phenolic ring or a size‐independent apolar substitution of that.

Synthesis and pharmacological study of new 3,4-dihydro-2H,6H-pyrimido-[2,1-b][1,3]thiazines

Summary A series of racemic pyrimido-thiazine derivatives was synthesized and many of their in vivo activities found to be comparable to acetylsalicylic acid and aminophenazone in an antiinflammatory model and an antipyretic test. Analogues 7a and 7e are the most potent in rat carrageenin and yeast fever assays. These compounds did not inhibit prostaglandin biosynthesis in vitro.

Neighboring group participation ☆: Part 15. Stereoselective synthesis of some steroidal tetrahydrooxazin-2-ones, as novel presumed inhibitors of human 5α-reductase

During the alkaline methanolysis of 3beta-acetoxy-21-chloromethyl-pregn-5-ene-20beta-N-phenylurethane, and its p-substituted phenyl derivatives, cyclization occurs, in the course of which 17beta-[3-(N-phenyl)tetrahydrooxazin-2-on-6-yl]androst-5-en-3beta-ol and its p-substituted phenyl derivatives are formed. The cyclization takes place with (N(-)-6) neighboring group participation. Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids yielded the corresponding delta4-3-ketosteroids. The structures of the new compounds were proved by IR, 1H and 13C NMR spectroscopy, using up-to-date measuring techniques such as 2D-COSY, HMQC, and HMBC. The inhibitory effects (CI50) of the delta4-3-ketosteroids on 5alpha-reductase were studied.

Stereochemical studies 83 saturated heterocycles 76. Preparation and conformational study of partially saturated 3,1-benzoxazines, 3,1-benzoxazin-2-ones and 3,1-benzoxazine-2-thiones

Abstract The cis - and trans -2-amino-4-cyclohexene-1-carboxylic acids 1 and 3 react with imidates to give the condensed-skeleton, bicyclic cis - and trans -pyrimidin-4-ones 8 and 9 . The amino acids 1 and 3 were reduced to the cis -and trans -1, 3-aminoalcohoIs 6 and 7 , which were cyclized by means of imidates to the bicyclic tetrahydro-4 H -3,1-benzoxazines 10 and 11 , or were converted, via the corresponding carbamates 14 and 15 into the tetrahydro-4 H -3,1-benzoxazin-2(1 H )-ones 16 and 17 . The 2-thioxo analogues 18 and 19 were prepared by cyclization of the dithiocarbamates obtained from the aminoalcohols 6 and 7 by treatment with carbon disulphide. The trans -aminoalcohol 7 and its saturated analogue reacted with p -chlorobenzaldehyde to furnish the hexahydro 13 and octahydro-4 H -3,1-benzoxazine 13a , respectively. 1 H and 13 C NMR studies showed that, similarly to the earlier-investigated analogues containing oxygen or unsubstituted nitrogen at position 1, the synthesized cis isomrs 8 , 10 , 16 and 18 occurred as the preferred conformer in the heterocyclic twist inverse form of N -inside type ( quasiaxial C 6 -N bond) (B). In the trans isomers containing a saturated C-2 atom ( 13 and 13a ), H-2 and H-6 are in cis relative positions.

Stereochemical studies-XXXIII.1 Saturated heterocycles-IX2: Synthesis and conformations of stereoisomeric cis- and troans-tetramethylene- and pentamethylenedihydro-1,3-oxazines

Abstract By the reaction of cis- and trans-2-aminomethylcyclohexanol (1, 2), cis- and trans-2-hydroxymethyl-cyclohexylamine (3,4) and the homologous cycloheptane derivatives (5-8) with ethyl p-chlorobenzimidate (11), cis- and trans-5,6-tetramethylene- and pentamethylene-2,3,5,6-tetrahydro-4H-1,3-oxazines (12,13,16,17) and cis- and trans-4,5-tetramethylene- and pentaimethylene-4,5-dihydro-6H-1,3-oxazines (14, 15, 18, 19) were prepared. The amidine intermediate of the ring-closure reaction was isolated, and the mechanism of the acid-catalysed reaction is discussed. It follows from the 1H NMR data that in the preferred conformations of the cis-tetramethylene-tetrahydrooxazines the methylene group of the hetero ring is equatorial and the hetero atom (O or N) axial. In contrast, the conformation equilibria of the cis pentamethylene derivatives, in accordance with earlier X-ray analysis, are shifted towards the conformer containing the methylene group in isoclinal and the hetero atom in equatorial position. The preferred conformations 12a and 14a of the tetramethylene derivatives 12 and 14 were also determined by X-ray crystal analysis.

Stereochemical studies — 79 synthesis and kinetic study on the retrodiene decomposition of norbornene-condensed 1,3-oxazin-4-ones

The cis-cxo- amino acid c with norbornene skeleton was converted into 2-aryvl-cis-cxo-1,3-oxazin-4-ones 5a-d. These compounds, similarly to the diendo isomers 1a-d studied by us earlier, undergo retrodiene decomposition under mild conditions to give 2-aryl-62-l,3-oxazin-6-ones (2a-d) in 50-60% yield. The ratio of the decomposition rate constants of the tricyclic diendo and diexo-1,3-oxazin-4-ones, measured in toluene solution, is about 2.

Stereochemical studies—76 saturated heterocycles—63 : synthesis of cis- and trans-n-methyl- and n-benzyl-4.5- and 5,6-tetramethylenetetrahydro-1,3-oxazines; an x-ray study of n-benzyl-cis-4,5-tetramethylenetetrahydro-1,-3-oxazinium- picrate

Abstract - The corresponding cis - and trans-N -methyl- and N -benzyl-5,6- and 4,5-tetramethylenetetrahydro-l,3-oxazines (5a,b-8a,b) were synthesized from cis - and trans-N -methyl and N -benzyl-2- aminomethyl-1-cyclohexanols 1a,b,2a,b , from cis - and trans-N -methyl- and N benzyl -2-hydroxymethyl-1-cyclohexylamines (3a,b,4a,b) by reaction with formaldehyde. The aminoalcohols 1a,2a,3a,b and 4a,b were prepared in considerably higher yields than in earlier procedures. NMR spectroscopy showed that the cis isomers of the synthesized oxazines were conformationally homogeneous in solution, and their preferred conformation (inside or outside) depended on the steric requirement of the groups attached to the anellation points, whereas a bulky C-2 substituent had no influence on the predominant conformation. The structure of N -benzyl- cis -4,5-tetramethylenetetrahydro-1,3-oxaziniumpicrate (7b) . determined by X-ray diffraction analysis, was in agreement with the predominant N-outside conformation of the corresponding base, established by means of NMR spectroscopy.

E-2-Benzylidenebenzocycloalkanones. Stereostructure and NMR spectroscopic investigation

Abstract Series of E-2-benzylideneindanones (a), -tetralones (b) and -benzosuberones (c) with OCH3 (2–4), NO2 (5–7) and F (8–10) substitutions (ortho, meta and para) on their benzylidene moiety were synthesized by aldol condensation of the appropriate aldehydes and benzocyclanones. The stereostructure (configuration and conformation) and the electronic properties (conjugation of the enone moiety with the aromatic rings) of the compounds were studied by IR, 1H and 13C NMR spectroscopy including also 2D-HSC, DNOE and DEPT measurements. Ab initio calculations were carried out to corroborate the experimental findings.

Saturated heterocycless—35 : Synthesis and conformational analysis of stereoisomeric 2-oxo- and 2-thioxo-cis- and trans-5,6-trimethylene-3,4,5,6-tetrahydro-1,3-oxazines

Abstract cis- and trans 5,6-Trimethylene-3,4,5,6-tetrahydro-1,3-oxazin-2-ones ane 2 thiones (11–20) were synthesized from cis and trans-2-aminomethylcyclopentanols (6–10) by reaction with urea ethyl chloroformate, carbon disulphide or thiophosgene. The cyclization reactions were also successful with the trans-amino-alcohols, at variance with earlier literature data relating to 1,2-disubstituted 1,3-bifunctional trans-cyclopentane derivatives X-Ray diffraction analysis of trans-5,6-trimethylene-3,4,5 6-tetrahydro-1,3 oxazine-2-thione (17) shows that the exocyclic CXXXS sp2 bond takes part in a co-planar delocalized pπ-pπ bond system formed on the S(10) O(1), N(3) and C(2) atoms and consequently both the C(2)-N(3) [1.304(7)a] and C(2)-O(1) [1.337(7)a] bonds gain some multiple bond character. The endocyclic bond angles at C(2) and N(3) are significantly opened, compared with those in related heterocycles. Of the bonds in the six membered hetero ring, C(5)-C(6) is significantly shortened [1.448(9)a] The remarkable ring-closure reaction of the trans cyclopentane derivatives can be explained by the above findings. 1H NMR data on compounds 11–20 suggest conformationally homogeneous systems and the predominance of the O-inside conformers of the cis isomers.

Stereochemical studies—75 : Saturated heterocycles—62. connection between the diastereoselectivity and the dominant conformation in the formation of condensed- skeleton 1,3-oxazines, first X-ray diffraction evidence of N-outside conformation

Abstract The rapid, spontaneous epimerization occurring at the C(2) chirality centre of a new diastereomeric (r-4,c-2,c-5)-2-(p-nitrophenyl)-3-methyl-4,5-tetramethylenetetrahydro-1,3-oxazine led to the conclusion that the configuration at C(2) of the bicyclic 1,3-oxazines formed by the cyclization of alicyclic 1,3-aminoalcohols with aldehydes is determined by the dominant conformation of the product. The first X-ray diffraction evidence is given for the N-outside conformation of compounds of this type.