Angela E. Szabó

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 — 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.

Phenyl-substituted cyclopentane- and cyclohexane-cis-fused-1,3-oxazines and -1,4-oxazepinones. Preparation and stereochemical study

Abstract The cycloadditions of cyclopentene and cyclohexene with benzonitrile oxide (BHO) yielded isoxazolines 1 and 2, which were reduced to 1,3-aminoalcohols 1 and 2 with LAH and cyclized to cycloalkane- cis -condensed 4-phenyl-1, 3-oxazines 3 and 4 5 , 6 . From the aminoalcohol 7 obtained by Na/EfcOH reduction of 2, the diastereomeric 4-phenyloxazine derivative 8 was obtained. 3 and 4 were transformed through carbamates to cis-5,6-trimethylene- and cis-5i6-tetramethylene-1, 3-oxazin-2-ones 3 and 10, while the analogous 2-thiones 7 8 and 9 10 were prepared via dithiocarbamates. With phenyl isothiocyanate, furnished the 2-phenylimino-1,3-oxazine 11 12 , while 1,4-oxazepinones ( 13 14 15 16 ) were obtained with ethyl chloroacetate an3 2-chloropropionate. The structures of the new compounds, Including the configurations and preferred conformations, were elucidated by means of ir, 1H and 13C-nmr investigations.

Saturated heterocycle-condensed diphenylisoindolones: Fused-skeleton tetrahydro-1,3-oxazines, oxazolidines and imidazolidines

Abstract The addition of benzene to cis -4-cyclohexene-1,2-dicarboxylic anhydride yielded c -2-benzoyl- t -5-phenyl- r -1-cyclohexanecarboxylic acid (72%), or in another reaction, the 4-phenyl isomer (67%). With bifunctional reagents, saturated tricyclic or partially saturated tetra- and pentacyclic hetero derivatives containing an isoindolone moiety were prepared. The cis → trans isomerization in the ring closures is promoted by enolization and by the two close-lying phenyl groups. The stereostructures of the products were determined via 1 H and 13 C NMR spectroscopy.

Structures of saturated azeto[1,2-a][3,1]- and azeto-[2,1-b][1,3]benzoxazines prepared by addition of chloroacetyl chlorides to cyclohexane-condensed dihydrooxazines

Saturated cis and trans 3,1- and 1,3-benzoxazines (1-4) reacted with chloroacetyl chlorides to yield azeto[1,2-a][3,1]- and [2,1-b][1,3]benzoxazines (5, 6, 8, 9a,b). In one case, the addition took place with partial cis-trans inversion of the starting compound. Adduct (7), containing two condensed 1,3-oxazine rings, was also isolated. The stereostructures of the new compounds were proved by 1 H- and 13 C-nmr spectroscopy, with NOE measurement data. The reaction mechanism is discussed

Stereochemical studies. Part 86. Saturated heterocycles. Part 81. Preparation of new thiouracils via retrodiene decomposition of methylene-bridged quinazolone thiones

endo- and exo-Norbornene (1) and (3) and norbornane (2) and (4) amino acids and isothiocyanates give methylene-bridged 2-thioxohexahydro-(10) and (11) and octahydro-(12) and (13)-quinazolin-4-ones. Compounds (10) and (11) decompose in a retro-Diels-Alder reaction when heated to melting, to give new 3-substituted thiouracils (14a–e); no convenient general suitable method was previously known for the preparation of these compounds.

Synthesis and steric structure determination of 9b-p-tolylperhydrothiazolo[2,3-a]isoindolone isomers☆

Abstract The reaction of cis -2-( p -methylbenzoyl)-1-cyclohexanecarboxylic acid ( 1 ) and 2-aminoethanethiol furnished three 9b- p -tolylperhydrothiazolo[2,3-a]isoindolone isomers ( 2–4 ). The steric structures of the saturated cis ( 3, 4 ) and trans ( 2 ) isoindolones were determined by 1 H and 13 C NMR spectroscopy, including DNOE, DEPT and HSC measurements. In the two cis isomers, the steric positions of the tolyl group are different. The cis → trans isomerization can be rationalized by enolization of the starting oxoacid 1 .

Preparation and steric structure elucidation of partially saturated isoindolo [2,1-a][3,1]benzoxazinones and -[1,2-b][2,4] benzoxazepinones

Abstract The reactions of 2-carboxybenzaldehyde (1) with different 1,3- or 1,4-aminoalcohols (2a–i, 3a,b) were used to prepare partially saturated terra- and pentacyclic compounds containing a condensed 1,3-oxazino- or oxazepinoisoindolone moiety and one terminal saturated carbocycle. Isoindolo[2,1-a][3,1]benzoxazinones (4a-d, 6, 7), stereoisomeric isoindolo[l,2-b][2,4]benzoxazepinones (5a–c) and pentacyclic derivatives (4e–g) were obtained. The diastereomers 5a–c differ in the ring annotation or in the positions of the NCHO hydrogens and annelational hydrogens. The stereostructures of these compounds were elucidated by means of 1 H and 13 C NMR spectroscopy, including DNOE, DEPT and 2D-HSC measurements.

Structures of pyrrolo-1,3-heterocycles prepared from 3-aroylpropionic acid and cyclic aminoalcohols: An NMR and X-ray diffraction study

By the reaction of 3-(4-chlorobenzoyl)propionic acid 1 with 1,2- and 1,3-bifunctional compounds, new condensed heterocycles have been prepared. Thus, the reaction of 1 with hydrazine gave the pyridazin-3-one 2 and with ethylenediamine, the pyrrolo[1,2-a]imidazole 3 was formed. Reaction of compound 1 and 2-aminoethanol yielded the pyrrolo[2,1-b]oxazolidinone 4 and the reaction with 3-aminopropan-1-ol resulted in the pyrrolo[2,1-b][1,3]oxazinone 5. With o-aminothiophenol tricyclic pyrrolo[2,1-b]benzothiazolone 6 was prepared. In comparison with 4–6, the structure of the new tri- and tetra-cyclic compounds 7–14 are discussed. With the starting oxoacid 1, the cyclic and bicyclic aminoalcohols gave the following fused heterocycles: cis- and trans-2-(hydroxymethyl)cyclohexane- and cyclohex-4-ene-amines yielded pyrrolo[1,2-a][3,1]benzoxazinones 7–10, diexo-3-(hydroxymethyl)bicyclo[2.2.1]heptane-2-amine and hept-5-ene-2-amine yielded the diexo (11 and 12) and diendo (13 and 14) methylene-bridged pyrrolo[1,2-a][3,1]benzoxazinones. The structures of the compounds were proved by 1D 1H and 13C NMR spectroscopy, NOE difference spectroscopy and several different homo- and hetero-nuclear multipulse techniques (COSY, NOESY, HETCOR). The 1D 1H NMR spectra were analysed by iterative spin-simulation using PERCH-software. Many interesting long-range couplings were found. Some aid for structural elucidation was gained from molecular modelling calculations. The crystal structures of 7, 9–11, 13 and 14 elucidated from the X-ray diffraction measurements do not differ significantly from the solution structures.

Application of t-2-benzoyl-t-5-phenylcyclohexane-r-1-carboxylic acid for the preparation of saturated isoindole-fused heterocycles

t-2-Benzoyl-t-5-phenylcyclohexane-r-1-carboxylic acid 1 reacts with cis-2-aminocyclohexanemethanol to give the saturated cis-isoindolo[2,1-a][3,1]benzoxazine 2. Reaction of 1 with trans-2-aminocyclohex-4-enemethanol yields three diastereomeric isoindolo derivatives 3a–c. Cyclization of 1 with 1,3-diaminopropane results in a diastereomeric mixture of cis-pyrimido[1,2-a]isoindolones 4a,b. With di-endo-norbornane aminoalcohol, 1 reacts to yield a mixture of cis- and trans-annelated diastereomers 5 and 6. In its reactions with di-exo-norbornane and norbornene aminoalcohols, 1 isomerizes to give cis-condensed isoindolo derivatives 7–10. After isolation, the structures were established by 1H and 13C NMR spectroscopy, with up-to-date measuring techniques such as NOEDIF, DEPT, HMQC, 2D-NOESY, 2D-COSY and HMBC and, for 10, X-ray measurements. The results show that, with two exceptions, the trans acid 1 undergoes isomerization to give cis-condensed products.