Earlier work in these laboratories on the heterotricyclic system 2,6-dioxa-10-azatricyclo[5.2.1.04,10]-decane, formed from 1,4-diketones and 2-amino-1,3-propanediols by a product-water-azeotroping procedure, was extended with the synthesis of analogous compounds, e.g., the 1,4,7-triethyl-, 1,7-dimethyl-4-isopropyl-1,7-diethyl-4-isopropyl-, 1,7-dimethyl-3- and 4-phenyl- compounds. The 1,7-dimethyl heterotricycle, the kinetically-controlled product, was accompanied by the thermodynamically-controlled product, 2-(2,5-dimethyl-1-pyrryl)-1,3-propanediol. The 1,7-diethyl heterotricycle was also accompanied by the isomeric pyrrole as were the 1,7-dimethyl-3- and 4-phenyl compounds. A scheme postulating a common intermediate is presented. The interesting analogous compounds, 1,7-dimethyl-2-oxa-6-thia-10-azatricyclo[5.2.1.04,10]decane, 1,4,7-trimethyl-2,6-dioxa-11-azatricyclo[5.3.1.04,11]undecane and 11-hydroxymethyl- and 11-methyl-9,13-dioxa-14- azatetracyclo[6.5.1.02,7 011,14]tetradeca-2,4,6-triene were also prepared. The syntheses in good yields of a considerable number of moderately to severely sterically crowded 1,2,5-trisubstituted pyrroles by means of modifications of the Knorr-Paal condensation are described in this work. The classical procedure succeeded in moderately sterically-crowded cases, e.g., R2=R5=Me, R1=i-Pr; R2=R5=Et, R1=i-Pr. A product-water azeotroping procedure succeeded in more severely sterically-crowded cases, e.g., R2=R5=Et, R1=i-Pr; R2=R5=Me, R1=Me3-CCH2; R2=R5=i-Pr, R1=PhCH2. Highly sterically-crowded pyrroles, e.g., R2=R5=Me, R1=t-Bu, PhSO2, adamantyl, PhCH2CMe2; R2=R5=Et, R1=t-Bu; R1=R2=R5=i-Pr; R2=R5=t-Bu, R1=Me, Et, PhCH2, were obtained using titanium tetrachloride as a Lewis acid catalyst and as a water scavenger. Infrared spectra of the reacting mixtures provided evidence pertinent to the mechanism of the reaction, which is discussed. All of the pyrroles described above were easily catalytically hydrogenated over platinum oxide or rhodium-on-alumina under low hydrogen pressure to the corresponding pyrrolidines. A study into the stereochemistry of the hydrogenation, using 1-benzyl-, 1-ethoxycarbonylmethyl-, and 1-(2,2,2-trifluoroethyl)-2,5-dialkylpyrroles, showed that when R2=R5=Me, Et, R1=PhCH2; R2=R5=Me, R1=CF3CH2 a mixture of cis- and trans-2,5-dialkylpyrrolidines was obtained. Only the cis-isomer was obtained when R2=R5=Me, Et, R1=CH2CO2Et; R2=R5=i-Pr, R1=PhCH2. Several of these heterotricyclics, pyrroles, and pyrrolidines were submitted for pharmacological testing. Results for these compounds as hypotensive agents are presented.
College and Department
Physical and Mathematical Sciences; Chemistry and Biochemistry
BYU ScholarsArchive Citation
Burnham, Weldron Severin, "Syntheses via modifications of the Knorr-Paal procedure :|bA. Derivatives of 2,6-dioxa-10-azatricyclo[126.96.36.199[superscript 4,10]]decane ; B. Highly sterically crowded 1,2,5-trialkylpyrroles and pyrrolidines" (1969). Theses and Dissertations. 8181.
Pyrrolidine, Hydrogenation, Hypertension, Chemistry, Organic, Research