Phenanthrylalkanoic acids, II: Syntheses and Antiinflammatory Activity of 2‐, 3‐ and 9‐Phenanthryl‐ and 9‐Chloro‐3‐phenanthrylacetic Acids

Abstract

Application of Willgerodt-Kindler reaction to the phenanthryl ketones la-d led to the thiomorpholides 2a-d, hydrolysis produced the acids mentioned in the title. An alternative route, of much better yield, was based on Phenanthrylalkansauren, 11: Synthese und entzundungshemmende Wirksamkeiten von 2-, 3-und 9-Phenanthryl-und 9-Chlor-3-phenanthrylessigsiiuren the oxythallation of la-d to give the methyl arylacetates 4 -4 which were Our interest for the exploration of the antiinflammatory properties of phenanthrylalkanoic acids') led us to perform the synthesis and pertinent pharmacological tests of the 2-phenanthrylacetic (3a), 3-phenanthrylacetic (3b), 9-phenanthrylacetic (3c) and 9-chloro-3-phenanthrylacetic (3d) acids.For the preparation of these compounds the clasical Willgerodt-Kindler reaction'), was first taken into consideration (Scheme l), since the acetyl derivatives la-d needed as starting materials would be commercially available and/or can be prepared easily3! None of the crude products from the Willgerodt-Kindler reactions of la-d solidified spontaneously and generally failed to crystallize from any solvent. Once purified by column-chromatography they gave TLC homogeneous materials that had to be recrystallized several times until sharp melting samples could be got. Only the thiomorpholide 2a had been previously reported by Gore et aL4); they quoted for it a m. p. 32 "C lower than that obtained by us. Identity and purity of our product 2a was undoubtfully checked by analytical and spectroscopic means (IR, NMR, MS); the product referred to by G o r d as 2a, if pure, could only be a polymorphism of ours. The barrier of the rotation around the C-N bond in simple thioamides can be as high a s 25 KcaI/mols), giving rise even to i?/E isomerism at room temp. in certain cases6), but such a situation is prevented here by the symmetry of the morpholine ring.'H-NMR spectra of all our thioamides showed the presence of four groups of signals, each for every methylene group of the morpholine moiety, occasionally seen as four slighty distorted triplets, though often the two central ones were mixed and are given as a multiplet. Differences in chemical shifts between these signals are attributed to the fact of methylene groups being a-with regard to the N or 0 atom, and s-cis cq s-trans with regard to the arylmethyl moiety, while virtual multiplicity and coupling constants point out to the near equivalence of both protons of each methylene group, thus meaning a fast chair-chair interconversion. On the other hand, MS of both 2a and 2b were very similar, indicating that their most important fragmentation patterns are due to their common aliphatic moiety. Fragmentations giving rise to their most prominent peaks are depicted in Scheme 2.Acid hydrolysis of the thiomorpholides 2a-d led to the corresponding acids 3a-d, with low to moderate yields (alkaline hydrolysis of 2b gave a poorer yield of 3b): these yields are referred to the products isolated after a first recrystallization or a reprecipitation from an alkaline extra...

Phenanthrylalkanoic acids, V: A useful access to α‐methylphenanthreneacetic acids

“…Oxidative rearrangement of acetylarenes by means of thallium trinitrate (TIN) in acidic methanol leads cleanly and almost quantitatively to the methyl arylacetates 1 2 ), and we have already reported the use of this approach for the preparation of the phenanthreneacetic acids 2a-d in excellent yields 3 ). Since it had been established that some arylacetic acids can be directly a-methylated by Me2S04 in the presence of KOH under Phase Transfer Catalysis conditlons", it occurred to us that the two procedures could be combined to achieve 3 from the corresponding acetylarene in a shorter, simpler sequence with better yield than the classical route.…”