The Search for Superior Drugs for Tropical Diseases. Ii. Synthetic Studies in the Quinoline and Phenan-Throline Series. Skraup and Conrad-Limpach-Knorr Reactions

Abstract

In continuation of our studies in this field (1, 2), we have investigated the serviceability of certain familiar reactions for the synthesis of a number of quinoline, isoquinoline, and phenanthroline derivatives in which we were interested. The results obtained with the Skraup and the Conrad-Limpach-Knorr procedures are described in the pages which follow. Some phenanthroline derivatives have been claimed (3,4,5) to possess analgesic properties, others (5) to exhibit bactericidal activity. Some have been prepared (6,7,34) for pharmacological testing in other directions. The 1,10-phenanthroline (XXXI) is best known from the work of Walden, Hammett, and Chapman (8), who called attention to its ferrous cation complex as a remarkably sensitive oxidation-reduction indicator.The 1,8-phenanthrolines (XXXIII) have been studied but little. The onlyinvestigation on record appears to be that of Borsche and Wagner-Roemmich (9), in which the Doebner pyruvic acid reaction was applied to 5-aminoisoquinoline.To determine the possible availability of some simple initial compounds, certain preliminary syntheses were carried out from guaiacol and vanillin as raw materials (See Flow Sheets la and lb).

An Expedient Phase Transfer Catalyst‐Mediated Synthesis of 2‐Alkyl/Aryl‐1,8‐phenanthrolines

“…A single product was formed. It was isolated in 68% yield after a simple work‐up, followed by chromatography over a column of silica gel, and identified as the known 2‐methyl‐1,8‐phenanthroline 3a by comparison (melting point and supportive 1 H and 13 C NMR data). The reaction is represented in Scheme .…”

“…Light brown needles (PE–DCM), 0.167 g (86%), mp 98–99°C (lit. mp [9] 97–99°C); IR: 1585, 1507, 1440, 1383, 1030, 854, 812, 730 cm −1 ; 1 H NMR: δ 2.84 (s, 3H, CH 3 ), 7.48, 7.75, 7.81, and 8.09 (d, each, 1H, H‐3, H‐5, H‐6, and H‐4, respectively, J = 8.5 Hz), 8.81 and 9.02 (d, each, 1H, H‐9, and H‐10, respectively, J = 5.5 Hz), 9.27 (s, 1H, H‐7); 13 C NMR: δ 25.7 (CH 3 ), 117.7 (CH‐10), 124.4 and 124.8 (CH‐3,6), 126.4 (C‐4a), 127.2 (CH‐5), 128.8 (C‐6a), 136.0 (C‐10a), 136.4 (CH‐4), 144.7 (C‐10b), 145.6 (CH‐9), 151.3 (CH‐7), 159.1 (C‐2); GC EI‐MS: m / z (%) 194 (M + , 100), 193 (40), 167 (26), 166 (13). Anal.…”

“…As regards their syntheses reported after the early synthesis of 2,3‐diphenyl‐1,8‐phenanthroline by the Doebner pyruvic acid reaction 8, nearly all the methods suffered from cognizable shortcomings like low yields (e.g., 5%) of the products and the use of strong mineral acid (e.g., conc. H 2 SO 4 ; refs.…”

“…H 2 SO 4 ; refs. 9 and 10) and toxic arsenic compounds (e.g., H 3 AsO 4 ; refs. and ), and As 2 O 5 [11].…”

“…9 and 10) and toxic arsenic compounds (e.g., H 3 AsO 4 ; refs. and ), and As 2 O 5 [11]. A latter, somewhat improved but multistep synthesis of 3,4‐disubstituted 1,8‐phenanthrolines notwithstanding, this situation called for the development of a short synthesis which would be void of these difficulties.…”