Studies in the Preparation of Antimalarials From Pyridine

Abstract

The addition of aryllithium compounds to pyridine followed by air oxidation gives satisfactory yields of several 2-arylpyridines. These are readily oxidized by pcrbenzoic acid to 2-arylpyridine-N-oxides, from which 2-aryl-4-and 6-chloropyridines may be obtained. 2-Arylpyridincs and aryllithiums give low yields of 2,6-diarylpyridines. From three different 2-arylpyridines three antimalarials modelled after the p l a s n~o~l~i n type have been prepared.In earlier investigations in this laboratory (8,9,14,15) For personal use only. ) showed slight activity. Somewhat surprisingly, 2-ptolylpyridine also gave indications of activity. I t inay be significant that the active compounds are vinylogues of a-picoline and a 2-aminop)~idine, in both of which there exists the possibility of a tautolileric shift of hydrogen to the hetero nitrogen atom (19, pp. 32, 91) ; such a possibility has been suggested in explaining the antimalarial activity of atebrin (23) and other compounds (4). The general method of synthesis of these plasmoquin models is illustrated by the example below. The aryllithium was prepared in all cases by direct interaction of the appropriate aryl bromide with lithium. I t has been observed that p-anisyllithium metalates p-bromoanisole so that the reaction of the latter with lithium ordinarily yields a mixture of p-anisyllithium and 2-rnethoxy-5-bromophenyllithium (10). However, if the p-anisyllithium is prepared very rapidly, the extent of metalation is slight and relatively pure p-anisyllithium is obtained. CANADIAA' JOURNAL 01; C H E M I S T R Y . I.OL. 31The addition of an aryllithium to pyridiilegives an N-lithiodihydropyridine (VI), which hitherto has been converted to the desired 2-arylpyridine (VII) by heating above 100" and splitting out lithium hydride (5,25,26,27). Oxidation of the N-lithiodihydro intermediate with dry air gives, particularly in the cases of 2-o-anisyl-and 2-p-anisylpyridine, sig;ificantly improved yields, though in the case of the o-anisyl compound the yield is still low.Since this work was completed, the preparation of 2-phenylpyridine in 60% yield by oxidation with nitrobenzene of 2-phenyl-l,2-dihydropyridine (produced from (VI; R = H) when the reaction mixture is poured into water) has been reported (7).The attempt to prepare 2-phenylpyridine by coupling 2-brornopyridine with phenyllithium gave only a low yield of the desired compound; the isolation of pyridine from the hydrolyzed reaction mixture indicates that a halogennletal interconversion reaction took place, giving bromobenzene and 2-pyridyllithium. A similar reaction with 3-bromopyridine, using n-butyllithium, has been described by Gilman and Spatz (12).The nitration of 2-phenyl-and 2-p-anisylpyridine gave nitro compounds of known orientation (6, 16); however, it was necessary to establish the position of nitration of 2-p-tolylpyridine (VII; R = CH3). This was done by an independent synthesis of the product, 2-(3'-nitro-4'-methylpheny1)-pyridine (VIII; R = CHJ, by the reaction of diazotized 2-nitro-4-aminotolu...

Reaction of pyridine N-oxide with acetic anhydride in anisole and in benzonitrile

“…The identification of 2-acetoxypyridine is based on its mass spectrometric fragmentation pattern which exhibited major peaks at m/e 137, 95, 67, and 43. The mass spectra of the other peaks are: peak 2, m/e 185 (100), 184 (93), 156 (55), 155 (81), 154 (92), 153 (11), 142 (16), 128 (51), 127 (15), 115 (18), 89 (16), 80 (96), 79 (18), 78 (24), 77 (28), 64 (10), 63 (23), 62 (14), 52 (14), 51 (29), 50 (15), 39 (32); peak 3, m/e 185 (92), 184 (100), 156 (33), 155 (59), 154 (55), 143 (10) , 142 (12), 115 (12), 95 (14), 89 (11), 78 (17), 77 (12), 63 (12), 52 (11), 51 (19), 50 (11), 39 (21); peak 4, m/e 185 (100), 184 (9), 154 (8), 143 (39), 142 (20), 115 (8), 63 (9), 51 (10), 39 (11). These spectra are consistent with those expected for methoxyphenylpyridines.…”

Intramolecular nitrene insertions into aromatic and heteroaromatic systmes. Part 7. Insertions into electron-deficient rings

“…Preparative t.1.c. (eluant toluene-ethyl acetate, 3 : 1 v/v) gave three major components A, B, and C. Component A was 2-acetamid0-4',4''-dimethyltriphenylmethane (24), m/e 329; 6 1.9 (3 H, s, CH,CO), 2.3 (6 HI s, CH,), 5.45 (1 H , s, methine), and 6. 8-7.8 (13 H, m).…”

“…3 430, 3 390, 1 720, 1 280, 1 110, and 1040 c1n-l; 6 3.3br ( s , 2 H, exch. D,O, NH,), 3.85 (6 H , s , CO,CH,), 5.5br (1 H , s ) , 6.5-7.1 (4 H, m), 7.1 (4 H d, J 8 Hz), and 7.9 (4 H , d , J 8 Hz); m/e 375 (Mf, loo), 360 (16, M -15), 344 (16), 316 (24), and 240 (20). 4"-dicarboxylate (29).-A solution of the amino-diester (28) (11.6 g) in 2 ~sulphuric acid (150 ml) with 1,4-dioxan (150 ml) was diazo-Diunet hyl tised a t -5 "C using sodium nitrite (2.21 g) in water (15 ml), then the solution was stirred a t -5 "C (30 min).…”

“…C14H14N,0 requires C,69.4;H,5.85;N,11.55%); vmax. (DMSO) 3 450, 1 675, 1 600, 1 580, 1 520, 1 480, 1 360, 1 265, 1 155, and 755 cm-l; 6 2.0 (3 H, s), 3.9 (2 H , s), 7.0-7.4 (6 H, m), 7.9 (2 H, m), 182 (100, M -28), 181 (96), 179 (37), 167 (24), 163 (43), and 0.3br (1 H , s, exch. D20); m/e 242 ( 5 % , iW), 2263-(2-Aminobenzyl)pyridine .-A suspension of the amide (43) (24.1 g) in 10% aqueous sodium hydroxide (550 nil) was boiled under reflux (4 11).…”

Azo Compounds.1 Oxidation of 1,1-Disubstituted Hydrazines. The Synthesis and Oxidation of cis- and trans-1-Amino-2,6-diphenylpiperidine. A New Stereospecific Ring Closure

“…169°). 26 Preparation of cis-and froroj-2,6-Diphenylpiperidine (Va, Vb).27•28 A solution of 500 ml. of absolute ethanol (dried by treating commercial absolute ethanol with Vmth its weight of sodium and distilling) and 80 g. (0.35 mole) of 2,6-diphenylpyridine was prepared under dry nitrogen and after solution, 113 g. (4.90 g. atoms) of sodium metal in large pieces was added as rapidly as possible.…”