Iodinated 5- and 8-Hydroxyisoquinolines as Potential Amebicides

Abstract

OHOR' IX IT', R = I, R' = H X , R = H, R ' = H XI. R = H. R' = Ac XII; R = I,' R' = AC salt of S-amino-8-isoyuiriolinol (V) was treated with potassium iodide and iodine. Treatminerit of the complex reaction mixt,ure with sodium sulfite and sodium hydroxide followed by neutralization gave a precipitate which, on acetylation with acetic anhydride in pyridine, afforded the pure phenol wetmate VI in an over-all yield of 577,. Alkaline hydrolysis of VI gave a quantitative yield of the monoiodopheriol VI1 as the free base; t'he corresponding hydrochloride was obtained by hydrolysis of VI mit'h hydrochloric acid. Iodination of t'his hydrochloride TVith iodine chloride in ethanol3 finally produced the desired ;j,T-diiodo-8-isoquiiiolinol (111) as its hydrochloride in 667, yield. It should be mentioned also that the catalytic reduction (in alkaline solution4) of VI1 gave 8-hydroxyisoquinolinol (YIII) which was identical with the jsoquiriolinol prepared according to Robinson.' The easily accessible 5-isoquinolinol (IX)5 was selected as the starting material for the synthesis of 6,8diiodo-5-isoquiiiolinol (IT). Iodination of IX with iodine chloride in ethanol resulted in a mixture of iodinated products from which a pure monoiodo derivat'ive was isolated in t'he form of its hydrochloride. Struct'ure X mas teritat'ively assigned to this compound which was also characterized as its free base and acetate XI. When the iodination was carried out in 3 N hydrochloric acid instead of ethanol, a product was obtained which, after acetylation with acetic anhydride in pyridine, afforded the pure diiodo acetate XI1 in 53% over-all yield. A41kali~ie hydrolysis of XI1 yielded, quantitatively, the desired 6,8-diiodo-5-isoquinoliiiol (IV). The structural assignments of the compounds described are supported by spectroscopic data (see Experimental Section)., 411 of the iodoisoquiriolines prepared (except XII) were tested against Endaiiioeba histolytica in vitro. I n addition, compounds 111, IT.', arid XI1 were examined for their effect in vivo against the iritracecal E. hisfolyfica I<-9 infection of mearilirig rats using the (2) L. F. Fieser and E. L. hIartin, [ J . Bm. Chem. Soc., 67, 1840 (1935 I ohtained this compound by electrolytic reduction of 5nitroisoquinoline. These authors did not know ahether their starting material n-as 5or 8-nitroisoquinoline. From the work of F. T . Tyson [ibid., 61, 183 (1939)], it was concluded that the compound in question was 5-nitroisoquinoline; Dewar and P. 31. hlaitlis, J . Chem. Soc., 2,521 (1957). hI. J( 3 ) Cf.

A Domino Michael–Dieckmann-Peterson Approach to the Synthesis of Substituted Hydroxyquinolines and Hydroxyisoquinolines

“…[1][2][3][4] In particular, hydroxyquinoline and hydroxyisoquinoline moieties are recognised as important structural elements in many pharmacologically important natural and non-natural products. [5][6][7][8][9][10][11] Although a number of synthetic routes have been developed for the synthesis of functionalised hydroxyquinolines and hydroxyisoquinolines, it is a significant challenge to explore a new approach for the synthesis of this class of compounds. In this context we anticipated that Michael-Dieckmann-Peterson type domino reaction of azaphthalides 1 with a silyl-substituted conjugated olefin 2 would lead to substituted 8-hydroxyisoquinolines and 5hydroxyquinolines 5 via spontaneous Peterson elimination from the cis-hydroxysilane 3 (Scheme 1).…”

The Partial O‐Demethylation of Aromatic‐Substituted 3,4‐Dihydroisoquinolines

“…Schenker of these Laboratories. [16] but not with 6-methoxy-2-methyl-l,2,3,4-tetrahydroisoquinoline4) [17]. Similarily, the monophenol 10 was transformed via 27-30 to afford a monomethoxy tetrahydroisoquinoline which was identical with 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (31) ") [18] but not with the 7-methoxy isomer4) [19].…”

“…The precipitate was filtered, the filtrate evaporated, the residue dissolved in benzene, and acidified with ethanolic hydrogen chloride. The crystals were collected and recrystallized from a mixture of methanol and ether to give 245 mg (73%) of 8- [16]; mixed m.p. 157-164" with an authentic specimen*) of 6-rnethoxy-Z-methyl-l,Z, 3,4-tetrahydroisoquinoline') [17] [18]; mixed n1.p.…”

“…: d 2.86 (GCH,), 3.10, 3.35 (CH,CH,) 3.79 (OCH,), 4.13 (CH,-l), 6.80, 6.87, 7.25 (CH-5,CH-6,CH-7); identical in mixed m.p., thin layer chromatography, and NMR. with an authentic specimen4) of 26.HC1 [16]; mixed m.p. 157-164" with an authentic specimen*) of 6rnethoxy-Z-methyl-l,Z, 3,4-tetrahydroisoquinoline') [17].…”

“…C,,H,,NO,~HCl (229.70) Calc. C 57.52 H 7.02% Found C 57.29 H 7.09% Alternatively, a mixture of 2.2 g (0.01 Mol) of 3-chloro-5,8-dimethoxy-isoquinoline(16)…”