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RXTISCCRETO~~Y 3-r~UIPLO-~-CHHORIASOSES
277
3-Amino-4-chronianone Hydrochlorides D. HUCKLE, I. _\I. L O C K N ~ .Hm~u,-\I. IV~IIGHT Keaiuic.h Dcpai tirctnf, l'uikc, Davis ant1 Compuny, Hounalow, JILddlesex, England
Receited August 9, 1968 T h e si iitlieiih of mrie j-a,,iiiio-4-chromaiione hydrochlorides described.
I n spite of the extensive literature on 4-chromanones and flavanones, a t the time this work was undertaken little attention had been paid to 3-amino-4-chromanone hydrochlorides. I n fact, the claim' to have prepared 3-diethylamino-4-chromanone had been shown to be incorrect.*r3 The synthesis of such compounds for biological evaluation was, therefore, undertaken. 3-Amino-4-chromanone hydrochloride was readily obtained from 4-chromanone 0-(p-tolylsulfony1)oxime by the Keber rearrangement. A similar reaction had been described with flavanones4and since this work mas completed it has also been reported with 4-chromanones. Biological examination of 3-amino-4-chromanone hydrochloride showed that it was an active gastric secretory inhibitor. The series of related compounds described in this paper was therefore prepared but little activity was shown by other members of the series. Chemistry.-The preparation of 4-chronianones1 their conversion to 0-(p-tolylsulfonyl)oximes,and the method used to effect the rearrangement of the latter to 3-amino-4-chromanone hydrochlorides are described in the Experimental Section. S o t unexpectedly, 3-amino-4-chromanone hydrochloride was unstable in base, an intermolecular Schiff's base being among the products of the reaction. The ether linkage of the chromanone ring, however, showed a high degree of stability to acid. Evidence for this, descriptions of the contrasting reactions of 3-amino-4chromanone hydrochloride with potassium cyanate and potassium thiocyanate, and some observations of the formation of cis and trans isomers of 3-amino-2methyl-4-chromanone hydrochloride are also given in the Experimental Section. Pharmacology.-The gastric antisecretory properties of many of the aminochromanone hydrvchlorides were studied by Dr. Paul Bass using a previously described technique.6 The results are given in Table 11. Experimental Section' Phenoxypropionitriles (from the reaction of phenols and acrylonitrile) and phenoxypropionic acids (either by hydrolysis of the appropriate nitrile or from the appropriate phenol and p(1) J. Colonge and A. Guyot, Bull. SOC.C h i m . France, 329 (1958).
( 2 ) P. W. Feit, A c t a Chem. Scand., 18,2.101 (1964). (3) I. hl. Lockhart and E. hf. Tanner, J . Chem. Sac., 3610 (1965). (41 C. O'Brien, E. AI. Philtiin, 19, 373 (1963).
S.Ushiorla, and T. 8.Wheeler. Tetrahedron,
( 5 ) N. V. Dudykina and V. A . Zagorevskii, J . Oru. Chem. U S S R , 2, 2179
(lYti6).
(6) K. F. Meyer, B. L. Curnmings, P. Bass, a n d H. 0. .J. Collier, J . M e d . Chem., 8 , 515 (lYS5).
ab
potential inhibitors of gastric secretion is
propiolactorie) were prepared by standard methods. 3 4 2 , ; Dich1oropheiioxy)propionic acid [white needles, mp 14.5-146" (from C6H6-petroleum ether) Anal. (C$H&1~03)C, HI and :3[(6-chloro-~n-tolyl)oxy]propionicacid [whitmeneedles, mp 121122" (from C&-pf?trOkLlm ether) Anal. ( C I O H I I C ~C, O ~HI ) do not appear to have been previously described. It has been notcd both in the case of 3-(2,5-dichlorophenoxy)propioriicacid aiid with 3-!,n-iiitropheiioxy)propioiiic acid that t,he partition coefficient of t.he acid in Et&saturated xaHCO3 favors the Et',O phase and yields are improved considerably if extraction into NaHCO3 is avoided. 4-Chromanones.-Cyclizations of phenoxypropionitriles or phenoxypropionic acids in the presence of a dehydrating agent or of phenoxypropionyl chlorides under Friedel-Craft conditions were used to prepare 4-chromanones unsubstituted in the 2 posit,ion.',B The following is an illustration of the preparation (based on the method of Cavill, et uL9)of 2-methyl-4-chromanone wing the Fries rearrangement. AlC13 (130 g, 1.1 moles) was added in portions to phenyl crotoriate (162 g, 1 mole) in petroleum ether (bp 80-100') (1100 ml). Bft.er allowing a 15-min induction period, the mixture was refluxed for 24 hr. (The mixture turiied hr, arid set solid after 5-6 hr.) .4 mixture of ice HC1 (300 ml) was added, t,he p e h l e u m e t h e r was separated, and the aqueous phase was extracted with CsH6. The and the organic phase was washed (HzO) and dried (NaPCOB), solvent was removed to give a dark oil (85 g) which, on dist.illation, afforded a mixture of 2-methyl-4-chromaiioiie, unchanged starting material, and some uncyclized intermediates (from both ortho and para migration). The latter were removed by washing with 2 AYXaOH and t.he 2-methyl-4-chromanone was isolated by distillatiori or as it,s oxime (50 9). The above conditiolis afforded 28.57, of the chromanone, 5.23rh unchanged startiiig material, and 6.4%, of uncyclized int,ermediates. \.arious other conditions were tried. Longer reflux times reduced the yield. Reduction of the time of reflux to 5 hr had little effect on the yield of 2-met~hyl-4-chromanone althoiigh there ivas a considerably higher amount, of iuichanged starting material. Iiicreasirig the proportion of AlC13 to 1.6 JI gave a 2645 yield of 2-met,hy1-4-chromaiioue aiid apparently no uiichanged crotonate, but a further increase i n the AlC1, t,o 2.2 JE gave mainly uncyclized intermediates. Kitroberuelie aiid CCl, rrere also used as solvents but x-ith no marked success. Previously inireported chromariones are listed in Table I. The following descriptioii illustrat.er an alternative pi,ocedtirc. p-Chloropheiiol (11.25 g, 0.1 mole) and crototiic acid (17.2 g, 0.2 mole) were st,irred vigorously with polyphosphoric acid (50-100 nil) a t 120' for 8 hr. The slightly cooled mixt,ure was poured oilto crushed ice and 2 S XaOH (450 ml) and CHC1, (500 nil) were added arid stirred until two homogeneous phases were obtained. The aqueous solution was extracted x i t h CHCl3 atid the conibined CHCl, solutions were washed wit,h 2 A' XaOH and H2O. livaporat'ion of the dried CHCL solution gave t,he chromarioiie as a gum (11 g ) which could be purified by distillatiori or converted t,o the oxime directly.
(7) Melting points are corrected and were determined in a capillitry lube. Boiling points are uncorrected. N m r spectra were determined in D20 using TlMS a s standard. Where analyses are indicated only by symbols of t h e elements or functions, analytical results obtained for those elements or functions were within zt0..1c/, of t h e theoretical values. Petroleum ether refers t o t h e fraction of IJP60-80' unless otherwise stated. ( 8 ) D. Huckle, I . AI. Lockhart, and AI. Wright, J . Chem. Sac., 1137 (1963). (Y) G. W. Ihemethod that, tmheuse of 0.1 S XaOH at 37" was replaced by an eqiiivalent amoiint of 1 JY YaOH at rooni temperature. This resulted in a considerable improvement i n the yield, raising it to about 80%. The method was convenient nnd combined the advantages of the various met,hods reported t)y Rejchel and his collaborators'"." wit,hoiit, suffering t'he ntt endant. disadvant,ages. 4-Chromanone O-(p-tolylsulfonyl)oximes.-4-Chro11ino1i~~~ were converted to their oximes and the (~-(p-tolyluulfonyI)osiine? prepared as described by O'Brien, EL ~ 1 The . ~ tosylates were not iicirndly purified hut mere washed with !LtOH, dried, and used t1ircv.t 1y. New 4-chronianone oximes and 4-rhrnniaiioiie O-(p-t~cilylhii1foiiyl)oximes which were obtained analytically piire are listed iii Table I. 3-Amino-4-chromanone Hydroc h1orides.-0-( p-Tolylsiilfoiiy1)oxirnes were suspended in CSH6and shaken or stirred with XaOEt a i room temperature for 21 hr as previously described.' :l-Arniiio-4-c.hromanorie hydrochlorides prepared by this method :ire 1ii;ted in Table 11. In the case of 5,7-dimethyl- and 2,5,i-tiiiiiet,h!.l-.l-chromanone 0-(p-tolylsulfong1)oximesit, was forind aclv:~iit:igeniifit.o heat the reaction mixture on a steam bath for iip 1 0 1 hr ill addition to the period of stirring at rooni temperaI III'P. Surh treatment increased the yield of she appropriate :+:iiiiiiio-l-rhromano~ie hydrochloride from 17 to 6 0 7 i n t'he ra-e of these sterically hindered 0-(p-tolylsrrlfony1)oximes. 111 a variety of instances, it was shown t.hat, there \$-as 1 1 0 ex* ( > i i t iirl difference in using KOEt or S a O E t in the Yeher reartion \vi1 h 4-rhromanone O-(p-tolylsulfony1)oximes unsahstitiit8ed i n t tic 2 posit ion. I n the case of 2-met,hy1-4-chromaiiolle O-(p-tolyl-iilf(riiyl)oxirne, a comparison was made using SaO;\Ie, NaOEt, YtiO-i-Pr, and SaO-t-Bu; the yields of 3-amino-2-methyl-4c.lii.(irnniioiie hydrochlorjde obtained were 50, 52, 60, a n d 2R';, i.c>cpcvtivcly. However, the prodiivts showed some variittion iir iI I V pi,oport ions of the different, ii,ereoisomers present as del el,initietl tiy nmr spectra. [Each isomer gave a doublet for 2-C11,, O I I C reiitered at. 7 X..il ( J = 6.5 cps), and the ot,her centered n t s.22 i./= 5.5 cps).] 3 4 Dimethylamino)-4-chromanoneHydrochloride.-3-;lmiiiir-4-c.lii.om;tnoiir hydrocahloride \vas dimethylated by hydroc ~ f l()lid ~ n filtered s off, wwhetl with T120. EtOll, and EtrC), and (tried. Re( t allization from I20 >25 pr'
9 >25
a Needles. Prisms. Plates. Microcrystalline. e Yellow microcrystalline monohydrobromide. f Rods. 0 EtOH. C6H60.5 S HC1. 1 c&. EtOH-EtzO. 1 2 A' HC1. MeOH. n C: calcd, 52.3; found, 51.8. Melts with no pdtroleum ether. decomposition. p N = compound inactive a t 25 mg/kg.
which separated on cooling was filtered off, washed (HzO), and dried. The solid was boiled with EtOH (300 ml), cooled, and filtered to give the crude thione as a yellow solid (14 g) which on analysis contained some inorganic residue. A sample of the crrtde thione (6.6 E) was stirred with H,O (100 mll for 1 hr. The solid was filtered'off, washed (H20, E k H , Etzd), and dried to give the thione as a pale yellow microcrystalline solid (5.7 g) \&jch decomposed with an indeterminate mp ,2700. Anal. (CioHsN2OS)C, H, S .
Acknowledgments.-The authors thank Dr. R. E. B ~ for his~interest ~ and advice, , Air. ~ R. B. ~ s c o t t~ for the nmr spectra, Miss E. hf. Tanner for ir and uv spectra, and ?tfr. F. H. Oliver for the microanalyses. The help of Dr. D. Evans and Jfr, D, J. Peters ivith the synthesis of aminoflavanone and aminobenzchromanones, respectively, is gratefully acknowledged.
