[COXTRIEcTIOh- FROM THE DICPARTMEXT O F CHEMISTRY,
UNIVERSITY
THE
O F TEXAS]
CERTAIN 5- (1-NAPHTHYL)d-SUBSTITUTED HYDANTOINS' HEKRY It. HENZE
AND
LESLIE GREY NUXK, JR.*
Receized February 26, 1947
Attempts have been made in this and other laboratories to produce satisfactory anticonvulsants by synthesis of derivatives of diphenylhydantoin (A)through introduction of substituents into one or both of the phenyl groups. To date, such alterations have yielded only less active compounds. However, some 5phenyl-5-substituted hydantoins have been prepared, chiefly in this Laboratory, and have been shown elsewhere (1) to possess a desirable degree of anticonvulsant activity. Likewise, anticonvulsant aclivity has been demonstrated in a few spirohydantoins whose structural formulas may be written to emphasize a close relationship to 5-phenylhydantoin, namely: fluorenone-spirohydantoin (B), (2), a-hydrindone-spirohydantoin (C), (3), and a-tetralone-spirohydantoin (D), (3).
I
I
ILY ___ C 0 A
I III\T----
I
I 0' 0
IIN-
c
B
I co
I
I
HN-
CO
D
The structural relationship of the napththyl groups to the phenyl group is well known, indeed the former may be thought of as being disubstituted phenyl groups (Le., phenylene radicals); or else the 1-naphthyl group (E) may be looked upon as being simultaneously a benzyl group (F) and a phenylbutadienyl radical (G). Likewise, the 2-naphthyl group (13) may be considered as being both a styryl group (J) and a cinnamyl radical (K). The pharmacological activity of these four groupings (F, G, J and K) when attached to the hydantoin nucleus has scarcely been investigated; however, the benzyl group, in certain alkaloids of the papaverine type and in simple esters, has been shcwn by Macht (4) to have a tendency to relax unstriated muscles. It seemed, therefore, of considerable interest to attempt to synthesize a series of 5-naphthylhydantoins; and the 1-naphthyl series was selected as being the more likely to possess useful pharmacological activity. In this investigation the series of 1-naphthyl ketones recently synthesized ( 5 ) was converted into 5,5-disubstituted hydantoins through utilization of the From the Ph. D. dissertation of L. G. Nunn, Jr., June, 1943. General Aniline and Film Corporation Fellow, Spring Semester, 1942; University Advanced Fellowship, The University of Texas, Session of 1942-1943. Present address. Carter Oil Co., Tulso, Ohla. 1
2
543
544
He Re HENZE AND Le Ge NU",
E
H
F
J
JR.
G
K
procedure developed in this Laboratory (6). In this manner, eleven 1-naphthyl ketones, separately dissolved in fused acetamide, reacted with ammonium carbonate and potassium cyanide to form the corresponding 5-(l-naphthyl)-5-substituted hydantoins. A survey of the chemical literature revealed a previous report of a single conversion of a 1-naphthyl ketone into a hydantoin (7). This preparation involved, in sequence, the conversion of ethyl 1-naphthyl ketone into a-amino-a-( 1naphthyl)butyronitrile, the formation of a-ethyl-a- (1-naphthyl)hydantonitrile and, finally, production of the corresponding 5-ethyl-5-naphthylhydantoinfor which the melting point 222-223" (cor.) was reported. The ethyl naphthyl ketone utilized in this synthesis was prepared by means of a Friedel-Crafts reaction following Caille's method (8); however, attention has been drawn (9) to the fact that this method does not always yield a pure product. In this study, an authentic sample of ethyl 1-naphthyl ketone was converted the latter was found to melt at 186" (cor.). into 5-ethyl-5-(l-naphthyl)hydantoin; In hope of clarifying the discrepancy in melting points reported in these two inwas allowed to react with vestigations, a. sample of purified 2-naphth~nitrile~ ethylmagnesium bromide to form ethyl 2-naphthyl ketone;* the latter was converted into 5-ethyl-5-(2-naphthyl)hydantoinfor which the melting point 222223" (cor.) was noted. EXPERIMENTAL
Preparation of 5-naphthyl-5-substituted hydantoins. The general method of preparation was as follows: Using a 1000-ml. Pyrex liner as a container, 0.05 mole of 1-naphthyl ketone was dissolved in 200 g. of fused acetamide ( 6 ) . Kine grams of potassium cyanide was added and the mixture was stirred until all of the cyanide had dissolved; this precaution was found to be essential in order t o avoid formation of an appreciable quantity of black tar during the course of the reaction. After placing the Pyrex container in a Monel metal bomb, An Eastman Kodak Company product, m.p. W 2 ' . Our sample of ethyl 2-naphthyl ketone melted at 56-57' (cor.), and its oxime melted a t 132-133" (cor.); Rousset (9) reported this ketone and its oxime as melting at 56-57' (cor.) and 133" (cor.), respectively. 3
4
545
5-NAParHYL-5-S~rBSTITUTED HYDANTOIN8
28.8 g. of ammonium carbonate (U.S.P. cubes) waa added and the bomb waa quickly closed t o avoid loss of carbon dioxide and/or of ammonia. The bomb was placed in an oven regulated at 110' and heated for twenty-five hours. The bomb was cooled to room temperature before being opened. A reddish-brown semisolid was obtained which was suspended in approximately 700 ml. of water and cautiously acidified with hydrochloric acid. The light brown, somewhat gummy material was filtered off and washed with water before being trttated with 200 ml. of 10% sodium hydroxide solution. Unreacted ketone was removed by ether extraction, and the crude material was reprecipitated from the alkaline solution with hydrochloric acid. The solid was digested with 500 ml. of boiling ethyl alcohol and the solution filtered t o remove a small amount of insoluble material. The alcoholic filtrate was diluted with 150 ml. of concentrated hydrochloric acid and warmed just below the boiling point for thirty minutes. After concenTABLE I
5- (l-NAPHTHP.L)-5-R-HYDANTOINS
HN--CO
I
I
I
OC HN-C-CioH7
I
R X.P.,
%.(cox.)
IELD,q
- 217.5 186" 168-169 273-274 234-235 200-201 183.5-184. fi 233-234 166-167 270-271 300-301
54.0 64.0 86.0 59.0 60.0 67.0 66.0 83.0 69.0 73.0 79.0
-
Calc'd Found Calc'd Found Calc'd Found
__-----
69.99 70.85 71.62 71.62 72.32 72.32 72.95 72.95 73.54 74.17 75.48,
69.85 70.78 71.53 71.46 72.22 71.98 72.67 72.93 73.22 73.78 75.55
5.04 5.55 6.01 6.01 6.43 6.43 6.80 6.80 7.15 6.55 4.67
5.29 5.69 5.99 6.19 6.57 6.45 6.87 7.00 7.19 6.67 4.92
11.66 11.02 10.44 10.44 9.92 9.92 9.45 9.45 9.03 9.11 9.27
11.58 11.19 10.35 10.65 9.95 10.02 9.43 9.37 8.89 9.07 9.30
Keach IJ. Am. Chem. Soc., 66, 2979 (1933)l reported m.p. 222-23', but that pro duct is now believed t o be the 2-naphthyl isomer. a
tration of the solution t o a volume of 150 ml., 400 ml. of water was added t o ensure complete precipitation of the crude hydantoin. After filtration, and drying at l l O o , the products were recrystallized from 50% methyl alcohol and from 50% dioxane solution or from both diluted solvents. Data concerning analyses and certain phyfiical properties of these hydantoins appear in Table I. Preparation of 6-ethyl-5-(l-naphthyl)hydantoin. Four and five-tenths grams (0.0246 mole) of ethyl 2-naphthyl ketone',' was dissolved in 100 g. of fused acetamide. After 4.5 g. (0.069 mole) of potassium cyanide had been dissolved in this solution, 14.4 g. of ammonium carbonate was added and the reaction mixture was heated in the glass-lined Monel metal bomb at 110' for twenty-four hours. !rhe product was purified in the same way as
546
H. R. HENZE AND L. 6. NU",
JR.
the isomeric I-naphthyl hydantoins; after two recrystallizations from 50% methyl alcohoi, 2.5 g. (38% yield) of light, white solid, melting at 222-223', was obtained. Anal. Calc'd for C1~HI,N2O2: C, 70.85; H, 5.55; N, 11.12. Found: C, 70.65; H, 5.66; N, 11.12. SUMXARY
1. Eleven 1-naphthyl ketones, five of which are new, have been converted into the corresponding 5-(1-naphthyl)-Bsubstitutedhydantoins. 2. 5-(2-Naphthyl)-5-ethylhydantoin has been synthesized and shown to bc identical in melting point with the hydantoin previously reported as being 5- (1-naphthyl)-5-ethylhydant oin. !lT;STIN,
TEXAB REFERENCES
(1) MERRITT,PUTNAM, AND RYWATER, J. Pharmucol., 84, 67 (1945). (2) MCCOWNWITH HENZE,J. Am. Chem. Soc., 64, 689 ref. 1, (1942); NOVELLI,Aiiales assoc. quim. argentina, 29, 83 (1941). (3) HENZEAND SPEER,J. Am. Chem. SOC.,64, 522 (1942). (4)MACIIT,Proc. SOC.Exp. Biol. Med., 15.63 (1918); J. PharmacoE., 11, 176, 389,419 (1918). (5) NUNNAND HENZE,J. Org. Chem.,12, 517 (1947). (6) HENZEAND LOXG, J. Am. Chem. SOC.,63,1936 (1941). (7) KEACI-I,J. Am. Chem. SOC.,66, 2980 (1933). (8) CAILLE,Compt. rend., 163, 393 (1911). (9) KUNNAND HENZE, J . Org. Chem., 12, 517 (1947); SA~WJELSSON, J. C h m . SOC.,122, (l), S23 (1922).
