J. H. BILLMAN,T. G. WARDAND P. H. HIDY
130
Vol. 67
The chemical data do not warrant the assignment of a definite structure to the semicarbazone in question, but a comparison of its ultraviolet H"C$S2-C_-H ;c=o absorption curve with that of cyclohexanone __ semicarbazone (Fig. 3) suggests that the semiHz' H-CHB carbazone in question is derived from isophorone i (I) rather than from its isomer (111). If such is CH, the fact, then when the semicarbazone is formed (111) (VI from (111), the double bond is shifted, during K3mo = 0 I17 Kareo = 0.126 the process of formation, from the P,-y to the alp absorption for hydroxyl, either associated or un- position. associated. The carbonyl absorption is that of a Summary normal ketone. 1. Ultraviolet and infrared absorption spectra These data indicate that both the infrared and ultraviolet absorption spectra of the new com- indicate that when isophorone is treated with pound are in accord with the keto structure (111). methylmagnesium bromide in the presence of Structure of the Semicarbazone Formed from small amounts of ferric chloride, the double bond Compounds (I) and (III).-Compounds (I) and in the ring is shifted from the a,p to the ply (111) each yields a semicarbazone which melts position. 2 . In the formation of the semicarbazone of at 186-187O.l Since these semicarbazones do not A3~4-3,5,5-trimethylcyclohexenone, the double depress each other's melting points, they may be concluded to be identical. This conclusion bond is shifted back to the a,@ position and the is supported by their ultraviolet absorption semicarbazone of isophorone is obtained. CHICAGO, ILLINOIS RECEIVED AUGUST28, 1944 curves (Fig. 3).
&
[CONTRIBUTION FROM THE CHEMICAL LABORATORY O F INDIANA cNIVERSITY
i
Antispasmodics and Anticonvulsants. N. N,N'-Substituted a-Aminodiphenylacetamides BY JOHN H. BILLMAN,THELMA G. WARD'AND PHILHARTERHIDY* I n an earlier publicationa it was shown that certain a-aminodiphenylacetamideshaving identical OH I
(1)
OH
O
,
JCBHS)~-C-C-OCHS
phenylacetamide. However, to verify this the following reactions were run
I
0 /I
+ CHJNHZ+(CsH6)2C---C--rU"CH3
radicals attached to both of the nitrogen atoms, possessed anticonvulsant as well as antispasmodic acitivity. It was decided, t4erefore, to synthesize a number of derivatives having dissimilar groups attached to the nitrogens by using a-chlorodiphenylacetyl chloride and two different amines. The a-chlorine atom of an a-chloroacyl chloride is normally much less reactive than the chlorine atom attached to the carbonyl group. Klinger4 has done some work which indicates that cu-chlorodiphenylacetyl chloride when treated with two moles of aniline produces N-phenyl-a-chlorodi(1) Submitted to the Faculty of t h e Graddate School in partial fulfillment of the requirements for the degree, Doctor of Philosophy, in t h e Department of Chemistry, Indiana University (2) Eli Lilly Fellow (3) Billman and Hidy, THISJOURNAL, 66, 700 (1943). (4) Klinger, A n n . , 389, 255 (1912)
+ CHaOH
The diphenylacetic acid derivatives (I) formed in reactions (1) and ( 2 ) were found to be identical. Both products melted a t 146-147' and gave no depression in melting point when fused together. This temperature is approximately 60' below the melting point of the isomeric a-methylaminodiphenylacetic acid.5 Neither product was soluble in alkali or hydrochloric acid. Thus the structure of Compound I1 is established. These results along with the fact that the a-chloroacetamides were obtained in yields of better than seventy per cent. confirm the order and relative ease of replacement of the chlorine atoms in a-chlorodiphenylacetyl chloride. It is this appreciable difference in reactivity which made possible the synthesis of a-aminodiphenylacetamides, with unlike radicals attached to each nitrogen atom, according to the reactions ( 5 ) Biltz and brydel, A J L N, 391, 227 (1912)
N,N'-SUBSTITUTEDCC-AMINODIPHENYLACETAMIDES
Jan., 1945
131
c1 0
cold dry ether was added two mole equivalents of gaseous ethylamine. The solution was then allowed t o warm up (3) (CeHs),C-C-Cl 2NHgR + to and remain at room temperature for five hours. The ethylamine hydrochloride was atered off and washed with c1 0 two 25-ml. portions of dry ether. The combined washings I 11 and filtrate were extracted with dilute hydrochloric acid (CeJ!Is)&-C-NHR 2NHaR' + to remove any excess amine. The ether solution was HNR' 0 dried over anhydrous sodium sulfate and then evaporated I II to dryness under reduced pressure. Recrystallization of (CeHs)iC-C-NHR the residue from ether and petroleum ether gave 9 g. The N-substituted a-chlorodiphenylacetamides (87.5% yield) of N-ethyl-or-chlorodiphenylacetamidemelta t 95.5-96'. which were isolated and chaxacterized are listed in ingThe a-chlorodiphenylacetamides listed in Table I were Table I. prepared by a procedure similar to the one above. N-Ethyl-a-diethy1amhodiphenylacetamide.-To a 125TABLE I ml. flask fitted with a reflux condenser was added 9 g. of N-SUBSTIT~ED U-CHLORODIPHENYLACETM~IDES ethyl-a-chlorodiphenylacetamide and 4.8 g. of diethylM. P. of Yield, , Nitrogen, % amine. A mercury trap was attached to the outlet of the Amine used % Calcd. Found amide, 'C. condenser and the solution then refluxed for twelve hours. 5.42 5.48 Methylamine 94.0-95.0 >70 The mixture was treated with 100 ml. of ether, warmed, and filtered to remove the diethylamine hydrochloride. 95.5-96.0 87.5 5.14 5.23 Ethylamine The filtrate was extracted with small portions of 0.1 N 73.5 4.88 5.07 68.5-69.0 n-Propylamine hydrochloric acid until the extractions proved to be acid 76.0-77.0 77.5 3.84 3.94 pphenetidine to litmus. The acid extracts were then neutralized with sodium carbonate and extracted with two 60-dportions . The N,N'-substituted a-aminodiphenylacet- of ether. The brown semi-crystalline product remaining amides prepared are listed in Table 11. was removed, washed with water and recrystallized from methyl alcohol to yield 3.7 g. (36%) of a white solid meltTABLE I1 ing a t 134.5-135'. The compounds listed in Table I1 were prepared by a N,N'-SUBSTITUTEDC~-~NODIPHENYLACETAMIDES procedure similar t o that used for synthesizing N-ethylR R' a-diethylaminodiphenylacetamide. When high boiling \/ amines were used, no mercury seal was attached to the N O condenser. N-Methylbenzilamide (I) was prepared by the following two methods: Method 1.-Methyl benzilate was prepared from benzilic M. p. of acid, methyl alcohol and sulfuric acid similar to the ,method Amines used amide, Nitrogen, % described by Acree.6 The ester was dissolved in ether and RR'NH R*RR"H OC. (uncor.) Calcd. Found tested with gaseous methylamine in a flask fitted with a Ammonia 8.08 8.06 167,5168 $-Phenetidine dry ice-cooled condenser to the top of which was attached .8.08 7.96 $-Phenetidine 138 Ammonia a mercury seal. The mixture was r d u x e d for six hours, 9.03 9.32 Ethylamine 134.6-135 Diethylamine poured into water and the insoluble portion recrystallized 6.88 6.96 $-Phenetidine 55 Diethylamine from methyl alcohol. The product melted at 146-147'. 7.29 7.22 $-Phenetidine 118 +Propylamine Method 2.-N-Methyl-a-chlorodiphenylacetamide was 6.83 6.96 $-Phenetidine 78 %-Butylamine prepared the same way as the corresponding ethylamide 6.27 6.11 110 Di-#-butylamine 9-Phenetidine described above. One gram of the methylamide was re6.54 6.20 Cyclohexylamine #-Phenetidine 160 (dec.) fluxed with 25 ml. of water for two and one-half hours. The pharmacological tests which have been run Upon cooling the pale yellow oil solidified to a white mass. Recrystallization from methyl alcohol on these compounds indicate that they do not crystalline yielded a white solid melting at 146-147' which when fused differ greatly in antispasmodic or anticonvulsant with the amide produced by method (1) also melted a t activity from the a-aminodiphenylacetamides 146-1 47 '.
1
I1
+
+
having identical groups attached to both nitrogen atoms. We are deeply grateful to Eli Lilly and Company for the grant which made this work possible and to Drs. H. M. Lee, C. E. Powell and E. E. Swanson of the same company who ran the pharmacological tests.
Experimental wChlorodiphenylacety1 Chloride.-Prepared from benzilic acid and phosphorus pentachloride as previously described.8 N-Ethyl-a-chlorodiphenylacetamide.-To 10 g. of achlorodiphenylacetyl chloride dissolved in 75 ml. of ice-
Summary 1. It has been proved that the chlorine atom attached to the carbonyl group in a-chlorodiphenylacetyl chloride is more readily replaced by an amine than is the a-chlorine atom. 2. A number of new a-chlorodiphenylacetamides have been isolated and characterized. 3. Eight N-alkyl a-aminodiphenylacetamides of a new type have been prepared. BLOOMINGTON, IND.
RECEIVED OCTOBER 23, 1944
(6) Acree, B e . , 87,2765 (1904).
