MARCH
1962
1093
NOTES
EXPERIMENTAL^ p-Hydroxyacetanilide. A mixture of 13.9 g. (0.1 mole) of p-nitrophenol, 75 cc. of glacial acetic acid, 10.2 g. (0.1 mole) of acetic anhydride, and 0.250 g. of 50/opalladium-on-carbon was hydrogenated under 2 atm. pressure. The uptake of hydrogen wm complete in about 1 hr. After filtration from the catalyst, t,he solution was concentrated under reduced pressure to a thick sirup. After addition of 100 cc. of water, the mixture was allowed to stand in the cold for several hours. It was then filtered and the product recrystallized from hot water containing about 0.5 g. of sodium hydrosulfite. A 79% yield of crystalline product melting a t 170171" was obtained; lit. 168',1 168-169'.* Anal. Calcd. for CsHpNpOZ:C, 63.54; H, 5.99; N, 9.26. Found: C, 63.35; H, 5.70; N, 9.06. In the preparation of o-hydroxyacetanilide the product crystallized during the course of reaction. It wm necessary then to add the reaction mixture to 600 cc. of water and heat to dissolve. The hot solution was then filtered from the catalyst through a heated funnel. Beautifully crystalline colorless material was obtained on cooling; yield, 82.5%, m.p. 208-209".' Anal. Calcd. for CaoNzOz: C, 63.54; H, 5.99; N, 9.26. Found: C, 63.38; H, 6.12; N, 9.25. m-Hydroxyacetanilide was prepared in a similar manner (2) Microanalyses were carried out by Mr. E. F. Shelberg and Mr. 0. Kolsto and their staff. (3) L. Claisen and F. Kremen, Ann., 418, 104 (1919). (4) E. Bamberger, Ber., 36,2042 (1903), reports 209" with sintering beginning a t 200". N. N. Crounse and L. C. Raiford, J. Org. Chem., 10, 419 (1945), give 207-208".
from m-nitrophenol. However, since this product is somewhat water-soluble, the residue resulting from concentration of the reduction solution was treated with 100 cc. of water and cooled thoroughly until precipitation was complete. It was then filtered and drained thoroughly without washing. A 73% yield was obtained, m.p. 151-151.5'; lit.6 148-149 '. Anal. Calcd. for CSHgN202: C, 63.54; H, 5.99; N, 9.26. Found: C, 63.40; H, 6.21; N, 9.32.
ABBOTTLABORATORIES ORGANIC RESEARCH DEPT. NORTHCHICAGO, ILL. (5) M. Ikuta, Am, Chsm. J., 15, 39 (1893).
N-Substituted Vanillamides HAROLD MONSIMER AND SOUREN AVAKIAN~
Received Septambsr 26, 1961
Recently, the preparation of a number of Nsubstituted vanillamides was reported.Z-' The fact ( I ) Present address, Denver Chemical Co., Stamford, Conn. (2)(a) K. Kratzl and E. Kvasnicka, Monatsh., 83, 18 (1952); (b) U. S. Patent 2,641,612 (1953); (c) Austrian Patents 168,059 (1950) and 172,341 (1952).
TABLE I VANILLAMIDES WITH
T w o CARBOXYLIC FUNCTIONSO R*
I
0
II
O=q--N (CH&C-R2
OH n 1 1 1 1
R'
R1 CeHs C2H6 CzHs CzHs
-N(CHdz -N(CzHs)z -N(CHzCH=CHz)z
M.P.b
Nitrogen, % Calcd. Found
Yield, %
56-57 91-92 112-1 13 140-142
9.99 9.09 8.43 9.52
9.79 9.11 8.43 9.46
70 40 30 80
144-145
9.15
8.93
40
74-76 94-95 88-89
8.74 8.74 8.19
8.67 8.69 8.08
30 40 55
149-150
8.80
8.71
40
133-134
8.43
8.42
46
?IH1
-N
\
H
1
CIHS
1 1 1
GHS CHzCH4Hs CH&H=CH*
-d L) -N(CZHS)~ -N( CHzCH=CHz)2
H 124-125 9.52 9.52 40 -N(CzHsk -N(C*Hsh glad 8.69 8.42 55 GH6 a The starting o-aminocarboxylic amides were prepared from the corresponding wchlorocarboxylic acid chlorides and the appropriate amines. Melting points are uncorrected. This compound was purified by distillation in a "Rota Film" molecular still at a jacket temperature of 20O0, 30 p. 2 2
~
~~
~
~
1094
that these compounds show physiological activity, notably as analeptic^,^^^ prompted us to investigate other amides of this acid. Kratzl and Kvasnicka2"noted that an additional carboxyl group on the aromatic ring of several analeptics increased their activity. It occurred to us that an extra carboxylic function in ail alkyl side chain might have the same effect. To test this assumption, we prepared the series of vanillamides which are listed in Table I. We have listed in Table I1 several vanillamides which were prepared but which do not belong in the above series. TABLE I1 SIMPLEVANILLAMIDES
O=C-R~
OCH3
OH
Nitrogen, Calcd. Found
Yield, %
RS
M.P.
CHzCH=CHz -N( CHzCH=CHz)z
86-87 63-64
6.76 5.66
6.99 5.75
25 64
128-129
6.33
6.28
40
10.52 10 43 11.10 11.OS
45 40
H
/ \
-a
--r\'(CHz)zN(C2H6)2 --N(CHzLN(CHs)z
115-116 139-140
27
N,N-Diallyl-d-( N'-vanilloyl-N'-ethylarnido)acetan~ide.To a cooled solution of 30 g. (0.13 mole) of acetylvanilloyl chloride in 100 ml. of dry benzene was added a solution of 22.4 g. (0.13 mole) of N,N-diallyl-2-ethylaminoacetaniide and 9 g. of triethylamine in 50 ml. of dry benzene. The reaction mixture was allowed to stand a t room temperature for 1 hr. The triethylamine hydrochloride which had formed was then removed by fi1trat)ionand the filtrate was concentrated to dryness. The residue was heated on a steam bath for 2 hr. with 12 g. of potassium carbonate in 100 ml. of water.' The eolution was made strongly basic by the addition of aqueous potassium hydroxide (10%) and, after unchanged starting material had been removed by extraction with chloroform, the aqueous phase was acidified with concentrated hydrochloric acid. The acidified solution was extracted with chloroform and the chloroform extract was dried and concentrated to dryness. The residue was crystallized from methanol-ether to give 24 g. of N,N-diallyl-2-(N'-vanilloylN'-ethylamido)acetamide, m.p. 112-1 13O .
Acknowledgment. The authors are grateful to Mr. Philip Grous for preparation of many of the intermediates used in this work, to Mr. Sidney Alpert for organic analyses, and to Dr. J. Morton Beiler for biological experimentation.
@ -N
VOL.
NOTES
These compounds were prepared by a simple two step procedure which is similar to that used by previous workers.204 Acetylvanilloyl chloride was treated with the appropriate amine and the resulting acetylvanillamide, which usually was not isolated, was then saponified with aqueous potassium carbonate. When compared with metrazole, the compounds reported here did not show significant analeptic activity. For example, a t dose of 10 mg./kg. in dogs, they did not show effects on respiration or blood pressure while metraeole a t dose of 1 mg./kg. gave an increase in both heart rate and respiratory volume.
THENATIONAL DRUGCOMPANY RESEARCH LABORATORIES DIVISIONOF RICHARDSON-MERRELL, INC. HAINESAND MCCALLUM STREETS PHILADELPHIA 44, PA. (7) In a number of cases i t was necessary to add ethanol in order to increase the solubility of the reactants in this solution.
Methylation of the Salts of N,N'-Dinitroso-pphenylenedih ydroxylamine S. R. RICCITIELLO AND A. H. GERBER Received September 25, 1961
The dimethyl ether of N,N'-dinitroso-p-phenylenedihydroxylamine has been reported in a previous paper.' The dimethyl ether as reported was prepared via the disilver salt in diethyl ether as the solvent. The methylation with a large excess of methyl iodide took nine days, giving less than 10% yield. This study was undertaken in order to find an improved method of preparing the ethers of N,Nf-dinitroso-p-phenylenedihydroxylamine. It has EXPERIMENTAL been found that when the disodium N,Nf-dinitrosoThe preparation of N,N-diallyl-2-(N'-vanilloyl-N'-ethylamido)acetamide will illustrate the method that was used p-phenylenedihydroxylamine is treated with methyl iodide in dry dimethylformamide with a catalyst, a to prepare these vanillamides. high yield of the dimethyl ether of N,N'-dinit,roso(3) Osterreichische Stickstoffwerke, A.-G., Brit. Patent p-phenylenedihydroxylamine is obtained. The cata683,435 (1952). (4) I. A. Pearl and D. L. Beyer, J . Am. Chem. Soc., 75, lyst employed is a quaternary ammonium salt 2627 (1953). which is soluble in dimethylformamide. (5) K. Kratzl, K. H. Ginzel, E. Kvasnicka, and M. The use of quaternary ammonium salts in the Nelbock-Hochstetter, Congr. intern. biochim., Resumes communs., %" Congr., Paris, 437 (1952). (6) B. Botta, L. Csnonica, and E. Pavanati, Atti. SOC. lombarda sci. med. e biol., 9 , 2 2 (1954).
(1) M. Danzig, R. Martel, and S. Riccitiello, J . Org. Chem., 26,3327 (1961).
