336
JOHN
A. KINGAND FREEMAN H. MCMILLAN
ChIoro Alkyl Esters.-These esters were prepared in the same manner as the alkyl esters with the exception that ethylene chlorobromide or propylene chlorobromide was used in place of the alkyl halide. Dialkylaminoalkyl Ester Hydrochlorides.-To a mixture of 10 g. of the chloro ester aiid 15 cc. of alcohol was added 10 g. of the appropriate amine. The mixture was refluxed on a steam-bath for two hours, and poured onto a tnlixture of cracked ice dilute hy&oxide, ‘)-he free base was removed arid dissolved in drv ether. The hydrochlorides were formed by pasiiiig dry hydrochloric acid into the ether solution. They were purified by recrystallization from absolute alcohol or by precipitation from an alcoholic solution by the addition of dry ether.
[ COXTRIBUTION
Vol. 67
The physical properties and analytical data are in the table.
Summary Some alkyl and alkamine esters of p-fluorothiobenzoic acid were synthesized and the phvsical were determined. These co&p~unds are rather toxic weak local anesthetics, indicating that the substitution of sulfur for an ester oxygen increases the toxicity and decreases the anesthetic eficiency of this series, CliICAGO, ILLINOIS RECEIVED SEPTEMBER 30, 1944
FROM THE RESEARCIi LABORATORIES OF WIXTHROP CHEMICAL COMPANY, I X C . ]
Diaryloxyalkane Derivatives. Diphenoxypropanesulfonamides BY JOHN A. KINGAND FREEMAN H. MCMILLAN At the same time that a series of diphenoxyethanesulfonamides was being prepared’ and before i t was learned that these substances were trypanocidally inactive, a few of the corresponding diphenoxypropanesulfonamides were prepared. This paper reports their preparation. a,y-Diphenoxypropane (I) was prepared by the procedure of Lohmann2 modified according to the method of Cope3 for diphenoxyethane. This was chlorosulfonated by a modification of the procedure of Huntress and Carten4 to yield qy-diphenoxypropane - 44‘ - disulfonyl chloride (11). This, on treatment with aqueous ammonia, gave the diamide 111, and on treatment with aqueous dirnethylamine yielded the corresponding N,N,N’,N’-tetramethyl amide IV. In order to prove the structure of IV and a t the same time of the disulfonyl chloride I1 arid all products derived from it, the tetramethyl amide
Other diphenoxypropwe derivatives prepared were the di-N-ethyl derivative V, from the disulfonyl chloride I1 and ethylamine, the diacetamido compound VI, and its sodium salt VII. Preliminary tests carried out with these diphenoxypropane derivatives indicate that these substances are devoid of trypanocidal activity. Experimental Part5.5 a,r-Diphenoxypropane (I).-A mixture of phenol (94 g.
1.00 mole), trimethylene bromide (101 g., 0.50 mole), potassium hydroxide (56 g., 1.00 mole; 66 g. of 85% c. P. base), and absolute alcohol (300 cc.) was refluxed with stirring for three hours and then poured into 3.5 liters of ice-water. The solid material (m. p. 52-54”) was recrystallized from aqueo!s alcohol to give 87 g. (76y0yieid) of product, m. p. 60-61 , Lohmann* reported m. p. 61 .
~,~-Diphenoxypropane-4,4’-disulfonyl Chloride (II).--
This was prepared by the general procedure developed with a,p-diphenoxyethane;l see the following paragraph. A small sample for analysis, aiter recrystallization from See Table I for analysis. petroleum ether, had m. p. 121
.
TABLE 1
Compound I ’ I1 I11
IV V VI VI 1
D.
--E -SOrCl -S02”, -SOZN(CHI)~ -SOzNHCeISs -SOINHCOCI-In -SOIN(Na) COCHr
yo yield of pure product i0 83 83 .
1)
‘\I;
.
,5
Formula
(
GO 4,l 121 10-1 5-19: 1I 1 I
69
143 3-1-14
67
10‘3 -170
CtaHirOeSiClz CibHisN206SP CiuHzsSzOaS CisHzsNzOsSi Cl~H**N*O~S2
i1ec.
C19HeNnOsS2Nan
I
.
100
42,35 46.63 jl.29 51.5!) 48.51 h’a,
H
N
C
H
3.32 4.66 5.88 5.88 4.68 8.95
7.23 6.33 6.33 5.97
42.26 46.67 51.69 51.65 48 75
3.38 4.72 6.02 4 68
Na.
9.06
5.89
7.48 6.68 6 3G 5 98
H O C _.I_ JSOI?;(CH~)~
was synthesized 5sy an unequivocal method. 4Hydroxybenzeii~sulfondimeth~l~iriide was condensed with triinetliylene broiiiide, in alcoholic alkaline solution, to give the same product as liad been obtained froin the disulfonyl chloride I1 and diethylarnine. J U U K X . A I . , 66, 2076 , t : J i 4 ) ( 2 ) Lohmann, Mil-.. 24, 2ti32 ,18!11). $1 Cupe, THISJ O U R N A L . 57, . i i 2 jl!lYJi. ( I 1 Huntress arid & r t e n , iDiJ., 62, GO5 ( l O l V ) .
(1) King, Tim
~,~-Diphenoxypropane-4,4’-disulfonamide (111).-The general preparative procedure is that previously described,‘ but some modification was necessary. Varying molar proportions of chloyosulfonic acid were used to determine the optimal conditions for the reaction. The crude chloroform solution of the disulfonyl chloride was stirred with excess aqueous ammonia and the resultant disulfonamicle was removed by filtration, dried and weighed. The results are given in Table 11. (GI .\I1 melting points are uncorrected. ,ti, \licn>.LuziIyscs by A1isst.s P. Curran and A. Rainey
NOTES
Feb., 1946 TABLE I1 % excess of
Molar proportion of DiphenoryChloropropane sulfonic acid
1 1 1 1
chlorosulfonic acid
disulfonamide
solvent was reyoved t o leave the crude product (33.0 g.), m. p. 138-142 After recrystallization from ethanol it weighed 30.7 g. (F9% yield) and melted at 143.5-144 (see Table I for analysis).
.
N,N'-Diacety1-~,~-diphenoxypropane4,4'-disulfon-
26
0 25 50 112
4 5
% yield of
337
amide (VI).-A mixture of a.r-di~henoxv~ro~ane-4,4'disulfonamide (31.5 g., 0.0815 mole) -and ac&c anhydride 6 83 (250 cc.) was refluxed one hour then poured onto ice and 8.5 64 allowed t o stand overnight. The solid product (m. p. 163-168') was recrystallized from aqueous acetic acid t o The disulfonamide, after recrystallization from an give the pure diacetyl derivative (25.6 g., 67% yield), m. p. ethanal-methyl ethyl ketone mixture, was in the form of 169-170' (see Table I for analysis). feather-like clusters, m. p. 194.5-195'7 (see Table I for The material crystallizes as a monohydrate and if the analysis). The structure of the material prepared in sample is dried in a vacuum a t not over 80" it analyzes for these Laboratories has been unequivocally proved, as will a monohydrate. be shown in the following paragraph. Z O46.71; : H, N,N,N',N'-Tetramethyl-~~,~~diphenoxypropme4,4'-Anal. Calcd. for C ~ , H ~ & T ~ O & C HC, disulfonamide (IV). A.-A portion of the same chloro- 4.92; N, 5.73. Found: C, 46.73; H , 4.72; N, 5.92. The diacetyl derivative VI (25.0 g., 0.0512 mole of form solution of a,y-diphenoxypropane-4,4'-disulfonyl chloride, of which part had been used to prepare the amide monohydrate) was dissolved in 106 cc. of 0.962 N sodium 111,m. p. 194.5-195", was treated with an excess of aqueous hydroxide (the theoretical amount), the solution was dimethylamine. The resultant solid, after two recrystal- evaporated to a thick paste and the residue was triturated lizations from ethanol, was in the form of flaky crystals, with ethanol to give the white solid disodium salt VI1 (see Table I for analysis). in.p. 191' (see Table I for analysis). B.-A mixture of 4-hydroxybenzenesulfondimethylSummary amide1 (620 mg., 3.1 millimoles), potassium hydroxide (175 mg., 3.1 millimoles), and trimethylene bromide (300 1. a,y-Diphenoxypropane has been converted mg., 1.5 millimoles) in ethanol (10 cc.) was refluxed one hour. The mixture was poured into water and the white by chlorosulfonic acid followed by ammonia into solid formed was recrystallized once ofrom ethanol then the 4,4'-disulfonamide. once from methanol; rn. p. 187-189 . When this sub2. The orientation of the two chlorosulfonyl stance (m. p. 187-189") was mixed with a sample of the groups entering the molecule has been proved by same material (m. p. 191") prepared by procedure A, the showing that an amide prepared from the dimixture melted a t 188-190". 85
N,N'-Diethyl-a,~-diphenoxypropane-4,4'-disulfonamide sulfonyl chloride is identical with that synthesized
(V) .-a,~-Diphenoxypropane-4,4'-disulfonylchloride (42.5 g., 0.10 mole, crude, m. p. 116-117') dissolved in chloroform (200 cc.) was stirred a t room temperature for forty five minutes with aqueous ethylamine (100 g. of 33% solu tion, 0.73 mole), the chloroform was separated and the
(7) A compound of m. p. 245-255' prepared in 44% yield from a,-,-diphenoxypropane with chlorosulfonic acid, and giving satisfactory analyses, was reported by Huntress and Carten.' In the light of results reported in the present paper, however, their product could not have been a,r-diphenoxypropane-4,4'-disiilfonamide.
directly from the corresponding 4-hydroxybenzenesulfonamide and trimethylene bromide. 3. The following four other N-substituted disulfonamides were prepared : dimethyl, ethyl acetyl, and sodio-acetyl. 4. None of these compounds have trypanocidal activity. RENSSELAER, NEWYORE RECEIVED NOVEMBER 1, 1944
NOTES Mechanism of the Reaction between Hindered . Allyl Esters and Grignard Reagents
An experimental result obtained over a year ago has forced us to make some drastic alterations BY RICHARDT. ARNOLDAND R. WINSTONLIGGETT' in the mechanism proposed earlier.2 I t has bee? found that the olefin produced when phenylmagIn two previous publications from this Labora- nesium bromide is allowed to react with n-crotyl t ~ r yit.was ~ . ~shown that allylic esters of hindered mesitoate is pure n-crotylbenzene (I) and apparcarboxylic acids react with Grignard reagents to ently contains none of the isomeric isocrotylgive hydrocarbons and halomagnesium salts benzene. according t o the following equation. //O 2,4,6-(CH8)3CsHlCOCHzCH=CHCH3 4- Cd&MgBr + R-C
+
//O R'MgX -~OCH~CH=CH~
+
(1) Dupont Post Doctorate Fellow 1941-1942.
(2) Arnold, Bank and Liggett, THISJOURNAL, 63, 3444 (1941). (3) Arnold and Liggett, ibid., 64, 2875 (1942).
+ CBI-ISCHZCH=CHCHI
2,4,6-(CHa)3C6H&02MgBr
I
This seems of especial interest since it is well known that either of the pure isomeric crotyl halides gives a mixture of isomeric hydrocarbons when treated with the Grignard reagent. We believe that the hew mechanism outlined
