[CONTRIBUTIONFROM ?rTOYES CHEMICAL LABORATORY, UNIVERSITY O F ILLINOIS]
SOME TERTIARY DIAMIXES DERIVED FROM 1,2-bis(&CHLOROETHYLTHIO)ETHANE1 CHARLES C. PRICEa A N D ROYSTON hl. ROBERTS3 Received August 19, 2946
In view of the reported activity of several long-chain diamines against certain tropical diseases (l),it seemed of interest to ascertain whether analogs, in which pairs of carbons had been replaced by sulfur atoms, might have similar activity. In particular, since the glycol I, 1,2-bis(p-hydroxyethylthio)ethane,is readily available, its conversion to a number of simple diamines has been investigated. The corresponding chloro compound, 11, was remarkably inert toward secondary amines in ether, petroleum ether or dioxane. It condensed with diethylamine in boiling ethanol (2) but dibutylamine failed to react under these conditions. The condensation of the latter amine, as well as piperidine and npropylaniline was accomplished satisfactorily in boiling 90% dioxane as solvent. The sulfone IV (3) was much more reactive, condensing readily with diethylamine or piperidine with the evolution of considerable heat to yield the diamino disulfones (VII), Attempts to convert three of the diamines 111 into disulfones by oxidation with hydrogen peroxide in acetic acid led to cleavage of the molecule. From the diethylamino and piperidyl compounds, the product isolated was the diamino sulfone V. From the dibutylamino compound, the product isolated after treatment with hydrochloric acid analyzed correctly for p-di-n-butylaminoethanesulonic acid (VI). f ( H O C H Z C H ~ S C H ~s°C1z )~ I ~
3
E 2 0 2 ( C ~ C H ~ C H ~ S C H Z ) ~ (ClCHzCH2S02CH2)z I1 IV
RzNHi
(R2NCHz CH2)2 S0 2
H202
cH=
V
+
R,KH~
(R2N CH2 C H2 SCH2)2
(R2NCH2CH2S02CH2)2
I11
VI I
RzNCHzCHzSO2OH VI
A somewhat similar cleavage of a dithioethane on oxidation with hydrogen peroxide in acetic acid has been previously observed (4). It seems likely that the 1 The work described in this paper was carried out under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Illinois. 2 Present address: University of Kotre Dame, Notre Dame, Indiana. 8 Present address: University of California, Los Angeles, Calif. 264
DIAMINES FROM
1, 2 - b h ( ~ - C H L O R O E T H Y L ~ I O ) E ~ A N E
265
course for the reaction may involve a reversible dissociation of the disulfone to a vinyl sulfone (VIII) and a sulfinic acid (IX) (5). The dissociation is then driven to completion by oxidation of the sulfinic acid.
(R2N CH2 C H2 S02 CH2) 2 VI I
+ZXZ?-
RzNCHz CH2S02CH=CH2 VI11
+
RzNCHz CHzSO2H IX
CH2=CHSOaH
+
t___f
R2 NH
The diamines derived from I1 and two related disulfones were submitted for assay against avian malaria. The diethyl (SN-6715)4and phenyl propyl (SN8788) diamines (111) showed activity about one-tenth that of quinine. EXPERIMENTAL'
1,8-bis(p-Chloroethylthio)ethane(ZI)@was prepared by addition over a period of one and one-half hours of 48 cc. (0.67 mole) of thionyl chloride in 192 cc. of dry ether to 60 g. (0.33 mole) of the glycol (I) in 300 cc. of cold dry ether. After an additiond half-hour of stirring, eight or ten g. of decolorieing charcoal was added, the mixture was stirred fifteen minutes while boiling to reflux and was filtered. After evaporation t o about 100 cc., cooling in an ice-salt bath precipitated 52 g. (72%) of white crystalline product, m.p. 46-50" [lit. (6), 54'1. 1,Z-bas (B-Diethylaminoethy1thio)ethanedihydrochloride (SN-6716).Fifty grams (0.275 mole) of glycol I was converted to the chloro compound I1 as described above. In order t o avoid handling this toxic and vesicant material, the ether and excess thionyl chloride were removed by distillation and 50 cc. of absolute ethanol, 35 g. (0.33 mole) of sodium carbonate and 65 cc. (0.63 mole) of diethylamine were added t o the residue. The mixture was heated to reflux and stirred overnight. The hot solution was decanted from the sodium chloride and this residue was boiled with two portions of ethanol which were decanted and added t o the rest of the solution. The alcohol was removed by distillation. T o the residue (two layers) was added 185 cc. of 10% hydrochloric acid and the acid solution was extracted with three 50-cc. portions of ether to remove any unchanged sulfide. Pellet potassium hydroxide was added to the acid layer until i t was distinctly basic. The oil which separated wae extracted with ether and the ether solution was dried with magnesium sulfate. Dry hydrogen chloride was bubbled rapidly into the ether solution, and the oil which began t o precipitate quickly solidified to a white solid, 47.3 g., m.p. 174-176'. Recrystallization from 250 cc. of absolute ethanol yielded 21.1 g. (21%), m.p. 184.5-185.5'.
-
The Survey Number, designated SN-, refers t o the number assigned a drug by the Survey of Antimalarial Drugs. The activities of these compounds will be tabulated in a forthcoming monograph. 6 Analyses by Miss Theta Spoor. All melting points uncorrected. 6 This toxic and vesicant material was handled with great care using rubber gloves over polyvinyl alcohol gloves.
266
C. C. PRICE AND R. M. ROBERTS
Anal. Calc'd for C1,Ha4CLNzSz:C, 46.01; H , 9.38; C1-, 19.4. Found: C, 46.15; H, 9.51; Cl-(Volhard), 19.5. 1,8-bis(B-Di-n-butylaminoethylihio)ethanedihydrobromide (SN-7286). T o 30 g. (0.14 mole) of I1 in 240 cc. of 90% dioxane was added 155 cc. (0.92 mole) of di-n-butylamine. The solution was boiled under reflux for five hours. The dioxane and most of the excess secondary amine were removed by distillation under diminished pressure. To the residue waa added 200 cc. of 10% sodium hydroxide and the mixed amines were extracted with four or five portions of ether. Most of the unreacted di-n-butylamine was removed by distillation and the residue was treated with 200 cc. of 10% sodium hydroxide and 25 cc. of benzenesulfonyl chloride. The mixture was shaken for several minutes in a stoppered flask and then ether and 150 cc. of 18% hydrochloric acid was added. The acid extract was made basic with sodium hydroxide pellets and the product was extracted with ether and the combined extracts dried over magnesium sulfate. Hydrogen bromide was bubbled through the mixture, and the salt precipitated as an oil which began to crystallize almost immediately. After standing overnight, the ether was decanted from the precipitate and replaced with enough hot ethyl acetate containing a little absolute ethanol to dissolve the salt. Darco waa added and the mixture was boiled and filtered. From the filtrate was obtained 19.5 g. (%0/0) of fine white crystals, m.p. 110-112'. A sample was prepared for analysis by another recrystallization from ethyl acetate, m.p. 111-112.5". Anal. Calc'd for C22H50Br2NzS2: C, 46.63; H , 8.90. Found: C, 46.52; H, 9.01. A picrate of the product was prepared by adding about 5 cc. of the ether solution to an equal volume of a saturated solution of picric acid in dry ether. The compound precipitated aa an oil but was induced to crystallize by scratching with a glass rod. After three recrystallizations from absolute ethanol, the picrate melted at 117-119' (mixed melting point with picric acid, 80-119'). Anal. Calc'd for CarHsnNsOiSz: C, 47.29; H , 6.30. Found: C, 47.23; H, 6.37. i,B-bis(&Piperidylethylthio)ethane dihydrochloride (SN-7286) was prepared i n a similar fashion. Recrystallization from ethanol afforded a 60% yield of small white needles, m.p. 266-268" (dec.). Anal. Calc'd for C,eH&12N:!S2: C, 49 34; H , 8.80. Found: C, 49.71; H, 8.87. 2,2-bis (8-n-Propylphenylaminoethylthio) ethane dihydrochloride (SN-8788) was prepared in a similar fashion, except that the reaction of n-propylaniline and I1 i n boiling 90% dioxane required at least twenty-four hours. The product, purified by crystallization from alcohol and ether, was obtained in 35% yield, m.p. 190-191". Anal. Calc'd for Ce4HasClzN:!Sz: C , 58.87; H, 7.82. Found: C, 59.01; H , 8.02. Treatment of 1 ,%-bis(P-dzethylaminoethy1thio)ethanedihydrochloride with hydrogen peroxide i n acetic acid. T o 4.4 g. (0.012 mole) of the diamine salt was added 20 cc. of glacial acetic acid and 10 cc. (0.097 mole) of 30% hydrogen peroxide. The solution was boiled under reflux for seventeen houre, the brown reaction solution was diluted with water and pellet sodium hydroxide was added until the solution was distinctly basic. A flocculent semi-solid precipitate separated and was extracted with three or four portions of ether. The ether was dried over magnerium sulfate and then evaporated under an air stream. A small amount of brown oil remsined which did not crystallize on standing a few hours. The oil was redissolved in dry ether and the solution was treated with hydrogen chloride. The amine salt precipitated as an oil but quickly crystallized. The ether was decanted and the crude salt was recrystallized from ethyl acetate after treatment with Darco: a powdery almost-white product was obtained which melted with decomposition a t 201202". Two recrystallizations from ethyl acetate-ethanol mixtures gave a product which melted a t 199-200". Half of this product was prepared for analysis by recrystallization from absolute ethanol; the melting point was then 197-197 5". The analysis did not agree with t h e romnnsition of t h e expected diamino disulfone (VII).
DIAMINES FBOY
1 ,2-b~~(~-CHLOROETHPL"HIO)E~ANE
267
The neutral equivalent found and the analysis correspond very well to the structure of the known diethylamino derivative of 8-chloroethyl sulfone (V), m.p. 202-202.5", corr. (2). Anal. Calc'd for C14Ha&1&20&: C, 39.15; H, 7.98; N.E., 215. Calc'd for ClzHdXzK20&3: C, 42.72; H, 8.96; N.E., 169. Found: C, 42.90; H, 9.18; N.E., 169f3. Treatment of 1,b-bis (8-N-piperidinoethy1thio)ethane dihydrochloride w i t h hydrogen peroxide in acetic acid. 9 solution of 3 g. (0.008 mole) of the diamine salt in 20 cc. of, glacial acetic acid and 10 cc. (0.097 mole) of 30% hydrogen peroxide was boiled under reflux for five hours. The reaction mixture was diluted with water, neutralized with pellet sodium hydroxide and extracted with ether. The solid which separated between layers waa collected, dissolved in about 100 cc. of water, and then extracted with ether, combiningthe ether layers with the main extracts. The ether was dried over magnesium sulfate and then saturated with hydrogen chloride. The oil which precipitated crystallized on standing. It was recrystallized from absolute ethanol-ethyl acetate, and a light tan powder waa obtained which darkened a t 210-215' and decomposed a t 220' t o a black liquid. After three recrystallizations from absolute ethanol, the product melted at 211-214', sintering from 200'. A sample was prepared for analysis by recrystallization from 20 cc. of absolute ethanol and was dried at 100" (2 mm.) for four hours. Most of the sample melted at 206", but i t did not completely liquefy until the temperature was 260". The analysis WFIS not correct for the expected diamino disulfone (VII), but checked fairly well for the corresponding 6-aminoethyl sulfone derivative (V). Anal. Calc'd for CI&&~&ZO&: C, 42.37; H, 7.56. Calc'd for CI4H2oCl2hT2O2S: C, 46.53; H, 8.37. Found: C, 46.67; H , 8.79. Treatment of l,.%bis (8-di-n-butylarninoethy1thio)ethanedihydrobromide w i t h hydrogen peroxide in acetic acid. A solution of 3 g. (0.005 mole) of the diamine salt in 20 cc. of glacial acetic and 10 cc. (0.097 mole) of 30% hydrogen peroxide waa boiled under reflux five hours. The reaction mixture was diluted with water and neutralized with pellet sodium hydroxide. The flocculent precipitate was extracted with ether, but some of the material waa not soluble in either water or ether. The combined ether layers were dried over magnesium sulfate and saturated with hydrogen chloride. The oily precipitate was recrystallized twice from absolute ethanol-ethyl acetate; the small amount of product obtained decomposed at 264" to a black liquid. The sample was prepared for analysis and the melting point of the fine crystals was the same after drying overnight a t 100" (2 mm.). The composition found did not correspond to either the expected disulfone (VII) or the B-aminoethyl sulfone derivative (V) but agreed fairly satisfactorily for the hydrochloride of 8-di-nbutylaminoethanesulfonic acid (VI). A n a l . Calc'd for CzzHsoC12NzOaS2: C, 48.78; II, 9.30. Calc'd for CzoH4&lzWzO~S:C, 53.35; H, 10.31. Calc'd for CloHz4ClN0$3: C, 43.85; H , 8.87. Found: C, 43.31, 43.03; H, 9.25, 9.08. Preparation of 1 , %bis (~-dieth~/lamznoeth$sulfonyl)ethane dihydrochloride ( V I I ,SAT-8786). T o 30 g. (0.106 mole) of disulfone I\' in 250 cc. of dioxane, 50 cc. (0.49 mole) of diethylamine was added dropwise within about five minutes. The temperature of the mixture rose nearly t o the boiling point, and the stirred mixture was heated t o reflux for one hour. After standing thirty-six hours at room temperature, the mixture was filtered and 22 g. (0.20 mole) of diethylamine hydrochloride (m.p. 222-223") was collected. The filtrate and washings were combined and the dioxane and excess diethylamine were removed by distillation a t reduced pressure. T o the red-brown residue was added 150 cc. of 10% sodium hydroxide and the mixture was extracted with four 100-cc. portions of ether. The ether was washed with 50 cc. of water and then dried over magnesium sulfate. A solution of 22 g. of hydrogen chloride in 500 cc. of absolute ethanol was prepared and heated to boiling. The ether solution of the amine was added with stirring t o this hot solution. The salt separated on cooling and, after the solution was cooled in the ice-bath, 20 g. (44%) of fine, white crystals, m.p. 184-185", was obtained.
268
C. C. PRICE AND R. M. ROBERTS
Anal. Calc'd for CtrH,oClzN,O,Sa: C, 39.15;H, 7.98. Found: C, 39.49;H , 8.12. 1 ,
[email protected])ethane dihydrochloride was prepared from 11 g. (0.039mole) of disulfone IV in 100 cc. of dioxane to which 20 cc. (0.20mole) of piperidine was added. The mixture was boiled vigorously under reflux for two hours. The reaction mixture was cooled in an ice-bath until the dioxane crystallized, allowed to warm up enough t o melt the dioxane and filtered. The filter cake was sucked almost dry, removed to a beaker and 50 cc. of cold water was added. The mixture was stirred well, filtered, and the crystals which were collected were washed with two or three portions of cold water. When dry, them crystals weighed 8.3 g. and melted at 145-146'. The dioxane filtrate from the first crystals was diluted with 300 cc. of distilled water and cooled in an ice-bath. When the mixture waa filtered, an additional 3.2 g. of product, m.p. 140-141", sintering from 136", waa obtained, making the total yield 11.5 g. (78%). A small sample of the first crop was prepared for analysis by recrystallization from 50% ethanol and the analysis was correct for the composition of 1 ,2-bis(P-N-piperidinoethylsulfonyl)ethane. Anal. Calc'd for ClsH82K'z04Sz: C, 50.49; H, 8.48. Found: C, 5057;H, 8.28. SUMMARY
1 ,2-bis(/3-Chloroethylthio)ethanehas been converted into several tertiary diamines. Oxidation of these diamines led to cleavage to a P-dialkylaminoethyl sulfone and, apparently, a P-dialkylaminoethanesulfonicacid. The disulfonyl diamines were successfully prepared by reaction of 1,2-bis(Bchloroethanaulfony1)ethane with secondary amines. URBANA, ILL. REFERENCES
(1) British Patent No. 433,086 (1935). (2) A procedure successfully applied t o p-chloroethyl sulfide by LAWSON AND REID,J . Am; Chem. Soc., 47,2821 (1925). (3) PEICEAND ROBERTS, J . Ory. Chem., 12, preceding paper. (4) SNYDER, HOWE,CANNON, . ~ N DNYMAN, J . Am. Chem. soc., 66, 2211 (1943). (5) See KRETOW, J . Russ. phys.-chem. Soc., 62, 1 (1930) and ALEXANDEB AND MCCOMBII, J . Chem. SOC.,1913, (1931)for examples of the ease of addition t o vinyl sulfone& (6) BENNETTAND WHINCOP, J . Chem. SOC.,119, 1860 (1921).
