THIOCIHBAJIATE DERIVATIVES OF ~-~IETHYL-~-PROPYL-~,~-PROPASEDIOL
][arch, 196-2
CHI
CH2
\ /
c
/ \
C3H7
\
S
175
Interpretation of the spectra shows that the two compounds have a methyl group on a completely substituted carbon, two methylene groups containing either hydroxy or thiol, and a terminal methyl group on an alkyl side chain. The presence of 16 hydrogens is shown in both cases by proton integration. These data are consistent with the structure features assigned to T'II. Treatment of VI1 with sodium cyanate and hydrogen chloride in anhydrous chloroform afforded the dithioldicarbamate (111) in low yield. The most favorable yields of I11 (38%) were obtained when anhydrous calcium sulfate was suspended in the reaction mixture, and the work up of the reaction was conducted under strictly anhydrous conditions. Thioncarbamate Derivatives.-Efforts to prepare the isomeric bis(thioncarbamate) (IV) directly from I, using thiophosgene and pyridine in an inert medium followed by ammonolysis, led to an intractable resinous product. M7e were successful in obtaining this compound according to the following sequence of reactions.
CH?SH
I
VI1
J HCiYO I11 Attempts to obtain VII via the bis(isothiouronium) salt by the reaction of TTa with thiourea were unproductive. KO reaction took place when the reactants were refluxed in 2-propanol for 21 hr. When the reaction was attempted a t 1.50' in dimethylformamide or propylene glycol, thiourea apparently underwent isomerization to ammonium thiocyanate6 a t a rate greater than it reacted with T'a, since ammonium tosylate was the only product which could be isolated from the reaction mixture. Bladon and Owen7 prepared dithiopentaerythritol in low yield from 0,O'-isopropylidenepentaerythritol ditosylate and excess potassium thiolacetate via the bis(thiolacetate) in either refluxing acetone or ethanol. Attempts to react T'a and T'b with potassium thiolacetate under the conditions employed by these authors were unsuccessful. When the reaction was conducted in ethanol or Methyl Cellosolve, the corresponding thietane (IX) was the major product formed. Compound T'II was successfully prepared when the reaction of Va or Vb with potassium thiolacetate was carried out in refluxing dimethylformamide. The reaction mixture was cooled, poured into water, and VI1 was isolated directly by ether extraction in 40% yield. The bis(thio1acetate) (T'III) could be isolated only when the reaction was carried out in dimethylformamide and worked up under anhydrous conditions. The dithiol compound (VII) mas also obtained in 10% yield by reacting TTa with potassium 0-ethylxanthate a t 130-140O in propylene glycol, followed by the reduction of the crude bis(0-ethylxanthate) (VI) with LiAlH,. I n view of the possibility of a neopentyl rearrangement occurring during the conversion of Va to VII, compounds I and VI1 were subjected to n.m.r. analysis. (6) N . F'. Sedgaick, "The Organic Chemistry of Nitrogen,'' T. W. J. Taylor a n d W. Baker, Ed., Oxford Unilprsity Press, London, England I U t U , p 290. (7) P. Rladon a n d 1.. N. O a ~ n Chem. Soc., 583 Cl050).
CHI
CHnOCSSNa
CHI
CHgOCSSR
\C/
\C/
/ \
CIH~
CHzOCSSNa
/ \
CaH?
CH?
CH&CSSCHy
\ /
c
CiHi
CHZOH
XI1
X
CHI
CH2OCSSCH
C'\
/-\
CH?OCSSCH,
/'
CiHi
SI
\
CH2OH
SI11
alr. N H ?
Iv
/ \
C3H7
CHzOH
XIV Reaction of I with 2 moIes of sodium hydride in refluxing xylene, followed by treatment with carbon bisulfide, formed the bis(S-sodium xanthate) derivative (X) which was converted to the bis(S-methylxanthate) derivative (XI) by reaction with methyl iodide. Treatment of crude XI with alcoholic ammonia led to IV in 60% yield. h monothioncarbamate (XIV) was obtained in low yield in another experiment by following the same reaction sequence outlined for IV but in the first step reacting I xith powdered potassium hydroxide in ether. Under these conditions the monopotassium xanthate derivative (XII) is apparently formed. The monothioncarbamate (XIV) on treatment with sodium cyanate and hydrogen chloride in chloroform yielded 2-methyl-2-propyl-l,3-propanediolmonothiondicarbamate (XVII). This compound was also prepared by thiophosgenation of the corresponding hydroxypropyl carbamate (XVI) followed by ammoniation of the intermediate chlorothiocarbonate. The
product of these reactions was identical in all respects with that formed from XIIT. Since the rompletioii of this ivork, a patent has heen issued to JYassoii arid Parker* T\ liich describes a coiiipound having the structure of the ~~is(t1iioiicarbarIlatc) derivative I V obtained by tlie iwctioii of tliioplio~geiic and I in tetrahydrofuran followed b y ammonoly;' Supporting analytical data for the componud arc not presented, but a comparison of the meltiiig point aiitl tlic infrared absorption maxima for the rompoiuitl with those of compormd I'i' iiidicates tliat tlic tivo substarices are riot identical. 'l'lie iiiiraietl q x c t r i i i i i 01 Wasson and Parker's compourid exliiliits tlie charactel istic C-0 stretching band for a primary alcoliol at I N 0 cm.- which is absent in the spectrum of coinpoiuitl IY. IIoreover, the maxima of tlicir compoiuid ai o idcntical with those of tlic n~oiiotl~io~icui~I,amatc' S I\ . 'l'liis eviderict', coupled itli t l i c incltiiig poilit data. leads us to conclude that the c ~ ) ~ i i p o ~dt+.ci.ik)td u~d 1)y TYasson and Parker is i n facat not tlic t,ih(tliioiic:irl)tLniatc) (IV) hut %-rnctliyvl-L'-pio p ~ ~ l - ~ H ioxypropyl ydi thioncarbamate (XIV). 1:urther proof of the identity oi IV IVRS affordctl 1)y its oxidation t o meprobamatr I I y d i o g t ~ i i pci okidc oxidation of IT.' yielded a compound identical uith 11 i l l its melting point and infrared absorption charactel istica. Muscle Paralyzing Activity.--l'hc tliioc.:2rt)amntc.r obtained in these studies n-ere cvaliiated for i n i i a c l c paralyzing activity arid lethality, risiiig wliitc mice of the CY-1 strain as previously dcscrik,cd Iiy I3ergci r , 1he PD60 and LDjU values. rrspecti\-ely, for these compounds in mg.1 kg. after iiitrapeiitoiieal administration were as follows. l,ih(tliiolcarbamate) (111) 212, 410; bis(thioncarba1nate) (117) ZLj, 4 i O ; moiiothioiidicarbaniate (XT.11) 138, .-ll.i. \ Y I i e i i coinpared to meprobamate (11) (23.5, SOOj, only tlic inoliotl~ioiidicarbamate possessed paialyzing activity sigiiificaiitly greater in iiiteiisity, and all ot tlic h i i l t u r aiia1og.s i v c ~ ~ : sonien hat inoi'c toxic thaii nic.pi.(,i):Lmatc. 7
I"
Experimental" P-;Methyl-2-propyl-1,3-propanediolDitosylate (Va).I2--p-Toluenesulfonyl chloride (191 g., 1 mole) JV:LS added portionivise with stirring to a solution of 66 g. (0.5 mole i of %-rnetlivl-2-prrrp~l-l,:3propanediol in 600 ml. of pJ,ridine. The temperature was mxintained at 18-20", A f k r standing overnight, the mixture was poured into a solution of 1850 ml. of methanol, '380 ml. of water, and 730 nil. of conrentrated hydrochloric acid. The mixture was refrigerated overnight and the white crystalline product (160 g., 72.59/,)was obtained bj- filtration. .1sample recrystallized from tlthanol melted a t 6 7 4 0 " . :Inal. Calcd. for C21H280&:8, l4..iii. Found: S, 14.55, 2-Methyl-2-propyI-l,3-propanediolBis(methanesu1fonate) (Vb).-To a solution of 66 g. (0.5 mole) of I in 400 ml. of pyridine a1 0-10", there was added tlropwise with stirring 125 g. (1.1 moles) (8) B. K. Wasson and J. 31. Parker, U. 9. P a t e n t 2,901,501 (1959). I n this reference, 2-rnethyl-2-propyl-l,3-bis(tliic1ncarbamate) is reported t o melt. a t 94-98' when crude, a n d a t 101-103° after recrystallization. The infrared spectrum ( R B r pellet) is reported a s showing maxima a t the followina frequencies: 3310, 3190, 2960, 1627, 1472, 1432, 1403, 1372, 1310, 1297, 1278, 1202, 1167, 1096, 1060, 1008, 979, 947, 932, 908, 747, and 644 tin.-'. (9) R. Kitamura. J . Pharm. Sor. J a p a n , 54, 1 (1934). (10) F. M. Rerger. J . Pharmacol. E x p ! l . Therap., 105, 450 (1952). (11) Microanalyses were performed b y Schwarzkopf hlicroanalytical Laboratory. Woodside. N. Y. Infrared spectra a-ere obtained using it I'erkin-Elmer Model 21 spectrophotometer; all solids were run in KBr pellets, liquids on NaCl plates. (12) This compound was first prepared b y hIr. Edward Simon and hlr. T o n y Cebalo of these laboratories.
of iiieth:inesulfonyl rhloritle. After standing a t 0" for I S hr., tlic rnistulc w.:is priiirrd into 2,.5 I. o f w:iicr and estrwteil with ctlit,r. 'Thr ethri. rstr:ic,i W:IS urislied v i t h :iqueous hydroi~iilriric:witl, 1 hy \%-:it c>r3 :in11 tlrird iiver :tnlijdri~us sotliiirli sirlfatr. crc~ils i i l i i l ion IV:F r(inc,t.ritr:liccl under reduc~rdprrssiire :ind 1ic~:itetlfor : i l i o i i i I lir. : i t 40' (0.1 iiini.) to rcjriiovc' unchanged riieth:inesiilf~in!I cliliiri~le. T l i e rrsit1u:il thick oil, which intainrtl rriitlh solxii,:ttcd was cstr:ic~id!\.it11 ether. The otlier ~ o l i i t i i i r iTV:IY \\-:isticd ivii h tlilutc alkali, fcdlovr.ec1 tiy water, dried over :inhydriius sodium sulfate, filtered, and concentrated under rediiretl pr~ssiirr. The red liqiiid residue (6,; g.) was used without, further purification fnr the. prrp:iration of YII. 2 Methyl 2 propyl 1,3 propanedithiol (VII). A. From 2I1Iethyl-2-propyl-l,3-propanedithiolBis(0-ethylxanthate).-The rrirtlc re3idur rcintainine \-I was dissolved in 250 ml. of anhydrous (stlier :ind :itlded dropwise with stirring to 21 g. of lithium d i i iiiiniitii 11)-dritlesuspended in 230 rn!. of ether. The mixture was lo\-r.etl to stand overnight. The excess with 123 nil. of aretone, :tnd the mixw i t h (i00 nil. of 9 AVsulfuric acid. The :itid c~str:ic~tetl witli three 100-nil. portlroxitle solution. The aqueous alkaline c,tl-ier, acidified with hydrorhloric arid, The dried ether extr:irt, was dist,illed ( 1 1 givv ;..i E. nf \.II, 11.p. :iO-(iO" (0.1 nini.): 1 ~ 1.2064. ~ 6 ~ BS1:C. 51.1; H, 9 3 2 ; S,39.0. F'oluid:
-
- -
-
-
-propyl-1,3-propanediol Ditosy1ate.---A rtiixture of 4s g . 10.11 1 niole) rrf T7a and 3 8 g. (0.333 mole) nf dry p(it :mi11i n t h i (rl:i(*et:it e in 300 nil. of ti i rnet h ylfor niamide w 3 s heated :it its refliis trniperature for IS hr. The cooled mixtiirc. wi.s poured into 300 nil. of water mid cxtmctecl with ether; the ct,hcr est rnct w:is a-ashcd with T a l e r and dried over anhydrous sodinrn siilfntr. 'Hie filirreti extract. was distilled giving 1 1 g. l o r ; , )lif vrr, k).ll. . i . i - x o 1 mini.); n2'9)I.slOi, il2Oor0.903. .t I m l . C:11rd. for r7fr1 I f D, -19.92. Fount1 : - l f ~49.37. , .I I,is!2,,l-tiinitr(iljhf~ri. sulfide) derivative, 1ii.p. '30-9%", w:is prep:ired f r o i i i VI1 with 2,4-dinitriic.lilort~~eii~~ne according t o the prorrtliirr of Thist. ct nl.Ia .Lnnl. ( " : i l i ~ I , f o r ( L"x-',o&: (1, -1.>.95: H, 4.06; s, 11.L"); 9,1?.
