h scrios of suhstitutcd 3-thiomorpholinoncs was syiithesizcd. tising thrce difiereiit nicthotls. T I i c ~I I W coiiipounds were tested for hypnotic activity and those with one or two alkyl groups in thc 2-positioii \\.(lr(afoiind to be active,. Most of tiic :3-thiomorpholinones were oxidized to thc corrcspondiiig sulfoxides :~,iiil/or sulfones. which w c e found to be practically inactive.
The 3~thiomorpholinone~, which form the subject of this communication, were hynthesized in the hope of finding a ne?? group of heterocyclic compounds with hypnotic ( r sedative activity. Only the unsubstituted 3-thiCmorpholinone (I),I a few of its substitution products,* and some closely related 2,3-dihydro-4H-1 ,4-thiazin-3-ones3 have SO far been described. The present paper describes a series of 3-thiomorpholinones, substituted in positions 2, 4 , 5 , or 6. Thrce methods mere used for their synthesis. Method A, condensation of ethyl thioglycolate i t h acety1atc)d nitro alcohols (11), then reductive ring closure of the resulting ethyl nitroalkylmercaptoaretates (111), yielded 3-thiomorpholinones substituted in position 0, or 3 and G (IIT). S
>CH2
H&6/ I
HZC;
I
4
2I
>CO
H
I
R2C"0
+ R'CHzNOz
-
1
R'CHOH R'CHNO?
jcHiCoc'
111
17
While homologs of ethyl thioglycolate, with one or two alkyl groups in the a-position, also could be coiidensed with acetylated nitro alcohols t'o the corresponding nitroalkylmercapto esters (111), the reduction of these nitro compounds, with ring closure to thrb corresponding 3-thiomorpholinones, failed in most cases. Only 2-ethyl-6-methyl-3-thiomorpholi1ione was obtained by this method, though in very low yield, hy using ethyl a-mercaptobutyrate and l-nitro-2acetoxypropaiie. hlethod B, condensation of a-mercapto esters (\lj n-ith ethylenimine or its homologs (V), yielded 3-thiomorpholinones substituted in position 2, 4 or 5 (\211). The end products usually were obtained in one step. ITowever, in some cases the intermediate aminoalkylmercapto esters (VII) could be isolated and then ringclosed t,o the corresponding 3-thiomorpholinones. either 1)y heating for several hours at 150-180°, or by refluxing with sodium ethoxide in ethanol. ( I ) H. Restinn. Ann., 566, 210 (19301. ( 2 , (a) I. L. Knunyants and Rf. G . Linkova. Bull. A c a d . .S,f., i 62 (1935); (b) F. S. Babiohev and 5'. -1. Shokul. L'krain. K h i r r i . Zh., 2 2 , 215 (1956). 13) C . S.Skinner, .J. S. Clnlsiie, .LII(I .I. I ) . UabL,ert. .I. A m . Ciiern. S u c . , 81,
3736 (1Q5Y).
I-.
HS, ,R' YR \
1
I
R5
VI1
-I
I
R" 1111
EtOOC VI
\\'hen C-substituted cthylenimines (\-, It = alkyl, 1:' = H or alkyl, It5 = H) were used for thc coildensation with a-mercapto esters (1I), the position of these substituents 111 the 3-thiomorpholinone ring nas uncertain, since the ring cleavage of the C-sub stituted ethylenimines can proceed in tn-0 nays, leading either to 5- or to 6-substituted 3-thiomorphohones. Since G-methyl-3-thiomorpholinone (I\-, li' = I I . ItL= CH,), obtained unequivocally by method ,1from I-nitro-2-acetoxypropane (11, R: = H ; It2 = CIIa, and cthyl thioglycolate, Isas not identical n i t l i t h o methyl-3-thiomorpholinone obtained 1 y method JZ from 2-methylethylenimine (V, R = C€15; R1,1t5 = €3)and ethyl thioglycolate (\-I, It3,R4= TI), thc laltcti rompound represents the isomeric 5-methy1-:3-thiomorpholinonr (YIII, R = CH3; R1,K3,R4,R5= J I ) The cthylenimine ring, when condensed I\ itli CYnwrcapto esters, 15 therefore opened betu ern thc, nitrogen atom and the unsubstituted methylene group 1Zethod C, c*ondcnsation of p-mercaptoalkylaminci t I S ) \ii t l i a-halo wters (X), yielded the corrcspondiag .~-thioIllorpholinorirs (XI), substitutcd in positioii\ 2 a i d or .i i n oiic step.
' 1I
'1111smethod \r, as iiwlul 111 those cases whcre thc U mercapto esters u c w difficvlt to obtain. The mcrc*aptoalkylaminti iI S ) were obtained from ethylenimine or its homologs by reaction with hydrogeii sulfide. TL itli a-mucapto esters, C-substitutcd ethylenimines were cleaved by hydrogen sulfido I)(>tn een the nitrogen atom and the unsubstituted methylt'nr group. Thus, condcn-ation of ethyl a-l)romoacetatc (S.IL8,,Ii4 = TI: S = 13r) with I-mtwaptot'-aminoprupaiit~ (IS,It' = CIIJ), dc~ivrtl from 2 nic~thylcthyli~iiiminc,J iclded 5 - methyl - :
