July 5, 1958
N,N ’-DI-(u-CARBOXYALKYLCARB AMYL) -POLYMETHYLENEDIAMINES
[CONTRIBUTION NO. 17 FROM
THE
3335
L. G. RYANRESEARCH LABORATORIES O F MONSANTO CANADA LTD.]
Amino Acids. VII. N,N’-Di-(o-carboxyalkylthiocarbamy1)-and N,N’-Di-(~-carboxyalkylcarbamyl)-polymethylenediaminesand their Derivatives BY A. F. MCKAY,S. GELBLUM, E. J. TARLTON, P. R. STEYERMARK AND M. A. MOSLEY RECEIVEDDECEMBER 16,1957
A series of N,N’-di-(w-carboxyalkylthiocarbamyl)-polymethylenediamines have been prepared by condensing w-amino acids with the salts of polymethylenebisdithiocarbamates. The N,N’-di-(w-carboxyalkylthiocarbamyl)-polymethylenediamines were converted into the corresponding N,N’-di-(w-carboxyalkylcarbamyl)-polymethylenediamines by oxidation in alkaline solution with hydrogen peroxide. A number of esters of these dicarboxylic acid derivatives have been prepared by esterification in the presence of either sulfuric acid or dry hydrogen chloride. Glycine condensed with disodium ethylene and bisdithiocarbamate to give 1,2-di-(3,3’-(2-thiohydantoinyl))-ethane,N,N’-Di-(ij-carboxyethylthiocarbamy1)-ethane -butane have been cyclized with polyphosphoric acid to 1,2-di-(3,3’-(2-thiohydrouracilyl))-ethaneand 1,4-di-(3,3’-(2-thiohydrouracily1))-butane, respectively. N,N’-Di-(p-carbomethoxyethylthiocarbamyl)-hydrazine gave 3,5-dithio-4-(p-carbomethoxyethyl)-2,3,4,5-tetrahydro1,2,4-triazole.
A new series of linear dibasic acids (111) have been prepared by heating aqueous solutions of the alkali metal salts of polymethylenebisdithiocarbamates with two equivalents of w-amino acids. Disodium tetramethylenebisdithiocarbamate (11, m = 4) and e-aminocaproic acid gave an Slyoyield of NJ’-di-( e-carboxypentylthiocarbamy1)-tetramethylenediamine (111,n = 5, m = 4) and a 17.S% yield of tetramethylenethiourea (IV, m = 4). The physical properties of the N,N’-di-(w-carboxyalkylthiocarbamy1)-polymethylenediamines pre-
pared during this study are described in Table I. Methylation of the dithiourea dibasic acid derivatives I11 was accomplished by the use of 1% dry methanolic hydrogen chloride or by using concentrated sulfuric acid as an esterifying agent. Several of these esters are listed in Table 11. The N,N’ - di - (w - carboxyalkylthiocarbamy1)polymethylenediamines (111) in aqueous alkaline solutions are converted in good yields into the corresponding N,N’-di - (w - carboxyalkylcarbamy1)polymethylenediamines (V) on oxidation with hy-
TABLE I N, N’-DI-(W-CARBOXYALKYLTHIOCARBAMYL) -POLYMETHYLENEDIAMINES S S
/I
I/
HOOC(CHz)nNHCNH(CHz),NHCNH( CHz)nCOOH 12
m
2 3 5 3 5 2 3 5 3 5 3 5
2 2 2 3 3 4 4 4 5 5 6 6
Yield,Q
%
M.P., o c .
201-202 161-162 133-134 128-130 132-133 165-166 153-154.5 150-152 138-140 126.5-128 158-159 144-145
22.3 29.9 36.0 40.1 59.4 41.0 61.4 64.9 18.6 42.5 43.9 46.3
Formula
Carbon, % Celcd. Found
CloHl~N404S2 37.25 C12H22N404S2 41.12 47.27 CIBH~~N~O& C ~ ~ H Z ~ N ~42.84 O~SZ Ci,HmN404Sz 48.54 41.12 C~~HZ~NIO ~SZ C ~ ~ H Z ~ N ~44.42 O~SZ C18H34N404S2 49.74 45.89 C~E,HZINIO~S* C ~ ~ H ~ S N ~50.86 O~SZ C ~ B H ~ ~ N ~47.27 O~SZ CmH38N40&32 51.91
37.30 41.28 46.91 42.58 48.16 41.05 44.26 49.55 45.88 50.75 47.21 52.08
Hydrogen, % Calcd. Found
5.63 6.33 7.44 6.64 7.67 6.33 6.93 7.89 7.19 8.09 7.44 8.28
6.00 6.43 7.53 6.42 7.81 6.31 7.05 8.14 7.06 8.19 7.56 8.46
Nitrogen, % Calcd. Found
Sulfur, % Calcd. Found
17.38 15.99 13.78 15.37 13.32 15.99 14.80 12.89 14.27 12.49 13.78 12.11
19.89 18.30 15.77 17.59 15.25 18.30 16.94 14.76 16.34 14.29 15.77 13.86
17.64 16.30 14.01 15.45 13.11 16.27 15.13 13.32 14.35 12.94 13.48 12.13
20.08 17.92 16.00 17.66 15.16 18.47 16.97 14.98 16.00 14.38 15.44 13.73
Yield of pure product. TABLE I1 ESTERSO F N,N’-DI-(W-CARBOXYALKYLTHIOCARBAMYL) -POLYMETHYLENEDIAMINES
S
S
/I
I/
R O E ( CHz),NHCNH(CHZ)~NHCNH( CH2)nC0zR Carbon, % Hydrogen, %
Yield,
R
n
CHs CH3 CH3
2 3 5 2 3 5
CH3 CHI
CHa n-C14Hze
5
CHa CH3
3
n-CirHzp
5
5
m
M.P., “ C .
%
Formula
Calcd.
Found
C~ZHZ~SPO~SZ 41.12 41.26 CiaHzeN404Sz 44.42 44.31 CleHasN404Sz 50.86 51.14 C14H~Nd04Sz 44.42 44.20 ClsHaoNaO4S2 47.26 47.47 CzoHssN4OdS2 51.91 51.65 C ~ S H ~ ~ N ~ O66.77 I S Z 66.89 C~SH~~N~O 49.74 ~ S Z 49.74 CzzH4zN404Sz 53.84 53.69 67.20 C ~ ~ H Q ~ N ~67.40 O~SZ
Calcd.
Found
Nitrogen, % Calcd. Found
6.33 6.92 8.08 6.92 7.43 8.27 10.96 7.88 8.62 11.07
6.36 6.88 8.01 6.88 7.36 8.25 10.96 7.90 8.64 10.77
15.99 14.80 12.48 14.80 13.78 12.11 6.77 12.89 11.42 6.55
18.30 18.15 16.94 17.09 14.29 13.90 16.94 17.27 15.77 15.91 13.85 13.71 7.75 7.83 14.76 14.77 13.06 12.68 7.49 7.91 yields were obtained in the reaction of 0-carbomethoxyethyl isothiocyanate with ethylenediamine and 1,42 2 3 4 4 4 4 6 6 6
138-139 117-118 103-105 94-95 122-123 122-123 113-114 73-74 79-80 97-98
5 The higher diaminobutane, respectively.
17(79)” 50.9 34.1 37(92)“ 84.5 31.0 43.6 29.5 81.1 38.4
16.25 14.60 12.28 15.11 13.44 12.10 6.64 12.98 11.80 6.79
Sulfur, % Calcd. Found
A. F.MCKAY,S. GELBLUM, E. J. TARLTON, P. R. STEYERMARK AND M. A. ~ T O S L E Y
3336
Vol. SO
TABLE I11
N,N’-~I-(W-CARBOXYAI,KYLCARBAMYL) -POI,YIMBTHYL&NEDIAMINES 0
0
I1
I1
€I0OC(CHz)~NIICNH(CHz)mNHCNH(CH~)~~C0OH n
m
M . p . , ‘C.
2 3 5 3 5 2 3 5 3 5 3 5
2 2 2 3 3 4 4 4 5 5 6 6
209-210 181-182 182-183 165-166 170-171 185-186 18.5186 188-189 168-169 169-170 172-173 183-184
Yield,
%
Carbon, 7% Calcd. Found
Formula
41.46 44.92 51.62 47.08 52.52 45.49 48.40 53.47 49.84 54.87 51.28 55.41
CioHlsN4Os 41.37 CizHzzNIO6 45.27 C16H30N408 51.32 C ~ ~ H Z ~ N ~ O46.98 K C17HjzN406 52.56 CizHzzN106 45.27 CiiHzsN408 48.54 C1&4N40( 53.71 CI~HZRNIOP, 49.99 Cl~H36NlO6 54.79 CiaHioN406 51.32 CzoH38N406 55.79
81.0 90.5 92 1 83.3 91.8 85.0 94.0 90.6 87.2 89.5 86.0
90.9
Hydrogen, % Calcd. Found
Nitrogen. %, Calcd. Found
6.25 6.97 8.08 7.28 8.31 6.97 7.57 8.52 7.82 8.71 8.08 8.90
19.42 17.60 14.96 16.86 14.42 17.60 16.18 13.92 15.55 13.45 14.96 13.01
6.45 6.91 8.12 7.25 8.46 7.36 7.57 8.61 7.97 8.71 8.14 8.90
19.09 17.70 14.91 16.97 14.37 17.78 16.67 13.79 15.78 13.58 15.17 12.80
TABLE IV
ESTERS OF N, N’-DI-(CO-CARBOXYALKYLCARBAMYL) -POLYMETHYLENBDIAMINES 0
0
I1
I1
ROzC( CHz)mNHCNH(CH*)mNHCNH(CH2)nCOzR R
n
m
M.p.,“C.
CH3 CH3
3 5 5 3 5 6 3 3 5 5 5
2 2 2 3 3 3 4 4 4 4 6
171-172 169-170 153-1 54 170-1 71 158-1 59 140-141 192-193 161-162 187- 188 166-169 192- 196
Yield,
Carbon, % ’ Calcd. Found
Hydrogen, % Calcd. Found
Nitrogen, % ’ Calcd. Found
99.8 91.8 56.0 52.3 85.7 73.5 83.9 46.5 87.3 91.5 61.2
48.54 53.71 68.86 49.98 54.79 69.16 51.33 68.23 55.80 69.46 57.61
7.57 8.51 11.30 7.83 8.71 11.35 8.08 11.19 8.89 11.41 9.23
16.17 13.92 7.31 15.55 13.45 7.17 14.96 7.58 13.02 7.05 12.22
75
drogen peroxide. The properties of these N,N’di - (w - carboxyalkylcarbamyl) - polymethylenediamines and some of their diesters are described in Tables I11 and IV, respectively.
S
S
1;
I/
48.67 53.81 69.18 49.75 54.53 69.07 51.27 67.96 55.54 69.21 57.43
7.60 8.53 11.31 7.91 8.46 11.05 8.28 10.78 8.81 11.21 9.36
15.67 13.72 7.72 15.38 13.37 7.08 14.72 7.77 13.27 7.54 12.61
ethylenediamine (111, n = 2, m = 2 ) and -tetramethylenediamine (111, n = 2, m = 4) were cyclized to 1,2-di-(3,3’-(2-thiohydrouracil yl)) ethane (VII, m = 2) and 1,4-di-(3,3’-(2-thiohydro-
0 11202
H0OC(CIIz)~?jHCNH(C€Iz)~~SIICSII(CIIz)nCO0H ---+
0
It
It
H~OC(CHI)~NHCNII(CHZ)~~NRCNH(CH~)~CO~H V
111
A cyclic product was obtained by heating two uracily1))-butane (VII, rn = 4), respectively, by equivalents of glycine together with an aqueous S S solution of disodium ethylenebisdithiocarbamate. /I tl C C The analytical values for the new compound agree with those calculated for the expected 1,3-di-(3,3’(2-thiohydantoinyl)) -ethane (VI). S S
I/
11
C
C
/ \
HN
I
N-CHzCH2-7S
1
CHz-C=O
/ \
I
SCHa I
NIT
1
N/
I
N,N’-Di-(P-carboxyethylthiocarbamy1)-
(1) The formation of thiohydantoins from substituted thioureas is J. Chem., 36, 496 (1958).
discussed fully i n Amino Acids I V . Can.
c
c
O~C-CHz
VI
The
SCIIS I
I
1
HzC C=O m = 2 or 4
/ kN
\N-(CHz),-N
\ /
CHZ
VI11
O=C
1 .2CHaHSO4 CHz
\ /
CHz
July 5 , 19%
N,N '-DI-(~-CARBOXYALKYLCARBAMYL)-POLYMETHYLENEDIAMINES 3337
5 ]./mole of ethylenediamine) in order t o separate pure material. Investigation of condensation conditions to produce this compound (111, n = 5, m = 2) revealed that a3070 increase of amino acid in the reaction mixture raised the yield of pure product from 29 to 36%. The impurity (pentamethylenethiourea or its polymer) of crude I11 (n = 3, m = 5 ) was less soluble than the thiourea diacid. The desired product was obtained by concentration of the mother liquors after crystallization of the crude material from 50% methanol-water. The remaining conipounds (111, n = 5, m = 5; n = 3, m = 6; n = 5, m = 6) were purified by reprecipitation with hydrochloric acid from their solutions in 5% aqueous sodium bicarbonate. The impurities (polymethylene thioureas) were insoluble in cold (10') bicarbonate solution. N,N '-Di-( carboxyalkylcarbamy1)-polymethylenediamines. -The N,N'-di-(carboxyalkylthiocarbamyl)-polyrnethylenediamines were oxidized with alkaline hydrogen peroxide solution into the corresponding N,N'-di-(carboxyalkylcarbamy1)-polymethylenediamines. The physical properties of the latter series of compounds are described in Table 111. The oxidation of one of these compounds was conducted as follows: a solution of N,N'-di-(E-carboxypentylthiocarbamy1)-tetramethylenediamine (1.O g., 0.0023 mole) and sodium hydroxide (0.55 g., 0.14 mole) in water (10 cc.) S was treated a t 20-25' with 2.40 cc. of 7.7 molar hydrogen II peroxide solution. This solution was allowed to stand a t C room temperature overnight after which it was acidified to a pH of 2.5. The mixture was diluted with water (50 cc.) CHrOOCCH1CH2d N 'H and the product was recovered by filtration, yield 0.82 g. I I (90.6Y0). The melting point was raised from 177-179" IX S=C-NH to 188-189" by two crystallizations from glacial acetic acid. I t was relatively insoluble in water, acetone, ethanol, Experimental2 aqueous methanol and aqueous ethanol but it was soluble in N ,N '-Di-( carboxyalkylthiocarbamy1)-polymethylenedi- dimethylformamide. amines.--A series of N,N'di-(carboxyalkylthiocarbamy1)Diesters of N,N'-Di-(w-carboxyalky1thiocarbmyl)-polypolymethylenediamines have been prepared and their prop- methylenediamines. Method A.-N,N '-Di - ( y carboxyerties are listed in Table I. The methods of preparing these propylthiocarbamyl )-tet ramethylenediamine (2.O g , 0.0053 compounds are very similar and only the preparation of mole) in 25 cc. of 1% methanolic hydrogen chloride solution h',N'- di ( e - carboxypentylthiocarbamyl)- tetramethylenediwas allowed to stand a t 10' for 16 hours. The solvent was amine is described in detail. removed in vacuo and the crystalline residue was crystalCarbon disulfide was added dropwise to a stirred solution lized from acetone-pentane solution, yield 1.90 g. (84.5%). of 1,4-diaminobutane (22.0 g., 0.25 mole) in water (91 cc.) This crude ester (m.p. 90-95') could not be purified easily a t 40" until the p H dropped from the original value of 12.5 by direct crystallization. A portion (1.03 9.)was dissolved t o 9.3. This required about 19 g. (0.25 mole) of carbon diacetone (20 cc.) and the solution was passed through a sulfide. A solution of sodium hydroxide (20 g., 0.50 mole) in column of neutral alumina (30 g.; 2.0 cm. dia.). The acein water (80 cc.) and carbon disulfide (19 g., 0.25 mole) were tone were combined and evaporated to dryness. added simultaneously so that the temperature remained a t After eluates the residue was crystallized from acetone, it melted 40-43' and the pH a t 9.8-10.5. The final clear orange a t 122-123". yield 0.48 g. solution had a pH of 10.7. Method B.-A mixture of N,N'-di-(ccarboxypentylA portion (87 cc.) of the above solution containing 0.1 thiocarbamy1)-tetramethylenediamine (5.0 g., 0.011 mole) mole of the 1,4-diaminobutane-carbon disulfide reaction and myristyl alcohol (6.17 g., 0.028 mole) heated in a product was combined with a solution of eaminocaproic wax-bath a t 130' until it became molten.wasSulfuric acid acid hydrochloride (33.5 g., 0.20 mole) and sodium hydroxide (8.0 g., 0.20 mole) in water (100 cc.). This mixture was (0.25 cc.) was added and the clear melt was heated a t 130' refluxed for 7 hours until the evolution of hydrogen sulfide under a stream of nitrogen for 2 hours. After the reaction had subsided. The cooled solution was filtered and the pH mixture had cooled to room temperature, it was triturated with ether. The insoluble ester (m.p. 105-110°) weighed of the filtrate was adjusted to 2 with 37% hydrochloric acid 4.16 g. (43.6%). It was dissolved in chloroform (100 cc.) solution. The resulting precipitate was removed by filtra- and the chloroform solution was passed through a column of tion and dried, yield 35.2 g. (8170). The product was neutral alumina (30 g.; 2.0 cm. dia.). The fractions on purified by two crystallizations from methanol-water solu- evaporation gave a crystalline residue which was recrystion. The filtrate was evaporated in Dam0 under nitrogen to a tallized from ethyl acetate (25 cc.). The pure dimyristyl volume of 100 cc. when crystals began to separate from the ester melted a t 113-114', yield 2.77 g. Diesters of N,N'-Di-( w-carboxyalkylcarbamy1)-polymethsolution. These crystals melted at 174-176", yield 2.31 g. ylenediamines. Method A.-N,N'-DL(ecarboxypenty1(17.8%). One crystallization from absolute alcohol raised the melting point to 179.5-180.5'. Strack3 reported a carbamyl)-trimethylenediamine (1.O g., 0.0025 mole) in melting point of 177" for tetramethylenethiourea. A methanol (30 cc.) containing 10% by weight of dry hydrogen mixed melting point determination with a known' sample chloride was allowed to stand a t room temperature overof tetramethylenethiourea (m.p. 177-179°) showed no de- night. The almost clear solution was filtered and the filtrate was evaporated to dryness. On addition of water (5 pression. The other dithiourea diacids were obtained in crude cc.) to the semi-liquid residue a crystalline product (m.p. yields of 40.0 to 84.4%. The following compounds (111) 153-156') was obtained, yield 0.917 g. (85.7%). Cryswere purified by straight-forward recrystallization: n = 2, tallization from metha201 raised the melting point to a conm = 2 (2074 ethanol-water); n = 3 , m = 3 (water); n = stant value of 158-159 Method B.-The myristyl esters of the N,N'-(w-car5 , m = 3 (28% methanol-water); n = 3 , m = 4 (acetonewater). The purification of 111 ( n = 5, m = 2 ) required boxyalkylcarbamy1)-polymethylenediamineswere prepared in the same manner as described above for the preparation careful recrystallization conditions (20y0 methanol-water, of the myristyl esters of the N,N'-di-(w-carboxyalkylthiocarbamyl)-polymethylenediamines. The dimyristyl esters (2) All melting points are uncorrected. Microanalyses were dewere purified by direct crystallization without previous termined by Micro Tech Laboratories, Skokie. Ill. passage through alumina. (3) E. Strack. 2. physiol. Chem., 180, 198 (1929). Reaction of Disodium Ethylenebisdithiocarbamate with (4) A. P. McKay and M.-E. Kreling. Can. J . C h m . , 86, 1438 Glycine.-An aqueous solution (37 cc.) containing 0.05 mole (1957).
heating with polyphosphoric acid. These bicyclic derivatives V I 1 were converted into the corresponding S-methyl derivatives VI11 by methylation with dimethyl sulfate. The free bases, 1,2-di(3,3' - (S - methyl - 2 - thiohydrouracilyl)) ethane and 1,4 - di - (3,3' - (S - methyl - 2 - thiohydrouracily1))-butane, were prepared from their di-(methyl hydrogen sulfate) salts by treatment in aqueous solution with aqueous ammonia. N,N' - Di - ( p - carbomethoxyethylthiocarbamy1)hydrazine was prepared by treating hydrazine hydrate with two equivaIents of @-carbomethoxyethyl isothiocyanate. This symmetrical hydrazine derivative on heating in the presence of polyphosphoric acid gave a new compound melting a t 142'. The analytical values of this new compound are in good agreement with those calculated for 3,5 - dithio - 4 - ( 6 -carbomethoxyethyl) - 2,3,4,5tetrahydro-l12,4-triazole (IX).
-
-
-
.
.
3338
A. F. MCKAY,S.GELBLUM, E. J. TARLTON, P. R . STEYERMARK AND h l . A. ~ I O S L E Y Vol. SO
of disodium ethylenebisdithiocarbamate was treated with glycine (7.5 g., 0.1 mole) in water (50 cc.). This mixture was refluxed for 7 hours and the solution was cooled and filtered. The filtrate was evaporated t o dryness zn vaczto and the residue treated with concentrated hydrochloric acid (50 cc.). The resulting mixture was heated for 45 minutes on a steam-bath and the insoluble yellow product (m.p. 280" with dec.) was recovered from the cooled mixture by filtration, yield 5.72 g. (44.370). This product was insoluble in boiling acetone, methanol, benzene, ethyl acetate, ethanol, chloroform, water and acetic acid, although it was slightly soluble in aqueous acetone and dilutc acetic acid. I t melted with decomposition around 280" after it was crystallized from dimethylformamide-water solution. The compound is soluble in cold diniethylformamide. Anal. Calcd. for C8H10N4O2S2: C, 37.19; H, 3.90; X, 21.69; S, 24.83. Found: C, 37.67; H, 3.99; S,21.55; S,24.45. p-Carbomethoxyethyl isothiocyanate (b.p. 110-112" ( 1 mm.)) was prepared in 81% yield as previouslys described. Reaction of p-Carbomethoxyethyl Isothiocyanate with Polymethy1enediamines.-p Carhomethoxyethyl isothiocyanate (2.7 g., 0.018 mole) was added to a solution of tetramethylenediamine (0.82 g., 0.009 mole) in absolute methanol (6 cc.). After the mixture was refluxed for 2 hours, it was cooled and then diluted with petroleum ether (90 cc.). On standing in t h e refrigerator for 3 hours, this solution gave 3.23 g. .(957$) of crystals. The melting point of the crudc N,X'-di - (6 - carbomethoxyethylthiocarbamy1)-tetramethylenediamine was raised from 88-90' to 94-95' by one crystallization from acetone-petroleum ether (2 :3 ) solution, yield 2.78 g. A similar reaction with ethylenediamine gave a 79yc yield of crude N,N'-di-( P-carbomethoxyethylthiocarbamy1)-ethylenediamine (m.p. 129-131'). Several crystallizations from acetonepetroleum ether (1 :4) raised the melting point to N,N'-Di-(P-carbomethoxyethylthiocarbamy1)138-139'. ethylenediamine and -tetramethylenediamine are described in Table 11. Alkaline hydrolysis of these diesters gave the corresponding diacids (111, IZ = 2, nz = 4 and n = 2 , 111 = 2 ) in 92-94% yields. N,N'-Di-( p-carbomethoxyethylthiocarbamy1)-hydrazine.A solution of @-carbomethoxyethyl isothiocyanate (2.98 g., 0.02 mole) and hydrazine hydrate (0.5 g., 0.01 mole) in methanol (10 cc.) was refluxed for 80 minutes. n'hen the solution cooled t o room temperature, it was diluted with acetone (20 cc.) and petroleum ether (TO cc.). .4fter the mixture was cooled for 2 hours, the crystals ( m . p . 169-17'0") were removed by filtration, yield 2.45 g. (7'6q). Crystallization from acetone-petroleum ether (1:1) solution raised t h e melting point t o 171-172". Anal. Calcd. for C I O H I ~ S ~ OC~, S37.25; ~: 13, 5.63; x, 17.38; S, 19.89. Foiilld: C, 37.28; H, 5.5.5; S , 17.56; s, 19.78. 1,Z-Di-( 3,3'-( 2-thiohydrouracilyl))-butane.-The polyphosphoric acid used in the following cyclization reaction was prepared by adding phosphoru3 pentoxide (36 9.) to 85Oj, phosphoric acid (25 cc.). This mixture was stirred for approximately 0.5 hour until no more phosphorus pentoxide dissolved. After t h e solution was filtered through glass wool, it was stored in a glass stoppered flask. hT,N'-Di-(p-carboxyethylthiocarbamy1)-tetramethylenediamine (9.67 g., 0.028 mole) was mixed into a thick paste with preheated (80') polyphosphoric acid ( c a . ;i cc.). Thc paste was heated a t 15C-l6OD with occasional stirring for l o minutes after which the reaction mixture was cooled and diluted with water (250 cc.). This diluted reaction product was allowed to stand in the refrigerator overnight, after which the crystalline product (m.p. 241-243' with dec.) was recovered by filtration, yield 747,. Three crystallizations from aqueous formic acid solution raised the melting point t o 253-254' dec. Anal. Calcd. for C12HlsX40&: C , 45.85; H, 5.77'; K, 17.82; S, 20.40. Found: C, 45.40; H , 5.88; N, 17.78; S,20.18. A sample of 1,4-di-(3,3'-(2-thiohydrouracilyl))-butane (1.12 g., 0.0035mole) in dimethyl sulfate ( A cc.) was heated a t 125" until a clear solution was obtained. ,!.fter the clear
-
( 5 ) D. L. Garmaise, R . Schwartz atid A . F. McKay. T i r r s J O I I R N A T . , BO, 3332 (1958).
solution was heated a t 100" for 1 hour, it was cooled. The solution was diluted with acetone (25 cc.) and ether (65 cc.) and the needle-like crystals were removed by filtration, yield 1.32 g. (65,37,). The melting point was raised from 152154" to l 5 R l 5 9 ' by one crystallization from 907' aqueous acetone. The analysis indicated that a di-(methyl hydrogen sulfate) salt of the methylated product was prepared. Anal. Calcd. for C&&401&: C, 33.92; H, 5.34; N, 9.89; S, 22.63. Found: C , 33.91; H, 5.67; S , 9.91; S, 22.78. The dipicrate of 1,4-di-(3,3'-(S-methy1-2-thiohydrouracily1))-butane was prepared in the usual manner from water. I t melted a t 182-183" dec., yield 83%. Anal. Calcd. for c2GIIzgS&6s2: C, 38.99; H, 3.52; S,17.49; S,8.01. Found: C,88.70; H,3.71; X, 17.55; S , 7.82. .I small sample of 1,4-di-(3,3'-(S-rnethy1-2-thiohyclrouracily1))-butane di-(meth>1 hydrogen sulfate) (0.20 g., 0.00035 mole) in water (1 cc.) ivaq treated dropwise with dilute ammonia solution until an alkaline reaction was obtained. The white precipitate (m.p. 185-186') was recovered b y filtration, yield 0.115 g. (92%,). The melting point did not change after several recrystallizations. Anal. Calcd. for ClrH?,N402S2: C , 49.10; Ii,6.48; X, 16.36; S, 18.72. Found: C, 49.31; IT, 6.51; X, 16.00; S,18.23. 1 ,2-Di-(3,3'-( 2-thiohydrouracilyl) )-ethane .--N ,S'-Di-( pcarboxyethylthiocarbamq-1)-ethylenediamine(9.42 g., 0.029 mole) was cyclized to 1,2-di-(3,3'-(2-thiohydrouracilyl))ethane i n 7'37, yield by the method described above for the preparation of 1,4-di-(3,3'-(2-thiohydrouracilyl))-butane. After crystallization from formic acid-mater (1: 3 ) , the melting point was raised from 291-293" to 294-296' dec. Anal. Calcd. for C~OH~~NIOZSZ: C, 41.95; H, 4.93; N, 19.57; S , 22.40. Found: C, 41.90; IT, 4.91; K, 19.65; s, 22.27. ,2 sample (3.63 g., 0.013 mole) of 1,24-(3,3'-(2-thiohydrouracily1))-ethane was methylated with dimethyl sulfate (initially a t 160" and finally a t 125") and the product was isolated under the conditions described above for the di(methyl hydrogen sulfate) salt of 1,4-di-(3,3'-(S-methyl-2thiohydrouracily1))-butane. Thc crudc product melted a t 185-190", yield 6.60 g. (97yc). Crystallization from mater-acetone (1: 13) solution arid methanol-acetone (1 :2.3) solution raised the melting point t o 202-203". Anal. Calcd. for Cl4H26T\i4o&4: C , 31.22; €1, 4.87; N, 10.40; S , 2 3 . 8 0 . Found: C,31.36; H,3.91; S , 10.18; S,24.13. The dipicrate (m.1). 214-210' dec.) was formed in 74% yield from aqueous solution. The picrate was purified by solution in methanol-acetone (1:I) solution and precipitation with petroleum ether. It melted a t 220-222" dec. Anal. Calcd. for C ? & ~ N J ~ O ~ C, ~ S 87.31; ~: H, 3.13; N, 18.13; S, 8.30. Found: C, 37.18; H, 3.40; N, 18.16;
S,8.17. 1,2-Di-(3,3'-(S-niethyl-2-thiohydrouracilyl))-cthanedi(methyl hydrogen sulfate) was converted into its free base in 63c7, yield by the dropwise addition of ammonia to its aqueous solution as described above in the preparation of the butane homolog. The melting point of the free base was raised from 165-166' t o 167-168" by two crystallizations from acetoile-petroleum ether (1:15) solution. Anal. Calcd. for C I Z H I ~ K ' ~ O ~CS, ~45.84; : H, 5.77; N , 17.82; S, 20.40. Found: C, 46.03; 13, 5.85; N, 17.82; s, 19.81. 3,5-Dithio-4-( p-carbomethoxyethyl)-2,3,4,5-tetrahydro1,2,4-triazole.--X thick paste of L-,h"-di-(p-carbomethoxyethylthiocarbamy1)-hydrazine (1 .O g., 0.003 mole) in polyphosphoric acid (ca. 5 cc.) was heated a t 120' for 7 minutes. After the cooled mixture was diluted with water (100 cc.), the aqueous mixture was placed in the refrigerator for 1.5 hours. The product (m.p. 141-142') was recovered by filtration, yield 0.3 g. (427,). The melting point was not changed by further crystallization. Annl. Calcd. for C S H ~ N ~ O ZC, S ~32.86; : H, 4.14; N , 19.16; S,29.21. Found: C, 32.78; H, 4.26; 9,19.12; S,28.60. VILLE LASAII E, Qr-EBEC,CANADA
