[CONTRIBUTION FROM THE
BIOTIN.
LEDERLELABORATORIES]
V. c i s 3 ,4-DIAMINOTHIOPHANE
B. R . BAKER, MERLE V. QUERRY, S. R. SAFIR, W. L. McEWEN, AND SEYMOUR BERNSTEIN
Received July 29, 1946
Previous communicatio& in this series (1, 2) have shown that treatment of 2-alkylthiophane-3 ,4-cis-dicarboxylic acid esters with hydrazine caused inversion of configuration to take place with the formation of 2-alkylthiophane-3, $-transdicarboxhydrazides. As other methods of degrading both cis-carboxyls simultaneously t o cis-diamines also failed, it became apparent that the carboxyl groups would have to be degraded one at a time. Investigation of the stepwise degradation of thiophane-3,4-dicarboxylicacid has now led to two methods of synthesizing cis-4-uranilinothiophane-3-carboxhydrazide(XIV) which in turn could be further degraded to cis-3 ,4-diaminothiophane. Thiophane-3 ,4-cis-dicarboxylic anhydride (IV) , when refluxed with methanol, gave a crystalline monomethyl ester (V), which was converted to the cis-methylanilide, VI, via the acid chloride. Heated with hydrazine, the cis-4-(N-methylcarbanilido)-3-carbomethoxythiophane (VI) failed t o give the desired cis hydrazide corresponding to VIII. Instead a mixture of trans-b(N-methy1carbanilido)thiophane-3-carboxhydrazide (VIII) in about 35% yield along with lesser amounts of thiophane-3 ,4-trans-dicarboxhydrazide and thiophane-3 ,4cis-dicarboxy-N ,N'-cyclic hydrazide were formed. The configuration of TI11 was established as trans in two ways. Acid hydrolysis resulted in trans-4-(Nmethylcarbanilido) thiophane-3-carboxylic acid which was identical with a sample synthesized by treating the diacid chloride of thiophane-3 ,4-trans-dicarboxylic acid (11) with a limited amount of methylaniline. The secondproof consisted of treating the cis ester anilide, VI, with methanolic sodium methoxide, causing inversion to the isomeric trans ester, VII, in 90% yield. The latter smoothly reacted with hydrazine with formation of trans-4-(N-methylcarbanilido) thiophane-3-carboxhydrazide (VIII) , identical with that obtained from cis ester anilide, VI. Although this method failed to give a cis hydrazide, the Curtius degradation was carried out in order to have reference compounds of the trans series. The so obtained trans-3-carbethoxyamino-4-(N-methylcarbanilido)thiophane (IX) was hydrolyzed with hydrobromic acid to trans-3-aminothiophane-4-carboxylic acid (X), characterized as its benzoyl and phenylurea (XI) derivatives. When the acid chloride of thiophane-3 ,4-cis-dicarboxylic acid monomethyl ester (V) was treated with sodium azide and the resulting azide rearranged t o cis-3-carbomethoxy-4-carbomethoxyaminothiophane, the latter could not be crystallized. Hydrobromic acid hydrolysis of the crude product followed by benzoylation gave cis-4-benzoylaminothiophane-3-carboxylic acid, isomeric with the trans acid described above. However, when the azide was rearranged and the isocyanate treated with aniline, crystalline cis-3-carbomethoxy-4-uranilino174
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V
0
/\ co co
COOH
trans IX
trans
trans VI11
cis VI
VI1
I
I
I"' 1
trans XI
TI
-I
NH C 0 "
COOH
HC*/,
CsH&
I
I
trans XVII
cis XI1
trans XVI
I
Tgg
NH-CQ-NCaHs
I
I
cis
xv
NHC ONHCsH6
cis
x IV 5. 0
NHCONHCsHs
~--,CONHNH~
\s/ trans XVIII R = -0CzHs X I X R = -NHCsHs
\S trans XX
II
It / c \
I;XHC~
NH COIGI CsHs
0
cis XXI
cis XXII
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BAKER, QUERRY, SAFIR, MCEWEN, BERNSTEIN
thiophane (XIII) was isolated. This was readily converted to cis-4-uranilinothiophane-3-carboxhydrazide(XIV) with hydrazine. That this was a cis hydrazide was demonstrated by the following procedure : trans-3,4-Dicarbomethoxythiophane(111)was hydrolyzed with one equivalent of alkali in good yield to the oily monomethyl ester, XVII. This was characterized by conversion to its N-methylanilide, identical with VI1 prepared as shown on the flow sheet. The monoester, XVII, was degraded via the acid chloride with sodium azide to trans-4-uranilino-3-carbomethoxythiophane (XYI), isomeric to the corresponding cis urea derivative, XIII. The ester, XVI, was converted to the trans hydrazide, XX. Although the cis hydrazide, XIV, and the trans hydrazide, XX, melted about 30" apart, mixtures did not give significant depressions. However, Curtius degradation readily distinguished them. The cis hydrazide, XIV, gave a n isocyanate which readily cyclized to 4-carbanilido-5ketoimidazolido[4,5 ,c,cis]thiophane (XXII), when the azide was boiled in chloroform. The trans hydrazide, XX, under the same conditions gave an isocyanate which would not cyclize and was characterized as the urethan, XT'III, or uranilino derivative, XIX. The imidazolone, XXII, was slowly hydrolyzed with 48% hydrobromic acid to 3,4-cis-diaminothiophane ( X I ) which was isolated as the dihydrobromide and the insoluble dipicrate. It was characterized as its dibenzoyl derivative, m.p. 230-231 ", which was isomeric with trans-3,4-dibenzoylaminothiophane, m.p. 295-300" (3). It was identical with the dibenzoate of "isomer B" of 3,4diaminothiophane, m.p. 238-239", described by Kilmer and McKennis (4). The cis and trans diamines were distinguished by another method. Treatment of the trans-diamine hydrobromide with phosgene a t 0" in excess aqueous sodium bicarbonate resulted in no reaction, as the highly insoluble dipicrate of the diamine could be recovered quantitatively. However, when the cis-diamine dihydrobromide mas treated under the same conditions, none of the highly insoluble dipicrate formed, indicating that a reaction had taken place. The cyclic urea derivative, XXIII, m.p. 231" was isolated. 0
II
/c\ HN NH I
I-!
I
'S'
cis XXIII
NH-C
O--NHC gH 5
NH-CO-N-C I I
BHS
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I n a subsequent communication (7) a synthesis of 2-(6-carboxybutyl)-4uranilinothiophane-3-2rans-carboxylic acid (XXIV) will be described. In this molecule it was necessary to degrade the ring carboxyl to an amine and leave the side chain carboxyl intact in order to obtain a 2-(6-carboxybutyl)-3 ,4-diaminothiophane. One of the possible ways of distinguishing between the carboxyl groups would be the formation of a uracil, XXV. For preliminary studies, the preparation and reactions of the model uracil, XV, was undertaken in order to avoid the complications caused by a side chain. When cis-4-uranilinothiophane-3-carboxhydrazide(XIV) was heated with dilute hydrochloric acid, ring closure (6) t o the insoluble 3-phenyl-5,6,8 ,9-tetrahydrothieno[3,4,e ,cis]uracil (XV) took place. In contrast, the corresponding trans hydrazide (XX) was merely hydrolyzed to trans-4-uranilinothiophane-3carboxylic acid (XI). This gives a second method of distinguishing between the cis and trans hydrazides, as the cis configuration is necessary for ring closure to take place under these conditions. Although the ring of dihydrouracils has been reported ( 5 ) to be difficultly opened, the thienouracil, XV, opened with extreme ease. The configuration obtained depended upon the reaction conditions. With hydrazine a t 100" for ten minutes, the ring of XV opened to give a 92% yield of cisl-uranilinothiophane-3-carboxhydrazide (XIV). The configuration was determined as cis by reclosure to XV. If the reaction was run with a larger excess of hydrazine and heated for two hours on the steam-bath, mainly the trans hydrazide was obtained. When XV was boiled for five minutes with methanolic sodium methoxidcb, the ring was rapidly ruptured with the formation of trans-3-carbomethoxy4-uranilinothiophane (XVI), identical with an authentic sample described previously. As hydrochloric acid treatment of k.ans-4-uranilinothiophane-3-carboxylic acid (XI) failed to cause ring closure, in contrast to the cis series, the use of boiling propionic or acetic anhydrides (6) was tried. This method appeared to give small yields of the impure uracil. However, when sodium acetate was introduced into the reaction mixture t o promote enolization, inversion and ring closure took place in ten minutes t o give a 69% yield of l-acetyl-3-phenyl-5,6 ,8,g-tetrahydrothieno[3,4,e ,cis]uracil (XII). The structure and configuration of this compound was demonstrated by acid hydrolysis to the cis uracil, XV, and its reformation by acetylation. The acetyl uracil, XII, reacted Tyith hydrazine or sodium methoxide in methanol with the same ease as the non-acetylated uracil, XV, losing the acetyl group x i t h the formation of cis-4-uranilinothiophane-3carboxhydrazide (XIIT) and trans-3-carbomethoxy-4-uranilinothiophane(XI-I), respectively. Acknowledgment. The authors wish t o thank Dr. Y . SubbaRow for many helpful suggestions and Louis Brancone, Philip Weiss, and Barbara Eames for the microanalyses. EXPERIMENTAL
Thiophane-S,4-cis-dicarboxylicanhydride (ZV). A solution of 16.5 g. of cis and transthiophane-3,4-dicarboxylicacid (m.p. 100-120")in 85 cc. of propionic anhydride was refluxed
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BAKER, QUERRY, SAFIR, MCEWEN, BERNSTEIN
for three hours. Distillation gave 12.8 g. (87%) of anhydride, b.p. 145-148" (1 mm.), m.p. 79-82' (2). Thiophane-S,~-cis-dicarbox~lic acid monomethyl ester (V). A mixture of 11 g. of thiophane-3,4-cis-dicarboxylicanhydride (IV) and 40 cc. of methanol was reffuxed for ninety minutes, then solvent removed in wacvo. The residue was recrystallized from benzenepetroleum ether, white crystals, m.p. 107-109'; yield, 10 g. (76%). Recrystallization of a sample from benzene raised the m.p. to 107.5-109". Anal. Calc'd for CIHIOO~S: C, 44.2;H, 5.3. Found: C, 44.4;H , 5.8. The corresponding ethyl ester was prepared i n the same manner, but was difficult t o crystallize: white crystals, m.p. 55-59'; yield, 417,. Anal. Calc'd for CsHtzOS: C, 47.2;H, 5.9. Found: C, 47.5;H, 5.8. cis-4-Carbanilidothzophane-3-carbozylicacid. To a warm solution of 200 mg. of thiophane-3,4-cis-dicarboxylicanhydride (IV) in 5 cc. of benzene was added 0.2 cc. of aniline. The anilic acid immediately crystallized and was collected on a filter; yield, 310 mg. (98%) of white crystals, m.p. 140-142". Anal. Calc'd for CllHlaNO$: C, 57.3;H, 5.2;N,5.6. Found: C, 57.1 ; H, 5.0;K, 5.9. N-Phenylthiophane-S,4-cis-dicarboximzde.( A ) . A solution of 200 mg. of thiophane-3,4&-dicarboxylic acid monomethyl ester (V) and 0.2 cc. of tbionyl chloride in 5 cc. of benzene was refluxed for thirty minutes, then evaporated i n vacuo. The residue in 10 cc. of benzen? was treated with 0.4 cc. of aniline and heated on the steam-bath for two minutes. The mixture was diluted with 10 cc. of ethyl acetate, washed twice with dilute hydrochloric acid, dilute sodium bicarbonate solution, and water. Evaporation t o dryness and trituration with petroleum ether gave 2E5 mg. (9570)of impure cis-4-carbanilido-3-carbomethoxythiophane, m.p. 122127'. Recrystallization from dilute methanol gave white crystals of N-phenylthiopliane-3,4-cis-dicarboximicle, m.p. 146-147". A mixture with the 122-127' material melted at 98-110". Anal. Calc'd for CIZH1IN02S: C, 61.8; H, 4.8; Tu', 6.0. Found: C, 61.9;H , 4.8;S , 6.4. Due to the ease of ring closure i t was necessary t o use the S-methylanilide instead of the anilide for further transformations. (I?) A mixture of 220 mg. of cis-3-carbanilidothiophane-4-carboxylicacid and 5 cc. of acetyl chloride was refluxed for ten minutes, then the excess reagent was evaporated. The residue was recrystallized from dilute methanol; yield, 140mg. (68%) of white crystals, m.p. 143-146"and identical with preparation A. The ring closure can also be carried out merely by heating a solution of the acid in 20% aqueous methanol. cis-lt-(~-'Clethylcarbanilido)thiophane-S-earboxylic acid. To a hot solution of 1 .O g. of thiophane-3,4-cis-dicarboxylicanhydride (IV), in 10 cc. of benzene was added 1 cc. of methylaniline. Scratching the wall of the flask caused immediate separation of the product; yield, 1.45 g. (87%), m.p. 160-162". For analysis a sample was recrystallized from benzene, white crystals, m.p. 161-162". Anal. Calc'd for ClsHJ?OaS: N, 5.3. Found: 5 , 5.3. cis-$-(Ai'-illethylcarbanilido)-S-carbontethoxythiophane ( V I ) . ( A ) . To a suspension of 1.45 g. of cis-4-(X-methylcarbanilido)thiophane-3-carboxylic acid i n ether was added an excess of ethereal diazomethane. The acid dissolved with nitrogen evolution i n about ten minutes. Evaporation of the solvent and trituration with petroleum ether gave 1.40 g. (92%) of product, m.p. 106-107.5". Recrystallization from benzene-petroleum ether gave white crystals, m.p. 107-107.5". Anal. Calc'd for C14H1,NOJS: C, 60.2;H, 6.1;N,5.0. Found: C,59.8;H, 6.3;N,5.4. (I?). A mixture of 5 g. of thiophane-3,4-cis-dicarboxylicacid monomethyl ester (V),5 cc. of thionyl chloride, and 10 cc. of benzene was refluxed for thirty minutes, then evap-
BIOTIN.
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179
orated t o dryness in vacuo (bath 50"). The residue, dissolved i n 50 cc. of benzene, was treated with 8.5 cc. of methylaniline and refluxed five minutes. Diluted with 50 cc. of ethyl acetate, the mixture was washed twice with dilute hydrochloric acid, then aqueous sodium bicarbonate, and finally with water. Evaporation in vacuo and trituration with petroleum ether gave 6.9 g. (95%) of product, m.p. 106-107". A mixed m.p. with preparation A was the same. Thiop1~ane-8,4-cis-dicarboxy-N,N'-cyclichydrazide. A mixture of 340 mg. of (IV), 0.3 CC. of 100% hydrazine hydrate, and 1.0 cc. of water was warmed until homogeneous (one minute). The solution, diluted with 5 cc. of water and acidified with acetic acid, was heated on the steam-bath for ten minutes, then continuously extracted with ethyl acetate for three hours. The extract was evaporated to dryness in vacuo and the crystalline residue triturated tvith petroleum ether; yield 320 mg. (870/,), m.p. 126-131". Several crystallizations from aIcohol gave blunt white needles, n1.p. 135-135.5". Anal. Calc'd for CsHsK20~S:X , 16.3. Found: K, 16.1. trans-4-(N-MethlJlcarbanzlzdo)-S-carbomethozytiiiophane( V I I ) . h solution of 5 g. of the corresponding cis isomer, (VI), in 25 cc. of methanol containing 0.62 g. of sodium was refluxed for two and one-half hours, cooled, and poured into excess cold dilute hydrochloric acid. The product was washed with water; yield, 4.6 g. (9270, m.p. 120-124". Recrystallization from benzene-petroleum ether gave white crystals, m.p. 124-126'. A n d . Calc'd for C I ~ H I I N O ~C, S : 60.2; 11,6.1; S , 5.0. Fcund: C, 60.0; H, 6.0; K , 5.2. On standing, the aqueous filtrate deposited 54 mg. of white crystals, m.p. 188-190'. A mixed m.p. identified i t as trans-4-(N-methy~carbanilido)thiophane-3-carboxylic acid, described later. trans-4-(N-IC1ethylcarbanilido)thiophar~e-~-carboxhydrazide (VIZI). (A).A mixture of 4.7 g. of cis-(4-S-methylcarbanilido)-3-carbomethoxythiophane(VI) and 1.5 cc. of 100% hydrazine hydrate n a s refluxed in an oil-bath at 140" for one hour. The mixture was extracted with three 30-cc. portions of hot water, decanting from the oil each time. On cooling, the oil crystallized and consisted of 0.6 g. (13y0) of starting material, m.p. 101-103". The aqueous extrmts, after several hours at 3", deposited crude VIII, m.p. 150-170O; yield, 1.5 g. (349"). The aqueous filtrate was concentrated to about 15 cc. and after five hours a t 3" a second crop of 0.2 g. (4y0), m.p. 165-170", was collected. Recrystallization of a sim-ilzr preparation several times from water gave white crystals, m.p. 176-1?8", which were readily soluble in 1 N hydrochloric acid. Anal. Calc'd for C13H1&30&: C, 55.8; H, 6.1; S , 15.0. Found: C, 55.5;H, 5.8; K , 14.7. The aqueous filtrate from the 0.2 g. of trans hydrazide on standing overnight at 3", deposited 0.4 g. (14%) of crude thiophane-3,4-cis-dicarboxy-S,5'-cyclichydrazide, m.p. 120-130". A mixed n1.p. with an authentic sample was 125-132". The filtrate from the cyclic hydrazide was evaporated to dryness and the residue dissolved in boiling alcohol. After several hours a t room temperature, 0.25 g. (7'37":) of thiophane-:3,4-trai~s-dicarboxhydrazide (3) %as obtained, m.p. and mixed m.p. 215-217'. The alcohol filtrate, after standing overnight a t - S o , deposited 0.42 g. (15%) of the ciscyclic liydrazide, m.p. 120-130". Thus, 00% of the reaction products was accounted for and could be found. no cis-4-(i\;-methylcarbanilido)thiophane-3-carboxhydrazide ( B ) . X mixture of 4 g. of trans-3-carbomethoxy-4-(N-metliylcarbanilido)thiophane (VII) and 2 cc. of 100% hydrazine hydrate was refluxed in an oil-bath at 140" for one hour. The excess reagent was removed in vacuo and the solid residue triturated with water; yield, 3.6 g. (go%), m.p. 174-176" and identical with preparation A. The isopropylidene derivative was formed by boiling a solution of the hydrazide in ecetone; R hite plates from acetone-heptane, m.p. 191-193'. Anal. Calc'd for ClaH21XaOzS: C, 60.2; H, 6.6; N , 13.2. Found: C,60.8; H, 6.6; h-, 13.4. trans-~-(i?i-iMethylcarbanilido)thiophane-d-carboxyEic acid. ( A ) . A solution of 160 mg.
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BAKER, QUERRY, SAFIR, MCEWEN, BERNSTEIN
of trans-4-(N-methylcarbanilido)thiophane-3-carboxhydrazide (VIII) in 2 cc. of 6 N hydrochloric acid was heated on the steam-bath under reflux for fourteen hours. After a few minutes heating, white crystals separated, most of which did not redissolve. The crystals had m.p. 189-190'; yield, 75 mg. (50%). Recrystallization from dilute alcohol raised the m.p. to 19C-191'. Anal. Calc'd for C1J3"5XO3S: C, 58.8; H, 5.7; S , 5.3. Found: C, 59.1; H , 5.8; Pi, 5.0. From the aqueous filtrate was isolated 7 mg. (iyO) of thiophane-3,4-trans-dicarboxylic acid (11), m.p. 126-127", resolidified and remelted at 136-137", which gave no depression in m.p. when mixed with an authentic sample. A mixture with the thiophane-3,4-cis-dicarboxylic acid melted a t 95-100°. ( B ) . A mixture of 670 mg. of thiophane-3,4-trans-dicarboxylic acid (11),1 cc. of thionyl chloride, and 5 cc. of benzene was refluxed for thirty minutes, then evaporated in vacuo. To the residue in 10 cc. of benzene was added 0.4 cc. of methylaniline in 5 cc. of benzene dropwise with swirling over a period of about three minutes. After ten minutes, the mixture was extracted three times with aqueous sodium bicarbonate, acidified, saturated with salt, and cooled a t 3". The product was washed with cold water; yield, 90 mg. (9yo),m.p. 178-180". Several recrystallizations from dilute alcohol gave white crystals, m.p. 190-191", identical with preparation A. tralias-S-Cranilino-4-(~~~-methylcarbnnilido)thiophane. T o a solution of 3.5 g. of trans-4(N-niethylcarbanilido)thiophane-3-carboxhydrazide(VIII) in 20 cc. of 1 -V hydrochloric acid and 5 cc. of chloroform was added dropn-is., with stirring and ice cooling, a solution of 0.94 g. of sodium nitrite in 20 cc. of water over a period of five minutes. After being stirred an additional one hour a t O", the layers were separated and the aqueous phase extracted again with chloroform. The combined organic solutions were dried with sodium sulfate, refluxed for thirty minutes, and treated with 20 cc. of aniline. Evaporation of the solvent and trituration with methanol gave 3.3 g. (77%) of white crystals, m.p. 215-317". Recrystallization from acetone raised the m.p. to 216-217". Anal. Calc'd for ClsH21Ns02S: S , 11.8. Found: S ,12.2. This compound failed to react with hot hydrazine due to its insolubility in the reagent. srans-S-Carbethoxyamino-4-(N-methylcarbanilido)thiophane( I X ) . A solution of 7.9 g. of VI11 in 1 N hydrochloric acid was treated with sodium nitrite as in the previousexperiment. The dried chloroform extract was diluted with 100 cc. of absolute alcohol, refluxed for seventy-five minutes and evaporated. The residue was crystallized from dilute alcohol, white needles, m.p. 162-164"; yield 7.35 g. (S470). Anal. Cslc'd for C1~H20S20J3:C, 58.4; H, 6.5; S,9.1. Found: C, 59.0; H, 6.4;N,9.5. trans-S-Aminothiophane-4-carboxylic acid (X).A mixture of 4.9 g. of IX and 50 CC. of 48% hydrobromic acid was refluxed for three hours, then evaporated to dryness i n vacuo. The residue was dissolved in 50 cc. of methanol and neutralized with concentrated ammonium hydroxide. After standing overnight at 3O, the mixture was filtered and the crystals washed with methanol; yield, 0.98 g. (42%), m.p. 223' dec. Crystallization of a similar preparation from nTater gave white crystals, m.p. 242-243' dec. Anal. Calc'd for C;H&O2S: S , 9.5. Found: S', 9.6. The N-benzoyl derivative was prepared in the usual manner with benzoyl chloride and dilute alkali a t 5'; white crystals from water, m.p. 202-203'. Anal. Calc'd for C12HlZNO3S: C, 57.3; H , 5.2; N, 5.6. Found: C, 57.6; H , 5.1; X, 5.9. trans-4-L'runilinothzophane-S-carboxylicacid ( X I ) . A solution of 0.98 g. of trans-3aminothiophane-4-carboxylic acid (X)in 13 cc. of 0.5 1%- sodium hydroxide was stirred a t 0" with 1.1 cc. of phenyl isocyanate for one hour, then warmed on the steam-bath to destroy the excess isocyanate. The filtered solution was acidified and the oil which separated soon solidified t o white crystals, m.p. 176' dec; yield, 1.52 g. (S6yO). Recrystallization from dilute methanol did not change the m.p.
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Anal. Calc'd for CI2Hl4S2O3S: C, 54.2; H , 5.3; N, 10.5. Found: C, 53.8; H, 5.4; N, 10.8. c-is-4-Benzoylamanothiophane-3-carboxylic acid. A mixture of 1 g. of thiophane-3,4-cisdicarboxylic acid monomethyl ester (V), 1.2 cc. of thionyl chloride, and 10 cc. of benzene m-as refluxed for twnety minutes, then evaporated to dryness in vacuo. The evaporation was repeated with 10 cc. of benzene. The residue was dissolved in 10 cc. of acetone and added dropwise to a stirred solution of 0.5 g. of sodium azide in 10 cc. of water at 20". After being stirred an additional hour, the mixture was diluted with water and the oily azide extracted n i t h two 25-cc. portions of cold chloroform. The extracts were dried with calcium chloride, 15 cc. of methanol was added and the solution was slowly evaporated. The did not crystallize. residue of crude cis-4-carbomethoxyamino-3-carbomethoxythiophane Anal. Calc'd for C8H1&O4S: N,6.4. Found: N , 7.2. The oil was refluxed for one hour with 10 cc. of 48% hydrobromic acid, diluted with water and evaporated to dryness in vacuo. The evaporation was repeated with 10 cc. of water. The residue was extracted five times mith ethyl acetate and the extracts rejected. A solution of the residue in 10 cc. of water r a s made just alkaline with sodium hydroxide, then benzoylated in the usual manner Kith benzoyl chloride; white crystals from water, m.p. 18&189*.
Anal. Calc'd for C12H&OSS: C, 57.3; H, 5.2; 5 , 5.6. Found: C, 57.3; H , 5.3; N , 5.5. il mixture with the corresponding trans isomer, m.p. 202-203", melted at 167-180'. c;s-4-Cranilino-3-carbomethoxythiophane( X I 1I). A chloroform solution of 3-carboniethoxythiophane-4-carboxazidefrom 1 g. of V was prepared as described in the previous experiment except that the acid chloride reaction with the sodium azide was carried out at 0'. This chloroform solution was refluxed for ninety minutes, when gas evolution was complete. After the addition of 2 cc. of aniline, the solution was refluxed for five minutes, then evaporated to dryness in vacuo. The residue, dissolved in ethyl acetate was washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate, and dilute hydrochloric acid. Evaporation gave an oil which crystallized from a mixture of ether and petroleum ether. Recrystallization from the same solvents gave 0.45 g. (317,) of product, m.p. 115-120". Further recrystallization did not change the m.p. Anal. Calc'd for ClsH16lrl2O3S:N, 10.0. Found: S , 10.3. This ester was difficult to recrystallize as i t tended to form an oil. cis-4-Cranilinothiophane-5-carboxhydrazide( X I V ) . A mixture of 0.27 g. of cis4-uranilino-3-carbomethoxythiophane(XEII) and 0.3 cc. of 100Vo hydrazine hydrate was heated on the steam-bath for one hour, then diluted with water; yield, 0.20 g. (74574, m.p. 176-184'. Recrystallization from water raised the m.p. to 183-185'. Anal. Calc'd for C I ~ H I O N ~ OC,~ S 51.3; : H, 5.8; X , 20.0. Found: C , 51.0; H, 6.2; K,20.6. For preparative purposes i t was much better not to purify XIII, as i t involved considerable loss. When the crude ester was treated with hydrazine, then diluted with water and benzene, a 5770 over-all yield of hydrazide, m.p. 174-176", was obtained from thiophane3,4-cis-dicarboxylic acid monomethyl ester (V) in contrast to a 23% yield when the intermediate ester was purified. trans-8,4-Diearbomethoxythiophane( I I I ) . ( A ) . A solution of 500 mg. of thiophane-3,4trans-dicarboxylic acid (11) in 3 cc. of methanol was treated with an excess of ethereal diazomethane. Evaporation left a quantitative yield of crystals, m.p. 51-53'. Recrystallization from ether-petroleum ether gave white crystals, m.p. 51.563'. A?kal. Calc'd for CsH1201S: C, 47.1; H, 5.9. Found: C, 47.6; H, 6.1. The corresponding cis dimethyl ester \?-as an oil, b.p. 154-156" (13 mm.). Anal. Calc'd for C J L t O S : C, 47.1; H, 5.9. Found: C, 47.0; H, 6.5. ( B ) . T o a solution of 10 g. of I1 in 350 cc. of methanol was added 15 cc. of acetyl chloride.
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BAKER, QUERRY, SSFIR, MCEWEN, BERNSTEIN
After being refluxed for thirty minutes, the solution was evaporated to dryness in vacuo; yield, 11.2 g. (96%) of product, m.p. 49-51'. Tlaiophane-%,4-trans-~icarboxylic acid monomethyl ester ( X V I I ) . A solution of 11.2 g. of trans-3,4-dicarbomethoxythiophane(111)in 50 cc. of methanol and 20 cc. of 10% sodium hydroxide was refluxed for twenty minutes, then concentrated to about one-third the volume. The solution n as diluted with water containing excess sodium bicarbonate and washed with benzene. Evaporation of the benzene gave 3 g. of unchanged diester. The aqueous layer was acidified, estracted twice with chloroform, and evaporated to dryness; yield, 8 g. of a n oil which did not crystallize. It was characterized by conversion in 56% yield to the methylanilide (VII) through the acid chloride as described for the corresponding cis methylanilide, VI, m.p. and mixed m.p. 119-123'. trans-~-Uranilino-S-carbomethox~thiophane ( X V I ) . From 3.8 g. of thiophane-3,4-transdicarboxylic acid monomethyl ester (XVII) was obtained 3.9 g. (7oyO) of product, m.p. 130-134", in the same manner as for the corresponding cis compound. Recrystallization from methanol gave white crvstals, m.p. 131-135'. Anal. Calc'd for ClsHl&\jP03S: C, 55.7; H , 5.8. Found: C, 55.9; H, 5.i. trans-4-Uranilinothiophane-3-carboxhydrazide( X X ) . A mixture of 3 g. of XVI, 6 cc. of 100% hydrazine hydrate, and 75 cc. of methanol was refluxed with stirring on the steambath for seventy minutes. The cooled mixture was filtered; yield, 2.55 g. (85%) of white crystals, m.p. 210-212" which was unchanged on recrystallization from water. Anal. Calc'd for C,2Hd,OZS: C, 51.3; H, 5.8; N, 20.0. Found: C, 51.7; H, 5.5; N, 20.7. ~-Carbanzlido-6-l;etoimidazolzdo[~,6,c,cislthiophane ( X X I I ) . To a stirred solution of 1.9 g. of cis-4-uranilinothiophane-3-carboxhydrazide(XIV) in 70 cc. of 1 N hydrochloric acid and 50 cc. of chloroform was added dropwise a solution of 0.56 g. of sodium nitrite with ice cooling over a period of ten minutes. The temperature was 5-7'. After being stirred for ten minutes more, the chloroform layer was separated and the aqueous phase extracted once more with chloroform. The combined extracts, dried with sodium sulfate a t 0", were refluxed for four hours. The chloroforn: was evaporated i n vacuo and the residue extracted n.ith hot benzene. Addition of heptane gave 1.17 g. (66%) of product, m.p. 156-158". Recrystallization from benzene-petroleum ether gave white crystals, m.p. 164-167". Anal. Calc'd for C12H18Na0&: C, 54.7; H, 5.0; N, 16.0. Found: C, 54.5; H, 5.6; S , 15.7. When ethyl acetate was used as a solvent instead of chloroform and the solution refluxed for seventy-five minutes, a cleaner product was obtained in 66% yield, m.p. 158-161". trans-3,4-Diuranzlinothzophane ( X I X ) . (A). From the diacid chloride of 1 g. of thiophane-3,4-dicarboxylic acid was obtained 1.1 g. (55%) of product, m.p. 238-229" dec. in the same manner as described for cis-3-carbomethoxyi-uranilinothiophane(XIII) Recrystallization from dilute alcohol with the aid of Norit gave white crystals, m.p. 217" dec. Anal. Calc'd for C I ~ H Z O N ~C,O60.7; ~ ~ : H, 5.6. Found: C, 60.8; H, 5.8. ( B ) A solution of 0.5 g. trans-4-uranilinothiophane-3-carboxhydrazide (XX) in 1 S hydrochloric acid was treated in the same manner as described f o r the corresponding cw compound. Evaporation of the chloroforin solution gave an oil with a strong isocyanate odor. It was dissolved in benzene and treated with 0.5 cc. of aniline. A Solid immediately separated, yield, 0.33 g. (52%), m.p. 223" dec., identical with preparation A. trans-3-Carbethoxyamino-+$-uranilinothiophane ( X V I I I ). ( A ) . From 0.5 g. of trans-4uranilinothiophane-3-carboxhydrazide(XX) was obtained 0.29 g. (52%) of product, m.p. 225-226" in the same manner as described for trans-3-carbethosy amino-.l-(S-methylcarbani1ido)thiophane (IX). Recrystallization from dilute alcohol gave white crystals, m.p. 228-229". Anal. Calc'd for ClnHloNsO&3: C, 51.3; H, 6.2; N , 13.6. Found: C, 53.9; 11, 6.0; K, 13.7.
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( B ). T o a suspension of 200 mg. of trans-4-uranilinothiophane-3-carboxylic acid (XI) in 2 cc. of a solution of one drop of pyridine in 5 cc. of dry ether was added 1 cc. of thionyl chloride. After fifteen minutes with occasional shaking, the solution was evaporated t o dryness i n vacuo (bath 40"). The residual acid chloride was degraded to the urethan in the same manner as described for cis-3-carbomethoxy-4-carbomethoxyaminothiophane except that the sodium azide reaction was carried out at 0" and ethanol was substituted for methanol; yield, 130 mg. (54 m.p. 208-212". A mixture with preparation A melted a t 216-220'. 3,&is-Diaminothiophane ( X X I ) dzhydrobromide and dipicrate. A mixture of 1.O g. of 4-carbanilido-5-ketoI4,5, c, cislthiophane (XXII) and 10 cc. of 48% hydrobromic acid was refluxed for fifteen hours, then cooled in ice. The dihydrobromide was collected on a glass filter and washed with 48% hydrobromic acid, alcohol, and ether; yield, 260nig. (25%), m.p. 307-309" dec. Recrystallization from 48% hydrobromic acid gave the pure salt, m.p. 309-310" dec. Anal. Calc'd for C4H12Br2S2S:C, 17.1; H, 4.4; S , 10.0. Found: C,17.1;H,4.4;N,10.5. The reaction mixture filtrate was combined with the washings and evaporated to dryness in vacuo. The residue vas dissolved in water, 500 mg. of anhydrous sodium acetate and 500 mg. of picric acid were added, and the mixture was heated on the steam-bath for a few minutes. The dipicrate was collected and extracted a-ith hot alcohol to remove excess picric acid; yield, 300 mg. (14%), m.p. 210'dec. The dipicrate was also prepared from the dihydrobromide with aqueous sodium acetate and picric acid i n quantitative yield. Ancl. Calc'd for C1SH&8014S: C, 33.4; H, 2.8; N , 19.4. Found: C, 33.7; H, 3.0; X, 19.1. The Irans-dipicrate was prepared in the same manner in 97% yield, n1.p. 250" dec., from trans-3,4-diaminothiophanedihydrobromide (2). The m.p. of this compound has been recorded in the literature as 250" dec. (3). cis-3,4-Dibenzoylaminothiophane.A solution of the solid cis-3,4-diaminothiophane (XSI) dihydrochloride from 200 mg. of the corresponding dipicrate in 5 cc. of 10% sodium hydroxide was shaken n i t h 0.4 cc. of benzoyl chloride until a solid was formed. It was removed by filtration and washed with dilute sodium hydroxide, water, alcohol, and ether; yield, 50 mg. (47%), ni .p. 227-229". Recrystallization from alcohol gave white crystals, m.p. 230-231". ~ S66.2; : H, 5.6; K,8.6. A n u l . Calc'd for C I ~ H I ~ S ? OC, Found: C, 65.5; H, 5.6; N, 8.9. This compound y a s identical' with the dibenaoyl derivative of "isomer B" of 3,4-diaminothiophane described by Kilmer and McKennis (4) as melting at 238-239". ~.Re~oimidazolido[~.5,c,cis]thiophane ( X X I I I ) . A solution of 260 mg. of czs-3,4-diaminothiophane (XXI) dihydrobromide in 50 cc. of saturated sodium bicarbonate was treated with phosgene a t 0' until acidic t o Congo Red paper. The solution was concentrated i n z'acuo to remove excess phosgene, then just neutralized with aqueous sodium bicarbonate. A test portion gave no precipitate when heated with picric acid. The solution mas evaporated to dryness in vacuo and the residue extracted with hot butanol. EGaporation in vacuo left a solid residue which was partially inorganic. SubIimation at 155" (1 mm.) gave GO mg. (45%) of white crystals, m.p. 231'.
so),
~
1 We wish to thank Dr. George Bosworth Brown of the Department of Biochemistry, Cornel1 University Medical College for the mixed m.p. determination. He reported, "Your sample melts at 233-236" when heated rapidly on the hot stage microscope. It sublimes and, &-henheated slowly (2"/min.), the sublimate melts at 238-239'. The sample of Kilmer and NcKennis also melts at 238-239" (sublimate). The mixed m.p. is 234" when heated rapidly and is 238" on the sublimate when heated a t 2"/min. The crystalline form of both sublimates (needles) is identical."
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BAKER, QUERRY, SAFIR, MCEWEN, BERNSTEIN
Calc'd for C6HsNtOS: C, 41.7;H, 5.6. Found: C, 41.7;H, 5.6. The corresponding trans-diamine when treated under the same conditions failed to react, as the diamine dipicrate could be recovered quantitatively. S-Pheny1-5,6,8,9-te~ruhydrothieno~3,/t,e,cisluracil ( X J 7 ) . A solution of 1.0 g. of cis 4-uranilinothiophane-3-carboxhydrazide (XIV) in 20 cc. of 6 hydrochloric acid w~ss heated on the steam-bath for two hours. During this time crystals of the uracil began t o separate. The cooled mixture was filtered and the product washed n-ith water, methanol, of white crystals, m.p. 237-238". Recrystallization from and ether; yield, 0.65 g. (74yG) Methyl Cellosolve raised the m.p. to 238-239". A d . Calc'd for C12H&2O2S: C, 55.1;H, 4.9;S ,11.3. Found: C, 58.1;€1, 5.4;S , 11.2. When trans-4-uranilinothiophane-3-carboxhydrazide (XX) was treated under the same conditions a 63Y0 yield of trans-4-uranilinothiophane-3-carboxylicacid (XI) was obtained. Actzon of hydrazine on 3-phenyE-5,6,8,9-tetrahydrothieno[J,4,e,cis] uracal (XI7). A solution of 100 mg. of the uracil in 0.1 cc. of 100% hydrazine hydrate was heated on the steambath for ten minutes during which time crystals separated from solution. Dilution with water gave 105 mg. (92%) of cis-4-uranilinothiophane-3-carboxhydrazide, XIV, m.p. and The compound was readily soluble in 6 N hydrochloric acid and mixed m.p. 184-185'. when the solution was heated on the steam-bath for one hour, the uracil, n1.p. 238-239' was reformed in 81% yield. When 100 mg. of the uracil was heated with 0.2 cc. of hydrazine for two hours, 40 mg. (35%) of a hydrazide was obtained, m.p. 191-193". It was mainly the trans hydrazide, XX, as i t gave trans-4-uranilinothiophane-3-carboxylicacid (XI), m.p. 169" dec., when heated with 6 N hydrochloric acid. Action of sodium methoxide on J-phenyl-6,6,8,9-tetrahydrothieno[3,,f, e,cis]uracil (Xv). T o a boiling suspension of 100 mg. of the uracil in 3 cc. of methanol was added 20 mg. of sodium in 1 cc. of methanol. The uracil immediately dissolved. After being boiled for five minutes, the solution was acidified with acetic acid and most of the methanol was evaporated under a n air stream on the s t e m - b a t h . The mixture, diluted with water, was extracted with benzene and the extract evaporated. Crystallization from ether gave 50 mg. (44%) of trans-3-carbomethoxy-4-uranilinothiophane (XVI), m.p. and mixed m p . 132-133". A mixture with the corresponding cis ester melted at 95-108". 1-Acetyl-J-pheny1-5,6,8,9-tetrahydrothieno[S,,f, e , cis]uracil ( X Z I ). (9). A mixture of 100 mg. of trans-4-uranilinothiophane-3-carboxylicacid (XI), 50 mg. of anhydrous sodium acetate, and 1 cc. of acetic anhydride %-asrefluxed for ten minutes, then diluted to 10 C C . with water, and cooled. The white crystals were collected on a filter; yield, 75 mg. (69%), m.p. 238-240'. Recrystallization from Methyl Cellosolve gave white crystals, m.p. 240-241'. A mixture with XV melted at 208-212'. ilnal. Calc'd for C U H I ~ N ~ OC, ~ S57.8; : H, 4.9;N, 9.7. Found: C, 57.6;H, 4.9;S,9.7. ( B ) . A mixture of 100 mg. of XV, 50 mg. of anhydrous sodium acetate, and 2 cc. of acetic anhydride was refluxed for twenty minutes, then diluted to 20 cc. with water; yield, 110 mg. (quant.) of white crystals, m.p. 240-241". A mixed m.p. v;ith preparation A was the same. The acetyl uracil (XII) was converted to cis-4-uranilinothiophane-3-carbo~hydrazide (XIV) with hydrazine in 82y0 yield and to trans-3-carbomethoxy-4-uranilinothiophane (XVI) with methanolic sodium methoxide in the same manner as the non-acetylated uracil, XV. The acetyl group was readily removed by hydrolysis. To a hot solution of 105 mg. of XI1 in 5 cc. of acetic acid was added 2 cc. of 6 N hydrochloric acid. After being heated on the steam-bath for thirty minutes, the solution was diluted to 25 cc. with water and cooled; yield, 70 mg. (78%) of S V , m.p. and mixed m.p. 237-239". Anal.
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SUMMARY
Methods for the synthesis of cis-3,4-diaminothiophaneby the stepwise degradation of the carboxyl groups of either the cis or the trans form of thiophane3,i-dicarboxylic acid have been described. PEARLRIVER,N. Y. REFERENCES (1) BAKER,QUERRY, SAFIR,AND BERNSTEIN, J. Org. Chem., 12,paper I of this series. (2) BROWN, BAKER,BERNSTEIN, AND SAFIR,J . Org. Chem., 12,paper I1 of this series. (3) KILIWER, ARMSTRONG,BROWN,AND DUVIGNEAUD, J. Biol. Chem., 146, 495 (1942). (4) KILMERAND MCKENNIS,J. Biol. Chem., 162, 103 (1944). (5) EVANS AND JOHNSON, J. A m . Chem. SOC.,62,4993,5001(1930). (6)JOHNSON AND LIVAK, J. A m . Chem. SOC.,68,299 (1936). (7) BAKER,QUERRY,MCEWEN,BERNSTEIN,SAFIR,DORFMAN, AND SUBBAROW, J. Org. ,Chem., 12, paper VI of this series.
