SEPTEMBER, 1962
C Y C L I Z A T I O N S L E A D I N G TO 3 - A N I L I S O H Y D A N T O I N
3 17;
221-223" when crystallized from a mixture of ether and Anal. Calcd. for C22H33N02:C, 76.92; H, 9.68. Found: hexane. C, 76.74; H, 9.44. Anal. Calcd. for C24H3iXOc: C, 66.17; H, 8.10. Found: The 5,-isomer (VIa) melted a t 310-320' and exhibited C, 66.00; H , 8.32. infrared spectrum similar to that of the 58-derivative. 3P-Acetoxy-l7a-(2-carboxyethy1)-17,9-amino-5p-androAnal. Calcd. for CnH,,N02: C, 76.92; H , 9.68. Found: stane Lactam (IVb).--I solution of 7.5 g. of the nitro derivaC, 76.72; H , 9.69. tive (IIIb) in 100 ml. of ethanol was treated with hydrogen 17~-(2-Carboxyethyl)-l7p-aminoandrost-4-en-3-one Lacat 1000 p.s.i. and 100" in the presence of 1.0 g. of W-5 Raney tam (VII).-A stirred solution of 1.75 g. of the ketone (VIb) nickel catalysti for 5 hr. After removal of catalyst and in 40 ml. of acetic acid was treated with 5 ml. of I *Vhydrostripping of solvent the residue was crystallized from a mix- bromic acid in acetic acid. Water (5 ml.) was added to disture of ethanol and water, yielding 5.2 g. of the lactam, m.p. solve the precipitate which formed. Bromine (1.8 9.) in 18 230-233', Ai:: 3.01, 3.2, 5.74, 5.84, and 8.0 M . ml. of acetic acid was added dropwise during a 10-min. The 5,-isomer (IVa) similarly obtained melted a t 308period. Dilution with 150 ml. of water gave a solid which 312' and exhibited congruent infrared spectrum. was collected and crystallized from a mixture of methanol Anal. Calcd. for C Z ~ H ~ ~ C, NO 74.32; ~ : H, 9.64. Found: and water. The 4-bromo ketone weighed 1.1 g. and melted C, 74.17; H , 9.42. a t 202-204', Xz:i3.0,5.75-5.95 p (doublet). 3p-Hydroxy-l7a-( P-carboxyethyl)-17p-amino-5p-androA mixture of 500 mg. of the 4-bromo ketone and 500 mg. stane Lactam (Vb).-A solution of 1.5 g. of the acetate (IVb) of lithium bromide in 15 ml. of dimethylformamide was and 2.0 g. of potassium carbonate in 80 ml. of methanol and heated a t 100" for 2 hr. Water was added slowly to the 20 ml. of water was stirred a t room temperature for 24 hr. point of crystallization and the solid was collected. ReAddition of 200 ml. of water and collection of the solid pre- crystallization from a mixture of chloroform and ethyl acecinitate on a funnel gave 1.3 g. of Vb melting a t 224-230", tate vielded 240 mg. of the conjugated ketone (VII) melting At: 2.9-3.1, 3.2, 5.83 with a shoulder a t 5.9 p . at 286-290", Xi: 3.1, 3.22, 5.8, 5.92, 6.17 p , X ~ ~ 241 ~ o H Anal. Calcd. for C?~H&OZ: C, 76.47; H, 10.21. m p , 15,500. Found: C, 76.36; H , 10.25. Anal. Calcd. for C2&?rTo~: C, 77.37; H, 9.15. Found: The 5a-isomer (Va) possessed an infrared spectrum es- C, 77.23; H , 9.20. sentially identical with the above and melted at 330-335'. 3,9-Hydroxy-5~androstan-17-spiro-2'-pyrrolidine-( 178-N) 17a-(2-Carboxyethyl)-l7p-amino-5,9-androstan-3-oneHydrochloride (VIII).--A solution of 2.5 g. of the lactam (VIb).--A rapidly stirred solution of 2.0 g. of the alcohol (IVa) in 50 ml. of tetrahydrofuran (THF) was added drop(Vb) in 50 ml. of acetic acid was treated during a 2-min. wise to a refluxing suspension of 4.0 g. of lithium aluminum period with 1.6 ml. of 8 M chromic acid in aqueous sulfuric hydride in 200 ml. of THF. After a 5-hr. reflux period, 4 arid. After an additional 2 min., 5 ml. of isopropyl alcohol ml. of water, 8 ml. of 20% sodium hydroxide, and finally was added and then the acetic acid was distilled in vacuum. 14 ml. of water were added successively. The precipitate A suspension of the residue in 120 ml. of 10% sodium hy- was suspended in 200 nil. of a 1:1 solution of T H F in ether droxide wa9 extracted with chloroform and the extract was and the insoluble material was removed by filtration. The washed with water. Removal of the solvent and crystal- dried amine weighed 2.0 g. Crude amine (1 9.) dissolved in lization of the residue from a mixture of chloroform and the minimum volume of methanol was treated with one hexane afforded 1.8 g. of the ketone (VIb), m.p. %5!3-261°, equivalent of methanolic hydrogen chloride. The warm XKR' 3.15, 3.25, 5.85, and 5.90 p. solution was diluted with ether until crystallization began. The crystalline hydrochloride (VIII) was washed well with ether and dried in vacuum. It weighed 0.75 g. and melted above 300°, A",: 2.91, :3 6-4.1, 6.28 1.1. (7) Subseqiient experiments have shown tliis rcdiirtion to 11,. q u a l l y sriccessful uiien conducted a t roolil t r l ~ i l ~ c ~ a t uand re atlliuyAnal. Calcd. for C&&lNO: C, 71.80; H, 10.41. plwric Ilrrssiire using T-1 Raney nickrl ab the catalyst. Found: C, 72.20; H, 10.45. ,nljlj
Cyclizations Leading to 3-Anilinohydantoin'
L)epartt/ieut oJ C'hcuiistry, ll'nshiriqton Stccte
['ti
ioersity. I ' ~ t l / i ~ i n t iIVtrshirqtou ,
lieceiced . I p i i l 2, 1!/62 :~-AIiiliIi~li~(iaiitoiii is foriiwtl i n t h base-caatalyzed cyclization of d-l)eii~yltliioc.:trt)oxyglycillephenylhydrazide, c:arhoelliosyglycine phenylhydrazide, and S-carboxyphenylhydrazidoglycine ethyl ester. Carboethoxyglycine phenylhydrazidd reacts with alcoholic potassium hydroxide to give the potassium salt of N-carboxyphenylhydrazidoglycine. The evidence indicates that this rc:trrangement proceeds though an 5-anilinohydantoin intermediatc.
:~-Aiiiliriohydaiitoiiiis formed in thc base-csatalyzed cyclizat'ions of S-benzylthiocarboxyglycine phenylhydrazide, carboethoxyglycine phenylhydrazidc, and N-carboxyphenylhydrazidoglycine ethyl (1) This investigation was supported in part by a research grant (R.G. 5259) from t h e U. S. Public Health Service. Presented in part a t t h e 140th Meeting of the American Chemical Society, Chicago, Illinois, September, 1961. ( 2 ) Portion of a thesis presented by I h a n e W. Fish in partial fulfillment of t h e retluirenients for the degree of Doctor of Philosophy, Washington State University.
ester. Carboethoxyglycinc phciiylhydrazidr, 1.cac.t s with alcoholic potassium hydroxide to give thc potassium salt of N-carboxyphenylhydrazidoglycinc. The evidence indicates that this rearrangement proceeds through an 3-anilinohydantoill intermediate. We recently reported a reaction in which Sbenzylthiocarboxyglycine phenylhydra~ide~ (I) was (3) H. B. AIiIne, S L. Rasnlak, Chcm. Soc., 82, 4582 (1960).
It. P. Bayer. and D. \I-. Visli, J . A rn.
MILNEAND FISH
3178
VOL.
27
treated with lead acetate in ethanol yielding a for known hydantoin$ and 3-aminohydantoin~~ compound (11), CsHsN30z. By analogy to the rather than to the frequencies observed for 1,2reaction of phenylthiocarboxyglycine carbobenz- succinyl-1-phenylhydrazine.’ (d) The ultraviolet oxyhydrazide with lead acetate, which Hofmann4 spectrum of I1 shows maxima a t 2300 and 2800 had reported as yielding 2-carbobenzoxy-3,6- A., characteristic of 2-acyl-1-phenylhydrazines dioxohexahydro-1,2,4-triazine,compound I1 was rather than l-acyl-l-phenylhydrazines.8 reported as 2-phenyl-3,6-dioxohexahydro-1,2,4-tri- The structure of N-carboxyphenylhydrazidoazine (IIA). However, because of the high car- glycine (IV) is based on the following evidence: bonyl frequencies in the infrared spectrum of (1) Its infrared spectrum shows a single peak a t I1 and the report by Schlcgl, et u Z . , ~ that, when 3247 cm.-l and an amide I1 absorption a t 1553 carbobenzoxyamino acid methyl esters were re- cm.-I, characteristic of secondary amide^.^ (2) fluxed with hydrazine in alcohol, 3-aminohydan- Its ultraviolet spectrum has maxima a t 2330 and toins rather than 3,6-dioxohexahydro-l,2,4-tri-2820 k., characteristic of 2-acyl-1-phenylhydraazines were formed, it was felt that compound I1 zines.s (3) Its ethyl ester was cleaved by Raney could be either 2-phenyl-3,6-dioxohexahydro-l,2,4- nickel to give hydantoic acid ethyl ester (VI). triazine (IIA) or 3-anilinohydantoin (IIB) and that the structure should be investigated further. 0 0
F/
0 II 2 C,H,CHLS-CC--NHCH~CIUHNHC~H~ -
Pb(0Ac)L
V 0 /I
0 I1
+
C ~ H ~ O ~ C H ~ N H C NCI ~I ~H ~ N H C ~ H ~
0
VI or
3-Anilinohydantoin formed several derivatives.
It reacted with acetic anhydride to form a di-
acetate3 (VII), Cl4HI3N3O4.The infrared spectrum showed carbonyl stretching frequencies a t 1802, 1754, and 1704 cm.-I. The ultraviolet spectrum (CsHjCHS)APb i 2 HIC-COH showeg no absorption maximum in the 3200 to On the basis of the cvideiicc presented below, 2200 A. region, but instead showed an increasing itj now appears that compound I1 is 3-aiiilinohy- absorption from 2900 to 2200 A. These observadantoin (IIB): (a) It was cleaved by Raney tions and the report of Harries and Weiss’O that nickel to give hydantoin (111) and ethylaniline6 hydantoin reacts with acetic anhydride and forms 1-acetylhydantoin under similar conditions indirather than 5-phenylhydantoin arid amide. cates that the diacetate has the following structure. 0 IIB
8
+
II
II
0 111
0
111:
(s~ti,Nltcf,Hr,
(1)) It was hydrolyxrd by tlilutc sodium hydroxide to give N-carboxyphenylhydrsaidoglycinc (IV). 0
IIB
11 + NaOH +NaOCCHgNH
g
NHXHC6Hs
(c) The infrared spectrum of compound I1 showed carbonyl stretching frequencies a t 1779 and 1724 cm.-l, corresponding to the frequencies reported
v11
3-hnilinohydantoin reacted wit11 liro~nii~c:i l l acetic acid to give a dibromide (VIII), CgH,Br&aOn. Because the carbonyl stretching frequencies in the infrared spectrum were essentially the same as in 3-anilinohydantoin and the maxima in the ultraviolet spectrum showed a shift to longer wave lengths, the dibromide is assigned the following structure.
(4) A. Lindenmann, N. H. Kahn, a n d K. Hofmann, J . A m . Chem. Soo., 74, 476 (1952).
(5) K. Schlogl, J. Derkosch, and E. Wawersich, Monatsh., 85, 607 (1954). (6) C. Ainsworth, J . A m . Chem. Soc., 78, 1635 (1956), reported t h a t N-ethylaniline is formed when aniline a n d Raney nickel are refluxed in ethyl alcohol.
(7) R. Gompper. Chem. Ber., 93, 200 (1960). ( 8 ) N. A. Valyashko a n d I. T. Depeshko, Zh. Obschei. Khim. ( J . Gen. Chcm.). 20, 1667 (1950). (9) L. J. Bellamy, “The Infrared Spectra of Complex Molecules,” 2nd ed., John Wiley a n d Sons, Inc., New York, 1958, pp. 206-209. (10) C. Rarries and hZ. Q’eiss, Ann., 327, 355 (1903).
SEPTEMBER, 1062
CYCLIZATIONS
LEADING TO
3-ANILINOHYDANTOIN
3 179
s o h tion of N-carboxyphenylhydrazidoglycine ethyl ester (V) and triethylamine in absolute ethanol was refluxed for four hours. It was of interest to compare the cyclization of X-carboxyphenylhydrazidoglycine ethyl ester (V) with that of the isomeric carboethoxyglycine b phenylhydrazide (X). Under conditions such VI11 that N-carboxyphenylhydrazidoglycine ethyl ester 3-Anilinohydantoin also gave a reaction ehar- (V) rapidly forms 3-anilinohydantoin, carboethacteristic of hydantoin, namely, it reacted with oxyglycine phenylhydrazide (X) was recovered benzaldehyde to give 5-benzal-3-anilinohydantoin unchanged after nine hours of refluxing in an (XI). The infrared spectrum of this compound ethanolic solution of triethylamine Carboethoxyglycine phenylhydrazide (X) did react, however, 0 when a stronger base was used; when it was reI/ fluxed with one equivalent of potassium hydroxide in absolute ethanol, a 71% yield of the potassium salt of N-carboxyphenylhydrazidoglycine (IV) was isolated. This rearrangement can be explained 0 if 3-anilinohydantoin (11) is an intermediate in the reaction. This reaction is a convenient method 0 of preparing N-carboxyphenylhydrazidoderivatives of D,L-amino acids starting with carboethoxy. carbobenzoxy, or carboallyloxy derivatives of the amino acids. However, a limitation has been obI1 served when working with optically active comO XI pounds; when L-carboallyloxyleucine phenylhyshowed carbonyl stretching frequencies a t 1764 drazide was refluxed with potassium hydroxide and 1715 cm.-l and a strong b m d a t 1656 cm.-’; in absolute ethanol, the resulting S-carboxythis was attributed to aliphatic C=C absorption. phenylhydrazidoleucine showed no optical activity. The products isolated from a reaction in which The ultraviolet spectrum showed one maximum oat 2300 A. and another strong maximum a t 3180 A.; rarboethoxyglycine phenylhydrazide (X) was rcthe latter is characteristic of benzalhydantoins.ll fluxed with an equivalent of sodium ethoxide iii 5-Benzal-3-anilinohydantoin was reduced to 5- absolute ethanol were 3-anilinohydantoin (11) carboethoxyglycine phenylhydrazide benzyl-3-anilinohydantoin with phosphorus and (22%), (11.8%), the sodium salt of N-carboxyphenylhydriodic acid and with Raney nickel. The cyclizations leading to 3-anilinohydantoin hydrazidoglycine (IV) (5.9%), and an unidentiwere base-catalyzed. When S-benzylthiocarboxy- fied acid (Spl,). These cyclizations are summarized in Chart I. glycine phenylhydrazide (I) was refluxcd with The several cyclizations above involve the formatriethylamine in absolute ethauol, a 62% yield of tion of an imide from compounds which are amides 3-anilinohydantoin (11) was obtained. Whcn chloand esters (or thio ester). Such changes are not roform was used as a solvcnt, the rate of 3-anilinohydantoin formation was slower, but the yield was without precedent. de Mouilpied and Rule1* 67%. 3-hnilinohydantoin (11) was formed also obtained succinimide by treating methyl succinimate with alkali. Sondheimer and Holley13found i i i 59% ykld when S-benzylthiocarboxyglycinc that treatment of glutamine and asparagine csters ethyl ester (TX) WRS rcfluxcd with phenylhydrawith alkali resulted in imide formation. The xiiic aiid triethylaminc in absolute ethanol. This I:ttt,er reaction is further evidence for 3-anilino- formation of products with an N-amino imidr hydantoin as the structure of I1 because, if tria- structure has been noted with other hydrazidc zines were formed in these reactious, l-phenyl- esters; for example, CurtiusL4obtained X-amino3,6-dioxohexahydro-l,2,4-triazinerather than 2- succinimide when diethyl succinate was heated phenyl-3,6-dioxohexahydro-l,2,4-triazine (11-4) with hydrazine hydrate. The cyclizations leading to 3-anilinohydantoin would have been produced. N-Carboxyphenylhydrazidoglycine ethyl ester are consistant with the mechanism proposed by (V) [an expected intermediate in the reaction of Sondheimer and Holleyi3to explain imide formation S-benzylthiocarboxyglycine ethyl ester (IX) with when carbobenzoxy-L-asparagine methyl ester was phenylhydrazine and triethylamine] was easily stirred with sodium hydroxide. I n this mechcyclized under similar conditions. A 74.4% yield anism, the base removes a proton from the amide of 3-anilinohydantoin (11) was obtained when a ( 1 2 ) A. T. de Xlouilpied and A. Rule, J . Cliem. Soc., 91, 176 (1907). 0 II
(11) AI. J. XIcLean and D. R. Seeger, J . A m . Chem. Soc., 62, 1416 (1940).
(13) E. Sondlieinier and R. W. Holley, J. A m . Chem. Soe., 1 6 , 2-167 (1951). (14) T. Curtius, J. p r a k l . Chem.. 92, 7.1 (191;).
3180
AIILNE! ANID
FISH
VOL. 27
Ultraviolet spectrum ill 95% ethanol:, , ,A 2300 A , , e 10,300;, , ,A 2800 .&., E 1160. Method B.--8 suspension of 1 g. of S-benzylthiocarboxyglycine phenylhydrazide and 4 ml. of triethylamine in 30 ml. chloroform was refluxed for 2 hr. The clear solution was cooled overnight in a refrigerator. The resulting crystals were filtered and recrystallized from water; yield, 0.40 g. (67%), of 3-anilinohydantoin, m.p. 165-166'. Method C.-S-Benzylthiocarboxyglycine (6.0 g., 27 mmoles) was dissolved in 100 ml. of absolute ethanol satuc I rated with hydrogen chloride. The solution was allowed to stand overnight at 5". The solution was then evaporated to an oil under reduced pressure. The oil was dissolved in 50 ml. of absolute ethanol and 3 ml. of phenylhydrazine and 3 ml. of triethylamine were added. The solution was refluxed for 24 hr. The solution was then cooled and allowed to stand overnight. The crystalline precipitate was filtered and recrystallized from water. The total yield of 3-anilinohydantoin was 3.0 g. (5970), m.p. 165-166'. When an excess of phenylhydrazine (6 ml.) was used in the above reaction, 3.0 g. of a compound (m.p. 204-205') was isolated with the correct analysis for N-carbozyphenylhydrazidoglycine phenylhydrazide. Anal. Calcd. for CljH17Nb02: C, 60.20; H, 5.67; N, 23.41. Found: C, 60.29; H, 5.87; N, 23.58. Samples of 3-anilinohydantoin (11) prepared by methods A, B, and C were shown to be identical by mixed melting point determinations and by comparison of their infrared Iv and ultraviolet spectra; they were shown to be identical 0 with the compound previously reported &s 2-phenyl-3,6-diII O H H O H oxohexahydro-l,2,4-triazineprepared by the reaction of SH 2 C 4 I1 I I II I benzylthiocarboxyglycine phenylhydrazide with lead aceC i H s OC-C-N-C-NH I " tate. I HN / H Reductive Cleavage of 3-Anilinohydantoin.-The proceC ' dure developed by HinmanlG was employed for this reaction. VI I1 0 A mixture of 1.5 g. (7.85 mmoles) of 3-anilinohydantoin and approximately 15.0 g. of W-2 Raney nickell7 in 75 ml. of I11 absolute ethanol was vigorously stirred while refluxing for C'liart I 30 hr. At the end of the reaction period, the liquid layer was separated by decantation. The catalyst was washed S---H giviiig a 1.esoiiaiicc-stabilized timidc ion with 50 ml. of absolute ethanol. The combined ethanol solutions were evaporated to an oil (aspirator, steam bath). nhich thrii attacks thc cster carbonyl to give a On standing, crystallization of hydantoin took place. The cyclic ion; this ion iii turn loses alcohol to give crystalline mass was washed with petroleum ether. The t lie cyclic product. remaining solid, on recrystallization from 95% ethanol, gave 0.16 g.(20.3% yield) of hydantoin (111). Identification was made by a mixed melting point determination (m.p. Experimental 219-220') and by comparison of the infrared spectrum with an authentic sample of hydantoin. S-Benzylthiocarboxyglycine Phenylhydrazide (I).-Thcl The petroleum ether washings were evaporated to an oil. preparation and properties of S-tieiizylthiocarbosygl~rine The oil was distilled and collected on a cold finger and was phenylhydrazide are described in a previous paper . 3 3-Anilinohydantoin (11). Method A.--A suspension con- identified as ethylaniline by comparison of the infrared taining 4.0 g. (12.7 mmoles) of S-benzylthiocarboxylg~cine spectrum with that of an authentic sample of ethylaniline. N-Carboxyphenylhydrazidoglycine (IV). A. From 3phenylhydrazide in 5 ml. (36.4 mmoles) of triethylamine and 100 ml. of absolute ethanol was refluxed for 30 min. Anilinohydantoin (11) and Sodium Hydroxide.-To a soluThe suspended material was removed by filtration, and the tion of 1.0 g. of sodium hydroxide in 50 ml. of water was solvent was evaporated under redwed pressure (aspirator, added 2.5 g. (13.0 nimoles) of 3-anilinohydantoin. After steam bath). The residue was washed with a small amount standing for 1.5 hr. a t room temperature, the 3-anilinohydof dry ether; yield, 1.5 g. (61.9(/(); m.p. 161-166". .i antoin had dissolved. The clear solution was acidified with sample of this material rrrrystallized from water melted a t concentrated hydrochloric acid (pH 2, pH paper). The solid that precipitated was removed by filtration and washrd 185-166'. 1 :iw- with 30 nil. of dry rther. Itecrystallisation from aretone Infrared sprctruni of scrl~tlfilm dtxpositctd from late: S - H stretch, 3Pd6 cm-1; ('=O strctch, 1779, 1724 vielded 2.15 g. (78.50;) of r\'-carboxyphenylhydrasido~l~cine (IV), m.p. 195-197' d w . C --I1 out-of-planc dcformatlon, 751, 603 cm.-l. Anal. Calcd. for C9HIlN,O,: C, 51.67; H, 5.30; N , (15) .\I1 melting ~ ~ o i nat rse iincu~~.rr,te
