XEV COMPOUNDS X
X
a OCN I1
N '
I,X=O IV, X = Hz
R 11,R = H : X = 0 111, R = CH3; X = 0 T',R=H;X=H,
Experimental Section3
N-Nicotinoylisoquinuclidine. Method A.-A
solution of 100 g (0.66 mole) of ethyl nicotinate, 73 g (0.66 mole) of isoquinuc.lidirie, and 700 ml of hexane was dried by azeotropic distillation using a Dean-Stark trap. After 2 hr, 4 g of commercial anhydrous sodium methoxide was added and heating was continued for 20 hr. The solvent was removed by vacuum distillation on the steam bat'h. Water was added and the product was extracted with chloroform. ilfter removal of the solvent the residue was recrystallized. N-Nipecotoylisoquinuclidine. Method B.-A solution of 30 g (0.14 mole) of X-nicotinoylisoquinuclidine, 2 g of PtOa, 11.7 ml of concentrated HC1, and 200 ml of absolute ethaiiol was reduced in a Parr hydrogenator at 4.2 kg/cm2. The reduction was complete in about 3 hr. The catalyst was filtered and the filtrate was concentrated in vacuo to a residue, whirh wa3 di+ solved in water, made basic with ?JH,OH, and extracted with chloroform. The product was purified by the method given in Table I. N-( 1-Methylnipecotoy1)isoquinuclidine. Method C.-A mixture of 18 g (0.08 mole) of N-nipecotoylisoquinuclidine, 30 g of formic acid (987,), and 24 ml of 377, formaldehyde was heated on the steam bath for 48 hr. The colorless solution was (soncentrated t o dryness in vacuo, the residue was suspended in water, made basic with ",OH, and extracted with chloroform, N-( 3-Picolyl)isoquinuclidine. Method D.-A suspension of N-nicotinoylisoquinuclidine (40 g, 0.185 mole) in 300 ml of ether was added to a refluxing suspension of 15 g (0.4 mole) of LiAlIT, in 1 1. of anhydrous ether, and the reaction mixture waq heated under reflux with stirring for 15-20 hr. After the usual deconiposition, the product was distilled. (3) All melting points are corrected. Edwin Connor of these laboratories.
Xicroanalysis was performed hy N r .
Substitution in the Hydantoin Ring. IV. N-3-p-Bromoanilinomethyl Derivatives XELDRUM B. \I'INSTE.'LD Deparlmenl of Chemistry, Bucknell rniuersiiy, Lewisburg, Pennsylvania Received September 9, 2 966
-
Y
The condensation of primary and secondary aliphatic or aromatic amines with formaldehyde and phthalimide or succinimide has been shown in previous studies in this laboratory to produce phthalimidomethyl and succinimidomethyl derivatives of amines which are particularly useful for identification purposes.' 3Iore recently a series of N-3-aryl- (and alkyl-) aminomethylhydantoins prepared by condensing various hydantoins with formaldehyde and amines has been reported.* I n the present study this condensation is extended to include the preparation of a number of N-3-p-bromoanilinomethylhydantoins. The hydantoins used in this investigation were prepared from the corresponding ketone, ammonium carbonate, and potassium cyanide according t o (1) (a) H. W. Heine, R.1. B. Winstead, and R. P. Blair, J . Am. Chem. Soc., 78, 672 (1956): (b) M. B. Winsteed, and H. N'. Heine, ibid., 77. 1913 (1955); (c) M. B. Winstead, K. V. Anthony, L. L. Thomas, R. G. Strachan, and H . J. Richwine, J . Chem. Eng. Data, 7, 414 (1962). ( 2 ) hl. B. Winstead, D. E. Barr, C. R. Hamel. D. J. Renn. H. I. Parker, and R. BI. Neumann, J . M e d . C h e m , 5, 11J (1965).
266
Substit iited tis dantom
.+)-Dicyclopropyi" r -
5,S-Diethyl 5,j-Dimethyl 5,s-Diphenyl 5,Z-Di-n-propyI 5-Ethj 1-5-phenvl 5,j-Hexamet hylene Hydantoind LIenthonespirod 5-p-Methoxyphenl 1 5-hfethyl-5-p-chlorophenj lL 5-Me thyl-5-iso butyl j-Met hyl-5-pentyl 5-Methyl-5-p henyl *;-Methyl-5-( 2-t hienyl) 5,5-Pentamethylened &Phenyld 3, 5-Tetrame Lhylene" 3-( p-Toly1) All melting points were determined using a AIel-Temp apparat)us :tiid are corrected. !' T i l e produc ubtaiiied from thc rcxctiiiii mixture n-ere of high purity, and the percentage yield reported is of unrecrystallized product. c Carhoii and hydrogen analyses w r e conducted by the Schwarzkopf 3licroanalytical Laboratory, IVoodside, ?;. Y. Kitrogeii analyses were by the semimicro Kjeldahl method and were determined by '\'ict,nr Krimsley and Eric Steinberg of this laboratory. The product precipitated out of sulut,ion shortly after refluxing had begun, and the reaction mixture was refluxed for 30 min. e 1:ecrystallized from aqueous acetone. E[!crystallized from aqueous ethanol. 0 Thie compound was reported.? ltecrystallized froin et'lianol. 1 A 2m p 194.5-195.5", d t repeated recrystallizations. j Recrvstallized from ethanol-dimethylformainide. k A mixtiirc of ethai1111mid dimetli;vlfor~natiiid~~ K:Lused as the reaction solvent. %
the method described by Goodson and co-workers.3 Equimolar quantities of the hydantoin, p-bromoaniline, and formaldehyde were refluxed for 1 hr or less in ethanol solvent following the procedure previously described.' The products were obtained upon filtering and cooling the filtrate and are reported in Table I. Acknowledgment.-The aiithur wishes to thank the members his 1964-1965 organic chemistry class who prepared the compounds reported herein as part of a special laboratory exercise. (if
( 3 ) 2. H. Goodson, 1. L. €lonigherg, J . .I. Lcllrnan, and TV. 11. Burton, J . Ory. Chcni., 26, 1920 (1960).
Quinoxaline Studies. XIII. N-(2-Quinoxalo~l)-cu-amino Acids"' P E L h R J. \I HIlM I S , AP~D HARRY SCHYLTZ
SHLOVO GERLII \KO\,
P.
Department of Chemzstru, 2 /it l *ntLersity oj Jlianii, Coral Gables, Florada 3312$ h k e z t r t l Octobri 27, 1,966
Several physiologically active polypeptides, such as levomycin,3 a~tinoleukin,~ e~hinomycin,~ and q u i n o m y ~ i n ,have ~ ? ~ been shown to possess one or more quinoxaloyl moieties. This prompted the preparation of a series of N-(2-quinoxaloyl)-ol-amino acids (Table I ) for testing as antitumor agents. (1) \.e gratefully acknowledge support of tliis work under National Institutes of Health Grant G;\I-11968. ( 2 ) Paper XI1 of this series: E. Brill and 11. P. Bcliultz, J . O r y . Chem., 29, 5 i 9 (1964). (3) H. E. Carter, C. P. Schaffner, and D. Cottlieb, Arch. Biochem. Biophiis., 63, 282 (1954). (4) 11. Ueda, Y . Tanigalra, 1 ' . Ogami, and €1. Gmezaua. J . Antibiofics (Tokyo), AT, 125 (1964). ( 5 ) 11.. Keller-Schierlain, 11. L. Mihailovic, and V. Prelog, H e 6 . Ch17n. Acta, 43, 305 (1959). (6) T. Yosiiida, K. Katagiri, and S. Yokozawa. 1. An2ihioiii:s ( T o k g d , A14, 330 (1961). (i) J. I. Shoji and I
