NOTES
January 1969
HO
HO la,R1=HR;!=C2H5 b,RI=H; R,=CH3
/
/
2a,R1=H;R;!=C2H5 b, R1 H; & = CH3 C, R1 CZH,; & = H d, R, CH,; &= H
-
Decarboxylation of the monoester 6 was chosen as the most convenient synthetic route to l b (Scheme I). SCHEME I
.I
COCH
193
ments the yield of diacid 4 varied from 0 to 60%. A recent investigation of the mechanism of this reaction revealed that molecular oxygen is i n ~ o l v e dand , ~ a new procedure incorporating aeration was devised. By employing methanolic 9aOMe as the solvent-base system the diester 5 was obtained in one step in 43% yield. The other products were a mixture of diacid 4 and the two possible monoestem6 Partial hydrolysis of 5 with IiOH gave the crude monoester 6, which on treatment with oxalyl chloride5 furnished the acid chloride 7. Reaction of the latter (7) with dry tbutyl hydroperoxide arid pyridine in benzene yielded the perester 8. The perester was decomposed7 in boiling cumene during 1 hr and the solvent was removed by distillation. Chromatography separated 1,2-diphenyltetramethylethane and gave the desired product 9 in 407, yield based on 6. Also isolated was a minor product which has tentatively been assigned structure 12 o n the basis of its nmr and ir spectra,
5
i
1.KO1
2.KOH
12
H 6
4
p 1 .
A
ACH2COCI
7
8 cumene
10 1;d-C
Finally, saponification of 9 gave 10. Both 9 and 10 were readily debenzylated by hydrogenolysis over Pd-C to give 11 and l b , respectively, thus completing the synthetic sequence Biological Data.-The estrogenicity of these compounds was determined by two different methods: assessing uterotropic and vaginal cornification activities. Uterotropic activity in mice after subcutaneous injection was measured using the assay described by Dorfman,s and vaginal cornification activity in rats was measured using essentially the procedure reported by T ~ c h o p p . ~Slight modification of the latter assay included larger size of rats (weighing 240 f 15 g) and a 4-day examination of vaginal smears. The compounds were given subcutaneously in sesame oil on two consecutive days. In the uterotropic test l b was found to be most active, followed by l a and 11. Compounds 9 and 10 were least active and displayed only a marginal estrogenicity (Table I). The threshold values for estrone (used as a reference compound) and l a in the vaginal cornification assay were approximately the same as those reported by T ~ c h o p p . ~Compound l a in this assay was 50% more potent than lb. Compound 11, however, had only one-ninth the activity of l a (Table 11).
d*.c02cH3 lb
HO
DCH3 H
\
11
The preparation of 6 was expected to offer little difficulty. Oxidative cleavage of the D ring of 17-keto steroids by base and iodine was employed earlier3t4 to give the prerequisite diacid 4. Esterification of 4 gave the diester 5 which upon partial hydrolysis4r5 yielded the monoester 6. However, in our hands the oxidative cleavage of 3 by the above procedure gave erratic results and the diacid 4 mas difficult to isolate. In a series of experi(3) A . Wettstein, H. Fritzsche, E". Hunziker, and K. Miescher, Helu. Chim. A c f a , 24, 3323 (1941). ( 4 ) J. Heer and IC. Miescher, ibid., 28, 156 (1945). ( 2 ) C. yon Seemann and G. A. Grant, J. A m . Chem. Soc., 72, 4073 (1950)
Experimental Sectionlo
3-Benz~loxy-16,17-secoestra-l,3,5(10)-triene-16,17-dioic Acid Dimethyl Ester (5).-A methanolic NaOlle solution was pre(6) L. A. Freiherg, ibid.. 89, 5297 (1967). (7) (a) P . D. Bartlett and R. R. Haitt, ibid., SO, 1398 (1958); (b) L. A. Freiberg [French Patent 1,509,769 (1967) I employed this procedure in the androstane series. (8) R. I. Dorfman, Methods Hormone Res., 2 , 713 (1962). (9) E. Tschopp, H e h . Physiol. Pharmacol. Acta, 4, 272 (1946). (10) Melting points are corrected. Optical rotations were measured in about 1% CHCla solutions a t 23-24' unless stated otherwise. Uv. ir. and nmr spectra were obtained for all new compounds. Most spectra were as expected and are therefore omitted. Analytical tlc was carried o u t on silica gel G from Brinkmann Instruments, Inc. Elemental analyses reported as symbols were within 0.4% of the theoretical values.
194
KOTES
TABLE I ESTROCJEX POTESCIZS.
~r'rSELOrTIKJPICASS \ \
Compd
Re1 potenryg
Estrone
1 0 0 , 00
I 11 1 :I II
4.10 2 . !IO I1 .!I[J 0 . 03 l i . (12
1 (i !)
Est,rone was used as a referelice cornpolllid aiid the t'ehlxiii-e t o it was assigned the value of 100!e (potency) of t,he ot,her snhataiic~eswas rcl:itd t o that of estroricx using a standard ciirve.
T.iei.>;11 ESL'ROGES
z%CTIYITT. Conipd
\-AGIX.\L
C h R S I P I l : . L T I I i S &'SS.LY
T tireshold valiie, gg"
Estroiie 1 .(i 1il I .I) I t) I ..? 11 !), 0 * 'The threshold value is defined as the a ~ i ( ~ i i i iof 1 substance ( i n p g ) needed to caiise vaginal mrtiifiratioti in :it least SO$;, of t.he animals employed in the test.9
pared from 12.i-1 g (0.554 g-atom) IJf S a and 3.0 1. of MeOIl. Estrone benzyl ether (3)" 120.00 g. 55.4 mmoles) \vas added and the mixture was stirred for 1 hr t u obtain a finely divided siiapension. After cooling to 5" with dry air bubbling through the stirred mixture L O maiiitain oxygen saturation, a solution of 28.10 g (110.8 mmoles) of I p in 320 ml of 1XeOH \vas added during 1 h r . After 3 hr the dark red mixtiire \vas hoInogeneuus. Stirring aiid aeration vere stopped and the fla-k x w stored at 5" for 16 h r . The resulting y e h v solittion was acidified with 40 ml of concentrated HC1 and MeOH wai removed under raciiiim to a final volume of 150 ml. The residue \vas partitioned betveeii io0 ml of H 2 0 aiid 700 nil of EtzO. The aqueous phase n-as separated and extracted with 200 nil of Et&. The combined EtyO layers were washed ( H 2 0 , three 300-ml purt'ioris of 1 0 5 sodium thiosulfate, H&). The acidic products were removed by extractioii xvith t\vo 250-ml portions of extracts were subsequently procesml as de I h O layer and 200 ml of 10Tc sodium thiosulfate SC)lllti(Jn\\'el'? exposed to light :11id pei~ivtiicallyagitated for 1.5 hr n-heti t h v c d o r of I, ceased t o reappetir. The aqueoiis l:iyer w a a .-epariited. The Et2()soluticrn \vazp washed (IIeO),dried (Sa2Y0i), and ewporated to give 17.0 g of crude 5 :is a yellow oil which cryhtallizetl on standing. Colored impiirities separated a i ai1 oil from CaI-Iu. The siipernatant liquid was decanted and the was evapThe residue wai crystallized from XeOH to give IO..i.i ) of 5 as colorless needles, mp SO-S3" !lit.12 mp 80-8L":, [ a ]+63". ~ The basic exti,ac.ts obtained atiove were acidified with IlCl ani1 the acids were extracted with Et&. The acids (7.10 g!, obtained after evaporation of t,he Et&), were refluxed for *5 days i n 1.01. of 0.47; iv !v) H22;O4-XIeOHto give an additional 3.40 g of 5.
3-Benzyloxy-16,17-secoestra-1,3,5jl0)-triene-l6,17-dioic Acid (4).-1n atiother esperiment, similar to that above, the crude mixture of acids ( 2 . 5 g ) was hydrolyzed diiring 20 hr n4th 3.3 g of KOH i n 150 ml of refluxing MeOH-H20 (4: 1). Crystallization from EtOhc-n-CsHI4 gave 1.5 g of 4 a,3 colorless prisms, mp 215220' B-ith softening a t 210" (evac tube), [a111 +84" (EtOR) [lit.4mp 226-227 dec, [a]n +83" (EtOH)]. 3-Benzyloxy-16,17-secoestra-l,3,5(10)-triene-16,17-dio~c Acid 17-Methyl Ester (6).-To a solution of 10.0 g of 5 in 500 ml (if w i r m NeOH \vas added 12.75 g of KO€€ in 50 ml of HJO. The sirlutioit \v:w refliixed for -1 hr, concentrated to 100 ml inider v:ii:utini, arid poiired intu 600 ml of HJO. The alkaline soliitiiiii \v:th \vastled ( P : t 2 0 ) and then acidified \ \ i t ti IICI. The produi*I :11) 31. N. Iluffman and 11. 11. I.utt, J . Bioi. Chem., 172, 323 (1948,. ( 1 2 ) BI LevitL and J. R. Syirzor, ahzd., 222, 979 (1956).
NEWCOMPOUNDS
January 1969
3-Hydroxy-16,17-seco-16-norestra-l,3,5(10)-tr~en-17-oic Acid (Ib).-The hydrogenolysis of the benzyl group of 1.00 g of 10 was accomplished as described in the preparation of 11. The solid residue was crystallized from Me2C0-n-CsH14 to give 0.63 g (84%) of l b , mp 19.5198" (evac tube). The analytical sample was obtained from CsH6 as thick needles, mp 198.5-200.5' (evac tube), [ a ]+ ~ 6 9 O (EtOH). Anal. (C1,H220a)C, H. Doisynolic Acid (la).-Doisynolic acid was prepared by the method of Heer and Alie~cher.~From 4.0 g of estrone there was obtained. after four crvstallizations from bIeOH-HI0 and one from ~\le,CO-n-C&~, "0.179 g of colorless needles, mp 198.5-
195
200" (evac tube), [ a ] flO5' ~ (c 0.470, EtOH) [ l k 4 mp 199200°, [ a ] D +102' (~0.475,in EtOH)].
Acknowledgments.-The
authors are indebted to
Drs. Leslie A. Freiberg, Wayne Cole, and Paul Burath for helpful discussions, and to Dr. R. E. lllauer and Thomas Kallal for biological evaluation. We are also grateful to Brigitte Fruehwirth, Evelyn Baker, Ruth Stanaszek, Victor Rauschel, and David Williamson for SpeCtrOsCOpiC and analytical SerViCeS.
New Compounds An Aziridinone Derived f r o m 1-Aminoadamantane E I ~ A CR. H TALATY A N D AUBRY E. DUPUY, JR.~
Department of Chemistry, Louisiana State University in S e w Orleans, Lakefront, X e w Orleans, Louisiana YO122
g (3.1 mmoles) of I11 in 150 ml of dry Eta0 was stirred with 0.55 g (4.9 mmoles) of KO-t-Bu a t 0' for 15 min (progress of the reaction was followed by ir spectroscopy). The reaction mixture was filtered through a sintered-glass funnel and the filtrate was removed under reduced pressure a t room temperature. The solid residue was recrystallized from heptane to afford 0.51 g (68%) of the aziridinone I : mp 82-83'; ir, 1830 cm-'; nmr, Anal. T 7.32 (1 H, s), 7.73-8.42 (15 H, m), 9.02 (9 H, s). Calcd for C16H25PIjO:C, 77.68; H, 10.19; K, 5.66. Found: C, 77.46; H, 10.07; N, 5.55.
Received August 29, 1968
Although the physiological properties of aziridines have been extensively investigated, especially in connection with the nitrogen mustards, there is no report in the literature regarding the biological properties of aziridinones. We report here the preparation of an aziridinone (I), which is a derivative of l-aminoadamantane, a compound in which there has been a considerable pharmacological interest since its antiviral activity was discovered.2 111CHBrCONHR2+ILCH-CO
ILCHBrCOCl+
\ /
?;112
I11
I1
I
1i1 = t-Bn = 1-adamantyl (C1OHlb)
1t2
Experimental Section3
Some Aromatic Fluorine Compounds JILLAI. BLUKCK, P. E. HUGHES,A N D J. G. SCROGGIE Department of Pathology, University of Melbourne, Victoria, Australia Received August 14, 1968
Fluorination of carcinogenic aminoazo dyes greatly enhances the activity of these compounds except when the sites involved in carcinogenesis are blocked by substitution with the As these sites are on the diamine ring, various difluoroanilines are required for synthesis of the dyes. This communication reports some observations and new compounds of interest which have arisen during attempts to prepare 2,3-difluoroaniline.
N-(l-Adamantyl)-2-bromo-3,3-dimethylbutyramide(III).--.4 solution of 1.00 g (8.6 mmoles) of 3,3-dimethylbutyric acid in SOClz (1.0 ml) was refluxed for 30 min and excess SOClz was removed under reduced pressure a t 30". The acid chloride was dissolved in 2.3 ml of CC14 and refluxed with Br2 (0.53 ml, 9.6 mmoles) for 2.5 hr. The resulting bromo acid chloride was treated gradually with an ice-cold solution of 1.31 g (8.6 mmoles) of 1-aminoadamantane and 1.14 g (11 mmoles) of Et3N in 60 ml of CH,C12. The reaction mixture was then treated with H,O, extracted with CHtCI,, and the combined CH&12 layers were washed (5% HCI, 5% NaOH, H,O, saturated NaCl solution) and dried (NazSOh). The solvent was removed in vacuo to give crude 111, which was recrystallized from heptane to furnish 2.30 g (827, over-all) of crystals, mp 182-183". $nul. (CleH.&rNO) C, H, Br, N. 1-( 1-Adamantyl)-3-t-butylaziridinone(I).-A solution of 1.00 ( 1 ) Recipient of a Graduate Traineeship from the Kational Science Foundation. (2) F.L. Davies, R. R. Grunert, R. F. Haff, J. W. McGahen, E. M. Neumayer, hi. Paulshock, J. C. Watts, T. R. IVood, E. C. Hermann, and C. E. Hoffmann, Science, 144, 862 (1964). (3) Melting points were taken on a hIel-Temp apparatus and are uncorrected. I r spectra were obtained in CHCla on a Perkin-Elmer spectrophotometer, Model 337, and nmr spectra were recorded in CClr as solvent on a Varian A-60 instrument (TMS a s internal standard). Microanalyses were performed by Galbraith Laboratories, Inc., Knoxville, Tenn.
Experimental Section3
2-Chloro-3-fluoronitrobenzene.-2,3-Dinitroaniline4 ( 162 g) was suspended in HCl (5.5 N , 490 ml) and a solution of NaNOZ (100 g) in HzO (120 ml) was added slowly with constant stirring, the temperature being maintained below 0" by the addition of solid CO, to the mixture. The mixture was stirred for a further 30 min and then a slight excess (204 g) of solid sodium fluoroborate was added slowly with constant stirring. After a further 30 min, the precipitate was filtered off under vacuum, washed with a small volume of chilled saturated sodium fluoroborate solution, and allowed to dry in the dark. The product, 2-chloro-3-nitrobenzenediazonium fluoroborate, was a bright yellow solid (193 g, 80y0) which darkened upon exposure to light. The diazonium salt was dried further in a desiccat,or (NaOH, silica gel) and then decomposed by intimately mixing small portions (10 g) with washed, dried sand (20 g) in a 500 ml round-bottomed flask fit,ted with a condenser and heating carefully in an oil bath.
____-
( I ) J. A . Miller, E. C. hiiller. and G. C. Finger, Cnncer Rea., 13, 93 (1953). (2) J. A . Riiller, E. C. &liller,and G. C. I'inger, ihid., 17, 387 (1957). (3) Rlelting points are corrected and were determined in a capillary tulie; boiling points are uncorrected. Analyses nere performed by the CSIRO Australian LMicroanalytical Service. (4) K. H. Pausackerand J. G . Scroggie, J . Chem. SOC.,1897 (1955).
