NEWCOMPOUSDS
July 1965
TABLE I 2-hIETHY 1 ~ - 3 - ~ ~ - 6 - 1 O D O - ~ - Q ~ ~ I ~ . ~ Z O I . O ~ E
0
_____ % calcd.-
Yield,
Rl
x p . , "C."
7c
Crystn. solvent
C
EtOH 49.7 151.2 50 (151-152) EtOH 51.06 13 Benzyl (121-123) EtOH-H2O 51.06 137,8-139.6 TO o-Tolyl" ( 142-1 44) EtOH-HYO 60 51.06 177-179 ni-Tolyl" (179-181 j 48.98 177-179 50 EtOH O-his~1" (178-180) 48 98 175-177 45 EtOH m-Anisyl EtOH 55 290 EtOH-AcOH 40 47 8 p-Aminophenyl >290 EtOH 439 40 Isopropyl 177- 178 40 00 EtOH 2-Hydrosyethyl 17i-179 40 43 9 1*5 EtOH n-Bii t y1 114-116 4; 7 35 AcOH-CsH, Anilino 217.5 KtOH 442 GO p-Sitrophenyl" 207-209 ( 209-2 10) 30 38.5 2,4-1)iiiitri~aiiili11(~ 171-172 CJL EtOH 46.3 70 2--Pyrid)-l 166-168 49 . 5 EtOH 70 3-?\IethS-l-3-pyrid)-l 159-161 These compounds have been synthesized earlier by a differeiit synthetic ni-thod. reported in the literature.
__
Phenyl"
-_
7----70 C
found
---
H
N
3.03
7.03
49.3
3.0
i.4
3.03 3.4
7.4 7.4
51.0 51.1
3.2 3.6
7.8 7.5
3.4
7,4
50.9
3.2
7.3
:3,:31
7.13
48.64
3.01
7.2
7.13 6.7 6.7 11.1 11.1 8.5 8.4 8.5 11.1 10.3
48.73 55.64 *55,85 47.3 47.5 43.6 39.8 43.5 47 5 44.00
3.45 3.53 3.18 3.09 3.23 4.4 3.7 3.9 3.0 2.7
7.4 6 . c5 6.2 11.45 11.0 8.4 8,Y 8.2 11 . 3 10.2
3 3 3 3 3 4 3 4
31 16 16 18 18 0 h
00
*J 1
2 4
h
7
ii
H
2.71 2.7 3. : Figiires
14.0 11 ..i6
35.2 46.11 49.3 1 . 1 pareiitheses are the
--
iii
14.5 2.5 11 . 5 3 2.2 7.6 3.00 melting points
~
Fluorofluorenes. Derivatives of Fluorene. XX. V. New Difluoro-2-acetamidofluorenes for the lalb
Study of Carcinogenic RIechanisms MOSESJ. XAMKI \ G , T. LLOYD FLETCHER,~~ A\D WILLIUI H. WETZEI.
Chenizstry Research Laboratory of the Department of Surgery, C'nzverszty of V7ashzngton School of Jledzczne, Seattle, Washangton 98106 Reteazed J l a r c h 9,1965 Six nioiioflrioro-9-acetamidofrilorenes (2-AL4E')% aiid the first two (1,7 and 3,T) difluoro-2-AAF have been report,ed.3 Restilts of testing of some of these substaiices, by 1Iiller and 1Iiller of the NrArdle ATemorial Laboratory, and reasons for testing these siibstances have been piiblished.' We here describe preparation of three iiew (4,7, 5,7, aiid 6,8) difliroro-2-AA4F and related cwmpounds. The first two have fliiorine in the 7-position which markedly enhances liver carciiiogeriicity of 2-AAF5 perhaps by blocking a detoxification site, (1) (a) This work was supported in part b y a grant (C.L-Oli44) from the Sational Cancer Institute and, in part, by a Career Development Award 5K3-G.\I-14,991 t o T. L. F. (b) For P a r t X I X see T. L. Fletcher, 11.J . Namkung. J. R. Dice, and 6 . li. Schaefer, J . .\fed. Chem., 8, 347 (1965). (c) T o whom requests for reprints should be addressed. (2) (a) T. L. Fletcher, 11.. H. \\-etael, AI. J . Namkung, and H. L. P a n , J . A m . Chem. Sor., 81, 1092 (1959): (b) T. L. Fletcher, R1. J . Kamkung, H . L. P a n , and W.H . \Vetael, J . Org. Chem., 26, 996 (1960); ( c j T. L. Fletcher. AI. J . Kamkung, W.H. \\-etael, and H. L. P a n , ibid., 25, 1342 (1960). (31 RI. J. Kamkung and T . L. Fletcher, i b i d . , 26, 2243 (1961). (4) E. C. lliller, T. L. I'letclier, .I. Margreth, and .J. .I. IIiIler, Caxcer Ifes., 22, 1002 (1962). (5) J . -1.Miller, R.B. Sandin, E. C. MiIler, and H . P.Rusch, i b i d . , 15, 188 (1955).
perhaps also by nlteriiig the potency of the X-hydroxy metabolite whicah is more c~arciiiogeiiicthaii the A4AFitself.6 Sirive some ~~olyctiloroflrioreiies show aiititiinior effects, a few o f the present cwrnporuids were tested by the CCNSC, brlt the resiilts indicate thttt none of them has c-ytotoxic,effec-ts.
Experimental; 2,5-Difluorofluorenone.-To 42.6 g. (0.2 inole) of 5-fluoro-9oxo-2-fluorenamine2b in 100 nil. of dimethyl sulfoside,* 200 ml. of 48% fluoroboric acid was added with stirring. After cooling to O", a saturated solution of 21 g. (0.3 niole) of XaX02was added slowly. After stirring for 30 niin., the salt was filtered off, washed with 20 nil. of 5% fluoroboric acid, 20 nil. of methanol, and 20 ml. of ether, and dried giving 58 g. (93'5) of salt, dec pt. 180". This was decomposed in 500 nil. of boiling o-dichlorobenzene which was boiled down to near dryness, 100 ml. of benzene was added, and the mixture was filtered. Upon rooling, a precipitate was filtered off, giving 31 g. ( 7 2 7 ) of product, m.p. 142-144'. Recrystallization from ethanol raised the melting point to 146-147'. h i analyt,ical sample was prepared by subliniat,ion a t 140" ( 1 m m . ) ; n1.p. 147-147.5': vlllilX 1721 (keto C-O), 1274, 1233 (C-F stretrhing) mi.-'. d n a l . Calcd. for CI,H,F,O: c', 72.22: H, 2.80; F, 17.58. Foiriid: C, 72.44: H, 2.80: F, 1i.22. 4,7-Difluoro-2-nitrofluorenone.-To GO n11. ot HNOa ( g o r ; ) , 3 1 g. (0.144 niole) of 2,3-difuorofluoreii:,iie was added in portions with stirring and rooling (below :30°). The mixture was removed from the ice bath, and with continued stirring, the temperature (6) E. C . Miller, J. .I.Miller, and H . A . Hartmann, ibzd.. 21, 815 (1961). (7) Nelting points, except those ahoye 300'. are corrected t o standards and were taken on a Fisher-Johns block. The infrared spectra a e r e taken in K B r disks with a Beckman IR-5 a t a concentration of c5. 1.5 mg./300 mg. of KBr. Band assignments for C-F stretching ure tentati\-e and a continuation of earlier data.xc .Inalgses were rim by Schwarskopf Microanalytical Laboratory, \Voodside. S . T.,and by .i. Bernliardt, .\Iiilheim ( R u h i ) , Germany. (8) T. L. Fletcher and 11.J. S a m k u n g , Ciiem. I n d . (London), 179 (1961).
