9G 1
YEWConipoums
September 1969 Oxidation of Fluorenamines and Preparation of 2,2'- and 4,4'-Azofluorene1 YULYosr Laboratorij .for Cancer Research, Veterans .ldmznzstration Hospital and Department of Baochemistry, University of Minnesota, Minneapolis, Minnesota
Received April 26, 1969
l'luorenylhydroxamic acids, particularly those obtained from 2-nitrofluorene, are strong carcinogens. The latter is commercially available. Certain derivatives of 1- and 3-nitrofluorene have recently been found to be carcinogens2 as well. 1-, 3-, and 4-nitrofluorene3 are best prepared (69-80%) by oxidation of the respective amines with m-chloroperbenzoic acid. 2.2'-hzoxyfluorene4 arid 2 , 2 t - a z ~ f l ~ ~ r are e n espectroscopically barely distinguishable. The reported identity of 2,2t-azoxyfluorene, isolated from rat liver incubated with K-(fluoren-2-y1)acetohydroxamic acid, is therefore questionab1e.j
ammonium sulfate (100 ml, 0.043 mole) was poured into the DRIF solution. An orange precipitate resulted. The reaction mixture was stirred under N:! for 15 min. The orange precipitate (2,2'-azoxyflnorene, determined by elemental analysis and IIV spectrum; mp 262" dec, lit.4 279') was removed; ice-cold HIO (1300 ml) was added to the filtrate. The resulting green precipitated product was collected by filtration, washed (cold H?O), and dried in vacuo (2.60 g, 47%), mp 72-78', lit.' 77-79". It had a uv spectrum identical with that of authentic compound. Priier product (mp 78-79') was obtained by recrystallizing the crude product from hexane. 2,2'-Azofluorene.-Fliioren-2-amine (1S1 mg, 1.00 mmole) i n AcOH (6 ml) was added to 2-nitrosofliiorene (195 mg, 1.00 mmole) in AcOH ( 8 ml), and then let stand at room temperatiire.'" The the orange precipitate was collected and washed with ,O mg, 70%): mp 260" dec. Analytically piire sample ned by recrystallization of the crirde prodiict from boiling C6HBto give orange prisms: mp 262' dec; X",iJ,"I3 252, 262 iirfl, 384 mp; mixture melting point with an analytical sample of 2,2'-azoxyfluorene (mp 265' dec, lit.? 279') was undepresaed. Anal. (CP&&;P) C, H, S. The identity of the compound was further establiahed by reducing it with Zn in AcOH to fluoren-2-amine (4Sc7O) and 2fluorenylacetamide (23%). 4,4'-Azofluorene.-4-X itrosofl~iorene~ ( 193 mg, 1.00 mmole) i i i CHC1, ( 3 ml) was added to a solution of fluoren-4-amine3 (181 mg, 1.00 mmole) in .4cOH (7 m1).10 The reaction flask was heated
TABLE I OXIU-Y~ION OF FLUORENAMINES WITH m-CPB .ACID Flriorena~nine used
Reflux time, min
1.i 13 1 1.i 4 2 13 4 3 90 All products were purified as described for 1-nitrofluoiene. 1 2 3
(1
Mole ratio (acid :amine) 1
3.03
Experimental Section6 1-Nitrofluorene (Table I).-Fliioren-l-amine3 (2.00 g, 0.011 mole) in CHCI, (40 ml) was added to a cold solution of mchloroperbenzoic (m-CPB) acid (0.0350 Af in CHCI,; 0.157 I., 0.055 mole). The reaction mixture was stirred at, 0" for 15 min, then broiight to room temperature with lukewarm H20, kept there for 30 min, and finally refluxed for 15 min. The organic phase was extrackd with 0.5 -17 NaOH (two 60-ml portions), witshed (HzO), and dried (MgSO?) and the solvent was evaporated. The residrie was applied on an alumina (50 g) coliimri packed with hexane and chromatographed with a 10% (v/v) soltition of CH?CIu in hexane. The per cent of CH2Cl2 was i r l creased as the chromatography proceeded. The eluate of initial fractioiis was concentrated and cooled and the prodirct was c:ollected by filtration (69%). 2-NitrosoAuorene.-A simplified method of a previous one was used.' The undried, filtered, and washed paste of 2-fluorenylhydroxylamine, obtained from partial reduction of 6.00 g (0.0286 mole) of 2-nitrofluorene with H2S in the presence of NH,, was dissolved in cold DlIF (600 ml).8,9 Cold aqueous 0.43 ferric (1) This work \vas supported in part by U . S. Piihlic Health Service Research Grant (2.4-20571-14, and the excellent technical assistance of Cliarles bluscoplat is acknowledged. (2) H. R . Gutmann, C. C. Chen, and D. Leaf. )'roc. Bmer. .4as. Cuticer IZes.. 10, 34 (1969). (3) Y.Yost and H. R . Gutmann. J . Chem. Soc., 345 (1969). (4) H. R . Gutmann, Erperientiii, 20, 128 (1964). ( 5 ) C. C. Irving, J . B i d . Ckem.. 239, 1589 (1964). ( 8 ) hIelting points n e r e taken with a Fisher-Johns apparatus and are uncorrected. U r spectra were recorded (in mp) with a Beckman DK-2 spectrophotometer. T h e fluorenamines were obtained from t h e respective aminofluorenones and 3-nitrofluoren-%one which were purchased from .-lldricli Chemical Co.. lnc.. Milwaukee, Wis. T h e m-chloroperhenaoic (m-CPIJ) arid iias oiitained from Organic, Inorganic Cliemical C o . , Siln Valley, Calif. (i) P. 11, Lotlikar, L. C. lIiIler, J Iiller, and A. XIargreth, C(tucer
..
25, 1744 (1965). (8) R . iyilstatter and H. liribli. B e r . , 41, 1908 (1936). ($1) J.. -1. l'oirier, L. A . Miller, and C. E. Miller, Cancer Ilea., 2 3 , 790 (lUti3).
He8
'70 Producta
JIp, " C
yield
Xitrofluorene Sitrofluorene Xitrofluorene Xitrosofluorene Nitrofluorene
104-106 154-1 57 99-103 110-1 12 72-7.5
69 81 72 80 80
on a steam bath for 1 hr. The product settled as reddish brown crystals after the reaction mixture stood a t room temperature for 1 week; it was collected and recrystallized from C&B ( 4 5 % ) ; mp 261" dec; 257, 265 infl, 343 mp. Anal. (C?&&r)
C, H, N. (10) E. Ilamberper, Ber., 2 9 , 102 (1896).
Stable Oxaziridinea' J. C H I K R ~ V U ZATNYD PKICL Trtaii r Department of Chemistry, S o T t h Texas State C'niverszty, Denton, Teras 76203 Received February 19, 1969
Although oxaziridines have been known for several years2 and a variety of methods have been utilized for their ~ y n t h e s i swe , ~ were unable to find a report on their physiological activities. Thus we decided to prepare a number of oxaziridines (Table I) in order to compare their physiological activities with particular reference to antitumor activity. (1) This investigation was s i i p y o r t d I'ulrlic liealtii Rrriice Researcli Grant No. C.410530 from the Sarionol Cancer Inztitiire an. Emmons. J . A m . Chem. Soc.. 78, 6208 (1956): I.. Horner and E . Jureens, B e r . , 9 0 , 2184 (1957); H. Iirimm, i b i d . . 9 1 , 10Si (1958). (3) IT. D. Emmons, "Heterocyclic Compounds iiith Three and Forir AIembered Kings," .I. \Veissberger. E d . , Interscience Publishers, Inc., Kew York, N. T., 1964, Chapter I T , 1: 6%.
I
Experimental Section 'Hie osaziridities were prepared tiy t h e peritcetic acid2 or tri-chloroperbettz~~ic~ acid' oxidation of the corresponding imiiies. The oxaziridines wei'e isolated by distillatiuri at, reduced pressure aiid iti so~iiec8ase.q additional purification was obtained by chroniatographiiig with a neiitral aliimina colrimii. (4)
11. G. P e u s , . I . Oiy. Chern , 32, 1628 ( l q 6 i ) .
Possible Anticonvulsant Thiazolo[3,2-a]benzimidazole RIannich Bases. XI'
Experimental Section Thiazole[ 3,2-u] benzimidazol-3(2H)-one.~--l'-C1~il)~?t has) iiiethylthiobe~izimidazole~ i.ig) in o-PhCl? (20 ml) x a - tx+lwed f o r 1 hr while removing EtOII. The mixtiire I I ~ ~ W I I V qiiitc cia1.k: 1s i l g ) sepmxted : l i d were rei
Diethylaminothiazolo[ 3,2-u]benzimidazol-3( 2H)-one.- A iiiixtiire of tliiazolo[3,2-a]betizimidazol-:3(2H)-olle ( 2 g), E t ? S I l ( 2 rnl), ArOH (10 nil), aiid CH20 ( 2 ml) heated ~ i ai strani bath for 7 hi. After cwoliiig, I1,O (20 ml) i v a ~added : i t i d the soliiwas iieiitralized with satiirated a filtered, washed (I*&), a ~ i dre , nip 210". .tr/u!. IC14HliXu'sO)?i The above procediii~rwa5 followed to prepaw 1 I i f ' ( i t ht'r l'o1ii~)oriIlciS.
