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FLUORO-DERIVATIVES F POLYCYCLIC ARCINOGENICcoMPolJNDs

Ernst D. Bergmann, Jochanan Blum, Sarah Butanaro and Adam HellerDepartment f Organic Chemistry, ebrew University, erusalem

(Received 0 February1959)

FROM the etrongly rtho-B-directing nature of fluorine atome inelectrophilic eactions of aromatic compounds, nd the unusually largereactivity f the ortho-positions, ne must conclude that the electro-philic electron looalisation nergies decreaee strongly in the immediateneighbourhood f the fluorine-substituted arbon atom.

Therefore, f one assumes 1,2 that the determining tep in thecarcinogenic rocess in an aromatic hydrocarbon s an electrophilicreaction of the "K" region, and if one compares the electrophilic lectronlocalisation nergies of the compounds (a) with an unsubstituted K"region and (b) with fluorine in the "K" region, one arrives at thefollowing redictions:

First possibility: f the electrophilic ubstitution akesonly at the fluorinated arbon atom, the carcinogenic ctivity ill

' C.A. Coulaon, dvances in Cancer Research,Vol. , p. 2, NewYork (1953).2 A. Pullman and B. Pullman, dvances in Cancer Research,P. 117,New ork (1955).

place

Vol. 3

15

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16 Polycycllc arcinogenic ompounds

deareaee, einoe this carbon atom will be ecreened y the fluorine.Second possibility: f the substitution akes place only at the

non-fluorinated tom or eimultaneouely n both oarbon atome, thecarcinogenio ctivity ill increase.

Aa It seemed interesting o compare these theoretical esultswith the experiment, number of fluoro-derivatives f carcinogenicpolycyclics as been eyntheeieed. he methoda of synthesis re brieflyreported here.

(1) 4-Fluoro-l-naphthylamineae condensed n the presence of atrace of iodine with E- and g-toluidine, eepectively. heI-p- and @olylderivatives 80 obtained (I, m.p. 74-75'; b.p.187-189' (2 mm); II, m.p. 53' b.p. 208' (10 mm)) were cyclisedwith zinc ohlorlde nd acetic anbydride o 3-fluoro-5:7-dimethyl-ltP-bensaoridineIII, m.p. 174'1 picrate, .p.218-220' (deo.)) nd 3-fluoro-5r8-dimethyl-l:2-benz~Orldine(Iv, m.P. 173-175'; rate, m.p. 210-213' (deo.)).(Anal. Found: (III) C, 83.2; H, 5.6; I, 5.0; F,, .8

(IV) C, 82.9; H, 5.0; N, 4.9; F, 7.2C19E14FN equires C, 82.9; H, 5.11 IJ, .1; I?, .9$)

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Polyoycllo arcinogenic ompounde 17,(2) The synthesis f suitably ethyl- and fluoro-eubetltuted

lr2-benzanthraoenee tarted from z-(4-fluoro-l-naphthoyl)-benzolo acid (V, from toluene, .p, 161), which oould beprepared in 53%~ield from phthalio anhydride nd 4-fluoro-1-naphthylmagnesium romide (4-fluoro-1-bromonaphthaleneboiled at 108' (0.8 mm) and melted at 36).

Y Yu

Reaction of V with methylmagneelum romide gave the lactane VI (fromethanol, .p. 140') which wae reduced by zinc and hydroohloric cid in4pk an by phosphorus nd hydriodic cid in lOO$ yield to 4-fluoro-l-a-(g-oarboxy-phenyl ethyl) naphthalene VII, from nitromethane, .p.170.5 - 171'). Cyclieation ith sulphuric cid gave in 8% yield J-fluoro-q-methyl-lr2-bensanthr-lo-oneVIII, from ethanol m.p. 130') and reductionwith zinc dust and sodium hydroxide nd subsequent ehydration ithalcoholic ydrochloric cid, 3-fluoro-q-methyl-1-1*2-benaanthrabeneIX,

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18 Polycyclic arcinogenic ompounds

R1=CH3, 2-R) hp. 54', rom ethanol; ield, 8%). &al. Found: C,87.4; 5.41 F, 7.5. ClVH13F ewires C, 87.7; I 5.0; F, 7.35).Reaction of VIII with methylmagnesium odide gave IX (Rl-R2-CH3) fromoyclohexane, .p. 94'; ield, 6). (&g. Found: , 87.9; , 5.5; F, 7.2.C20H15F requirea C, 87.9~ , 5.5; , 6.W.

U.V. spectra in CRC13) II: 274 w (4.65); 83 IQI 4.72); 85 w(4.75); % w (4.70); 42 + (3.88); 69 nc1 3.92); 90 w (3.90).I'JI 64 w (4.52); 72 w (4.58); 84 w (4.71); 94 w (4.64); 22 IIIP

(3.83); 36 w (3.89)~ 55 w (3.83); 74 w (3.90); 95 w (3.95).IX: (Rl - CH3, R2 = H): 285 w (4.78); 95 JW (4.38);

348 mc~ 3.79)5 96 w (3.04).IX: (RI - R2 = Crr,): 289 w (4.65); 00 w (4.68); 66 w (3.78).A more detailed description f these and related experiments s well asthe results of the biological esting of the compounds II, IV and IX(R~=R~=cHJ nd Rl-cH3, R2-H) will be reported elsewhere.