G. R. PETTIT, S. I(. GUPTA,A K D P. A. WHITEHOCSE
692
Antineoplastic Agents.
XVIII.
\-Ill. 10
N-(2-Haloethyl)benzylamines'
A ,ei,ies of N-berizyl-N-(%-haloethyl)amiiie~have bee11 *yiithesized for c.oriip:wisoii of pubsible aiitiueoplastic: properties with those of the corresponding S-bis(2-chloroethy1)amines. Coiiversioii of 3,4-dichlorobenzoylaziridiiie (11)with HC1 or FIBr to, respectively, amides I I I a arid I I I b followed by a diboraiie reductio11 sequence yielding nrniiiei I\-a aiid I \ % outlines the synthetic methods employed. Several S-2-iodoethylamides of the type illustrated by strrictwe I I I c were prepared from the correrpoiidi~igaziridine amide employing H I or from a K-2cahloroethylimide precursor using N a I i i i acet,one. Reaction hetweeii the N-2-iodoethylamides and diborane (in tetrahydrofuran) at approximately 60' for 2 hr or at room temperatiire (overnight j was sho~v11to c'ause virtually complete hydrogetiolysis of the C-I bond. Presetit,ly available biological resulta indicate the N-(2-chloroethyl)I)eiizylamiIies to be considerably less active than t,he c~)rre\poiidiiigN-hi~(2-chloroethyl)beii~ylamiiie~.
&sed 011 an earlier study4aof the aromatic sybteni oi pod(iphyl1otosiri as a carrier group for nitrogen mustardh, i t bec~amenecessary to prepare a number of Stieiizyl-X-bib( %haloethyl) amines. 411-d Several of the rciulting hcnzylamines displayed potentially useful :tiitincoplast I(* propertieq 411~11 The present investigati011 ~ - a uiidcrt:il;en \ t o evaluate the possibility of uiic~)vcring uheful canccr cahemotherapeutic properties :~iiioiig the rorresponding S-benzyl-S-(2-haloethyl):tmiiws ( e 8.. amine I a L S . Ib) Sonic S-(L'-c.hloroethyl)amiiies such as l,B-(%-chloroct hylani~~io)-l ,fi-dideoxy-n-maiinitol dihydrochloride 1i:ir.c reached clinical trial: and others have given cvidcncae of antineoplastic3 Generally these "~i~i~~-:triiied" iiitrogen mustards have been considered le- ubeful. To determine the relative merits of ccrtail] hcmzylamine carrier groups for S-(%haloethyl)miiiies, 5ynthem of the wbstatices summarized in undertalien. Scheme I illustrates the geiic~alroute found most batisfactory for obtaining bclrizylamirics of this type.' Selection of the aziridiiie heiimmides a s intermediates reqided with their ready ontry l l l t ( J ring-opening reactions aiid availability of t h c correhpoudirig benzoic ac2id.i. 111 each case the aniidc wa5 prepared from the correbponding aroyl hloride arid aziridine i n the preqence of aqueous KOH.
SCHEME
I
R
C1 Ia, R = R t = OCHJ; Nz= CHzCHzCl b, R=Ri=OCHs; Rz=H C, R = R l = C l ; Rz=CHzCHaCl d , R = R i = C l ; Rz=H
I1
-
C I ~ C O N H C H ~ C H BHJ ~ X e1
IIIa, X = C1 b,X=Br c,X=I
c1-f-J-
CH~NHCH~CH~X
C1
IVa, X = C1 b,X=Br c,X-H
( 8
[ I ) l o r Part S T ' I I refer t o G . R. Pettit and 31. R . Chamberland, Can. J . ('he'fn., 44, 81:1 (1968). ' l i This in\-estiEation mas aided b y Grants pio. T-T9F and T-79G from (lie .\merican Cancer Society.
Ilepartment of Chemistry, Arizona d t a t e University. G R. Pettit a n d J. .L Settepani. J . O r g . Chem., 27, 2962 (1962): C;. I?. Pettit, hf, R , Chamberland, D. S. Dlonda, a n d 31. Vickers, Can. J . 4 2 , 1699 (1964): ( e ) G . R . Pettit a n d R . L. Smith, ?bid., 42, 5 i 2 ( r l i C . R . Pettit. D. S.lilonda, and E. Harrington, ihzd.. 41, 2962
1-11 ( a i (It1
c.7) I,. 1'. Lariunuv, "Cancer Chemotherapy." PerKamon Press Inc.. S r a 1 urk, K , \.., 196;. rj 2'34. 16) R . 31. P e r k , . A . P.O'vonnell, and ti. .J. Crepcli, .J. M e i l . Chem., 9, 217 i11)titii: E l . %. S?inmer, C'. Sclier, S. Ilien, G. OIsen, .I. IC. Chakraharti, a n d 0. h l . Friedman, ibzri., 9, 81 (1966); P. Hebhorn a n d D. .I. Triggle, ibid..8 , .-,11 (l!l6.5i: R. F. Pittillo. .\. .T. h-arkates, and .J. l%urns.Cnnrer R e s . , 24, 1'222 i l 9 6 4 ) ; 1:. 31. ,Sctialiel. .T T . P. Jolinston, G. 8.3lcCaleh. J . .i. RlonrSkipper, ? h i d , 23, 725 11963); TV. IV. Lee, and I,. Goodman, J . J l e d . Chem., 6 , ,567 hcirm. Bull. (Tokyo), 10, 390 (1962). ( 7 ) For a recent rerien of synthetic routes to pi-(2-haloethSlfamines see: .I. S . Sinx11 and .\. Ii. L a l , $7. Inrliiin Chem. S o r . . 4 3 , 808 (1966); C-Y. \Til a r i i l ti. l?. Rohertson, Chem. I n d . (London), I95 (1966): N. .I. Leonard, 11 ) . Ninr. a n d I t . L. liootli, J . O r g . Chem., 30, 4357 (1965): G. F. Hennion and .\. C . H a z y , ibid., 30, 2650 (1965): K . .J. Leonard and J. V. Paukstelis, I / , < < / . ,3 0 , 821 ( 1 9 6 5 ) : R . 11. 3loffett. .I. .Wed. Chem., 7 , 319 (1964); L. 8. ~~airiizliinskii ani1 .\. )-a, I%erlin.J . Gcn. Ciiern. L.SSR. 33, 3004 (1'368); N. I:. ( ' h a p m a n and 1). .J. Triggle, J . Ciiern. Soc., 1885 (1963): S . J. Leonard, I
