N-(3-L)imethylaminopro~yl)-3-azatrispiro[ 5.2.2.5.2.21heneicosane Dihydrochloride (4).--The acicl 15 (0.4 g, 0.001 riiolc~) w a s refluxed with 1.5 ml of A c 2 0 for 1.5 iniii: the 1: \vas vac.iium-distilled. T h e crude trispiro :tiiiiytiride :It, 200' for 1 hr Lt-ith 0.5 g of hIe2N(CI12)gSII?.Is:scws niiiiiic w:w reriioved it^ i"a7Lo. Tlie remaining, criide imide i n 100 1111 I>[ tlry EtYOw a y added slowly t o a stirred solritioii of Li.lIlT4 ( 1 g I i t t 100 nil of dry Et,O. After 2 h y , the misliii~ew ' a b tlecoriipowl with II,O ntid filtered. The filtrate was dried (S:i?Wl), niid i l i c .solvent was distilled. The residrial oil iri alcohol \viis 1 i,e:itctt with HCl gas. The prodiict wa? rc allizeti i'rorn I2tOII)', yield 0.35 g, 77'.; (based i i p o i i 15). , I r i a / . (C,,IT*,S2CI,) c, 11, N, c1.
v
1v
'HCHJ
l u r i i o r Localizing Agents.
+
C=CH,
I\7.
Radioiodinated Analogs of l,l-Z)ichloro-2,2-di(chlorophenyl)e thane
VI, !A= H VII, R =Ts
VI11 ~ i i o r ccoiiveiiierit untl affordctl thc studies in this area, this paper describeh the preparation tlcsirecl alcohol\ iii uver SO > icld i I i each cabe. 'rhehc of ridioiodinated D D D analogs in which the aliphatic alcoliol~TI cre i c d i l y coiiverted t o the toiylatcs u 4 i g rhlorines have been replaced with ladioiodine (VIII). tile ge~ieralp r o ~ d i l r ot c ~TipsOli.' l'revioii- stutlleb h v €€:iniricl, and Hauserl" hiid showll t h:it 2,2-dipheri\ lc~tliylto>\ late afforded unrexrrangcd eliminatiori aiid,'or subhtitution products when treated n Ith v:iriou\ ~ ~ i ~ ~ l e o ~ ~Inl isuch i l c ~cabes, . riucleophilic ciisplacciiietit (:I) : i t i d climInntion (1)) :LIT competing reactions :mtl t i i v :miourits ot onch priiduct depend 011 the relativc rat(?.: of tlie t n o reaction< H - _ _+ H I I1 (( H I - ~ H The synthetic approach to the appropriately substituted 2,2-diphenylethyl iodides involved a study of tlie nucleophilic displacenierit of the corresponding tosylates (VII) with iodide. B s shown in Scheme I, the required tosylates were obtained in t \ w steps from the substituted diphenylacetaldehydes (17). The alde(1) R . E. Counsel1 R. E. \\ illette. and \ V . IliGui IO. J . M t d . C h e m . 10, 975 (1967). , ( 2 ) L,. A . S < u i i i u l . i k , ~iri " 1 ) r u g s o l C'lioice lWX3-l1Jtii,'' \\ , ~ l d e l l Ed.. C. V. AIcisl,y Co., St. Louis, AIo., 1966, p 617. (3) C . Cueto and J. €1. V. Drown, Endocrinology, 62, 326 (1988). (4) \\-. DiGuilio, Chief of the Radioisotope Unit, V. A. Hospital, Ann Arbor, Acicli., perional curiiniunica.ion.
March 196s
SOTES
the starting tosylate. I n the case of the o,p'-tosylate (VIIa), reaction with potassium iodide in refluxing acetone, aqueous acetone or 2-propanol resulted in the recovery of starting material in each case. When the displacement was carried out in D b I F or DRISO at 140°, the corresponding olefin, 1-(o-chloropheny1)1-(p-chloropheny1)ethylene (IXa), was isolated as the sole product. The desired iodo compound (VIIIa) was obtained, however, \Then the displacement was performed in refluxing acetonitrile over a 4-day period. S m r analysis of the crude reaction product showed a ratio of displacement to elimination product of 2 : 1. On the other hand, all attempts to carry out the same displacement with the p,p'-tosylate (VIIb) under identical conditions gave only the elimination product IXb. Although halide ions are not usually considered to be strong bases, iodide has been noted to cause dehydrohalogenation in dipolar aprotic solvents." Steric factors are known to play an important role in bimolecular elimination reactions. l 2 llolecular models of VIIa clearly illustrate the steric hindrance imposed by the o-chlorine on the P-hydrogen and undoubtedly accounted for the isolation of substitution product in this case. This consideration prompted a study of the o,o'-tosylate (VIIc), and in this instance no elimination occurred and the iodide (VIIIc) was isolated in essentially quantitative yield. Radioiodine-labeled VIIIa and c were obtained by isotope exchange with Sa1251in refluxing acetone and acetonitrile, respectively. With the former, isotope exchange was accompanied by elimination and necessitated purification of the radioiodinated product by column chromatography. This complication mas not encountered with VIIIc. Preliminary tissue distribution studies with the radioiodinated compounds have been carried out in rats, and tissues were analyzed 4 and 24 hr after intravenous administration.13 For VIIIa, most of the radioactivity was found in the thyroid after 4 hr with little radioactivity appearing in other tissues. Considerable thyroidal radioactivity was also noted 4 hr following the administration of VIIIc. I n this case, however, high concentrations of radioactivity were also found in fat tissue and whole blood. Twenty-four hours after the administration of VIIIc, the concentration of radioactivity decreased slightly in fat, increased slightly in blood, and increased to a considerable degree in thyroid. Oiily low concentrations of radioactivity were found in the adrenals which is in contrast with the results obtained 11 ith ring-iodinated DDD analogs.' These data are consistent with the premise that these compounds are metabolized in a manner similar to DDTI4 giving rise to substituted diphenylacetic acids and inorganic iodide. The apparent slower metabolism of VIIIc could be accounted for on steric grounds similar to those discussed above. Experimental Section': Ethyl p,p-Di(p-chloropheny1)glycidate (IVb).-To a solution of ethyl chloroacetate (13.6 ml) and p,p'-dichlorobenzophenone (11) A . J. Parker, Quart. Rev. (London), 16, 183 (1962). (12) C / . D. J. Cram in "Steric Effects in Organic Chemistry," AI. S. Neoman, Eil.. .John \Vilex and SOIIP.l n r . , IVe\\- York, K.Y., 1956, p 3 3 3 . (1:3) T h e authors are grateful to Dr. IValter DiGuilio and h l r . Scott Skinner of the Radioisotope C n i t , V. A. Hospital, :inn .&rbor, hlich., f o r iurnisliing this iniorination. (14) JV. J . Ilayes, J r . , A n n . I?er,. I'hurvrucol., 6 , 27
(lYti5).
381
(20 g) in anhydrous CSII, (20 ml) was added NaH (54%,dispersion, 6.4 g ) in portions with stirring. The addition ivas carried out under N2 over a period of 4 hr. The addition flask was riiised with anhydrous CsH6 (20 ml) which was added to the reaction mixture. Stirring a t room temperature was continued overnight and the reaction mixture was poured onto ice water-HC1 (1:l). The mixture was extracted (C&) and the dried extract (Na&04) was concentrated to dryness. The yellowish, solid residue was recrystallized from 1IeOH to afford crude I\-b (22 g), mp 93105'. Recrystallization from ether-cyclohexaiie furnished pure IVb (18.3 g, 69%): nip 110-112"; nmr peaks, 1.02 (CH,, triplet, JAX = 7 cps), 3.97 (CH), 4.03 (CHZ,quartet, J A X = 7 cps), 7.32, and 7.41 ppm (aromat>ic). Anal. (CliH14C1?03)C, H. 2,Z-Bis(p-chloropheny1)acetaldehyde (Vb).-A solution of IVb (13.(J g ) in EtOH (100 ml) aiid 20% aqueous KOH (23 ml) was refliixed with stirring for 8 hr. The EtOH was removed by evaporation, HzO (50 ml) was added, aiid the mixture was extracted with ether (two Z - m l portions). The aqueous phase was warmed oii the steam bath t o remove residual ether, allowed to cool, arid acidified by the additioii of dilute HCI. The mixture was extracted (EtnO) and the extract' was washed (H,O) aiid dried (Na2S04). The solveiit !vas removed aiid the residue u-as heated in an oil bath a t 1.50' under reduced p Distillation of the crude decarboxylated product (11.3 g ) afforded pure 1-b (9.4 g, 8 0 % ) : bp 158-162' (0.35 mm); vmax 1720 em-' (C=O); iimr peaks a t 4.83 (doublet',benzylic H, J a x = 2 cps), 6.86-7.68 (aromatic), arid 9.90 ppm (doublet, aldehyde H, JAX= 2 cps). Anal. (Cl4Hl&Iz0)C, H. The 2,4-dinitrophenylhydrazoiie was re EtOH-EtOBc, mp 178-180". Anal. (CzoH&l&4Oz) C, H. Borohydride Reduction of Bis(chloropheny1)acetaldehydes.The aldehyde ( V ) I 6 was added with external cooling to a solution containing NaBH4 (1.0 g) in EtOH (20 ml). The solution was allowed to stand at, room temperature overnight and poured into 10% YH4C1 solution (100 ml). The mixture was extracted (Et20)and the extract' was washed (HzO), dried (SaeS04),and concentrated in vacuo. The resulting crude alcohol was purified by distillation or recrystallization (see Table I). Tosylation of Bis(chloropheny1)ethanols.-p-Toluenesulfonyl chloride (2.4 g) u-as added to a solution of the alcohol (VI, 2.0 g ) in pyridiiie (20 ml). The mixture was cooled in an ice-salt bath and stirred until all of the acid chloride had dissolved. The solution was kept below 0" for an additional 2 hr and then refrigerated for 17 hr. Water (1 ml) was added dropwise maiiitaiiiirig the temperatare belox 15' and the solution was poured into cold water (20 nil) with stirriiig. The crude product w a s collected by filtration, washed well with water, &lidrecrystallized (see T a b l e I ) . 1 4 o-Chloro~henvl)-l -i~-chloroohenvl )-a-iodoethane IVIIIa). -To 'a solution of kIIa ('4.0 g ) in freshly distilled 1 I e C S ( l i 0 ml) was added KI (4.0 g) and the mixture refluxed for 4 days. The solvent was removed in z'acuo and the residue was shaken with HzO and CHC1,. The organic phase wah separated aiid dried (Na2S04),aiid the solvent was removed. The residual oil was fractionally distilled to give two coilstant-boiling fractions. The first (0.43 g)! bp 110-114' (0.15 mm), proved to be identical with an authentic sample of 1-(o-chloropheny1)-1-(p-chloropheriy1)ethgleiie (IXa) prepared according to Zee-Cheng aiid Cheng.17 The higher boiliiig fractioii (1.5 g), bp 164-166' (0.1; nini), wa5 the desired product \'IIIa (see Table I). Nmr aiialyais of the
(15) Melting points were taken on a Fisher-Johns melting point apparatus and are corrected. Elemental analyses u-ere performed b y Spang Microanalytical Laboratories, .inn Arbor, Alich. Kliere analyses are indicated only tiy s>-ml>olsof t h e elements, analytical results ohtained for those elements uere within +0.?LJc of the theoretical values. I r spectra were taken on a Perkin-Eliner :iYi spectropliotometer. T h e ninr spectra were obtaineii vi111 a Yarian &60 spectrumeter in CDCli a t a concentration of lOYc, with T I I S as internal reference. Thin layer chromatograms (tlc) were run u i t h 1-in. wide Eastman cliromagrams, T y p e KBOlR, with fluorescence indicator and spots detected with uv light. Chromatograms of radioiodinated compounds were scanned with a n Atomic Associates RCS-363 radiochromatogram scanner. T h e specific activities were determined with a n Atomic .Associates well-scintillation counter RIodel EIOC and scintillation spectrometer Model 530. Silicic acid used in the column chromatography was Raker and Adamson reagent, grade. (18) T h e o,p'-slilehydP (Va) v a s prppared acrorrlinr t o TTorton, ~1 n1.,8 ancl the o,o'-aldeliyde (Vc) was obtained from hldricli Clieinical Co., Alilrr artkee, ]\is, 53210. ( l i ) li. Y. ZetLClieng aiid C. C. Clieng, J . ,Ifed. I'hurm. Cliem., 5 , 1008 (1962).
