July 1969
CYCLICDISULFIDES.I1
Cyclic Disulfides.
ti17
11. 1,2-Dithiepan-5-amine'
H. F. HERBRAKDSON AND REBECCA H. WOOD Department of Chemistry, Rensselaer Polytechnic Institute, Troy, S e w Yorlc 12181 Received A u g u s t 21, 1968 -4s part of a study of the effect of ring strain on the radiation-protective action provided by amino-lj2-dithiacyclanes and related compounds, the comparatively unstrained 1,2-dithiepan-Samine was synthesized. 3Bromo-l-(2-bromoethyl)propylamine was converted to 3-amino-l18-pentanedithiolhydrochloride and t o 3amino-l,.i-pentanebis(2-thiopseudourea)trihydrobromide. Although oxidation of the 3-amino-1,s-pentanedithiol by a number of methods gave polymeric disulfide, oxidation with iodine in high dilution gave 1,2-dithiepan-5-amine. None of the compounds tested, ll2-dithiepan-8-amine hydrochloride, 3-amino-1,5-pentanedithiol hydrochloride, 3-amino-l,S-pentanebis(2-thiopseudourea)trihydrobromide, or tetrahydro-l-thiapyran4-amine hydrobromide, provided significant protection from the effects of radiation.
Twisting of the dihedral S-S angle from the normal value of about 90-looo2to 27" as found for the fivemembered cyclic disulfide 1,2-dithiolane-4-carboxylic acid3 gives rise to ring strain which has prevented isolation in the pure state of the unsubstituted l12-dithiolane. *-lo The six- and seven-membered ring disulfides, o-dithiane and 1,2-dithiepane1 are more stable l1 as a consequence of diminished dihedral strain, but there is conflicting evidence concerning the relative reactivities of these two compounds to ring-opening reactions.'* Since numerous compounds that contain a thiol group or a potential thiol group p or y to an amine function protect, to a degree, experimental animals from the effects of ionizing radiation,13 it was of interest to synthesize amine-substituted cyclic disulfides and the related acyclic dithiols in order to determine the effect of ring size on protective action. Whatever may be the mechanism or mechanisms for the protection afforded by amino disulfides, variation in ring strain with ring size in cyclic amino disulfides might be reflected in the degree of protection provided by these compounds. Similarly, if oxidation of thiol to disulfide in any way were involved in the protective action of thiols, the degree of protection afforded by dithiols might be (1) (a) This investigation was supported by t h e U. S. Army Medical Research and Development Command, Department of t h e Army, under Research Contract No. DA-49-193-MD-2068. (b) P a r t I : N. Isenberg and H . F. Herbrandson, Tetrahedron, 21, 1067 (1965). (2) G. Bergson, B r k i u Kemi. 16, 315 (1961). (3) 0. Foss and 0.Tjomsland, A c t a C h e m . S c a d . , 12, 1810 (1958). (4) Calvin, et al,,6 has isolated l,Z-dithiolene, t h e molecular \\.eight of which he determined t o be 104, a s a n unstable oil. On attempted purification the oil gave a polymeric disulfide. From t h e preparation also was isolated a colorless, crystalline solid of mp ~ 7 3 'which has been much studied a n d which has t h e same empirical formula a s does 12-dithiolane. I n spite of continuing doubts expressed in t h e literature, it seems clear t h a t is the cyclic dimer, CeHnSa. Brintzingere and this compound of mp ~ i 3 O Gagon7 and their coworkers have reported a molecular weight essentially equal t o t h a t of the dimer although Yur'ev a n d Levi8 reported the compound t o h e t h e monomer. Wallace8 attributed t h e peak a t m j e 106 in its mass spectrum t o the parent ion and Moreau a n d M-eisslo reported a ut- spectrum which he considers t o be t h a t of the monomer. ( 5 ) J. .\. Barltrop, P. 11.Hayes, and RI. Calvin, J . A m e r . C h e m . Soc., 76, 4848 (1954); see also L. Field and R. B. Barbee, J . Ore. Chem., 34, 36 (1969). (6) H . Brintzinger, 11. Langheck, and H . Ellwanger, Chem. Ber., 87, 320 (1954). (7) P. E. Gagon. J. L. Uoivin, and G . A l . Brown, C a n . J . C h e m . , 37, 159i ( 1959). ( 8 ) Yu. K. Yur'ev a n d I. S. Levi, Dokl. A k a d . N a u k S S S R , 73, 936 (1950). (9) T. J. IVallace, J . -4mt.r. C h e m . Soc., 86, 2018 (1964). (10) W. M. Moreau a n d K. Weiss, ibid.. 88, 204 (1966). (11) F. S. Dainton, K. J. Ivin, and D. A. G. Falmsley, T r a n s . F a r a d a y S o c . , 66, 1784 (1960). (12) A. Schiiberl a n d H. Griifje, A n n . , 614, 66 (1958); J. G. .iffleck and G. Dorigherty, J . Org. C h e m . , 16, 865 (1950). (13) J. F. Thomson, "Radiation Protection in Mammals," Reinhold Publisllinp Cory., New York, s.I-,, 1962.
related to the ease of ring closure to the cyclic disulfides. Aminodithiols, furthermore, should form very stable chelates with numerous metal ions, a property of aminothiols which has been correlated with radiation-protective proper tie^.'^ In this and subsequent papers we shall report on the synthesis and properties of a variety of amine-substituted five-, six-, and seven-membered ring disulfides and related compounds. lJ2-Dithiepan-5-amine (V) was prepared from 3bromo-1-(2-bromoethyl) propylamine (I) according to Chart I. Prelog has used this amine'j and the analogous 3-chloro-1-(2-chloroethyl)propylamine16 in the preparation of 4-aminopiperidines, and our objective was to cyclize similarly the dibromo compound with insertion of the disulfide link. The reaction with sodium disulfide, paralleling Gunther and 3Iautner'sl7 synthesis of 1,Zdithia-j-azepane from 2,2'-dichlorodiethylamine, was unsuccessful yielding only tetrahydro-1-thiapyran-4-amine(11) and a large amount of polymer. Since the steam distillate from treatment of the polymer with C S - contained an excellent yield of 11, one can conclude that the polymer was a di- or polysulfide and the depolymerization to I1 was similar to other reactions which form dialkyl sulfides from the reaction of C N - on dialkyl disulfides. l8 The synthesis of 1,2-dithiepan-5-amine (V) was successfully accomplished through the intermediate 3-(benzylthio)-1-[ 2-(benzylthio)ethyl ]propylamine (111) obtained by treatment of I with sodium benzyl sulfide in alcoholic solution. Although the half-life for ring closure of 3-bromopropylamine to azetidine in HSO at 78" is only about 4 mi11,19 no evidence was obtained that a comparable ring closure occurred with I during reaction with the sodium benzyl sulfide. Reduction of I11 with ?;a-liquid NHXz0 containing added propylamine21 gave 3-amino-1,j-pentanedithiol (IV), purified through its Hg salt. Isolation of the dimercaptan as its hydrochloride without prior conversion to the mercury mercaptide led to difficulties in purification. (14) E. C. Knoblook and IT. C. Purdy, Kudiuliori R e s . . 16, 94 (1961); J . Electrounul. C h e m . , 2 , 493 (1961). (15) E. Cerkovnikov a n d V. Prelog, Ber., 74, 1648 (1941). (16) V. Halin, E. Cerkovnikov, a n d V. Prelog, Helu. C h i m . A c t a , 26, 1132 (1943). (17) \IH..13. Guntlier and H . G . Mautner, J . A m e r . Chem. Soc.. 82, 2762 (1960); c f . also F. 0.Davis, U. S. Patent 2,715,635 ( d u g 16, 1955). (18) R . G . Hiskey a n d F. I. Carroll, J . -4mer. Chem. SOC.,88, 4647 (1961). (19) Extrapolated from data given by G. Salomon. Hefir. C h i m . d c t a , 16, 1361 (1933). (20) R . H. Sifferd and V. du Vigneeud, J . Bid. C h e m . , 106, 753 (193.5). (21) C. G. Overherger and H . Asciikenasy, J . A m e r . Clrem. SOL..,62, 435T (1960).
(ilS
[ B r - ( N H ~ ) ? + C S C H , C H 2 ] , ~ H;+Br~H VI1
of a11 increav i i i energy of the ground state :is the disulfide ring becomes smaller. l,~-Dithiepaii-3-:tmiile hydrochloridc x\ith: : :A 257 mp ( E 404) exhibits a slight hathochromic shift from typical acyclic disulfide absorption and from th:tt of the polymeric amino disulfide YI, perhaps indicating it small deviutiori from the preferred dihedral angle for the disulfide link The availability of 3-bromo-l-("-bronioethyl)propylamine (I) from this work and the fact that aminoisothiouronium salth provide protection from the effects of radiatiori"l also led u h to -ynthesize :3-amino-l,3pentanebii(.'-tliiopseudourea) trihydrobromide (VII). S o n e of tlie chompoundb tested, 11, IV, V. or VII, cvhibited signihcarit activity i i i the aritiradiatiori test -yzterx27 The testing methodb have been described.?*
The l,~-ditliiepaii-j-amirie(Vj was obtained from oxidatiori of the dithiol with 1, a t high dilut'ion. It was esseiit,ialtoextract,thel,%dithiepan-s-amine fromthe aqueous Experimental Section2s solution with benzene rather t'hari ether since use of the Tetrahydropyran-4-amine Hydrobromide.-l)i,y CllCI, (1.43 latter solvent, resulted in complete polymerizat,ion of t'he I . ) was added to a solution of 162 g (1.24 moles) of tetrahydroproduct when gaseous HCl was passed into tjhe dried P!.'aii-4-carboxylic ac.id,'" in 300 nil uf coticentrat,ed H280,, and extract. This may have been i~ consequelice of cationic if powdered S a y s was added in small portions itre over a period of :3 hr, the rate of addition polymerizatiori",'*,?~in t'he more polar ethereal solvent e mixtiire remained below reflux temperatwe or of free-radical pol~meriznt,ion",'" initiated by and no excessive foamitig occurred. The mixture was stirred at peroxides in Et20. r00111 temperature for 15 hr. The CIICI, layer was decanted and Polymeric disulfide VI was the major product, wheii disarded. T h e acid layer wah C Y X J ~arid ~ ~ then slowly poured 011 ice. Safety pr(:cu'~"tionsshould be tcikcn during this step.31 -4 other met,hods were used for oxidation of the aminosingle loud "pop" was heard ill this preparation. The soliition dit'hiol IV: oxidation with I, iiot, under conditions of was covered with a layer of KtlO, made bahic t u pH 12 with 10 high dilution or oxidat,iorl by (I2 in basic solution. .\ YaOH solut,ion, and allowed to stand overnight,. The superOxidation by air in basic solution proceeded very slowly natant liquid va.: decaiited from the large aniouiit of Iia2SOd. 10and oxidat'ion by air or oxygen using FeC13 as a catalyst H20which had crystallized. The X a 2 S O r .10H20 was dehydrated to small crystals t)y heating OIL a steam bath and was washed was unsuccessful. The polymer VI) as the hydrochloi K 2 0 ) . The HZ0 solut'ioii arid washings were extracted continuride, had a uv spectrum commensurate wit,h that to be IJld!,' wit.h Et2() for 7 2 hr. Iiemoval of ether froin the extract expected of a disulfidez4 polymer (A$: 249 mp, t per left the free amine HS :I yellow liquid. The amine was cooled itr ail ice bath atid treated with excess 48L'; HBr. Removal of S--S unit 393) and was soluble in H&, giving a solutioii acid at reduced pressure left 145 g (64. of pH =5. In more basic solut'ions the polymer ~ ~ n s i sample decolorized nniiiie hydrobromide. : insoluble as the free amiiie. cq-stallized twice from ahrolute i-PrOH had nip 189..i-19X0 dec, The uv spectra of cyclic &sulfides reflect t'he change lit.32mp 190-191' cor. in the dihedral S-S angle. This has been att,ributed by 3-Bromo-l-(2-bromoethyl)propylamine Hydrobromide (I).-Crude tetrahydropyran-4-amine hydrobromide (77.0 g, 0.482 I3ergsonZ6to the ground-state conformation being of mole) was heated iinder reflux with 960 ml (8.42 moles) of 48% lowest energy if t'he dihedral angle is 90" and the energy of the lowest excited stat'e being indeperiderit, of the ( 2 7 ) These determinations ivere made by Ilr. .J. 1'. Jacobus and his dihedral angle. The observed shift of the uv maximum associates, I i a l t e r Repd .\Tiny Institute of Research, Waslrington, I). c'. 20012. from about 250 mp found for acyclic disulfidesz4and 1,%(28) E. R. .atkinaon, 6. 14. Ilandrick. I t , .I. 13runi, a n d F. IS. C~ranclielli. clithiepanes; to about 290 rnp for o-dithianes"'~~arid .I. .\fed. Ctiem.. 8, 29 tl'JS.5). :tbout, 330 mp for 1,2-dithiola1ie,*?~ is t'hus a cotisequericv ( 2 9 ) Some experimental details are presented in Table I. .\I1 melting l ) a \ ie*. 1'. E. Alarming, and d. .\. Zalrir, T r u m lq'araday Soc.. 63, 813 (195i): .\. J . Parker a n d K. Kharasoh, Chem. X e i . , 69, 583 (1969). (2:3) W. H. Stockmayer, R. 11. Hoivard, and J. T. Clarke, J . Amer. Chem. Soc., 7 6 , 1756 ( 1 9 5 3 ) ; A . T. Toholsky a n d R. Eaysal, ibid., 7 6 , 1737
(1953). (2.1) E t h y l disulfide has A ~ ~ ? 2 4 O .? l I: S.1'. ~ I c G I ~ n.J. n .Sag-('haiidliuri a n d Ll. Good, ibid.. 84, Y (1962). ( 2 6 ) G . I3ergson, ;Irkiu Kemi. 18, 409 ilY62); G . I
