FcCH,XHCHCHIOH
I
('HOH
I
I
,SCOCH FcCH=NN=C, NHCOCH 111
ococ,I! I
Y Ileqpite the
i c k interc-t 111 ferroceiir chemistrj. re1:itively few ferrocene derivatives have been tested for bio1ogic:d activities. lar2--j This paper reports the prep:ir:ition (qee Experimental Section) of a number of nrw ferrocene drrivntivci which had no yignificant antibacteri:il. antifungal, or antip:~rasiticactivitl .
(2) J. L. Madinaveitia, Brit. J . I'harmucol., 24, 35% (1985). i 3 ) 13. L o w and A I . Flures, J . Org. Chrnr., 26, 8595 (1961). ~ 4 1t'. L).P'opp, S. Koth, nnd J. Kirby, J . .Wad. C h r m . , 6, 88 (1Y63). ( 5 ) 1J. hl. R'iies and T. Suprunchuk. Cirn. .I. C h n r . . 46, 1865 ( 1 ~ 6 8 ) . ( 6 1 A ~ i a l ~ s e[by s Spang I\Iicruaunlytica1 I.al,urrttory. in . i r b u r , h l i c l ~I. itre within 0.3'70 u n l ~ s sotherwise nuterl. Mass spectra was b y AIuruan ScilaRer, AIontreal, Canada, ,Iieitinp are taken i n capil,f ail coInuoundJ ,vcre ai ~ , ~ i eorrc.cte,i. ~ ~ 'rileinfrared
crpected;
Fc = C,,,H,Fe.
Ad = adamant yl
iollo~viiig manlier. 1:qiiiniolar ~liiaiititie,~ of ierr~,~.et~cc.arl,~,.\aldehyde and the reactants s11un.n iri 'Table I were diisolved i i i :L niini~niiinof nbs E t O H and heated o i i a. steam bath for L: maxiiiiiim of 30 m i ~ ~After . cooliiig to room temperat iii,c, the prodiii,ts ~ I i o t v i i l l Table I were collected by filtrnt ion. Condensation with D-Cycloserine.-- .I iiiist lire i)i 5.0 g iO.O.5
15.0 g (0.07mole) of ferroceiiecarboxaldehyde, 0.05 g of p-tol~~enesulfonic acid, and 1'200 nil of CsH6 was refluxed for 'L hl iii :I em contaiiiiiig a Ileaii-Stark trap. The solrltiiili \\:is filt eiwl I u i L arid co~ieetitrittedin z'ocuo to give the protl1ic.t itidic.:~~rtl ill Table I. Preparation of I.--.To :I solutiot~of 11.0 g of 1 l i r :ll)ove S;c,tiifT tiwe in 500 nil of a 4: 1 niistiire of abs Et011 :itid di(imiic w:i:Ltltied 3.3 g of SaBI14. After stirriiig a t room ter~ipw:itiiref i ~ r
Journal of Medicinal Chemistry, 1970, Vol. 13, ,Yo.b 1021 12 hr, the mixture was poured into ice-water and a yellow solid was collected. A small quantity of this solid was recrystallized from ethanol, mp 198', and was shown to be a borat,e ester. Anal. (CzoHzlBFeNzOa) H, N ; C: calcd, 53.08; found, 55.57. The yellow solid and extracts from the filtrate were combined and dissolved in a minimum of glacial acetic acid. This solution was diluted with water and a cold 20% solution of sodium hydroxide was slowly added. The basic solution was extracted with chloroform and the washed (HzO) and dried (hIgs04) extracts were concentrated in vacuo to give 7.29 g (66%) of I, mp 122-124" from benzene-heptane. Anal. (CzaHSzFeNzOa) C, H I N. Treatment of I11 in benzene with dry HCI gave a hydrochloC1. ride, mp 175-180' from ethanol. Anal. (C20Hz3C1FeNZ01) Preparation of II.-.4 mixture of 1.15 g (0.005 mole) of ferrocenecarboxaldehyde thiosemicarbazone,b 0.71 g of chloroacet'ic acid, 0.41 g of anhydrous sodium acetate, and 15 ml of glacial acetic acid was heated' on the steam bath for 45 min. The mixture was allowed to cool to room temperature and was filtered to give 0.66 g (387,) of 11; mp 234-236' from ethanol; ir (KBr) 3300 (sh), 3100 (wk), 2940, 2750, 1785 (wk), 1725, 1640, 1110, 1005 cm-l, mass spect,rum 327 (loo%), 262 (l6%), 220 (8%), 212 (16%), 211 (18%), 185 (25)%, 162 (loyo), 146 (11%))129 (18%), 121 (42%), 56 (27%). Bnal. (C1rHlaFeN3OS) C, H, Fe, N, s. Preparation of 111.-A mixture of 1.15 g (0.005 mole) of ferroceriecarboxaldehyde thiosemicarbazone and 10 ml of acetic anhydride was heated on a steam bath for 25 min. The mixture \vas allowed to cool and filtered t o give 1.14 g (617') of 111; mp > 21.5' (decompositiori,began at this temperature but no calearly defined melting or decomposition point could be determined) from EtOH; ir (KBr) 3220 (sh), 3160, 3050 (wk), 2940, 1720, 1640, 1610, 1110, 1010 cm-'; nmr (DMSO-&): 12.07 (l), 7.00 (I), 4.37 (Y), 2.17 (6) S. Anal. (C26HliFex302s)C, H, N. The discetyl compound I11 wits also obtained, contaminated with a Inoiioacetyl-moiiochloroacetyl compound by replacing AcOH used in t,he preparation of I1 by AczO. Adamantoylferrocene (IV).-A complex of 5.0 g (0.025 mole) of adamatitat~ecarboxylicacid chloride and 3.35 g of anhyd .41c13 i n 150 ml of CS2 was formed under SSover 2.5 hr. This solution was then added dropwiae to a solution of 5.0 g (0.027 mole) of ferrocene in 100 ml of CSa under NZ a t room temperature. The solution was stirred a t room temperature for 12 hr, HzO added, and the organic layer separated. After washing (HzO) and drying (CaCL) the CY2 x a s removed in uacuo to give an orange solid. Chiomatography of bhis solid on alumina with Skellysolve B gave ferrocene and 2.45 g (2900) of IV, mp 128129Ofroin heptane. Anal. (CzlHnaFeO) C, H. Condensation of Ferrocenecarboxhydrazide with Steroids.A mixtiire of 0.73 g (0.003 mole) of the hydrazide and 1.18 g (0.0OU mole) of androstanolone benzoate in 30 ml of abs. EtOH was heated on the steam bath for 15 min and filtered hot. Upon of V, mp 183-185' from EtOH, ,vas obcooling 1.53 g (%ITG) tained. ilnal. (C3,H44FeSZO3) Fe. N. In a similar manner 0.015 mole of the hydrazide and 0.015 mole of testosterone benzoate in abs EtOH gave, after heating, for 3 hr the expected hydrazide. Recrystallization from EtOH gave 5.68 g (61%) of the porduct, mp 205-206'. Anal. (C37H4ZFeNzOn)C, H, N.
_____
(7) S . hf. Turkerich and 0. F. Lymar, Khim. Farm. Zh., 3, 26 (1969); Chem. Abatr., 71, 30314 (1969).
Bis(a-lactams) Derived from Adamantane EILICH 1:. T.\I..\TY~~ A S D ACBRYE. I ~ P U YJ R , .'~ Dcpartments of Chemistry of Wichita State Cnivcmily, V i c h i t a , Kansas 67208, and I,oitisiana Stat? Cniversit?)in .\ew Odeans, S e w Orleans, Louisiana 70122
Received Februavy 6.3, 1970
Compounds containing two or more aziridine rings, such as trietli3lenenielnmiile or L',.j-bis(l-aziridinyl)(a) .iddress inciuiries t u this aiitlinr a t the IYicIlita, Kansas address; recipient of a Graduate Traineeship from t h e Kational Science Founda-
(1)
(1,)
tion.
3,6-di-n-propoxy-1,4-benzoquinone,have been of interest as antitumor agents for many years.2 However, compounds having more than one aziridinone function have not been isolated. We report here the first examples of such compounds, namely, bis(a-lactams) (la, lb) derived from adamantane-1,3-diacetic acid (2a). RN-
I
la, R = t-Bu b, R = 1-adamantyl(CloH,,)
R,
I
CH-CO-R, I
2a, R,-H,R,=OH b, R, = H; R, = C1 c. R, = Br; RZ= C1 d, R, = Br; R, = NH-t-Bu e. R, = Br; R2 = SH-1-adamantyl
Experimental Section3
Adamantane-l,3-bis(NV-t-butyl-2-bromoacetamide) (2d).-A mixture of 1.00 g (3.96 mmoles) of adamantane-l,3-diacetic acid (2a) (Aldrich Chemical Go.) and 5 ml of SOClz (Matheson Coleman and Bell) was refluxed for 60 min and the excess SOClz was removed under reduced pressure a t 50'. Anhydrous C6H6(2 ml) was added to the residue and then removed under reduced pressure to ensure complete removal of SOC1,. The acid chloride 2b was dissolved in 6 ml of cc14 and refluxed with Brz (1.44 g, 9.00 mmoles) for 5 hr. The resulting bromoacid chloride Zc was added gradually to an ice-cold solution of 1.35 g (18.2 mmol) of tbutylamine in 100 ml of CH~CIZ.The reaction mixture was then treated with HzO, extracted with CHZC11, and the combined CHzCll layers were washed (5% HC1, 570 NaOH, H20, satd NaCl solution) and dried (XlgSO,). The solvent was removed in vacuo to give crude 2d, which was recrystallized from CHC13heptane to furnish 1.89 g (917' overall) of crystals: mp 261-262' dec; ir (CHC13) 3395,1660 cm-l; nmr (CDC13) 7 4.01-4.31 (2 H, broad s), 6.12 (2 H, s), 7.75-8.51 (14 H, m), 8.64 (18 H, s). Anal. (CZZH&~&"OZ) C, H, X. Adamantane-1,3-bis [N-(l-adamantyl)-2-bromoacetamide] (2e). -The crude bromoacid chloride 2c prepared, as described above, from 1.OO g (3.96 mmoles) of 2a was added gradually to an ice-cold solution of 1.20 g (7.92 mmoles) of 1-aminoadamantane and 1.04 g (10.28 mmol) of Et3N in 100 ml of CHzClt. The reaction mixture was worked up as described above to afford, after recrystallization from CHCl3-heptane, 2.43 g (917' overall) of 2e: mp 299302" dec; ir (CHCla) 3390, 1660 cm-1; nmr (CDCl,) T 4.154.48 ( 2 H, broad s), 6.12 (2 H, s) 7.60-8.52 (44 H, m). Anal. ( C ~ J L B ~ Z N C, ~ OH,ZN. ) 1,3-Bis(l-t-butyl-2-0~0-3-aziridinyl)adamantane (la).-A mix(2) See, for example, D. F. Gamble, H. W. Bond, and A. Burger, "Medicinal Chemistry," A. Burger, Ed., Interscience, N e w York, N. Y., 1980,p 1083. (3) Melting points were taken in sealed capillary tubes on a Mel-Temp apparatus and are uncorrected. N m r spectra were recorded on a Varian A-60 instrument (ThlS a8 internal standard). Unless otherwise mentioned the solvent used for ir and nmr measurements was CCli.
