March 19ti9
339
XOTES
Experimental Section When analyses are indicat,ed, analytical results obtained for those elements were within f 0 . 4 7 , of the theoretical values. Catalytic Hydrogenation of 6-Benzylmethylamino-4,4-diphenylheptan-3-one and Its 5-Methylhexan-3-one Isomer.--& mixture of the amino ketone 5a'* (20 g), 4 S €IC1 (20 ml), 1070 Pd-C (2.5 g), and EtOH (400 ml) was shaken with H Zat room temperature and pressure until gas uptake ceased. The filtered product was evaporated and the residual salt (11 g) gave the pyrrolidine base 8: bp 128-132" (0.5 mm) (8 g); mp 56-38' from EtOH; N-Ale pmr characteristics in CDC13 (Hz from TAIS), base 147 (singlet), HC1 176 (doublet J = 5 Hz). Anal. (CZOHW N ) C, H, N. The same product, mp and mmp 36-58', was obtained by shaking a mixture of the freshly distilled base (2.5 g) from 2ethyl-4-methyl-3,3-diphenyl-A'-pyrroline hydriodide S,s.10 10% Pd-C (0.2 g), and EtOH (70 ml) with H2 at 60". The hydriodide 9 resisted hydrogenation under these conditions. The same rediiction procedure applied to the benzylmethylamino ketone 712 gave the 4-methylpyrrolidine isomer 10 as a hydrochloride monohydrate, mp 226-227" from EtOH-EtZO. Anal. (c&26C l S . H z 0 ) C, H, N. Debenzylation of 6-Benzylmethylamino-4,4-diphenylheptan3-oL-The benzylmethylaminomethadol 5b ( 0 1 isomer) was obtained as a hydrochloride, mp 188-190" ( l i t 8 178-179') from EtCO-EtsO, by treating the ketone 5a with LAH. Anal. (C27H34C1SO)C, H, N. A mixture of the free base 5b (6 g), 4 AVHC1 ( 6 ml), 10% Pd-C (1 g), and EtOH (120 ml) was shaken with H2 and processed as described for the reduction of 58. The sec-amine reaction product l l b was isolated as a hydrochloride (3 9 ) : mp 183-185" from EtOH-EtzO; N-Me pmr characteristics of HC1 (Hz from TJIS), 135 (triplet J = 5 ) in DMSO-&, 143 (triplet J = 5 ) in CDC1,. The salt had a sharp ir absorption a t 3400 cm-I ( Y O = ) and the base at 3280 cm-' superimposed upon a broad shoulder between 3500 and 3100 cm-I typical of methadols ( P O = and Y K H ) . -4nal. (CzoH&l?r'O)
la, X = H b, X=C1
2a.X=H
b. X = C1 CH,
3a, X = H
b, X = C1
C, H, K. Hydrolysis of ~~3-Acetoxy-6-cyanomethylamino-4.4-diphenylheptane.--h mixture of the N-cyanomethyl derivat,ive 12 (15 g)' and 6% HC1 in HzO (300 ml) was heated under reflux for 12 hr, cooled, and extracted (EtaO) to remove nonbasic products. The base (3.5 g) recovered from the aqueous phase as usual was treated with HBr-EtOH to give the sec-amine l l b hydrobromide, mp 206-207" from EtOH-EtzO. Anal. (CzoHZ8BrXO) C, H, N. The melting point of this salt was undepressed by the hydrobromide of the sec-amine derived from 5b. Pmr spectra were recorded on a Varian A4-60 spectromeler with CDCL or DMSO-& as solvents and ThIS as standard. (12)
4a,X=H b. X = C1
aq NaOH
Me,CO
5
W.Wilson, J . Chem. Soc., 3524 (1952).
Synthesis of Some Lreidodihydrofurans and Related Pyrimidones as Potential Antimalarials'J G
E. CAMPAIGXE, R. L. ELLIS,AI. BRADFORD, AND J. Ho Chemistry Laboratories of Indiana Universaty, Bloomington, Indiana 4r40l Received August 13, 1968
Extensive studies have been carried out in these laboratories concerning sulfuric acid cyclizations of ylidenemalonitriles derived from aryl- and alkyl- subst'ituted aromatic k e t o ~ i e s ~leading -~ t o the forma(1) Contribution No. 1640 from t h e Chemistry Laboratories of Indiana. Gniversit y. (2) T a k e n i n p a r t f r o m t h e thesis of R . L. E. submitted t o t h e G r a d u a t e School of Indiana University i n partial fulfillment of t h e requirements for t h e Pi1.D. degree, M a y 1967, ( 3 ) E. Campaigne a n d G . F. Bulllenko, .I. Oro. Chem., 26, 4703 (1061). ( 4 ) E. C a m p a i r n e , G. F. Rull~enko,J\-. E. lireiylil>aum,a n d 11. R . Mauldi n r , i t ~ f d . ,27, 4-128 (lY62). ( 5 ) E. Campaigne, D. R . Xlaulding, a n d I\-. L. Roelofs, ibid., 29, 1543 (1964). (6) E. Campaigne a n d I\-.L. Roelofs, ibid., 30, 396 (1966).
a,X=Y=H b, X=H;Y =C1 C, X = H; Y =OCH3 d,X=H;Y=CH3 e. X=H;Y=NO,
f , X = C1; Y = H g, = Y = c1 h, X = C1;Y = OCH3 i, X = C1; Y =CH3 j, X = C1; Y = NO,
x
tion of both iridenone arid indanorie derivatives. Cyclization, however, of certain alkyl-substituted ylidenemalorionitriles in polyphosphoric acid (PPA) leads to the formation of b u t y r o l a c t ~ n e s which ~~~ contain functional groups susceptible to metathesis. For example, cyclization of a-cyano-p-isopropylcinnamonitrile (la) in hot PPA produces the lactone 2a (see Chart I). It was eiiviioned that 2a offered ( 7 ) E. Camyaigne a n d R . L. Ellis, Chem. Commun., 1-11 (1066). (8) E. Campaigne a n d R . L. Ellis, J . Oro. Chem., 32, 2372 (1967).
C'll.\Iil~ II
Discussion Sirice it h i s been reported that cr-cS.Llrio-y-lactoiie~arc c.apable of coridensatiori with guanidine, urea, or i hiourca" arid :ire susecptible t o re:irrangemeiit employing :I sodium allioxide salt lo or roncentr:itcd SH,OH t o yield 2-amino-~-carboallioxydihydrofurnlii and "-nmirio-:~-carboxamidodihydrofuraIi~,respectively, :lttcnipts werc directed toward the preparatioii of ac,y:iriobutyrolactoiies of type 3. Reaction of 2a or 2b with 1'0('1312 proceeded smoothly to yield 3a or 3b, but tiwtnient with either dicyclohesglcarbodiimide~~lor toluene-ulfortyl chloride in pyridiric14 rcturned only iiiirc:xtcd itartirig materi:il. 'l'hr conversion of 3a to 4a mu+t 1)e carried out, cinploying only t i catalytic :imount of allioxide (see ISspcrinieritul Section). I\ortr aucl Trautrier'" theorize thiit i t i the preience of 1 molar cquiv of nlkoxide ion. :i sliift of the c~cluilibrium occur- toward tlic cyanolacionc (from the :irnirio citcr) 1)y forni:itioii of t l i r cviijugatc atiioii of the c\-:inol:ictoiicl. Surpri+iiigly, the, coiiversion of 3b a i d 4k w:ih nioi'e refractory. Under irlciitical coriditiorir the latter cyanolactone required :I lotigc1r rcxtioii time (60 i 2 111, I *A.4s hr) t o give ,ati .f :IC t o ry yi el (1. 'I'h(1 firit exploitation ~i coiiderisiiig :imine- itli 0rg:iiiic i+ocyari:ites to gencratc a pyriniictine ring 'in N'CL tlie initially formed ureas w a h tjy Hreuliiiih : t i i d \~crl;:ide'J who reported t h e condensation of phenyl ocy:iri:ito :uid anthraniloiiitrile to geiierate ail Su h f itutcd quimzoliiic. Taylor and 1iaviridr:uiatli:iii I ' outid th:tt by employing plieiiyl iwcyaiiate the sani(' o i i would occur under milder condition-. of tlie uriwb~titutc juiriazoliiie employc acid und K C S O I ropol~tedby 1,arigc. 'e coiideri+ed with :I a i i c l Sheihly. l i Wheii 4a : i d 4b ic1 i c y of p i a-iubitituted phenyl iiocy:in:itei thc coriwpoiidiiig urc:i~ (5) ~ v e r cisolated in good yield. vinployiiig the coriditioiis of l3reuliinli :itid T'tlrkadc. I' l)i.s:ipp')ir~tiriglS., coridcri-atioii of 4a \\it11 KC'S0 cwiployitig either BOc; acjueoui -\cOH" or 1 molal cquiv of KCSO a r i d .IcOH" did riot product t l i v nict~ioiubitituted urea> :i. mticipatcd. I t 1 ~ x 5tlirorizcd that the prcseiicc' of -IcOH re-ultcd i i i rcwsixngcnitiiit of 4a t o 7 ~ i the a iiiiiiio ether dei.iv:itiw of 4a followctl 1)y hytlld3 rrfluxiug 4a iii chloroform I\ i t h :I tr:iccl o t thy HCI i'ollon et1 hy hydrolyii- ( v e Chart 11). ('yclimt ion o t h u l ) + t i t u t d u i w h hiniilitr t o 5 have I)oc~rii.c~l)ortcd,l" uiiig itroiig h ~ e such h :I> :Llkoxide.
&"I. CH
S
/
0
341
March 19G9
PIIYSlCAL Ii , , , yield I
Urea
A l p , "C
IMl1tx Ijeriod, h r
'r.tlJLlC 1 Cosar.m,rs 0 1 7 ultl,:.\s (5) .-
Kecrystm solvent
A,,,,,,
I~oriiiiilnc
U,."
C*JI*?N%04 208,240,286 16 !IS(,& Et,OI-I 130-132 C21I-IilClN?04 207, 247, 287 16 95yGEtOH 167-169 C ~ ~ H ~ S S O207, ~ 230,2.52, 28s 16 0,5YGEtOH c 82 130-1.52 C&hN204 207,233,288 16 9*5YcEtOH d 91 158-159 207, 220 (a), 278, 327 192--194 C21H21N306 8 EtOAc-cydohexane e 91 C ~ ~ H Z ~ C I X Z O207,224,241,288 ~ 16 CsH6 f 73' 171-173 208,224,230,285 C21H2oC12NyO4 g 74b 184-186 54 C~HG h 63' 164-166 66 C6H6 C22H23ClN205 208,224,230 (s), 290 207,223,254,289 C2zH23ClN204 i 71' 144-146 18 C6H6-hexane 208,225,274,326 C2iH2oClS30R j 72' 137-140 52 C6H6 Second crop of cr a Spectra wei'e recorded on a Bausch and Lomb 503 spectrometer in 93yGEtOH. All compounds gave a correct anal) tempted, while yields of 5a-e are based on first and second crops. .in
{J3
1)
'37
..-
c
ill#
'
x
7
10-
3 ! ) . 2 ,17.8,34.0 39.8, 19.0, 33.8 3 3 . 0 , 15.8,5, l.;.,;, 31.7 42.3,19.33,31.6 3'2.3,25.2, 14.6,26.3 34.0,19.2,13.0,32.0 28.0,13.2,14.0,27.0 21.0,18.8, 15.8,20.0 31.0, 19.0, 15.5,2.i.O 26.0,21.5,11.0,23.0
TAHLI~: I1 PHYSICAL CONST.IKTS OF ~ ~ i ~ 1 . \ i i u 1 ~ . , ; - % , 4 - ~(1 6o) r \ . l l s ( 9
' .
Reflux period, h r
--___L-v"
Reorystn
Spectra
x 10-3 213,266 18.0,16.7 232.5-233.5 12' CHC13 CzoH1aSzO3 248-250 12 95% EtmO13 C2oHijClS2Oa 210,220,268 19.3, 18.9, 15.6 226-228 12 9.5ycEtOH CZIHYJJ~OJ 208,223,267 26.2,21.0,16.0 77 229-231 12 C C ~ H Z O S Z O ~ 216,264 23.0,19.1 28d 2 17-21 9 24d EtOAc C2oHljN30: 208,211,267 24.5,2.5.0, 18.2 82 214-216 18 EtOAc C2oII1,clx2os 212 (SI, 222,265 16.2,17.3,9.1 a 50 24 7-24 9 1s 93%, EtOH C ~ O H I & ~ ~ N I O ~209,223,268 28.0,27.0,8.0 h 70 231-233 18 9.5% EtOH C21Hi~ClS204 208, 22,.i, 267 3.5.0, 32.0, 14.0 1 70 238-240 18 Et,OAc C2iHi&lN,03 209,222,267 34.0,26.0, 11.0 1 33 269-271 4 95% EtOH C20Hi~ClN30s 209,218,267 2 7 , 0 , 2 7 . 0 ,21. .i Spectra were recorded on a Baiinch and Lomb 505 spectrometer in 93% EtOT-I. Compomids 6a-e employed 10 nil of lIe2CO/g of iirea while 6f-j employed 4 ml of l\IezCO/g of urea. c Recrystallized from 93% EtOH and subsequently from CHCl3 for an analytical sample. Ring closure via NaOlIe and 1IeOH. e All compounds gitve a correct analysis for C, H, N. Pyriiiiidine
yield
6a b r d e f
73 92 87
M y , "C
solvent
k'orinu1ae
Amax,
w
'
of HOAc was added and reflusing was continued for an addit,ional 10 hr. The cooled solution was washed (t,wice wit.h H20, a 5% solution of NaHCO3, HzO), dried (RlgS04),concentrated to an oil at reduced pressure, and distilled yielding 11 g of st'arting ketone. The remaining residue solidified on cooling and was recrystalljzed from 95% Et,OH yielding 87 g (8870 based on consumed ketone) of product, m p 76-78'. Anal. (C13H11Cl;lj~) C, H, N.
a-Carboxamido-p-(p-chloropheny1)-r,y-dimethylbutyrolactone (2b).--.4 mixture of 50 g (0.216 mole) of lb and 500 g of PPA was heated with stirring for 6 hr a t 100". The mixture was then poured into 3 1. of H20 and stirred for 2 hr and the solid product was filtered off. The product was taken up in EtOAc, dried (lIgS04), and concentrated t o approximately one-third its initial volume and hexane was added to induce crystallization. Recrystallization from EtOAc and hexane yielded 49 g (85%) of white crystalline product, mp 176-178". Anal. (C13H14ClNO3) C, H, N. a-Cyano-p-phenyl--/,-/-dimethylbutyrolactone (3a).-'4 solution of 23.3 g (0.10 mole) of 2a8 in 85 ml of POC13 was refluxed with stirring for 13-20 min in a 100" oil bath. The resulting solution was poured cautiously onto 1 kg of crushed ice with stirring. The solid which precipitated was extracted with C6H6 and the residual aqueous solution was saturated with h'aC1 and extracted with two smaller portions of CsH6. The combined organic extracts oc-ere washed (HzO, 3% aqueous NaHC03, H20), dried (nIgs04), treated with charcoal, and taken to dryness a t reduced pressure. The resulting product was recrystallized from Et>OAcand cyclohexane yielding 16.3 g (76Yc) of a colorless product, mp 17.5-176". Anal. ( C I ~ H I ~ X O C,ZH, ) N. a-Cyano-p-(p-chlorophenyl)-r,y-dimethylbutyrolactone (3b). --A mixture of 20 g (0.075 mole) of 2b and 70 ml of POCla was heated with stirring in a 100' oil bath for 1 hr. After cooling, the mixt,iire was poured rantioilsly over 1 kg of criished ice with stirring. The resiilting solid was filtered, taken i ~ in p C61T,, dried (lIgSO4), and concent rated to one-third its initial volume and hesane was added to indiice crystallization. After cooling, 18 g (%if;;) of white crystals were ubtained, nip 129-130'. Anal. (ClaHi,C11\;0,) C, H, N.
2-Amino-3-carbomethoxy-4-phenyl-5,5-dimethyl-4,5-dihydrofuran (4a).--4 mixture of 21.5 g (0.10 mole) of 3a and 1.08 g (0.02 mole) of XaOCH3 in 200 ml of anhydrous MeOH was refluxed for 48 hr. The cooled solution was neutralized carefully with HOAc to p H 6.5-7.0. The excess MeOH was then removed at reduced pressure, the residue was taken up in CHC13, washed (HnO), and dried (Na2S04), and CHCl, was removed. The resnlt,ing solid mass was recrystallized from EtOAc and cyclohexane giving 21 g (8574) of floculent needlelike cryst,als wit,h m p 115-116'; uv max (95% EtOH) [mp ( e ) ] , 210 (7300), 269 (11,400), and 273 (11,500). Anal. (Cl4H17XO3)C, II, N.
2-Amino-3-carbomethoxy-4-( p-chlorophenyl)-5,5-dimethyl4,5-dihydrofuran(4b).--A mixture of 5 g (0.02 mole) of 3b and 0.216 g (0.004 mole) of NaOCH3 in 40 ml of anhydrous IIeOH was refluxed for 60 hr. The homogeneous solution was cooled, neutralized with H 0 . 4 ~ to p H 6.5-7.0, the excess MeOH was removed at reduced pressure, and the residue was taken up in CHC13. The organic solution was washed (HgO), dried ( l l g SO4), and concentrated at reduced pressure to yield a solid product which was recrystallized from EtOAc and hexane to yield 3.9 g (69%) of white crystals, mp 141-143". Anal. (ClrH1&1SO,) C, H, N. General Procedure for Ureido-4,5-dihydrofurans(5).-A solution of 4a or 4b and a 107, 31 excess of the aryl isocyanate in 8-10 ml of anhydrous CsHs/g of 5 was refluxed in a flame-dried, round-bottom flask with stirring (see Table I for reflux periods of individual compounds). After chilling in a refrigerator for 2-4 hr the precipitated products were collected by vaciium filtration, washed with a small portion of anhydroiis C6H6,and dried. h second crop was obtained by concentration a t reduced pressure t o one-fourth the init,ial volume and chilling. The products were recryst,allized as summarized in Table I. General Procedure for 2,4-Dioxopyrimidines(6).*l-A solution of 0.01 mole of 5 in I00 nil of 5'j; XaOII arid lIepCOwas reflused (see Table I1 for individiial details), cooled to room temperittiire, (21) Cornpound 60
\\ab
nut yreysred by this general yrocaduie.
a i i t l iieritialized by dropwise additioii of IIOA(, t o p l I t%i. 'I'tw pi'ec'ipitated prodiict was collected by filtration, washed (I&C)), dried (P,O:) nt reduced pressure, and recrystnllized as siiiiim:tiixed in Table 11. 2,4-Dioxo-lH-3-(N-p-nitrophenyl)-5-phenyl-6,6-dimethyl5,6-dihydrofuro[2,3-d]pyrimidine (6e).--A ,diitioii of (0.0093 mole) of 5e and 0.4 g (0.0075 mole) of ?;aOCIla in 130 nil of :inhydloiir 3IeOIT was reflirxed for 24 hr, cimcentrnied :it IYtlriceti presslire io one-tenth its initial volime, aiid h:-drol II,O (200 nil). The aqueoiis solirt ion was neirtralizetl ti. addition of BOXc cawing the pi~ecipilarionof :ipale ~-elloiv wlid Xvhich TVRS siihsequentl!- vollected hy vac'iiiim filii,atioii. w ~ d i e dwell (FLO), dried (P20h) at redtired pre tallized t w i w fmm EtOAc affoi,ding 1.0 g (28' tals, 1 1 1 ~217--21!1°. ; I T L u ~ . (C20HiiN305) C, 11, S . Lu-Carbomethoxy-p-phenyl-~i,~-dimethylbutyrolactone (7).-- A sollition of 1.0 g (0.004 mole) of 4a in 25 ml nf CE1c13 was refluxed l'oi, 10 h i , with HC1 gas hiihhlirig through i h r sollition roiitiniioiisly. After rooling t o i'ooni teniperattii,e, thrl wliiticin w:i-hect ( 1 1 2 0 > 5' TaHCOa, I r , O ) aiid dried (.\IgSO,). ( ' O I I -
5
tnllized f r o m $I>('; I*;tOFT aft'ortiiiig 790 mg (80' ; i iiie prodiici, nip 1 I:{.>- 1 I.?'. . l m l . IC14111~Or~ (. ackiioivledge thr. )f this irivestigatiori hj- the L7. S.Army Alediarch und Ilevelopmerit Command, Departthe Xrm>., under ('oiitract SO.IIX-49-193.\I I)-3001. This is C'ontributioii So. 190 from th(. .\mi\. 1itw:irch I'rogram o n :\ I:&trix.
w-Dithiolano Amino Acids'
.\l:iny t h e o r b have been forwarded t o esplaiii the de-tructive action of ionizing r:tdiatioii oil the cell.? Although the chemical theorie- include ii wide array of target molecules :I> the primary reaction in the cell, common agreement points to either a direct ionizing action on a cellular constituent or ail indirect action mediated hy peroxides formed in the cell. Based on thc radioprotection :iff orded h y cysteine arid cysteamine marly related aminothiols have been +ynthesized arid examined. In thih invebtigation intere-t was focused on thc 1,B-dithiolane ring. The eaye of chemical oxidation of thit hyqteiii to a disulfonyl would make i t :L likely candidatc for radioprotection. Three 1.3dit hiolario :imino :Lcids were prepared for biologiciil (valuation a\ rdioprotective agenti : 2-amino-2- [ 2 (1 .:{-dithiolaiio) ]:icetic (1). -propioiiic (2), :ind -butyric acid< (3). 1:thgl pht haliniidoacctwtc (4) TI et 1iy1 formate uiid SaOKt iii xylene to give ethyl 2~~1ith:tlimidomalonaldehydate~ ( 5 ) . The 1,8-dithiolane {
u p p o r t e d liy Graiit G l l - 1 : 3 4 1 , l)i\ ision of General IIi,iIii,iiI &.irnces, a n d l ~ yGrant 1K3-('.-\-10739 from t h e Xatiunal Cancer Inititutes, National Inutitnte. of IIealtli. T a k e n i n p a r t from the dissertation presented 1)y .\. .\. Rarnsey, 1 1 a s lYti8, t u t h e G r a d u a t e School of t h e 1Tnii-rrsity O S Kansas in iiartial fulfillment of t h e requirements for t h e Doctor o f I'liihmphy Ilegree. ( 2 ) (a) .I. Pili1 a n d T. Sanner, I'royr. Biociiem. J'hurmorol., 1, 85 (1965); [ I B I %. 1 1 . I l a r , ~ "Clie~nicai , Protection .ipainst Ionizing Radinliun," ('harlf.. c ' 'I'liomai. l'iiI~!idi~r,Springfield. Ill., 1'363, 1, I 4 T . (:i) ,L Ii. Ume, O r y . .Si,,#., 40, 82 ( I W 3 J ) . ,lolinsoii, d . .1mrr. Che7t~.Soc.. 76, 158 (1954 I . ( 1) .I. ( ' , Slieelian a n d U
Url~ucces,.tul :lp~,ro~lchc+ t 0 t he -ynt he aldehyde 10 ~ r e i m:idc ~l hy alLy1,itioii of diethyl : i c ~ t amidomalonntc with ch1oroacet:ildehytlc diethyl :ic.('tal and through ozoiiolysi+ :arid reduction of tlicthyl :Illylacetaniidom:iloiiatc (8). Thc ;..iithc.i< of 2 (eel 2 )
