«Tbe cy n th e s is o f an open-chain Analogue of. tori ophyllo toxin 5 - PDF

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A pprval B h et ' '-llam Bruce TustmLer, Ph«D«, 19$3 T itle f Thesis? «Tbe cy n th e s is f an pen-chain Analgue f tri phyll txin 5 and A b stra c t apprved* ' J 1 r\v X 't \ x/ ^ ; ** \ Itrfssr in charge

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A pprval B h et ' '-llam Bruce TustmLer, Ph«D«, 19$3 T itle f Thesis? «Tbe cy n th e s is f an pen-chain Analgue f tri phyll txin 5 and A b stra c t apprved* ' J 1 r\v X 't \ x/ ^ ; ** \ Itrfssr in charge f th e s is bead, Departm ent f Chem istry J u ly 1 1, 1S 3 vat m m m is r m w m m m Thesis subfgltted t i# Faculty f the Graduate Sehyl in p a r tia l fulfilxisisit f ^b rquirmatmi# fr th «$ f Dctr f Phil^er UMI Number: D P All rights reserved INFORMATION TO ALL USERS The quality f this reprductin is dependent upn the quality f the cpy submitted. In the unlikely event that the authr did nt send a cmplete manuscript and there are missing pages, these will be nted. Als, if material had t be remved, a nte will indicate the deletin. Dissertatin Publishing UMI DP71150 Published by PrQuest LLC (2015). Cpyright in the Dissertatin held by the Authr. Micrfrm Editin PrQuest LLC. All rights reserved. This wrk is prtected against unauthrized cpying under Title 17, United States Cde PrQuest LLC. 789 East Eisenhwer Parkway P.O. Bx 1346 Ann Arbr, Ml ACKU0M3DGMSMt3 Th» g r a te f u l l y atiirledgefl t» ^ n t i s a l i i f i n t r e s t m d gui«rk»» c» im M M p «*tmai i«# iitm during w e urn r m s rwsttsixtibi* The w ifly y wiii ioa is sspr M i f r generus fin a n c ia l jaw id d the ffijn w r Instd.taite s^dlcenax I n s titu te s f ealth, Betheada, Maryland, and a ls V E# I. dupnt d aan and C*, W ilmingtn, Delaware* ... ( i x ) XAipaxci fc * v p-q^a: (llik) Q%vv T^x&uci& x&okrpaj,-^ r\*i *(1A) apt^nd I^«q^s:tfq.&'P%-* **?* q. (AX) %^2uq^t^feipii*-5 xafl.*? j utesiau;) %jh;u...* (IA) ppcw J X ^ s iia q v & t^ ^ rp Q w./ ]«(: ^ g pqpp ( a ) xpqty W j 1 * IS pom^«-. *(a) t q iv li^ucpacti^su.x-ax-s**? * C * * * ^ su9qatxp*fci^j~ #7 (XI) 0UO^DI.sTCkli^nq^(p^l4S^3^OIPSU itaf4. S;J Tj c I I - A w j p A f O e ) - - ( t i f c u t q & ' f t w w - g ** )~ i *XI rio K ^ L,,L...# * *.. ( IA ;-1 ) a n ^ x ^ iiq - ( xi^uq^ ^p^l -- ) ~ ~ T ^ n ^i~ j * XXIA X I & X. t *» upcq.n^{dpx j ai^i??u Y p ^ r c m e q tie u r, JO ex 0 t& u /S m u #I I A Mj IXDJ*.; ;. t V ^ ^ JJf V ^ X**0 O'X ^uxivqxmajfe:*cpiax{-2~^;ii^qabs - -*iii'0iy-*t? xa t&)ixoc j r '* Xc ixt) 5 «^nq-(i^tt qd^jcdt 5.0UiiJK.- S* s X** ) -T^iCxi{^q4^D^-GUOij^auLiCx0^pJCtf-*2-^ xaumfdlfitcrtp * )- i JO sie^u ics nindvm-vi &U *A mi&q'js...*... (!XliiXX) PP 0^a^Xamii d -JtTpeuT&B.ew-i I «* j^ ^ tisk 'ii^ r q ^ ai^ w ;*ifc & fjm jj.;: S i... (xx) ymiw^j&bu0qti^xpk 1I * * C - I^ tj ^ li^ tp i, c rp ;i-s *h* *111 X I I X. : xi (xxx) appear: xjtvw \$j&xp \xri m«*»-*! i *n m u m 5 ( I I A ) a ^ u x x m i^ ii q ^ q i& u i5s rs,t] #c I& T W u #I X U t t U J... X 2 XI10 J X; J - -X' X w i k.! vjj - - X u l i i ^ X O JO XTEVA D ieth y l 3, 1 *, tiixyben^xr^ariatc (V II). ^fefhd B *»* AlethyX (IK)******* Fydrf^rmtln f M e th y l 3,h»5«'JW^tiK3^bna^lEnalnate ( IX) Uni ny Fss.ctxnis OiarcaX* * #* # *** #** * * #* ydrgenatin f P i th y l 3#h*!^Tri^tbcri^benayl33jalcsnate ( I I ) tlsiny; Platinis***** * ««*»* * *» * * 1,2 f 3,3,3,?w ^ % i^tt?y«-9,ld -^ll^rdraiitiirae ^i (XIII)******» Pxprncpy 1. IxXrxd (Xvl)* ** * * # * 1--ILthyX Fi ^xrcyixxjihhvo ( .AXX)»******» ** * * 3,li- 1ttlwlenerfijg'ace t^iencn (If I I I ) * 1* sthd A * «** 3, liiy lenedla-^ac tphenne (XVIII)*?-%thd 3 *» * «3, ij.-''fet*^/iendia x ^ p h im a ^ l i^rk&d (XXX)** * i^eri& eylatin f D ieth y l % l «s t s * * * * * * ifie& grl Bm a^x ptaiac^lm alim t (XXIX)* # # * * * «* # Ipliiisc^fXiticiX Cicii Acirf * # * * * * «* «B ns^lplieaacylacetate * * * D ieti^rl TriDth3Qrbaas^rl«-3 % h. alnte (0 2-( 3 * h9!^tri^1^xrbn^l)-*2«-c^tibeth3iy 4 *(35ii*-nthiy'ln9«- d i ^ jh & n ^ l)-%a ity r la c t n (XXI) * * «* 39U» * h * ^ ^l^ ^ len e iax y p ii ria cy l^ a lciiic Acid (XXVII)... *.. * t^trisse tli ^ b e n s^ rl-l *$L W istb^lsk sdi^rit^naqsrlactic Acid ( x x v m )... ***** x-et3r 1 3, k, c'^ r lm t} K ^ r ^ n z fi^ 3 ** h. l**^t3xylenedi^i5h mac^l«- rcu.-tj (XXXII)... ;«' 3 f It.$!%»1frlrth:KybsR^l~3 8»h 1 1;^ylensdiaypbnacy X~ aetat (XXIX)..... *... 2-{ 3fli# ^Trima'fcha^bQn^jrl) Ji**( 3 *, h #*-?:ietl^l ndic^ ^0ryl) - b u tt/r laet n e (XXXI) *. «*** «* ** ««*. *»* «TfensJ'^fcix y ls u e e in ic Acid (XXXVIII) «* ** ** **. * I~PPenyl-3 -.c a rb ^ t tra lc m -l (XL)*... 89... c m ii) m u v ie & r i c * *»... * «n ^d': jc a a ju x AO *... ****... 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(IIIA li) l i *# * * ( XI 111) I-^UOt^^v +.O&JfcflDJp 2 -A^2 OC^0^~l,A Uai^'{ 2. * * # # * ^ IX ) X - ^X ^^^t S.0 i4j^*C^X -^0Tr ^ 1; C.p'djA4*1f I TXT U S f OF CARTS Chart X-* Chart 2** ch a rt 3 *. Chart h»* Chart * Chart 6** Chart?.* Chart 0*» C hart 9 * Chart 1 0. Chart 11* Chart 12 Chart 13' Chart 2Ji XM TRem if rib d isc v ery t h a t pdps^lltaxin causes re g re s s i n f murn :.arem& 3? has renewed i n t e r e s t in th is substance and in empunda r e la te d t i t (! ) artw ell and Sehmckssr (2 ) have re c e n tly re v ised the r ig in a l f n m la prpsed by Brsch (3) and Spath (h}» s that 1 (C hart 1) re p re s e n ts th e jm wm tly accepted stru c tu re * the h i # t x ic ity f p d p ty ll t x in has prevented i t s us l a cancer therapy* T his has p r fited a in arch f r analgu es lisic h m ight r e ta in th e d e sir a b le p r p e r tie s f p d p ly ll t x ln, b it have lw er t x ic it ie s * t h is themis dssertb the ^ n t iis s is f XI, ih pc?i-ciiain analgue f pdphyxxaixin* th e D isc u ssi n i s diwidd in t S e c ti n s, each d e sc rib in g the resea rch dn n th e p rep aratin f a key in term ed iate as w e ll a s n r e la ted cmpunds which are n t in term ed ia tes In Us main g y n th esis* Each -' ctiai i s accmpanied by a # a r t which d e p ic ts the aynthetie rut under d iscu ssi n * A s lid arrw in d ic a te s a ciaplsted r e a c ti n f r which an m p m 'lm m k a l prcedure i s g iv en in th e Experim ental S ectin * Unsuccessful r e a c ti n s are in d ica ted by a brken arrw and arc b r ie f ly d escrib ed in the D isc u ssi n. Many f th e cmpunds prepared in t h is wrk have b mi subm itted t th e Cancer I n s t it u t e, U* S. P u b lic ealth S e r v ic e, B ethesda, Maryland, f r valuatin f th e ir e f f e c t s m muse S&rema 3?* Xhs r e s u lt s f th ese test am n t y e t knwn* 2 Chart 1 C jo OCR CJD O C R OC i i Chart 2 XIX C C.O OC CO COOC COOCj C jo C jo OC O C 3 \ \ XXXIII \ ii DXSCtSSSSON Thm rig in a lly prpsed s y n th e tic r u te t I I i s u tlin e d in C hart 2* O T I D ie th y l 3$k*g ^ T ^ a ^ th ^ b a n ^ ig m l n a te (fii)* rk and e-w rkara (5) h a w d sc rib e d a sy n th e s is f d ie th y l 3,1, ^trlmth^^n^lifmxanbte ( 11) in which 3 mas emwrbed t 3,ti,5-1 ^ im th 3 y - h enaaldehyde which mm th en hydr&sxi&hed t 3, li,! ^ t r Im cthxyben^yl a lc hl* tti re p rte d y ie ld f th e a lc h l based n 39l^ ^ tr la s th e s ^ b e n c a n illd e mss s ix ty - th r e e percent* C m srtl n f th e a lc h l t 3*1* J -trim e th jy - bemsiyi c h l rid e fllw ed fcy re a c ti n w ith d ie th y l sdim alnate aff rd ed d ie th y l 3, It, i n u n sp e c ifie d y ie ld * The red u cti n f 2 k9^ -trii^ th a x y b n s le a cid (III) by lith iu m alus&nur- hydride (C hart 35 appeared t be a mre s a tisfa c t r y ru te t 3*iif ^ triise1 ^ ^ y l3 «m syl a lc h l ( ) ahich wuld avid th e trublesm e p rep aratin f 3»Ii,?-t^.r^thq?ybensaldehyda and I t s subsequent hydrgenatin* th e redu ctin f 3, 3 -d fi^ thcnybensie a cid fcy lith iu m aluminum hydride in th er i s reprted t p r e y e d in n in e t y th ree p ercen t y ie ld (&) Because f th e lim ite d s lu b ilit y f 3, ii,! -trim ethssybens lc acid in e th e r, th e technique f cntinuus e x tra c ti n was emplyed t in trd u ce th e a cid in t th e re a c ti n m ixture* The a cid prved t be extrem ely r e s is ta n t t r ed u cti n, prbably because f th e in s lu b ility f th e i n i t i a l l y frmed s a l t in th e r e a c ti n medium* Since th d ir e c t re d u c ti n f 3, U, 5 -trlm eth a^ben ss ie a c id was unprm ising, a tte n ti n mm d ire c te d t th e re d u c ti n f th e crrespnding e th y l e s t e r If* R thyl 3, ^ th^ybsnsate m prep ared fey h e a tin g a s&xtaire f 3 # U,^ trlm e tfe ^ b e iis lc a c id, a b s lu te e th a n l, and ben- % ne with p -t lu enesu tlf n ie acid and slw ly remving th e feensee-alehxw ater a ie tr p e by f r a c ti n a l d i s t illa t i n * R eductin f th e e s t e r by lith iu m aluminum hydride in e th e r aff rd e d a fifty p e rc e n t y ie ld f a p r d u ct which prred t be a m ixture f s t a r t ing m a te ria l and 3, U,S-triniethQxyfcen^yl alchl* In anther experim ent in which th e r e a c ti n m ixture was trea ted w ith aqueus a lk a li in s te a d f a cid t decmpse th e e$ lax, th e prduct r e s ln ifie d t a red g la s s upn attem pted d is t illa t i n * Because f th e e ase f redu ctin f acid c h l rid e s, 3,b,5 - trtm ethrqrben&eyl c h l rid e ( f i l l ) was prepared (7 ) and su b jected t re d u c ti n by lith iu m axundxwn hydride i n eth er* A f i f t y p e rc e n t y ie ld f 3»U*$- trim eth c^ybens^ l a lc h l m s btained* th e mmrmfm f 3, it, S-triraeth xybensyl a lc h l t th e c h l rid e VT m s re p rte d t prceed in s lx t y - e i^ it p ercen t y i e l d, w h ile th e y ie ld in th e subsequent a lk y la ti n step m s n t in d ic a te d ( ) E e p e titi n f the p u blished d ir e c ti n s re s u lte d in nly a f r ty -th r e e p ercen t y ie ld f th e c h l rid e, and frm t h is ily a s n a il m u n t f d ie th y l 3, 1, ^ triia e th a s y b m ^ lm a lim a te culd be b tain ed upn re a c ti n w ith d ie th y l sdleijialim&be* Since t h i s s y n th e tic r u te t th e d e sire d p r d u ct 11 appeared u n a t t r a c tiv e, th e p s s ib i l i ty f red u cin g d ie th y l 3, ii,^-tsrim ixybenscyl- m alnat# ( ) mm cn sid ered ( c h a r t Ii)* I t was fund p s s ib le t d u p lic a te th e re p rte d p re p a ra ti n f IX in e ig h ty -fiv e p e rc e n t y ie ld by re a c tin g a susp ensin f d ie th y l s d i m l n a te i n 'bmmmm w ith 3,li, - C jo -^ y ^ O C j OC, I I I C.O OC, IV Cl C(COOC1f) - C l C p * V ^ CJ O C, \T C O - S x ^ O C, O C, VII I C K O -1= = y ^ l ' 0 ' O C, C hart 4 C O C ( c OOCjj^ C. C. O - K ^ O t O C 3 v m IX O C d-c^coocj,^ C: jl + C.f C O ^ ) f K hp C p y ^ C r ^ p V ' O C, X II X XI CtO A s. v C j O J ^ y ^ - O C, C 0 O C j J V c h 3k - S3 t*» **» 8 I % & a 3* ^ triiisth ^ b sn ^ lim l n a t ms btained, this aaeetsragttd the b e lie f Islated nly 3,u,trim eth C B ^ b cm sic acid arid & smell amunt f a w h ite s lid f unknwn stru c tu re* sa a itln f a t 203U202 * which had a carbn and hydrgen c n ten t f 66*6 p ercen t and 6*T p ercen t re s p e c tiv e ly. Ck and c-wrker (5 ) btained a sim ila r m aterial* m alting a t 201, as a byprduct frm th e p rep arati n f 3, k,5-trirrsetlixybensyl alc h l by th e m ethylatlcci f g y rin g ic alc h l u sin g m ethyl p-tluenesulfnat and ptassium hydrxide* fkmgr c h a rac te rise d th m a te ria l ms 1* 2,3# 5*6,7- hex^-jeth5?y-9j lc -diiydranthracene (X III) (Fr f* ^6*?j, S*? 0C,*SX#7 Fund*, S?.Xj, 3.7$ 0C-* 5 2.0). ** j? I t seemed lik e ly th a t th e m a teria l isla te d by uang, T arb ll and A m stein m m th e mmm m th a t b tain ed by Ck. I f th e i n i t i a l hydrgenati n a ffrded 3,1, ^ -trim cth isyb ^ i^ l a lc h l, i t was n t u n lik e ly th a t th subsequent W ilin g f th e m a ter ia l w ith ten p ercen t s u lfu r ic acid a ff rded su m f th e dibydranthracan d e r iv a tiv e. In rder t t e s t t h is h y p th e sis, 3,1, 5-trintlx :xybenByl a lc h l m s W ile d w ith ten p ercen t s u lfu r ic a d d. A sm all amunt f e th e r in s lu b le prduct m ltin g a t was isla t e d, th e a n a ly tic! d&tm war in agreem ent w ith th ery f r X III* and i t i s cncluded th a t T srbelx 'e cmpund i s ih same a s th a t I s la te d by Ck. The re*$y hydrgenlyais f th e carbn carbn bnd in d ie th y l 3,if.#^trimethas^b f»scylmaln t i s cnsistent w ith mam th e r bservati n s. v$ym m attempt mm made t 3$rdrgeaate the ketcne u sin g c p p er- c h r m iu ^ b a riin cn&d in thanl, th e nly p r d u ct islated was e th y l 3$hf5^trlmetha3Qfem&ate (I?)* in d ic a tin g t h a t the mlecule had undergne a lc h ly s is. In the determinatin f th e sapnificatin e q u iv a le n t u sin g O.I a lc h lic ptassium hydrxide, I t was fund that tha mlec u le r a p i d l y cnsumed three equivalents f alkali, and trimethjybnsi e 9 a cid m isla te d t r m th e rea cti n * The renewed a v a ila b ilit y f 3 * k* ^ trim th x^ b eii^ rl a lc h l frm the platinum ca ta ly sed hydrgenly s&s f dltfcgrl 3»l4» 5^trirathx3rbenaK3(f 1 - m aiaat preipted a r in v stig a ti n f th e apprach f i r s t cnsid ered (C hart 3)* In Ck** prcedure f r c n vertin g 3*1*5-trim e th c ^ h en sy 1 a lc h l t th e c h l r id e 71 a m ixture f th e a lc h l and d lm etlylan iltri a t 0 wee trea ted w ith th ick y l c h l rid e t a ff rd a s ix t y - e ig h t p ercen t y ie ld f tlx? ch l rid e* R e p e titi n f t h is prcedure affrded a f r t y - th ree p ercen t y ie ld f prduct* C nsiderable d if f ic u lt y was experienced in s tir r in g th e v isc u s r e a c ti n m ixture e f f ic ie n t ly * I t was fund th a t Jy d ilu tin g th e r e a c ti n M ixture w ith benaen* e f f ic ie n t s tir r in g was p ssib le * and the y ie ld was in crea sed t s e v e n ty -s ix percent* Since th e Xkylatin f d ie th y l sdim alcxiate t y 3*1* ^ -trisie ttejsy - ben^rl c h l rid e in eth a n l gave a pr y ie ld f iispur* prduct* th e a lk y la tl n f d ie th y l sdlem alcs& te in e x c e ss d ie th y l m alnate was in v e stig a ted* M i techn iqu e h m been eaaplcyad w ith su cc ess in th e prep a ra ti n f d ie th y l benssylm lnate (16 )* lb s r e a c ti n was fund t prceed in aeventy-fiv t e ig h ty -fiv e p w w t y ie ld t a ff rd d ie th y l 3 * l* ^ t r i^ t h a y b e n ^ 7 iia l n a t e * She dem nstratin f th e f e a s i b i li t y f m rsrtlng 3*!i, -trim ethcffiybenayl a lc h l t th e m l n ic e s t e r 711 renewed in t e r e s t in d e v isin g an a ttr a c tiv e sy n th e sis f th e a lc h l* % lle t h is wrk was in prgress* a r ep rt appeared d e sc rib in g th e lith iu m aluzslmua hyd rid e redu ctin in e th e r f m ethyl 3,h,S-triiasthxybenw ate t 3, h*5-trim nsyl a lc h l in sevim ty-thre p ercen t y ie ld (1?)* The red u cti n f e th y l 3 * ^ t r l ^ ttasybns& t in b ilin g t trahydrfursn was fund t prceed ID in p ersnt y i e l d, The u m f te te sh y d r fu ra n, in a d d iti n t p e rm ittin g a h ig h e r r e a c ti n tem p erature, had th e perhaps mre s ig n i fic a n t advantage th a t n csgalsx separated fr tf re a c ti n m ixture m had b a m bserved i t n thr m s emplyed a s th slv en t* te s u p e ri rity f teteahydrfuran ver th er m s fu r th e r dem nstrated ^hn i t m s shrn t h a t 3,k95 - t r a cid m id be reduced t th e a lc h l in f i f t y - e i g h t p e rc e n t y ie ld in b ilin g tetra ly d r fu r a n. In th e r, s ta r tin g m a te ria l was recvered i n gd y ie ld. Again, t h i s d iffer e n c e m^r be a sc rib e d t s lu b ility d iffe re n c e s* w hile th e r e a c ti n f i x tu r e in ^ t r a - lycirfuran m s Imsmgeneus, th e s a l t f th a c id p re c ip ita te d frm s t e e r, thu s in h ib itin g f u r th e r rea cti n * Sine tear m s l i t t l e by-prduct frm atin in th e red u cti n f th e e s t e r, i t appeared f e a s ib le t e n w r i te c crude a lc h l t tb s c h l r id e, sfcsn t h is w m dne, th e v e r a ll y ie ld f tea ch l rid e m s ev sn ty -six p e rc e n t based cm th e e s t e r. Ih e K hevsnagel cndensatin f 3,2i, -trim th ^ b m teid e ly d w ith d ie te y l n sl e a te fa ll w ed by hydrgenatin f th e r e s u ltin g tens& lm alni e s te r I I appeared t be an a ttr a c t i v e a lte r n a tiv e sy n th e sis f th e feensyl- m alcsiic e s t e r VII (C h art ) wever, i n i t i a l experim ents in v&deh th e cndensatin m s imducted in eth a n l u sin g p lp rid iiie bens&be as th e c a ta ly s t aff rd ed y ie ld s f a p p ra d ta s te ly t h ir t y - f iv e p ercen t f X I, and t e l e apprach m s abandned. Subsequently hwever, te e use f the prcedure f f tr a tt and iftrh te ( Id ), affrded a se v en ty -f u r p e rc e n t y ie ld f II* This m a te ria l m s r e a d ily hydrgenated in th e presence f platinum t affrd, m i# 1 y -fiv p ercen t y ie ld f VII* 11 when a sample f th e riginally prepared d ie th y l 3, li, * -triraethxybenzalm alnate which. had std f r tw enty mnths m s r e p u r if ie d f r a n a ly s is, i t was smewhat s u rp ris in g t fin d th a t th e m a te ria l, althugh r ig in a lly re crystallised fr petrleum e th e r, was n l n g er cm pletely s lu b le in t h i s slvent* th e in s lu b le m a te ria l, which c n s titu te d n e a rly h a lf f th e sam ple, was high m eltin g, b u t gave a carbn and hydrgen a n a ly s is i d e n tic a l w ith t h a t btained n th e s lu b le p rti n. I t i s b e lie v e d th a t d im e ris a ti n ccurred t a ff rd the cyclbutane d e riv a tiv e X I?. The diaerisatlec* f cinnam ic acid t frm t r u x i l l i c a cid I s w ell ten wn, as i s th e dimerisatin f m etbylenem alriic e s t e r t frm % 3,3-ttracarb thxy- cyclbutane (1 9 ). In view f th e frm atin f a sym m etrical p r d u ct in th e case f metfeylene alnic e s t e r, i t i s b e lie v e d t h a t th e pr d u ct XI? i s a ls sy n sn etrical. The tw su c c e ssfu l r u te s t d ie th y l 3,li,^-trim ethxybensylm alnate d escrib ed in t h i s S e c ti n re p re s e n t s a tis f a c t r y syntheses f th e cmpund. ie scheme shwn i n C hart 3 h as been emplyed a s th e prim ary sy n th e sis f V II in an v e ra ll y ie ld f six ty - n e p e rc e n t, based n th e ptimum y ie ld s btained in t h i s wrk. An a lte r n a tiv e sy n th e s is f V II, u tlin e d in C hart 9, h as been cnducted n a sm all sc a le t a ff rd V II in s ix ty -f u r p e rc e n t y ie ld, based n 3,ii-, ^-trim eth^sybnsaldshyde SSCflOK I I 3,it-B ^eth^enedixyphenacyl Brmide (XIX). Sp&th and L ed erer (CO) have d escrib ed a sy n th e sis f 3,1-420thylenedixyphenacyl brmide (XIX) by th e u l t r a v i l e t c a ta ly se d hrm inatin f Ifli-w thylenedio K yaetphenne (X V III) in a c e tic a c id. S everal sy n th eses f XVIII have been re p rte d, 12 Chart 5 O c h C = C (C O O C &, ) t C.O OC. X II O C, V OC3 XI OC, C,0 ^ 5 ^ O C 3 OC. ( C O O C J V ) X I OC, C 0 ~ f Y P O C» j ). C O C, XIV OC VII C hart 6 C O ' c- ^ $ 0 C O C (C O O C i!), xv XVI XVII,. ' P ~ f tf!?v C 0 C *B ' - O ^ V C O C, ^ X J - c x* 0b X J 5 XIX XVIII 13 amng them b ein g th e r e a c ti n f piprn&x w ith m ethylm agnesiua i d id e fll w ed by dlchrm ate x id a ti n f th e r e s u ltin g 3 * Jwn tfcylan edixypfce^lm e tfrylc&rbinx ( 5 1 ), th e cndensatin f metfeyl plperenyl& t with, e th y l eetat f ll w ed by h y d r ly sis and d eca rb x y la ti n f th e r e e u ltin g e th y l pip ernylacetat (5 2 ), and the d ir e c t FriedeX-^Crafts a c y la tl n f ^ t^ le m d l sy h e n se fi (53 ) Of th e se m ethds, th e f i r s t seamed th e n e s t prm ising* th e r ig in a l wrk f KXage (5 1 ) in d ic a ted th a t t
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