Derivatives of Iceane : a Study in Molecular Architecture

23.t\'87

DERIVATIVES OF ICEAIIE:

A STUDY IN MOLECULAR ARCHITECTURE

A Thesis

Presented for the Degree of

Doctor of Philosophy

TTIE T'NIVERSITY OF ADELAIDE

PauL Raynond Spunr, B.Se.(Hons.) Department of Organic Chenistry

L982 (ii¡

OONTENTS

SUMMARY (iv)

STATE MENT (vi)

ACKNOI^ILEDGEMENTS (vii)

P RE FACE (vr-r-r-)

CHAPTER ONE

Studfes directed towards a flnal constructlon of the Lceane skelet,on by a sequentlal bond forning process.

1.1 Procedures Lnvolving Diels-Alder reactLons 2 between dienes and benzoqufnones.

L.2 A procedure lnvolvfng a Dlels-Alder reactfon 30 between an o-xylylene and ¡ualeic anhydride.

CHAPTER TIitO

Studies concernfng a final construction of the iceane skeleÈon by a simulCaneous bond formfng process.

2.L Procedures Lnvolving Diels-Alder reactions 37 of tetrachlorothlophene dloxide with lsotetralln and propellanes.

2.2 The synÈhesls of reagents 1n Sectlon 2.I 63 (iii)

CHAPTER THREE

A rnf scellany of approaches.

3.1 Some heterocycllc examples. 72

3.2 Procedures based on an Aldol-type reacËion. 81

3 .3 Procedures based on a pfnacol-type reacÈfon. 9L

CITAPlER FOUR

Experl.¡nental.

4 .1 General. 97

4.2 [{ork descrf bed Ln Chapter One. 101

4.3 I{ork descrf bed in Chapter Two. r24

4.4 I{ork descrlbed Ín Chapter Three. 159

REFERENCF,..q L64

PI]BLTCATIONS L82 FRß.ÂTÂ t83 (Ív)

SUMMARY

The construction of the tetracyclo[5.3 .L.L2'6.04' 9ldodecane (iceane) system (I) was approached according to the straÈegies outlined in the scheme below.

H III H-

H Scheme

In chapter one' a rnet,hod is discussed for converting substructure (III) to (r) by a sequent,ial bond forming process whích involves a double intra-

molecular alkylation reactÍon. Two precursors to a key interrnediate based on substructure III were prepared by two types of intermolecular Diels-Alder

reactíons. The cis stereochemistry at the ríng junct,ion was generated by

a cycloaddition reaction becween benzoquinone and a suitable diene. It was hoped that this st.ereochemistry would conÈrol the introduction of the

remaining stereochemical requirements. rn an alternative approach, the cis orÍentaEion of the side groups r"las achieved by a cycloaddítion reaction between an o-xylylene and maleic anhydride. However, both of these reactions

involved the formation of a teErasubstituted double bond which could not, be removed satisfactorily Ëo give the stereochemistry necessary for the trans- formati.on of substruccure (III) to (I).

In chapter two, a method is discussed for converEing substructure (tlt) to (I) by a símultaneous bond forming process r¡hich involves an intramole- (v)

cular Diels-Alder reactÍon. This required the Íncorporation of an exÈra ring system i-nto subsËructure III. The stereochemÍstry of one of the rÍng junctions ín this new subsÈrucÈure hras controlled by an inÈermolecular Dlels-Alder reacËion between a regenerabl-e diene and an approprÍate bis- dienophile. The correct sÈereochemistry at the other ring junction r¿as obtained only after a series of ínvestigatÍons in which lt was íntroduced either into Ëhe bÍsdienophlle before, or into the product obtained afËer, the inÈermolecular Diels-Alder reacÈion. The former procedure has allowed the preparation of a number of molecules Èhat contain the iceane skeleton.

Some novel chenistry rüas encountered in the converslon of these compounds to derivatÍves of Íceane.

In chapter three, a míscellany of related rouËes was investigaËed that was hoped would lead to a variety of iceane derívatfves including some dÍazaiceane compounds. Although interesËfng chemíst.ry has been revealed by these studies, none of the procedures r^ras successful in pro- viding the target compounds. (vi)

STATBMENT

Thts thesfs contalns no nateriar prevfously subml-tted for a degree Ln any Unl.versLty, and to the best, of ny knowredge and berfef, contaf.ns no material prevLousry published or wrftten by another person except ¡¡here due reference ls made ln the text.

XT.t¿.re

Paul Spurr. (vi1)

ACKNOWLEDGE }IENTS

I wish to express ny sfncere thanks Ëo Dr D.p .G. Hamon for hfs advlce and encouragement durfng the supervl.sÍon of this work. The helpful asslstance and suggestions from

other members of the Depar t,ment are also acknow.Iedged .

i Thts research rpas conducted durlng the tenure of a

I Common¡¡ealth Postgraduate Award, for whfch I an grateful. I

r an indebted to my typfsts, Mrs pat coe and Miss Julie Taylor, and to ny family for thelr patfence, tolerance and care duríng the course of my studies. l (vili) I l

I i PREFACE

The work presented ln thls thesfs does not repiesent a chronologlcar accounÈ of the chenistry developed in the course of thfs research. Rather, the format is constructed to best suit the discusslon of ideas report,ed hereln. consequentry, some sections, êspegrarry Èhose begun towards the end of this proJect, are incomplete. The actual order 1n whfch the research has been carrLed out was parts 1.1, 3.2, 2.I12.2, L.2, 3.3 and 3.1. There was, of course, aome overlap between sectlons. 1

CHAPTER ONE 2

1. I The highly symmeÈric (pofnr group D3t ) cage strucÈure, têÈracyclo t5.3.I.12,u .ou,t l dodecane (1) was I origfnally conceLved l_n I940 by MuIler . In 1965, 2 FLeser , upon examlnlng a nodel of a sectl.on of an fce

crys Èal conEaining Èwelve water molecules (2) , fndependently pos tulated the existence of the hydrocarbon (I) with an analogous conflguratf.on havfng Èhe formula 3 CfZHte . The compound was approprLately named lceane

3 6 o'Å

9 t 7

H I I , '-o/'I I l0 TI I I (t) 2

lt SLnce Èhen, three separat,e synÈheses of fceane have

appeared and slx other subs tances thaE lncorporate Èhe lceane framervork have also been reported: hexagonal 5 dlaroond f ound 1n some met,eorlÈes, the heptacycllc 67 compound (3) , the fused adamantane-l-ceane sys tem (4) , I a pyrolysls product of teÈrauerhyls llane (5) and the )t"-" and (ro)tu

A molecular model of lceane appears to have a stable

sCraln-free sÈructure slmllar Eo thaÈ of adamanÈane and tr¿lsÈane. 3

(3)

(4) c H3

(a) H3 X o (b) NH cHg H3 CH¡ \.r,

H3 (6) (s) Ilowever, of the fLve slx-membered rlngs Ln the Lceane skeIeEon, tvo are ln Ëhe chair and three are ln the non- twfst boaE conflguratlon. This makes Èhe structure of lceane partlcularly LnÈeresting frorn an archfË.ecturaI point of view because, on account of thls unusual arrangement of atoEs, the molecule contains corisiderable non-bonded' interactions which have to be taken into account when deslgning a synthesis.

4 I n each of the prevlous syntheses of derivatlves of lceane, only one functlonal group has been l-ncorporate d lnto fhe nolecule. It was expected EhaÈ the preparaÈion of fceane derivatlves Èhat were dlfunctlonallzed at t.he ts¡o flagpole positfons of one of Ehe rlngs whlch 1s ln Èhe lnflexlble boat conflguraÈ1on would lnÈroduce non-bonded lnteracEfons more severe Ehan were already presenÈ. These compounds would have unusual physlcal and chemi ca I 4 propertles as Lrell as presenÈ a syntheÈic challenge. Fur Ehermore, 1n vl-er¡ of the growlng lnterest 1n the wfde IO physiological act,lviÈy of many cage compounds , a more general and efficlent synthes 1s of lceane derfvatfves should be devlsed that would make them uore acces s ible l+ for s tudy than exfsting routes have allowed. Therefore the synEhetic s Èrategy should allor¡ the lntroducÈl-on of functlonality LnÈo more than one rfng of the lceane molecule so that a wlde range of derivat fves could be prepared.

tI- Retrosynthet,lc analysls d of the lceane structure has t2 been summarlzed prevLously . Owing to the sixfold inversion axLs of symnetry Ín the molecule, there are only tl'o types of carbon-carbon bonds present.. The analysis 1s thereby slnpllfted conslderably and a ffnal constructfon of the tceane skeleton Èhat lnvolves the formatlon of a s lngle bond ls 1tmlÈed t,o one of the two clas s es of subs tructures (7) or (8) .

(7) (8) 5

Of these two posstbilltfes, substructure (7) appears more synthetically accesslble than substructure (8) sLnce, as O has been envLsaged befo..u , Èhe correct orient.aElon of the two three-carbon bridges fn the lat ter rutght be dlfficulE Èo assemble.

An analys is of the subs tructure (7) suggests that a II synthon for rlng closure would be an Lntramolecular alkylaElon 13 of the ketone (9) provlded the ruethylene carbon bearing a leaving group X has the endo- conflguraÈlon as shown.

(e) (10)

lt{ IÈ is generally accepted thar the synthesf.s of a symmetrlcal molecule ls norrnally bes E accomplished from precursors havlng the same synmeÈry elements comparably located. Thts pract,lce facllitates the interpretatLon of spectra, ln partlcular NMR spectra, and frequently leads to a more dlrect and conceptually s1'npler synLhesls than might otherwlse be the case. I.¡1th thls fn mind and by Èhe applfcaElon of a synthon slmllar to chat, suggesEed for the preparaÈlon of compound (lO), the ketone (9) mlght lEself 6 be derived from the lntranolecular alkylation of elEher of Èhe compound Èypes (11) or (12). Further.., examination of the problems as socf ated wi th the che¡nis t ry of the

o o X X X

H (11) (11)

H.. hl X X t{- H- X X ri H o

(r2) ( r2)

ke t one (11) has already been dlscussed at. l+ d T2 length ' whereas work lnvolvlng the preparation of Ehe t5 diketone (12) is comparatively recenE and warranËs furÈher LnvestfgaÈ1on.

The molecule (12) rnlght yteld, upon a sf ngle rlng closure, a mixture of the trlcycllc compounds (13a) and

( 14a) and Èhelr enantlomers (13b) and (14b). Although a study of a molecular model shows thaÈ Èhe molecule (12) fs 7 sufffclenÈly flextble Eo allow Ehe formatlon of both t,he

o o H

X ¡l o o (13a) ( 13b)

o l¡l o X

É o o

( 14a) (r4b)

trfcyclfc co¡Dpounds (13) and (14), the conformaÈlonaI analysfs of such a system fs somewhat complex and one cannot say r¡1th any cerEalnty thaE one dfrectLon of a1kyIaÈfon would be preferred over the oÈher. Subsequent rlng closure ls only possfble wlth Ëhe dlkeÈones (13a) and (13b) and rsould produce the tetracyclic dlketone (15). Thls compound, contaLnfng funcEfonallty fn Èhree rLngs, would be a precursor to derlvatlves, for example the dlol (16), whLch nfght exhlblt unusual non-bonded 1nÈeractfons, as well as lceane (1). HO

HO o ( rs) (16)

Slnce Èhe cycllzatÍon of the btcycllc ketone (12) must occur through the thermodynarulcally less stable enolate anion (17a) , s sul-Èable choLce of base and reactlon condftlons would be requfred to prevent Ëhe formatlon of the thermodynamlc enolate anLon (17b) whlch would gLve rlse to an equÍllbrlusr mixture of the Ísomers (12), (18a) and (18b). However, as only lsomer (12) can react

o o-

H 7 H 7t I T I x X 8a

6 x 4a 6 I H É ù ú 6t o o

( 17a) (r7b) 9

o o X X o o o

o X

(i2) ( IBa) (l8b)

further, via enolate (L7a), to produce the diketone (15), the equillbrfun rnight be shlfted towards the rlng closed products (14) and (15) 1n whfch ca'se equillbratlng condttions may be feasible* and the st.ereochernistry at the rlng Junctlon may not be crftlcal. As thls latter point ls uncerEal-n and as crn all-cis, alI-syn (acas)

s tereocheruls t,ry wlth respect to the hydrogen atoms at Cqa, Ct, and ,U is requlred for Lnternal alkylation, âû r", attempt Ìras made Èo devLse a scheme for Èhe synthesis of a key lntermedlate whtch lncorporaÈed both of Ehese sÈereocherufcal features. the acas arrangement 1s l8 unfavourable Èhermodynamlcally and r¡ould have to be prepared by a process controlled kineEically. The Diels-

* AlkylaEion of enolate (17b) f roro CU, to C5 roight also

be a competlELve mode of rlng closure and would generaÈe a

norbornene sys tem . Howeverr Ehere does noE seem Èo be any

precedenL for thls type of reacElon ln Èhe t7^ I1Èerat.ure a The alterna tlve dfrecElon of alkylaElon

from Ct" to C7 1s les s Ifkely as Èhls would produce a four membered rlng although see refs. I7b-d. 10

Alder reactionl9 1s a general ruethod for Èhe productlon of a cls-fused rfng JunctLon. Thus a sultable twelve-carbon precursor (21) t,o Ehe key lntermediat,e (L2) night be

constructed by the cycloaddltf.on of a diene (20) to Èhe dienophlle benzoqufnone (19), (eq.1).

x r ( er.1) X -+ Ét o o (re) (20) (2r)

I.Ihen vier.¡ed side oD¡ a molecular model of compound 20 (21) appears C-shaped . Catalyric hydrogenation, whfch usually delivers Èwo hydrogen atoms cfs to the less hÍndered slde of a multtple bond, might add hydrogen to t.he outer convex of the tetrasubstltuted double "1d"2t bond, âs well as to the conjugated double bond of the enone (21) to gfve the desired ketone (12). The reduction of the adduct (21) would be expect,ed to proceed by lray of the saturated ketone (22) slnce the rate of hydrogenaÈ1on ('r:cr¡1^g*te.t) of a dlsubs Eltuted ¡ double bond is considerably greaEer 22 than t,hat of a t,et,rasubs Èltuted double bond 11.

o H

(22)

In su.mmary, the strategy for the construcElon of the lceane skeleton nas dtvlded fnto four stages: the synthesis of the diene systems (2O), the Dfels-AIder reactlons between the dienes (2O) and benzoqufnone (19), the reductLve elaboratlon of the adducts (2L, to a key LnÈermedl.ate of the type (12) and f1na11y, rhe ring closure of the ketone (12) to the Lceane derlvative (15).

The dfenes (20).

Flve dienes (20 a-c) lrere selected for study. The dfenedlbrornlde (20a) has been prevlously prepared t2.

(a), X = Br CH¡ Br r (b), x = r B r (c), X = OCOCHg cHa (d), X = OH (20) ( 20e) (23)

23 a respectively in 537" and 7L7" yield by Èhe Èf.n-copper and zLnc-copper coup1.23b'" reductLve debroml-natlon of the tetrabronl-de (2Ð2) Before ful1 experlmental detaLls nere avallable, dlfffculties that, were encountered in attempts to reproduce Èhfs work led Èo Ëhe development of an alternative procedurel5 '25

Reductfve-ellruinatfon of broml,ne from Èhe Èetrabromlde (23) by means of excess poÈassLum lodfde fn acetone was f ollor¡ed by the Lmruedlate addl tion of lodf ne bronide to the generated dlene. However, 1n the Presence of sodium thlosulphaÈe, the halogen was reduced and the relaEed dlene (2Od) was formed 1n 951¿ yteld. The dlbrornlde (2Oa), which should be produced lnltfally, could not be fsolaÈed sfnce 1t lras converÈed entfrely to Ehe dltodo-derl-vatÍve

(20b) 1n the presence of the excess lodide f.on. Wfth a catalytic amount (102) of todlde 1on, the reacÈion was slor¿er and a mlxture of dibromo- and dìtododlenes was obEained.

The dlenedilodlde (2Ob) was charact erLzed by I resonances 1n Èhe H Nl"lR specEri¡m aÈ ô 5.50 and 6 5.68 13.

PPM, assf.gned to the vf nyl hydrogens, and at ô 4.16 PPM whlch were assLgned Eo the ¡uethylene hydrogens. The IR spectrum shou¡ed olef ln.lc absorptlons at 3100, L540 and 900 I cm These daEa are slmllar Èo those recorded for Èhe 23b," dlbromlde (2Oa) Further characEerl-zation was noÈ carried out as the pure diene (2Ob) was Ilght and heat sensitive. Although the compound polyroerlzed readily in the solld state, 0.1M ether solutions of rhe dltodide (2Ob) were sÈable for several months aÈ 0"C.

Treatment of the dibronide (2Oa) with sodlum acetate Ln refluxfng acetlc acfd has been reported Eo glve the 23b," dfaceÈate (2Oc) fn moderate yield . srnirar acetolysfs of the difodide (2Ob) resulted only Ln the productlon of polyroer. The dLenediaceÈate (20c) could be prepared under nllder condlÈlons by the reactlon of the dltodfde (2Ob) wtth sllver acetaËe in acetlc r.ia'l or more 25 convenlently, 1n acetonf.trile . In thls wâyr an overall yield of 75-857" of the diaeeÈate (2Oc) fron che tetrabromlde (23) was obtalned.

The dfenediol (2Od) was readily obEalned by base hydrolysls of Èhe diacetaEe (2Oc) according to literature 23b, procedures et26 However, lsolatlon of the diol (2Od) ÍIas hampered by f ts appreclable solubf lity ln $rater. The materlal was even soluble fn saturaled brine. In an early 26^ reference,- a conClnuous exÈracElve work-up !¡as requlred to recover Èhe compound . Prlor Eo Ehe publlcat lon of a 23^ recenÈ meEhod - 1t was found Èhat good yfelds of Èhe diol 14.

(20d) could be obrained by saEuratlon of the reactfon mixture wlth sodlum chlorfde - followed by extractlon with Èe t rahydrofuran .

The known dienedlester qzo"¡28 üras arso prepared by an extenslon of the reductive ellmfnatLon proc.d,r..2, descrlbed above for the synthesfs of Èhe diiodfde(2Ob). Allylic bromÍnatf on27 ^,b of dlnethyl 2 ,3_diruethyl butenedioate (24)27 c wlth N-bro¡nosuccf nf nf de

COOCH3 Br COOCH3 Br oocH3

B coocH3 coocH3 cH3ooc (24) (2sa) (2sb)

gave an equal amount of (E)_ and (z)_dimethyl 2,3_ bfs(brouonerhyl)burenedioares (25a) and (25b), whfch courd 'O,.e separated by chromaÈography. When sub jecEed to the fodÍd"/thfosulphate reagent, the nixture of bromoes ters (25) underwenÈ debronfnatr-on to produce Èhe dlenedlesÈer (20e) Ín B5"r yietd. The preparaÈ10n of rhe dlesrer (20e) fn r"t 1s shorrer 'nTr and hlgher yfeldlng than exisrfng routes to thfs compound.

The Dfels-Ald er Reactfo DS.

The second s Èage of the synthes ls of the Cetracycllc compound (f5) lnvolved Èhe cycloaddltfon reactlons, (eq. l), beÈween the foregofng dienes (2O) and benzoquinone 15.

(1f¡ to produce adducts of the type (21).

o H T c00cH3 X (a), X=Br

(b) , X=I

I (c) , X = OCOCHg H É COOCH3 (d), X=OH o (2r) (21e)

Although a synthesfs of the adduct (21a) is descrtbed T2 1n the 11Èeratur"t'U, åttempt,s 1n this Iaboratory to repeat the reaction nere unsuccessful. Instead, a hlgh molecular eretght polymer, presunably due to preferentlal

polymerfzatfon of the df.ene (2Oa), was claLmed as Ehe maJor product. A mlnor product, obtalned 1n very low

OH OH

coocH3 X ("), x = Br (b), x = r (c), x = oCoCHg coocH3 (d), X = OH OH (26) OH (26e)

yfeld appeared , from spect roscopic evÍdence, Èo be Èhe hydroqufnone (26a) derlved from enollzatlon of t,he adduct (21a). Under condlttons slmllar to Èhosc descrtbed for t6

Èhe preparatlon of Èhe adduct (21a), the dlenedflodide (20b) also fatled to react w"rth benzoquLnone (19) and more vlgorous conditlons caused extensive decomposltlon of the dfene (2Ob) . Furthermore, none of the hydroqulnone (26b) was detected.

The reaction beÈween the dienedfacetaEe (2Oc) and benzoquLnone (19) to gfve the adduct has been achieved l5 prevfously . The present study hes 1ed, af Ëer a great deal of experimentatLon, to reproducfble results . The reactfon ls successful only if precaut.Lons are taken to rfgorously purffy all reagents before use as the product (21c) has a uarked propensLty to aromatLze to the 15 t hydroquLnone (26c) Nevertheless, even though H NMR analysis of the crude reactlon product normally tndfcated a quantfEatLve converslon to the deslred product, the actual lsolated yietd of the adduct (21c) anounted to only 68i¿, fn splte of the precautLons Èaken. A qulck workup procedure is necessary Èo avoLd a complete conversion of the producÈ to Ehe hydroqufnone (26c). The adduct (21c) fs more stable ln the solld sÈat,e than 1n solutlon and can be stored as such at 15oC.

The structure of compound (21c) was esËabllshed by the I followlng daÈa. The H Nì4R specÈruro showed resonances at

ô 6.75 ppm for Ehe Èú¡o vfnyllc hydrogens and at ô 2.10 ppm for the slx hydrogens of Ehe aceLate groups. Two multlplets centred aE ô 3.25 and 6 2.43 Ppm were asslgned t.o Ehe meÈhine hydrogens adjacent co Èhe keEone groups t7.

(Hq and the neighbourl-ng al1y11c rnethylene hydrogens dt- I d^ ) (HS respectlvely. Although the compound is achiral rg ) due to lnternal compensatlon (neso), the meÈhylene hydrogens on the carbons bearlng the acetaEe grouPs are nevertheless diastereotopic and the resonance for Èhem appeared as a very distorËed AB quartet cenEred at 6 4-75 I ppmr J = L2 Hz. These II NMR values are similar Eo Èhose 23: given " for Ehe bromoadduct (21a). In accordance with the synmet,ry of Ëhe molecule, the broadband decoupled l3 C NMR spectrum cons 1s ted of only efght llnes for the total slxÈeen carbon atoms. AbsorptLons rùere observed Ln .I the IR specÈrum at 1735 cm for the esÈer functions and aÈ 1690 cm-I for the unsaEuraÈed ketone groups.

The cycloaddition of the diol (2Od) wiÈh benzoquinone (19) proceeded readily to afford the adduct (21d) r¿hich, by Judfclous choice of solvenE, crystalllzed Ín 84ll yle1d, and analytically pure, from Ehe reactlon nLxÈure- In thls wây, no hydroquinone (26d) was formed . The sPecÈraI characterlstlcs of the diol adduct (zld) were slmflar Èo those of the dfaceEate adduc t (21c) . Notable dlfferences were Èhe replacenenÈ of acetate peaks by hydroxyl peaks 1n I the H NMR and IR spectra.

The dlenedles ter (2Oe) underwenÈ a DfeIs-Alder reaction

r¿L.th benzoquinone (19) to afford the adduct (2Le) in 7L7" r5 yfeld unaccompanLed by any hydroqufnone (26e). The I lI NMR spectrum displayed a Ewo hydrogen vinyllc resonance at ô 6.83 ppm (llz ¡ ) and a six hydrogen resonance aE 18.

ô 3.83 ppn for Èhe Ewo carbomethoxy groups. The remainlng hydrogens appeared as ¡uultlplets cenÈred at ô 3.83

(H,*^ ) and at 6 2.73 (Hs ) ppn. Absorptions ln the 4, B^4 , s IR specErum at 1730 and 1690 crn-I were consisEenÈ wlth the presence of unsaturated ester and ketone groups t¿ithln the molecule.

The key LntermedÍate (12).

The elaboratfon of the adducts (2L), descrlbed above,

to a key lntermedfate of the ÈyP e (LZ) constftuted the

thi rd stage ln the synthesis of Èhe teEracyclfc compound (ls).

HydrogenaÈion of the dÍacetate adduct (2lc) in 957" eEhanol over 5% rhodlu¡n on carbon catalyst at ambienÈ temperaÈure and pressure afforded a ketoacetat.e (v = 1730' _t I710 cm. ) resultfng from the uptake of one equivalenE of I hydrogen. However, a spectral comparlson with Ëhe H NMR 29 daÈa of Èhe ketone (28) revealed EhaE Ehis subsÈance was actually the trans isomer (27). Hydrogens HZ 3 of

T hl ococH3 2 8a 4a 3 ococH3 5 o (27) (28) 19.

B hl ljl 2 ococH3

3 OCOCH3 A 5 ri (2e) (30) ketone (28> occur as a singlet at 6 2.72 pPm and those on carbons 4a and 8a appear as a mulEiplet at 6 2.59 PPxo. By comparLson, hydrogens ,r of the reductlon producE (27> r, appeared as a singlet aÈ 6 2.77 ppxo whereas hydrogens

HU.rg and tt were lndistl-nguf shable and occured as a " ,t multiplet cenÈred at, ô 2.50 ppn. On the oÈher hand, reductf.on of the dlaceEate adduct (21c) wtth zLnc Ln aceÈfc acld gave the fsomerLc ketoaceEate (29). Evfdence that the cls stereochenlstry had been malntaLned tras provided by comparison of the spectrum wlth EhaE of the 29 ketone (30) , whlch !üas prepared by reductlon of Èhe

I8-d enone (31 ) with zinc 1n aceELc acld . In contras t co (28), hydrogens ,r of ketone (30) the trans Lsomer rt resonaEe as tüto peaks at 6 2.77 and ô 2.80 PPm whereas Èhose on carbons 4a and 8a appear as a multtPlet at 6 3.f7 ppn. The correspondlng hydrogens ,rrt and Hu",B" ln Èhe cfs-ketoacetate (29) are sfEuated respect,lvely at 6 2.77 ppm as a poorly resolved Ëwo peak s lgnaI and as a mult fplet at ô 3 .05 ppm . o r

É o (:t¡ 20

Posslbly traces of acld formed by hydrogenation of resfdual metal salts fn the catalyst acted to compleÈeIy LsomexLze the lnlttalry expected cfs-ketoacetat e (29 ) to the trans fsoner (27). Curiouslyr tro hydroquinone (26c) nas forrued under these condf È lons . ThLs Lnprles Èhat Èhe adduct (21c) rnus t be reduced f Írs t bef ore being Ísouerf.zed Ëo the Èrans keÈoacet,ate (27).

EfforEs Èo hydrogenaÈe Èhe ÈetrasubsElÈuted double bond of efther the cfs or trans-ketoacetates (2?> and (21)ce<|. were unrerrardlng. The double bond proved very resfstant towards reductfon under a varfety of condÍtlons, (TabIe 1). tlfth more forcing condl.tLons, a mtxture of products

$taE- obtalned that appeared to be derlved bo th from reductl.on of the double bond wtth concoml,t; ant hydrogenolysfs of the allylfc acet groups as well as reductlon of the ketone groups. Resonances at ca. ô 0.9, I 1 .6 and 4.0 ppn 1n the H NMR spectra of the reducÈ1on (P.r.o.) 2r.

Table 1

Condltlonsa for the attenpted reductlons of

compounds {27 ) and (29r.

CatalysÈs Io7" Ptlc, Pr02 , sl"Pd/c, 5ZRh/c, sZRt-lAr203 r s"AF:nlSi02b , S%Ru/Cr

Ru02 , 1%Re/sfo2b , 4%rrl.A'1203b , Zzr.t-Lu(1 :1)/SrOrb, 2it1t- Au(3 :1)/S10zb, LZPt-Re(1 :1)SrO2b

Solvents acetlc acldr úêthano1, ethanol, ethylaceCate, tetrahydrofuran, benzene.

P re s sures aEmospheric pressure, 60 psf, 1000 pst.

TenperaÈures anblent Èemperature, 25" C.

(a) not all possible permutatf.ons were examlned. (b) ref. 30. ))

mixtures were respectively atËrlbuted co the presence of saturated and vlnyllc rnethyl groups and a meÈhlne hydrogen aù, a carbon bearlng oxygen. Absorptfons characterlsÈl-c of both carbonyl and hydroxyl functfons were observed ln Èhe IR spectra. The use of nonpolar solvents such as 3t- 3rb benz ene d or low temperatures is reporEed to reduce the extent of hydrogenolysts aÈ allyllc positions. Possfbly these modffications were effectÍve 1n preventing hydrogenolysfs buÈ they fafled to afd ln the reductlon of the olefinic bond.

A nethod ot,her than catalytic hydrogenaÈ1on, therefore was necessary for the Eransformation of the tetrasubst.ituEed double bond lnto the cl-s stereochemlstry requfred ln the key lntermedlate of the type (12). Posslble methods lncluded epoxidaÈlon and cyclopropanatLon. However, l-n the formation of an epoxlde rfng, two additl-onal sites for poÈenËial alkylaÈion are Lntroduced lnto the key lnLermediaÈe (32). Four modes of intramolecular alkylat.ion are now possible which could glve rlse Èo a variet.y of rlng closed products. For Èhl-s

o H I X )o o I H (rz¡ 23.

reason, epoxidatlon was consfdered an unsultable solution Eo the fetrasubsElEuted double bond problern and met.hods lnvolvlng cyclopropanatlon were lnves tigaËed in pref erence.

Phenyl( trihalomethyt)ruercurials react, under neuÈral conditions, wtth oleflns Eo give gen-dlhalo 32 -cyclopropanes . This procedure ls applicable for olefins cont.alning functLonal groups sensltlve to basic reagents and for weakly nucLeophiltc oleflns, e.g. ethylene and tetrachloroeÈhyIene, (provided that the alkene is employed fn vast excess). The cis-ketoacetate (29) reacted only sluggishly with large l-ncremental amounÈs of phenyl brornodf chloromethylmet..r.rt'" in refluxlng benzene solution and Èhe reactlon became fncreasingly slower as s Earting materlal sras consumed . Evidence that some carbene addition to the double bond of t (2g) had Èaken place was obÈalned fron the NMR spectrun " of the crude reacElon mfxture. A new resonance for the rne Ehylene hydrogens adjacent Eo the acetate groups was present 0 .3 ppn upfleld from iÈs orlglnal posiEion.

TLC analysis indtcated that one lsomer had been forued predominately. The lack of reacElviÈy of the oleflnic bond towards Ehe addf t, lon of dtchlorocarbene lras thought to be, fn part,, due Eo the electron wlthdrawlng effect of the acetate groups. ConsequenEly, Rolecules conËalnlng oEher types of allylic funcElonal groups were prepared 1n order to lnvesElgaEe Ehelr reacÈlons wiEh dichlorocarbene. 24

Solvolysis of either of Èhe ketoacetates (27) and (2.9) in 33"/" hydrogen brourid,elacetlc acid produced the trans- I ketobronide (33a) Ln 8L"/" yÍeld . In the H NMR spectrum, acetate res onances were absenÈ. and the dlasEereotoPic

(a), X = Br X (b), X = OH

H o (33) rnethylene hydrogens, or the carbon atom bearing bromfne appeared as a well resolved AB quartet at ô 4.05 and 3.89 ppn¡ J = 10 Hz. That cls-Frqns LsomexLzation had occurred rras lnplied by the presence of a large broadened singleÈ at ô 2.58 ppo (H's4rr5rBrB. ) and a sharp singlet at 6 2 .7 5 ppn dl-agnos Elc of Èhe methylene hydrogens (Itz 3 ) adjacent Eo the keÈone group. A sma1l slnglet at ô 2.35 ppxû and weak resonances fn the arouatfc region of I the H NMR spectra of Ëhe crude reactlon product were always noÈiced. These nere thought to be a consequence of the formation of small amounts of Èhe naphthol (34), as lllustrated 1n (eq. 2).

The ketobromlde (33a) was even less reactive than the keEoacetate (2g) Eowards boÈh Ehe crlchloroseÈhy132 - and t Èhe more reactlve bromodlchloromethylphen.trl mercr,rryt " reagents. Startlng materlal tras recovered vlrÈualIy unEouched 1n boÈh cases. Art a11y11c f,unctlonal group wtth a greaEer elecEron denstt.y than elEher Ehe bromo- or H+ + OAc Br r _ÐBr repeaL OAc OAc

O e7) or (2s) o O (33a)

OH o N) + (Jl (eq'2) s- 0Ac H+ o o

OH H+ o H ) o H Ê

H + \-4 )* - H OH (3+¡ H o H 26. aceÈaÈe groups was therefore needed Èo lncrease the

nucleophiliclty of the teErasubstituted double bond. A hydroxyl group seemed a likely candidate for Èh1s 33 requlrement .

Hydrolysls of Èhe ketoaceEates (27) and (29) under alkallne conditlons caused ext,ensfve deconposiÈLon. Even wlth reagents as rulld as meÈhanolic potassium carbonate, the reactfon mlxtures dfscoloured rapidly and no useful maÈerlal could be lsolaÈed. This problero was probably due to Èhe unprotected keÈone groups undergofng undeslrable

polycondensatlon rectlons . In fact 1 r 4-cyclohexanedfone also decornposed in alkallne solutlon. Consequently, thls observatlon lent doubts as to whether Lntramolecular cycloaddition of a trans-key Lntermedfate (18a) under equlllbratfng condlElons üras feaslble. Perhaps under conditlons approachlng fnflnlte dflution, thls potenElal problem might be avoLded.

In contrast to basic media, solvolysis of the ketoacetates (27) and (29) in acldic aqueous soluÈ1on

cleanly provlded the Erans-ketoalcohol (33b) 1n 767" yteId. An absorption 1n the IR spectrum at 3400 was "*-t lndicatl-ve of hydroxyllc funct,lonaltty and the absence of _l a peak at 1730 cm Ln the IR spectrum or aE ca. ,S 2.1 pp. I ln the H NMR spectrum conflrrned Èhat the ester group had

been removed. The correspondfng cls-keEoalcohol ( 35 ) r¡Ias obEalned by Èhe reducË1on of Ehe adduct (21d) wtth zlnc 1n

acetlc acld. Both ketoalcohols (33b) and (35) could be 27.

OH ù (3s)

t easlly dlfferenElated on Èhe basls of thelr H NMR sPectra

Ln a manner s 1nllar to t.hat descrlbed for the ketoacetates (27) and (29).

Due to the poor solublltty of these comPounds fn common organLc solvents, reactions wlth elther ketoalcohol were difficult Eo conduct. The compounds were quite soluble in protlc solvents, Lncludlng !¡ater, buÈ almosE totally Lnsoluble ln less polar solvents such as aceÈone, teÈrahydrofuran and ethyl acetate. Thts greatly restrlcted Èhe types of reacÈ10n and workup condltions thaE could be used. The cls-keÈoalcohol (35) proved to be apprecfably more soluble Èhan the rrans-isomer (33b) and furÈher r¡ork !¡as theref ore carrf-ed out wlth this cotnpound.

By means of specÈroscoplc evldence, lt rdas shown that caËalyctc hydrogenatfon, under a varlety of condlElons (TabIe 1), of elther Ehe cls-ketolcohol (35) or the adducÈ (21d) fafled Èo remove Ëhe EeErasubs clEuted double bond . Dependent upon Èhe actlvfty of Èhe caEalyst used, aEtemPÈs 28.

at the reduction of Ehe adduct (2fd) ylelded only varying amount.s of starElng mat.erial, hydroqulnone (26d,) nonoreduced products (33b) and (35) and compounds of unknown composLtlon, some of. whlch were possibly derlved from hydrogenolysls of Èhe allyIfc hydroxyl functfons.

An explanat.ion for Ehe fallure of the olefLnlc bond to undergo reductlon is not readfly apparent. IlydrogenaElon

of tetrasubstltuted do ub Ie bonds ls not well documented ln the llterature and the najority of subs ÈraEes 34 descrlbed have either straLned or conjugated double bonds which are t,hus actlvated t,owards attack. Endeavours to effect electrophllfc additl.ons of carbenoids (e.g. 33^o 33r- 33^- PhHgCBTCI2 , cHzr 2/za/ cucl ' or CuClz ) were also frus trated noÈ only by the Lnertnes s of the teErasubstltuted double bond but by the Lnsolublllty of the ketoalcohol (35) in solvents tha t were compattble wLth the reagenÈs.

For convenience Ln handltng, the alcohols (21d) and (35) were converted, under neutral condiElons to Che ketal dertvarives (36) and (rr)T:r'ñiY.nough these compounds had acceptable solublllty properÈies, thei r behavlour towards

furEher addiË1on reactÍons was as unbecoming as thel r

parent compounds .

AÈ thls sÈage, 1t lIas clear EhaÈ the constructlon of a

key lntermedlate (L2) from any of Ehe adducts (2Lc) and (21d) ras noÈ feaslble. Since Èhe allyllc substttuenE 29.

ï o r

É{ o È o (:o¡ (:z¡

appeared Èo suffer hydrogenolysts before the adjacent double bond was reduced, a substftuent was needed that was cap ab le of wfÈhstanding the forclng conditlons required for the reductf.on.

The diester adduct (2Le) was cons fdered a suf table subs t rate r¡h I ch offered a potentlal solution to thts df lemma . The saturaÈed ketoester (38) r¿as obtafned by reductfon of the adduct (21e) with zL¡c 1n aceÈfc acLd. As yet, efforts to reproduclbly hydrogenate the

o lìl COO CH 3

Ét coo cH 3

( 38)

unsaEurated esEer molety 1n the presence of comnercial catalys cs have been unrewardlng and the prepara È fon and 36 use of more Tele,dtive cataly" t" remalns t.o be underEaken. 30

I.2 In the precedlng sectlon, a Diels-A1der reacÈ1on e¡as used Èo construct the S_lå-fused rlng junctlon of the key LntermedfaÈe (12) . However, thts f.nvolved Èhe generatlon

of a tetrasubstiEuted double bond whlch could noE be removed 1n a satl-sfactory manner eÍ ther by catalytlc

hydrogenation, without concomLt anÈ hydrogerrolysl-s of Èhe allyllc functfonal groups, or by reactlon wtÈh electrophll 1c reagents . In a ques t, to avold this situation, Lt r{ras considered thaÈ Ehe requlred Sta- substltuÈion of the side groups nlght Lnstead be constructed by a Dfels-Alder reaction (eq. 3) . This

f.g fg

T X X (eq.3) +

X --{> É{ g fg fg = functional group

type of reacElon would sc111 l-ntroduce a teErasubsEiEuted double bond but if the sLEe of unsaturaÈ1on r^ras made parÈ of an arornatlc or con jugaEed system, alternat,Lve ¡nethods of reduct,lon oÈher Ehan hydrogenaÈlon (e.g. by dlssolving metal or electrochemical means ) would be avallable parÈlcuIarly 1f Èhe stereochemlstry aE the ring junctlon

rr¡as noE crltlcal (see p. 9 ) . 31.

37 A1t hough the o-xylyle ne ( 39 ) has been generated ln

sLtu from the dlbronide (42, by rhe acrlon of zlnc l_n dimeÈhyl forrnarufde and lts reactfon r¡lÈh certaLn dlenophfles studied, the reactLon with ¡nalelc anhydrlde

(40), has not been documented. The dlbroulde (42) was

OCH3

ocH3

(42)

prepared ln five steps from commercfally avaflable 2 13- dlmethyrphenol following slightly nodified llrerature

procedures (see experlmental). By the use of a

3 0cH 3 r

(eq. 4) + --+ A

ocII3 OCH3

( 3e) (40) (41) 32 procedure lnvolving conditlons approaching ínftnit.e ,p¡ll r+sgcct t', (¡ï) 3 I dllutlon¡ l¡hich ls reported for a relaced system , the cycloaddltion of Èhe o-qulnodimethane (39) wiÈh malel-c anhydride (40) was achleved and provlded Èhe adduct (41)

f n 657" yteld , (.q. 4) .

I Absorptlons at 1860 and 1790 cm Ln the IR spectrum of adduct (41) lrere characteristlc of an anhydrlde I f unctlonal group. The II NMR spectrum showed tr¡o singlets at 6 6.67 and 3 .73 ppn whLch r¡ere dlagnos tf c f or a dirnethoxybenzene resLdue. The remalnlng nethylene and methlne hydrogens appeared as multlplets at higher field between ô 3.4 and 2.4 ppn. In agreement wlth Ehe symmeÈry of t.he molecule, seven lines srere observed ln the tta broadband decoupled NMR spectrum. The appearance of a molecular lon aÈ ru/e 262 Ln the mass spectrum ltas consistent wÍth the assLgned foruula of the adduct (41).

SubsequenÈ to Èhis work, a more direcÈ ¡¡ethod for produclng 2r3-disubstltuted-1 r4-dimeÈhoxybenzenes appeared t 1n the lite."a,rr"t . In addtt.Lon, a meÈhod f or carrying out reõÉEÍons of the type (eq. 4) with Èhe aid of 40 u1Ërasound was publtshed . Appllctlon of eprch of Ehese technlques to Èhe synthesls of adduct (41) could well Lmprove the overall yteld of the sequence but this has not

been fnves Ëfgated .

ReducÈlon of Ehe anhydride adducE (41) wirh llrhium

aluminlum hydrfde afforded the diol (43) in almos È 33.

quantirative yleld. The absence of bands in the carbonyl _t absorpÈion region and an absorptfon aÈ 3380 cm Ln the IR spectrum clearly dernonstraÈed that Èhe desired transformaÈ1on had taken place. Further conflrmatlon of the presence of the CH2 0H noÍety ln structure (43) was I given by the exÍ s tence in Ehe H NlfR spectrum of a doublet cenEred at ô 3.57 ppn and a broad slnglet at ô 4.23 ppn which rùas excl'rangeable with DzO. In order to facilitate

OCH3 OCH 3 H r I H

OH ll ù

OCH3 OCH3 (43) (4+¡

the handllng of the d1o1 (43) ln furÈher transformat ions , the compound was converted into Èhe ketaL (44) in 777" yteld by a copper sulphace cataLyzed transketalfzaÈion 35 reacElon wlth 2, 2-d lrne thoxyp ro pane Resonances at

ô 1.3s, L.26 ppm and ô 101 .0, 25.O ppm f.n the respective I l3 H and c NMR specrra of the keÈal (44) verlfted the

Pres ence of Ehe C( CH3 ) z9r oup .

The compounds (43) and (44) are clearly related to the key lnEermedlaEe (12) and can be considered Èo be masked 34

f orms of f t. I^Ihat ls needed at Èhls stage ls a change ln Ehe oxidatlon 1evel of t,he aroma Elc ring to that of the dlketone (L2) . An aÈ tempt Èo reduce Èhe ketal (44) with

s od iun and e thano I tn 1 tquid ammonla re t urned only starEing materlal. A survey of the 1lÈerature revealed that electron rich aromatlc compounds are dlfflculE to 4I reduce wl Èh alkali metals Ln Èhf s ú¡ay . The l+t reduction of l r 4-dimethoxybenzene, for example, required

Èhe use of llthium ln propylanfne contalnlng t-butanol aÈ

0o C . Thus such reductlons requlre a metal of hfgh reductLon poEential, an amine solvenË Ehat allows the reductlon to be carried out aE a htgher temperature than the bofltng polnt of ammonla and an alcohol that reacts s1owly wlth the meÈal but stl11 functions as a proton qì' source. Even though the reported redueÈion of 1 r 4- dlmethoxybenzene ü¡as shown to be reproducible, under these condf.tf ons, the ketal (44) r¡ras recovered vtrtually unehanged. 0nly when Èhe reactlon was conducted aÈ room Ëemperature over a perlod of a week was any appreclable amounÈ of reductlon observed. The reslst,ance of the ketal (44) to reductlon 1s qulte surprlslng. IIowever, since the work described Ín this secEion q¡as begun tor.¡ards Èhe end of the t'i¡ne available for sEudy, furEher dlagnosls of thls problem could not be completed. Perhaps the development of an alternative rnethod of reducÈ1on 1s requlred Ehat 1s more amenable Èo the preparaÈ1on of a key fnÈermediat,e (12) efficlently fn synthecfcally useful amounts. Procedures lnvolvlng elecErochemical reducEion or catalytic hydrogenaÈlon of elther the dlol (43) or ketal 35

(44) have not yet been studled.

In summary, the foregofng methodology has shown thaE the consËructlon of the fceane skeleton, based on lntermolecular Dlels-Alder reacÈlons (eqts I and 3), has lnvolved the formatlon of a tetrasubsEftuted double bond or an aromatÍc systen fn compounds that have so far Proven dffficult to elaboraÈe to a key lntermedLaÈe of the Èype (12). In the followlng chapter, a successful alternative to the above approach, based on an lntramoÌecular Dlels- AIder reactfon Ís presented that has allowed the preparatlon of a range of lceane derlvatLves. 36

CHAPTER TI^IO 37.

1.1 It was dlscussed fn Chapter 1 that a sEepwfse rlng closure of the key Lnteruediate (12) nlght yfeld the undesfred nonoalkylated producEs (14a,b) by the bond formatlon C2 + C6' or C3 + C7' as well as the desired Lceane derfvatfve (15) resulting from diaIkyIaElon. If the preferred roode of ring closure, through C2 + C7' and

C3 + C6't could be achieved concurrent ly, then thl s poEentfal difffculty would be avolded.

o H I r H.. 2 2 X 3 x H- 3 X É tl 6r H o 6t ( 12) (12)

The capaclty to form two bonds sfmultaneously has made fntranolecular cycloaddltfon reactfons very effective for the synchesfs of a large varlety of polycycllc t+z compounds. The applfcatlon of Èhls nethodology to the problem fn hand r+ould requlre the consEructlon of a triene of Ëhe Eype (45) . !{owever r cycllzatlon of the molecule

(45) would lnvolve the formatlon of 4in" p.oduct (46) whìe-h contalns a EeÈrasubs Èltuted double brfdgehead double

bond. Although thls sÈrucÈure can be consldered Èo have a

1n etghÈ membered rlng and a trans-double bond an "f"fUu tr3 type of zero brldge olefin , a molecular model tndtcates 38

(4s ) (46>

that a greaÈ deal of straln r¡ouId be present 1n Èhe molecule. Sfnce the Dfels-A1der reactÍon ls usually reversfble, t9 the amount of l-cene (46) at the equLlibrLun posltfon of thls reactLon would be expected to be neglfgtble.

An extensLon of the molecular framework, âs shor¡n Ln Ehe trfene (47> would avold the problen of a brtdgehead

H H H I I

H I I H H H

(47 ) (47)

double bond. An examfnatlon of molecular uodels suggesÈs Èhat the proxlmlty of the dlene and dLenophlle ends of the molecule (47> should allow favourable overlap of orbftals 39

for cycloaddl t lon Èo Èhe hexacyclfc compound (48). &tlo*-4 b ,1 R.-f{,t.. clalooralion, Cleavage of the ethylene brfdge 6 woul d then aIlow an alternatfve synthesls of the dlsubsËftuted lceane derlvatLves (15) and (16).

(48) ( 48)

of partlcular utiltty for Èhe PreParaËfon of systems contalnfng a cyclohe.xa-1 r 3-dlene and a sultably dfsposed double bond are the Diets-Alder reactlons of c Pyrone qqa'b, cycropentadfenone"tu"' rrrd their acetalsh4t'd'8 and f thfophene dloxfd.sbh ", wfth appropriaEely substltuÈed bisdienophiles. The btsdlenophile (49) was consldered Èo be an lnapproprlate precursor to the requÍred ÈrÍene (47) as fCs addtÈfon to any one of the above regenerable dlenes would probably result 1n the productfon of the qþ-antt- cls fsomer of the type (50) sLnce epproach of the reagent would be expec.t to cone from Èhe less htndered convex face of the molecule (49) ln accordance wlth the t{5 s Ee reo s e 1e c È lvf Èy rule s of the Dlels-Alder reactfon- 40

H H H I !

I A H H (4s¡ (50)

Cycloaddition of a regenerable dl-ene unf t to the trlene (51) fs a more aÈtractl-ve proposltlon as not on 1y l+6 1s thls compound readily avallable from naphthalene but a l so 1È l-s p lanar and therefore free fron stereochenLcal

H X I (a), x = H (b), X = C1 I H (s1) (sz¡

a¡oblgufties. The product (52) has three Èypes of unsaturatfon whlch chenlcally, one ntght be able to dffferentiate between. Under sultable condftions, an electrophfllc reagent would be expecEed Èo add to the most electronrLch posltlon, the ÈetrasubsLfÈuted double bond and, as fs generally found wfth cls-fused oct,allns (cf p 4L.

10), the orientatlon of additfon should agaln be from Ehe Iess hlndered convex side of the molecule (52). If the electrophil i 1c reagent fs bldentat.e, the resulÈant triene (53) would have the necessary all-ciq, all-syn stereo-

H I H..

I H

(s 3) (s3) (s4)

chernfstry for internal cycloaddition to form the polycycle (54) from whlch subsequently a teÈrafunctLonaLJ-zed l-ceane derivat,ive mtght be formed.

An inves Elgatlon of Èhe reactlons of fsotetralln (51) tslËh two readlly avaÍlabIe regenerable dfenes was noE very successful . a -Pyrone falled to react and 1 r 1-dimethoxy- 2 r3,4,5-teÈrachlorocyclopentadlene gave a mfxture of produc ts whlch appeared Ëo be derl ved from mono- and diaddltlon reactlons as well as aromatLzatlon of Ehe t des lred produc t ( 55a) . Thi s was evldent from Èhe NMR " spectrum of the crrrde reaction mfxture whlch showed both olef lnlc and aromatlc resonances. l.Ihereas the diadducÈ

(55b) could be easlly separaÈed from Ehe mixture on Èrituratfon with petroleum ether, separaElon of compounds 42.

(55a) and (55c) hras dlfflcult and could only be achleved on an analytlcal scale by reverse phase HPLC.

CI ct

H H cl I cl I

H¡C H o OCH 3c 3 ct I cr I H H

CI CI CI (55e) (55a) ct H I H cr CI

H c OCH 3 -ocH3 3 cr I cl H H

cl ct (ssu¡ The dfadduct (55b) had a sharp meltlng point (mp 231-

233'C) and r¡as presumed to be a sÍngle fsomer. Two slnglet resonances for the methoxyl groups at ô 3.55 and tlI 3.49 ppn !¡ere observed fn lts NMR spectrum and the remalnlng protons appeared as nultlplets beÈween ô 1.5 and 3.0 ppn. These data closely resembled those glven for the 44 ¡ monoadduct ' of 1 r 4-cyclohexadlene and dtmeÈhoxy- ì* tetrachlorocyclopentadlene. Slnce¡the syn-isomer of (55b)

Ehere ls a plane of symmetry and ln Ëhe antl isomer, a tldo-fo1d axls of symmeÈry, through the central double bond

the two pafrs of. gemf.nal methoxyl groups would be ldentlcal but the fndfvidual ¡¡ethoxyl groups fn each pair would be nonequivalenÈ. Therefore the sÈereochemfstry of 'tìnìx simy'qr¡ the dfadduct (55b) could not be asslgned from ¡ NMR spectra. Its sÈructure was consldered to be Èhe antl - lsomer shown on the basls of an approach by Ehe dlene to Èhe least hfndered slde of Èhe monoadduct (55a). 43.

AroruaELzaÈ1on of the adduct (55a) to the aromatic compound (55c) was envisaged as takfng place by atmospherlc oxldaEl-on. However, the use of a radlcal fnhibitor and an fnert atmosphere dld not alter the course of the reactlon. At thfs tlme, a report, on Ehe use of EeËrachlorothlophene dioxlde (56) as a regenerable dlene 4qf in Diels-AIder reacEions appeared ln the 1lÈeraÈure

cl ct H ct c I oz

ct I H cl (s6) (szu¡

Slnce the reactlon of thts compound wlth lsoÈetra1ln (51) cleanly gave the monoadduct (52b) Ín hfgh yteld, further wo rk L n vo I v I n g d f me E ho xy t e t. r a c h I o r o c yc I o p e n È a d f e ne lta s discontLnued. The spectral data of the adducE (52b) were l+4 r very similar to t,hose quoEed ^ for the producE derl-ved from annelatlon of L,4-cyclohexadl-ene wlÈh tetrachloro- thtophene dioxfde (56).

Unfortunately, the only electrophll lc reacEfon found that. eras selectlve for the EeÈrasubstftuted double bond f.n sysÈer0 (52b) was epoxfdaElon. Two oÈher reagents tried 44.

were dichlorocarbene, whlch was generaÈed in several 47 trtays , and chlorosulphonyl lsocyanate. The absence of t" olefínic resonances 1n the NMR spectra of the crude reaction producEs lndfcated in each c4se thaÈ these reagents were adding predominately Eo the dlsubstituted double bond. The product lsolated frorn epoxfdatlon of the adduct (52b) was shown to be a sfngle compound by TLC and HPLC analysls as well as by iEs neltLng polnt (*p 181- 183'C). The appearance of a broadened slnglet at ô 5.33 I ppn in :h" H NMR spectrum clearly showed that epoxidation had taken place at the t,etrasubstltuted double bond and a t3 resonance at 6 60.3 ppn f n the C NMR spectrum lras consistent with the presence of a carbon atom bearlng oxygen. The compound l¡as Eentatively assigned the all- cls, all-syn stereochemls try as 1n structure (57) based on the expected dlrectlon of additlon.

cl ct H H ct I ct I o

CI I I H H ct ct (s7) (sB)

The epoxfde (57) remalned unchanged hor¿ever when heaÈed as a buffered solutlon 1n refluxlnB 1 r 2-díchloro- benzene (bp 180"C). On furEher heaclng Eo 25O" C fn a 46.

sealed t,ube, the solutlon became turbid. The only product detecÈed ltas the aromatLc compound (58) whlch could be derived fion the epoxlde (57) by the ellnination of water fn a process perhaps caraLyzed by acidlc surfaces.

Since the requfred sÈereo- and reglochenlstry of the bridging group Z Ln the ÈrLene (53) could not be produced effecElvely fron Ehe adduct (52b), lt had to be prepared one sÈage earlier, from fsotetralln (51). A varLety of propellanes represented by structure (59) 1s known in the llterature. The most crltlcal requLrement for the formatÍon of the polycycle (62), (Scheme 1) ls the control of the stereochemtstry of the lnltial Dlels-Alder reactfon so thaÈ the second Íntramolecular cyclLzatfon can take place. The product (62) can result only by cycloaddÍtion of the dlene component (56) to the dlenophfle (59) on the sLde that fs antf Èo the brldge Z. At leasË three factors ntght fnfluence Èhe course of thls reaction : the d thedral ang le be t ween the two cyclohexene rlngs in the propellanes (59), the rlng sfze of group Z and the Èype of

subsÈíÈuents contal-ned wfthin 1t. Drieding models show

that the angle betr¿een the Er¡o cyclohexene rLngs becomes more acute as Èhe remalning rfng Z of. the propellane fncreases in slze. IÈ was considered that the alEernative mode of addlÈLon, syn to Z, would be less favoured, the

bulkler the sl.ze of Z, as long as the dfhedral angle does uot become too acute as the ring slze of Z fncreases. l+8 When a ;' '. mLxture of the epoxlde (63) and

tetrachlorothlophene dtoxlde (56) h¡as melted aE I20oC, a 47.

highly exothermlc reacÈion ensued. Sulphur dtoxlde r¡ras vLgorously evolved and the reacÈion mlxt.ure became yellow- I orange. H NMR analysls of the crude reactlon mixture showed Èhat the product was the aromatlc compound (58).

ct H

cl H

ct (63 ) (6'4)

l.Ihen the above reacÈion !¡as carrLed out. Ln solutlon at a lower tempe.raÈure in the presence of ,sodium blcarbonate, an lnterrnediate adduct (64) was isolated. If this reactlon hras performed 1n the absence of base, the aromatic compound (58) r¡as agaJ.n the only product. These result,s lnp11ed that the ellninaEion reaction was acld cataLyzed.. Trace amounÈs of acfd Ì¡ere perhaps beLng formed fron the lnteracÈLon of sulphur dl-oxide and mof.sture f n the acmosph.ere. EliminaÈion of waÈer f rom Èhe epoxlde adduct (64) would then afford the tetrahydroanthracene (58). The water llberated from this reacÈ1on night react wfth more sulphur dfoxlde to generaEe furËher acld and so the reacÈ1on could become auÈocatalytlc and exothermlc.

By elemental analysls, rnass spectrometry and ureltlng polnt. comparlsons, Èhe epoxlde adducE (64) appeared Eo be 48.

an lsorner of the product, (57) whfch was produced by

epoxfdatlon of Ëhe adduct (55). Furthermore, TLC arrd HPLC analysis tndicated that conpound (64) was homogeneous buÈ not ldenElcal to compound (57). Nevertheless, the epoxfde (64) behaved ln a simllar Danner to the lsomeric epoxlde (57) when 1t was heated to 250" C fn L r2-dichlorobenzene solutlon. Only the aromatLc compound (58) was generated.

Success was flnally attained when the reection of the cyclopropane (65a), (eq. 5), wlth Èetrachlorothfophene 50 dioxide (56) rùas l-nvesÈlgated . When a mlxture of these two cornpounds was heated as a melt at 130"C, sulphur dioxl-de was evolved and two produc¿s, (67a) and (68a), htere obtaLned. The hexacycllc compound (68a) crysÈalLlzed ouÈ readlly ln 30"Á yield on recrystalLLzatlon of the €rom g¿t"ot.*"t eii¡cr mLxtürê¡. The fsomerLc compound (67a), which accounted for the balance of maÈerla1, was recovered from the mother Ifquors.

cl ct

CI H cr xl-x.; --+ li CI

CI ct (60¡ (oa¡

cl (6s) ct H c1 Br H (eq. 5) ct (67 ) 49.

The sEructure of the hexachloride (68a) tas supported by the following data. EIementaI ana Iys is and Lons aÈ nr/e 402, 404, 406, 408 and 410 Ín the ¡nass spectrum were consfsÈenÈ wfth the urolecular formula Ct5H¡2C16 An t absorption at f603 cm , characterls Èfc of the CtC = CCI lrlr c t rooef ty ^ was present fn the IR spectrum. The H NMR spectrum exhibfted a broadened singlet for the four

¡ne thine hydrogens at 6 2.35 ppE superiroposed on one resonance of an AB quarteÈ for the etght methylene hydrogens at 6 2.22 and 1.48 ppn, J = 15 Hz. Thfs 9 6pectrum fs very sf¡nlIar to thaÈ of fceane Ltself e Sfgnals at 131.8(s) , 82.8(s), 74.7(s) , 46.1(d), 28.7(s) and 24 .6 ( t ) pp¡0 !¡ere observed f n the comblned broadband decoupled and off-resonanc" 'c NMR spectra whfch are 1n accordance wfth the sfx dlfferenÈ carbon aÈoms requfred by the c!¡o planes of syxlnetry ln structure (68a).

Ln contras t, the spectra of the fsomerfc Èrfene (67a) were trore coDpllcated., A resonance at ô 5.51 ppn ln the t 13 H NMR and at ô f23.7 ppm fn the C NMR spectra clearly demonstrated the presence of an fsolaÈed double bond. In t3 additlon, the C NllR daEa fndlcaËed ÈhaÈ there were etght types of carbon nuclei and the multipltcities Ln the of f- res onance spectrum were consfst.enE wfth Èhls strucEure.

The triene (67a) remalned unchanged when heat.ed to 170" C whtch conflrued that 1È had the r.trong stereochenlstry for lnt,ernal cycl Lzat fon. Evfdent ly, ln Èhe reactfon of propellane (65a) wtth Èetrachlorothlophene dloxlde (56), the triene (66a), whlch must be Èhe Precursor Èo Ehe polycycle (68a) react.s further and s¡as not detecced.

The cycloaddtrion reacllon betwecrl Èhe propellane Scheme 2

H 667 m.p. > 310"C (dec.) 4

(6e) ( 70)

ct 10oU (N.M.R. ) m.p. 215-6'c CH¡

(zt¡ (72) I

1..¡¡ O

70l m.p. 344-5'C

ct (t +¡ (73)

cl 401 m.p. 201-3'C

(7s) (7 6)

ì 51.

t{9 ( 65b ) and diene (56) produced an almost equal amount of the trfene (67b) and the cycl Lzeð, compound (68b) , as t evfdenced by H NMR analysis although the actual lsolated yteld of the polycycle (68b) by crystalllzaÈlon $ras s lmi lar to Èhat of the hexachlorfde (68a). Scheme 2 shows the reactfon products of some larger ring Propellanes. In trdo lnstances, the products (70) and (74) from the amide 5r^ 53 (69) oand the anhydride (73)oE crystallLzed analytically pure fron solut.ion as they forrned and this facllltated thelr Lsolatfon. The assignment of the structures for conpounds (72), (74) and (76) ú¡ere based upon synnetry arguments slmllar to those presented for the I structure of compound (68a). Although the H NMR sPectrum of the anlde (70) rnight be expected to be Ðore complicated than Èhose for the Inore' synmetrical structures (72), (74> and (76), ln fact the spectrum was very sfnilar. The lor¿er symmetry of the anlde (70) was revealed ln the t3 C NMR spectrum. The presence of only a sfngle plane of symmetry ln the molecule caused Ehe signals for the carbon aEoms C.n the upper and lower r lngs Èo occur as pairs ra ther than as s lng 1e peaks as ln the more symmetrfcal cases. The differences of cheml ca I shlfE w1Ëhfn these pafrs be c ame less the more remo te thë carbon atoms were from the anide funcÈLon.

The fsomerfc products of Ehe Èype (6O) formed fn the reacElons of the propellanes (69), (73> and (75) wtth teÈrachloroÈhlophene dtoxfde (56), (Schene 2), remained in soluElon and llere not. characterlzed. In the correspondlng 52.

52 I reaction of the ketal (71) , the H NMR sPectrum of the crude product showed no olefinlc resonances and only peaks consfstenË with the cyclLzeð' structure (72)' This fndlcated that only the desfred hexacycllc compound (72) had formed tn this case. UnfortunaÈelY, the use 'of flash chroT0atography to remove coloured lnpurities resulted in a substantial loss of material probably due to some hydrotysls of. Ehe keÈaL (72) to a dlol which Ì{as retaíned 54 on the column. Although the reactlon of the eÈher(75) gave rhe polycycle (76) in only 407" yleld, thts coüpound

could be prepared by tL'o s Èeps , but ln higher overall 55 yleId, from Ehe anhydride (74) . Reductf-on of the anhydrfde (74) wfth lithfum alumlnlum hydrlde gave a diol whLch rlras treated with p-toluene sulphonic acid ln refluxing toluene to effect. dehydration and the formaEion

of the eÈher (76) .

An assessment of the product raLLos (62) : (6O), (Schene 1) of the reactlons fn Scheme 2 indlcaEes that the direcÈ1on of attack by the dlene on the dienophile is not entirely based on steric considerations. Both the amide and anhydrlde bridges of Èhe proPellanes (69) and (73) would be expected to Present llttle sÈerfc hind rance towards t,he lncomLng dfene (56) Yet, remarkably, the major producÈ l-n each case 1s due to an approach of the diene fron the side opposlte the funcEional grouP. Evfdencly dfpolar electrostat.lc rePulslons nust be influenclng the 53.

reactlon pathways. Thus the direction of the lnlÈial Diels-Alder reactlon (Schene f) appear s to be dependent both on the sterlc and electronfc characÈer as well as the

rlng sLze of the brldge element Z

A fur ther compllcatlng factor involves the conformat.ional preferences of the propellanes (59) The approachlng dLene can encounÈer three conformatlons of the dl-enophiles (59), (eq. 6) . The population distributlon

(eq. 6) -_> - (59a) (seu¡ (59c)

of. each conformer would be dictated by the tyPe of 56 substftuenÈs contained wl thin grou p Z. I t can be

envlsaged that as L becomes bulkier or increases ln electron density, the concornít ant increase 1n nonbonded inEeract.fons would tend to cause the propellane (59) to adopt. uore of conformatlons (59b) and (59c). In these

conforuatÍons, Èhe s lde that fs syn to Z Ls more exposed towards aÈEack than fs the slde ÈhaE ls anti. Consequently, the amount of the fsomer (60) chal is produced should predomlnat.e over thaÈ of the deslred 54

polycycle (62). This 1s Ln facE what fs observed wl-Ëh the reactlons of the cyclopropyl propellanes (65). In the extreme case, the ruethyl substlÈuents of the ketal propellane (71) must be 1n a posftlon sufffcl-ently extended that completely hlnders additlon to the upper slde of all the conformatl-ons (59) . Accordlngly, only the hexacyclfc product (72) r¡¡as formed although at a somewhaÈ slov¡er rate. 0n the other hand, the planar shape of the functl-onaI group bridges 1n propellanes (69) and (73) should facilitate an fncrease ln the relative popula tlon 56 of conforner ( 59a) This , 1n additLon to an electronic repuls ion of the dlene ( 56) , presunably by Èhe anide and anhydrÍde carbonyl groups, is expected to contrfbute to the favourable formatf.on of the polycycles (70) and (74).

I.lhen the carbonyl groups of Èhe propellane anhydride (73) ü¡ere replaced wfth methylene groups as ln the ether (75), the selectfvfty of Êhe reacÈ1on with tetrachlorothiophene dioxlde (56) decreased. This was attrfbuted Èo a resultant reducÈfon ln the number of polar functional groups capable of dlrectlng the course of Èhe initial Diels-Alder reactlon (Schene 1).

An examinatlon of a Driedlng model of the epoxfde (57) reveals Èhat the angle between Ehe Èwo rings attached to the epoxide bridge 1s approxfmately 150o. It ls posslble that the orbltal overlap between the diene and dlenophtle 55.

ends of the molecule is reduced to the extent that no fntraEolecular cycllzatlon takes place and that elLnLnatlon of water to glve compound (58) becóroes ìì"g a.tlern¿Lti.ve'' reaction. That only one lsomer ls f ormed f rom the reactlon of the epoxlde propellane (63) and tetrachlorothiophene dioxide (58) is surprlsing but since boÈh epoxide l-somers (57) and (64) gave the same product (58) on heatfng, no conclusion as Èo Èhe nature of their respect.ive stereochernistries can be reached.

In all the examples discussed so far, the selectlvlty of the DieI-s-Alder reactlons (Scheme 1) have been deternfned by the type of brfdging ring Z. IE tla s consfdered that if the group Z vas cons tructed so as to form another cyclohexene rfng as 1n the propellane (77),

(77)

then the orientatlon of atÈack by Èhe dlene (56) would be 54 frrelevant. However, Èhe reported synÈhesfs of compound (77) ls long and was noÈ underEaken. Alternatlvely, alterlng the archftecÈual design of the dlenophfle (59) to 56

perxoit conformatLonal fnverslon of the rfng junctLon would also make the course of the lnitlal Diels-Alder reactl0n fmmaÈerla1. An obvLous way to accomplish thts would be Èo replace Èhe carbon brfdge atoms ¡¿1th nitrogen atoms (eq- 7>. Based on the abtltty of Èhe nLtrogen lone electron pafrs to fn vert, both of the rlngs containing Èhe diene and olefin moietles of an fntermediate adduct (79) rnight come fnto sufffcient proxfnlÈy to each oÈher to allow orbftal overlap and cycllzatfon to the dLaza-compound (80). The dlenophile (78) ls the fsoelectronlc equivalent

H I N (eq'7) t

I H ( 7B) (4e>

ct cr H cl I ct T Ì -.+ N CI N I ct H ct cl (7e) (80) of the unsultable carbon anaÌogue (49) discussed prevlously (p 30). In practlce, the pyrtdazLnopyridazLne 57 o^ (78) ptoved Eo be rat.her lablle and rdas unsËable to the 57.

reactlon condit.lons. A dark red coloratÍon formed lnsÈantIy in lts reaction wlth tetrachlorothiophene dtoxfde (56) and no recogr.lzable products could be isolated. The colour may have resulted from the creatlon i7 : of a charge transfer specfes by the lnteraction of the elecEron rich hydr azl¡e (78) and the elecÈron poor thiophene (56). AÈtenpÈs to work around this problen are described Ln Chapter 3.

The next stage of the synthetlc straÈegy towards the preparation of derlvatfves of lceane requlred the cleavage of the ethylene brldge of the polycycles of the type (62). Initia1ly, the removal of the chlorine atoms ltas inves tlgated . Reductive dechlorlnatLon of the hexa- 58 chloride (68a) with sodium 1n ethanol afforded a mixture of two compounds . The uÍxture was separat.ed by revers e 55 phase HPLC and the najor product was the expected olefin (81). The minor product ltas assLgned the LnterestLng trfene structure (82). Evidence for Ëhese sEructures fs as follours. CharacÈerlstic differences between these

(et ¡ ( B2) 58

t, t'a products were observed tn thef, and NMR spectra . I3 The broadband decoupled C NMR sPectrum of the trlene (82) consfsted of elght llnes, three of them ln the l3 olefinfc reglon, whereas the C NMR specÈrum of the alkene (8f ) contained slx lines, only one of which v¡as l-n the vinylic regf on. Synuretry dlf f erences betr¡een the I molecules lrere evfdenË from their H NMR sPectra. Notfceably, the cyclopropyl methylene hydrogens appeared as a singlet ln the spectrum of the alkene (81) but as an AB quartet fn that of the trlene (82). Further studies of

Èhe cheml-s try of Èhe Erlene (82) are belng undertaken 50 elsewhere.

The trLene (82) rras consLdered to arLse by a fraguentatlon reaction of the type discussed by (o Grob ". Thfs úras supporÈed by the fact that the problern of fragnentaEion could be overcome by neplacing the offendlng bridgehead chlorlne atoms of compound (68a) wfth

hydrogen atoms (eq,8). The fntermedlate (83) was noE

cl ct cl ct cl nBu3SnCl(cat)

CI ct (68a) NaBHq/ErOH ct ct (eq.8)

Na (83) EIOH

(8r) 59

ttl f u11y characEer !zed buË lÈs Nl'{R spectrum displayed no cyclopropyl or oleflnlc resonances. Moreover, the presence of a nultlplet at 6 3.1 ppm lnferred that only the bridgehead chlorfne atoms had been exchanged for hydrogen aÈoms . Interes È1ng1y, no f ragrnentatLon lras observed under these conditlons which sugges ts thaÈ the

fragroentatLon reaction to the triene (82) occurs vLa an anlonic rather than a radlcal process.

The procedure whlch fnvolved a cat.alyttc generatlon of 6l tributyls tannane , (eq. 8) was not always reproduc fble . The ketaL (72), for lnstance¡ wâs ¡nore efflclently reduced with sEoichiometric aDounts of trfbutylsËannane (eq,9). Further reduction of the vinylchlorfdes (83) and (84), tt separat.ely wtth sodium fn ethanol gave only the alkenes

3 SnH/ to1 CI ct (7 2)

(eq. 9)

ETOII (84)

(85) 60

(Bl) and (85) r+sg, Dissolvlng metal reductions of other hexacycllc systens of Èhe type (62) also induced 60 f,ragmentaÈlon reactfons to varylng extents . Ins Eead of attemptlng to overcome these slde reactLons, an endeavour

was made Èo make use of the fragmentatlons -

Hydrogenatlon of the hexacycllc ether (76) over a palladium caÈaIyst 1n ethyl acetate containing

trÍethylanine produced the dtchloroether (86) fn 8O7" yield. That only the vinylic chlorine aÈoms had undergone hydrogenolysts !¡as ascertafned by Èhe appearance of moIecular Lons at 298, 300 and 3OZ 1n the mass spectrum and the presence of a slnglet res onance at 6 2.29 ppm, t lntegrating for four hydrogens, ln the H NMR spectrum r¿hich was assigned Ëo the ethylene bridglng group' Furthermore, the absorptfon aÈ ca. 1600 .t-t ln the IR spectrum that is characCerlstlc of the CIC=CC1 noeity tltas absent. Fragmentatlon of the dlchloroeEher (86) could take place by one of two pathways Èo glve elther of the dienes (87) or (88) , (eq. 10) . In pracÈ 1ce, rfng cleavage induced by sodtum-potasslum allorttbin eÈher Produced the undesired diene (87) exclusively, by way of internal bond flssfon. A small amount of reduction without fragmentaÈ1on occurred to glve the ether (89) and the resultant mlxEure was separaEed by reverse phase 55 HPLC . ThaE Ehe dlrecLlon of fragnentaElon of the dichloroeEher (86) nas Eo Ehe dlene (87) was ascertalned by the presence of a t.rlplet resonance for the vlnYllc I hydrogens at '5 5.1f ppm ln the ll NMR spectrum. The 61.

cr (88)

o Na-K A Et 20

CI (Bo ¡ o

(eq. 10) (87)

I rest of the spectrum nas remfnLscent of the H spectrum of the triene (82) . In particular, the nethylene hydrogens in the teÈrahydrofuran rlng of the dfene (87) occurred as an AB quartet at ô 3.65 and 3.30 ppm, J = 10 Hz and elght ttc Ifnes úrere present ln the broadband decoupled NMR I spectrum. The H NMR spectrum of. the eÈher (89) contalned no resonances at lower field than 6 2.0 ppt apart from a slngleE at 6 3.27 ppn for the nethylene hydrogens adjacenÈ to the oxygen atom.

(8e) 62.

The dfene (AZ) ts related Èo the dfene (88) by an lnternal Cope rearrangemenE and lndeed was convert,ed to on pyrolysis . In contras È co Èhe diene (87) the latter ' I the It NMR specÈrum of dlene (88) ltas very sfnple. Stngle resonances aÈ ô 4.46, 3.47 and 2.25 ppE¡ each lntegrating for four hydrogens, !/ere assfgned respectfvely to the vfnyl and CH2 0 groups, and the allylfc nethlne hydrogens. The remaining nethylene groups appeared as an

AB quartet at ô I .91 and 1.22 ppmr J = LZ Hz.

OxfdatLve cleavage of the diene (88) has noE yeÈ been carried out. Tf. this can be achleved then the product should be the diketone (90) which could, ln princlple, be also derived from a key LnÈermedlate of the Èype (91),

o H o I X o 2 X ù o (so¡ (e 1)

(Z = CHZOCH2 ) by a double lntramolecular alkylatlon reactfon analogous to chaE dlscussed ln Chapter 1. Thus the lnftlal al-n of Èhe project has been accompltshed albelt by a rouÈe dffferenÈ to that flrs t concefved buE then Èhls fs the nature of synEhetlc organtc chemlstry. 63.

2 2 The 1lteraÈure ruethods by whfch the reagents menÈfoned 1n the preceding sect.ion lrere prepared q¡ere noÈ found to be rellable Ln all cases. Because of various dlfflculEf.es and low yields Èhat. trtere encountered fn efforEs to

reproduce some of the lfteraÈure procedures, endeavours

were undert.aken to revlew and lmprove upon thls work. The results of this study are presented belor¡.

Tetrachlorothl,ophene dfoxfde (56) !¡as prepared by the

reaction of hexachloro-1 r 3-butadiene and strlphur at 210'C 44 r according to the procedure of Raasch ^ . However, aÈ Ehls tenperature, the byproduct suLphur monochloride

codistflled wfth unreacted startlng materlal. To obtaln a yteld conparable Èo Èhat claimed, Èhe dlstlllate had to be recycled whlch enabled all of the chlorobutadlene to react . OxidatLon of the product, t.etrachlorothJ.ophene, wlth u-chloroperbenzolc acld in refluxlng 1,2-dlchloro- ethane $ras best carrf.ed out fn the presence of a radfcal 70 fnhibitor ".^ Thts reduced Ehe arnount of decomposltlon of the oxidanÈ and consequent.ly Èhe amount of sEarÈing materfal recovered upon workup. Isolatfon of the thlophene dloxlde (56) was facilltated if unchanged ÈeErachlorothlophene was removed by dlstlllatlon prior to Èhe crystalllzaEl-on of Èhe product from peÈroleum eËher.

IsoteEralfn (51) was obtalned by a Blrch reductlon of 64

l{6 l+6 naphthalene . Of Èhe exLstcrnt ' procedures , 1t was found that addttLon of sodlum to the naphthalene solutfon t+6 containl-ng a proton source a rather than the reverse a6b procedure was more rellable as lt prevented the forma t ion of soda¡ulde which leads to undesirable sLde reactfons. On one occaslon, Ehe alternative . ,r6b procedure gave a product, contamlnated wfth Èetra11n, 62 which lras difficult to purify

Treatment of fsoteÈralln ( 51) wlth buffered m- chloroperbenzoic acfd, fns tead of peracetlc acid as described by Vogel et alhB , was used to produce the epoxfde (63) sLnce the lat t.er reagent was not available.

The dichloride (65a) was prepared by the addition of dfchlorocarbene to isot.etralLn (51) at low temperatures. u Although the rnethod of Vogel eE rlu b was rellable, the q9^ workup procedure proposed by Paquette et al o Ln the preparat lon of the dlbrorolde (65b) was more convenlent . The dfbrornfde (65b) was acquired 1n a slmllar manner to the dtchloride (65a).

Ìlonocycloaddlclon of chlorosulphonyl tsocyanate to l-sotetralln (51), ln the absence of a solvent, and subsequent hydrolysis of Èhe resultant N-chlorosulphonyl ß -lactam (92) wlth sodium hydroxfde solution lras reported 5t _ by PaqueÈEe eÈ al o Èo gfve the Ê -IacEam ln 397" yfeld. 65.

IÈ has been found subsequently that. the overall yleld can be almost doubled tf the lnitfal addftlon reactLon 1s conducted 1n an ether solutLon. From Èhis solutlon, the internedLate N-chlorosulphonyl lactar (92) crystallf.zed, analyÈicalIy pure, in 86"/" yteld and 1t could be efflclently reduced ln 887" yteld to the B -lactam (69) by t an adaptatlon of a known procedur"u O which uses sodium sulphlte solutl,on ln a t!¡o phase system.

So2ct o H I

I OH (sz¡ (e3)

The selecÈlve oxidatlon of lsoteÈralin (51) to the cis-dlol (93), accordlng to the procedure Â of Gl-nsberg 52 et a1 , proved to be e capricious reacEl.on. Often the reacÈion falled almos t completely, wlthouË apparent cause, especfally when carrLed out on Ëhe same scale as that descrlbed. All actempts to resoÌve thls problem were lneffectual. The condltlons under whlch the best yleld fn several runs ú¡as achleved are descrlbed 1n the 66

experlmental secÈfon.

Ketal exchange of 2,2-dfrnethoxypropane wlth the diol (93) in hot (110'C) acldlc dlnethyl sulphoxLde, as reporEed by t,he llterature method52, produced very IltLle of the required ketat (71). Instead, a complex mixture of products rras obÈained. 0nIy st.arÈ1ng material was recovered when the reactlon was performed ln refluxing acldified 2 r2-dirnethoxypropane ln the absence of dfnethyl sulphoxLde. Possibly the d1¡uethyl sulphoxfde solvent enabled Èhe reactlon to be carrLed out at higher temperatures . Indeed, when a solutLon of the diol (93) and p-toluene sulphonLc acld in 2 rz-ð,lmethoxypropane was heated at 130'C ln a sealed tube, rhe ketal (71) was f orroed, f ree of any byproducts, and lras lsolated ln 87"Á yfeld after disttllatlon. It lras cruclal to use pure dfol

(93) in thls reacÈion b""",r". ff Lnpure materlal üras subjected to ketaLtzation fn this way, no reacEfon occurred.

53 The lnformatlon presented in the lfterature concernlng the preparation of Ehe anhydrlde (73) is a raEher vague descripElon that lacks speciflc experlmenEal 55 detall. After sone experiment.aElon , conditlons have been found whlch allow Ehe productlon of the anhydride (73) ln 367" overall yield from butadlene and acetylene dlcarboxyllc acld. The yleld qras found Èo depend upon the 67.

purlty of Èhe diacfd and the Èemperature of the Diels- Alder reacÈfon. Á,cetylene dlcarboxylfc acfd ls best prepared fron lcs monopoÈassium salt and used fmmedlaÈely. By keeping the temperature of the reactfon lov¡er than that suggested 1n the llterat.ur.tt, the exÈ.ent. of diacid decomposLt.ion and butadiene polymerLzation was reduced . The product (73) from thts reactlon fs bes t obtained pute by a convers fon Èo the correspondlng dlcarboxyllc acid, whfch 1s easlly separaÈed from the reactl,on byproducts by exËractfon fnto base, and then by dehydratlon of this acfd back to Èhe anhydrld.e (73). The dehydratlon could be achieved 1n a variety oî. ltays. The most expedient method rlas the azeotroplc removal wlth toluene of the vrater forrned fn the presence of p-toluenesulphonic acid as catalyst.

The eËher (75) was prepared 1n several steps from the 54 anhydrlde (73) after the ¡nethod of Ginsburi , wLthout any compllcatlons.

The synthesis of the pyrldazlnopyrldazlne (78) as 57-ois descrf bed by Hinshaw shown belor.¡, (eq lf ). Oxidatlon of malel-c hydrazfde (94) wfth lead ÈetracetaEe to the dLazoqulnone (95), fn the presence of butadlene, generaÈed rhe pyrfd,azlnopyrldazl¡e system (96) in comparable yfeld to Èhat reporced.uto. IÈ was found to be more convenlenE t.o add Èhe oxldant as a soluElon raÈher 68.

57b than Ln the solld foru which was proposed by Clement and sfnce the success of the reacÈLon was dependent upon Èhe puriEy of Ehe lead tetracetaEe, the oxLdant, was besE purified by recrystaLLLzaEfon shortly before iÈ hras used.

o o o

H Pb (oAc) q cH2cI2

o (e6 ) (e4) (ls¡ Bx2 CHC1 3 o Br Br

(eq. 11)

Br Br ( 7B) (e7) BzHo l(eLi,/bz Br Br

Br Br (e8)

The olefinlc bonds of Èhe diene (96) llere proÈecEed by bronínatl,on Èo glve the Leloþtrabromlde (97) whlch lras then reduced wlth dtborane Èo the tetrabrornfde (98). According to Hinshaw, the product (98) ltas lsolated by acidlfytng the reactlon mlxt.ure wlth concentraÈed hydrochlorlc acld and fllterlng Èhe prectptÈate. At Èh1s stage' the tet rabromide (98) should be a hydrochlorlde salt yet 69

Hfnshaw dfd not Eake this lnto account. The only lnformatfon presented was a partlal mass spectrum and

analytlcal data whl-ch lnferred ÈhaÈ Èhe free base was obtalned. However, the IR spectrum of thfs materlal reveals the presence of a broad absorptlon band at 3230 _t crn characterlstic of a protonated nl-trogen aEom.

Furthermore, r¿hen the coupound 1s treaÈed with alkali, a white solld ls recovered that has the sa¡ne physical characterf.s tics as the analytLcal sample prepared by Hlnshaw. Hinshaw's procedure for the conversion of the ketobromide (97) to Ehe tetrabronlde (98) was Lnproved by the applicatlon of a nethod of Brown et . Thfs "1tt" method involves Èhe reductlon of tertlary anldes wLth borane-dlnethyl sulphide Ln the presence of boron trtfluoride etherate and when applied to the reduction of ketabronl-de (97), the tetrabromide (98) was obtained ln .74i¿ yleId.

Debromfnatlon of the tetrabromlde (98) r¡ith nethyllfthium afforded Èhe final producÈ (78) in 45i[ 75^ yield o buE the workup procedure of Hinshaw was altered for convenlence l-n the following lday. The addltion of

only enough water to desËroy excess methylltthiun and Èo prectpltate the Lnorganlc salts avolded Èhe poÈenÈlaI loss of the producÈ f,nto an aqueous phase. The dlene (78) q¡as suiflclently f.nvolatlle for Èhe solvent to be removed under reduced pressure lnstead of careful dlstlllaÈion at 70

57^o. a Èmo I p-her 1c pressure as descrlbed. Bulb to bulb distfllatlon of the ree fdue provlded the pyr l,daz ino- pyrldazlne (78) as a whlte solÍd, mp 4ß-4I'o C, rather t,han 57a a colourles s 1lqufd a8 reported by IIf ns haw - I Nevertheless, the H NMR data for thts compound was 57a ldentlcal to that publlshed 7L.

CHAPTER THREE 72.

The r¿ork presenÈed ln thfs chapter summa rLzes the

lnves ElgaEions lnto a number of poÈentfaI, alchough to date unsuccessf u1, rout.es to varlous functlonalized iceane derlvatLves. Sfnce noc all posslble approaches in Ehls secÈfon have been fuIly studf ed, some areas of thf s ç¡ork are lncomplete.

3.1 The fallure of the pyrfð,azlnopyrldazfne (78) to react ln the desfred fashlon wlth tetrachlorothlophene dloxide (56) was consldered to be due posslbly to the nucleophiltc N-N functlonality pro¡notfng unnanted sfde reactlons. If

the reactfvlEy of thls centre could be lowered Èhen perhaps Èhe exEenÈ, of decorûposftfon encountered fn thls reactlon mlghE be reduced. the amlde functlonal group

seemed a E)romislng candldate sfnce the avaf.labtlfty of Ehe nltrogen electron palr to engage fn deleÈerfous slde

reactfons would be decreased by their deloca LLzatlon 1nÈo the carbonyl oxygen aEoru but the electrons should also sEf II be avaflable to allor.¡ the crltlcal rlng lnverslon requlred for the flnal cyclfzaÈlon sÈep. Three Èypes of key lnÈermedfates (I0t), (IO8) and (f14) thus are

poss fble, (Scheues 3-5) . Both of the trlenes (IO1) and (1I4) , (Schenes 3 aud 5), r¡ouId gfve the hydra zLde (102) Lf. they underlrenÈ an lnEramolecular Dlels-Alder reacÈfon vhereas Èrlene (lO8), (Scheme 4) vould produce an lsooerlc hydrazLde (109). Scheure 3

\ + )

(es) a cf (s6) o2 Y b ct o (e6 ) c ct cr f. + (,\t cr cr o (ee) ct o (1or) ( ro2)

cf H + d H 2 --+ ct o (ee ) (s6) cr ( loo) 74.

RetrosynEhetic analysis Ln aIl three schemes Lnvolved three mafn types of slrnulÈaneous bond dlsconnectfons

(a-y ) , namely the carbonyl carbon-nltrogen bonds (a ) , the rnethylene carbon-nftrogen bonds (ß ) and the carbon- carbon bonds (y ) between Èhe diene portlon and the res t of thè molecule. Sinultaneous anide bond formatfon

(") was approached by a condensaÈion reacË1on betr.¡een a suitable dla¡uine and anhydride and both diene annelatlon (f ) and methylene carbon-n1Èrogen bond f ormatl-on (Ê ) rdere envfsaged to be accompllshed by an appropriat,e cycloadditlon reactlon.

An applfcatlon of the retrosynthetic analysls, outllned above, to the key fntermediate Èrfene (1O1) ytelded tvro feasfble path!¡ays r¡hich are outllned Ln scheme *r* oo.t,ue{Þ$ 3: annelatlon of the dfene (96) at ther, fsolated double bond r¡1th tetrachlorothlophene dfoxLde (56), shown as reactl,on (c), or Èhe condensation of the diene (1OO) with nalelc anhydride, (e). The diene (96) was prepared by the Ilterature proced,rr.ttb which Lnvolved a DieIs-Alder reactlon bet,ween r r 3-butadiene and dLazoqulnone (95) which was generaÈed by the oxidaEfon of malelc hydr azLde with Iead tetraacecaÈe. The annelatl,on reacElon, (c), proceeded, albeit slowly, to form the triene (101) at high temperatures buÈ no further cyclLzed, materlal (102) was detected even on prolonged heatlng, (f). posstbly, the diene and dlenophiltc moletles are too electron deftcienE to allow the subsequent reacÈ1on to occur. The trlene

(10r) was not fully characterLzed but iEs formacron r"ras Scheme 4

+ ct a

(es) (ss¡ cl ( cl ( 103) b + 0 ( c o ct cl CI ct e (e4) oxid- ;* 2- ct cl (se¡ CI cl d ( ( 106) g tos) ß'Y + NH2NH2 ( 108) ( roe) ct 0 ( io4) o o cooEr cl f ( 104) ( I o2 107) N

I l*cr N (s6 ) COOET

\ 76.

t, supporÈed by the appearance of ne!¡ peaks ln the NMR spectrun of Èhe reactlon mf.xture at ô 4.2 (m) ppn for the meÈhylene hydrogens and at ô 3 .4 (ru) f or the allyli c methl.ne hydrogens. Since the key Lntermedlate (1O1) failed to react furt.herr a study of routes (d) and (e) Ín Ehe second pathway of Scheme 3 was noÈ underEaken.

Three convergent routes to the key fntermediate (1OB) rrere devlsed and are shown in Scheme 4. Concelvably a Diels-Alder reactlon, between elther 1r3-buÈadLene and the enedLone (I03), (b), or between d,LazonaphthoquLnone (1O6) and tetrachloroÈhlophene dfoxide (56) , (e ) , rntght be enployed to construct the cyclohexene and dlene rings conÈaLned wfthin comp ound (108) . However, both of these approaches úrere thwarted when thlophene dloxfde (56) 57' fal1ed to react wlth both of Èhe known-' D dLazoqulnones

(106), (e), and (95), (a) . The fmmediate precursor Ëo compound (106), êts-2,3,4a,5,8,8a-hexahydro-L,4- phthalazlnedione (1O5), lras prepared by reactÍon (d) of the anhydrlde (104) with hydrazLne hydrate accordlng Eo a 63 literature proceduçe . The a1Ëernatlve route (c) therefore lras not needed. A thlrd approach to the key lntermedlaÈe (1OB), fn princlple, rêquired a condensaÈLon reactf.on (g) of the dlhydropyrfdazlne (107) wtth Èhe anhydrlde (1O4). Compound (107) was unllkely Èo be very sÈable slnce fÈ ntght possfbly undergo a tauÈomeric shlft followed by ellmlnatfon of hydrogen chloride Eo glve the aromatlc pyrldazLne sysEem (1fO). ConsequenEly pathway (g) e¡as noE pursued. Scheme 5

o cf

+ o2 ct o ct (e6) (56 ) a

+ ct Y ß cr \ (sa¡ (s6 ) cr cf H oxid. d f

H ct CI o o o ct CI o c cr ct g ! (112) (1r3) ! (114) ' + NH2NH2 (102)

CI (r11) cl +

(ee )

(111) 78

(1 10)

The procedures outllned fn Scheu.e 5 result from a sllght reorganizatlon of the events dtscussed fn Scheue 3. Pathway (a) rùas dlscounted at thls sÈage as thls reactlon nas shown (Scheme 3) to effecÈ dfene annelaElon only at the fsolated double bond posltl.on. Followlng an analogous procedure fn which dihydrodLazoqulnone (115) and

1 r 3-butadiene undertrent a Dtels-Alder reactlon (eq. L2) to 57ru glve the adduct (116) , 1È ltas envfsaged that Èhe dtazonaphthoqulnone (113) nfght undergo a sfmllar reactLon (d) to generate the key Lntetmedlate (114). The hydrazLde (112) corresponding to the dlazonaphthoqul.none (1f3)

(eq. 12)

o o (1rs) (116)

nfght 1n turn be prepared by el cher of Èhe reactlon pathways (b) or (c). Surprtslngly, Eâlelc hydrazlde (94) 79. rùas lnert towards dÍene annelatlon wfth Èhfophene dioxlde

(56), âû observatfon tha È contras ted remarkably to Èhe ,rhf analogous reactLons of both maleimide and benzoqulnone. Thfs lack of reacttvlty is reflected in the fallure of the key Lntermedlate (10f) (scheme 3) to gLve the hydrazLd.e (102).

Under conditions sLmilar Èo those used to converE the 3 anhydrlde (104) to the phth alazinedfone (105)6 ( Scheme 4) , none of the hydr azLde (1L2) , (c) , !¡as fsolared frou the reactÍon of the anhydrlde (111) wfth hydrazlne t hydrate. A resonance f n the aromatLc regf on of the Nl'fR " spect.rum lndtcaÈed that aronatLzatlon of the diene nol-ety had occurred. This was presurnably Lnduced by the baslc naÈure of hydrazf-ne hydrate. Slnce thfs type of reacEÍon was also lfkely to occur fn the reactlon of teÈrahydropyrazfne (99) with the anhydrlde (111), reactlon pathway (e) rJas not examined.

I,iIf th the Èhree schemes presented above, the rna jor drawback appeared to be the use of Èhe regenerable diene tecrachlorothlophene dloxide (56). It was reasoned Èhat If. Èhe dlene portfon of all the precursors to Èhe key lntermediates (101), (1OB) and (114) were protected 1n a masked form unEll the flnal lntranolecular cycllzation react.f.ons, then some of Èhe dlf f lcultles thaE were encountered 1n each scheme rnlghE be avolded. To Èhls end, Èhe replacement of Ehlophene dloxfde (56) wlEh d lme Èho xy E e Ë rach lo ro cyc 1o pen tad 1e ne , as 11lu s È r a E.e d f n 80

(eq. l3), may suft thls requLrement. Thls chemlsrry has yeÈ to be lnvestfgated.

ct cr H3 + ^,)t¿ H3 t-¿ --+ ct

-l- (eq. 13) H3o'

..¿ -+ ct ..¿ ct

ct 81.

3.2 In the LntroductÍon to Chapter 1, syntheÈlc approaches towards Èhe formatLon of the fceane skeleÈon rùere present.ed based upon the consÈructlon of substructure (7). It was suggesÈed that suitable activatfon for rlng closure would be provided by a compound such as the ketone ll+ (8). Based on synnet,ry consfderatlons and with the use

(7) (8)

of a slmflar synthon, lt rùas further proposed Èhat ketone (8) rnlght 1n Èurn be derfved from an Íntramolecular alkylatlon of elther compound (11) or (f2). A third alternaË1ve lfes wlth the dfketone (1f7). Alkylatlon

o o

H..

X X X H. X H H o (ll) ( r2)

t¿1th a dihalomethane mtghE gfve t.he lceane derlvaÈLve 6ha (ffB) by analogy to Ehe method used by Prelog for 82

o o

(117) (118)

constructtng an adamantane derivatfve (120) fron the ketoes ter (119) , (eq . 14) . In a sirnflar sltuatlon, Eaton tt+ et a1 fntroduced the ftfteenth carbon fnto thè dlketone

(121) to form the pertsrylane (L22), (eq. t5) .

cooc H3

o Br (eq. 14) NaOCIl3

c H3OOC c t-too

(1re) ( 120)

OH I o o o o

Hf'ôfì['r (eq.15) rBuOK/rBuOH

( 121) (r22) 83

Two related pathways to Ehe Èrfcycllc keÈone (117) 5 were envlsaged : an 1nÈernal aldol reacÈlort,6 of the

keroaldehyde (I23) followed by oxfdaclo1165l'67¡ and an 66 fnternal clafsen reactfon of the keÈoacld or ester (L24). Care would have to be exercl-sed fn these

Act oHC ROOc

H (123) (r24) ( 12s)

R HorCH Act = CHO, COOH 3 or COOCH3

reactfons to avold Èhe alternative mode of rLng clo s ure t,o

an adamantane sys tem of the type (125) . Thfs rnt gh t be

dlfflcult ln the case of the ketoaldehyde (123), where Èhe pKats of Èhe c -methylenes Èo the carbonyl groups are

simL lar , but should be less of a probleru wfth the ketoacld or es ter (L24) where the pKa of Èhe c -ne Èhylene Èo the

ket,one group fs qufte lor¡er Èhan those ad JacenE to Eh e ester or acld groups.

The most lmportant features of cornpounds (123) and (L24) are Ehetr st,ereochemlstrles. The cwo-carbon slde chafns 84

must be endo for Lntramolecular cyclfzatlon to occur. An I 0 applfcatlon of sorue exls Eing adamantane cher¡fstry " presented a good opporÈunity for stereochenical control slnce rlng cleavage of a sultably functÍonalfzed

adamantane derlvatfve (l-26) usually generates a 3 r7- dlsubstlrured btcycllc [3.3.1] nonane sysrem (L27) thar 67 contains an aIl-endo conflguratlon ,(Ftg. 1).

(Fís. 1) 7

(126) (r27)

fg = functional group

To correlate st,rucÈure (L27) wfth compounds (123) and (124), the overall transformaÈlon (Ffg 1. ) must achfeve the lntroductlon of oxygen funct,ionalfty at C-3 (group A) and a f unctlonallzed tr.¡o - carbon chain at C-7 (group CH2B) by a conbLnaÈ1on of rfng expänslon (RE), ring cleavage (Rc) and chaln elongation (cE) reactlons. These reactlons can be applled in three hrays as ouÈlfned in Schenes 6-8.

The pathway shown Ln Scheue 6 involves the constructlon of Ehe túro-carbon stde chaln whilst ft ls

stlll part of the rlng system so EhaÈ the deslred endo

conflgurat. lon w111 be malnt.alned. rnÈroductlon of Èhe 85

CH2N2/MeOH 68a ref { Bayer-Vi11i ger } IO ( 128) (tze) o RE

Scheme 6

( 130) OH { reductíon} OH

{oxidation} (123) or (124)

(131)

68" second carbon ato¡o eras achfeved by rfng expanslon of adamantanone (128) wlth dlazomethane to furnlsh homoadamanLanone (L29) . AE thfs stage, the two carbon

unit, had to be separated at Ehe carbonyl functlon from Èhe rest of the rlng system. It was expecÈed that, a Bayer- Vflllger reaction would resulÈ 1n cleavage and nigratl.on of the ruore substftuEed of the ketone (L2g) to "ld"69t glve the lactone (130) whlch could be reductlvely cleaved to the dfo1 (f31). Oxtdatfon urfght then provLde the ketoaldehyde (L23) or acld (L24> . UnforEunaÈe1y, dffffculELes were encountered when homoadamanEanone (129) fafled to undergo any further rlng enlargement. 0ccaslonally trace amounts of lacÈonfc naÈerlal were produced, but 1n Èhe rnajorlEy of cases only sÈarÈ1ng 86 material l¡ras recovered. The variety of reagent,s, used ln att,empts to carry out this reacÈ1on, ls llsted ln Table 2.

Table 2 CondiElons used for attempÈed Bayer-V1111ger

reactlon of homoadamantanone (129) .

Reagent and solvent system Ref .

85z McPBA/NaIlco3 lcu'rcL2/H2o 70(a) 85i¿ MCPBA/CHCI3 70(b)

857" MCPBA/CII3 s0 zoP^l cHcl3 14 852 MCPBA/BF¡.Et20lbenzene 70(c)

85"/" MCPBA/pTSA/benzene 70(d)

85"Á MCPBA/CICH2 CH2C1 70(e) 3o7" Hzozlseo2/rnuou 67(f)

3o7" Hzoz/cttrcooH 7o(f ) N(cH2ërt\N.2ld^2o2lnaoul THF/H2o 70(e) N(cH2C¡tì)3N.z[zoz/st3.Er 2oltnE 70(c,h) N(cHacHÀl}N .2H202l(cF¡co)zolcHzcLz or Et20/Na2HP04 70(f , i) 3o%Hzoz/(cF3c0)zo/cH2cL2 or Et20lNa2HPoq 70(k)

Ce( NH¡+ ) z ( No z) ol CH3 CN or THF/tt2o 70( d ) psychochemotaxis one I s fnaginatfon .

The reacElons were followed by thln layer I chromatography and H NMR specÈroscopy and Ehe react lon

Elcnes ranged from one hour t.o a week aÈ either amblent or reflux ÈemperaÈure 1n Èhe presence of the radical 8l

fnhfbltor 2r6-d,L-terE-butyl-4-merhylphenoIT0" . SLnce 901. hydrogen peroxlde nas unavaflable, the hexamethylene- t dlanlne dfhydrogenperoxlde compl.*7 1r"or" 2> was prepared f ro¡n conmercf al 3O7" hydrogen peroxtde.

The converslon of ket.one (L29) involves Èhe enlargement of a seven-nembered to an eighE-membered rfng. Whereas homologation of adamanCane systems is ,gr68 widely reporÈed fn the lfterat,ur."erf , only ÈLro types of honologatLon of homoadamantones has been described6T¡'585. A literature survey on Bayer-vfrltger reacLlons revealed that many cyclfc systems thaÈ contain greater than six carbon atoms undergo rlng expansLons wlth 72 dtfflculty . In polycycllc systems, thls unreacElvlty has been attributed to sterfc hlnderance of nearby groups obstructLng the lnltfal atEack by the reagent. For example, the fallure of bfcyclo t3.3.11 nonan-7-one (132) to undergo oxldatlon to the lactone (134) was considered to be due to through-space fnt.eracÈfons between the axial

( endo ) hydrogen at C-7 and the hydroxyl group at C-3 Ln 73 the intermedlaEe(133), (eq. 14) . Sfnilar 1nÈeractl-ons

7 (ec. L4) 3 s- + coPh o

(132) ( 133) (134) BB. at C-2, C-10 or C-7 , C-1 I of the ketone (L29 ) rnfght explaln fÈs fallure to react.

The lnpracttcablllty of a double rlng expanslon of keÈone (L29) necesslÈated a reorderlng of the reacÈ1on scheme

3oT.Hzoz /seoz >, TBUOH

RE ref. 67f ( 128) (13s) 1) hydrolysis

Scheme 7 oRc"

(2) oxidation ooR cooH {Arndt-uis tert} 7

(r24) ( 136)

as shown in Scheme 7. As only a slngle rlng expanslon seemed possfble, oxygen functlonalfty had to be lntroduced aE the poÈentfal C-3 slte before chain homologatLon. This Itas achieved by a Bayer-V111fger oxidatLon of t adamantanone (128) whtch gave the lactone (135 ,67 OxfdaÈfve cleavage co the ketoacld (136) was expecEed to release a C-7 sidechafn progenltor r¿hlch would have funcElonallty thac 1s chemlcally dlstingulshable Srum Èhat 89.

74 aÈ C-3. However desplte good llterature precedenÈs for other lacËones, this reacÈ1on, whfch utllLzeð. ruthenLum tetroxlde as Èhe oxldfzlng agent, could not be carrfed ouÈ reproducibly Ln good yield part,lcularly when the reactlon was scaled up. The problem lras probably lnherent Ln the mode of ruthenium t,etroxfde generatlon sfnce qulEe often only starÈ1ng materlal was recovered. Thfs fruplied thaE the oxf dant lras not always belng generated ef f ectf.vely, a tuO. s1Èuation that has been encounÈered by other" Insertfon of the second carbon atom lnto the C-7 side chaln ¡¡ith retentfon of conffguratlon can be envisaged as befng approached by an Arndt-Elst,erÈ reacÈlon.

t-l

t'RC ù

Pb (oAc) T2/bz u ( r38) ref. 67b,j (137)

CE Scheme 8 { cyanatíon}

cooR CN {hydrolysis }

(124) (r3e) 90.

The Èhird pathway (Scheue 8) to the ketoacfd (124) involved an lnltfal rfng cleavage of an adamanÈane system that already conÈalned oxygen funcÈfonaltty aE the potentlal C-3 posftlon. Thfs Procedure would, ln prLnciple, ledd,to a shorÈer synÈhesls of the lntermediate

(L24) than etther of Ëhe previous tno rouÈes, Schemes 6 and 7 . The llterature proc"d.rt.67b' i of treatment of adamantan-1-ol with lead Eetracetate and lodfne Ín hot benzene f.nduced a radical fragmentatlon reacÈ1on and produced Ehe therrnally uns table ketotodfde (138) . The correct numb,er of carbon atoms requlred fn the C'7 sl-de chaln of the ketoacfd (LZe) was exPected to be obtalned by a nucleophll'tc substitutlon on tþe ketotodtde(138) by cyanlde Lon to glve the ketonltrlle(139). Subsequent hydrolysls rnighE Èhen yfeld the deslred acld

( r40)

the hfndered naÈure of the CH2I grouP 1n compound (138), the cyanide lon was acttng preferentlally as a base ra the r than as a nucleophtle. 91.

3.3 In Chapter 1, 1È lras shown that, ret.rosynthetlc

analysfs of the lceane ca r bon skeleton gave rfse to Ewo

pos s lble subs Èructures (7) and (8) thaE lrere derlved from

a s l-ng Ie bond disconnectlon. Further analysts of the subsÈructure (7) was dLscussed at length. However, the

(7) (8)

construcÈ1on of the Lceane framework from substructure (8) has not been prevlously studfed. Sultable actlvatlon for rLng closure nfght be provided by the dtketone (141). Although co¡trpound (1ó1) would possibly exlst fn the aldol

OH o

(14r) (r42)

75 form (142) , lhe tno components nlght form an equllfbratfng ml-xture ln solutlon and a pinacol coupllng 76 procedure mlght generate the dlol (143). I È rJas envfsaged that Ehe correcE orfenËatlon of che two three- carbon brtdges ln the dtkeEone (141) mtghE be dlfflculc 92.

( 143)

to assemble. An adaptatÍon of the lntramolecular Dlels-

A1 der chenlstry descrfbed ln Chap Èer 2 ¡vas consfdered to

I bea possible solutfon to thts problen (eq. 15).

H ct ct I l Z+ cl É

( 14s) (so¡ (144)

(eq. 15)

OH cl

cl (r47) - (146) 93.

77 a Annelatlon of cyclodeca-3 ,8-diene-1 , 6-dlone (f44) with tetrachlorothfophene-1r1-dfoxfde (56) was expecÈed Eo give the int,ermediate (145) whlch mlght then further 76 cycllze to the dlone (146). A plnacol type reacÈLon of the dlone (146) would yleld the pentacycllc dlol (147).

Unexpectedly, under conditlons s fnllar Èo those used fn previous examples descrlbed 1n Chapter 2, the dlenedione (144) fafled t,o react with the thlophene dioxfde (56). At higher tenperatures, extensive deconposltlon occurred both when the reactlons rÍere conducted 1n the melt and in solut.lon and no recognlzable products could be fsolaÈed. As sulphur dloxfde rtas evolved 1n these reactfons, 1t appeared that at leasÈ the fnttfal Dlels-Alder reactfon was taking place. Some evldence for this lras provl.ded by the IR spectruo of the crude reactlon produced whtch had _l an absorption of 1610 cm that could be consfs tenÈ wlth elther of the structures (145) and (146) but addftlonal absorptions between I66O and 1680 .r-t tnferred that double bond conJugatlon nas also occurring at some stage to form an unsaÈurated carbonyl system. The presence of I rnulÈtple resonances ln the olefinic region of the H NMR spectrum made 1E unclear as to wheÈher any furEher lntramolecular cycllzatlon nas proceedlng to glve the teEracycllc dlone (146) or related conpounds.

Slnce the requlred Dlels-Alder reactlon (eq. 15) could

no E be achleved aÈ the dlenedlone (1áó) stage, the cycloaddlrlon of ÈeErachloroÈhtophene dloxtde (56) wlÈh the lmmedlare precursor Ëo Èhe dienedlone (f44), trans- 94.

9, 10-dfhydroxy-1 ,4 , 5,8,9 , 10-hexahydronaphthalene q6^o (148) , (eq. 16) , was lnves tigated . Thfs react Lon

cl OH ct + ct OH

cl (s6 ) ( 148) H OH I

(eq. 16) ct ri OH ct (r4e) CI

cr É

o ( 145)

proceeded cleanly to give the adduct (149) 1n virtu- alIy quantitative yield. Although many literature precedent,s exist for the cleavage of trans L r2-diols to diketone conditions have yet to be found that " 177 wiIl transform the diol adduct (149)to the dione (f45) . 95.

In conclusfon, the ulÈimaÈe success of Èhe chemlcal potpourrf presented 1n this Chapter 3 can only be deÈermfned by furÈher experlmentattron. 96.

CHAPTER FOUR 97.

GENERAL :

(1) Melting polnts (np) were determined using a Kofler hot-stage nelting point apparatus, arranged under a Reichart microscope, and are uncorrected.

(2) Infrared spectra (IR) were recorded on either a

Jasco IRA-1 or a Perkin-Elmer 397 grating

lnf rar ed spect.rometer. they rlere measured as

solutlon filus or as Nujol muI1s, us ing the I 1603 cm band of polystyrene as a reference. Only the signlficanE bands are quoted.

(3) P"oþ,." nuclear nagnetic resonance specrra(rliNMR)

were recorded on either a Jeol JNM-P MX 60

spectroneter operatfng at 60 MHz or a Bruker I,¡P

80 spectroneter operatlng at 80 MHz. They Iùere measured in an approprfate deuterated solvent, uslng ÈeÈramethylsllane as an Lnternal reference. The characterisÈ1cs of Ehe spect,ra are expressed as follor¿s: solvent; chemícal shift (ô) ; multiplicity, s(singlet), d(doublec), t(trfplet), q(quart,et), rn(multtplet), b(broad), flrst order coupling constanÈ (J) ln Hz, to the nearesE I Hz; 98.

relative intensfÈy as Ëhe number of hydrogens (tt); assignnent. The centres of doubleËs and multiplets are usually quoÈed.

(4) 6o"bon nuclear nagnetic resonance spectra(tNMR)

!¡ere recorded on a I,JP B0 spectromeÈer oPeraÈ1ng at 20.1 MHz. They llere measured in an appropriate d.euterated solvent using either the cenËral Iine of the deuterochloroform tríp1eÈ or tet.ranethylsilane as an lnternal reference. The data are expressed as follows: solvent; chemlcal shtft (6 ); multipliclty, lf determLned 1n a separate off- resonance experlment; assfgnment . All sPectra of chlorfnated compounds of the type (62) were measured using a pulse delay time of 4 sec.

(5) Mass spect,ra (MS) were reêorded on either a HiEachÍ Perkin-Elmer RMU-7D or an AEI MS-3074 double focussfng spectrometer which both operaEed at 7O eV. Only the molecular and/or major fragmenE ions are quoted.

(6) Elemental analyses Ì.Iere carried out by the Australian Microanalytical. ServÍce 1n Melbourne. 99.

(7) Analytical gas-11quÍd chromaEography (GLC ) was carriéd out on either a Pye Unicam 104 or a Pye Unicam GCD chromatographs equipped wíth flame f.onizatlon detecÈors. The following columns

I^tef e uSed:

(a) 1.6ru x 4 ¡nn L5% 0V 101 on VaraporÈ 30 (80- 100 mesh), (b) 2ur x 3.2 mm Li¿ SE 30 on Varaport 30 (80- r00 mesh), (c) 2m x 3.2 mm lsi¿ FFAP on Varaport 30 (80-

100 mesh).

Nitrogen was used as the carrier gas and the

flow rate was 40 nl/min for all columns.

(8) Htgh pressure llqufd chronatograph (HPLC ) was carrled ouÈ on a I.Iaters Assocfates ltquid chromatograph equipped wlth a R401 differential anl * Kün po l?qd'L'( (3o,nr¡trc53io6 lvlel.r&. refracEometer¡ The following columns were used:

(a) [.laters Assoclates Radial-Pak B carE,ridge, (b) I.Iaters AssociaÈes Radfal-Pak A cartridge (reverse phase),

Size B (310-25), (reverse phase).

(e) Flash chromatográphy was carried out accordLng 80 to the meÈhod of SttLl et al . The absorbent used was ùlerck Kleselgel 60, # 9385 (230-400 mesh).

(10) Analytlcal thtn layer chromatography (TLC) was carrfed out on 2 x 7 cn alurnLnLurn sheets precoated wtth Kf eselgel 60 FZS'+ ,ll 5554.

(11) All organic solvents were puriffed by standard 8I procedures . In thls text ¡ peÈroleum ether refers to Èhe fraction of bp 63-67oC.

( 12) AlI (dried) organLc extracts lrere evaporated at aspfrator pressure on a Buchf. rotary evaporat,or. t0I .

CHÀPTER 1

t.1 2 ,3- Bis ( bromometh11l ) - 1 , A-dibromo-2-butene ( 23 ) . 24 The tetrabromide (23,, mp 158-159"C (1it. mp 158- 159oC), was prepared in 65S yield by the successive

treatment of 2 r3- dimethyl- 1 ,3-butadiene v¡ith bromine and. 24 N-bromosuccinimide. The method, of Cope and Kagen was

¡nodif ied l-n the f ollowing way. À cata Iytic amount of

azobisJ-sobutyronLtrlle rather than benzoyl peroxide was added after the addition of N-bromosucclnirnide and the mixture was heated at reflux for 3h under a 100vI lamp.

2 ,.3- Bis ( iodomethyl ) - 1 ,3-butadLene ( 20b) . To a partial solution of the tetrabromj-de (,231 ( 20 .09, 0.05 ¡nol) in acetone (200 ¡rI) ltere added sodium thiosulphate pentahydrate (25.79, 0.15 moI) and potassium

lodide ( 38 .59, 0 . 15 ¡nol- ) . The mixture was vigorously stirred. for th at 45oC during which time the colour of the mixture changed from orange to dark red to pale yellow. The suspension was poured onto ice ( 3009) and extracted with ether (1 x 200 ml, 2 x 100 mI). The combined ether extracts were washed with saturated sodium chloride solution l2 x 50 mI), dried (MgsOq) and evaporated to give a pale yellow solid, (15.5g, 93$) that decomposed on standing at room temperature.

Recrys ta I I i za t ion from aqueous ace ton e ga ve the di - r02.

iodide (20b) as white needles, mp 95-96"C (dec). The product was stored at 0" C as a 0. 1 molar solution in ether.

The above procedure could be scaled up to at least 80g of the tetrabromide (23) with similar results.

IR (NujoI) u = 3I00r1590,900 ..-l I H NMR ( cDcI3 ) [ = 5.64(s,1H, :st1lL;, H-CH=)r

5.50(s r 1H, ü}î: H-CH=) r

4.16 ( s,4H, CH2 I) ppm.

2,3-Bis ( acetoxvmethvl ) - 1, 3-butadiene (20c). To a solutlon oE the crude di-iodide (20b) ( 15.59,

46 .0 rnmol ) Ín acetonitri Ie (200 ¡nI) was added silver acetate (15.69, 93 .0 nmol ) . The mixture was stirred, in the dark for th at 40oC then poured. onto ice ( 200g) , filtered, and extracted with ether (2 x 100 ml, 1 x 50 nI). The combined ether extracts vtere washed with 1 0S sodium Èhiosulphate solution (50 url) and saturated sodium chloride solution (2 x 50 mI ) , dried ( MgsOa ) and evaporated to give a yellow oil ( I .5g, 92\, . Evapora t iv e distillation at 90-95" C/0.2 mm gave the d,iacetate (2Ocl , 23 l7 .959, 86t ) as colourless prisms, mp 41-43oC (Iit. mp 42-43oc).

The above procedure could be scaled, up to at least 50g of the di-iodide (20b) with similar results. r03.

2,3.-Bis(hydroxymethyl)-1,3-butadiene (20d) .

To an emu I s ion of the crude diacetate (20c) (3.89,

19.1 mmol) in water ( 15 mI) was added a solution of sodium hy droxi de (1.69g, 42.3 mmol ) in water (15 ¡nI). the ¡nixture was stirred for th at 40" C' then diluted with tetrahydrofuran ( 15 rrl) and saturated with sodium chloride. The organic Iayer was seParated and the aqueous phase was extracted with tetrahydrofuran (4 x 10 ¡nl). The

combined, extracÈs vere dried ( l'tgSOq ) and evaporated to

glve an orange oi Ly 6o I id . The crud,e product rta s

dissolved, 1n methanol ( 25 nI ) and treated with decolori zíng charcoal. Re¡novaI of the qolv.ent gave a white crystalline solid, ( 1.7g ,77\) which was recrystallized from chloroform to afford the diol (20d) as white needles, mp 63.5-65oc (Iit.tt*n 64-65'C).

( Z ) -Dimethvt-2 ,3-Dimethvl-2-butenedioqte (2 +l . tt The diester (2+l ( bp 217 -218. C/ 1 atm, rit. "on

1O6" / 17 mm) was prepared in 85t yield from 2,3-

dimethy Ìma Ie i c anhydride by the method of Ànwers and 27^ Cauer. u

IR (neat) u = 1740 , 1655, 1265 .*-l I H NMR ( cclq ) [ = 3.60(s,6H,oCH3 )r l-85

( s,6H, CH3 C) ppm. 104.

E)-and (zl-Dí methyl 2,3- Bis ( br omome thy I ) -2-butenedioate (25).

A mixture of the diester (2*l ( 2 ' 589, 15 ' 0 mmol) ¡ N- bromosuccinimide (5.8?g, 33.0 mmol) and azobisÍso butyro- nitrile (- 3 ¡ng ) in carbon tetrachloride ( 50 nrl ) s'as heated at reflux for 1.8h under a 100w Iight and a nitrogen atmosphere. The hot suspension was filtered and evaporated to give an equal amount of the E- and z- bromoesters (25a,b) (5.11g, æ lOOt), as a pale yellow oiI which was of satlsfactory purity for subseguent use.

I IR (neat) v = 1735r1640'12'70 c¡r- I NMR ( ccr'{ ) S = 4.40(s) ánd 4.16 " (s ), (4H¡CH2 Br) r 3 -83 ( s) and 3.75(s)(6H¡0CH3 ) ppm.

À portion (350 ng) of the crude pnoduct was Purified by flash chromatograPhY on silica geI with 7t ethYt acetate,/petroleum ether as the eluent. Further purification of þo.?h isomer could be achieved bY evaporative distillation at 100"C/0.05 mm.

E-isomer (25a) (first to elute) : Iiquid, 170 mg'

I IR (neat) u = 1740, 1635, 1270 cm- I H ( CCI ) S = 4.40(s,4H,cHZBtl' NMR '{ 3.83 (s,6H,OCH3 ) Pp..

Ìts m/e = 332, 330, 328 (Ì4t ) 105.

Z- ís ome r (25b) : Iiquid, 17O mg.

I IR (neat) : U = 1'135, 1640, 1270 cm- I H NMR (CCIq ): $ = 4.16(s,4H,CH2Br), 3.75 (sr6H,OCH3) pPm. l'{S z m/e = 332' 330, 328 (ut )

ÀnaI. Calcd for CeHtgBr20q : C 29.12 ¡ H 3.05.

Found. : C 28.92 ¡ H 3.03.

Dimethyl 1 , 3-Butadiene -2 ,3-dicarboxylate ( 20e) .

To a solution of the crude bromoesters ( 29a,b ) (4.809, 14.5 mmol) in acetone (50 nt) were added sodium thiosulphate pentahydrate (11.189, 45.1 mmol) and potassium iodide (7 .499' 45.1 mmol) . The mixture rta s stirred for th at 45"C, then poured. onto ice (75g) and extracted with ether (3 x 25 nl). The combined et,her extracts were washed, with saturated sodÍum chloride solution ( 10 ml), dried ( MgsOq ) and evaporated. The residue vras evaporatively distilled at 75-80"C/O.5 mm to give the diester (2oel , (2.19, 85c ) as a colourless Iiquid. The spectral data for this compound erere in 28 a greement with those reported. 106 .

6 ,7 - Bis ( acetoxymethyL ) - cis -4a ,5r8rBa- tetrahydrona phtha lene - 1 ,4-di one (21c).

A solution of fteshly sublimed ( 120" C/25mm ) benzoquinone (2.18g, 20.2mmot) and redistÍlred diacetate (20c) (4.0g, 20.2 mmol), in benzene (25 mI) was heated. at refrux for 18h under a nitrogen atmosphere in the dark. The resurtant light yeJ,row sorution was evaporated. to give a dark yellow oir which crystarrized. on trituration with cold ( 0 o C) ether. The product was filtered and. washed with cold ether to yield the diacetate adduct (21c) as an off-white sorid ( 3.ag) . The combined washings and supernatant were evaporated to give a yerlow-bro$¡n oil which was crystarlized from and washed. with ether to provÍde an additional 0.8g of add,uct l21c) (totaI yietd : 4.2g, 68t). Recrystallization from benzene/carbon tetrachroride produced off-white needres, mp 139-141oc.

IR (NujoI) U = 1735, 1690, 1230 cm- I I H NrfR ( cDct3 ) $ = 6.75(s,2H,H2;1, 4.75 (poorly resolved ABq, J = 12 Hz, 4H,CH2ORc), 3.25(m,2H,Hh.,g.),

2.43 ( m,4H, HS ) 2 .10 ,g ( s,6H, OCOCH3 ) ppm. l3 C NMR ( cDcl3 ) 6 - 198.8(s,C¡,q), 170.5(s,OCOCH3 l, 139.1 (d,C2,31, 129.4 (s,C5,Z ), 62.9 (t,CH2OAc), 45.9(d, Cq",g"), 26.9(t, CS g l, r07.

20.7 (q, oCoCH3 ) Ppm. + MS m/e = 246 ( u. CH3 CooH ) , 204, 186.

AnaI. CaIcd for C15H1g0r{ : C 62.74 ; H 5.92. Found :C62.52¡H5.88.

6,'l -Bis- ( hydroxymethyl ) -cis-4 d, 5,8,8a- tetrahydronaphthalene-1, 4-dione (21d) . À solution of recrystallized diot (20d1 (45L m9, 4.0 mmol) and freshly sublimed benzoquinone (4rZ urg,4.0 nmol) fn 1,2-dimethoxyethane (8 nI) $ras heated at reflux for th under a nitrogen atmosphere in the dark. On slowly cooling to room temperature the pale yeIlow solution deposited fine off-white needles which s¡ere filtered and washed with ether to give an analytically pure sample of the diol adduct (516 mÇ) r mp 1 16-1 18oC. Àn additionaL 234 mg of adduct ( 21d) was obtained by evaporating the filtrates and washing the residue wit,h ether r ( toÈaI yield : 750 R9, 84t ) .

IR (Nujol) : u = 3340, 1680 cm- I NMR ( cDcI 3 / co3 oo , 221) :ô = 6.67(s,2H,2,3 ), 4.23(s,2HrOH), 4.03(poorly

resolved ÀBq, J = 12H2, 4H,CH2Ol ¡ 3.35(m,2H, Hb.,g, l, 2.43 (m,4H,HS,g ) ppm. t3 C NMR (cD3OD) ô - 201.7(s,Ct q )140.5(d,C2 3 ), 108.

132.5'(s'C6,7 | ' 61.7(t,CH2OH), 47.5(d,Cqa,Ba 27.9 (È,C5 ), )' t I

Ppm. 186. MS .m/e= 222 (Mt l, 204.

Anal. CaIcd for C¡2H1t+0'{ : c 64.85 : H 6.35. Found C 64.51 : H 6.2O.

Dime thvl 1 ,4-Dioxo-cis-4 a,5,8,8a-tetrah v dronapthalene-6,7- dic arboxvlate (21e). A solution of f reshly subl-imed benzoquinone (2 ' 48g ' 23.0 mmol) and dist,illed d.iester (20e) (3.91S' 23'O mmol) inbenzene(30urI)lfasheatedatrefluxfor32hunder a nitrogen atmosphere in the dark' The solvent was (0"c) evaporated and the residue htas washed with col-d (4'69 72\1. ether to yield an off-wnite sotid ' Recrystallization from dichloromethane'/petroleum ethe r afforded the diester adduct (21e.) as of f -white f Iakes, mP 133-1350C. u 1740 1730 1690, 1650, 1600, IR (Nujot ) = ' '

1 260 .*-l I 3.83 H Nl,lR ( cDCf 3 ) 6 = 6.83(sr2H,HZ,3 ), (s,6H¡oCH3 ),3.38(m ¡2H¡H4a,8a I '

2.7 3 ( m, 4H, H5 I ) pPm.

l3 ( ô 197.7 (s,CI q t L67 .3 s, CooCH 3 ) r C NMR (CDCI3 ) : , ( C6 139.1(d,CZ 3 132.6 ) , t ", ,7 52.2(d,Cq- ) , 45.0(q, OCH3 ), 6t I a 25.3(d,CS ) ppm. t I (Mt l'1s m/e = 278 ). 109 (-- tto)

6 r7-Bis-(acetoxymethyt )-trans-2,3, 4a, 5, 8,8a- hexahydronaphthalene-1' 4-díone (2"1, .

To a prehydrogenated suspension of 5t rhod,ium on carbon catalyst (ilohnson Matthey Chemicals, 27Oyg) in 95t ethanol (60 ¡nl) was added the diacetate adduct (21c)

(2.69, 8.5 mmol ) . The mixture was stirred at ambient temperature and atmospheric pressure until the uptake of hydrogen had ceased (ca. 2h). The solution vras filtered through ceIíte and the solvent vras evaporated to give a pale yellow oiI (2.56g, 98t ) , which crystalLized on standing. Recrystallization from chloroform,/ether afforded the trans-ketoacetate 121 ; I as colourless prisms, mp 90-92oC.

I IR (NujoI) u = 1730, 1'l'l 0, 1230 cm- I H Nl.{R ( CDC13 ) ô = 4.62 (poorly resolved ABq, iI

13 Hz ,4H, CH2 OAc ) ,2 .7'l (sr4H'HZ 2.50(m,6H, 13 l' Hb"rB. and ), "trt 2.03(s,6HrOCOCH3 ) ppm. l3 c N¡4R ( cDcr 6 207.4(s,C1 3) = ,q),, 170.0 ( s,OCOCH3 129.A ) r ls,C5 ,71 , 63.0(t,CH2OAc ), 46.2(d,Cq",Bà, 37.2 (8,C2 28.7 (t,C5,B ; ,, ) ' 20.7 (qrOCOCH3 ) pprn.

MS m/e = 24A (Mt - CH¡ COoH ) , 206 , 188. I r0.

6 ,7 - Bis - ( acetoxymethy I ) -tra ns -2 , 3 ,4ar5,8,8a- hexahydronaphtha lene - 1, 4-dione 121'. To a prehydrogenated suspension of 5C rhodium on carbon catalyst (.fohnson Matthey Chernicals, 27Oyg) in 95t ethanol (60 ml) was added the diacetate adduct (21c)

(2.6g, I .5 mmol ) . The mixture tiras stirred at ambient temperature and atmospheric pressure until the uptake of hydrogen had ceased (ca. 2h). The solution vras filtered through ceIíte and the solvent was evaporated to give a pale yellow oiI (2.569, 98t ), which crystallized. on standing. Recrystallization from chloroform,/ether afforded the trans-ketoacetate (21 ) as colourless prisms, mp 90-92oC.

I IR (NujoI) u = 1730, 17 10, 1230 cm- t H Nl,lR ( CDCI3 ) ô - 4.62(poorly resolved ÀBer J

13 Hz ,4 H, CH2 OAc ) ,2 .7 7 (s,4H,HZ (m,6H, 13 ), 2.50 Hh"rB, and ), "t rt 2.03(s,6H¡oCoCH3 ) pp*. l3 C NI'IR ( CDcI3) 6 207.4(s,CI = ,4), 170 .0 ( s, oCoCH3 129 .A ( s, C5, ) r ,7 ) , 63.0(t,CH2OAc l, 46.2(d'C4",8À, 37.2 (t,C2,3 l, 2A.7(t,C5,g ),

20 .7 ( g, OCoCH3 ) ppm.

MS m/e = 248 ( ¡¿t - CH¡ CooH ) , 206 , 188. 111 .

6 ,7- Bis- ( acetoxymethyl ) -ci s-? ,3 ,4a r5 ,8,8a-hexahydronaphthalene -1 ,4- d.ione l21l . To a rapidly stirred, ice-cooled solution of Lhe diacetate adduct (21c) (3.06g, 10.o mmol ) in acetic acid

( 1 5 mI ) was added zinc dust ( 1 .50 g, 23 .0 mmol) in small portions over 5 min. The mixture was stirred at 10oC for 10 min then at ambient temperature for 1/Z n. Acetone ( 5 mI ) vras added and the míxture was filtered through celite. The filtercake was washed with acetone (2 x 5 mI) and the combined filtrates v¡ere concentrated under reduced pressure. The residue rlas taken up in dichloromethane ( 5 0 mI ) and. washed wit,h water (2 x l0 mt ) and saturated sodium bicarbonate solution (2 x 20 mI). Removal of the solvent af ter drying ( lrgSOq ) gave a white solld (2 .75g , 89t ) , which was recrystallízed from dichloromethane,/petroleum ether to provide the cis-ketoacetate (29'l as colourless flakes, mp 109-111oC.

t IR (Nujol) u = 1730 1715, 1240 cm- I H NI'{R ( CDCI3 ) 6 = 4.64 (poorly resolved ABÇ[r J

12Hz , 4H , CH2 OAc ) . 3 . 0 5 ( m , 2 H H4 g ) . , . 2.77 (m,4H,H2,3), 2.35(m, 4H, H5rg), 2.08 (s,6HroCoCH3 ) ppm. l3 c Nl'lR ( CDC13 : $ 207.9(s,Cl ) = ,4),

170.4 (s,OCOCH3 ) r 129.5 (s,c6 l' 63.0(t¡cH2oAc), 17 IT2.

44.7(d,Crr",g.), 35.9 (t,C2,3 ) r

26.3 ( t, CS (qroCoCH3 ) PPm. ,Bl ,20.7 MS I tt/e = 308 (Ut ), 248, 206, 188' Àna1. CaIcd for C¡5HZO0S: C 62'33 e B 6'54' Found : C 62.00 ¡ H 6.70.

6,7-Bis - ( bromometh v1 ) -trans-2 , 3 ,4a, 5 ,8 , 8a- hexahy dronaphthalene-1, 4-dione (33a) . À solution of the cis-ketoacetate ( 29 ) ( 308 m9, 1 ' 0 mmol) in 33$ hydrogen bromið,e/acetic acid (5 ¡nL) was stoppered and stirred tor 1/2 tr aÈ ambient temPerature. The solutÍon was then poured into ice-coId 1 0t sodium hydroxide solution (,25 mI ) and extracted with dichloromethane (1 x 20 ¡nI, 2 x 10 rnl)' The combined extracts were washed with water (2 x l0 mI), dried (MgSOt+) and evaporated to give a white solid. Recrystallization from dichloromethane,/petroleum ether gave the ketobromide (33a), 285 mg (81t) as colourless flakes, mP 141-142oc'

I IR ( Nujot ) u = 1710 cm- I 10 Hz, H NI'IR ( cDcI3 ) ö = 4.05 and 3.89(ABq, J = 4H,CH2Br),2.75(s,4H,H2,3 l, 2'58' and nt (bs,6H,Hha,Ba rt ) PPm' l3 (CDC13): 6 ), 132.4(s,C6,7 c NÞlR 207.5(s,C1 ,r* 46.6(d,Cqa,Ba ), 37.5(E,C2,3 l,

30.3(t¡CH2Br), 29 -2(t,C5 I ) PPM.

MS m/e = 270, 26A (Mt HBr), 190. 113.

Anal. Calcd for CIZH¡qBr202 : C 41.17 ¡ H 4.03.

Found : C 41.03 ; H 4.38. Under similar conditions, the trans-ketoacetate (27, also gave (3la).

6,7-Bís ( hy droxvmethvl ) -tran s-2 ,3 ,4a ,5 ,8 ,8a-hexahydronaphthalene -1 ,4- dione ( 33b) . To a suspension of the cis-ketoacetate lzq, (462 m9,

1 .5 mmol ) in water (+ mr) was added p-toluenesulphonic acid (50 ng). The míxture eras stirred for 30h at 40 o C then neutralÍzed with potassium carbonate and. saturated with saIt. The product v¡as extracted into tetrahydrofuran ( 1 x 20 mI , 4 t. 10 ¡nI ) and treated with de co louri zing charcoal. Evaporation of the solvent gave an off-white solid , 255 mg ( 76t ) , which was recrystallized from methanol to give the E-æ-ketoalcohol ( 33b) as colourless plates, mp 175'177oC.

I IR ( Nujot ) u = 3400, 1710' 1120 cm-' I H NMR ( cD3 0D) ô = 4.47(s,2H,oH), 4.04 and 4.16(ABq, J = 12Hz,4H,CH2OIt

2.78(s,4H,H2 3 )' 2.5O(m,6H, Hb",B" and I "u,, PPm' I3 C NIt'tR (CD3OD) : ô 211.4(ct q ),132.9(c6 71, tt

61.5(cHzol ) 37 .7 '47.2(Ca a, I a (C2,31,29.5(CS,B) pPm. tts m/e = 206 (¡lt H20), 188. 114.

Anal. Calcd for C¡2H15O4 : C 64.27 ¡ H 7.19. Found : C 64.01 ; H 7.17. Under similar conditions, the trans-ketoacetate (21l- al-so gave ( 33b) .

6 ( 8a-hexahydro- '7- Bis hydroxymethyl ) -ci s-2 ,3 ,4a ,5 ,8, naphthalene-1,A-dione (fs ¡ .

To a cooled ( 5" C) solr¡tion of the diol adduct ( 21d)

( 1 .1 1 g, 5 .0 mmol ) in acetic acid (10 ml-) r/ùas added zínc dust (654 m9, 10.0 murol) in small portions over 3 min.

The mixture was stirred and. a I lowed to \.ra rm to ambient t émpe ra ture over 2h. Acetone ( 10 mI ) r.tas added and the mixture t¡tas filtered through celite. The filtercake vtas rinsed with hot acetone (20 rnl) and the combined filÈrates r.¡ere concentrated under reduced. pressure. The residual oiI lras dissolved in warm chlorof orm ( 10 mI ) and the product riras precipitated by the dropwise addition of ether ( 15 nl ) with vigorous stirring. The precipit.ate $tas filtered and washed with dichloromethane,/ether (1:1) to give the cis-ketoalcohol (3Ê), (1.08g, 96t) as a white soIid. Recrystallization from chloroform yielded an analytical sample, mp 105-107oC.

I IR ( cDcl3 ) u 3240, 17 10 cm- I H NMR ( cDcI3 ) ô = 4.05r(bs,4H,CHZ0)' 3.20(vbs,2H,OH), 3.05 (mr2H,

H,*. ) 2.74 (bs,4H ) rBa , 'H2 ,3 ' 115.

2.40 (m,4H,HS ) ppm. I3 18 C NMR ( CDC13./Co3 Oo, 3: 1) : ô 2O9.6 ( C¡ ) = ,q , 134.7 ( C6 61.3( CH20) ,Z ), , 45.0 I C4 35.7( CZ a,B"), ,g ) , 26.4(cS e) ppm. Ms z m/e = 206 (¡¿t - H20), 1BB. ÀnaI. Calcd for C¡2H¡5Oq : C 64.27 ; H 7.19. Found. : C 64.34 ¡ H 7.44.

cis- 2, 2-Dimethyl -6, 9-dioxo- 5, 5a ,6r7 rg,g,9a,10-

octahydroriaphtho 1.6, 7 -e I oxeÞa ne (37).

Method 1 To a partial solution of the cis-ketoalcohol (39, (224

m9, 1 .0 mmol ) in acet.one (7 nI ) was added anhydrous copper sulphate (640 m9, 4.0 mmol). The mixture lras heated for 5h at refrux under a nitrogen atnosphere then coored, and firtered through celite. The sorvent vras evaporated, to yield the ketal (371 (222 m9, 84r) as a white sotid.

I IR ( Cocl3 ) V= 1715, 1390, 1370, 1210 cm I H NI'{R ( COCt3 6 - 4.03, (bs,4H,H,rrIl 2.96(m,2H,H5a,9a ), 2.73(bs,4H,HZ,g ) 1.7- 2.6(,bmr4H,HSrl0 l, 1.38 (s,6H,CH3's) ppm.

MS m/e = 264 (Mt ). Àccurate mass : CISHZO0q requires 264.136148 Calcd 264.135170. 116

Method 2 À. À partial solution of the diol adduct (Ztd, (222 19, 1.0 mmol) in acetone (Z ml) containing anhydrous copper sulphate (240 m9, 1.5 mmol) was sLirred. for 6h at room

temperature under a nitrogen atmosphere. The mixture was filtered and the firtrate nas evaporated to give the ketar (36) C215 m9,85t) as an off-white solid. This material tended to aromatize on storage and. sras not purified before subsequent use.

IR ( cDct3 ) v = 3010, 1695, 1600, 1380, 137O. _l 1210 m I H NMR ( cDcl3 ) : $ = 6.56(sr2HrH7 I ) t 4.04(bsr4H,H,r rIl ) t 3.15(m,2H,Hq q 1.6- 'âr-â | , 2.6(bm,4H,H5 rI0 t I 1 . 4 0 ( s , 6H, CH3 s ) PPM.

¡.{s m/e = 262 (Mt

Àccurate mass : CI S Hl g 0q requÍres 262 .120499 ¡ CaIcd 262.120302.

B. To a cooled (5oC) solution of the foregoing ketal (36)

(36 m9, 0.14 mmol) in acetic acid/acetone (3:1, 2 mI) was added zinc dust (90 m9, 15. 1 mmol ) in small portions over

1/z min. The mixture vras stirred and a llowed to tdarm to ambienÈ temperature over t6h. The zinc salts hrere rt7 .

filtered and the acetone \iras removed under reduced pressure. Dtchloromethane ( 15 ml) was added to the

residue and the solution $ras washed with rdater (2 x 5 ml)

and 5t aqueous sodium bicarbonate (5 ¡nl). The solvent vra s

dried (MgSOq ) and evaporated to give an off-white solid

(28 m9, 77*') . Thi s mat,eria I wa s identica I in all respects

to the ketal ( 37 ) prepared by t{ethod 1

2.2 2, 3-Dimethyl - 1, 4-benzoquinone .

A ¡nixture of sulphanilic acid dihydrate (52.5g, O .2 5 moI) and anhydrous sodium carbonate (13.25g, O.125 ¡noI)

was dissolved, in warm water ( 250 mI) then cooled to 15oC. A solution of sodium nitrite ( 18.5g, O.27 ¡nol) in

water ( 50 ¡nI) was added and the resultant solution was immediately poured on to a mixture of concentrated

hydrochloric acid (53 ml, 1.375 moI) and ice (300g). The diazonium solution nas placed in an ice bath for 25 min then sIowly poured, into a vrell-stirred solut,ion of 2,3- dimethylphenol (¡0.5g, 0.25 noI) and. sodium hydroxide

( 55q , 1 .375 mol ) in water ( 300 ml ) containing ice ( 2009) . The mixture eras stirred for th without external cooling then heated to 45oC. Sod,ium hydrosulphite (1159,

0.55 mol ) was added and the suspension which formed vuas coagulaÈed by further heating to 65"C. After cooling to 5o C, the aminopheno). t¡as f iltered and washed with cold water until the filtrate vras colourless. The cream- 1IB. coloured product (ca. 55g) was added to water (50 mI) acidif iecl with concentrat.ed sulphuric acid ( 30 mI ) and the mixt,ure was briefly boiled with decolourizing charcoal and filtered. The pink filtrate was added dropwise over Ih to a solution of ferric sulphate nonahydrate (179.Ag, 0.32 moI) in 3t v/v sulphuric acid (500 mI) contained within an apparatus arranged for steam distillation under reduced pressure. Steam at a pressure of 80-90 mm was passed continuously through the mixture during the addition of the aminophenol and distillation was continued for 1/z ¡. About one litre of distillate rras collected. The product (5.59) was filtered and by extraction of the filtrate with ether (200 mI, 100 ml), an additional 10.59 of quinone

(total yield 169, 45S) ldas obtained as yeLlow needles, mp 55-5?oc (tit.78" mP 56.5-57.50C).

2, 3-Dimethyl - 1, A-hydroquinone . To a solution of 2,3-dimethyl-1,4-benzoquinone ( 16.09, 0. Il8 mol ) in acetic acid (70 mI), $ras added water (35 mI) and zinc dust (16.0g, O.245 moI). The mixture was boiled for th h then filtered. The residue vtas washed with hot

$rater (2 x 60 mI ) and on cool ing the h ydroqu ino n e crystallized from the filtrate as smalI white plates (159,

92t), Rp 195-198"C ( subI. ) ( Iit..78b mp 22oo c, dec). 119 .

1 ,4- Dimethyl -2 ,3-dimethoxybenzene . To a stirredr t€fluxing solution of 2r3-dimethyl-1r4- hydroquinone (13.09, 94.2 mmol) in methanol (100 nl) containing dimethyl sulphate ( 100 ml), was added a solution of potassium hydroxide ( 1309, 2.32 ¡nol) in methanol (650 nt) over 1/qn. The mixture s¡as heated for 11/2 h then steam distilled at atmospheric pressure. As the methanol $ras removed, the volume of the pot was kept constant by the periodic addition of hot water to prevent the mixture going dry. The distilLate (ca. 2Ll was coo le d and filtered to give the dimethyl ether as white flakes (12g)t mp 78.5-79.5oc (rit.78a mp 78oc). Extraction of the filtrate with ether (2 x 100 url) afforded an additional 1.69 of product (totaI yield 13.69, 87t). t H N!4R ( Cctu ) ô = 6.36(s'2HrArH),

3.65(s,6H¡OCH3 L

2 .08 ( s,6H, ÀrCH3 ) ppm.

2,3-gis (bromomethyl) -1, 4-dimethoxybenzene (42) . À mixture of 1,A-dimethoxy-2,3-dimethylbenzene (6.649,

4.0 mmol ) , N-bromosuccinimide ( 16.09, 9.0 mmol- ) and azobisisobutyronitrile (2 mg) in carbon tetrachloride ( 250

¡nI ) vras heated at ref Iux for 4h under a 200W lamp and a nitrogen atmosphere. The suspension tras cooled, filtered and. evaporated to give an off-white solid which htas washed with acet,one,/petroleum ether ( 1:1). An additional amount r20

of product was obtained from the filtrate; (ÈotaI yield

10.59, 81t), mp 148- 152"C ( rir .37a mp 147-149oC) . The crude dibromide gradually decomposed on storage becoming yeIlow and releasing hydrogen bromide. It was therefore best to use it immediately for the next step.

I H Nl4R ( cDcl3 ) : S = 6.'l 2(s'2H,ArH), 4.66(sr4H,CH2Br), 3.81(s,6H¡oCH3 ) ppm.

5 r 8-Dimethoxy -1,2, 3, 4-tetrahydronaphthalene-cis-2, 3- dicarboxylic anhydride (41 ). Zinc dust (1.4S, 21.4 mmol) was added to an ice-cold

(9 94 .0 mmol in solution of ma Ieic anhydride .239 ' ) dimethyl f ormamide ( 100 mI ) . The suspension vtas Ì^tarmed to ambient temperature and a solution of crude 2 r3-

( (42 (6 21 .4 bis bromomethyl ) '1 ,4-dimethoxybenzene ) .929 ' mr¡tol) and maleic anhydride (2.1g, 21.4 mmol) in dirnethyl formamide (100 nI) $¡as added over 6h with the aid of a perfusor. After each hour, additional zÍnc ( 0 - 289' 4.3 mmol ) was adde<1 . The reaction rátas stirred f ot a f urther hour then filtered. The residue was washed with ether/díchloromethane (3:1, 2 x I00 ¡nI) and the filtrate was diluted with 1t v/v hydrochloric acid (400 mI). Upon separation of the layers, the aqueous phase was extracted wiÈh ether/díchloromethane (3:1, 2 x 100 nt) and the combined organic extracts were washed with watet l2 x 100 I2I.

ml ) and brine ( 100 ¡nI) . The solvent r.ras dried (MgSOq ) and evaporated to yield a yellow solid which vras washed with cold et,her to give the anhydride (+l;) (3.65g, 65t) as a white powder. A smaIl sample, recrystallized from et,hyl a c eta terlpetro Ieum ether, had a mp 210-211oC.

IR (cDcl g ) v = 3040, 2860, 1860, 1790, 1600 I cm I H NMR ( CDCI3 ) $ = 6.67(s,2HrH6 7 l, 3.73(sr6H¡OCH3 's),

3.43(mr4HrH¡ 4 ), 2.4-2.7 t (mr2H,H2,3 ) ppm. l3 c NMR ( CDCI3 ) : $ = 173.8(srCo), 150.7(s,Cs I

124.2(s,Cr+a,ga ), 110.1(d,c6 7 t

56.3 (q,OCH3 's), 40. 1( d, cz 3 , 21.5(trCI pp¡n. ,,* ) MS ß/e = 262 (ut ) .

Ac c ura te Mass: C¡aH1405 requires 262.084 1 1 5; Calcd 262.08328.

cis-6,7-Bis ( hydroxymet.hyl l-1 ,4-dimethoxy-5 ,6,7 ,8- tetrahydrona phtha lene (.+â ) . To a partial solution of lithium aluminium hydride (0.9049, 23.8 mmol) in tetrahydrofuran (80 ¡nI) h¡as added, dropwise over 10 min, a solution of 5r8-dimethoxy-1,2r3r4- tetrahydronaphtha Iene-cis - 2 ,3- dicarboxylic anhydride ( 4l:,

( 3.13g, 1 1.9 mmol) in tetrahydrofuran (50 ml). The r22. mixture s¡as heated at reflux for 5h under a nitrogen atmosphere then cooled to ambient temperature. !{ater (1 mI), 15$ sodium hydroxide solution (1 ml) and more water

( 3 mI) utere added sequentially and the inorganic salts r.rere f iltered. The f iltrate was dried (Na2 So4 ) and evaporated to leave a colourless oiI (3 .2g t c;a. 1 0 0t ) which crystallized on standing. Recrystallization from chloroform,/petroleum ether afforded an analytícaI sample of the diol (43) as colourless needles, mP 120-l22oC.

I ( v 3380 3020 2860, 1605 cm IR cDCI3 ) = ' ' t H ( Cocl-3 ) $ = 6.49(s,2H,H2rt+ ),

4.23(bs,2HrOHrs) r

369(s¡6H¡OCH3 ts), 3.57(d, ,t =

6Hz r 4H, CHZOrs),3.66(d, J =

H5 2.17 (m, 2H, H6 6Hz,4H, ,g ) , z PPM. l3 C Nt{R (CoCI3 ): ô 151.4(s,C¡ 4 ), 125.7(srCr+a,Ba ) t

106.9(d,Cz 3 )63.7 (t CH20rs)r t 55.5(q,oCH3 's), 37.3(d,C6 7 l, 24.9 (t,C5,B ) pprn.

MS m/e = 252 (Mt ), 234 (- Hzo).

AnaI. Calcd for C¡4H290'+ : C 66.65 ; H 7.99.

Foun d : C 67.0? ¡ H 7.82. I23. cis-6, 9-Dimethoxy -4a,5, 10, 10a-tetrahydronaphtho- t6'7-el -

2,2-dimethyloxepane (4+l .

A solution of crude cis-6,7-bis(hydroxymethyl)-1 '4- (43) ( dimethoxy-5 r 6,7 ,8-tetrahydronaphthalene 3.0S ' 11.9 mmol) in acetone,/2r2-dimethoxyproPane (221, 30 ml) containing anhydrous copPer sulphate ( 3. ag , 24 mmol ) was heated for 48h at reflux under a nitrogen atmosphere. The mixture q¡as cooled and poured Ínto 5t sodium bicarbonate solution ( 30 ml ) . The rna jority of the acetone !{as evaporated and the residue v¡as filtered through celite.

The f i Iter cake r,ras wa shed with dichloromethane ( 2 x 1 5

¡nI). The organic Layer stas separated, dried ( Mgsoq ) and concentrated to give the ketal (44) as a white solid (2.47g,71t) which was not purified further.

t IR (CDCI3 ) : v = 3000,2860. 1600 cm I H NMR (CDCI3 ): $ = 6.49(s,2H,H7,8 l, 3.73(s,6H¡OCH3 's), 3.60(d' J =

Aflz,4H,H4,lI l, 2.77(ð" J = 6Hz,4HrH5rl0 ), 2.06 (m,2H,H¡+arl0. ), 1.35 and 1.26(s,6H¡CH3 's) ppm. I3 C NMR (CDC13 ) : 6 = 151.3(s,C5,9 ) 125.4(s,C5ar9a ),101.0(s,C2 ), 64.5 (t,C4 55.5(q,OCH3 rt I l, 's), 36.2(d,C4a,I0. ¡, 25.0(q,CH3's), 23.2(t,C5,10 ) ppn.

¡4s I rî/e = 292, (Mt I, 234 (-C3H60 )

Accurate l'lass : CtZHZrr 0q requires 292.167447 ¡ Calcd 292.168003. I24.

CEÀPTER 2

2 I Attex0pted preparatfon of cis-11r11-Diuethoxy-7-,2,3,4- tetrachloro-1,4,4a, 5, 8. 9,9a, 10-octahydro-1 ,4-methano- anthracene (55a).

A ml-xture of 5 , 5-dimethoxy- L ,2 ,3,,4- te t rachloro- cyclopentadiene (529 Bg, 2.O mmol), isoreÈralin (51) (264

mB, 2.O mnol) and 2,6-di-t-butyl-4-nethylphenol (5 Eg) hras heated for 12h ac 130'C under an aÈEosphere of nf Erogen. The resulEant yellorr-orange syrup \ras cooled to aubLent

tenperature and trfÈurated wfth peÈroleun ether to yield a whiEe soltd ( 100 EC) whlch Ìüas purified by flash chromatography on sfllca ge1. Elutlon wlth petroleum

eÈher gave the dLadduct (55b) as smaIl r¡hlre plares, mp

23L-233" C .

I IR (cDcr3 ) v = 2880, 1605, 1190 cm I H NMR (CDC13) $ - 3.55(s) and 3.49(s) (12II,OCH3's), 2.85(rn,4H, Ht",*ar6arlo" I.5- ,r2^ ), 2.4(mrSHrH's5 ) ppm. 16 rIl rl2 MS : n/e = 622, 624, 626, 628 ,630 ,632

634, 636 (Mt HCr ) .

Anal Calcd f or CZ+EZq Clg 0¡r : C 43 .67 ; H 3 .66 . Found : C 43.36 ; H 3.66. r25.

The fflÈrate from Èhe trlturaÈ1on above was concenErated and then distilled at 50-t00oC/1-0.1 mm to reDove unchanged scartlng materlals. The PoË resfdue contalned an almos t equal mlxture of Ehe adduct (55a) and the aromatlc compound (55c).

_t IR (nea t ) v = 3040, 2880, 1605 , 730 cm I H NlfR (CC1'+) g = 6.92(s), 5.48(bs), 3.53(s), 3.45(s), 2.4-3.1(rn), 2.54(bs), L.7-2.3(n) ppn.

These components could be separated analytically by

HPLC on a Radial Pak A column wlth 157" aqueous methanol (4 rnI/uin) as the eluent.

1,2,3, 4-Tetrach loro-cls -4a,5,8,9,9a, I 0-hexahydroanthrac ene

( szb) . A solutlon of lr4r5,8-tetrahydronaphthalene (51) (1.32g, IO.O mmol) and teÈrachloroEhiophene-1,1-dioxide (56) (2.54g, 1O.O mmol) in carbon teÈrachloride (L2 nl) conÈaining a Ërace aüount of 2 r6-di-E-butyl-4-ureÈhyl- phenol (5 mg) was heated ac reflux for 3 '5h under a nftrogen aEmosphere. The solvent was removed Èo Ieave a whtre solld (3.3g, r00z) whlch r.¡as of saÈlsfacÈory purity for subsequent use. Flash chromatograPhy on sllica geI wlÈh peÈroleum eÈher as Ehe eluent Provfded Èhe Pure adducÈ (52b), mp 105-107"C. 126.

t IR (cDC13 ) : v = 1040, 1660, 1600 cn I H NMR ( CDCl3 ) : ô = 5.56(sr2HrH617 )' 3.05, (tr2HrHqar9a ), 2.44(s,4H, ), 2.L7(m,4H,Hs I0 ) ppm. t3 "t,t c NMR (cDc13) : ( Eentatfve assLgnment ) $ = f34.4(Cr,q ), 134.0 (Cr.,t0" ), L24.6(CZ,¡ ) 124.I (Ce 40.7(C+r,Sr) ,z), ), 30.91C5,8 ), 29.7(s,ro ) ppn.

MS : n/e = 32O,322,324 ,326 (Mt ) , 294,2g6,2g8 (Mt HCl) . Ana1. Calcd for Cr,*H¡2C1'+ : C 52.21 ; H 3.76. Found : C 52.47 7 3.85.

r e 1 - ( 4 a R , 1 0 a R , 8 a S , 9 a S ) - 5 , 6 ,7 , 8 - E e t r a c h I o r o - | , 4 , 4 a , I a ,

9 ,9a, 10 , 10a-octahyd ro-4a, 9a-oxldoanthracene (57) .

A solutfon of 857" m-chloroperbenzoLc ac 1d (225 mB, 1.1 mmol) fn dlchloromethane (10 nl) was added over 10 min to sÈl,rred suspensLon of the adduc t ( 52b) (322 mB, 1 .0 mmol) and anhydrous sodium acetate (r23 m8t 1.5 mmol) in dichloromethane (5 n1) cooled to 5" C. The mixture üras stlrred for 3.5h at 0oC then treated wlth L07" aqueous sodfum hydroxlde solutf.on (10 nl). The aqueous layer was separated and extracted wlth dichloromeEhane ( f0 Inl) and Ëhe combfned organic phases were washed wfEh saturated sodium chlorlde soluÈÍon ( 10 nl ) . The solvent was drled r27 .

(MgSOq ) and evaporated to give a whfte solfd (332 ng) whlch was purifled by flash chromaÈography on sllfca ge1. EIutlon rrlth 25I dlchloromethane lpetroleum eÈher (- 350 El) followed by 5Oi4 dichlorornethane/petroleum ether (- I50 nl) Provided the epoxlde (57) (200 m8, 597")' RecrysEalLLzatlon from chloroforn/Petroleum ether afforded an analytical sample, mp I81-183'C (s1. dec.) as whlte f lakes. The epoxide (57) rlas judged t.o be a single isomer by TLC on sllica gel (Rf . = 0'26 wlth 5O7" dlchloromethane lpetroleum eEher) and by HPLC on a liaters Radial PAK B coluron (L77t dichloromeÈhane/petroleum eÈher at 3 mt/ntn).

I IR (cDc13 ) v = 3030, 1595 cm t H NMR (CDCr3 ) ô = 5 .36(bs,2H,H2,3 ), 2.97 (*,2Il,Hs- 2.43(bs,4Il, cl¡ t0^é ), ), 2.16(rn,4HrH9.,t0" ) PPm' t3 "tru c NMR (cDcrs ): ô = 133.6(CS,e ), L24.5 (Cs L22.3(C2 ), 60 .3 ,z ) , ; (Cq",9" ), 38.8(cu",to" ), 30.9

(ar,r. ), 29.4(Cg,to) PPm.

MS mle = 336, 338, 340, 342 (Mt ) AnaI. Calcd for CrqHl2CIq0 : C 49.74 ; H 3'58' Found : C 49.76 ; H 3.7L. 128 .

r e 1 ( 4 a S , 1 0 a R , I a S , 9 a R ) - 5 , 6 ,7 , I - T e t r a c h 1o r o - I , l+ , 4 a , B ,

9,10,10a-octahydro-4a,9a-oxfdoanthracene (64) . l6 A soluÈfon of 11-oxatrlcyclo [4.4.1.0 ' ) undeca-3,8- diene (63) (296 mg, 2.0 mmol) and tetrachloroÈhlophene dioxide (56) (508 mB, 2.O mmol) fn carbon Eet,rachloride (5

El) conCalnlng 2,6-di-E-butyl-4-methylphenoL (2 mg) and anhydrous sodium bicarbonate (336 mB, 4.0 mmol) was heated for l2h at reflux under a niÈrogen atmosphere. The

nlxture was filËered whllsÈ hot and evaporated t.o glve a white solid (730 ng) which sras purlfied by flash

chromatography on silf ca ge1. EluEion wlth 25"4 dfchloromethane / pet roleum eÈher provlded the epoxide (64) (377 mB, 567"). RecrystaLLLzation from chloroforn/ petroleum eEher afforded an analyElcal sample, np 159-

l6I " C, as small white flakes . The epoxlde (64) !¡as judged to be a sfngle lsomer by TLC on slllca geI (Rf = O.29 ç¡lth

5ÙiL dlchloromethane/peÈroleum ether) and by HPLC on a WaEers Radlal PAK B column (l7Z dtchloromeÈhane/peÈroleum ether aÈ 3 nl/mfn).

IR (cDcI3 ) v 3025, 1595 crn I H NMR (CDC13 ) ô 5.38(bs,2H,H2 ), 2-76 , 3 (rn,2H,H8^ ) 2.4L(bs,4H, cr l0-d tr,u ), 2.16(m,4H,ll9 r0 ) ppm. l3 t c NMR (cDcI3 ) ô = f33.7(s,C5,g ),

L23.7(s,C6 7 ), L22. 4(d,C2 3 ) , I29.

58.6(s;Cq ar'ã ) 38.9 (d, CB",l0, ), 30.8(t,

arsl l{ 9 r0 ) ppm. r t, MS z mle 336, 338, 340, 342 (Mt ) Anal. Calcd for Ct,rH¡2C1q0 :c 49.74 ; H 3.58. ' Found c 49.70 ; H 3.76.

L,2,3,4-Tetachloro-4a,9,9Â, 10a-teErahydroanÈhracene (58) .

Ìf e chod 1 I6 A mixÈure of l1-oxatricyclo [4 .4 .1 .0 ' J undeca-1 r 3- dfene (63) (l4B mB, 1.0 mmol) and tetrachlorothlophene dioxide (56) (254 mB, 1 .0 mmol) was heaEed for 2h aE 120'C. Af ter t,he mLxture had rnelted, a vf.gorous evolutlon of sulphur dloxlde ensued. A yellow:orange oil q¡as produced whlch stas purifled by flash chromatography on sf1fca ge1. Elutlon with petroleum ether (I50 nl) followed by lOf dtchloromethane/petroleum eÈher (150 nl) and 207" dtChloromeÈhane lpetroleum ether (300 rnl) provided the tetrahydroanthracene (58) (190 mg, 597"). RecrystalLLzaEfon frorn nethanol afforded an analytical sarople, mp 125-L26" C, as white f Iakes .

rR ( cDcl3 ) v= 3050, 3010, 1595, 1580, 1500, t 740 cm I H NMR (CDC13 ) : ô = 7.00(s,4H,H's5,6,2,8 )

3.05(bs,6H,H'sb ) ppm - a,9 ,9 r,10 l'{S : m/e = 3lB , 32O ,322 ,324 (Mt ) Anal. Calcd for Ctq HrOClq : C 49 .74 ; H 3.58. Found : C 49.70 ; lt 3.76. 130 .

Method 2

A solutfon of the ether (63) (962 mg, 6.5 mmol) and tetrachloroÈhiophene dloxfde (56) (1.65, 6.5 ¡nuroI) tn L,2- dfchloroethane (LZ ml) contafning 2,6-df-t-butyI-4- methylphenol (5 r0g) r.¡as heaEed for I6h ar reflux under a nit.rogen aÈmosphere. The nixture was cooled and concentrat,ed t.o glve an o11 whlch crystalllzed on s t,anding . Recrys tallf zatf on f rom chlorof orr/petroleum eÈher af forded a r¡hite soltd (1.55g, 7L"Á) which sras ldenÈlcaI in all respects to the tetrahydroanthracene (58) obrained by Merhod 1.

Method 3

A solutlon of Èhe epoxide (57) (67 mg, 0.2 mmol) 1n L,2-ð.lchlorobenzene (3 rDl) cont,afnfng 2r6-df-t-buryl-4- neÈhylphenol (1 ng) and sodlum blcarbonate 142 mg, 0.5 mmol) wi:s heaEed for 4 .5h aÈ reflux under an aÈmosphere of nftrogen. TLC analysls showed tha È no reac È ion had occurred. The mixÈure was ffltered and heated for l8h at

250"C fn a sealed tube. The solution beccrrne turbid I and analysls by TLC and H NMR shor¡ed tha t the aroura t 1c compound (58) had been produced. A siml lar result was obtalned when the epoxlde (64) was subjecÈed to the same condlÈlons descrlbed above. 131 .

2,3 r4, 5, 10, l0-Hexachlorohexacyclo 6 tt 2 7 5 t3 9 rl 17.4.1 I .0 .0 t 0 l-3-pentadecene (68a) an

I IR (CDc13 ) v 1603 cm I NMR (cDc13 6 2.35(bs,4H,Hrs1 ) ,,,6 7 tl) 2.22(H.-'sB,t2, tl+ ts) and 1.48, t (Ho* tsg J rlz rl4 l5 ,BHrABq, l5Hz) ppr. l3 C NMR (cDCr3 ): ô 13f.8(s,C3 l+ ), 82.B(s,Cro ) t

74.7(s,Cz 5 ), 46.L(d,C's , l 6 7 13 ) 28.7(",ar,r, ), 24.6 ttt

(t,C'sg I 2 lq,t5 ) pPn. t MS z a/e 402, 404, 406, 4og, 410

(Mt )

Anal. Calcd for CtSHt2CI6 : C 44.48; H 2.99.

Found : c 44.18 H 2.94. r32.

The nother lfquors from Èhe crys tallLzation of Èhe carbocycre (68a) above nere concentraEed and the resf.due Iras recrystallLzed Èhree times from pet.roleum eÈher to glve the fsomeric trlene (67a), mp 148-149"C.

I IR ( cDcl3 ) ô = 3060, L62O cm I H ( Nl-fR CDCl3 ) 6 = 5.51(bs,2H,H2 3 ) L.4-3.2

(wnits oÇ rrt0Hrremalntng H's) ppn. t3 c NUR (cDc13 ) $ = L32 .0( s, C5 L23 .7 (s,C5 ,B ) , ,7 ), L23.7(d,,C2; ), 74.0(s,Çrr ),

39.f (d,Cea,r0" ), 31.3(t,Cr,,r ) 26.2(t,Cg l0 ), 25.5(s,C4",8" )

PPM.

MSzmle= 4o2,404,406,409,410 (Mt )

Anal. Calcd for CtSHtZClO : c 44.48; H 2.99.

Found : c 44.27 ; H 2.93.

The trLene (67a) could also be purffted on reverse phase

HPLC us lng 5% aqueous me thano I a t 4 ¡nl/min as the eluent. Analytlcal sêparatlon of the isomers (67a) and

(68a) was achfeved by GLC on a I% SE 30 column at 240"C. 133 .

10 10-Dfbromo-2 3 4 5-teÈ rachlorohexac clo- 6 lr 2 7 5 t3 9 rt Í7.4.1.1 ' .0 0'.0'l-3-pentadecene (68b). t6 A solutlon of 11,11-dibromoEricyclo [4.4.1 .0 ' ] undeca-3,8-dLene (65b) (L.2Lg, 4.0 mmol) and Ëetrachlorothfophene dloxlde (56) (1.01g, 4.0 mmol) tn p- xylene (2 nl) was heated for 24h aE reflux under a nitrogen aEmosphere. The mixture lras parttally cooled and peÈroleum ether (3 nl) was added. Cooling to room temperaÈure then to 0"C preclpftated a brown solld (f.11g) which was filtered and recrystattized from carbon t,etrachloride/petroleum ether to yleld the he.xacycllc product (68b), (0 .58g, 29"/.) as small needles . A second recrysÈalLl-zatlon provfded an analyËicaI sample, rop 2L6- 2L7"C.

t IR (CDC13 ) 6 1610 cm I H NMR (cDc13 ) $ = 2.28(bs,4HrH'sl16rTrlt ), 2.I5("* and r .43 "8,t2,1r{,t5), (","*, (BH,ABq, J= '"8rrz rL| rl5), 13Hz) ppm. t3 c NMR (CDC13 ): ô 13I.5(Cs,,r ), 96.2(Ct0 ) t 74.8

(Cz,s ), 46.L(C'sL,6,1 t3 ) 28 .3 , (Cs,rr ), 26.5(C'sB,t2, tt+ l5 )

P px0 .

MS rn/e = 490, 492, 494, 496, 49g, soo (Mt ). 134 .

Anal. Calcd f or Cf SH¡2Br2C1'r c 36.48 H 2.45.

Found c 36.58 H 2.5L .

1 O-Aza- 1 1-oxo- 2,3, 4, 5-È e trachlorohexacye 1o 6 12 2.'r 5.í+ I ) 2 [7.5.1. I' .0,'O'.0' l-3-hexadecene (70). t6 A solutlon of 11-aza-12-oxa-tricyclo [4.4.2.0 ' ] dodeca-3,8-diene (69) (5.0g, 28.6 mmol) and teÈrachloro thtophene dioxfde (56) (7.30g, 28.7 mmol) in L,2- dichloroeËhane (25 n1) was heaÈed for 14h at reflux. Durfng this time, a flne preclpf Èate was for¡ned . The

"l I roixture was cooled and the product was ftltered,änd washed with echer to give the lactam (70), analyÈlca1ly pure, âs sma1l whlte flakes, (6.87g,667"), mp > 310'C (dec.).

IR (NujoI) v = 3160, 3090, 1750, 1705, I 1610 cm I 80 MHz tt NMR (Ds DMSO) : ô = 8.30(s,lH,HtO ), 1.98

(sr4HrHtslrtrTrt*) , 2.I2("*.'"8,t3,t5,16) and 1,75 (t*-'"8,I3,15,16 )'(8H'ABq' J = 13 Hz) ppn. l3 c NMR (Ds DMSO) rS = L75.4(Crt ), 130.6(Ct,+ ) 74.L and 73.9(Cz,s ), 52.5 and 51.3(Cs,tZ ), 45.2 and 42.7 (Ctsl,617rlr{ ), 29.3 and 24.5 (c'sB,r3,r5,t6 ) Ppn-

MS m/e = 322, 324, 326, 328 (Mt-Nllco).

Anal. Calcd for Ct SH¡3CIqNO c 49.35 ; H 3.59. Found c 49.42 H 3.71. I35 .

1 1, 1 1-Dfure thyl-10, I 2-dLoxa- 2,3, 4, 5-te t rachlorohexacyclo 6 t3 2 7 5 5 9 t3 t7.6.1.1 ' .0 ' .0 .0 l-3-hep tadecene (72). A solutfon of crude L2,12-dinethyl-11,13-dioxatricyclo l6 [4.4.3.0' I trideca-3,8-diene (7f)(2.354g, f1.42 mmol) and teErachlorothiophene df oxide (56) (2.9L9, 11.46 rnrnol) 1n toluene ( 15 ml), conEaf ning anhydrous poË.assium carbonate (3-146g, 22.8 mmol), was heaEed for 16h at reflux. The resulÈant pink-orange solutlon rdas cooled, flltered and evaporated to glve a moLs t solid which hras recrystalLLzed, from carbon Èetrachloride lpetroleum. ether to glve the ketal (72), (1.84g [Li¿), as nLcrocrysÈalline needles, mp 2L5-2L6" C. AÈtempted chromatography of Èhe moÈher llquors on s111ca get caused extensive loss of uaterial.

t IR (cDCr3 ) v = 1610, 1100, 1080 cm I H NMR ( CDCl3 ) ô = 2.35 (bs,4H, H'sl1617rr5 )' 2.33 (t"n's,Brl4.l6,Iz ) and 1.88 (t*'"8,14,16,17 ), (8H,ABq, J L2 Hz), L.42 (s,6H, CH3 's) ppn. t3 c NMR (CDC13) $ = 131.0(s,C3 r, ), 108.3 , (s,Crr ), 79.4(s,Cg r3 ), t 72.8(s,Cz ), 44,2(d,, t.s C'sl 32.7(t, ,rt6 7 l5 ), C'sB ),30.0(q, CH3rs) pPm. tttlr+ l6 t7 136.

MS : m/e = 379,381, 383, 385, 387 (Mt cHs )' Anal. Calcd for CrZH1gCl402 : C 51 .54 ; H 4.53. Found : c 51.69 ; H 4.44.

2 r3, 4, 5-TetrachloropenEacyclo t2 6 t0 2 7 5 , t7.3.r.1 0 ' .0 I -3-teÈ radecene-9, 10-dicarboxyllc anhydride (7Ir). A solution of Lr4r4a,5r8,8a-hexahydronaphthalene-

4a,8a-dicarboxyllc anhydrlde (73) (7.62g,30.0 mmol) and tetrachlorothfophene dloxide (56) (6.L2g, 30.0 mmol) tn toluene ( 15 nI) nas heated for 15h at reflux. The product, whfch preclpttated fron solutfon as it formed, rtas flltered from the cooled reactlon mlxture and washed with ether. In thts way, the anhydrfde (74) was Lsolated, analytically pure, âs colourless granules (8.32g, 7O"Á) r mp 344-345"C.

IR (NuJol) v = 1870, 1850, 1835, L775, 1605, I L235,1200 cm t H NMR (CDC13 ) : 6 - 2.4L (bs,4H,Hrs I 6 7 , r2 ), 2 .5t ( He? '"e lt r3 Ir{ ) and 1.86 (Hsf t J 13 "g ,l I . t3 lr{) ,(BH,ABq, Hz ) ppn. r3 C NMR (cDCr¡ ): ô L74.2(s,CO), I32.1(s,Ca,q ),

72.L(s,Cz 5 ), 43.4(s,C9¡10), r37.

4r .7 (d, . ,51r 6 7 L2 ) 27 .L(t, arsg It,l3rtq ) ppn. r MS 3 nle = 392, 394, 396, 398, 4oo (Mt ), 32O, 322, 324, 326, (Mt CO,C02 ) .

AnaI . Calcd f or Cr O H12 C1¡+ 03 : C 48.77 ; H 3.07. Found : C 48.34 ; H 3.10.

1 l-Oxa-2 .3 . 4, 5-Èe Erachlorohexacyclo 6 13 2 7 5 15 9 13 t7.6.1.1 , 0 .0 0 l-3-heptadecene (76).

Method 1 t6 A soluËfon of 12-oxatrfcyclo [4.4.3.0 ' ] trideca- 3,8-diene (75) (352 mB, 2.O mmol) and tetrachlorothlophene dioxide (56) (5OS mB, 2.O n¡nol) tn toluene (3 EI) r{as

heaEed for 15h at reflux. The sólvenE was evaporated Ëo

leave an olI whLch partfally crystallLzed on s Eanding. Crys talllzat fon of the res Ldue - fron carbon tetrachlorlde lpeEroleum eÈher provfded Ehe ether (76> (293 m8, 4O7") as snall whtËe crysËa1s. An analytlcal sanple, rûP 201-203"C, was obtalned by two recrystalLlzatlons from chloroforrn/

petroleum ether followed by sublimation at 190'C I O .L mm.

I IR (cDC13 ) v = 1605, 1050 cm t H NMR (cDc13 ) g = 3.43(s,4H,Hto 12 ), 2 -25 t (bsr4HrH'sl 6 z I5 ), 1.93

(H t ) and 1.67 e? "g lt+ t6 17 I38 .

(Hox'"grlr+rì.6r17 ),(8H,ABq, J = r3 Hz) ppn. I3 C NMR (CDC13 ): $ = 131.5(s,C3,4 ), 80.0(t' Cl0,l2 ),

7 4 .5(s, C2 43.L ,5 ), (d,C'"1,6,7,15) , 40.6(s,C9,13 ) 29.4(trC'"B ) ppt. rlr+ rl6 rt9 Ms : n/e = 364, 366, 368, 37O (Mt ). Anal. Calcd for CrOH15C140 : C 52.49; H 4.41 . Found : C 52.53 ; H 4.44.

Method 2 (a) The anhydride (74) (1.5769, 4.0 mmol) was added portLonwise over \t, h to a partlal solutLon of ltthiun alumlnlum hydrlde (0.38g, 10.0 mmol) tn tetrahydrofuran (15 nl). The mlxÈure was heaÈed for 2h at reflux under a nftrogen atmosphere then cooled to amblent tenperature. tÞ/, so¿ul* h1./traú4e- ( o,s.-4-) I{ater (0.5 nl),¡ and more water (1.0 nl) were added dropwf se. The lnorganl-c salts rùere f t1Èered through cellte and the flltercake was washed Èhoroughly with tetrahydrofuran. The ftltrate !ùas dried (MgSOa ) and evaporated t,o glve 9,10-bts (hydroxymethyl)-2,3,4,5- o tetrachroropentacycto 17 .3.1 .16 .o1;toEf -3-tetradecene as " a whlte foam (1.332g, 87iÁ) whlch nas not purifled further. 139 .

I IR (Nujol) : ì 3250,1610 cm- I H NMR (cDc13/CO3OO, 1:1)

ô 4 .29 ( s ,2H, OH's ) , 3.52(s,4H,CH2o 's), 2.25(bs,4H,H'st 1.88 and ,6 r?, L2) 1.58 (ABq, J = L4 HzrSHrH'"g rll,l3 rl4) PPN. I MS m/ e = 382, 384, 386, 388 (nl¡.

(b) A suspenston of rhe foregolng dtol (L.2g, 3.1 mmol) Ín toluene (25 nl) conÈaf.nfng p-toluenesulphonfc acl-d (70 ng) was heated for l6h at reflux under an aÈmosphere of nfÈrogen. water was azeotropicalty removed from Èhe reaction mLxture with the ald of a Dean-stark apparatus. The sorutlon was cooled and vigorousry stlrred over anhydrous potassium carbonaÈe for 5 nln.

The mixEure rdas ffltered and Èhe solvent was evaporated Èo gfve a pale yellow solld ( I .16g, ca 1o0z ) . Re c ry s t a l Lrz at l on f r ou d i ch ro r ome thane/ pe t r o l eum e t h e r provlded a whlEe crystalllne solid which lras idenÈical in all respects ro Ëhe ether adducr (76) obtalned by Merhod 1. r40.

6 Ir 2 7 5 13 9 tl IlexacycloÍ7 .4.f.1 .0 t 0 0 -3-pentadecene (8r¡.

l{ethod 1

To a partial solution of the hexachloride (6Ba) (162 mB, O.4 mmol) and sodium borohydride (150 mg,, 4.0 mmol) in 95"/" eEhanol (4 DI) r¡ras added tri-n-butylstannyl chloride ( 15 mB, 46 U rnol) and azobLsisobutyroniErile (2 mg ) . The mlxture was heated for 36h aÈ reflux under a nitrogen atmosphere then cooled to arnbient temperature and treated with oxalic acid (30 xng). Afrer srirring for |4 h, water ( 10 !nt) was added and the organic material rùas extracted into dichloromethane (3 x 7 ml ) . The combined organic ext.racts !/ere washed wlth LO?" sodiun bicarbonate solution ( 10 ml ) and saturated sodiu¡n chloride solution

(10 El). The solvent was dried (MgS0q) and evaporated to gi ve crude tetrachloride (83) as a whÍte solid (- 180 x0g) - The residue was dissolved in 9si| eÈhanol (5 nl) heated at reflux and sodium metaL (736 mB, 32.O mmol) was added porÈionwise over th. Re f Iuxing was continued for 4h and the mixËure was worked up as in ¡nethod 2 to yield a pale yel1ow solid (120 mg). An analysls of the crude I product by H NMR showed thaE no triene (82) had been formed. RecrystaLJ-Tzation from meÈhanol fo I lowed by subllmation at l2O" /L2 mm provfded the olefin (81) (s0 mB, 637")¡ mp f66-L67"C. 14r.

I IR (ccla ) v = 3050, L620 crn I H NMR (CC14 ) $ = 6.11(dd,J2r3 = 5Hz,J3r5 2.5H2,2H,H3,4), 2.O7(bs,2H, nr,t ), I.82(bs,4H, Iltsl,5rZ,13) , 1.34 and 1.04(ABq, J = L2Hz,BH, Htsgr12rlr+rl5) ' 0.40(s,2H,Hro ) ppm. t3 c Nr-fR ( cDcl3 ) 6 = 135.1(d,C3,q) , 40.5(d,.Cz,S),36.0(d, atsI16rzr13)

32.5(t,C'"t ) , , tZ,lq ,IS 20.0(t,C t0) 15.5(s, Ce t0) Ppn. +). MS m/e 198 (M

Anal. Calcd for CtSHtA c 90.85 ; H 9.r5.

Found : C 9r.05 ; H 9.r4.

Method 2

Small pieces of cleaned (ethanol ) sodium metal (7 36 l|r mB, 32 .O nq-bs) were added over 3/4h^heated at reflux. The

mixture was refluxed for a further 4h then cooled and

t,reated wlth lced water (20 url). The organic materlal vras

exÈracCed lnto petroleum ether (3 x 10 ml ) and Èhe combfned extracts rdere washed wlth water (2 x 10 nl) and saturaÈed sodlum chlorlde solution (10 m1). The solvenÈ was dried (MgSOq ) and evaporated to glve a r¿hlte solÍd (80

r,r c-llrrrr.*4- (-S',f¡r ' Ä , ù" a ¡a.t.,.{ sol*t,í.on R hne [.*^o.*-{^t.o*,'ol¿ f6ta) (-.tUt-r,o.4,",^ol) t42. mB, LOO1¿ ) which consisted of a ca . 2z 1 rnixEure of Èhe olefin (8f), and the rriene (82). An analysis by cLC-MS (L57"0V101, 190'C) showed that the molecular weighrs of these compounds dlffered by Èwo mass uniÈs. The two components were separaÈed by eíther reverse phase HPLC on a l,laters Radial Pak A column (511 aqueous methanol, 4 ml/rnin) or by medium pressure chromatography on a reverse l\erh sir. Ù phasen RP8 Lobar column (57" aqueous meÈhano1, B u1/min) . ^ t+ 12 6 13 r+ 6 First Èo elute was penÈacyclo Í7 ,2.2.1 ' .1 '' .0 ' l pentadeca-1 r 8 r 10-triene (82) which was conEanínated with a sma1l amount of the olefin (81).

I rR (ccl¡+) : v 3050, 3030, L620 cm I 80 MHz H NMR (CClq ): ô 6.42(s,2H,Ht0,tt) , 5.26(d, J = 6.5 Hz,2HrHZ,B) 2.56(bs,2H,Ht2,t3), 2.47 and 1.59(ABq, J = l5 Hz,4H, H3,z) , 1.58 and 1.ff(ABq, J 13 Hzr4H,Ht+rt5) , 0.58 and 0.45(ABq, J = $ llz,2ll, Hs) ppm- t3 c Nr'fR (cDcI3 ô 146.3(s,CI ) = ,9) ,

134.3(d,Cr0,tt) , L25.3(d,C2,s ), 44.2(d,

CrZ,tl) , 31.9(t, Ca,7) , 29.I(t,Cl'+,15), 2L.3(s, Cq,6) , 19.0(t,Cs) ppt ¿ MS 196 (M:) Accurate mass CtSHre requires f96.125L94 Calcd. 196.125078. r43

The olefin (BI) which eluted second r¡ras idenEical in all respects to Èhe product isolated 1n Method 1.

I 1, I I-Dinethyl- 10, I 2-dioxahexacyclo 6 13 2 7 5 l5 9 I3 t7.6.1.1 0 0 0 I -3-he ptadecene (8s).

A solution of rhe ketaL (72) (198 Eg, 0.5 mmol), tri-n-butylstannane (320 mg, 1.1 mmol) and azobisiso- butyronitrÍ1e (2 ng) in roruene (1 ml) was heared for z3]n at reflux under an atmosphere of nLtrogen. Carbon tetachloride (1 ml) was added and refruxlng was continued f or 2h. The solution was cooled to arubient t.emperature and diluted wirh ether/dichloromerhane (22I, l5 nl) . The mixture r{ras treated with a solution ot potassfum fluoride

(2Ð in urater (I0 nI) and was vigorously stlrred for Vrr h. The suspension of tri-n-butylsÈannyl fluoride was fÍltered and the aqueous layer was separated and extracted wiÈh etheÊ/dichloromerhane (2:L, lO nl). The combined organic ext.racts were washed with L07" aqueous sodium bicarbonate (15 m1) then dried (Mgsoq) and concenrrared. The residue (84) üras dissolved in 957" eÈhanoI (5 mI) heated at ref lux and sodium meEal (805 mg, 35.0 rngatâ") üras added in porELons over 1.5h. More 95i¿ eÈhanol (2 nl) was added to the thick mixture and refluxlng was contLnued for 2 .5h . The solutlon was cooled Èo ambienÈ temperature and poured lnto lced water (r5 rur). The organfc material was extracted lnto peÈroleum ether (3 x l0 ml) and the L44. combined exÈracts were washed wíth r^rater (r0 ml ) and saturated sodium chloride soluEion (10 ml) . The solvent r{as drÍed (MgSOq ) and evaporaÈed Eo give a pale yellow oil (180 ns). Chromatography on neutral alumina- (Woelm, acEivity 1) with dichloromethane /peEroleum ether ( 1:1) as rhe eluent afforded the ketal (85) as a white crystalline solÍd, np 84-86"C.

_l IR (ccrq ) v = 3050, 1365, L375 cm I ( H Nr"rR ccl,+ ) $ = 6.03(dd,J2 3 = J Hz,J3 5

2 Hz,2H,H3,q) , ,.r6(bs,Zff ,

H2 I .87 and 1 .39(ABq, J ,S ) , 9 Hz r BH, II'sg tr+ l6 l? ) , 1.81(bs,4H, "i"r,r,r,rr), 1.30(s,6H,CH3's) pp¡tr. a\ MS ur/e = 258 ( M'.' , 24 3( -cHg ) l¿E¡ Accurate mass CfZ HZ2 02¡CH3 requires

243.138496 ; Calcd ,243.138077 .

1 1-Oxa -2, 5-di chlorohexa cyclo 6 13 2 7 5 t5 9 t3 17.6.L.1 ' .O ' .O o I hep Eadecane (86) .

To a solution of the eEher (76) (L.464 E, 4.0 nmol) in ethyl aceÈaÈe (40 nl) r^ras added 5Z palladium on carbon catalyst (75 ng) and triethylamine (1.01g, 10 mmol). The mixÈure vras stirred for 3h at amblenÈ t.emperature and pressure under a hydrogen atmosphere. The catalyst and Èriethylamlne hydrochloride were removed by fllEration r45. through celi te and t.he filtrace r¡/as evaporaEed to give the dichloroeÈher (86) (0.957g, BOi¿) as a white solld. An analytical sample, mp 98-99"C, was prepared by sùbl-irnat,ion aE 90oC /O.S mm.

I H NMR (CDC13 ) 6 = 3.52(s,4H,Ht0, t2>

2.1+L(bs,4H,H's1,6, , 7t rs) *nk-.a o? 2.29(s,4H,H3,4) , 1.80ÇBoorly

resolved ABq, J = L4 Hz,

I 8Il, H s q r 6 r 7 ) ppB. I , l , , MS ¡n/e = 298, 300, 302 (Mt)

262,264 (- HCI) .

Anal. Calcd for CTSHZg C12 0 : C 64.22 ; H 6.74. Found : C 64.47 H 6.99.

l+ t4 I I5 l+ I 6-Oxapentacyclo [ 9 .2.2.L I o heptadeca-1,10- diene (82¡ and 11-oxahexacyclo 6 13 2 7 5 r5 9 l3 t7.6.1.1 0 o 0 hep tadecane (8e). To a suspension of sodium-potassium alloy (0.4 ml, 346 m8, 9.6 mmol) 1n ether (25 ml) nas added the dichloroeÈher (86) (530 mg, L.77 mmol) in one porrion.

The mixture Eurned dark blue and üras s t irred for 16h at room temperaÈure under a nitrogen aÈmosphere. Excess a1loy !¡as destroyed by the cautlous addition of ethanoL (2

¡nl). l.Iater (50 ml) was added and the organl-c phase was separated. The aqueous layer was extracted with eÈher (2 x 50 ml) and Èhe cornblned organlc extracÈs ü/ere dried

(MgSO¡{) and evaporaEed to gfve a whiEe solld (380 mg, 94"Á) which conslsÈed of a nixture of Ehe diene (87) and the ether (89), (ca. 3:l). 146.

The two components were separated by chroma t.ography using

a reverse phase Lobar column with 7.5"Á aqueous methanol as Ehe eluenÈ.

Dlene (87), mp 9I-94'C : ¿\,^t",{ Ri"t _l IR (cDc13 ) : v = 3040, 1650, 1070 cm t H NMR (cDc13 ) : ô = 5.11(t,J = 4 Hz, 2H,H2,1g) , 3.68 and

3.30(ABq,J E 10 Hz,4H,Hs,Z) , 2.5L(bsr2H,Ht,*,I5), 1.5-

2.4(complexr SHrII t "3 ,9 ,12 ,13 ) , -t .gl and 1 .08(ABq,J = LZ Hz, 4H,HI6,tZ ) ppn. l3 c NllR (cDc13 ) : ô E L42.1(s,Cl,rlI) ,

L20.5(d,C2,1g) , 79.5(t,CS,z), 4L.6(s,au,t), 38.0(d,Ct'+,I5), 34.0(t),

29 .6(t) and 28 .9 ( t )

(at ,ct 2 tz ) ppn. ,9 ,t3,ct6 , MS : m/e = 226 (Mt) Ac cura t e Mas s C16H2gO requires 2282151406 ; Calcd

228 .L5L629 .

Ether(89), mp 51-53oC : ¿\qt{Å teco'\

I H NMR (cDcr3 ) : $ = 3.27(s,4H,HI0,l2) , 1.93 ( 3oo r", r: ( r, ) 1,= 3.,/,i "i,, i1,..,,..'.,. t.+ < ( A.., uU, and 1.90(two overlappfng bs, il,,b,',,,s), r'rs ('(, S" r:rtr-*) 3 o,.lr ur,ÏiT',i and H2,s) , z.86 tâ ¡ )r lLH-r ) . Rt-, {llX,r,,,rc, rr)r l,q8 ¿[s, r{.H,ll¡,,r) ..1"r ,ìr1,5) and I.62 (ABq,J = 11 Hz, ¿ lt,s,zìÌ ppn¡, r47 .

SHrH'"gr14rI6, t7) Ppm. t3 c NMR (CDC13 ) : ô = 80.0(t,C¡g ,t2) ' 40.7(",Cg,tg) ,34.2(d) and 33.s(d)

(cts I and C2 5) , rG rT ,ls , 32.6 ( t, C'.t tu l5 17) , ,t ' 25.1(t,Cg,q ) Ppm.

MS : m/e 230 (M1) , 200( cn2o) . Accurate Mas s C16H22O requires 230 .167055 ; Calcd 230.L67785.

3, I 3-D lme thylene-8-oxapentac yc 1o 26 4t2 é.to f8.3.1.1 , .0"r o 'ìo"rrtadecane (88).

The diene (87) (120 mg, 0.53 mmol) was vìrgol'riz€d ar 120o c/0.4 mm and pyroLyzed through a hollow quartz tube (40 x 3 cn) heated at 5oo'c. The pyrolysate was condensed as a clear waxy solid (100 mg, 837") on a cold finger held at 15oC. Flash chromatography on silica geI wiÈh 5OZ dichloromethane/peÈroleum ether as the eluent, atforded the diene (88) as a whiÈe solid, rnp 93-96oC.

rR (cDcr3 ) v= 3080, 16 50, 1050, Bg0 _l cm I H NMR (CDCI3) 6 = 4.46(s,4H,C = CHZ 's),

3.47(s,4H,HZ,g) ,

2.75(bs,4H,H'sI,2 l+ r2) I .91

and L .22 (ABq,J = L2 Hz,

SHrH'"5 Ppm. l3 rrl,14 rr5) c NMR ( cDcr3 ).' ô = 153.9(Ca l3) , 104.2(C-CH2), 148.

80.5 (Cz,g), 42.7(Cs,ro)

41.0(C'sl l+ ) ,2, 12 ' 36.2(C's5,tI t 15 ) ppm. t, 'r I MS mle = 228 (M:) Accurate Mass C15H290 requires 228.151406 Calcd

228 .L5r629 .

2 2 5, 5-Dimethoxy-1,2, 3, 4-tetrachlorocyclo pentadiene. 4t+ This dÍene, bp 86-B8oC/lmrn (1ir. c bp 79-84"c10.6

nxû) was prepared ln 7 57" yield from hexachlorocyclopentadiene by the procedure of Gassman and 4bo Marshall Õ .

I3 c NMR (CDC13 ) $ = L29 .3 ( Cg ) , I28 .6(Cz) 51.8(OCH3rs) ppn.

T e t r a c h I o r o t h i o p h e n e - I . 1 - d i o x i d e (56). 44f The thiophene dioxide (56), mp B9-90" C (fir . mp 91-92oC), was made in ca. 3O7" overall yield from hexachloro-1,3-butadiene by the method of Raas"hth f In order Èo obtain the reported yieId, the literature procedure ú¡as alEered ín the following manner. The flrst 75 ml of distfllate from Èhe reacÈion of hexachloro-1 ,3- but.adiene with sulphur (/z scale) was recycled. OxidaEion of the crude product, teErachlorothiophene, was carried out in the presence of the radical lnhibitot 2,6-di-r-

bu Eyl-4-me thyl-pheno I . Upon work up, remalning s farting

material was removed by disclllaEion, bp 68-69"C/L.5 mm L49.

44f (1ir. bp 93-94"C/7.7 mm), prfor Èo crys Ealllzation of the thfophene dloxide frorn petroleum ether. Final

purlfication of the product was achieved by sublimaELon at 130'C/5 mm or 90oC/O.05 nm.

1, 4, 5, B-Tetradronaphthalene (51). a5b IsoteEralin (5r), mp 53-55'C (1it. mp 52- 53 "C ) was obtained in 88"Á yield from naphthalene by the 46 procedure of Grob and Schless 6^

_t IR ( cclq ) v 3040, I 66 5 cm I H NMR ( CC14 ) $ = 5.56(s,4H,Hrs2 3 6 7) t 2.45(s,8H,H'sI,4,5 I ) ppn. l3c ( g NtrlR cD ct 3 ) = L24.4(C's2 3 6 7)

123.2(C+",e") ,

30.8(C'sr q s B) ppn.

t6 11-Oxatricyclo [ 4 .4 .f .O I undeca-3,8-diene (63) . 45b The epoxide (63), np 59-61'C (fit. mp 58-61oC), lras made Ín ca. 1007" yield f rom lsoteEralin (51) after the 46u rnethod of Voge1, Klug and Breuer us ing m- chloroperbenzoic acid lns tead of peraceEic acid.

I H NMR (CC1,{) 6 = 5.35(s,4H,H's3 l{ I s)

2 .37 ( bs , 8H, H's2 5 7 r0) ppm.

I5 11, l1-DichloroËricyclo [4 .4 .1 .0 I undeca-3 ,8-diene (65a) . t+g The dlchloride (65a), mp 9L-92" C (fft . mp B8- 89"C) was prepared 1n 232 yield from lsoÈeÈralin (51) 150.

48 after the method of Vogel, Klug and Breuer wi Ëh Èhe l+9- o following nodificat.ions The crude react íon produc È

lras Eaken up ln a minlmum amount of hoÈ ethyl acetate and

dlluted with an equal volume of methanol. The crystalline

materlal Èhat formed on coolfng the mixture to 15oC eras ffltered, sublÍmed (80'C/O.g rnm) and recrystalllzed three times from methanol.

T H NMR (CC1,+ ) g = 5.43(s,4H, Hts3 ru rt rg) , 1.85-3.95(n,8H,

Hts2r5rzrIo) rPPn I3 c NMR (CDC13) $ = L23.4(Ca,4 and cs s) 74.2(Crr) , 30.4 (cz,s and cz,to)

24 .8(Cr pprn. ,e )

l6 11,11-DibromoÈrÍcyclo [ 4 .4 .1 .O I undeca-3 ,8-dÍene (65b) . a9b The dibrornide (65b), np 115-117"C (1ir. ¡trp L24-

125"C) Itas prepared in 27"/. yleld from lsotetralin (51) \ arl- q6b ad.q¡'lto,," o( Ëhe method of Vogel, Klug and Breuer r.¡f th the lr9- work up procedure of PaqueÈte et al a A product of.

satlsfacÈory purlty for subsequent use was obÈalned by sublf,mat,ion at 100'C/1 mn.

I H NMR (cDcr3) S = 5.45(s,4H,H's3 lf I e)

2 .43 ( bs , 8H, Hts2 5 ppm. 7 t t0) 151.

11-Aza-11-chlorosul hon l--L2- o xa - T6 , trlcyclo [ 4.4.2.O I dodeca-3 ,8-diene (e2) . A solutLon of chlorosulphonyl isoc,yanate (3 .0g, 21.0 mmol, 4.8 rn1) in anhydrous erher (5 nl) was added, dropwise over 5 mln, Èo a solution of fsoÈetralfn (5I) (2.64g, 20 rnmol), f n ether (5 ml) cooled to 0oC. The mÍxture was warmed to ambient temperat.ure and set aside overnighË (16h) by which rlme rhe adducr had crystallízed. The product was filtered and washed wíth eÈhet /petroleum ether ( I :1) to give the N-chlorosulphonyl B -lactam (92), analytically pure¡ âs long colourless spars, 3.0g, (86ll), mp 120-121'C.

IR ( cDcl3 ) v = 3070,1810, L645,1400, _t L]-z5 cm I H NMR (cDc13) ô = 1.82-3.31(m,8H, Hts215rTrIo) , 5.61- 6.10(rur4HrH's3,u,g,9) pptrr.

MS n/e = L32 (M1 - clso2 Nco)

L27 ,9L . Ana1. Calcd for CtrHI2CtN03S : C 48.27 ; lI 4.42. Found : C 48.24 ; H 4.47.

I5 11-Az a-I2- oxo-tricyclo I 4 .4 .2.O I dodeca-3 ,8-diene (6e). The foregoing N-chlorosulphonyl p -lacEam (92) was dissolved in eÈherfa,eeÈone (2:1, l5 ml) and added, dropwise, to a vigorously stirred mixÈure of ether/acetone

(2:I, 15 ml) and 251¿ sodfum sulphiÈe solurion. The aqueous phasg' was kepE bet.ween pH 7 and I r52.

(phenolphthalein) by rhe addiElon of LO?" sodium hydroxide solutÍon. After sËirring for a Ëotal of l.5h at ambienE temperature, thê layers were separated and Ehe aqueous phase r¡as exÈracted wfth eÈher (20 n1). The combined organic extract.s were dried (MgS0,+ ) and evaporat.ed to yield a colourless oil, | .47g (BBZ), which crystallized on standing. ThÍs maÈeria1 rüas noÈ purified furËher and had 5I^ fdentical spectral properties to Ehose published o.

l6 L2 ,I 2-Dfnethyl-1 1 , 13 -dioxotricyclo [ 4 .4 .3 .O I trideca-

2 B-dfene (71).

A To a cooled (15'C) solution of lsorerralin (51) (6 .6g, 50.0 mmol) in glacial acetic acid (225 nl) containlng water (f 81, 55.0 rnmol) was added stlver aceEate (18.5g,

110.0 mmol). The slurry r¡ras vigorously stirred whilst a solution of bromine (8.5g, 53.0 mmol) in glacial aceríc acid (20 xûl) was added over 3h. Stirring was then

continued for 3h at 7 5o C in the absence of light . After cooling the mixture to a¡ubienÈ tenperature, the sílver bromide Lras filÈered and the filÈrate was concentrated at 50oC at water punp pressure. The residue was dissolved in

methanol (I50 mI)and Ëhe solurion was taken ro pH 10 by the addition of solid potassium hydroxide. The suspension

was cooled to 5o C, treated with more potassl-um hydroxide

(3g) and afÈer sEanding for ll,r h, the preciplEate riras ftltered. The flltraÈe was concstr']raËed at 25" C under reduced pressure and Èhe residue qras poured fnto saturated

arnmonium sulphaEe solution ( 50 m1 ) . The aqueous soluElon rdas exÈracted wì.rh eÈherfatchloromethane (322, 4 x 5O ml) 153.

and the combined organlc extracts urere decolourízed, dried (MgSOa) and evaporated to give a brown oit (7e) which crystallLzed. on standing. RecrystaLJ-lzatlon from eÈher (10 nl) at l0oC provided purifled Sl"-4a,8a-dfhydroxy- L,4,4â,5,8,8a-hexahydronaphthalene (93) (1.5g) as small 52 whlEe cr)rsÈals, np 79-82"C (11t. mp 82-85'C) . An additional L.259 (roral yleld 2.759,, 351¿) of producr was obtafned from the mother IÍquors.

å The recrystallized cis diol (93) from parÈ A (f .87 5e. 11.3 mmol) and p-Èoluene sulphonic acid (50 nC) were dissolved in 2r2-dimethoxypropane f acetone (5:1, 30 n1) and heated for 5h at 130oC in a sealed tube. The almost

colourless soluEfon tras cooled to ambient temperature and vlgorously st.irred for 5 rufn over powdered anhydrous

potassium carbonate. The solvent ¡das evaporated and the

res idual pale yellow oil r¡ras bulb to bulb distilled at 80-

90oc/0.5 mm. The ketal (71) (2.0g,877") was obÈained as a colourless otl r¡hich sras not purified further. Spectral data of this compound were identical with those reported 52

l, 4, 4â, 5, 8, 8a-Ilexahydrona ph Èhalene-4a, 8a-di carboxy 1l c anhydride (73).

4 The monopotassfum salt of acetylene dlcarboxyllc acid (60 B, 0.39 mol) üras added to 2O7" sulphurlc acld soluEion (500 nl). After the salt had completely dfssolved, the

aqueous soluÈfon was exEracted wlrh eEher (2 x 500 ml). I54.

The combined organic extracts were dried ( MgSOa ) and evapora Ëed to yteld Èhe free acid (45g, ca. IOO1I) as an off-white solfd which was used immediately for Ehe next step.

A solution of acetylene dicarboxylic acid (35g, 0.3r mor) and butadiene (90g,145 ml, r.67 ruor) in dÍoxane

(75 mr) was sÈirred and heated for 20h aÈ 140"c in an autoclave. The mixture was coored to about loo"c and excess butadiene and dioxane \{ere venEed. on further coollrg, the resfdual yellow syrup was poured into saturated sodiurn carbonate solutLon (450 nl) and the

mfxture qras heaEed for 2h at 7s"c. The solutlon was coored, extracÈed wíth ether (4 x 250 nl) then acl,dlfled with concentrated hydrochloric acld. The whl-te precipÍtate thaÈ formed was separated from a small amount of brown gum and filtered to glve the crude product, L, 4 r4a, 5, 8, 8a-hexahydronaphthalene-cis -ha,Ba-dicarboxylic

acid (40.7g, 651l) as a whfÈe solfd. A small porrion was recrysEallized from aceEonftriler mp 190-195"C, 53^ (lit. o mp 225"C).

B A mlxture of Ehe crude dlacfd from parÈ A (38.7g, O.l-74 moI) and p-toluene sulphonlc acld (0.5g) fn toluene (100 ml) Íras heaÈed for 4Bh at reflux under a nltrogen aÈmosphere. A Dean-stark apparatus was used to remove the water formed during the reacËion. undissolved ¡naterial (3.0g) was fllÈered aE amblenÈ temperature and the

f tltraÈe was e.üaporaÈed Ëo leave a yellow-brown solld, u.,hiah o¡1 155.

fecrys ta LLtzation from dichlorome Ehane / pet roleum ether afforded the anhydride (73) (19.56g, 557!) as a fine white '53^ crystalllne soIid, mp 9B-99'C (1it. ' rtrp 102-103'C). SpectraL data of this compound rdere identlcal to . those 53r- published '

Ir6 12-Oxa-tricyclo t 4 .4 .3 .0 I trldeca-3,8-diene (75)

The ether (75¡,^,,a prepared ultimately f rom the anhydride (tz\ as

* sweet smelllng o11 which I¡ras not f urther purif Íed. It rs spectral characterlstics were cons ls tenË wi th those 5l+ I reporÈed and indicated a puriry of > 957. ( H NMR).

I, 4, 6, 9-TetrahydroDyrida zlno lL,2-alpyridazLr.e (78).

A 6,9-dihydropyridazino [ 1,2:g ] pyr Ldazine-1,4-dione (e6),

mp 159-161'c (1ir.57b np I56-157'c), was prepared ln 7 37 yteld from rnalelc hydrazrde and buÈadlene after the ¡nethod

of ClemenaStb. The lead tetraacet.ate oxidant was added

as a 0.1M sorution 1n dtchloromethane rather than as a solid.

I IR (cDc13 ) v 1630, I580 crn I H NMR ( CDCl3 ) 6 = 6.85(s,2H,H2 3) 5.98(bs,2H,Hz,B)

4.46(s,4H,H6,8) PPM. 156.

å Bronfnation of the dione (96) from part A following the procedure of Hinsh."ut" provlded 2,3,7 ,B- Ëetra- '-llt-"trone' bromoperhydropyrida zlno [ 1, 2-a I pyrf dazTnen (97) , mp L7 3- 57 t L76"C (1ir. .n 183-IB4"C, in 987" yield.

_t IR (cDc13 ) v= 1690 cm I H NMR ( CDCl3 ) $ = 3.8-5.2(m,6H,llrs5, 7 I s) 4.52(s,2H,H2,3) pprtr.

C.(i) To a parrlal solurfon o'f the ketobromide (97) from part B ( 13 .669, 28 .2 mmol) and boron trifluorfde etherate (8.09g, 9.3 ml, 57.0 mmol) in rerrahydrofuran (50 nl) ' heated at ref1ux, rùas added, dropwÍse over lO ml-n, boron- dinethyl sulphtde (5.7 ml, 57.0'rnnol). As the reactlon proceeded, the diruethyl sulphide liberated was distilled and after 3h, the solutlon rüas cooled and treat.ed cautÍously wlth 50"Á v/v hydrochlorfc acld solutLon (15 ml). The mixt,ure lras heated for 2h aË ref lux then cooled and diluted r.¡1th waEer (I5 nl). 2,3,7,8-Tetrabromoper-

hydropyridazino[ L,2-3] pyridazine hydrochloride (7 .I7 g) hras

collected as a whfÈe powder, np ZO4-2O7" C (dec) . The

filtrate r¡ras concentrat.ed and refiltered Eo provide an addltional 2.499 of rhe hydrochloride saIÈ.

IR (Nujol) v = 3230, 1360,1335, 1305,L260,L225,1195,

1165, 1120, 1060,970, 970, 800, 750 _t 700 cm r57 .

(ii¡ To the hydrochlorfde, from (i) (7.I7g)

suspended in r.rater (20 ul) was added, wlth sEirring, ]-sr"

sodÍum hydroxfde sorutlon unt 1r pH l0 q¡as reached . The mfxture was stirred for 10 ruin at a¡nbíent temperature then filtered. The residue lras washed wlth water and dried to glve the f ree base , 2,3 r7 ,8-tetrabromoper hydropyrldazir"o

[ 1,2-q]pyridazine (98) (5.26g) , as ¡,rhÍre f lakes, mp 2lO" C 57 (dec), (1ir. ^ mp ZIO-211"C). The addirion of sodium

hydroxide to rhe fÍnal filLrate from Èhe acid salt in (í ) produced a further 2.39 of product.

IR (Nujol) v = 1360, 1335, 1305 , L26O,

122 5 , 1 I 9 5 , 1 I 6 5 , 1 I 2 0 , 1 0 6 0 , _t 970, 870, 750, 700 cm

MS n/e = 452, 454 , 456 , 4 58 , l- 460 (M'.) , 372, 374, 376, 378(- HBr).

D The teErabromide (98) from parr C (4 .43g, 9.8 mmol) was added in one portl-on to a sorution of methylllthiurn (1.6M

1n ether, 24.5 ml, 39.2 mmol) fn benzene (l50 ml). The mi;tture lras stirred f or 2.5h aÈ arnblent temperature under an atmosphere of nlErogen. l.Jater (5 m1) üras added and the preclpiÈated salts were f11Èered and washed with eÈher.

The pale yellow filErate was dried ( Na2 SO4 ) and

concentrated to a volume of about t0 m1. Glass wool r{¡as

added and Èhe remalnlng benzene was removed by butb Ëo

bulb dlstlllatlon. The air bath temperaEure h¡as malnt.alned aÈ,.' 80o C as Èhe pressure was gradually 158.

reduced. Distillarlon at 8O-9O"Cl1 mm ylelde¿1,4,6,9-

tetrahydropyrtdaztnoIL,2-g]pyrldazlne (78) (ca. 0.6g, 457") as a crystalllne white solid, mp 40-4L"c (1ft .57a bp 72-

7 5" | 4nm) . The product gradualLy darkened on exposure to air and rapidly 1f Lmpure. Chrornatography on neutral alunLna (lJoelm, actlvlty 1) wlth ethyl acetate/petroleum ether (I:3) naa used to purlfy aged maEerfa1.

_l IR ( CCl'+ ) v=3050cm. I H NMR ( CC14 ) $ = 5.55(bsr4H,H's2 3 Z B) ' ' 2.5-1 .8(broad enver;n., SHrIIt"l ppn. ,q rr r9) 159 .

CHAPTER 3

3 I 7 r8,9, 10-Tetrachloro-6. 6a. I0a. 11-tetrahydro pyridazino

[ 1 , 2-b ] phrh alaz ine-l .4-dione (101).

A uÍxt,ure of 6,9-dihydropyr idazino I L,2-4] pyr ldazine- 1,4-dione (96) (89 EB r 0.5 mmol) and rerrachloror,hiophene dioxide (56) (L27 Eg, 0.5 mmol) was heared for 3h and 150"c. sulphur dÍoxfde evolution Ìdas slow and afEer ca. t, 1.5h the melt had become dark brown. A NMR analysis of the cooled mixture showed resonances Èhat ú/ere attributable to the adduct (101) as well as a sma1l amount of starting material (96).

I H NMR (CDC13) $ = 6.80(s,2H,H2 3)

4 .2(m, 4H, H6 I I )

3.4(mr2H,H6a,IIa) Ppm.

cis-2,3,4a, 5, 8 . 8a-Hexahydro phthalaz ine-I . 4-dione (10s). This compound rdas prepared afÈer the meÈhod abstracted 53 by Murakarni, IchLkal¡a and Sone zak!

To a part ial solutlon of rhe anhydride (104) , ( 3 .04g, 20.0 mmol) in 959l ethanor (30 url) was added a sorurion of hydrazfne hydraEe (1.0g, 20.0 rnmol) in 9sT" eEhanol (zo nr) dropwise over 10 min at ambienË temperature. The mixËure was heaLed aÈ reflux for 5h then concentraÈed under reduced pressure to yteld a pale yellow oil (3.5g) which crystallrzed on sËanding. RecrystalLlzation from g5y" eËhanol afforded the hydrazLde (lO5) as flakes, (2.56g, 777"), Dp 99-10loC. 160.

IR (cDc13 ) v = 3320, 3240, 3160, L670, _t 1685 cm I H NMR (CDC13) ô 5.80(rn,2H,lI5, 7) 5.08(bs,2H,Hz 3) t 3.06(m,2H,H4r,Br), 1.9- 2.9(bm,4H,HS,B) ppm.

MS : n/e = 166

38 3.2 Tricyclo [ 4 .3 .1 .1 ì undecan-4-one (12e). Honoadamantanone (129), np 267-269" C (sublimed at 68 o^ 130'ClO.O5 nn), (lit. ¡np 269 .5-27 0 .5" C) r{as obtalned in 897" yleld from adamantanone (f28) by the method C of Black 68^ and Gill 4

I3 c NMR (cDc13 ) $ = 208.1, 49 .6, 48.7 , 37 .L, 34 .8 , 3l .7 , 26 .8, 26 .O pprn.

38 4-Oxa Èricyclo[4.3.1.1 I undecan-5-one (135). 0xahomoadamantanone (135), np 285- 288'C (sublirned at 67cr 140"C/0.2 mm), (1ir. mp 286-289'C) nas prepared 1n 947" yield from adamantânone (128) by the meEhod of Faulkner 67 and McKervey f.

I3 c NMR (cDcr3 ) ô = 178.8, 73.O, 4L.2, 35.6, 33.7, 30.9, 25.7 ppm. 16I . endo-3-Oxoblcyclo [ 3 .3 .1 I nonane-7-carboxylic acid (136).

The ketoacid (I36) *.¡as prepared by a method sl-mÍ1ar Eo 74 a tha t of Gopal, Adams and Moriarty The bes t of several runs ls presented below.

The lactone (I35) (f66 mg, 1.0 mmol) was added to a solution of sodium hydroxide (40 mg, 1.0 mmol) in qrater (3 x01). The míxture Lras heated on a sÈeambath for L/Zn to obtafn a homogenous solution whlch sras then cooled to ambient temperature. The pH of Èhe solution was adjusted to ca. pH 8 (phenolphthalein) wlth 2i( aqueous sulphurlc acld. Rutheniu¡u trfchloride (- 3 rg) was added and a solutÍon of sodium metaperlodate (642 mg, 3 .0 mmol) tn water (5 nl) was added dropwfse over Ih. During this time, the colour of the mf.xt.ure alternaEed between yellow- brown and green-black . After the addition, the solution r¡ras stirred for L/Z n then basif ied with saturaËed aqueous sodÍum bicarbonaÈe Èo pH 9 and extracÈed with dichloromethane (2 x 5 nl). From the organic extract, lras obtained a small amount (6 ng) of starEing material. The aqueous phase was acidlfied with 3O"/" aqueo.us sulphuric acid to pH 2, saturaEed with sodium chloride and exÈracted nrith dtchloromethane (3 x 7 m1). The combined organic exEracts were rvashed with LOi¿ aqueous sodium thiosulphat.e solution (5 ml) and saturated sodium chlorlde solution (5 nl). The solvent was dried (MgSOq ) and evaporated to glve the ketoacld (136) as a r¿hf Ee solld (f70 mg, 937", 98"Å based on recovered lactone (135).

t rR (cDc13 ) v 3400-24OO, 17I0-1690 cm 162.

I H NMR (cDc13 ) ô = 10.34(bs,lH,OH), L.47-

3 .05(ru, l3Hrmethylene and

methine Hts) ppnû.

Thfs material has not been furÈher characterized.

endo -7 -I odome thylbí cyc to [ 3 .3 .1 I nonane-3-one (138).

The ketoiodide (138) was prepared from adamantan-l-o1 67t by the method of -Lunn . This thermally uns table compound rùas stored aÈ 0"C as a dflute solutlon in ether over copper ¡¡ire and rùas isolated only s¡hen requlred.

3.3 €yclodeca-3,8-dÍene-1,6-dione (144). 77 d^ The dlenedl-one (144), np L7 5-L77" C (1f r. mp L82- 185'C) was made 1n 527" yield from the trans-diol (148) by 77 the method of Roberts, Vollmer and Servis a

trans-4a, 8a-Dlhydroxy-1, 4, 4a,5. 8. 8a-hexahydrona ph tha 1e ne (148). 46" The trans-dio1 (148), np 78-81"C (1Ír. np 80-83"C) was obtained in 871¿ yield from the isoEetralin epoxÍde 46a (63) by the procedure of Grob and Schies s 163.

9ac rl0aß -Dihydroxy-L r2,3r4-tetrachloro-

I 4acr ,5 ,8 ,8a, 9 ,9ac , 10 , 10a-octahydroanthacene (14e). i A urixture of tetrachlorothlophene dfoxlde(56) (254 mg,

1.0 mnol) and Ëhe t,rans-df of (148) (166 mg, 1.0 mmol) was

heaÈed f or th at 120oC. The mf xture rnelted and af t,er the

evolutlon of sulphur dioxfde had ceased, a solidtffed mass (360 mB, l00Z) was produced. Reeryst.allfzatLon from

acetone/petroleum ether afforded Ehe diol adduct (149) as fine whlte needles, mp 206-20BoC.

IR (cDc13 ) v = 3580 , 347 5, 3030, 1600 I cm I H NMR (cDC13 ) $ = 5.60(bs,2H,H2,6) ,

3.10(nr2H,He",9") , 1 .4-2.7(mr SH,HtsS ,g ,9 ,I0 ) , I.68(s,2H,OÅ'") ppr.

MS n/e = 354,356,358,360 (M1) , 336, 338, 340 (-Hzo) Anal . Calcd f or Ctq H1r¡ Cla 02 : C 47.22; H 3.96. Found c 47 .L6 ; H 4.09. 164.

REFERENCES r65 .

REFBRENCES

I E. Mü11er, "Neuere Anshauungen der 0rganischen Chemie ", Jul ius Springer, Ber11n, 1940, p30.

2 L.F. Fieser. J. Chem. Ed. 42, 408 (1e6s).

3 Owing Èo its sinilarlty Èo a unlt of the wurËzlEe

sËructure, fceane has also been cal le d wurEzÍtane4a'b

4. (a) C.A. Cupas, L. Hadokowski, J. Am. Chem.

Soc., 96, 4668 (L97 4) . (b) C. Ganter, R.O . Klaus, H. Tobler, He1v. Chirn. Acta 58, L455 (1975). (c) D.P.G. Hamon, G.F.Taylor, Aust. J. Chem., 29 172L (1976) and refs. cited therein. (d) see also G.F. Taylor, Ph.D Thesis, UniverslÈy of Adelalde, (1975).

5 (a) F.P . Bundy, J.S . Kaper, J. Chen. Phys ., -46,3437 (1967). (b) F.P. Bundy, R.E. Hanneman, H.M. Strong, ScLence, 155, 995 (L967). 6. V. Bockelheide, R.A. Ho111ns. J. Am. Chem., Soc., 95,32OL (1973).

7 E. õ""rr, P .R.v . Schleyer et al, J. Org . Chem., 45, 2985 (1980).

G. Frltz, G. Marguardt, H. Sheer. Angew. Chern. Int. Ed. Engl., L2, 654 (1973). 166.

9. (a) C. Ganter, R.O . Klaus, H. Tobler, HeIv. Cht¡n. Acta 58, 25L7 (1954). (b) D.P .G. Hamon, G.F. Taylor, R.N. Young, Tetrahedron Lett., L623 (1e7s). (c) D.P.G. Hamon, G.F. Taylor, R.N. Young,

Aust. J. Chem. 30, 589 (1977) . (d) C. Ganter, R.O. Klaus, Helv. Chi¡n. Acta, 63, 2559 (1980). 10. (a) R.J. Stednan, L.S. Ml1ler, J. Org. Chem.,

32, 35 (L967) . (b) J. MeinwaId, B.E. Kaplan, J. Arn. Chen.

Soc., 89, 26LL (1967) . (c)G.t. Grunewald et a1, J. Med. Chem., 15,

7 47 (L97 2) .

(d) J.S. hIÍshnok, J . Chern. Ed . 50, 780 (1e73).

(e) E.M. Engler, R.von R. Schleyer, MTP Int. Rev. Sci., ed. [,]. Parker, Butterworthy, London, (1973), Vol 5, p 239.

(f) S.A. MonÈi, J.M. Harless, J. An. Chem. Soc., 99, 269O (L977) and refs. thereln. (g) I. ChatztLosiftdfs et al, Angew. Chen. Int. Ed. Engl ., 18, 74 (1979). 11. (a) E .J. Corey, a. Rev. Chen. Soc., 25' 4ss (r971). (b) See also E.J. Corey, Pure Appl. Chem., ,!1 , r9 (L967>. t67 .

L2. A.l.l. Brown, Hon. ThesLs, Unlverslty of AdelaLde, (1e76).

13. See f or exarnple: (a) C.H. Heathcock, TeËrahedron Lett. 2043 (re66).

(b) J.E. McMurray ¡ S .J . Isser, J. An. Chen.

Soc., 94, L45 (Le7 2) .

(c) D.P.G. Hamon, R.N. Young, Aust. J. Cheru. 98, 145 (t976) and ref. clted thereLn. (d) Ref . 10(e). (e) Y. Inamoto eE a1, J. Org. Chem., 44,

6s0 (Le7 e) .

(f) E.J. Corey, J.G. Smlth, J. Arn. Chern. Soc 101, 1038 (1979). (g) E.J. Corey, M. Behforouz, Masaji Is higuro, J. Am. Chem. Soc., 101, 1608 (1 e7e). (h) M. Nakazakt et al, J. Org. Chen., 45,

4440 ( 19 B0) . (i) I. Janjatovió Z. Majerski, J. Org. Chem., 45, 4892 (1e80). ( j ) M.E . Jung et al, J. Am. Chem. Soc., 103, 6677 (1e81). L4. For a recent paper which tllusEraËes the appllcatlon of Èhis princlple to the ,s'ynthesis of perlsÈylane, see P.E. Eaton et al, J. Am. Chern. Soc. 99 , 27 5L (L977 ). l6B.

15. P.R Spurr , IIon . Thes is , Universlty of Adelalde, (1978).

16. For sl.¡nf lar examples, see

(a) R.C. Cookson eÈ a1, J . Chem. Soc . 3062 (1964).

(b) O. Ermer, An err. Chen. Int. Ed. En I 16, 798 (L977). (c) D.C. Dong, J.T. Edward, J. Org. Chem., 45t239s (1980). (d) D.S. Kenp, K.S. Petrakis, J. Org. Chem., 46 , 5140 (1981). L7. (a) R.O . Rieke et al, Org. Synth., 59, 85 (1e80).

(b) S.A. Montl, S.S. Yuan, J. Or . Chen. 36, 3350 (1971).

( c ) D .P .G . Ilamon, R.N . Young , Aust. J. Chem.

-29 , 14 5 (L97 6) . (d ) E .J . Corey, N. Behforouz , M. I shlguro, J . Am. Chero. Soc. 10r, 1608 (1979). 18. Conpare:

(a) E.E. van Tamelan et al, J. Arn. Chern. Soc., 91, 73L5 (1969). (b) T. Matsuura, A. Ilorinaka, Nippon Kagaku ZasshL, 92, L023 (1971), (C.A., 76,

L40280k, (Le7 2)) .

19. L.W. Butz, A. I^¡. Rytina, Org. React., 5, 136 (1e48). 169.

20. For structural analogies, see :

(a) E .L. Eliel, " Stereochemistry of carbon

compounds " , McGraw-tll11 Book Co . , Inc . (L962), p279-280.

(b) J.R. Scheffer, A.A. Dzakpasu, J. Am. Chem. Soc., 100, 2L63 (1978). 2L. See, for example (a) Ref. 18(b).

(b) J. Siegel, M. Dunkel, Adv. in Ca t . 9, ls (19s7). (c) It.0. House, "Modern Synthetic Reactions", 2nd ed., I{.4. Benjamin, Inc. (I972), p28.

22. (a) J. March, "Advanced Organic Cherû1stry", 2nð, êd., McGraw-Hi11 Kogakusha, Ltd. (L977), p708-711. (b) Iù. Carruthers, "Some Modern Methods of Organic Synthesis ", 2nd ed. Cambridge University Press (1978), p4L4.

23. (a) P . Dowd, K. Marwaha, J . Org . Chem. , 41, 403s (1976). (b) Y. Gaonl, Tetrahedron Lett., 2361 (1973). (c) Y. Gaoni, S. Sadeh, J. Org. Chem., 45, 870 (1980). (d) The dienedfbromide (2Oa) has also been prepared by the Èhermal decomposlÈfon of

3, 4-bt s ( bromome thyl ) -2, 5-dihydro- thlophene-1r1-dloxlde : G.B. BuEler, R.M.

Ottenbrite, Tetrahedron Lett ., 4873 (I967) . 170 .

24. A.C. Cope, F. Kagan, J. Arn. Chern. Soc. 80, 549e (1es8).

25. D.P.G. Ilamon, P,R. Spurr, Synthesls., 873 (1e81).

26. (a) $f .J. Batley, I{.R. Sorenson, J. An. Chern.

Soc., 78, 2287 (1e56).

(b) u.r. zânor s zky, II Musso, Justus Liebigs Ann. Chem., L777 (1973). 27. (a) F.lJ.Sum, L. Itreiler, J. Org. Chem., 44, 1012 (r979).

(b) R.K. Boeckman JË., S.S . Ko, J. Am. Chem.

Soc., LOz, 7146 ( 1980) . (c) K.v. Auwers, E. Cauer, Justus Lleblgs Ann. Chem., 470, 284 (1929).

28. (a) D. Belluð, c.D . Wels, TetrahedronLett. 999 (1e73).

(b) D . Belluð et al, He1v. Chin. Acta. ¡ 56, 3004 (1973).

(d) However, see M.F. Semme thack e,t al , J . Am .

Chem. Soc. 103 , 6460 (1981). 29. S.I .. Sa11ay, Tetrahedron Lett. 2443 (1964). 30. These caEalysts were klndly donated by Dr J. Sanders, Dept. of Tribophyslcs, UniverslÈy of Melbourne. 17t.

31. (a) C.A. Brown, J. Am. Chen. Soc. 91,

s901 ( 1969) . (b) Ref . 13 (j).

32. D . Seyferth, AccÈ . Chem . Res . , 5, 65 (L972). 33. (a) D. Seyferth, R.L. Lambert JE, J. Organomet. Chem. 16, 2L (1969).

(b) R.J. Rawson, I .T. Harrlson, J. Org. Chem. , 35, 2057 (1970).

34. See, for example :

(a) T. tludlf cky, S.R. I,Iilson et â1, J. Am.

Cheu. Soc . , LOz, 6351 (1980). (b) M.L. Greenlee, J. An. Chern. Soc. 103, 2,42s (1981). (c) H. Yamanoto eÈ â1, J. Aur. Chen. Soc. 103, 7368 (1981).

35. E. Vedejs et â1, J. Am. Chern. Soc., 101 , 68e (1979). 36. (a) S. Nfshlmura, Bul1. Chen. Soc. JapâD.,

33, 566 ( 1960) . (b) H.C. Brown, C.A. Brown, TeÈrahedron

Suppl., 8, part 1, L49, (1966) .

Chem. Soc. Chem. Comm., 357 (1980). L72. 37. (a) M.P. Cava er al, J Org. Chem., 46, I 483 (1e81).

(b) For a related case, see M.P . Cava et. al, J A¡n. Chen. Soc. 103, L992 (1e81). (c) For a revfew on this type of reactlon, see R.P . Thummel, Acc . Chem. Res., 13., 70

( 1e80) .

38. K. Alder, M. Fremery, Tetrahedron L4, 190 (1961).

39. P.A. Harland, P. Ilodge, Synthesf.s., 223 (1e82).

40. B .It . Han, P . Boud jouk, J . Org . Chen, . 47, 75L (1982). 4L. H. Kwart, R.A. Conley, J . Org . Chem., 38, 2011 (1973) and refs. clted thereLn.

42. For comprehensive reviews, see

(a) I,ù. Oppo l-zer , Angew. Chen. Int. Ed. Ens1.. 16, 10 (L977). (b) W. 0ppoLzer, SynÈhesls. ,793 (1978).

(d) P.L. Funk, K.P.C. Vollhardt, Chem. Rev., 80, 4L (1980). 43. I,{.F. Maier, P.v R. Schleyer, J. Am. Chem. Soc.

1ffi, 189r ( 1981 ) .

44. (a) J.A. Akhtar, G.I . Fray, J.M. yarrow, J Chem. Soc., (c), 8L2 (1968). 173.

(b) A. Krantz, C.Y. Lin, J. Am. Cheru. Soc. 95, 5662 (r973). (c) G.I. Fray, A.W. Oppenhefmer, J. Chen. Soc.

Chem. Comm., 599 (1e67). (d) I.A. Akhtar, G.I . Fray, J. Chen. Soc. (c), 2802 (1971). (e) It. Bluestone et al, J. Org. Chem., 26, 346 (1961).

(f) M.S. Raasch, J. Or . Chen. 45 , 8s6 (1e80). ( j) P.G. Gassman, J.L. Marshall, Org. Synth., 48, 68 (1968). 45. (a) R.K. Itill et al, J. Org. Chem., 45, 1se3 (1e80). (b) K. A1der, G. Steln, Justus Liebigs Ann. Chem., 501, 247 (1933).

46. (a) C.A. Grob, P .W. Schiess, Helv. Chirn.

AcÈa., 43, 1846 ( 1960) .

(b) E. Vogel, I.{. Klug, A. Breuer, Org . Synth., 54, 11 (L97 4) and refs. ÈhereLn. 47. (a) D. SeyferEh eÈ a1, J. Am. Chem. Soc., 87, 681 (1965). (b) Ref . 33(a).

(d) M.G. Banwell, B. Halton, Ausr. J. Chem. 33, 2277 (1980). 174.

48. E. Vogel, I^1. Klug, A. Breuer, Org . Synth . 55, 86 (1975).

49. (a) G.L. Thompson, Lr E Heyd, L.A. Paquette, J.

Am. Chem. Soc ., 96, 3L77 (L97 4) .

(b) E. Voge1, hI. GrÍnme, S. Korte, Tet rahedron Lett. 3625 (r96s).

50. D .P .G . llamon, P .R . Spurr, J. Chem. Soc. Chem. Conm., 372 (1982). 51. (a) L.A. Paquette eÈ al, J. An. Chen. Soc., 93, L52 (1971).

(b) T. Durst, M.J. OrSullLvan, J. Or Chen. 35, 2043 (1970). 52. D. Glnsburg eÈ al, Tetrahedron 34, 2r6L (1e78).

53. (a ) K. Alder, K.H . Backendorf , Chen . Ber . 7L, 2L99 (1938). (b) G. Snatzke, G. ZaaaEL, JusÈus Lfeblgs Ann. Chem., 684, 62 (1965). (c) tù.8. Scott, R.E. Pfncock, J. Org. Chem., 33, 3374 (L967). 54. D. Ginsburg et a1, Tetrahedron Supp1., 8, par t 1, 279 (1966).

55. Thfs work was done Ln collaboraLlon wfth Mr R. Snyth.

56. See , f or exarnp 1e : G.R. Newkome, F.R Fronc zek,

G.R. Baker, TeÈrahedron Lett., 27 25 (1e82). 175.

57. (a) J.C . Hinshaw, J. Org. Chem., 4O, 47 (1e75).

(b) R.A. Clemenr, J. Org. Chem., 27, 1115 (Le62). (c) H.C. .Brown, S. Naraslmhan, y.N. ChoL, Synthesls., 966 (1e81). (d) See, for example, R.Ì"I. Alder, R.B. Sesslons, J. An. Chem. Soc., -l!1, 3651 (1e7e).

58. B.V . Lap, M.N. Padden-Row, J. Org . Chem., 44 , 4979 (Le79). s9. (a) C.A. Grob, P.W. SchLess, Angew. Chen. Int. Ed. Engl., 6, 1 (1967). (b) see also, D.P.G. Hamon, G.F. Taylor, R.N.

Young, Synthesis., 428 (1975) .

60. D .P .G . Hamon, R. SnyÈh, P .R . Spurr, unpubllshed results.

61. E .J . Corey, J .hI. Suggs, J . Org . Chern., 40 , 25s4 (1e7s). 62. D.P .G . Ilamon, private communlcat,f on.

63. M. Murakami, K. Ichlkawa, I. Sonezakt, Chem.

Abstr., P7B, L47984 (1973) . 64. (a) V. Prelog, R. Selwerth, Che¡n. Ber. 74, L644, L769 (1941). for other slurllar examples, see: (b) H. StetEer, H. Held, J. Mayer, Justus Lteblgs Annalen Chem., 658, 151 (1962). L76.

(c) P .H . McCabe, W. Routledge, Tet rahedron LeÈt., 3919 (1e73). (d) H. Stetter, V.P. Dorsch, Justus Liebles Ann. Chem., L4o6 (1976).

65. See for example, (a) R.D. Allan, B.G. Cordiner, R.J. I{eIls, Tetrahedron Lett. 6oss (1968).

(b) B.M. Trost et aL, J . An. Chem. Soc . ,

r01, 1328 (L979) .

(d) E .G. Glbbons, J. Org . Chem. , 1 540 45, (1980).

(e) C.H. Ileathcock, E.F. KleLnman, J. Am.

Chem. Soc . 103, 222 (1981). (f) F.E. Zíegler, J,M. Fang, J. Org . Chem., 46, 825 (1981).

(g) L.A. Paquette, Y.K. Ilan, J. An. Chem. Soc., 103, 1831 (1981). (h) R.E. Ireland et al, J. Org. Chem., 46, 4863 (1981).

( f ) R.M. Coates , S .K . Shah, R.W. Mason J. An. Chen. Soc., 104, 2L98 (1982). 66. See for example,

(a) E.l,I. Colvln, R.A Raphael, J .S. Roberts, J

Chen. Soc. Chem. Comm. 858 (1e71). r77.

(b) II. Gerlach, I.l . Müller, Ang . Chen . Inr . Ed . Engl., 11, 1030 (L97 2)

1 1989 (1e73).

(d) Ref . 14.

(e) M.L . Que s ada , R.H. SchlessLnger, I.{.H

Parsons, J. Org . Chem. , 43, 3969 (1e78).

(f) C.M. Tlce, C.H. Ileathcock, J. Org. Chem., 46, 9 (1981).

(e) I.I .G. Dauben, D.M. I,Ialker, J. Org. Chem., 46, 1103 (1981).

(h) S .C. I.Ielch et al, J. 0rg . Chem., 46 48L6 (1981). 67. See for example, (a) A.c. Uddlng, H. I^Iynberg, J. Strating, TeÈrahedron Lett. 57Le (1968). (b) W.H.l.¡. Lunn, J. Chem. Soc., (c) 2124 (1970). (c) T. Sasakl, S. Eguchl, T. Toru, J. Org.

Chen., 35, 4109 ( 1970) .

(d) R.M. Black, G.B. G111, J. Cheru. Soc. Chern. Comm., L72 (I97f). (e) T. Sasakl, S. Eguchl, T. Toru, J. Org. Chem., 36, 3460 (1971).

(f) D . Faulkner, M.A. McKervey, J . Chern . Soc . (c), 3906 (1971). 178.

(g) P. Kovacic et al , J. An. Chem. Soc ., 93, s801 (1971). (h) T. Sasaki, S. Eguchl, M. lfizutani, J. Org. Chem., 37, 3961 (L972). (i) D.P .G. Hamon, G.F. Taylor, J. Org. Chem.,

39, 2803 (L97 4) .

( j ) Z. Majerskl , Z. HamerEak, Org . Synth . , 59, L47 (1979). 68. (a) R.M. Bl-ack, G.B. ci11, J. Chen. Soc. (c) 67r (1970).

(b) T. Sasakl ec al, J. Am Chen. Soc. 94 t L3s7 (r972). 69. (a) Ref. 22(b), p396. (b) ibid , p2.

70. (a) f.I .K. Anderson, T. Veysoglu, J. Org . Chem., 38, 2267 (1973).

(b) P. Köll er al, Tetrahedron Lett., 5081

(Le7 2) . (c) B.D. Mookherjee, R.W. Trenkle, R.P. Patel,

J. Org. Chem., 37 , 3846 (r972) . (d) G. Mehta, P.N. Pandey, T.L. Ho, J. Org. Chem., 4I , 953 (1976). (e) Y. Ktshl et al, J. Chem. Soc. Chen.

Comm., 64 (Le72).

(f) c. MehEa, P .N. Pandey, SynthesLs ., 404 (1e7s). 179.

(g) N.M. I{elnshenker, R. Stephenson, J. Org .

Chem. , 37 , 37 4l (L97 2) . (h) J.D. McClure, P.H. LIfIllans, J. Org. Chem., 27, 24 (1962). (f) E.E. Smfssman, J.F. Muren, N.A. Dahle, J. Org. Chem., 29, 35L7 (1e64). (j) L. Svensson, Acta Chem. Scand. 26,

237 2 (L97 2) . (k) R. Lfotta, l¡.S. Hoff , J. Org. Chérn., 45, 2887 (1980).

7r. A.A. Oswald, D .L . Guertin, J . Org . Chem. , 28, 6s1 (1963).

72. See for example, (a) M. Stoll, A. Rouvé, IIelv. Chlru. Acta., 18, 1087 (1935).

(b) S.L. Friess, P.E. Frankenburg, J. Am. Chem. Soc. 74, 2679 (1952).

(c) P.S . Starcher, B. Phtlllps, J. Am. Chem. Soc., 80, 4O79 (1958). (d) Ref . 70(i). (e) K. Kosswfg, I^I. Stumpf , I.I. Klrchhof , Justus Lleblgs Annalen Chem., 681, 28 (196s). (f) Ref .70(j). (g) Ref .70(c).

73. 1. MomoSe, S . Atarashf, O. Muraoka, Te È rahedron Lett., 3697 (I974). 180.

74. (a) H. Gopal, T. Adams, R.M. MorlarEy,

Tetrahedron ?8, 4259 (r97 2) . (b) K.B . Sharpless Chem., -e_!., al, J. Org. 46, 3936 (1e81). 75. For an analogy, see: T. Momose, O. Muraoka, S. AtarashL, Heterocycles., L2, 37 (1979). 76. (a) E.J. Corey, R.L. Danheiser, S. Chandrasekaran, J. Org. Chem., 4L, 260 (1e76).

(b) J .T . Mi11er, C.W. DeKock, J. Or . Chem. 46, 516 (1981). (c) A. Nlcken, P. St. J. Zurer, J. Org. Chem., 46, 4685 (1981). (d) see also: H. NozakL et a1 letrahedron

Lett ., 24L9 ( 1970) .

77 . (a) B.l,¡. RoberÈs, J.J. Vollmer, K.L. Servfs, J

An. Chern. Soc., 96, 4578 (re7 4) . (b) Ref. 24. (c) A. Goosen, H.A.H. Laue, J. Cheru. Soc.,

(B) ee5 ( 1e6e) . (d) T.L. McDonald, D.E. OrDell, J. Org. Chem., 46, 1501 (1981).

(e) T.R. Beebe, P. Hl1, P. Reinking, J. Or Chem., 46, L927 (1e81).

78. Sinllar difficulty was encountered by A. ShanL, F. Sondhefmer! J. An. Chen. Soc., 89, 6310 (r967). 181.

79. (a) L.I . Smtth, F.L. AustLn, J. Au. Chern.

Soc., 64, 528 (L942) .

(b) L.I . SmLth, R.$1.H. Tess, J. An. Chem.

Soc., 66, L523 (L944) . 80. W.C. St111, M. Kahn, A. MiËra, J. Org. Chem., 43, 2923 (1978). 81. D.D. Perrln, W.L.F. Armarego, D.R. PerrLn,

"Purfflcatfon of Laboratory Chenlcals", 2r.d. ed., Pergamon Press, 1980. r82

PUBLI CATI ONS

Part of Èhe work descrlbed in thls thesfs has been reported ln the foLlowing publfcatlons :

I . "Reductive Elf ml.natlon of Bromine f ron 2 13-

Dlsubstituted I,4-dlbromo-2-butgnes by Iodlde Ion : A convenient Route to 2,3-Bis(todomethyl)-lr3-butadlene and Related Compounds", D.P.G. Hamon¡ p.R. Spurr, s nthes I s 873, (1981).

2. "A Slrnple, Constructf on of the Iceane Skeleton l¡lra an Intramolecular Dlele-Alder Reactfon" , D .p .G. Hamon, P.R. Spurr, J. Che¡n. Soc. Chen. Conm.. 372, (1982). 183

ERRATA

The following corrections have been made to some of the nomenclature

used ln this chesls on the reco¡nmendatlon of the examlners. Since the

nunbering sysÈem and, accordingly, the assfgnment of the spectral character- ístics are dlfferent to those listed herein, both the correct and incorrect

names and numberings are gÍven below. lage l3l

2 I,10 4,5,6, 7, 15, l5-Hexachlorohexacyclo[8. 4. l. 0. cl 3'80.4' l3o. t' ttl-t-oenradecene 0. (6ga). ct

not 2,3,415, I0, lO-Hexachlorohexacyclo[7 .4.1.- cl 30.9' I l1-:-p"ntadecene 1.6,110.2,70.5,1 (68a) . I ct cl +

age 133

2 3 I 5, I 5-Dibromo-4, 5, 6, 7- c er rachlorohexac yc lo- ct Br l' 100.4' 130.7'12l-5-pentadecene t8.4. l.o. (68b). Br

rl (t \ åt{

not l0, lO-Dtbrono-2, 3,4 , 5-tetracl¡lorohexacyclo- ct I 130.9' llJ-3-pentadecene 17.h.1. 1.6' llo.2'70.5' (6Bb).

1¡ ct

Page 134

I l. l0 ¡t I 5-Aza-4, 5, 6, 7-tetrachlorohexacyclo I I . 4. 2.O. ct 0.3'80. 4'1307' l2lh"*rdec-5-en-16-one (70). tô

¡¡ ct

t tc NH not lO-Aza- I l-oxo-2,3, 4, 5- teÈrachlorohexacyc 1o- ,t 6' L20.2' 70.5' l4o. 9' 12 (zo). 17.5.1. l. J-3-r,exadecene o rl

Paee 136

¡ 5 3' 80' 4' I 3- 3 8. 4. 0. o. 4, 5, 6, 7-Te crachroropen Èacyc lo [ ß 7' l2l o. -5-cetradecene-I, lO-dicarboxyllc anhydrlde rt Qa¡. ct t'í

t 6, Io_ tc noÈ 213r4,5-1eÈrachloropentacyclo [ 7.3. l. l. 2' 70. 5' I 2¡ o. tetradecene-9, l0-df carboxyllc -3- ¡,

anhydride (74r. 5 tt

Paee 138

, H I , l0-bl,s (hydrox¡'ulethyl)-4 r 5,6,7-Èetrachloropentaclc lo- q 30. 7 l2 [8.4. o.0.3'80.4't ' ¡-5-a"aradecene. cH2oH c¡

(hydroxyae t not 9 , l0-bis chyl)-2 ,3 ¡ 4 ¡ 5- tetrachloro- o a cHzoh 6, l0g. 2' 70. 5' l2 pentacyclo [2. 3. t. I . ¡-3-a"aradecene. cH2Ot cr t

Page t40

l, l0 3rB 4,13 7 ,12 I Hexacyclo [8.4. 1.0 0 0. 0 - 5-penr l a- g r3 decene (81). 3

1 ¡ û("

6, I 10. 2.7 130.9' I I I noc Hexacyclo [7.4. l. l. O.5' l-3- t lo pencadecene (81). I

Pae.e L42

tt l30. 7' l2 Pentacyclo 1.0. I' lOO.4. [8.4. ¡penÈadeca- 5 r3 3,5,7-trlene (82).

r+ 4,121.6,130.4,6 not Pentacye1ol7.2.2.l. lpentadeca- t 5 1,8, l0-trlene (82).

Paqe t¿3

¡.¡00.4,130.7,121- r¡ I 6-O>:apent acyc lo I B. 4. 3. 0. t Qr heptodcca-3. 7-dlcnc (87).

3 at I t t_l'1 ,

rg 4 I 4 8. r5 4,8' noc 6-OxaPentacYclo19.2.2.l. I 0 t- rl Qc heptadeca-lO-dlene (87) . r¡ 1 Í

Hamon, D. P. G. & Spurr, P. R. (1982). A simple construction of the iceane skeleton via an intramolecular Diels-Alder reaction. Journal of the Chemical Society, Chemical Communications, (7), 372-373.

NOTE:

This publication is included in the print copy

of the thesis held in the University of Adelaide Library.

It is also available online to authorised users at:

https://doi.org/10.1039/C39820000372

REPR I NT

lntornat¡onal Journal 1981 of Methods in SYnthetic No. 11: SYNTHESIS Organic ChemirtrY November

With Compliments of the Author'

' NEW YORK GE,ORG THIEME VERLAG ' STUTTGART November 1981 Communications 873 Reductive Elimination of Bromine lrom 2,3- The attempted acetolysis of the diiodo compound 3, by means Dísubstituted 1,4-Dibromo-2-butenes by Iodide Ion: of sodium acetate in acetic acidt'2, gave only polymer. The A Convenient Route to 2,3-Bis[iodomethylþ1,3- diacetate 4 could be prepared, in 86% yield, by the reaction of butadiene and Related Compounds 3 with silver acetate in acetic acid or, more conveniently, in acetonitrile. The diol 5 was readily obtained by hydrolysis of David P. G. HAMoN*, Paul R. Spunn the diacetate 41.

Department of Organic Chemistry, The University of Adelaide, Ade- No conditionsT have been found which allow the Diels-Alder laide, South Australia, 5000, Australia reaction between the diiodo-diene 3 and benzoquinone. The dienes 4 and 5, however, do react with benzoquinone to give A recent paper has described the preparation and extolled the the adducts 6 and 7, ¡espectively. These adducts have a value of 2,3-bisþromomethyll-1,3-butadiene t. (1) marked propensity to enolize to the corresponding hydroqui- nones and they could be isolated only if precautions were H2C.a 'c'rCH2-Br taken to rigorously purify all reagents before use. I -c\cHr-Br Hrc'l l" 1 with 4: benzene, V .;:xJ; with 5:1.2 -dimethoxyethane,V Before the full experimental details for the preparation of this .ï compound were published, we required dienes of this type, in '+ particular the derivedl 2,3-bis[acetoxymethyl]-1,3-butaàiene 4n= ac (4) and 2,3-bis[hydroxymethyl]-1,3-butadiene (5), for Diels_ 5n= ¡ z-oR Alder reactions. From the details then available2 we were una_ H2-OR ble to prepare the dibromide 1 in a reproducible manner and s was sought. synthesis of 6 R =ac utadiene (3), 7n =n n to the acetoxy derivative 4 by an alternative method to that described The Diels-Alder reaction of p-benzoquinone with dimethyl previously. Hydrolysis of the acetoxy derivative 4 gives the butadiene-2,3-dicarboxylate (10) was also required. The diene diol 5t'3. In this way, both compounds 4 and 5 are obtained lOa was prepared in 85% overall yield by alþlic bromination in higher overall yield than reported earlier. of dimethyl 2,3-dimethylbutenedioate8 (S) with N-bromosuc_ cinimide to give (^E.)- and (Z)-dimethyl 2,3-bis[bromomethyl]- of bromine from 2,3_bis[bromomethyl]_ butenedioate (9) followed by debromination of 9 by use of óul (2) by means of excess potassium iod_ above described reductive elimination method. Diene l0 un_ owed by the immediate addition of ha_ derwent the Diels-Alder reaction with p-benzoquinone af- logen to the generated diene. However, in the presence to of so_ ford adduct 17 in 72% yield. dium thiosulphate, the halogen was reduced und th" diene 3 was then produced in high yield (930/o). Hac.arcoocH' Br NBS / CCtl / -CH2 razcoocHa Br-CH2l H2 -Br radical ¡nitiator .rc il + il 3 KJ/3 Na2S2O3 . 5 H2O / acetone,45oC Hrclc\coocH, Br-CH 2 Br-CH2 H2-Br 8 rzr-9 [rer-9]"taooar, 2

H Hz-J 3KJ/3 Na2s203. 5 H20 / H2C-..a-cooc H3 oc / acetonitr¡te acetone,45 I

Hrczc-cooc H3 H Hz-J 3 10

Hz\rrcHz-oAc H2-OH NaOH / H20/C2H5OH benzene, V I ...... - R"tf HrltcHr-oa, H2-OH 45 H3 11 The diene produced initially should be the dibromo com_ pound 1 but in the presence of excess iodide ion this diene was iiodo_derivative 3. In the pres_ 2,3-Bis{iodomethytþ1,3-butadiene (3) : ence odide ion (10%), the reaction is slow and bromo-dienes is obtained. Compound 3 (m.p. ymerizes rapidly in the solid s in ether (0.1 molar), however, at 0"C. orange to dark red to pale yellow. The suspension is poured onto ice 0039-7881 /81 /1 1 32-0873 $ 03.00 @ 1981 Georg Thieme Verlag . Stuttgart . New york SYNTHESIS 874 Communications

100 light and a nitrogen atmosphere for l'8 h' The hot sus- (300 g) and extracted with ether (1 x 200 ml, 2 x 100 ml)' The combined under a W pension is filteted and evapotated to give 9 as a pale yellow oil; yield: àthei-extracts are washed with satutated sodium chloride solution -S.f yield of crude product). The crude bromoester ob- (2 x 50 ml), dried with magnesium su t g 1-100% satisfactory purity lor use in the next step' as a pale yellow solid; Yield: 15.5 g tained is of 1. 95-96'C (dec., from acetone/water). I.R. (neat): v : 1735; 1640; 7270 cm- standing (analytical data were not obtained)' 1H-N.M.R. (CClalTMS): 6:4.40 (s),4.16 (s,4H); 3.83 (s),3'75 ppm I.R. (Nujot): v:3100; 1590; 900 cm-r. (s, óH). rH-N.M.R. (cDCl¡,zrMS): ô:5.64 (s, 1H); 5'50 (s, I H); 4'16 ppm (s' A portion (350 mg) ofthe prod hromatogra- 4H). phy'on silica gel with ethyl a P' 65-68"C) Further purifi be achieved This procedure can be scaled up to at least 80 g ofthe tetrabromide 2, Ù iSÐ eluent. "t distillation at 100'C/0'05 torr. with similar results. by evaporative E-isomer (first to elute): liquid, 170 mg. 2, M.S.: m/e:332,330,328 (M1). r a solution of the crude t. Si I.R. (neat): v:1740 1635;7270 cm tonitrile (200 ml) heated di rH-N.M.R. (CClalTMS): 6:4.40 (s,4H); 3.83 ppm (s' 6H)' al this temPerature for t h' Z-isomer, liquid, 170 mg. CsHroBrzO¿ calc. C 29.12 H 3.05 (330.0) found 28'92 3'03 M.S.: m/ e:332, 330, 328 (M). r. I.R. (neat): v:1735; 1640:1270 cm rH-N.M.R. (CCl¿): ô:4.1ó (s, 4H); 3'75 ppm (s' 6H)' m.p.42-43"C). (10) This procedure can be scaled up to at least 50 g of 3, with similar re- Dimethyl 1,3-Butadiene-2,3-dicarboxylate : bromoesters 9 (4.80 g, 14'5 mmol) in acc- sults. To a solution of the crude tone (50 ml) are added sodium thiosulphate pentahydrate (11'18 g' (7.49 g, 45.1 mmol)' The mixture is 6,7-Bislacetoxymethyll-cÍs'4a,5,8r8a-tetrahydronaphthalene-1,4-dione 45.1 mmol) and potassium iodide (75 g), extracted with (6): stirred for I h at 45'C, then poured onto ice and are washed with satu- A solution of freshly sublimed (120"C/25 torr) benzoquinone (2'18 g, ether ombined ether extracts (10 ml), dried with magnesium sul- 0.02 mol) and redistilled diacetate a $0 g' 0.02 mol) in benzene (25 rated chloride is evaporatively distilled at 75- ml) is heated at reflux under a nitrogen atmosphere in the dark for 18 -SO"Cphate The residue liquid; yield: 2'l g (850/o)' h. The resulting light yellow solution is evaporated to give a dark yel- 10 as a colourless with those re- tow oil which is crystallized on trituration with cold (0'C) ether. The Spectral data for this compound are in agreement product is hlte porteda. yield 6 as an o Dimethyl 1'4-Dioxo-cís-44r5,8,8a-tetrahydronaphthalene-6,7-dicarboxy- pefnatant are e lized f¡om and total yield: 4.2 g(680/o); off-white needles; m.p. 139-141 'C (from ben- ze¡e / carb on tetrachlori de). CroHr¡O¿ caic. C 6'274 'tt 5'92 (306.3) found 62.52 5.88 r: r-r-----rL^-^ /L^-^--\ ulellluturtrçL¡rdr¡ç/ ¡¡v^¿rr!.J'' M.S.: m/ e :246 (M1- CH3COOH)' IJJ L (lfolll H 5'07 LR. (Nujol): v:1735;1690; 1230 cm-r' Cr¿Hr¿Oe calc' C 60.43 5'21 IH-N.M.R. (GDCI¡/TMS): õ:6;75 (s, 2H); 4'75 (poorlv resolved (27S.3) found 59.86 ABq,4H, l=12Hz);3.25 (m,2H);2.43 (m, aH); 2.10 ppm (s,6H)' Vt.S: m/e:278 (M1. I.R. (Nujol): v:1740:1730; 1690; 1650; 1600; 1260 cm-r' 6,7-Bislhydroxymethyll'cis-4a,5,8,8a-tetrahydronaphthalene-1,4'dione rH-N.M.R. (cDCl3,zrMS): ô:6.83 (s, 2H); 3.83 (s, óH); 3'38 (m, (7)t 2H):2.73 ppm (m, 4H). A solution of recrystallized diolr'3 5 (432 mg,4.0 mmol) and freshly P. R. S. acknowledges the rcceipt of a Commonwealth Postgraduate sublimed benzoquinone (456 mg,4.0 mmol) in 1,2-dimethoxyethane (8 Scholarship. ml) is heated at On slowly cool posits fine off- Received: May 14, 1981 a and washed wi mg), m.p. 116-118"C. Evaporation of the filtrates gives a residue * for correspondence. *hi.h i" washed with ether to give an additional amount of 7; total Address I S. Sadeh, J. Org. Chem.45' 870 (1980). yield: 750 mg (8a%). Y. Gaoni, 2 Y. Gaoni, Tetrahedron Lell' 1973,2361. calc. C 64.85 H 6.35 CrzHr¿O¿ see also: S. Sadeh, Y. Gaoni, Tetrahedron Leu- 1973' 2365' ()')) )\ found 64.51 6.20 3 w. J. Bailey, W. R. Sorensen , J ' Am. Chem. Soc. 78, 2287 (1956)' MS: m/e:222 (M!. see also: U. I. Zahorszky, H. Musso, Jusltts Liebigs Ann' Chem' I.R. (Nujol): v:3340', 1680 cm '. 1973,7777. 4 rùr'eis, rH-N.M.R. (2/1)/TMS]: õ:6.67 (s, 2H); 4.21 (s, D. Bellus, C. D. Telrahedron Lett. 1913,999. [cDCli/cD3oD (1973)' 2H); 4.03 (poorly resolved ABq, 4H' J=12 Hz)i 3.35 (m' 2H); 2'43 D. Bellu5 et al., HelD. Chim. Acta 56, 3004 5 (1958)' ppm (m,4H). A. C. Cope, F. Kagan, J. Am. Chem' Sac. 80, 5499 6 D. Landini, S. Quici, F. Rolla, Synthesis 1915,397- t M. Ottenbrite, Telrahedron Lett. 1967' 4873' (E)- and (Z)-Dimethyl 2,3-Bislbromomethylþbutenedioate (9): G. B. Butler, R. 8 Auwers, E. Cauer, Juslus Liebigs Ann. Chem' 470, 307 A ¡-nixture ol (Z)-dimethyl 2,3-Cirnethylbutenedioate8 (8; 2'58 e' 15'0 K. von mmol), N-bromosuccinimide (5.87 g, 33.0 mmol), and azobisisobuty- (1e2e). e Org- Chem. 43' 2923 (1978)' ronitrile (-3 me) in carbon tetrachloride (50 ml) is heated at reflux w. c. Still, M. Kahn, A. Mitra, "L