Electrochemical epoxidation of cholesterol and avarol dimethyl ether with bromide as heteromediator was performed, and its mechanism discussed. The influence of the solvent, the mediator concentration, and different electrolytic techniques on yield of the products was examined. Under optimal conditions, the yield of the cholesterol epoxides (5α,6α and 5β, 6β) was 88%, and of the corresponding epoxides of the avarol dimethyl ether 72%

Gašić, M.J.

Ignjatović, Ljubiša

Putniković, B.

Sladić, Dušan

Zlatović, Mario

Journal of the Serbian Chemical Society

English

Cherry - Repository of the Faculty of Chemistry;  University of Belgrade

J. Serb. Chem.Soc. 61(11)1033-1037(1996)
JSCS-2323
U DC 547.922/.5:541.13S/.2
Original scientificpaper
Improvedelectrochemicalepoxidationof cholesterolandavarol
dimethylether*
MIROSLA v J. GASIC,I MARlO ZLA TOVIC,! LJUBISA M. IGNJA TOVIC,2 BOGDAN PUTNIKOVIC3 and
DUSAN SLADICI
1Faculty o/Chemistry, University o/Belgrade, P.O.Box 158, YU-Il 001 Belgrade, Yugoslavia,2Faculty 0/
Physical Chemistry,University o/Belgrade, Belgrade, Yugoslavia and 3Schoolo/Chemistry,
Universityo/Leeds, Leeds, UK
(Received 15July 1996)
Electrochemicalepoxidationof cholesteroland avarol dimethyl etherwith bromide
asheteromediatorwas performed,and itsmechanismdiscussed.The intlueneeof thesolvent,
themediatorconcentration,anddifferentelectrolytictechniqueson yield of theproductswas
examined.Underoptimalconditions,theyield of thecholesterolepoxides(5a,6a and 5~,6~)
was SS%, and of thecorrespondingepoxidesof theavaroldimethyl ether72%.
Key words: electrochemicalepoxidation,cholesterol,avarol dimethyl ether.
Epoxidesareveryusefulintermediatesfor variouschemicaltransformations.IThey
havebeenwidelyusedin synthesesof naturalproductsaswell asin industrialprocesses,so
thatnumerousmethodsfor theirpr~parationhavebeendeveloped..
Indirectelectrochemicalepoxidationof olefinsusinghalogenanionsasheteromedia-
tors is a well known procedure.2-9We wish to reporthere our complementarystudyoo
1
CHPM
P-=w
2 Scheme 1.
* Dedicatedto Professor Dragomir K. Vitorovic on theoccasionof his 70th birthday.
1033
1034 GAStCelal.
concernedwith thenatureandadvantagesof thisrelativelysimple,cheapandpotentially
usefulprocess.Weoutlinebelowexamplesof theelectrochemicalepoxidationoftwonatural
products:cholesterol!andavaroldimethylether2 (Scheme1).
RESULTS AND DISCUSSION
Electrochemicalepoxidationof cholesterolwasperformedin a mixtureof anorganic
solventandwaterin thepresenceof sodiumbromide.We investigatedtheinfluenceof the
compositionof themixture,theconcentrationof themediatoranddifferentelectrolytictech-
niquesontheyieldsanddistributionof theproducts.TheresultsarepresentedinTable1.
TABLE I. Influence of the reactionconditionson theyield of products
Experiment
ncholcs(nNaBr
CNaBrVS.w
Solvent (v/v)
ConditionsYield ('Yo)
(mol/dm3)
1:1
0.26McCN:HZO50 mA'
124:1
6.1 F/mol
2
1: 1410
235: I
.9 / l
3
1.2:I .0 SMcCN:Hz
462.6: I
7. F/mol
4
1025e ZO
701
6 9
5
0.4
6
9
SO
MeCN:HzO
100mA"
7
06 7.9 F/molXX
O.IM TEAP"
S
Id I0.025 "". :I
7 / l
9
( . 099 V V.I'. SCEg56
O IM TEAP"
MeCN:HZO
O.':! V V.I'. CEg
10
lei 0.1 M TEAP"72
7.1 mM Et)
"Electrolysis at constantcurrent;hI'S. NaBr; "Divided cell; dcholcstanol; "Cholcstanonc; J:••••varol dimcthyl
cthcr;gElectrolysis at constantpotcntial
The firststepin theindirectelectrochemicalepoxidationis theanodicoxidationof
themediator(bromideion) tomolecularbromine.Rapiddisproportionationof brominein
thepresenceof wateraffordsbromideion andhypobromousacid.IO The latterelectophilic
speciesdiffusesintothesolutionandaddstothedoublebondbytheAdE2mechanism.The
resultingbromohydrinundergoesa fastintramolecularSN2substitutionreactionfollowed
by deprotonationof theintermediateoxoniumcationII (Scheme2). The majorityof our
electrochemicalepoxidationswasperformedin thepresenceof anequimolaramount(or
smallexcess)of themediatorwith respecto theolefin.Theoretically,thereactioncycle
requiresonlyacatalyticamountof themediatorbuta largefractionof bromineiseffectively
"trapped"in thethreeconsecutivereactions,whicharemuchslowerthantheelectrochemical
ELEc.TROCIJEMICI\L ErOXIDI\TlO
R.\1>H H_+ __ R~)' . '/
R2 Rz
lizO
Scheme2.
1035
process;alsohalfof theoxidizedbromide,afterdisproportionationis returnedto theanode
andsomeof thehypobromousaciddissociatesandthuslosesitselectrophiliccharacter.A
certainamountofthe generatedhy obromiteis oxidizedintobromate.
100
80
~60
~
~ 40
.~
20
o
0.0 0.1 0.2
c (molldmJ)
(NaBrvs.HP)
0.3
Fig. I. Influenceof thesodium
bromide concentrationon the
yield of the epoxide.
The presenceof waterin theelectrolyteis necessaryfor thedisproportionationof
molecularbromineandthegenerationof theelectrophilicagent.In theabsenceofwateronly
brominationtakesplace.Too muchwaterresultsin thesubstratebeinginsoluble,andthe
yieldsarereduced.Bestyields(80%)wereobtainedin themixtureof acetonitrileandwater
of thecomposition2.6: I (v/v).
Theyieldsoftheepoxidestronglydependontheratioof sodiumbromideandwater(Fig.
1).Theyieldsof theepoxidevariedfrom12%(CNaBr vs. water=0.26M) to 80%(CNaBrvs. water
=0.009M) undersimilarreactionconditions.Thecompositionof thesolventmixtureis not
1036 Gi\~I(:el"'.
responsiblefor thisphenomenon(TableI, experiments3 and4). In thepresenceof a high
concentrationof bromideion,anodicoxidationproducesa largeamountofmolecularbromine
whichdiffusesandreactswith theolefinto affordthedibromide.3In thepresenceof a low
concentrationofbromidewithrespectowater,mostlyhypobromitediffusesintothesolution.
Changeof organicsolvent(MeCN, DME, acetoneor TMF), reactiontemperatures
(from0°Cto250q,oranodematerial(platinumandgraphite)didnotsignificantlyinfluence
thereactionyields.It is veryinterestingthattheratioofthestereoisomericepoxidesis 1 : 1,
asdeterminedby polarimetry,aresultthatremainstobeclarified.
Whenelectrolysiswasperformedinadividedcell(withaglassfrit diaplu'agm)yields
wereon theaverage,10%higher(TableI, experiment7). In thesecases,themixturewas
supplementedwith0.1M tetraethylanunoniumperchlorate(TEAP) asasupportingelectro-
lytetoreducetheresistanceof themedium,so thatsidereactionsonthecounterelectrode
wereminimized.
Duringtheelectrolysisthereareseveralsidereactions(e.g,oxidationofhypobromitesto
bromates,oxidationof secondaIYalcoholsetc.),so thatCWTentefficiencyis in therangeof
25-33%.WenoticedthatunderhigherCWTentdensities(j=50-I00mAcm-2) thereweresmaller
amountsof sideproductsgenerated,becauseof shorterelectrolysistime.However,a higher
cunentdensitycaninducelocaloverheatingintheaI'eaof theworkingelectrode,andcauseboth
thetllelmaldegradationof theproductandthefavoringofaltemativereactionpathways.12
Epoxidationof olefinstypicallyrequires6-7Fmol-I VS. NaBr while fortheoxidation
of thesecondaIYalcoholcholestanol,27Fmol-I wereusedunderidenticalreactioncondi-
tions.13
Epoxidationof avaroldim-ethyletller2 was performedundercontrolledpotential
conditions(0.9V VS. SCE), in orderto preventpossiblesidereactions.In thepresenceof
triethylamine(1.1eq)asanextemalbase,theyieldincreasedii'om56%to 72%.
EXPERIMENTAL
A varol dimethyl etherwas preparedby the usual proeedure.4Acetonitrile and triethylaminewere
purified in the usualway.IS Tetraethylammoniumperchlorate(TEAP) was preparedby dropwise addition
of perehlorie acid (10% in excess) into the aqueous solution of tetraethylammoniumbromide. TEAP
separatedas a white precipitate.It was recrystallizedthreetimes from water, and dried at 105"C for three
hours.
A 200W Volteraft DIG 140was usedfor synthesesataconstantcurrentanda potentiostat/galvanostat
EG&G PAR 173for synthesesat a constantpotential.
A platinumcylindrical gauzewas used as the working electrode,a platinum gauzeas the counter
electrodeandsaturatedcalomeleleetl'ode(SCE) as a referenceelectrodefor thepreparativeelectrolysis ata
constantpotential.A platinumfoil was theworking electrodeand DSE, thecounterelectrodefor syntheses
at aconstantcurrent.Diaphragmsweresoakedin concentratednitric acid and rinsed in water.
The cells lVereconical, andtheirvolumes were between15to 50 ml.
Polarimetric measurementswere performedon aCarl Zeiss lena PolamatA polarimeter.
Gellera/ procedure
Cholesterol (0.10 g, 0.26 mmol) and sodium bromide (0.02X g, 0.26 mmol) were added into an
acetonitrile:water mixture (2.6 : 1 v/v). Electrolysis was performedin the undivided cell with a platinum
anodeandgraphiteasthecounterelectrode,underconstantcurrentconditionsU=100mAem 2).The reaction
mixturewas electrolyzeduntil TLC indicatedtheabsenceofstarting material.A saturatedaqueoussolution
of potassiumbisulfite was thenaddedand themixturewas extractedwith methylenechloride, washedwith
saturatedsodium chloride solution anddried (Na2S04).The organic solventwas evaporatedunder reduced
ELECTROCIIEMICAL ErOXIDATION 1037
pressureand the resultingoily residuewas purified by column chromatography(silica-gcl, toluene: cthyl
acctate,9: lv/v), followcd by crystallization(acetone:watcr, 88: 12v/v) to afford thc product as colorless
crystals, identificdby publisheddata.
Ackllowledgemellt.This work was supportedbyM inistlY of ScienccandTechnology of theRcpublic
of Serbia.
113BOil
ODTHMH30BAHA EflEKTPOXEMHJCKA EDOKCHJ]:AUHJA XOflECTEPOflA H
J],HMETHfl-ETPA ABAPOflA
MI1POCJJAB J. rAlIII1Tl.' MAPI10 3J1ATOBI1Tl.' JbYE>l1l11AM.l1rIbATOBI1Tl.' E>OrilAHnYTHI1KOBI1TlJ II
ilYlIIAH CJJAill1Tl I
I XCMUjCKII cPaK)'Jlilieili, YHlIoep3111Ticl7i )' 6eolpaoy, iI.ilp. 158, 1/001 Eeozpao, l<bllK)'/Ii1ietTi 3a cjJf/3/1'tKY xeMlljy, YHll(jep311i1ielTi y
5eozpaoy, 5eozpao It JSclwo[ ojChemisllY. U"i~'t!,..\·ityof Leed.\",Leed.,",UK
Ypa~CHajc CJlCKTpoxcMMjcKacnOKCM).IaJ.wjaxOJlccrcpoJla M).IMMCTMJI-CTpaaBapOJlaca 6POMM).IOM
Kao XCTCPOMC).IMjaTopoM,np0).lMcKYTOBaHlbCHMcxaHM3aM.HcnMTaHjc YTMl..\ajpaCTBapa'la,KOHl..\CH-
Tpal..\MjcMC1~MjaTopaMpa3JIM'II1TMXCJlCKTPOJlMTM'IKMXTCXHMKaHa npHl'IOcnpOM3B01~a.YKynHM npMHOc
06a CTCpCOMJOMCpHacnOKCM).IaxOJlccrcpoJla (5a,6a M 5P,6P) 6MOjc 88%, a o).lf'oBapajyliMxcnOKCM).Ia
).IMMCTMJI-CTpaaBapOJla72%.
(np"MJbellO 15.jyno 1~~6)
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Improved electrochemical epoxidation of cholesterol and avarol dimethyl ether

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Improved electrochemical epoxidation of cholesterol and avarol dimethyl ether

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